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The Brigham Renal

Board Review Course
Provided by:
The Renal Division
Brigham and Women’s Hospital and
The Department of Continuing Education
Harvard Medical School
Release Date
October 1, 2010
1-800-284-8433 • www.cmeinfo.com
738
Oakstone
®
Medical Publishing, LLC
The Brigham Renal Board Review Course
Harvard Medical School
October 1, 2010
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ELECTROLYTES AND ACID BASE
Basic Physiology for Tackling Electrolyte/Acid Base Cases
Alan S.L. Yu, MD
1 1:17:37 1 1 1-17
Sodium Disorders
Mark L. Zeidel, MD
27 0:41:59 1 2 1-9
Potassium Disorders
Julian L. Seifter, MD
68 0:42:39 2 3 1-9
Disorders of Divalent Metabolism
David B. Mount, MD
98 0:38:20 2 4 1-8
Electrolytes and Acid Base Practice for the Boards I
Alan S.L. Yu, MD
133 1:28:52 2
5
6
1-14
1-5
Electrolytes and Acid Base Practice for the Boards II
Alan S.L. Yu, MD
218 0:41:04 3 6 6-14
Take-Home Messages
David B. Mount, MD
271 0:31:51 3 7 1-7
Pathology Refresher
Helmut G. Rennke, MD
309 1:39:27 4
8
9
1-15
1-6
Lupus Nephritis
Gerald B. Appel, MD
402 0:46:36 5 9 7-16
Nephrology Board Review 1 (Glomerulonephritis)
Gerald B. Appel, MD
429 0:56:11 5 10 1-12
Workshop: Challenging GN Cases for the Boards
Gerald B. Appel, MD
486 0:57:44 6 11 1-12
RPGN
David J. Salant, MD
523 0:43:00 6 12 1-9
Genetic Renal Disease: Overview
Martin A. Pollak, MD
549 0:42:26 6 13 1-9
Pediatric Kidney Disease: A Board Primer
Julie R. Ingelfinger, MD
584 0:43:35 7 14 1-9
Membranous and FSGS
Johannes S. Schlondorff, MD, PhD
620 0:50:07 7 15 1-11
Polycystic Kidney Disease
Theodore I. Steinman, MD
650 0:45:37 7 16 1-10
IgA Nephropathy
Gerald B. Appel, MD
685 0:39:23 7 17 1-8
Light Chain Deposition Disease and Amyloidosis
Laura M. Dember, MD
708 0:36:37 8 17 9-16
ELECTROLYTES AND ACID BASE
GLOMERULONEPHRITIS
Harvard Medical School
The Brigham Renal Board Review Course
October 1, 2010
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Pregnancy and Renal Disease
Robert A. Cohen, MD
744 0:35:17 8 18 1-7
Treating GN
Ajay K. Singh, MD
769 0:43:52 8 18 8-16
GN Board Review Cases
Dana Miskulin, MD
791 0:23:27 8 19 1-5
Take Home Messages
Ajay K. Singh, MD
812 0:40:52 8 19 6-14
Nephrology Board Review 2
Ajay K. Singh, MD
847 1:05:20 9 20 1-14
Kidney Stone Cases
Gary C. Curhan, MD, ScD
910 0:57:16 9 21 1-12
Hypertension: An Overview
John Forman, MD
939 0:33:31 9 22 1-7
Cardiovascular Disease and Renal Disease
David M. Charytan, MD, MSc
974 0:44:49 10 22 8-16
Renovascular Disease
Joseph M. Garasic, MD
998 0:44:09 10 23 1-9
AKI Epidemiology
Sushrut S. Waikar, MD
1038 0:28:38 10 23 10-15
Pathophysiology of AKI
Joseph V. Bonventre, MD, PhD
1055 0:42:20 11 24 1-9
CVVH: An Overview
Kenneth B. Christopher, MD
1082 0:35:48 11 24 10-17
AKI Syndromes
Sushrut S. Waikar, MD
1109 0:47:56 11 25 1-10
AKI and Cancer
Benjamin Humphreys, MD, PhD
1139 0:43:14 12 26 1-9
Nephrology Board Review 3
Bradley M. Denker, MD
1171 1:09:08 12 27 1-14
Take Home Messages
Sushrut S. Waikar, MD
1236 0:10:51 12 27 15-17
Nephrology Board Review 4
Daniel W. Coyne, MD
1247 1:16:51 13 28 1-16
CKD AND GENERAL NEPHROLOGY
ACUTE KIDNEY INJURY
Harvard Medical School
The Brigham Renal Board Review Course
October 1, 2010
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CKD (Cont'd) AND DIALYSIS
Dialysis: An Overview for the Boards
J. Kevin Tucker, MD
1311 0:44:34 13 29 1-10
Vascular Calcifications: Clinical Implications
Eduardo Slatopolsky, MD
1362 0:50:33 13 30 1-11
Iron in Anemia Management
Daniel Coyne, MD
1408 0:39:35 14 31 1-8
Dialysis Vascular Access
Dirk M. Hentschel, MD, PhD
1436 0:46:42 14 32 1-10
Peritoneal Dialysis: An Overview
Joanne M. Bargman, MD
1478 0:50:19 14 33 1-11
Dialysis Pearls for the Boards
J. Kevin Tucker, MD
1521 0:24:47 15 33 12-17
PD Complications
Joanne M. Bargman, MD
1552 0:52:06 15 34 1-11
Poisonings and Intoxications
J. Kevin Tucker, MD
1605 0:23:22 15 34 12-17
Epo in Anemia Management
Ajay K. Singh, MD
1644 0:48:17 15 35 1-10
Dialysis Complications
Bertrand Jaber, MD
1673 0:31:35 16 35 11-17
Dialysis Dose
J. Kevin Tucker, MD
1702 0:27:44 16 36 1-6
Take-Home Messages
J. Kevin Tucker, MD
1723 0:18:54 16 36 7-12
Nephrology Board Review 5
Steven M. Brunelli, MD
1755 1:18:08 16 37 1-16
Nephrology Board Review 6
David M. Charytan, MD, MSc
1805 1:02:27 17 38 1-13
Key Transplant Studies - What You Should Know for the
Boards
Anil Chandraker, MD
1850 0:43:02 17 39 1-10
Transplantation Immunobiology for the Boards
Nader Najafian, MD
1883 0:47:25 18 40 1-10
Transplant Immunosuppression for the Boards
Steven Gabardi, PharmD & Anil Chandraker, MD
1914 0:50:35 18 41 1-11
TRANSPLANTATION
CKD (Cont'd) AND DIALYSIS
Harvard Medical School
The Brigham Renal Board Review Course
October 1, 2010
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Tissue Typing — a Boards Primer
Edgar L. Milford, MD
1955 0:45:37 18 42 1-10
Pre-Transplant Evaluation of Recipients
M. Javeed Ansari, MD
1975 0:26:06 19 42 11-16
Donor Evaluation: Living & Deceased
Didier Mandelbrot, MD
2006 0:28:11 19 43 1-6
Early Post-Transplant Medical & Surgical Complications:
Cases for the Boards
Nidyanandh Vadivel, MD & Sayeed Malek, MD
2025 0:42:23 19 43 7-15
Late Post-Transplant Medical Complications
John Vella, MD
2053 0:31:05 19 44 1-7
Infections in Immunocompromised Hosts
Sarah P. Hammond, MD
2080 0:43:21 19 44 8-17
Take-Home Messages in Transplantation
Anil Chandraker, MD
2113 0:23:41 19 45 1-5
Transplant Board Review
Martha Pavlakis, MD
2137 0:56:38 20 45 6-17
Basic Physiology for Tackling
Electrolyte/Acid Base Cases
Alan S. L. Yu, M.B., B. Chir.
University of Southern California Keck School of
Medicine
Financial disclosures
No conflict of interest to disclose.
Alan S. L. Yu, M.B., B. Chir.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1
Outline
1. Volume regulation - Na
+
handling
2. Osmoregulation - Water handling
3. K
+
handling
4. Renal acid-base homeostasis
Outline
1. Volume regulation - Na
+
handling
2. Osmoregulation - Water handling
3. K
+
handling
4. Renal acid-base homeostasis
Copyright Harvard Medical School, 2010. All Rights Reserved.
2
Extracellular volume regulation
Extracellular volume is maintained by regulating the
rate of Na
+
and water excretion (primarily by regulating
Na
+
)
Na
+
is freely filtered at the glomerulus(25,000
mmol/day)
Na
+
excretion is regulated at the level of tubule
reabsorption
Na
+
reabsorption along the nephron
Proxi mal tubul e
60-70%
Thi ck ascendi ng l i mb
20-30%
Di stal convol uted tubul e
5-10%
Col l ecti ng duct
1-3%
Uri ne
1-2% ( =F
E
Na)
Copyright Harvard Medical School, 2010. All Rights Reserved.
3
Sites of action of natriuretics
Proxi mal tubul e
Osmotic diuretics
Carbonic
anhydrase
inhibitors
Thi ck ascendi ng l i mb
Loop diuretics
Di stal convol uted tubul e
Thiazide diuretics
Col l ecti ng duct
K
+
-sparing diuretics
Proximal tubule Na
+
absorption
Cl
-
H
2
O
Lumen Bl ood
AngII
+
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4
Carbonic anhydraseinhibitors
Cl
-
H
2
O
Thick ascending limb Na
+
absorption
NKCC2
Lumen Bl ood
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5
Loop diuretics: Mechanism of action
Bartter’s
syndrome
DCT Na
+
absorption
Na
+
Na
+
K
+
Cl
-
NCC
Lumen Bl ood
WNK4
-
Gitelman’s
syndrome
PHAII
Gordon’s syndrome
Thiazide
diuretics
PHA =pseudohypoaldosteronism
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6
CCD Na
+
absorption
Arachi doni c
aci d
Angi otensi nogen JGA
PGE
2
Reni n
COX2
AngI AngII
ACE
AT1R
Corti sol
Corti sone
b-HSD
Tubule
flow
CCD Na
+
absorption
PHA I
PHA I
+
Liddle’s syndrome
Copyright Harvard Medical School, 2010. All Rights Reserved.
7
K
+
-sparing diuretics
Epl erenone
Regulation of ECF volume
 ECV
AngII, aldosterone
 ANP
 Tubule Na
+
reabsorption
Copyright Harvard Medical School, 2010. All Rights Reserved.
8
Outline
1. Volume regulation - Na
+
handling
2. Osmoregulation - Water handling
3. K
+
handling
4. Renal acid-base homeostasis
Serum [Na
+
] is simply a surrogate marker for
serum osmolality
Regulation of osmolality
The body senses and regulates serum osmolality
(not serum Na
+
)
Copyright Harvard Medical School, 2010. All Rights Reserved.
9
Na
+
concentration =
Amount of Na
+
Volume of water
Serum osmolality is regulated by regulating
water balance (not Na
+
balance)
Regulation of osmolality
1400
Urinary concentration and dilution
290
290
290
140
Antidiuresis: 1150
Water diuresis: 65
NaCl
Water
N
a
C
l
N
a
C
l
Water Water
NaCl NaCl
ADH
Interstitial
osmotic gradient
290
Copyright Harvard Medical School, 2010. All Rights Reserved.
10
Mechanism of action of ADH
V2 receptor
cAMP
CD principal cells
Apical membrane
aquaporin-2
Osmotic water
reabsorption(equilibrate
with interstitium)
U
Osm
PGE
2
Aquaretic
NSAIDs
ADH
Regulation of serum osmolality
 P
OSM
 ADH
 U
OSM
 Thirst
Copyright Harvard Medical School, 2010. All Rights Reserved.
11
Expected U
Osm
(mOsm/kg)
Normal Hyponatremia Hypernatremia
50-1200 Low (<100) High (>800)
Non-osmolar stimuli to ADH secretion
 U
OSM
 Thirst
 P
OSM
 ADH
 ECV
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12
Regulation of ADH secretion
Plasma osmolality
280
P
l
a
s
m
a

A
D
H
Blood volume depletion (%)
0
P
l
a
s
m
a

A
D
H
10 5 15 20
Outline
1. Volume regulation - Na
+
handling
2. Osmoregulation - Water handling
3. K
+
handling
4. Renal acid-base homeostasis
Copyright Harvard Medical School, 2010. All Rights Reserved.
13
Intracellular pool of K
+
acts as buffer
Na
+
K
+
K
+
[K
+
] 120 mEq/L
H
+
Acidosis
Hemolysis
Rhabdomyolysis
Tumor lysis
Digitalis
Insulin
Catechols (b2)
Diabetic ketoacidosis
bblocker
K
+
handling along the nephron
Proxi mal tubul e
100% K
+
reabsorbed
Corti cal
col l ecti ng duct
K
+
secretion
Copyright Harvard Medical School, 2010. All Rights Reserved.
14
CCD K
+
secretion
4 mmol/L 32 mmol/L [K
+
]:
Transtubular K gradient (TTKG) =32/4 =8
CCD K
+
secretion
Arachidonic
acid
Angiotensinogen JGA
PGE
2
Renin
COX2
AngI AngII
ACE
AT1R
Cortisol
Cortisone
b-HSD
Tubule
flow
K
+
Copyright Harvard Medical School, 2010. All Rights Reserved.
15
Regulation of CD K
+
secretion: summary
• Distal tubule flow and NaCl delivery
(dependent on upstream Na reabsorption)
• Mineralocorticoid receptor
– Aldosterone
•Renin-angiotensin system
•Serum K
+
– Glucocorticoids
Regulation of serum K
+
 K+
 CCD K
+
secretion
 Aldosterone
 Na-K-ATPase, ROMK
Copyright Harvard Medical School, 2010. All Rights Reserved.
16
Expected urine K
+
Hyperkalemia Hypokalemia
24 hr urine K
+
High (>40 mEq) Low (<25 mEq)
TTKG >6 <3
Outline
1. Volume regulation - Na
+
handling
2. Osmoregulation - Water handling
3. K
+
handling
4. Renal acid-base homeostasis
Copyright Harvard Medical School, 2010. All Rights Reserved.
17
Acid-Base homeostasis
1. Extracellular buffering by HCO
3
-
(immediate)
2. Respiratory regulation of pCO
2
(minutes)
3. Intracellular and bone buffering (hours)
4. Renal regulation of acid excretion (1-5 days)
Extracellular buffering of acid by the
CO
2
/HCO
3
buffer system
pH =6.10 +log
[HCO
3
-
]
0.03 P
CO
2
HCO
3
-
+ H
+
H
2
CO
3
CO
2
+ H
2
O
Copyright Harvard Medical School, 2010. All Rights Reserved.
18
Arterial pH P
CO2
and HCO
3
-
Primary disturbance
Acidemia  HCO
3
-
Metabolic acidosis
 P
CO2
Respiratory acidosis
Alkalemia  HCO
3
-
Metabolic alkalosis
 P
CO2
Respiratory alkalosis
Respiratory and renal compensation
Primary disorder Expected compensation
Metabolic acidosis Each 1 mEq/L  HCO
3
-
1.2 mm Hg  P
CO2
Metabolic alkalosis Each 1 mEq/L  HCO
3
-
0.7 mm Hg P
CO2
Respiratory acidosis
Acute Each 1 mm Hg P
CO2
0.1 mEq/L  HCO
3
-
Chronic Each 1 mm Hg P
CO2
0.3 mEq/L  HCO
3
-
Respiratory alkalosis
Acute Each 1 mm Hg P
CO2
0.2 mEq/L  HCO
3
-
Chronic Each 1 mm Hg P
CO2
0.4 mEq/L  HCO
3
-
Copyright Harvard Medical School, 2010. All Rights Reserved.
19
Daily Acid Generation
(mostly dietary)
~1 mmol/kg
Net acid excretion ~1 mmol/kg
Glomerulus 4200 mmol HCO
3
-
filtered
Proximal tubule (& TALH) Reabsorb almost all
HCO
3
-
Collecting duct Secrete H
+
Titratable acidity (phosphate) 30%
NH
4
+
70% (can be )
Free H
+
10
-5
mol/L (@ pH 5)
Renal acid handling: Overview
Acid excretion mechanisms in renal tubule
Type 2 RTA
Type 1 RTA
Type 4 RTA
Copyright Harvard Medical School, 2010. All Rights Reserved.
20
Proximal tubule HCO
3
-
absorption
Cl
-
Lumen
Bl ood
AngII
+
ProxRTA
Carbonic anhydraseinhibitors
Cl
-
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21
CCD H
+
secretion
NH
3
NH
4
+
Distal
(Type I)
RTA
CCD HCO
3
-
secretion
NH
3
NH
4
+
H
+
HCO
3
-
Cl
-
Pendrin
H-ATPase
b-IC cell
Copyright Harvard Medical School, 2010. All Rights Reserved.
22
NH
3
NH
4
+
Arachidoni
c acid
Angiotensinogen JGA
PGE
2
Renin
COX2
AngI AngII
ACE
AT1R
Cortisol
Cortisone
b-
HSD
Tubule
flow
Regulation of extracellular pH
Blood pH
 NH
4
+
/Urine pH
Net acid excretion
 H-ATPase
 NH
3
generation
Copyright Harvard Medical School, 2010. All Rights Reserved.
23
Urine anion gap is a surrogate marker of
urine ammonium
Measured cations – measured anions =unmeasured anions – unmeasured cations
Na
+
+K
+
- Cl
- e.g. NH
4
+
Urine anion gap
U
r
i
n
e

N
H
4
+
-40 0 -20 +20 +40
Expected urine acid excretion
Acidemia
Urine pH <5.5
Urine NH
4
+
>20 mEq/L
Urine anion gap <0
Copyright Harvard Medical School, 2010. All Rights Reserved.
24
Diarrhea
Proximal
RTA
Distal RTA
Type I Type 4
Serum K
+
 
Urine AG Negative Variable Positive
Urine pH Variable >5.5 <5.5
Other
Fanconi
syndrome
Nephro-
calcinosis
Clinical features of RTA
Regulation of acid-base handling
H
+
secretion
• Extracellular pH
• Distal tubule Na
+
delivery
• AngII, aldosterone
• ECV depletion (AngII, aldo)
• Hypokalemia ( Intracellular pH in tubule cells 
H
+
secretion)
HCO
3
-
secretion
• Cl
-
depletion (inactvates pendrin)
Copyright Harvard Medical School, 2010. All Rights Reserved.
25
Suggested reading
• Rennke, H.G., Denker, B.M., Renal Pathophysiology – The
Essentials, 2nd Edition, Lippincott Williams & Wilkins, 2010
• Eaton, D., Pooler, J ., Vander, A. Vander's Renal Physiology, 9th
Edition, McGraw-Hill Medical, 2009
• Koeppen, B.M. and Stanton, B.A., Renal Physiology, 4th Edition,
Mosby, 2006
Financial disclosures
No conflict of interest to disclose.
Alan S. L. Yu, M.B., B. Chir.
Copyright Harvard Medical School, 2010. All Rights Reserved.
26
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine
Mark L. Zeidel, M.D.
Herrman L. Blumgart Professor of
Medicine
Harvard Medical School
Chair, Department of Medicine
Physician-in-Chief
Beth Israel Deaconess Medical Center
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine
Mark L. Zeidel, M.D.
Disclosures: None
Copyright Harvard Medical School, 2010. All Rights Reserved.
27
Each of these
creatures
survives in the
Galapagos by
highly effective
t f management of
salt and water
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
Copyright Harvard Medical School, 2010. All Rights Reserved.
28
Case1
A 45 year old woman with a history of depression
presents wtih disorientation and inappropriate presents wtih disorientation and inappropriate
behavior. Her husband notes that she has had
nausea recently and has eaten little, but has
continued to take her amitryptaline.
PE reveals a BP of 125/70 and lethargy. She is oriented
to person only, exhibiting intact cranial nerves and
slurred speech slurred speech.
Na
+
108; Urine Na
+
is 28. Serum Osmolality is 221;
Urine osmolality is 685.
Case 2
• A 67 year old man suffers a major MI, from which he
recovers. One month later he notes increased
edema d spnea on e ertion and 2 pillo edema, dyspnea on exertion, and 2 pillow
orthopnea.
• PE reveals P = 120, BP = 100/65, RR = 22, afebrile.
Exam notable for distended neck veins, rales 1/3 up,
a palpable S3, and 2+ pitting edema to the mid calf.
• Serum Na
+
125
• Urine Na
+
is 2. Urine osmolality is 685; Serum
Osmolality is 262.
Copyright Harvard Medical School, 2010. All Rights Reserved.
29
Case #3
A 66 year old man with no significant prior illnesses
presents to the Emergency Ward complaining of
feeling “ out of sorts.” History is notable for 50 pack
years of smoking. He was seen two weeks
previously in the outpatient clinic where a routine
chest X-ray was obtained. Physical exam is entirely
benign. reveals: BP = 105/70; P = 100; R = 18;
Afebrile Neck flat Chest clear Cardiac e am Afebrile. Neck vv flat, Chest clear, Cardiac exam
benign, Extr. No edema.
Na
+
188; K
+
4.2; Cl
-
153; HCO
3
-
25; S
osm
385; U
OSM
88.
CXR from 2 weeks ago: Solitary 2cm lung nodule.
Major Premise: A fundamental
understanding of transport understanding of transport
processes and their regulation
permits the physician to manage
fluid and electrolyte
disturbances in patients on the disturbances in patients on the
basis of mechanisms rather than
rote memorization.
Copyright Harvard Medical School, 2010. All Rights Reserved.
30
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
Water Balance
P
Osm
= 285
P
Na
= 140
Copyright Harvard Medical School, 2010. All Rights Reserved.
31
Free water excretion: First morning
void
Compare urine osmolality with that of plasma (approx. Compare urine osmolality with that of plasma (approx.
300 mOsm/kg).
If you void 600 ml of urine with an osmolality of 800
mOsm/kg, you excreted 480 mOsm of solute (800
mOsm/kg X 0.6 kg). If you had excreted a urine of
300 mOsm/kg, you would have required 1.6 liters of
urine (480 mOsm/300 mOsm/kg) to excrete this urine (480 mOsm/300 mOsm/kg) to excrete this
solute load.
0.6 liters – 1.6 liters = -1.0 liters
You therefore absorbed 1.0 liter of free water.
Free water excretion: Drinking during
the day
Compare urine osmolality with that of plasma (approx. Compare urine osmolality with that of plasma (approx.
300 mOsm/kg).
Assume you void 200 mOsm of solute in 2 liters of
urine. If you had excreted a urine of 300 mOsm/kg,
you would have required 0.67 liters of urine (200
mOsm/300 mOsm/kg) to excrete this solute load.
2 0 liters – 0 67 liters = 1 33 liters 2.0 liters – 0.67 liters = 1.33 liters
You therefore excreted 1.33 liters of free water.
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32
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33
Control of ADH Release
Control of ADH Release
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34
Hyperosmolality & ADH release
thirst
adapted from
Robertson et al, Robertson et al,
Am J Med 1982
Volume depletion & ADH release
adapted from Dunn et al. J Clin Invest, 1973
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35
Control of ADH Release
Regulation of ADH
Release
•Hypertonicity
•Volume Depletion
•Beta-adrenergic stimulation
•CNS dysfunction CNS dysfunction
•Drugs/stress
•Pulmonary diseases
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36
Actions of ADH
Renal water
Reabsorption of
water in water in
distal neprhon
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
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37
Control of Body Fluid Tonicity:
Renal Water Excretion
Proximal tubule
Thin Descending Limb of Henle
Thin Ascending Limb of Henle
Thi k A di i b f H l Thick Ascending Limb of Henle
Cortical and Medullary Collecting Ducts
Nephron Structure
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38
No ADH, Excretion of a Dilute
Urine
High ADH, Excretion of a
Concentrated Urine
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39
Diffusion of water
through the lipid bilayer
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40
Water-tight barrier apical
membrane
Nephron Structure
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41
mTAL: Transport Function and
regulation by Ca
2+
mTAL: Cation-selective
paracellular pathway
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42
Anatomy of urinary concentrating
mechanism
Nephron Structure
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43
Cortical Collecting Duct:
Microanatomy
Cortical Collecting Duct:
Transport Function
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44
Transporters: Aquaporin I
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45
How did we figure out how
vasopressin works?
????
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46
+ AVP
No AVP
AQP2 localization
and Water Permeability
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47
Arrows
P i t t AQP2 Point to AQP2
ATP
AC
AVP
cAMP
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48
ATP
AC
AVP
cAMP
Nephron Structure
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49
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
Neurological effects of altered
serum osmolality and its correction
•Brain edema with increased intracranial
pressure.
•Losses of volume in the brain with traction
on fixed structures.
•Direct neuronal damage due to the g
disturbance.
•Osmotic demyelination syndrome following
overly rapid correction of the disturbance.
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50
Why are neurons
so sensitive to
osmotic damage?
Volume Regulation in Neurons
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51
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52
Osmotic Demyelinating Syndrome
• AKA central pontine myelinosis
• Follows overly rapid and excessive • Follows overly rapid and excessive
correction of severe hyponatremia.
• May involve the pons, subcortical
regions, corpus callosum, and basal
ganglia. g g
• May be diagnosed on MRI.
• Susceptability of individual patients to
ODS may vary widely.
Osmotic Demylination
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53
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
Case1
A 45 year old woman with a history of depression
presents wtih disorientation and inappropriate presents wtih disorientation and inappropriate
behavior. Her husband notes that she has had
nausea recently and has eaten little, but has
continued to take her amitryptaline.
PE reveals a BP of 125/70 and lethargy. She is oriented
to person only, exhibiting intact cranial nerves and
slurred speech slurred speech.
Na
+
108; Urine Na
+
is 28. Serum Osmolality is 221;
Urine osmolality is 685.
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54
Factors determining the rate of
correction of hyponatremia
• What are the risks of uncorrected
hyponatremia?
Wh t th i k f th ti • What are the risks of the correction
itself?
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55
Rapid Correction of Hyponatremia
• For patients with acute hyponatremia
ith l i fi di with neurologic findings.
• For volume depletion: normal saline
• For SIADH: Use hypertonic saline (3%
rather than 0.9%).
Optimal rate of correction is 0 5 1 • Optimal rate of correction is 0.5 - 1
mEq/h, < 12 mEq/D, or until a “ safe”
level is achieved and/or neurological
symptoms improve.
Case 2
• A 67 year old man suffers a major MI, from which he
recovers. One month later he notes increased
edema, dyspnea on exertion, and 2 pillow orthopnea.
• PE reveals P = 120, BP = 100/65, RR = 22, afebrile.
Exam notable for distended neck veins, rales 1/3 up,
a palpable S3, and 2+ pitting edema to the mid calf.
• Serum Na
+
125
• Urine Na
+
is 2. Urine osmolality is 685; Serum U e a s U e os o a ty s 685; Se u
Osmolality is 262.
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56
Therapy of Chronic Hyponatremia
Congestive Heart Failure • Congestive Heart Failure
• Cirrhosis
• Spinal Cord Injured Patients
• SIADH
Studies show that low serum sodium
predicts poor prognosis.
Pharmacologic Treatment of SIADH:
Lithium and Demeclocycline
Pharmacologic Treatment of SIADH:
Lithium and Demeclocycline
ATP
AVP
Demeclocycline
Lithium
AC
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57
Pharmacologic Treatment of SIADH:
Vasopressin Receptor Antagonists
Pharmacologic Treatment of SIADH:
Vasopressin Receptor Antagonists
AC
AVP
Tolvaptan Trials: SALT1 and
SALT2, Schrier et al., NEJ M
2006
Euvolemic or Hypervolemic
Hyponatremia, Tolvaptan
dose 15 mg to 30 mg to 60
mg depending on serum
sodium.
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58
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59
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
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60
Case #3
A 66 year old man with no significant prior illnesses y g p
presents to the Emergency Ward complaining of
feeling “ out of sorts.” History is notable for 50 pack
years of smoking. He was seen two weeks
previously in the outpatient clinic where a routine
chest X-ray was obtained. Physical exam is entirely
benign. reveals: BP = 105/70; P = 100; R = 18;
Afebrile. Neck vv flat, Chest clear, Cardiac exam
benign, Extr. No edema.
Na
+
188; K
+
4.2; Cl
-
153; HCO
3
-
25; S
osm
385; U
OSM
88.
CXR from 2 weeks ago: Solitary 2cm lung nodule.
Hypernatremia: Case 2
Causes for hypernatremia in this patient:
1. Loss of secretion of ADH (despite a
strong osmotic stimulus) indicating
central diabetes insipidus.
2. Lack of thirst in response to a strong
osmotic stimulus.
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61
Hypernatremia: Symptoms
• Muscle weakness • Muscle weakness
• Fasciculations
• Seizures
• Lethargy
• Altered mental status • Altered mental status
• Coma
Control of ADH Release
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62
No ADH, Excretion of a Dilute Urine
Hypernatremia: CNS Adaptation Hypernatremia: CNS Adaptation
H
2
O
Hypertonicity
H
2
O
O l t
Rapid Adaptation
El t l t
Chronic Adaptation
Osmolytes
Electrolytes
Electrolytes
H
2
O
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63
Hypernatremia: CNS Pathology Hypernatremia: CNS Pathology
• Vascular injury due to brain shrinkage • Vascular injury due to brain shrinkage
– Subdural hematoma
– Petechial hemorrhages in cortex and
subcortical white matter
• Osmotic cell injury
– Myelinolysis
Treatment of Hypernatremia Treatment of Hypernatremia
• Restore intravascular volume
• Replace free-water deficits
– Replace 50% of deficit over 24 hours
– Replace remaining 50% of deficit over the
next 24 to 48 hours
• Replace ongoing renal and extra-renal Replace ongoing renal and extra-renal
fluid losses
• Treat underlying causes of fluid losses
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64
Hypernatremia in Hospitalized Patients:
Outcome
Hypernatremia in Hospitalized Patients:
Outcome
All Patients Appropriate
Therapy
Delayed
Therapy
(n=103)
py
(n=50)
py
(n=53)
Overall Mortality 41 % 32 % 49 %
Mortality related to
hypernatremia
*
16 % 8 % 25 %
Decreased functional status
related to hypernatremia
14 % 12 % 15 %
*
p <0.05; Appropriate Therapy v Delayed Therapy
Palevsky PM, et al, Ann Intern Med 1996; 124:197-203
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine Medicine
•Scope of the problem.
•Control of body fluid tonicity: Regulation of ADH
release.
•Control of body fluid tonicity: Renal water excretion.
•Disturbances of body fluid tonicity: Neural effects Disturbances of body fluid tonicity: Neural effects
•Disturbances of body fluid tonicity: Hyponatremia.
•Disturbances of body fluid tonicity: Hypernatremia.
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65
A 47 year old high thoracic cord quadraplegic man
presents with 3 days of increasing confusion and
obtundation. Serum chemistries reveal: Na
+
= 118,
K
+
= 3.6, Cl
-
= 85, HCO
3
-
= 24, BUN = 7, S
Osm
= 232,
U 546 H h ld th h t i b t t d? U
Osm
= 546. How should the hyponatremia be treated?
A. Normal saline with recheck of electrolytes in the morning.
B. Hypertonic saline dosed according to Adrogue and Madias
formula, with recheck of electrolytes in the morning.
C. Normal saline with furosemide with check of serum
electrolytes and urine osmolality every 2 – 3 hours. y y y
D. Normal saline with furosemide or hypertonic saline with
check of serum electrolytes and urine osmolality every 2 – 3
hours. Limit correction rate to 0.5 - 1 MEq/kg/hr; < 12 mEq/D.
A 67 year old reformed alcoholic with chronic severe
cirrhosis has a serum sodium of 122 – 125 over several
months of care. He has chronic ascites, and edema,
partially controlled with spironolactone and
furosemide. He complains of chronic thirst. Which of
the following statements is not true?
A. Low serum sodium predicts adverse outcome in chronic
cirrhosis.
B. Chronic administration of tolvaptan has been shown to raise
serum sodium in patients with chronic cirrhosis, with an
acceptable profile of side effects.
C. Chronic administration of tolvaptan has been shown to raise
di i ti t ith h i i h i ith serum sodium in patients with chronic cirrhosis, with an
acceptable profile of side effects, and has been shown to
reduce mortality.
D. Chronic administration of tolvaptan raises serum sodium to
normal or near normal levels equally effectively in patients
with severe or mild hyponatremia.
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66
Disorders of Osmolality: From
Molecular Mechanisms to Clinical
Medicine
Mark L. Zeidel, M.D.
Disclosures: None
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67
A Physiological Approach to
Potassium Disorders
Julian L. Seifter, MD
• Overview of the relevant physiology
– New developments in regulated K
+
secretion by
the distal nephron
– Renal and adrenal RAS and K
+
homeostasis
• Hyper/hypokalemia
– Urinary indices and other diagnostic tests
– Clinical consequences
– Treatment of both disorders
– DD
x
of both disorders
Disclosures
• None
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68
Giebisch, AJP-Renal, 274, 1998
Factors Affecting K
+
Shift
Factor Transmembrane K
+

Shift
Insulin  uptake
β-catecholamine  uptake
α-catecholamine  uptake
Acidosis  uptake
Alkalosis  uptake
Hyperosmolarity  efflux

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69
Giebisch, AJP-Renal, 274, 1998
Na
+
, K
+
and H
2
O
Transport in
Principal Cells
ENaC – epithelial Na channel
ROMK – secretory K channel
Maxi-K – flow-activated K
channel
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70
K
+
Secretion is Proportional to Distal Flow
Animals
on
different
K
+
diets
Giebisch, AJP-Renal, 274, 1998
K
+
Excretion is Dependent on Na
+
Intake
Young et al, AJP-Renal, 246, 1984
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71
K
+
Excretion as a Function of Plasma K
+
and Circulating Aldosterone
Adrenalectomized
with different
levels of aldo
replacement
Young et al, AJP-Renal, 255, 1988
Aldo-Dependent and Aldo–Independent
Regulation of K
+
Excretion
Wang and Giebisch, Eur J Physiol, 2009
TAKE-HOME:
K
+
channels are
mostly regulated
by K
+
intake,
whereas
aldosterone
mostly regulates
ENaC, and thus
the “driving force”
for K
+
excretion.
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72
Transtubular K
+
Gradient (TTKG)
• Useful to assess the renal response to  or 
serum K+
• TTKG =[urine K+÷(urine Osm/ Plasma Osm)]
Plasma K+
• Should be >7 during hyperkalemia
• Should be <3 during hypokalemia
• Urine Na
+
needs to be >20-25 mEqu/L; if <20-
25, distal Na
+
delivery and distal flow rate may
be limiting
Causes of Hyperkalemia
• Increased intake
– K
+
supplements, diet, transfusions, iatrogenic
• Decreased renal excretion
– Renal disease, particularly with type IV RTA
– DRUGS
– Adrenal insufficiency – not universal
• Intra extracellular shifts
– Hyperosmolarity
– Insulinopenia
– Metabolic acidemia
– DRUGS
• Artifactual
– in vitro hemolysis, leukocytosis, thrombocytosis
– “pseudohyperkalemia”
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73
Take A Dietary History!
• Highest content (>25 mmol/100 g)
– Dried figs, molasses, seaweed
• Very high (>12.5 mmol/100 g)
– Dried fruits, nuts, avocados, bran cereals,
wheat germ, lima beans
• High content (>6.2 mmol/100 g)
– Vegetables: spinach, tomatoes, broccoli,
beets, carrots, potatoes
– Fruits: bananas, cantaloupe, oranges,
mangos, kiwis
– Meats: ground beef, steak, pork, veal, lamb
Gennari, NEJM, 1998
Hyporeninemic Hypoaldosteronism
• Hyperchloremic acidosis in ~50%, with
urine pH classically < 5.5
• Hyperkalemia
•  Plasma renin activity (PRA) and  aldo
•  Response of PRA to stimuli such as
furosemideand captopril
• Commonly with  age and  GFR,
classically in diabetics
• Often hypertensive, with clinical  ECFV
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74
Causes of Hyporeninemic
Hypoaldosteronism
• Diabetic nephropathy
• Acute GN, i.e. nephritic syndrome
• Tubulointerstitial nephropathies, eg. Sickle
cell disease
• Drugs, e.g. NSAIDS, cyclosporin, FK-506
• Hereditary causes, e.g.
pseudohypoaldosteronismtype II
The Juxtaglomerular Apparatus,
Intra-Renal Source of Renin
MD, macula densa
AA, afferent arteriole
EA, efferent arteriole
GC: granular cell
SMC: smooth muscle cell
Schnermann & Briggs, JCI, 1999
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75
ANP Blunts the
Aldo from K
+
Healthy young
subjects, infused
With K +/- ANP
Clark et al, J Am Soc Nephrol. 1995 Nov;6(5):1459-62
Drugs and the RAS
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76
TAKE HOME MESSAGES:
The Renin-Angiotensin-Aldosterone Axis
• ANP, systemic and local RAS, and prostaglandins all
affect renal renin release AND adrenal aldosterone
release, i.e. remember the adrenal effect
• The role in hyporeninemic hypoaldosteronismof
volume expansion and ANP/BNP
  renal renin and  adrenal aldosterone release
• The evolving risk of hyperkalemia from combining
multiple RAS inhibitors, e.g. MLR antagonist and
ACE-I in CHF
Question #1
• You are referred a 17 year-old high school student for
management of high blood pressure. He has not seen a
physician since childhood, is on no medications.
• He denies drug abuse, including cocaine.
• FH: His 50 year-old father is also hypertensive, with a
history of renal stones.
• Since you have access to a clinical research center, you
admit the father and son for biochemical profiling while
ingesting a diet with rigorously controlled salt content.
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77
Parameter Son

Father
Dietary Na
+

(mmol/day)
200 10 200 10
BP 150/90 110/64 142/90 110/70
K
+
6.0 4.5 5.6 4.6
Cl
-
119 102 114 102
HCO
3
-
18 25 21 27
pH 7.33 7.41 7.36 7.38
PRA 0.2 6.3 0.4 2.6
Aldo 15 61 13 41
ANP 48 9 32 14
FE
K
(%)
basal
7.8 10.3 8.5 7.8
FE
K
(%)
saline
8.1 33.8 8.2 15.0

A. Aggressive K restriction
B. NaCl restriction to 10 mEqu/day
C. Nifedipine
D. Amiloride
E. Hydrochlorothiazide
Which of the following is the most
appropriate therapy for this patient?
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78
Pseudohypoaldosteronism Type II (PHA-II)
• Also known as Gordon’s syndrome or the
“chloride-shunt” disorder
• The “mirror image” of Gitelman’s syndrome:
- hypertension
- hyperkalemic acidosis
- suppression of plasma renin, aldosterone
- hypercalciuria, nephrolithiasis
• Responsive to thiazides
• Autosomal dominant transmission; three
different genes, two characterized (WNK1/4)
• An evolving BOARDS favorite….
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79
WNK1 and WNK4 are Homologous
Serine/Threonine Kinases
WNK1 is Expressed in the DCT and CCD
B) WNK1 (red) and Aqp-2 (green)
D) WNK1 (red) and NCC (green)
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80
WNK4 is Expressed in the DCT and CCD
B) Co-expression of WNK4 (red) and Aqp-2 (green)
D) Co-expression of WNK1 (red) and NCC (green)
PHA-II Mutations in the WNK4 Kinase
Abrogate Its Inhibition of the Thiazide-
Sensitive Na-Cl Cotransporter
NCCT – Na-Cl cotransporter
Choate et al, PNAS, 100, 2003
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81
WNK-Dependent Signaling;
A molecular switch controlling NaCl and K
excretion
Welling et al, Kidney Int, 2010 green arrows – activating
red blunt end – inhibiting
Hypokalemia - Causes
• Pseudohypokalemia – leukocytosis, with uptake
of K
+
by WBCs, e.g. in AML
• Redistribution
– InsulinopeniaDKA
– Sympathomimetics
– β
2
-agonists, dopamine, theophyline
– Hypokalemic periodic paralysis, incl. thyrotoxic
– Acute anabolic state pernicious anemia
• Non-renal loss skin, stomach (suctioning),
intestine (diarrhea, laxatives)
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82
Renal Loss and Hypokalemia
• Drugs
– Diuretics
– Antibiotics
• Non-reabsorbable anions,
e.g. Penicillin
• Aldosterone excess
• Bicarbonaturia
• Magnesium deficiency
– inhibition of muscle Na/K-
ATPaseand  Mg
2+
-
dependent block of ROMK
 distal K
+
excretion
• Tubular damage
– ATN
– Cisplatin,
aminoglycosides,
amphotericin
• Intrinsic renal
transport defects
– Liddle’s syndrome
– Bartter’s syndrome
– Gitelman’s syndrome
– Hereditary dRTA
Consequences of Hyperkalemia
• Excitable tissue – change in resting
membrane potential
– Cardiac, decreased myocardial conduction
velocity, PR and QRS and increased rate of
repolarization (T wave changes)
– Skeletal muscle – weakness, fatigue,
paralysis
• Kidney – decreased ability to secrete NH
4
+
acidosis
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83
Typical Electrocardiographic Features of
Hyperkalemia
Serum K+ Major change
5.5-6.5 Tall peaked T waves
6.5-7.5 Loss of P waves
7.0-8.0 Widening of QRS
8.0-10 Sine wave,
ventricular arrhythmia,
asystole

Caveats: ECGs and Hyperkalemia
• Remember “the first symptom of
hyperkalemiais death…..”
• ECG changes are not sensitive, particularly in
ESRD
• Peaked T’s in other disorders
• Atypical ECGs
– Complete heart block
– Intraventricular conduction delays
– QRS axis shift
– Brugada sign - pseudo-RBBB and “coved” ST 
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84
Treatment of Hyperkalemia
Mechanism Therapy Dose Onset Duration
Stabilize membrane
potential
Calcium 10% Ca-gluconate,
10 ml over 10 min.
1-3 min. 30-60
min
Cellular K
+
uptake Insulin


β2-agonist

10 U R with 50 ml
of D50, if BS<250

nebulized albuterol,
10 mg
30 min.


30 min.
4-6 h


2-4 h

K
+
removal Kayexalate


Hemodialysis
30-60 g PO

?


Immediate
?

Bicarb
Doesn’t
Work!
Blumberg et al, Am J Med, 85, 1988
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85
Insulin and Glucose
• Recommended dose is 10 units of regular
insulin followed by 50 g of 50% glucose
• Followed by 10% dextrose infusion at a rate of
50-75 ml/hour (to prevent hypoglycemia)
• In hyperglycemic patients (glucose >200-250
mg/dl) insulin alone is enough
• D50W alone should be avoided 
hyperosmolality can increase K
+
, primarily in
predisposed patients (e.g. DM with type IV RTA)

2
-Adrenergic Agonists (Inhaled)
• 10-20 mg of nebulized albuterol in 4 ml of
normal saline, inhaled over 10 minutes
• Hypokalemic effect starts in 30 minutes,
peaks at 90 minutes and lasts for 2-6
hours
• Reduces K
+
level by 0.5-1.0 mmol/L
• Synergistic with insulin, but ineffective
as the sole agent in ESRD
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86
Kayexalate/SPS Complications
• Ischemic colitis and colonic necrosis
- risk in enema form
- often fatal
-  risk with sorbitol - but can occur without sorbitol
and is associated with intestinal SPS crystals
- post-transplant and post-op patients at  risk
• Volume overload
• Reduction in serum calcium
• Iatrogenic hypokalemia
Caveats/Concerns re
Kayexalate/SPS
• Slow onset of effect ? makes SPS unnecessary
and inappropriate in most patients with acute
hyperkalemia.
• Intestinal necrosis due to SPS in sorbitol is often a
fatal complication, NOT restricted to post-op setting.
• New FDA advisory September, 2009 – do NOT
administer SPS with sorbitol.
• Yet SPS with sorbitol remains a very popular “reflex”
mechanism of therapy for hyperkalemia, often the
only formulation of SPS available.
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87
Hemodialysis
• Serum K
+
level reaches a nadir at ~3
hours, but potassium removal continues to
the end of the session
• The amount of K
+
removed depends on:
- type and surface area of the dialyzer
- blood flow rate
- dialysate flow rate
- dialysis duration
- serum:dialysate K
+
gradient
The Serum - Dialysate Gradient
• Dialysates with lower K
+
concentration are more
effective, but may lead to rebound hypertension
• Dialysates with very low K
+
concentration (0 or 1
mmol/L) should be used cautiously, given the risk
of arrhythmia
• Graded reduction in K
+
concentration is effective,
with less arrhythmia, and is the standard of care
at BWH
• Continuous cardiac monitoring is recommended
when using very low K
+
concentration dialysates
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88
Consequences of Hypokalemia
• Arrhythmias
• Muscles – weakness,
paralysis, myopathy
• Metabolic alkalosis
• Insulin resistance
• HYPERTENSION
• Polydipsia, polyuria,
nephrogenic DI
• Structural renal
disease – AKI, ESRD
• Predisposition to
– Rhabdomyolysis
– Hepatic encephalopathy
Treatment of Hypokalemia
• First replete magnesium
• Usually oral therapy, preferably K-Cl
• IV can be given safely at 10 mEqu/hour,
but up to 40-60 mEqu/hr in a monitored
setting – need central line, preferably
femoral
• DO NOT USE DEXTROSE SOLUTIONS
acute  in K
+
, due to the induced insulin
release
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89
Question #2
32 yo Hispanic man admitted to Brigham and
Women's Hospital with weakness and a K of 2.0
HPI: The patient was very healthy until 2 months
PTA, when he developed leg weakness. This
weakness fluctuated, and was more severe at
night-time. He denies drug abuse, laxative
abuse, is on no medications.
ROS: no nausea, no vomiting or diarrhea.
SH: Taxi driver, married with one child
FH: 10 siblings, mother has DM, one sister has
thyroid disease.
Physical Exam
Temp 97.2 bp 176/96 HR 102, RR 16
HEENT normal
J VP visible and not elevated, good peripheral
pulses, no edema
S1, S2 normal, no murmurs
Abdomen – soft, non-tender, no organomegaly
Neuro – decreased DTRs, otherwise normal
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90
Admission: 5 months PTA:
Na 139 143
K 2.0 3.8
Cl 105 107
HCO
3
-
26 29
BUN 11 16
Creat 0.6 1.0
Glu 145 136
PO4 1.2
Ca 8.8 8.8
Mg 1.3 1.9
Alb 3.8
Posm 290 TTKG =2.0
UOsm 590
UK 10
A. TSH
B. Genetic sequence of the gene encoding
the Na/K-ATPasealpha-1 subunit
C. Genetic sequence of the gene encoding
a muscle-specific K
+
channel
D. A & C
E. A, B & C
Which of the following is likely to be
abnormal in this patient?
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91
Question #3
67 year-old man with peri-operative hyperkalemia
PMH inclusive of hypertension, hyperlipidemia, and chronic
renal failure (baseline creatinine3.8 mg/dL).
Patient had been admitted for elective 3-vessel CABG.
Admission medications included:
Lasix60 mg bid calcitriol 0.5 g three times per week
Lisinopril 10 mg OD calcium carbonate 500 mg PO tid
Isordil 30 mg tid EPO 2000 units per week
Amlodipine 10 mg OD lovostatin 20 mg PO OD
The patient underwent CABG without any
intraoperative events (other than hyperkalemia).
Bypass time: 1 hour 39 minutes
Cross-clamp time: 65 minutes
The patient received:
– two units of packed RBCs
– 1200 ml of D5W/NS
– three 10 gm boluses of epsilon-aminocaproicacid
Urine output during surgery was 376 ml, the
patient urinated 475 ml in the six hour
postoperative period.
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92
Development of Hyperkalemia
Na
+
K
+

Pre-op 134 4.9

Intra-op
30 min 131 5.4
60 min
90 min 6.2
140 min 6.7
(insulin/D50)
180 min 132 6.6



Post-op
0 min 6.2
90 min 5.4
4 hours 5.1
Day 1 135 4.6
Day 2 4.2

A. Transfusion with older-than-ideal pRBCs
B. Lisinopril
C. Epsilon-aminocaproic acid
D. Transient hemolysis due to cardiac
bypass
E. Efflux of K
+
due to cardiac bypass
What was the likely cause of this
patient’s hyperkalemia?
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93
A 66 year-old man was admitted to hospital with a plasma K
+
concentration of 1.7 mEqu/L and profound weakness. The patient
had noted progressive weakness over several days, to the point that
he was unable to rise from bed. The past medical history was
notable for small cell lung cancer with metastases to brain, liver, and
adrenals. The patient had been treated with one cycle of
cisplatin/etoposideone year prior this admission, complicated by
acute kidney injury (peak creatinineof 5, with residual chronic
kidney disease) and three subsequent cycles of
cyclophosphamide/doxorubicin/vincristine, in addition to fifteen
treatments with whole brain radiation.
On physical examination the patient was jaundiced. BP was 130/70,
increasing to 160/98 after a liter of saline, with a J VP at 8 cm. There
was generalized muscle weakness.
Question #4
Laboratory Data: 2 Months PTA: Admission: HD2: Units
Sodium 143 149 144 mEq/L
Potassium 3.7 1.7 3.5 mEq/L
Chloride 103 84 96 mEq/L
Bicarbonate 26 44 34 mEq/L
Venous pH 7.47 pH
Venous pCO2 62 mm Hg
BUN 21 41 40 mg/dL
Creatinine 2.8 2.9 2.3 mg/dL
Magnesium 1.3 1.6 2.4 mg/dL
ALT 8 75 Units/L
Albumin 3.4 2.8 2.3
Adjusted anion gap 15 24 18
Tot bilirubin 0.65 5.19 mg/dL
Urine sodium 35 28 mEq/L
Urine Potassium 25 49 mEq/L
Urine Chloride 48 51 mEq/L
Urine Osmolality 391 mOsm/kg
Plasma Osmolality 312 mOsm/kg
TTKG 12
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94
A. ACTH
B. Circulating aldosterone level
C. Circulating cortisol level
D. A & C
E. A, B & C
Which of the following is likely to be
elevated in this patient?
•Why is he hypokalemic?
•Why is he hypertensive?
•What is the underlying
pathophysiology?
•How should he be treated?
•Explain his acid-base picture.
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95
Syndrome of Apparent Mineralocorticoid
Excess (SAME)
• Low-reninhypertension with hypokalemic alkalosis,
subnormal aldosterone
• DDxis Liddle’s syndrome; Liddle’s R
x
by amiloride, but
not spironolactone, which treats SAME
• Exacerbated by ACTH, suppressed by dexamethasone
• Also associated with nephrocalcinosis
• Decrease in peripheral conversion of cortisol to inactive
cortisonedefect in 11-hydroxysteroid
dehydrogenase-2 (11-HSD2)
• Mimicked by licorice and other inhibitors of 11-HSD2
K
K
Cl
Na
NCC
+
+
+
+
+
+
Aldo
ML Receptor
Cortisol
Cortisone
11BHSD2
ENaC
ROMK
Cl
Aldosterone, Cortisol, and Distal Ion Transport
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96
Disclosures
• None
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97
David B. Mount, MD
Renal Division, BWH
Renal Division,
VA Boston Healthcare System
Calcium and Magnesium
Disorders
Disclosures
• None relevant to calcium and
magnesium disorders
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98
Calcium and Magnesium Homeostasis
• The role of the calcium receptor in calcium
homeostasis and renal pathophysiology
• Molecular physiology and pathophysiology
of vitamin D
• Calcium and magnesium transport in the
kidney and intestine
• The role of FGF23 in controlling serum
phosphate and calcium
• Disorders of serum magnesium and
calcium
Calcium and Phosphate Balance
• Regulated absorption (intestine), resorption or
incorporation (bone), and reabsorption or
excretion (kidney)
• Bone a major reservoir
hydroxyapatite: Ca
10
(PO4)
6
(OH)
2
• Serum calcium: 8.5-10.2 mg/dL (women), 9.0-
10.9 mg/dL (men)
– ~40% albumin-bound, 15% citrate/PO
4
/SO
4
-bound,
~45% ionized (free) Ca
2+
• Ionized calcium: 1.12-1.23 mM
• Serum phosphorus: 3.0-4.5 mg/dL
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99
Key Hormonal Mediators
• Ca
2+
itself Calcium-sensing receptor
• Parathyroid hormone, PTH – secreted by
the parathyroid gland
• Vitamin D, specifically 1,25-(OH)
2
D
3
(calcitriol)
• Fibroblast growth factor-23 (FGF23)
• Complex inter-relationships
e.g., FGF23   calcitriol,
calcitriol   FGF23
The Role of PTH in Defending Serum Ca
2+
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100
Regulation of PTH Secretion by the
Parathyroid Calcium-Sensing Receptor
(CaSR)
Human Disorders Due to Loss-of-Function
in the Calcium Sensing Receptor (CaSR)
• Familial benign (hypocalciuric) hypercalcemia (FHH)
– Lifelong hypercalcemia, autosomal dominant inheritance
– Normal or  PTH, inappropriately  urinary calcium excretion
– Hypocalciuriapersists after parathyroidectomy
– Can have chondrocalcinosis, pancreatitis, but generally
asymptomatic
– Rightward shift in set point of PTH response to  Ca
2+
• Neonatal severe hyperparathyroidism
– Severe neonatal hypercalcemia, failure to thrive,
hypophosphatemia, bony undermineralization, multiple fractures
and rib cage deformity
– Autosomal recessive, i.e. bi-allelic loss-of-function in CaSR
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101
Structure of the Calcium Receptor
Gain-of-Function Mutations in the CaSR
• Autosomal dominant hypocalcemia with
hypercalciuria
– Hypocalcemia with associated hypomagnesemia,
PTH inappropriately in the low to normal range
– Asymptomatic, although some have tetany, muscle
spasms, febrile seizures
– Inappropriately high or normal urinary calcium
excretion
– Treatment with 1,25-(OH)
2
D
3
leads to marked
hypercalciuria, can cause nephrocalcinosis and
CKD
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102
TAKE HOME MESSAGES
• Loss-of-function mutations in CaSR cause
“familial benign (hypocalciuric) hypercalcemia
(FHH)” and “neonatal severe
hyperparathyroidism”, both with
inappropriately increased/normal PTH for
degree of hypercalcemia.
• Gain-of-function mutations cause “autosomal
dominant hypocalcemia with hypercalciuria”
Calcium and Urinary
Concentrating Ability
• Hypercalcemia is associated with
nephrogenic DI, in part due to induction of
medullaryCOX-2 (as in lithium R
x
)
• In addition, activation of the calcium-
sensing receptor (CaSR) in the thick
ascending limb and collecting duct directly
inhibits urinary concentrating ability
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103
The CaSR Inhibits Transport in the
Thick Ascending Limb
Apical Expression of the CaSR in the
Renal Collecting Duct
A)Aquaporin-2 C) Aquaporin-4
B) Aquaporin-3 D) CaSR
E) CaSR immunoab
Sands, et al, JCI, 1997
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104
Activation of the Luminal CaSR
Inhibits Vasopressin-Stimulated Water
Transport in the Collecting Duct
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105
Low Calcium Diet in Hypercal ci uric Enuretic
Children Restores Aquaporin-2 Excretion (AVP
Response) and Reduces Enuresis
Valenti et al, AJP-Renal, 2002
↓ Nocturnal Aqp-2 excretion indicates AVP-resistance,
reversed by calcium restriction
TAKE HOME MESSAGES
• The calcium-sensing receptor directly
modulates renal function.
• Specifically, activation of CaSR reduces
salt transport by the TAL and water
transport by the collecting duct.
• These effects in large part underlie the
polyuria and the renal concentrating
defect that is seen with hypercalcemiaand
hypercalciuria.
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106
Vitamin 1,25-(OH)
2
D
3
and Calcium Homeostasis
Jones et al, Physiol Rev, 1998
Vitamin D
Is
Activated
by UVB Light
and
Hydroxylation in
Liver and Kidney
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107
Regulation of 1-Hydroxyl ase in Proximal
Tubule:
 Activi ty by 1,25(OH)D
3
,  by PTH
con control F forskolin (PKA)
D3 1,25(OH)D
3
PTH
Bland et al, Endocrinology, 1999
Vitamin D Hydroxylation by the
Proximal Tubule
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108
1 Hydroxylase in Lymphoid Tissue
E) Normal lymph node
G) Granuloma (sarcoid)
H) Sarcoidosis skin
Granolomas are associated with hypercalcemia,
due to UNREGULATED generation of calcitriol
Take Home Messages
• Generation of the active form of vitamin D (1,25-
(OH)
2
D
3
) requires UVB light and two P450 hydroxylase
enzymes
• Deficiency in vitamin D, its receptor, the 1α-hydroxylase,
or of megalin (the endocytic receptor for vitamin D
binding protein in the proximal tubule) causes
hypocalcemia and rickets
• 1,25-(OH)
2
D
3
and Ca
2+
inhibit 1α-hydroxylase, whereas
PTH and low PO
4
activate the enzyme
• 1,25-(OH)
2
D
3
increases renal and intestinal
absorption/reabsorptionof Ca
2+
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109
Renal Tubular Re-Absorption of Cations
Ion Transport in the TAL (Thick Ascending Limb)
Ca
2+
/Mg
2+
are
reabsorbed via
the
paracellular path
in the TAL,
driven by the
lumen-positi ve
potential
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110
Familial Hypomagnesemia/Hypercalciuria;
Loss of Paracellular Transport in the TAL
• Invariably accompanied by hypercalciuria
• Often have renal colic, UTIs,
nephrocalcinosis renal failure
• Marked increase in fractional excretion of
magnesium, cured by renal transplantation
• Associated polyuria and isosthenuria
(inability to concentrate the urine)
Science, 285, 1999
Paracellin-1 (Claudin-16)
is the disease gene for
familial hypomagnesemia
with hypercalciuria
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111
Paracellin/Claudin-16 is Expressed in the
Thick Ascending Limb and DCT
Ion Transport in the TAL (Thick Ascending
Limb)
Paracellin
affects
cation
permeability
of the
paracellular
pathway
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112
The DCT (Distal Convoluted Tubule)
Na
+
2K
+
ATP
K
+
Mg
2+
Ca
2+
Na
+
K
+
ROMK
ECaC-1
TRPM-6
NCC
KCC4
CLC-K1
Lumen
Ca /Mg
2+ 2+
3Na
+
Cl
-
Cl
-
Cl
-
Ca
2+
/Mg
2+
Transport in the DCT
Calbindins function
as intracellul ar
calcium “ buffers” .
What are the
DCT pathways for
magnesium
Transport ?
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113
The DCT (Distal Convoluted Tubule)
Na
+
2K
+
ATP
K
+
Mg
2+
Ca
2+
Na
+
K
+
ROMK
ECaC-1
TRPM-6
NCC
KCC4
CLC-K1
Lumen
Ca /Mg
2+ 2+
3Na
+
Cl
-
Cl
-
Cl
-
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114
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115
The EGFR Inhibitor CetuximabCauses
Magnesium Wasting
B:

Normagnesemic control pts
 Cetuximab-treated pts
 P1070L EGF pts
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116
TAKE-HOME MESSAGES
• Ca
2+
/Mg
2+
absorption by the thick
ascending limb is paracellular, requiring
paracellin/claudin-16
• Vitamin D responsive epithelial calcium
channels (ECaC) have been identified.
• Ca
2+
/Mg
2+
absorption in the DCT is a
transcellular process, involving ECaC1
and TRPM6
• ParacrineEGF regulates DCT magnesium
transport
Renal Phosphate Transport
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117
Phosphate Transport in the
Proximal Tubule
Expression pattern of FGF23
Renal phosphate wasting, hypophosphatemia,
low or inappropriately normal calcitriol concentrations,
and osteomalacia
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118
FGF-23 Inhibits Phosphate Transport
in Proximal Tubular Cells
FGF23 and Oncogenic
Hypophosphatemic Osteomalacia (OHO)
Hypophosphatemia,
low calcitriol, and osteomalacia
Over-expression of FGF23
in sarcomas associated
with OHO
White et al, J Clin Endo Met, 2001
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119
Hypervitaminosis D and Suppressed PTH
in FGF23 Knockout Mice
FGF23
inhibits
generation
of calcitriol,
by inhibiting
1α-hydroxylase
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120
Loss-of-Function in FGF23 and
Familial Hyperphosphatemic
Tumoral Calcinosis
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121
TAKE-HOME MESSAGES
• FGF23 is a novel factor that increases
renal phosphate excretion by inhibiting
NPT2a; FGF23 is associated with both
hereditary and paraneoplastic
hypophosphatemicbone disease.
• FGF23 also inhibits generation of calcitriol
• Loss of function in FGF23 causes
hypercalcemia, due to ↑ in 1,25-(OH)D
3
• Evolving role for FGF23 in CKD
Common Causes of
Hypercalcemia
• Primary Hyperparathyroidism
– Adenoma
– Carcinoma
– Hyperplasia
• Malignancy
– Humoral hypercalcemia – PTH-RP, TNF/LT
(myeloma OAFs)
– Lytic bone disease, incl. myeloma
– Ectopic/lymphoid calcitriol production
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122
Less Common Causes of
Hypercalcemia
• Inherited disease – MENI/II, FHH
• Granulomatous disease
• Drugs – lithium, thiazides, vitamin D,
estrogens
• Milk alkali syndrome
• Immobilization
• Neonatal/childhood hypercalcemia
Milk-Alkali Syndrome
HYPERCALCEMIA
RENAL FAILURE ALKALOSIS
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123
PTH Reduces Apical Expression of
NPT2a
The Vicious Cycle of
Milk Alkali Syndrome
Increased
calcium
Decreased
GFR +
volume
depletion
+ emesis
Worsening
Alkalosis
Ca
excretion
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124
Initial Workup of Hypercalcemia
• PTH – should be suppressed, if WNL or
increased → hyperparathyroidism
• PTH-RP
• 1,25-OHD
3
and 25-OHD
2
levels
• SPEP, urine IEP, and serum light chains
• CXR +/- chest CT
• Bone scan if biochemistry unrevealing
Management of Hypercalcemia
• Saline hydration
• Loop diuretcs, once euvolemic
• Calcitonin
• Bisphosphonates
– zolendrate→ ATN,
– pamidronate → collapsing FSGS
– Ibandronatemay be safer, ? less effective
• Dialysis
• Specific therapy
– Sensipar or PTHx for  PTH
– Steroids for  1α-hydroxylase
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125
Causes of Hypocalcemia
• Hypoparathyroidism
– Hereditary – CaSR, PTH, etc.
– Post-surgical, post irradiation
• PTH resistance, e.g. with hypomagnesemia
• Vitamin D abnormality
– Genetic – VDR, 1α-hydroxylase
– Nutritional, hypovitaminosis D / rickets
– GI disease, hepatobiliarydisease
– Renal insufficiency
• Drugs – foscarnet, kayexalate, citrate, dilantin,
phenobarbital
Hypomagnesemia
• Renal – FeMgof >3% in someone with
normal GFR is consistent with renal
magnesium wasting
• Extra-renal
– Nutritional – alcoholics (also renal), TPN
– Intestinal malabsorption – celiac, proton-pump
inhibitors, etc.
– Diarrhea
– Redistribution to bone, e.g. in hungry bone
syndrome
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126
Renal Hypomagnesemia
• Polyuria
• ECFV expansion
• Diuretics, particularly loop diuretics
• EGF receptor inhibition - cetuximab
• Hypercalcemia
• Tubule toxins / acute tubular injury
– Cisplatin - cyclosporine
– Aminoglycosides - Foscarnet
– Amphotericin
– Pentamidine
Manifestations of Hypomagnesemia
• Cardiac
– ECG changes
– Arrhythmias – ectopy, torsades, VF
• Neuromuscular
– Weakness
– Tremor, twitching, +Troussea/Chvostek’s
– Seizures, nystagmus
• Metabolic
– HYPOKALEMIA
– Hypocalcemia
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127
Question #1
A 70 yo man with a history of DM, hyporeninemic
hypoaldosteronism, CKD, and recently treated
hypovitaminosis D is admitted to the hospital
with recurrent hypocalcemia.
Daily medications include lasix, calcitriol,
amlodipine, kayexalate, amlodipine,
omeprazole, bicitra, and hydralazine.
Laboratory Studies:
Ca: 6.0, I Ca: 2.7, Mg: 1.7, Phos: 6.2, iPTH: 906,
Albumin 3.4, 25-Vitamin D: 67 ng/ml (20 – 100)
1,25-Vitamin D
3
: 74 pg/ml (6-62)
A. Therapy with furosemide
B. Delayed intestinal response to
calcitriol
C. Therapy with omeprazole
D. Therapy with kayexalate
E. Therapy with Bicitra
Which of the following is the most likely
cause of his hypocalcemia?
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128
Question #2
A 70 yo man with a history of
hypercalemiaand biopsy-proven
sarcoidosis presents after a New Years
Eve party with a fractured leg. He was lost
to follow up just after his sarcoidosis
diagnosis 5 months prior to admission,
and has never received prednisone. Other
medical issues include mild CKD.
His peak calcium was 13.0 mg/dL five
months ago, but now it is 9.0 mg/dL with
an albumin of 3.0
A. His corrected calcium is in fact in the
hypercalcemic range
B. His sarcoidosis has undergone spontaneous
remission
C. He is taking another immunosuppressive
medication
D. He had previously been abusing Rolaids
E. His serum levels of 25-hydroxyvi tami n D
have decreased
Why is he now normocalcemic, without
having received prednisone?
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129
Seasonal Hypercalcemia in
Sarcoidosis
Tayl or et al , Am J Med, 1963
Response to UV Light Treatment in a Patient
With Sarcoidosis and Seasonal Hypercal cemi a
Smi th et al , Postgrad Med J, 1976
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130
Question #3
A 60 yo man presents with hypomagnesemia
despite oral replacement. He has type II DM,
with minimal proteinuria and a creatinine of 1.4.
PMH is notable for CAD, HTN, peptic ulcer
disease, and alcoholism. He says he has been
abstinent for several years. ROS is negative for
diarrhea, polyuria, or other Sx.
Medications include metoprolol, glipizide,
lisinopril, magnesium oxide 420 mg tid, and
omeprazole. Physical exam is unremarkable.
Labs are notable for a serum magnesium of 1.4,
a 24 hour urine contains ZERO magnesium and
150 mg of calcium.
A. Poorly controlled diabetes
B. Alcoholism
C. Glipizide
D. Celiac disease
E. Omeprazole
What is the most likely cause of his
hypomagnesemia?
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131
Disclosures
• None relevant to calcium and
magnesium disorders
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132
Electrolytes and Acid-Base
Practice for the Boards I
2:15-3:45 pm
Alan S. L. Yu, M.B., B.Chir.
University of Southern California Keck School
of Medicine
30 cases
Financial disclosures
No conflict of interest to disclose.
Alan S. L. Yu, M.B., B. Chir.
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133
A 55 year-old man with colonic carcinoma undergoes
resection of his tumor and diverting colostomy. Post-
operatively he has prolonged ileus and is therefore started
on intravenous total parenteral nutrition. Four days later, a
renal consult is called for hypernatremia. On examination,
the patient is clinicallyeuvolemic.
Serum sodium 151 mEq/L
Blood glucose 138 mg/dL
Blood urea nitrogen 33 mg/dL
Serum creatinine 0.9 mg/dL
Urine osmolality 480 mOsm/kg
Urine sodium 30 mEq/L
Urine volume (24 h) 3700 mL
Case 1
Case 1
Which of the following is the MOST LIKELY cause
of his hypernatremia?
(A) Central diabetes insipidus
(B) Nephrogenic diabetes insipidus
(C) Osmotic diarrhea
(D) Osmotic diuresis
(E) Excess intravenous saline
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134
Hypernatremia
• Insensible H
2
O loss
• GI H
2
O loss
• Na
+
intake
• Renal H
2
O loss
U
Osm
<800 mOsm/kg >800 mOsm/kg
+
 Water intake
Glucose, urea,
mannitol
DI Osmotic
diuresis
CDI NDI
Polyuria (UO > 3L/d)
Osmolar excretion rate (UO x U
Osm
)
>1000 mOsm/d <1000 mOsm/d
Osmotic diuresis
NaCl, glucose,
urea, mannitol
Water diuresis
Serum Na
>140 mEq/L <140 mEq/L
Diabetes insipidus Polydipsia
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135
Case 1
Which of the following is the MOST LIKELY cause
of his hypernatremia?
(A) Central diabetes insipidus
(B) Nephrogenic diabetes insipidus
(C) Osmotic diarrhea
(D) Osmotic diuresis
(E) Excess intravenous saline
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136
A 35-year-old man with bipolar disorder, maintained on
lithiumfor 10 years, is referred to you for chronic polyuria
and polydipsia. He complains that he has to void once
everyhour.
Serumsodium 144mEq/L
Bloodurea nitrogen 35mg/dL
Serumcreatinine 1.9mg/dL
Serumosmolality 292mOsm/kg
24-hr urine volume 5L
Urine sodium 28mEq/L
Urine osmolality 190mOsm/kg
Case 2
Case 2
All of the following might be appropriate in the
management of this patient EXCEPT:
(A) Thiazide diuretic
(B) Dietary salt reduction
(C) Discontinuation of lithium
(D) Fluid restriction
(E) Amiloride
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137
Polyuria (UO > 3L/d)
Osmolar excretion rate (UO x U
Osm
)
>1000 mOsm/d <1000 mOsm/d
Osmotic diuresis
NaCl, glucose,
urea, mannitol
Water diuresis
Serum Na
>140 mEq/L <140 mEq/L
Diabetes insipidus Polydipsia
Case 2
All of the following might be appropriate in the
management of this patient EXCEPT:
(A) Thiazide diuretic
(B) Dietary salt reduction
(C) Discontinuation of lithium
(D) Fluid restriction
(E) Amiloride
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138
A 17-year-old woman who is otherwise fit and well, and on
no medications, presents with a history of polyuria since
earlychildhood.
On presentation:
Serum sodium 141 mEq/L
Serum osmolality 285 mOsm/kg
Urine osmolality 210 mOsm/kg
Urine volume 4 L
Case 3
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139
After 4 hrs of water deprivation:
Serum sodium 146 mEq/L
Serum osmolality 298 mOsm/kg
Urine osmolality 250 mOsm/kg
1 hr after administration of 10 µg intranasal DDAVP:
Serum sodium 145 mEq/L
Serum osmolality 296 mOsm/kg
Urine osmolality 425 mOsm/kg
Case 3
Case 3
Which of the following statements could be TRUE?
(A) She is entirely normal since her baseline serum
sodium is normal
(B) Her condition may have been caused by head trauma
(C) She may have an inherited mutation in a vasopressin
receptor gene
(D) She has an osmotic diuresis with washout of her
medullaryinterstitiumconcentrating gradient
(E) The water deprivation test is non-diagnostic because
water deprivation was not continued for long enough
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140
Water deprivation test
P
osm
≥ 295 mOsm/kg
U
Osm
>800 300-800 <300
Not renal
water loss
Complete DI Partial DI
DDAVP
D+50% No D
CDI NDI
DDX of renal water loss
Hypernatremia
Case 3
Which of the following statements could be TRUE?
(A) She is entirely normal since her baseline serum
sodium is normal
(B) Her condition may have been caused by head trauma
(C) She may have an inherited mutation in a vasopressin
receptor gene
(D) She has an osmotic diuresis with washout of her
medullaryinterstitiumconcentrating gradient
(E) The water deprivation test is non-diagnostic because
water deprivation was not continued for long enough
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141
An 87-year-old woman trippedinher bedroomat home and
was unable to get up. She was found by her neighbor 3
days later, and brought into the emergency room. On
examination she has a broken left hip, appears severely
dehydrated, and is making small volumes of very
concentratedurine.
Laboratory studies:
Serum sodium 157 mEq/L
Urine sodium <5 mEq/L
Urine osmolality 850 mOsm/kg
Case 4
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142
Case 4
Which of the following statements is TRUE?
(A) Her hypernatremia is most likely to be due to osmotic
diuresis
(B) She likely has underlying diabetes insipidus
(C) Treatment carries a potential risk of cerebral edema
(D) Non-steroidal anti-inflammatory drug would be helpful
(E) Her intracellular fluid volume is increased
Hypernatremia
• Insensible H
2
O loss
• GI H
2
O loss
• Na
+
intake
• Renal H
2
O loss
U
Osm
<800 mOsm/kg >800 mOsm/kg
+
 Water intake
Glucose, urea,
mannitol
DI Osmotic
diuresis
CDI NDI
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143
Case 4
Which of the following statements is TRUE?
(A) Her hypernatremia is most likely to be due to osmotic
diuresis
(B) She likely has underlying diabetes insipidus
(C) Treatment carries a potential risk of cerebral edema
(D) Non-steroidal anti-inflammatory drug would be helpful
(E) Her intracellular fluid volume is increased
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144
A 45-year-old female underwent transsphenoidal resection
of a pituitary adenoma 1 week ago. Immediately
postoperatively she developed severe polyuria and was
started on DDAVP. She returns with change in mental
status, has a seizure in the emergency room, and is found
to have a serumsodiumof 114 mEq/L.
Case 5
Case 5
Which of the following statements is TRUE?
(A) Her postoperative condition was almost certainly
misdiagnosed and she should never have been
treated with DDAVP
(B) She currently has diabetes insipidus
(C) Her hyponatremia now is most likely due to central
(pituitary) hypothyroidism
(D) Her hyponatremia is primarily due to psychogenic
polydipsia
(E) She is at risk of developing diabetes insipidus
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145
Hensenet al. Clin Endocrinol. 1999;50, 431
Pathogenesis of disordered water metabolism
after transsphenoidal surgery
Day 1 - Day 4-5
Day 6-11
AVP
secretion
normal
Before
surgery
Day 1 Day 7 Day 14
Secretiona
l arrest
Degeneration
& AVP release
Residual
AVP
secretion
Monophasic (40%)
Biphasic (3%)
Triphasic (1%)
H
y
p
o
n
a
t
r
e
m
i
a
H
y
p
e
r
n
a
t
r
e
m
i
a
/
p
o
l
y
u
r
i
a
Case 5
Which of the following statements is TRUE?
(A) Her postoperative condition was almost certainly
misdiagnosed and she should never have been
treated with DDAVP
(B) She currently has diabetes insipidus
(C) Her hyponatremia now is most likely due to central
(pituitary) hypothyroidism
(D) Her hyponatremia is primarily due to psychogenic
polydipsia
(E) She is at risk of developing diabetes insipidus
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146
A 64-yr-old woman with coronary artery disease, multiple prior
myocardial infarctions and ischemic cardiomyopathy, with a left
ventricular ejection fraction of 15%, is admitted with pulmonary edema.
Her medications include aspirin, metoprolol, furosemide,
spironolactone, digoxin, isosorbide dinitrate, and lisinopril. On
examination, the blood pressure is 97/54 mm Hg, pulse rate 85 per
minute, jugular venous pressure 9 cm, moist mucous membranes,
lungs with diffuse inspiratorycrackles, heart with an S3 gallop, and
cool, clammy extremities with 1+peripheral edema.
Serum sodium 128 mEq/L
Serum potassium 3.6 mEq/L
Serum chloride 87 mEq/L
Serum bicarbonate 34 mEq/L
Blood urea nitrogen 46 mg/dL
Serum creatinine 1.2 mg/dL
Serum osmolality 264 mOsm/L
Case 6
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147
Urine electrolytes (6 hrs after last diuretic dose):
Urine sodium 15 mEq/L
Urine chloride <5 mEq/L
Urine osmolality 220 mOsm/kg
Case 6
Case 6
All of the following might be appropriate in the
management of this patient EXCEPT:
(A) Intravenous 0.9% saline
(B) Restriction of free water intake
(C) Dietary sodium restriction
(D) Dobutamine
(E) Acetazolamide
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148
Hyponatremia
P
osm
>290 mOsm/kg <275 mOsm/kg Normal
Glucose 
Mannitol
Hypoosmolal
hyponatremia
Lipid 
Protein 
Volume status
Hypovolemic Edematous Euvolemic
Dehydration*
Addison’s
Diuretics
CHF*
Nephrosis*
Liver failure*
Renal failure
U
Osm
> 100
<100
SIADH
Hypothyroid
Polydipsia
* U
Na
< 20
Hypoosmolal hyponatremia
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149
Case 6
All of the following might be appropriate in the
management of this patient EXCEPT:
(A) Intravenous 0.9% saline
(B) Restriction of free water intake
(C) Dietary sodium restriction
(D) Dobutamine
(E) Acetazolamide
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150
A 45-year-old male smoker presents with confusion and
drowsiness. His only medications are bronchodilator and
steroid inhalers. On examination, his BP is 125/86, HR 78,
moist mucous membranes, good skin turgor, jugular venous
pressure 4 cm, lung fields clear to auscultation, no
peripheral edema. Chest radiograph shows
emphysematous changes but is otherwise normal.
Serum sodium 116 mEq/L
Serum osmolality 256 mOsm/kg
Urine sodium 96 mEq/L
Urine potassium 87 mEq/L
Urine osmolality 670 mOsm/kg
Case 7
The appropriate management of this patient should include:
(A) Thyroid radioiodine scan
(B) Computed tomography scan of the chest
(C) Thiazidediuretic
(D) Haloperidol
(E) Intravenous 0.9% sodium chloride to correct the
serum sodium
Case 7
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151
Volume status
Hypovolemic Edematous Euvolemic
Dehydration*
Addison’s
Diuretics
CHF*
Nephrosis*
Liver failure*
Renal failure
U
Osm
> 100
<100
SIADH
Hypothyroid
Polydipsia
* U
Na
< 20
Hypoosmolal hyponatremia
What is the effect of this IV fluid on patient’s serum
Na
+
/osmolality?
Urine:
Na 96 mEq/L
K 87 mEq/L
Urea 900 mg/dL
Osm 670 mOsm/L
Ineffective osmoles
0.9% saline IV
Na 154 mEq/L
Effective osmoles:
2(Na +K) =366 mOsm/L
Urine tonicity >isotonic saline
Electrolyte-free water
clearance is negative
Infusion of isotonic saline
would lower serum Na
+
!
Serum Na
+
116 mEq/L
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152
Rx of hyponatremia
Hypovolemia Isotonic saline
Polydipsia Water restriction
SIADH Water restriction
Isotonic (U
Na
+U
K
<150) saline
Hypertonic saline / Na tablets
Furosemide
Demeclocycline/Conivaptan
Case 7
The appropriate management of this patient should include:
(A) Thyroid radioiodine scan
(B) Computed tomography scan of the chest
(C) Thiazidediuretic
(D) Haloperidol
(E) Intravenous 0.9% sodium chloride to correct the
serum sodium
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153
An 18-year-old woman with schizophrenia, maintained on
haloperidol, presents with a generalized seizure.
Serum sodium 120 mEq/L
Serum osmolality 252 mOsm/kg
Urine sodium 20 mEq/L
Urine osmolality 90 mOsm/kg
Case 8
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154
Case 8
Which of the following statements about this patient is
TRUE:
(A) The serum lipid and total protein must be measured to
exclude pseudohyponatremia
(B) Her condition has been caused by haloperidol, which
should be discontinued
(C) Correction of the hyponatremia may be complicated
by cerebral edema
(D) The serum sodium can be corrected at 1-2 mEq/L per
hour
(E) Fluid restriction will not correct the hyponatremia
Hyponatremia
P
osm
>290 mOsm/kg <275 mOsm/kg Normal
Glucose 
Mannitol
Hypoosmolal
hyponatremia
Lipid 
Protein 
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155
Volume status
Hypovolemic Edematous Euvolemic
Dehydration*
Addison’s
Diuretics
CHF*
Nephrosis*
Liver failure*
Renal failure
U
Osm
> 100
<100
SIADH
Hypothyroid
Polydipsia
* U
Na
< 20
Hypoosmolal hyponatremia
Case 8
Which of the following statements about this patient is
TRUE:
(A) The serum lipid and total protein must be measured to
exclude pseudohyponatremia
(B) Her condition has been caused by haloperidol, which
should be discontinued
(C) Correction of the hyponatremia may be complicated
by cerebral edema
(D) The serum sodium can be corrected at 1-2 mEq/L per
hour
(E) Fluid restriction will not correct the hyponatremia
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156
A 19-year-old male who recently returned from trekking in
the Himalayas has had watery diarrhea for one week. On
examination he appears tired and mucous membranes are
dry. BP is 105/70 and HR 80 sitting, BP 95/60 and HR 102
standing.
Serum sodium 128 mEq/L
Serum potassium 2.8 mEq/L
Serum chloride 102 mEq/L
Serum bicarbonate 18 mEq/L
Blood urea nitrogen 48 mg/dL
Serum creatinine 1.1 mg/dL
Urine sodium <5 mEq/L
Urine osmolality 350 mOsm/kg
Case 9
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157
Case 9
Which of the following would be the most appropriate
management of this patient:
(A) Hypertonic saline
(B) Conivaptan
(C) 0.9% NaCl and hydrocortisone
(D) 0.9% NaCl and furosemide
(E) 0.9% NaCl and KCl
Volume status
Hypovolemic Edematous Euvolemic
Dehydration*
Addison’s
Diuretics
CHF*
Nephrosis*
Liver failure*
Renal failure
U
Osm
> 100
<100
SIADH
Hypothyroid
Polydipsia
* U
Na
< 20
Hypoosmolal hyponatremia
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158
Rx of hyponatremia
Hypovolemia Isotonic saline
Polydipsia Water restriction
SIADH Water restriction
Isotonic (U
Na
+U
K
<150) saline
Hypertonic saline / Na tablets
Furosemide
Demeclocycline/Conivaptan
Case 9
Which of the following would be the most appropriate
management of this patient:
(A) Hypertonic saline
(B) Conivaptan
(C) 0.9% NaCl and hydrocortisone
(D) 0.9% NaCl and furosemide
(E) 0.9% NaCl and KCl
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159
An 18 year-old female college student runs the Boston
marathon. It is her first marathon and so she is careful
to keep well hydrated before and during the race. At
the finish line, she feels severely nauseated, dyspneic
and has generalized headache. BP is 102/64, HR 95,
otherwise normal exam.
Her serum sodium concentration is 112 mEq/L.
Case 10
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160
Case 10
Which of the following would be the best initial treatment
for this patient:
(A) 1 liter of intravenous 0.9% NaCl
(B) Fluid restriction
(C) Salt tablets orally
(D) 100 mL intravenous 3% NaCl
(E) 1 liter of sports drink
Exercise-associated hyponatremia (EAH)
Pathogenesis of EAH
• EAH is dilutional due to
excessive water or sports
drink consumption, not due
tosalt loss/dehydration
• In addition, ADH levels are
inappropriately elevated and
U
osm
is high
Almond et al.(2005) NEJ M 352:1550
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161
• Drinkonlyaccordingto thirst
• Use the USATF guidelines, or analogous methods, to estimate
hourly sweat losses during exercise and avoid consuming amounts
greater than this duringendurance exerciseevents
• Any athlete with EAH and respiratory insufficiency, confusion,
obtundation, N/V can be treated on-site with 100 mL of 3% NaCl
over 10 min (expectedD[Na
+
] ~2-3mmol/L)
• If symptomatic EAH persists, repeat 100 mL 3% NaCl hourly at a
rateof 100 mL/hand monitor serumNa hourly
• Osmotic demyelination in association with the rapid correction of an
acute hyponatremia has not been reported and should never be an
impedimentto rapidlycorrectinghyponatremiainsymptomaticEAH
Hew Butler et al. (2005) Clin J Sport Med 15:208
Consensus Statement of the 1st International Exercise-
Associated Hyponatremia Consensus Development
Conference, Cape Town 2005:
Case 10
Which of the following would be the best initial treatment
for this patient:
(A) 1 liter of intravenous 0.9% NaCl
(B) Fluid restriction
(C) Salt tablets orally
(D) 100 mL intravenous 3% NaCl
(E) 1 liter of sports drink
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162
An 30-year-old female with anorexia nervosa is found on
routine laboratory examination to be hypokalemic. BP
95/45, HR 66.
Serum sodium 133 mEq/L
Serum potassium 3.2 mEq/L
Serum chloride 93 mEq/L
Serum bicarbonate 32 mEq/L
Blood urea nitrogen 6 mg/dL
Serum creatinine 0.6 mg/dL
24 hour urine
Volume 1 L
Potassium 80 mEq/L
Chloride 44 mEq/L
Calcium 300 mg/day (normal <150)
Case 11
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163
Which of the following is the most likely cause of this
patient’s laboratory findings:
(A) Loop diuretic abuse
(B) Laxative abuse
(C) Gitelman syndrome
(D) Thiazide diuretic abuse
(E) Surreptitious vomiting
Case 11
DDX of hypokalemia
Cellular shift GI loss Urinary K wasting
Alkalemia
Insulin
-agonist
HypoKPP
Vomiting
Diarrhea
24 hr U
K
>25 mEq
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164
BP/volume
Aldo
Bartter
Loop diuretic
Renin
Cushing
Liddle
Licorice
AME
RAS
Reninoma
Malig HTN
1° aldo
GRA
Urine Cl
Consider:
Diarrhea/laxatives
RTA
Toluene
Ampho
Low HCO
3
-
Vomiting
Gitelman
Thiazide
Urine Ca
High Low
High Low
Low High
High Low
High Low
Consider:
1° HypoMg
V. low Mg
2+
Renal K wasting with  CCD [K
+
]
Which of the following is the most likely cause of this
patient’s laboratory findings:
(A) Loop diuretic abuse
(B) Laxative abuse
(C) Gitelman syndrome
(D) Thiazide diuretic abuse
(E) Surreptitious vomiting
Case 11
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165
A 23-year-old male is referred for work-up of newly
diagnosed hypertension. He is otherwise asymptomatic.
Family history is non-contributory. BP 145/97. He is mildly
obese.
Serum sodium 143 mEq/L
Serum potassium 3.0 mEq/L
Serum chloride 106 mEq/L
Serum bicarbonate 29 mEq/L
Blood urea nitrogen 12 mg/dL
Serum creatinine 1.2 mg/dL
Plasma reninactivity 0.7 ng/mL/hr (NR 1-6)
Plasma aldosterone 3.9 ng/dl (NR 5-20)
24 hour urine potassium 65 mEq
Case 12
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166
Which of the following tests would be most likely to be
helpful in the diagnosis:
(A) Serum metanephrines
(B) Doppler ultrasound of the renal arteries
(C) 24 hr urine aldosterone
(D) 24 hr urine 18-hydroxycortisol and 18-oxocortisol
(E) 24 hr urine cortisol
Case 12
BP/volume
Aldo
Bartter
Loop diuretic
Renin
Cushing
Liddle
Licorice
AME
RAS
Reninoma
Malig HTN
1° aldo
GRA
Urine Cl
Consider:
RTA
Toluene
Ampho
Low HCO
3
-
Vomiting
Gitelman
Thiazide
Urine Ca
High Low
High Low
Low High
High Low
High Low
Consider:
1° HypoMg
V. low Mg
2+
Renal K wasting with  CCD [K
+
]
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167
Case 12
Which of the following tests would be the most likely to be
helpful in the diagnosis:
(A) Serum metanephrines
(B) Doppler ultrasound of the renal arteries
(C) 24 hr urine aldosterone
(D) 24 hr urine 18-hydroxycortisol and 18-oxocortisol
(E) 24 hr urine cortisol
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168
A 19-year-old male student visiting from Taiwan presents to
the emergency room with acute onset of flaccid muscle
weakness. He denies diarrhea or vomiting and is using no
medications. BP 125/88, HR 95.
Serum sodium 139 mEq/L
Serum potassium 1.7 mEq/L
Serum chloride 105 mEq/L
Serum bicarbonate 25 mEq/L
Serum glucose 100 mg/dL
Blood urea nitrogen 11 mg/dL
Urine potassium <5 mEq/L
Case 13
Which of the following would be appropriate in the
management of this patient:
(A) Repletion with KCl, 160 mEq daily
(B) Loperamide
(C) Indomethacin
(D) Check serum thyroid-stimulating hormone level
(E) None of the above
Case 13
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169
DDX of hypokalemia
Cellular shift GI loss Urinary K wasting
Alkalemia
Insulin
-agonist
Hypokalemic periodic paralysis
Vomiting
Diarrhea
24 hr U
K
>25 mEq
Thyrotoxic hypokalemic periodic
paralysis
• Presents age 20-40 yr
• Predominantly Asians
• Mostly male (20:1 male:female ratio)
• Only with thyrotoxicosis (~2% of Asians with
thyrotoxicosis) which may be asymptomatic
• Clinical features identical to familial form
Copyright Harvard Medical School, 2010. All Rights Reserved.
170
Which of the following would be appropriate in the
management of this patient:
(A) Repletion with KCl, 160 mEq daily
(B) Loperamide
(C) Indomethacin
(D) Check serum thyroid-stimulating hormone level
(E) None of the above
Case 13
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171
A 67 year-old male with hypertension for 30 years has
been having worsening blood pressure control over the
past year. He had a myocardial infarction 2 years ago. His
current medications are aspirin, atenolol, amlodipine,
lisinopril and spironolactone. On a clinic visit, his BP is
163/95.
Serum sodium 141 mEq/L
Serum potassium 3.4 mEq/L
Serum chloride 108 mEq/L
Serum bicarbonate 27 mEq/L
Blood urea nitrogen 15 mg/dL
Serum creatinine 1.6 mg/dL
Urinalysis: pH 5, 1+protein, no cells or casts
Case 14
Which of the following test would be most likely to identify
the cause of this patient's hypertension:
(A) Magnetic resonance angiography of the renal
arteries
(B) CT scan of the adrenal glands
(C) Serum metanephrines
(D) Urine tetrahydrocortisol/tetrahydrocortisoneratio
(E) None of the above
Case 14
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172
Renal K-wasting with hypertension
Aldo
Renin
Cushing
Liddle
Licorice
Syndrome apparent
mineralocorticoid excess
Renal artery stenosis
Reninoma
Malignant HTN
Primary aldosteronism
Glucocorticoid-remediable
aldosteronism
High Low
High Low
Captopril renal scan
Doppler US
MRA
PAC/PRA
Serum/urine aldosterone
Urine 18-oxo- & -hydroxycortisol
Serum/urine cortisol
ENaC mutation
analysis
Urine THC/THE
ratio
Which of the following test would be most likely to identify
the cause of this patient's hypertension:
(A) Magnetic resonance angiography of the renal
arteries
(B) CT scan of the adrenal glands
(C) Serum metanephrines
(D) Urine tetrahydrocortisol/tetrahydrocortisoneratio
(E) None of the above
Case 14
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173
A 41-year-old female with lupus nephritis and chronic renal
insufficiency maintained on prednisone and candesartan
presents for a routine clinic visit. On exam, BP is 146/95
and there is moderate dependent edema.
Laboratory studies:
Serum sodium 136 mEq/L
Serum potassium 6.3 mEq/L
Serum chloride 109 mEq/L
Serum bicarbonate 18 mEq/L
Blood urea nitrogen 25 mg/dL
Serum creatinine 1.6 mg/dL
Case 15
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174
Which of the following would NOT be appropriate in the
management of this patient:
(A) Hydrochlorothiazide
(B) Discontinue candesartan
(C) Fludrocortisone
(D) Low potassium diet
(E) Sodium polystyrene sulfonate
Case 15
Hyperkalemia
 Intake
Cell shift
Metabolic acidosis
Hyperglycemia
b-blocker
Digitalis
Hyperkalemic
periodic paralysis
Cell lysis
Decreased urinary
K
+
excretion
24 hr urine K
+
<40 mEq
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175
ACTH test Hyporenin
hypoaldo
Meds
Addison’s
1° hypoaldo
NSAIDs
ACEI/ARB
Heparin
Spironolactone
Amiloride
Trimethoprim
Pentamidine
Cyclosporine
Decreased urinary K
+
excretion
Renal
failure
CCD [K
+
] Tubular flow
ECV
Which of the following would NOT be appropriate in the
management of this patient:
(A) Hydrochlorothiazide
(B) Discontinue candesartan
(C) Fludrocortisone
(D) Low potassium diet
(E) Sodium polystyrene sulfonate
Case 15
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176
A 26-year-old male with AIDS is admitted with
pneumocystis pneumonia and treated with prednisone and
intravenous trimethoprim-sulfamethoxazole. On
examination, BP is 115/65, HR 90, RR 24. He appears
tachpneic with diffuse rales on chest auscultation. EKG
appears normal.
Serum sodium 134 mEq/L
Serum potassium 5.9 mEq/L
Serum chloride 105 mEq/L
Serum bicarbonate 22 mEq/L
Blood urea nitrogen 8 mg/dL
Serum creatinine 0.7 mg/dL
Case 16
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177
Which of the following would be the best treatment for the
hyperkalemia in this patient:
(A) Fludrocortisone
(B) Sodium bicarbonate
(C) Discontinue trimethoprim-sulfamethoxazole and
start pentamidine
(D) Discontinue trimethoprim-sulfamethoxazole and
start atovaquone
(E) None of the above
Case 16
Arachidonic
acid
Angiotensinogen
Adrenal
glomerulosa
JGA
PGE
2
Renin
COX2
AngI AngII
ACE
AT1R
Aldosterone
MCR
ENaC block:
Amiloride
Trimethoprim
Pentamidine
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178
Which of the following would be the best treatment for the
hyperkalemia in this patient:
(A) Fludrocortisone
(B) Sodium bicarbonate
(C) Discontinue trimethoprim-sulfamethoxazole and
start pentamidine
(D) Discontinue trimethoprim-sulfamethoxazole and
start atovaquone
(E) None of the above
Case 16
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179
A 57-year-old female with end-stage renal disease
secondary to diabetic nephropathy maintained on chronic
hemodialysis is seen on a non-dialysis day.
Serum sodium 139 mEq/L
Serum potassium 7.1 mEq/L
Serum chloride 108 mEq/L
Serum bicarbonate 20 mEq/L
Blood urea nitrogen 26 mg/dL
Serum creatinine 4.5 mg/dL
Case 17
All of the following would lower the serum potassium
substantially EXCEPT:
(A) Insulin and glucose
(B) Sodium bicarbonate
(C) Albuterol
(D) Sodium polystyrene sulfonate
(E) Hemodialysis
Case 17
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180
Treatment of hyperkalemia
• Stabilize membrane excitability
– Calcium chloride or gluconate, 1 g IV
• Increase K
+
entry into cells
– Glucose 25 g and insulin 10 U
– b
2
-adrenergic agonist (albuterol 10-20 mg inh)
– NaHCO
3
(poor efficacy in ESRD patients)
• Removal of excess K
+
– Cationexchange resin (Kayexalate)
– Diuretics
– Dialysis
• Dietary K
+
restriction
All of the following would lower the serum potassium
substantially EXCEPT:
(A) Insulin and glucose
(B) Sodium bicarbonate
(C) Albuterol
(D) Sodium polystyrene sulfonate
(E) Hemodialysis
Case 17
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181
A 23 year-old male with diabetes mellitus presents with 5
days of polyuria, polydipsiaandabdominal pain.
Serum sodium 134 mEq/L
Serum potassium 6.5 mEq/L
Serum chloride 99 mEq/L
Serum bicarbonate 15 mEq/L
Serum glucose 296 mg/dL
Blood urea nitrogen 38 mg/dL
Serum creatinine 1.6 mg/dL
Urinalysis:
Specific gravity 1.028, pH 4.5, 1+protein, 2+ketones
Case 18
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182
Which of the following statements about the total body
stores in this patient is most likely to be correct:
(A) Total body potassium depleted
(B) Total body potassium overloaded
(C) Normal total body potassium stores, total body
sodium depleted
(D) Normal total body potassium stores, total body
sodium overloaded
(E) None of the above
Case 18
Osmotic diuresis:
Free water
Na
+
K
+
Electrolyte imbalance in diabetic ketoacidosis
ICF => ECF
K
+
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183
Which of the following statements about the total body
stores in this patient is most likely to be correct:
(A) Total body potassium depleted
(B) Total body potassium overloaded
(C) Normal total body potassium stores, total body
sodium depleted
(D) Normal total body potassium stores, total body
sodium overloaded
(E) None of the above
Case 18
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184
A 27-year-old African-American female presents with dyspnea,
fatigue and weight loss.
Blood urea nitrogen 32 mg/dL
Serum creatinine 2.1 mg/dL
Serum albumin 4 g/dL
Serum calcium 11.5 mg/dL
Serum phosphorus 5.5 mg/dL
Serum immunoreactiveparathyroid hormone (intact)
3.1 pg/mL (Normal range 10-65 pg/mL)
Serum 25-hydroxycholecalciferol
8.3 pg/mL (Normal range 9-43 pg/mL)
Serum 1,25-dihydroxycholecalciferol
95 pg/mL (Normal range 15-60 pg/mL)
Case 19
The most likely cause of hypercalcemia in this patient is:
(A) Primary hyperparathyroidism
(B) Familial hypocalciuric hypercalcemia
(C) Sarcoidosis
(D) Munchausen’s syndrome
(E) Occult malignancy
Case 19
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185
Hypercalcemia: Work-up
iPTH
High Low
Urine Ca
FHH 1°  PTH
1,25-D
HypervitD
Sarcoidosis
TFTs
 T4 Malignancy
Skeletal survey
Bone scan
SPEP
UPEP
PTHrP
High Low High Low
High Low
The most likely cause of hypercalcemia in this patient is:
(A) Primary hyperparathyroidism
(B) Familial hypocalciuric hypercalcemia
(C) Sarcoidosis
(D) Munchausen’s syndrome
(E) Occult malignancy
Case 19
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186
An 18-year-old female presents with severe muscle weakness. She has
no past medical history, denies taking any medications, and the family
history is non-contributory. BP 90/67.
Serum sodium 136 mEq/L
Serum potassium 3.4 mEq/L
Serum chloride 106 mEq/L
Serum bicarbonate 29 mEq/L
Blood urea nitrogen 15 mg/dL
Serum creatinine 1.0 mg/dL
Serum calcium 8.8 mg/dL
Serum magnesium 1.2 mg/dL
Serum phosphorus 3.1 mg/dL
24-hour urine magnesium 151 mg
24-hour urine calcium 58 mg
Case 20
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187
Which of the following is the most likely cause of her
hypomagnesemia:
(A) Gitelman’s syndrome
(B) Conn’s syndrome
(C) Surreptitious loop diuretic use
(D) Surreptitious vomiting
(E) Laxative abuse
Case 20
Differential diagnosis of hypomagnesemia
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188
Diagnosis of renal Mg wasting
F
E
Mg > 1%
24 hr urine Mg > 24 mg
Renal Mg
2+
wasting
Polyuria
 Tubule
reabsorption
DKA
ATN recovery
Postobstructive
 PCT reabs  TAL reabs  DCT reabs
Tubule toxins
Aminoglycosides
Cisplatin
Amphotericin
Cyclosporine
Pentamidine
Loop diuretics
Bartter’s
Familial
hypercalciuric
hypomagnesemia
Thiazides
Gitelman’s
Autosomal recessive
hypomagnesemia
Volume expansion
Hyperaldosteronism
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189
Which of the following is the most likely cause of his
hypomagnesemia:
(A) Gitelman’s syndrome
(B) Conn’s syndrome
(C) Surreptitious loop diuretic use
(D) Surreptitious vomiting
(E) Laxative abuse
Case 20
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190
A 47 yr old man with Type II diabetes mellitus is seen for
routine follow up for chronic kidney disease, stage III,
thought to be due to diabetic nephropathy. Medications
include glipizide, hydrochlorothiazide, losartan, ferrous
sulfate, darbepoietin, calcium acetate, and vitamin D.
Serum sodium 156 mEq/L
Serum potassium 5.1 mEq/L
Serum chloride 117 mEq/L
Serum bicarbonate 24 mEq/L
Blood urea nitrogen 21 mg/dL
Serum creatinine 1.9 mg/dL
Serum glucose 135 mg/dL
Serum calcium 11.6 mg/dL
Serum phosphate 4.1 mg/dL
S1
Which of the following is the most likely cause of the
hypernatremia in this patient?
(A) Hydrochlorothiazide
(B) Losartan
(C) Vitamin D
(D) Osmotic diuresis from glucose
(E) Surreptitious laxative abuse
S1
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191
Nephrogenic diabetes insipidus
• Hypokalemia
• Hypercalcemia
• Tubulointerstitial nephropathies
– Sickle cell disease
– Myeloma
– Obstructive uropathy
– Recovery from ATN
– Lithium
• Familial (rare)
– X-linked recessive (mutations in V2 receptor)
– Autosomal recessive (mutations in AQP2)
S1
Which of the following is the most likely cause of the
hypernatremia in this patient?
(A) Hydrochlorothiazide
(B) Losartan
(C) Vitamin D
(D) Osmotic diuresis from glucose
(E) Surreptitious laxative abuse
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192
A 34 yr old male with alcoholic cirrhosis is admitted with
esophageal variceal bleeding and hepatic encephalopathy.
He underwent variceal banding, was maintained NPO and
was treated with propanolol, octreotide, lactulose and
maintenance fluids with D5-1/2 NS.
Serum sodium 151 mEq/L
Serum potassium 3.0 mEq/L
Serum chloride 124 mEq/L
Serum bicarbonate 19 mEq/L
Blood urea nitrogen 25 mg/dL
Serum creatinine 1.2 mg/dL
Urine osmolality 855 mOsm/kg
S2
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193
Which of the following would be the BEST treatment to
prevent worsening hypernatremia in this patient:
(A) Reduce the dose of lactulose
(B) Reduce the dose of octreotide
(C) Change fluids to 5% dextrose
(D) Start hydrochlorothiazide
(E) Start democlocycline
S2
Hypernatremia
• Insensible H
2
O loss
• GI H
2
O loss
• Na
+
intake
• Renal H
2
O loss
U
Osm
<800 mOsm/kg >800 mOsm/kg
+
 Water intake
Glucose, urea,
mannitol
DI Osmotic
diuresis
CDI NDI
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194
Osmotic diarrhea
S
t
o
o
l

o
s
m
o
l
a
l
i
t
y
Which of the following would be the BEST treatment to
prevent worsening hypernatremia in this patient:
(A) Reduce the dose of lactulose
(B) Reduce the dose of octreotide
(C) Change fluids to 5% dextrose
(D) Start hydrochlorothiazide
(E) Start democlocycline
S2
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195
A 66 yr old female with NIDDM presents with several days
of malaise,lethargy, polyuriaand decreased oral intake.
Physical examination reveals tachycardia, orthostatic
hypotension and dry mucous membranes.
Serum sodium 134 mEq/L
Serum potassium 5.4 mEq/L
Serum chloride 94 mEq/L
Serum bicarbonate 25 mEq/L
Blood urea nitrogen 42 mg/dL
Serum creatinine 1.8 mg/dL
Serum glucose 975 mg/dL
S3
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196
After initial resuscitation with insulin and isotonic saline,
which of the following treatments would be appropriate in
this patient:
(A) Hypertonic saline
(B) Oral fluid restriction
(C) Hypotonic saline
(D) Tolvaptan
(E) Furosemide
S3
Hyponatremia
P
osm
>290 mOsm/kg <275 mOsm/kg Normal
Glucose 
Mannitol
Hypoosmolal
hyponatremia
Lipid 
Protein 
Correction for hyperglycemia:
For every 100 mg/dL increase in glucose, add 1.6 mEq/L to Na
+
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197
S3
After initial resuscitation with insulin and isotonic saline,
which of the following treatments would be appropriate in
this patient:
(A) Hypertonic saline
(B) Oral fluid restriction
(C) Hypotonic saline
(D) Tolvaptan
(E) Furosemide
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198
A 74 yr old female with a history of hypertension and
hyperlipidemiais admitted with unsteady gait and a fall at home.
Medications: Hydrochlorothiazide, lisinopril, simvastatin, aspirin.
On exam she appears euvolemic.
Serum sodium 117 mEq/L
Serum potassium 4.6 mEq/L
Serum chloride 92 mEq/L
Blood urea nitrogen 7 mg/dL
Serum creatinine 0.5 mg/dL
Serum triglycerides 345 mg/dL
Serum cortisol 15 µg/dL (NR 5-15 µg/dL)
Serum free T4 0.5 ng/dL (NR 0.7-2.0 ng/dL)
Urine sodium 38 mEq/L
Urine osmolality 230 mOsm/kg
S4
What is the most likely cause of her hyponatremia
(A) Pseudohyponatremia
(B) Adrenal insufficiency
(C) Hypothyroidism
(D) SIADH
(E) Adverse effect of medications
S4
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199
Volume status
Hypovolemic Edematous Euvolemic
Dehydration*
Addison’s
Diuretics
CHF*
Nephrosis*
Liver failure*
Renal failure
U
Osm
> 100
<100
SIADH
Hypothyroid
Thiazides
Polydipsia
* U
Na
< 20
Hypoosmolal hyponatremia
S4
What is the most likely cause of her hyponatremia
(A) Pseudohyponatremia
(B) Adrenal insufficiency
(C) Hypothyroidism
(D) SIADH
(E) Adverse effect of medications
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200
A 48 yr old female with small cell lung cancer has been
noted to have a low serum Na
+
for 3 months. She presents
to the ER with nausea and inability to tolerate oral fluids.
On exam, her weight is 55 kg. She appears mildly
hypovolemic but alert and oriented.
Admission:
Serum sodium 108 mEq/L
Urine osmolality 800 mg/dL
She is initiated on 3% NaCl at 200 mL/hr. Five hours later
her serum sodium is 121 mEq/L. Her mental status is
unchanged.
S5
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201
Which of the following would be the most appropriate next
step in the management of this patient:
(A) 3% NaCl at 80 mL/hr
(B) Discontinue fluids and initiate tolvaptan
(C) Discontinue fluids and initiate 1 L daily oral fluid
restriction
(D) 5% dextrose at 150 mL/hr for 2 hr
(E) None of the above
S5
Rate of correction of hyponatremia
• Acute (<48 hr) and symptomatic
– 1-2 mEq/l per hour
• Chronic (>48 hr) including SIADH and
asymptomatic
– 0.5 mEq/l per hour
• Do not exceed 12 mEq/L increase, or correct to
>120-125 mEq/L in the 1st day
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202
Osmotic demyelination syndrome
• Central and extrapontine myelinolysis
• Risk factors :
– Excessive rate or amount of correction of serum Na
+
– Malnutrition and alcoholism
– Severe liver disease
– Hypoxia
• Classic CPM presents with dysphagia, quadriparesis,
locked-in syndrome
• Can be permanent or fatal
S5
Which of the following would be the most appropriate
next step in the management of this patient:
(A) 3% NaCl at 80 mL/hr
(B) Discontinue fluids and initiate tolvaptan
(C) Discontinue fluids and initiate 1 L daily oral fluid
restriction
(D) 5% dextrose at 150 mL/hr for 2 hr
(E) None of the above
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203
A 25 yr-old male is evaluated because of elevated blood
pressure found on routine exam. In clinic, blood pressure is
160/110 mm Hg. Exam is otherwise normal.
Serum sodium 145 mEq/L
Serum potassium 3.0 mEq/L
Serum chloride 106 mEq/L
Serum bicarbonate 29 mEq/L
Blood urea nitrogen 14 mg/dL
Serum creatinine 0.9 mg/dL
Plasma reninactivity 0.2 ng/mL/hr (NR 1-6)
Plasma aldosterone 2.5 ng/dl (NR 5-20)
24 hr urine cortisol 24 µg (NR 10-100)
Urine free cortisol/cortisone ratio 0.4 (NR 0.1–0.7)
S6
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204
Which of the following would be MOST effective at
lowering the blood pressure in this patient:
(A) Amiloride and spironolactone
(B) Amiloride but not spironolactone
(C) Phenoxybenzamine
(D) Renal artery angioplasty
(E) Adrenalectomy
S6
Aldo
Renin
Cushing
Liddle
Licorice
Syndrome apparent
mineralocorticoid excess
Renal artery stenosis
Reninoma
Malignant HTN
Primary aldosteronism
Glucocorticoid-
remediable aldosteronism
High Low
High Low
Hyperaldosteronism
Hypokalemic metabolic alkalosis with hypertension
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205
Hyperaldosteronism
Hypokalemic metabolic alkalosis with hypertension
Aldo
Renin
Cushing
Liddle
Licorice
Syndrome apparent
mineralocorticoid excess
Renal artery stenosis
Reninoma
Malignant HTN
Primary aldosteronism
Glucocorticoid-remediable
aldosteronism
High Low
High Low
 Urine
cortisol/cortisone ratio
 Serum &
urine cortisol
Reni n
Angi otensi nogen
AngI AngII
ACE
Al dosterone
MCR
Corti sol
Corti sone
b-
HSD
1° hyperal do
GRA
RAS
Reni noma
Cushi ng’s
Li cori ce
AME
Li ddl e’s
Hyperal dosteroni sm
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206
S6
Which of the following would be MOST effective at
lowering the blood pressure in this patient:
(A) Amiloride and spironolactone
(B) Amiloride but not spironolactone
(C) Phenoxybenzamine
(D) Renal artery angioplasty
(E) Adrenalectomy
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207
A 17 yr-old male presents with symmetrical thigh
weakness. He has otherwise been in good health, and
denies using any medications. Blood pressure is 105/70
mm Hg.
Serum sodium 136 mEq/L
Serum potassium 2.8 mEq/L
Serum chloride 101 mEq/L
Serum bicarbonate 27 mEq/L
24 hour urine volume 3 L
Urine sodium 35 mEq/L
Urine potassium 40 mEq/L
Urine chloride 55 mEq/L
S7
What is the most likely diagnosis in this patient:
(A) Gitelman’s syndrome
(B) Familial hypokalemic periodic paralysis
(C) Hyperthyroidism
(D) Bulimia
(E) Adrenal adenoma
S7
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208
DDX of hypokalemia
Cellular shift GI loss Urinary K wasting
Alkalemia
Insulin
-agonist
Hypokalemic periodic paralysis
Vomiting
Diarrhea
24 hr U
K
>25 mEq
Cryptogenic hypokalemic metabolic
alkalosis
Volume
status/BP
Urine Cl
-
Urine
diuretics
Hyperaldosteronis
m
 >40 mEq/L -
Surreptitous
vomiting
Nl or  <25 mEq/L -
Diuretic abuse Nl or  >40 mEq/L +
Bartter/Gitelman
syndrome
Nl or  >40 mEq/L -
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209
What is the most likely diagnosis in this patient:
(A) Gitelman’s syndrome
(B) Familial hypokalemic periodic paralysis
(C) Hyperthyroidism
(D) Bulimia
(E) Adrenal adenoma
S7
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210
A 48 yr-old female was evaluated for several weeks of
fatigue and nausea. Exam revealed a thin, tanned female
with blood pressure of 90/45 mm Hg.
Serum sodium 131 mEq/L
Serum potassium 6.1 mEq/L
Serum chloride 105 mEq/L
Serum bicarbonate 20 mEq/L
Blood urea nitrogen 11 mg/dL
Serum creatinine 0.5 mg/dL
Serum glucose 40 mg/dL
S8
Which of the following tests would be most likely to
establish the diagnosis in this patient:
(A) Plasma reninand aldosterone
(B) Serum cortisol at baseline and after ACTH
(C) Serum C-peptide
(D) Iothalamate GFR determination
(E) Genetic testing of the sodium channel gene,
SCN4A
S8
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211
S8
Which of the following tests would be most likely to
establish the diagnosis in this patient:
(A) Plasma renin and aldosterone
(B) Serum cortisol at baseline and after ACTH
(C) Serum C-peptide
(D) Iothalamate GFR determination
(E) Genetic testing of the sodium channel gene,
SCN4A
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212
A 65 yr old female with a history of hypertension, diabetes
mellitus, ischemic cardiomyopathyand diabetic nephropathy
presents with a 1 week history of nausea, confusion, blurry vision
and hallucinations. Medications were insulin, carvedilol,
amlodipine, furosemide, and digoxin. EKG showed bradycardia,
peaked T waves and widened QRS complexes.
Serum sodium 134 mEq/L
Serum potassium 5.9 mEq/L
Serum chloride 103 mEq/L
Serum bicarbonate 21 mEq/L
Blood urea nitrogen 18 mg/dL
Serum creatinine 1.5 mg/dL
Serum glucose 135 mg/dL
S9
Which of the following would be the most appropriate
INITIAL treatment for this patient:
(A) Calcium chloride or gluconate
(B) Hydrocortisone
(C) Hemodialysis
(D) Digoxin-specific Fab fragments (Digibind)
(E) None of the above
S9
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213
Which of the following would be the most appropriate
INITIAL treatment for this patient:
(A) Calcium chloride or gluconate
(B) Hydrocortisone
(C) Hemodialysis
(D) Digoxin-specific Fab fragments (Digibind)
(E) None of the above
S9
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214
A 48 yr old male with hypertension and end-stage renal
disease who had been on hemodialysis for 4 yrs underwent
cadaveric renal transplantation. The operation was
uneventful and the patient was initiated on routine
immunosuppression with anti-thymocyte globulin,
mycophenolate and prednisone.
Post-operatively, the patient remained oliguric and serum
K
+
rose to 6.5 mEq/L. This was treated with 60 g of sodium
polystyrene sulfonate (Kayexalate) and sorbitol as an
enema. 12 hr later, the patient complained of diffuse
abdominal pain. On exam, the abdomen was distended
and tympanitic with hypoactive bowel sounds.
S10
What is the most likely cause of abdominal pain in this
patient?
(A) Ileus due to hypokalemia
(B) Stress-induced gastric ulceration
(C) Mycophenolate side-effect
(D) Adrenal insufficiency
(E) Colonic necrosis
S10
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215
S10
What is the most likely cause of abdominal pain in this
patient?
(A) Ileus due to hypokalemia
(B) Stress-induced gastric ulceration
(C) Mycophenolate side-effect
(D) Adrenal insufficiency
(E) Colonic necrosis
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216
Intestinal necrosis due to sodium
polystyrene sulfonate (SPS) in sorbitol
• Present with abdominal pain, distention or GI bleed
• Onset 3 hr-11 days after treatment with SPS (both oral
and enema) for hyperkalemia
• Risk factors: age (mean 70 yr), ESRD, post-operative,
critically ill
• Colon affected most commonly, but also small intestine
and stomach
• Pathology shows SPS crystals and intestinal wall
necrosis resembling ischemia, but with preserved
vessels
• Rat studies suggest sorbitol is the culprit
Financial disclosures
No conflict of interest to disclose.
Alan S. L. Yu, M.B., B. Chir.
Copyright Harvard Medical School, 2010. All Rights Reserved.
217
Electrolytes and Acid-Base
Practice for the Boards II
4:00-4:45 pm
Alan S. L. Yu, M.B., B.Chir.
University of Southern California Keck School
of Medicine
19 cases
Financial disclosures
No conflict of interest to disclose.
Alan S. L. Yu, M.B., B. Chir.
Copyright Harvard Medical School, 2010. All Rights Reserved.
218
An 18-year-old female is brought in after a suspected suicidal attempt.
Unidentified pills were found in her pocket. On exam she is obtunded.
BP 101/64 mm Hg, HR 112/min, RR 30/min, T 101.8° C.
Serum sodium 140 mEq/L
Serum potassium 3.8 mEq/L
Serum chloride 99 mEq/L
Serum bicarbonate 15 mEq/L
Blood urea nitrogen 9 mg/dL
Serum creatinine 0.8 mg/dL
Serum glucose 81 mg/dL
Arterial pH 7.35
Arterial PCO
2
26 mm Hg
Case A1
Which of the following is most likely to be helpful in this
patient:
(A) Forced alkaline diuresis
(B) Intravenous ethanol
(C) Insulin drip
(D) Glucagon
(E) Potassium citrate
Case A1
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219
pH 7.35, HCO
3
15
Actual PCO
2
=26 (expected: 1.5(15)+8 ~30)
Primary metabolic acidosis and primary respiratory alkalosis
AG =140 - 99 - 15 =27
DAG/DHCO
3
=(27-10)/(24-15) ~2
Anion gap acidosis and metabolic alkalosis (i.e. triple acid-base disorder)
Pt is febrile, tachycardic, tachypneic and had probable drug overdose
Suspect salicylate poisoning
Rx is alkaline diuresis +/- hemodialysis
Case A1
COO
OCOCH
3
COOH
OCOCH
3
-
Blood
pH 7.4
Urine
pH 4.5
Renal tubule
Active secretion by
organic anion transporter
Reabsorption by nonionic
diffusion
-
COO
OCOCH
3
Urine
pH 6.5
Ionized form trapped in
tubule lumen
Alkaline diuresis increases urinary salicylate
excretion by ion trapping
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220
Which of the following is most likely to be helpful in this
patient:
(A) Forced alkaline diuresis
(B) Intravenous ethanol
(C) Insulin drip
(D) Glucagon
(E) Potassium citrate
Case A1
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221
A 29-year-old female is found unconscious and brought into the
emergency room. BP 105/67 mm Hg. She is comatose and has an
alcoholic fetor.
Serum sodium 129 mEq/L
Serum potassium 3.4 mEq/L
Serum chloride 94 mEq/L
Serum bicarbonate 11 mEq/L
Blood urea nitrogen 11 mg/dL
Serum creatinine 1.6 mg/dL
Serum glucose 72 mg/dL
Serum lactate 1 mmol/L
Serum creatine kinase 20 mU/mL
Serum osmolality 300 mOsm/kg
Arterial pH 7.22
Arterial PCO
2
24 mm Hg
Serum levels of ethanol, ketones by the nitroprusside test, -
hydroxybutyrate, and salicylate were all negative.
Case A2
The most appropriate first step in the management of this
patient is:
(A) Forced alkaline diuresis
(B) Dopamine
(C) Fomepizole
(D) Thiamine
(E) Hemodialysis
Case A2
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222
pH 7.22, HCO
3
11
Actual PCO
2
=24 (expected: 1.5(11)+8 =24)
Pure metabolic acidosis
AG =129 - 94 - 11 =24
DAG/DHCO
3
=(24-10)/(24-11) =1.1
Pure anion gap acidosis
Case A2
Serum osmolal gap
Osmolal gap = Measured S
osm
- Calc S
osm
Calculated S
osm
:
2 [Na
+
] +[glucose]/18 +[BUN]/2.8
Calculated serum osmolality =2(129) +72/18 +11/2.8
=266
Osmolar gap =300-266 =34(normal <10)
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223
Anion gap
acidosis
Osmolal gap
+ Normal
High
-
Salicylates
Ethanol
Ethylene glycol
Propylene glycol
Methanol
Isopropanol
+
High
Anion and osmolar gap in diagnosis of intoxications
Alcohol
dehydrogenase
Ethylene glycol
Glycolic acid
Glyoxylic acid
Oxalic acid
Ethanol
Fomepizole
Glycine
-hydroxy--
ketoadipate
Pyridoxine
Thiamine
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224
• GI decontamination
• Sodium bicarbonate
• Inhibit alcohol dehydrogenase
• Hemodialysis (level >50 mg/dL, renal failure or
severe acidosis)
• Thiamine
• Pyridoxine
Management of (suspected) ethylene
glycol or methanol poisoning
The most appropriate first step in the management of this
patient is:
(A) Forced alkaline diuresis
(B) Dopamine
(C) Fomepizole
(D) Thiamine
(E) Hemodialysis
Case A2
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225
A 16-year-old male has a witnessed grand mal seizure and is brought
immediately to the emergency room. He is post-ictal and has vomitus
on his shirt. BP 120/83.
Serum sodium 139 mEq/L
Serum potassium 4.2 mEq/L
Serum chloride 95 mEq/L
Serum bicarbonate 14 mEq/L
Blood urea nitrogen 12 mg/dL
Serum creatinine 1.1 mg/dL
Serum glucose 75 mg/dL
Serum creatine kinase 35 mU/mL
Serum osmolality 289 mOsm/kg
Serum and urine toxicology screen Negative
Urine ketones Negative
Arterial pH 7.30
Arterial PCO
2
33 mm Hg
Case A3
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226
The most appropriate first step in the management of this
patient is:
(A) Alkaline diuresis
(B) Ethanol infusion
(C) Fomepizole
(D) Hemodialysis
(E) None of the above
Case A3
pH 7.30, HCO
3
14
Actual PCO
2
=33 (expected: 1.5(14)+8 =29)
Mixed metabolic and respiratory acidosis
AG =139 - 95 - 14 =30
DAG/DHCO
3
=(30-10)/(24-14) =2
Mixed anion gap acidosis and metabolic alkalosis
Calculated serum osmolality =2(139) +75/18 +12/2.8 =286
Osmolar gap =289-286 =3
No osmolar gap
Most likely cause is lactic acidosis from the seizure
Case A3
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227
The most appropriate first step in the management of this
patient is:
(A) Alkaline diuresis
(B) Ethanol infusion
(C) Fomepizole
(D) Hemodialysis
(E) None of the above
Case A3
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228
A 48-year-old male in the ICU is intubated for respiratory failure due to
severe pneumonia and is paralysed with vecuronium and sedated with
lorazepam. A renal consult is called because of the laboratory finding of
metabolic acidosis.
Serum sodium 143 mEq/L
Serum potassium 4.9 mEq/L
Serum chloride 109 mEq/L
Serum bicarbonate 16 mEq/L
Blood urea nitrogen 12 mg/dL
Serum creatinine 1.1 mg/dL
Serum glucose 194 mg/dL
Serum lactate 8 mmol/L
Serum osmolality 312 mOsm/kg
Arterial pH 7.40
Arterial PCO
2
24 mm Hg
Case A4
The most appropriate next step in the management of
this patient is:
(A) Dopamine
(B) Dobutamine
(C) Abdominal computed tomography
(D) Discontinue vecuronium
(E) Discontinue lorazepam
Case A4
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229
pH 7.40, HCO
3
16, PCO
2
24
Mixed metabolic acidosis and respiratory alkalosis
AG =143 - 109 - 16 =18
DAG/DHCO
3
=(18-10)/(24-16) =1
Pure anion gap acidosis
Calculated serum osmolality =2(143) +194/18 +12/2.8 =301
Osmolar gap =312 - 301 =11
Osmolar gap
DDX is AKA, ethylene glycol, methanol, propylene glycol
Case A4
Common IV drugs containing
propylene glycol
Arroliga 2004 Crit Care Med, 32(8):1709
Drug Propylene glycol (% v/v)
Lorazepam, 2 mg/mL 80
Phenobarbital, 30-130 mg/mL 68-75
Diazepam, 5 mg/mL 40
Pentobarbital, 50 mg/mL 20-40
Phenytoin, 50 mg/mL 40
TMP-SMX, 16:80 mg/mL 40
Nitroglycerin, 5 mg/mL 35
Esmolol, 250 mg/mL 25
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230
The most appropriate next step in the management of
this patient is:
(A) Dopamine
(B) Dobutamine
(C) Abdominal computed tomography
(D) Discontinue vecuronium
(E) Discontinue lorazepam
Case A4
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231
A 78 year-old female has been in the ICU for 2 weeks because of
cholecystitis, gram negative sepsis, hypotension, and ARDS requiring
mechanical ventilation. A renal consult is called because of a
persistently low serum bicarbonate. Her medications include imipenem,
acetaminophen, dopamine, and noradrenaline.
Serum sodium 134 mEq/L
Serum potassium 3.8 mEq/L
Serum chloride 99 mEq/L
Serum bicarbonate 18 mEq/L
Blood urea nitrogen 14 mg/dL
Serum creatinine 1.4 mg/dL
Serum glucose 187 mg/dL
Serum lactate 1.6 mmol/L
Arterial pH 7.27
Arterial PCO
2
41 mm Hg
Case A5
Which of the following are appropriate in the management
of this patient’s acid-base disturbance:
(A) CT scan to rule out ischemic bowel
(B) Discontinue acetaminophen
(C) Increase minute ventilation
(D) A and C
(E) B and C
Case A5
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232
pH 7.27, HCO
3
18, PCO
2
41
Actual PCO
2
=41 (expected: 1.5(18)+8 =35)
Mixed metabolic and respiratory acidosis
AG =134 - 99 - 18 =17
DAG/DHCO
3
=(17-10)/(24-18) ~1
Pure anion gap acidosis
Case A5
Pyroglutamic acidemia (5-oxoprolinemia)
Glutathione
Cysteine Glutamate
Pyroglutamate
g-glutamyl
cysteine
g-glutamyl cysteine
synthetase
Glutathione
synthetase
Acetaminophen
Sepsis
5-oxoprolinase
Flucloxacillin
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233
Pyroglutamic acidemia (5-oxoprolinemia)
18 cases described so far
• 16 female
• 9 sepsis, 5 SIRS
• 14 liver dysfunction, 3 renal failure
• 12 treated with acetaminophen, 2 with
flucloxacillin
• All have anion gap acidosis with elevated blood
and urine pyroglutamic acid
• Discontinue acetaminophen, flucloxacillin,
supportive care
Case A5
Which of the following are appropriate in the
management of this patient’s acid-base disturbance:
(A) CT scan to rule out ischemic bowel
(B) Discontinue acetaminophen
(C) Increase minute ventilation
(D) A and C
(E) B and C
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234
A 39 year-old African-American female with AIDS and recently
diagnosed liver failure was admitted for vague abdominal discomfort
and nausea. Her only medications are stavudine, didanosine, tenofovir
and ritonavir. Exam: BP 98/56 mm Hg, HR 83/min, afebrile, cachectic.
Serum sodium 132 mEq/L
Serum potassium 4.9 mEq/L
Serum chloride 97 mEq/L
Serum bicarbonate 9 mEq/L
Blood urea nitrogen 18 mg/dL
Serum creatinine 1.7 mg/dL
Serum glucose 74 mg/dL
Serum lactate 12.8 mmol/L
AST 59 U/L (NR 10-40)
ALT 64 U/L (NR 10-40)
Prothrombin time 18 s, INR =1.5
Arterial pH 7.22
Arterial PCO
2
19 mm Hg
Case A6
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235
What is the most likely cause of the acid-base
disturbance:
(A) Seizure
(B) Drug-induced lactic acidosis
(C) Ischemic bowel
(D) Occult sepsis
(E) D-lactic acidosis
Case A6
Type B lactic acidosis
Lactic acidosis that is not associated with
impaired tissue oxygenation
• Seizures
• Malignancy (acute leukemia, lymphoma, solid
tumor with liver metastases)
• Liver failure
• Vitamin deficiency (thiamine, riboflavin)
• Drugs/toxins (ethanol, methanol, ethylene glycol,
propylene glycol, salicylates, metformin, NRTI,
isoniazid)
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236
• Inhibition of mitochondrial DNA polymerase-g
• DDI and stavudine most common cause
• Often associated with hepatotoxicity
• 2 mth - 2 yr after start of Rx
• Risk factors: Female gender, low GFR, low CD4
• N/V, abdo pain, fatigue, wt loss
• Can be induced by drug interaction (tenofovir increases
AUC of DDI by 50%)
• 30-60% mortality
Type B lactic acidosis 2° to nucleoside
reverse transcriptase inhibitors (NRTI)
What is the most likely cause of the acid-base disturbance:
(A) Seizure
(B) Drug-induced lactic acidosis
(C) Ischemic bowel
(D) Occult sepsis
(E) D-lactic acidosis
Case A6
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237
A 28-year-old Asian female with an erythematous malar rash is referred
to renal clinic because of abnormal laboratory electrolyte values.
Laboratory studies:
Serum sodium 138 mEq/L
Serum potassium 3.2 mEq/L
Serum chloride 114 mEq/L
Serum bicarbonate 15 mEq/L
Blood urea nitrogen 7 mg/dL
Serum creatinine 0.5 mg/dL
Urine pH 6.5
Urine sodium 25 mEq/L
Urine potassium 35 mEq/L
Urine chloride 34 mEq/L
Case A7
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238
The most appropriate management for this patient is:
(A) Loperamide
(B) Hydrochlorothiazide
(C) Cyclophosphamide
(D) Potassium citrate, 1-3 mEq/kg/day
(E) Sodium bicarbonate, 5-15 mEq/kg/day
Case A7
Non-gap (hyperchloremic)
metabolic acidosis
• Lower GI bicarbonate loss
• Renal tubular acidosis
• Dilutional acidosis
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239
Diagnosis of RTA
Determination of the urine anion gap
Urine anion gap = [Na
+
] + [K
+
] - [Cl
-
]
Normal < 0
Urine anion gap
= Measured cations - Measured anions
= (Na
+
+K
+
) - (Cl
-
+HCO
3
-
)
= Unmeasured anions - unmeasured cations
Sulfate
Phosphate
Bicarbonate
Organic anions
Calcium
Magnesium
NH
4
+
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240
Urine anion gap
In the setting of acidemia, urine HCO
3
-
should be negligible, and urine NH
4
+
should be HIGH
=> Urine AG should be LOW
A
m
m
o
n
i
u
m

e
x
c
r
e
t
i
o
n
Urine anion gap
-50 0 +50 +100
90
60
30
Diarrhea
Distal RTA
-100
Batlle, N Engl J Med. 1988; 318: 594
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241
Acid excretion mechanisms in renal tubule
Type 2
Type 1
Type 4
Hyperkalemic
distal
Diarrhea
Proximal
RTA
Distal RTA
Type I Type 4 Hyperkalemic
distal
Serum K
+
 
Urine AG Negative Variable Positive
Urine pH Variable >5.5 <5.5
Other
Fanconi
syndrome
Nephro-
calcinosis
Clinical features of RTA
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242
The most appropriate management for this patient is:
(A) Loperamide
(B) Hydrochlorothiazide
(C) Cyclophosphamide
(D) Potassium citrate, 1-3 mEq/kg/day
(E) Sodium bicarbonate, 5-15 mEq/kg/day
Case A7
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243
A 54-year-old male with a 12 year history of Type 2 diabetes mellitus
maintained on insulin, and proliferative diabetic retinopathy, is referred
because of proteinuria.
Laboratory studies:
Serum sodium 140 mEq/L
Serum potassium 6.0 mEq/L
Serum chloride 112 mEq/L
Serum bicarbonate 19 mEq/L
Blood urea nitrogen 27 mg/dL
Serum creatinine 1.6 mg/dL
Serum glucose 206 mg/dL
Urinalysis shows 3+proteinuria.
Case A8
The most likely cause of this patient’s metabolic acidosis is:
(A) Diarrhea due to diabetic autonomic neuropathy
(B) Diabetic ketoacidosis
(C) Chronic renal failure
(D) Type I renal tubular acidosis
(E) Type IV renal tubular acidosis
Case A8
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244
Diarrhea
Proximal
RTA
Distal RTA
Type I Type 4 Hyperkalemic
distal
Serum K
+
 
Urine AG Negative Variable Positive
Urine pH Variable >5.5 <5.5
Other
Fanconi
syndrome
Nephro-
calcinosis
Clinical features of RTA
Type IV RTA (hyporeninemic
hypoaldosteronism)
Hyperkalemia (disproportionate to level of GFR)
Non-gap metabolic acidosis with normal urine acidifying
ability
Mild CRF
Often underlying tubulointerstitial disease:
- Diabetes mellitus
- SLE, obstruction, myeloma/amyloid, HIV etc.
- NSAIDs
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245
The most likely cause of this patient’s metabolic acidosis is:
(A) Diarrhea due to diabetic autonomic neuropathy
(B) Diabetic ketoacidosis
(C) Chronic renal failure
(D) Type I renal tubular acidosis
(E) Type IV renal tubular acidosis
Case A8
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246
A 22-year-old male with HIV infection was started on HAART three
months ago. His medications are didanosine, tenofovirand lopinavir.
Serum sodium 141 mEq/L
Serum potassium 3.4 mEq/L
Serum chloride 115 mEq/L
Serum bicarbonate 18 mEq/L
Serum glucose 76 mg/dL
Blood urea nitrogen 7 mg/dL
Serum creatinine 0.4 mg/dL
Serum calcium 8.6 mg/dL
Serum phosphorus 0.9 mg/dL
Serum uric acid 1.7 mg/dL
Urinalysis: pH 6.0, specific gravity 1.015, 3+glucose, trace protein
Urine phosphorus 25 mg/dL
Urine creatinine 38 mg/dL
Case A9
The most likely cause of this patient acid-base
disturbance is:
(A) HIV-related diarrhea
(B) D-lactic acidosis
(C) Didanosine-induced lactic acidosis
(D) Hepatic failure-associated renal tubular acidosis
(E) Tenofovir toxicity
Case A9
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247
Serum bicarbonate is 18 mEq/L
Anion gap =141 - 115 - 18 =8
Probably non-gap metabolic acidosis
Urine pH 6, serum K 3.4
Inappropriately alkaline urine and hypokalemiasuggests Type I
or II renal tubular acidosis
Case A9
Diarrhea
Proximal
RTA
Distal RTA
Type I Type 4 Hyperkalemic
distal
Serum K
+
 
Urine AG Negative Variable Positive
Urine pH Variable >5.5 <5.5
Other
Fanconi
syndrome
Nephro-
calcinosis
Clinical features of RTA
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248
Diagnosis of renal phosphate
wasting
F
E
PO
4
=
UPO
4
x SCr
SPO
4
x UCr
F
E
PO
4
=(25 x 0.4)/(0.9 x 38) =29% (normal 5-15%)
Renal phosphate wasting
Glycosuriadespite normoglycemia, hypouricemia
Fanconi syndrome
Cause:
Tenofovir
Case A9
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249
• Acyclic nucleoside phosphonates: adefovir (22-50%),
cidofovir (12% ARF, 1% Fanconi), tenofovir (2-4%)
• Transported into prox. tubule by organic anion
transporter (OAT1), causing mitochondrial toxicity
• Both Fanconi syndrome and ARF (due to ATN)
• Can be induced by drug interaction (most pts with
tenofovir toxicity were on ritonavir)
• Can be induced by renal insufficiency (all renally
excreted)
• Can occur 3 wk to 18 mth after start of Rx
Fanconi syndrome & ARF 2° to nucleotide-
analog reverse transcriptase inhibitors
The most likely cause of this patient acid-base
disturbance is:
(A) HIV-related diarrhea
(B) D-lactic acidosis
(C) Didanosine-induced lactic acidosis
(D) Hepatic failure-associated renal tubular acidosis
(E) Tenofovir toxicity
Case A9
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250
A10-14
For each patient with hyperchloremic metabolic acidosis
described below, select the most likely cause of the
acidosis (A-E).
(A) Proximal (Type II) renal tubular acidosis
(B) Classic distal (Type I) renal tubular acidosis
(C) Hyporeninemic hypoaldosteronism(Type IV renal
tubular acidosis)
(D) Gastrointestinal bicarbonate loss
(E) Toluene intoxication
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251
38-year-old woman with dry eyes and polyarthritis. The
serum potassium is 3.4 mEq/L, the urine pH is 6.5 and the
urine sodium is 28 mEq/L, potassium 50 mEq/L and
chloride 57 mEq/L.
Case A10
(A) Proximal (Type II) renal tubular acidosis
(B) Classic distal (Type I) renal tubular acidosis
(C) Hyporeninemic hypoaldosteronism(Type IV renal
tubular acidosis)
(D) Gastrointestinal bicarbonate loss
(E) Toluene intoxication
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252
56-year-old Hispanic male with Type II diabetes mellitus,
diabetic nephropathy, and chronic renal insufficencywith a
serum Cr of 2.3 mg/dL. He is unable to tolerate
angiotensin-converting enzyme inhibitors due to
hyperkalemia. The urine pH is 5.0 and the urine sodium is
43 mEq/L, potassium 13 mEq/L and chloride 41 mEq/L.
Case A11
(A) Proximal (Type II) renal tubular acidosis
(B) Classic distal (Type I) renal tubular acidosis
(C) Hyporeninemic hypoaldosteronism(Type IV renal
tubular acidosis)
(D) Gastrointestinal bicarbonate loss
(E) Toluene intoxication
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253
21-year-old college senior with a history of substance
abuse. The serum potassium is 1.9 mEq/L and the urine
sodium is 42 mEq/L, potassium 48 mEq/L and chloride 12
mEq/L. The urine sediment shows numerous needle-
shaped crystals.
Case A12
(A) Proximal (Type II) renal tubular acidosis
(B) Classic distal (Type I) renal tubular acidosis
(C) Hyporeninemic hypoaldosteronism (Type IV renal
tubular acidosis)
(D) Gastrointestinal bicarbonate loss
(E) Toluene intoxication
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254
Toluene intoxication
Due to inhalation of toluene which is used as an
organic solvent in glues, paint thinners etc.
1. Non-anion gap metabolic acidosis
2. Hypokalemia
3. Severe hypophosphatemia
Hippuric acid
Distal RTA (esp.
chronic use)
26-year-old woman with osteosarcoma of the humerus,
undergoing chemotherapy with ifosfamide. The serum
potassium is 2.3 mEq/L, glucose 97 mg/dL, phosphate 1.5
mg/dL. The urinalysis shows pH 7.0, 1+protein, 2+glucose.
The urine sodium is 27 mEq/L, potassium 48 mEq/L and
chloride 56 mEq/L.
Case A13
(A) Proximal (Type II) renal tubular acidosis
(B) Classic distal (Type I) renal tubular acidosis
(C) Hyporeninemic hypoaldosteronism(Type IV renal
tubular acidosis)
(D) Gastrointestinal bicarbonate loss
(E) Toluene intoxication
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255
24-year-old man with Type I diabetes mellitus complicated
by diabetic nephropathy, chronic renal failure with a serum
Cr of 1.8 mg/dL, potassium 3.0 mg/dL, autonomic
neuropathy and chronic diarrhea. The urine sodium is 10
mEq/L, potassium 14 mEq/L and chloride 36 mEq/L.
Case A14
(A) Proximal (Type II) renal tubular acidosis
(B) Classic distal (Type I) renal tubular acidosis
(C) Hyporeninemic hypoaldosteronism(Type IV renal
tubular acidosis)
(D) Gastrointestinal bicarbonate loss
(E) Toluene intoxication
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256
A 22-year-old female presents with polyuria, constipation and fatigue.
She denies taking any prescription or over-the-counter medication. BP
96/54. Exam shows only mild bilateral parotid enlargement.
Serum sodium 133 mEq/L
Serum potassium 2.9 mEq/L
Serum chloride 82 mEq/L
Serum bicarbonate 38 mEq/L
Blood urea nitrogen 5 mg/dL
Serum creatinine 0.6 mg/dL
Urine sodium 15 mEq/L
Urine potassium 17 mEq/L
Urine chloride <5 mEq/L
Urinalysis: pH 4.5, 1+ketones
Case A15
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257
What is the most likely cause of this patient’s hypokalemia
and alkalosis:
(A) Liddle's syndrome
(B) Gitelmansyndrome
(C) Conn's syndrome
(D) Diuretic abuse
(E) Bulimia
Case A15
Cryptogenic metabolic alkalosis
Volume
status
Urine Cl
-
Urine
diuretics
Hyperaldo  > 40 mEq/L -
Surreptitous
vomiting
Nl or  < 25 mEq/L -
Diuretic abuse Nl or  > 40 mEq/L +
Bartter’s
syndrome
Nl or  > 40 mEq/L -
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258
Time-dependent change in urine lytes
in vomiting
Na
+
K
+
Cl
-
HCO
3
-
pH
Early     > 6. 5
Late     < 5. 5
What is the most likely cause of this patient’s
hypokalemia and alkalosis:
(A) Liddle's syndrome
(B) Gitelmansyndrome
(C) Conn's syndrome
(D) Diuretic abuse
(E) Bulimia
Case A15
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259
A 48 year-old male with congestive cardiac failure is seen in clinic for
dyspnea and orthopnea. He has known systolic dysfunction with an
ejection fraction of 20% and is maintained on aspirin, carvedilol,
furosemide, metolazone, candesartan and digoxin. BP 109/74. Exam
shows bilateral diffuse inspiratorycrackles in the lung fields, and 1+
dependent pitting edema.
Serum sodium 128 mEq/L
Serum potassium 3.5 mEq/L
Serum chloride 87 mEq/L
Serum bicarbonate 31 mEq/L
Blood urea nitrogen 64 mg/dL
Serum creatinine 2.6 mg/dL
Arterial pH 7.51
Arterial PCO
2
42 mm Hg
Arterial PO
2
68 mm Hg
Case A16
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260
All of the following are contributing to this patient’s
alkalemia EXCEPT:
(A) Metolazone
(B) Candesartan
(C) Hypokalemia
(D) Secondary hyperaldosteronism
(E) Renal failure
Case A16
Reni n
Angi otensi nogen
AngI AngII
ACE
Al dosterone
MCR
Na
+
del i very:
Loop & thiazide
diuretics
Secondary
hyperal dosteroni sm
K
+
K
+
H
+
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261
All of the following are contributing to this patient’s
alkalemia EXCEPT:
(A) Metolazone
(B) Candesartan
(C) Hypokalemia
(D) Secondary hyperaldosteronism
(E) Renal failure
Case A16
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262
A 16-year-old male presents with muscle weakness. He has had
several prior episodes that have resolved spontaneously. He denies
vomiting and is taking no medications. Physical exam is normal.
Serum sodium 136 mEq/L
Serum potassium 2.8 mEq/L
Serum chloride 90 mEq/L
Serum bicarbonate 33 mEq/L
Blood urea nitrogen 13 mg/dL
Serum creatinine 0.9 mg/dL
Urine sodium 33 mEq/L
Urine potassium 48 mEq/L
Urine chloride 72 mEq/L
Case A17
All of these disorders could be the cause of this patient’s
alkalosis EXCEPT:
(A) Bartter syndrome
(B) Gitelmansyndrome
(C) Loop diuretic abuse
(D) Thiazidediuretic abuse
(E) Surreptitious vomiting
Case A17
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263
Cryptogenic metabolic alkalosis
Volume
status
Urine Cl
-
Urine
diuretics
Hyperaldo  > 40 mEq/L -
Surreptitous
vomiting
Nl or  < 25 mEq/L -
Diuretic abuse Nl or  > 40 mEq/L +
Bartter’s
syndrome
Nl or  > 40 mEq/L -
All of these disorders could be the cause of this patient’s alkalosis
EXCEPT:
(A) Bartter syndrome
(B) Gitelman syndrome
(C) Loop diuretic abuse
(D) Thiazide diuretic abuse
(E) Surreptitious vomiting
Case A17
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264
A 31 year-old stockbroker with a several month history of acid reflux
and heartburn was admitted with nausea, vomiting, abdominal pain,
and confusion. He avoids seeing doctors and takes only over-the-
counter medications including ibuprofen, omeprazole, calcium
carbonate and sodium bicarbonate. On exam he appears dehydrated
and his abdomen is mildly tender.
Serum sodium 147 mEq/L
Serum potassium 5.1 mEq/L
Serum chloride 102 mEq/L
Serum bicarbonate 38 mEq/L
Blood urea nitrogen 68 mg/dL
Serum creatinine 4.1 mg/dL
Serum calcium 12.1 mg/dL
Serum albumin 4.5 g/dL
Case A18
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265
The most likely diagnosis in this patient is:
(A) Vomiting-induced metabolic alkalosis
(B) Hyporeninemic hypoaldosteronism
(C) Primary hyperparathyroidism
(D) Milk-alkali syndrome
(E) Acute pancreatitis
Case A18
• Metabolic alkalosis +hypercalcemia +ARF
• Most commonly due to CaCO
3
ingestion
Synergistic effects:
• Alkalosis inhibits renal Ca
2+
excretion
• Hypercalcemia inhibits renal bicarbonate
excretion
• Hypercalcemia causes ARF
• Renal failure inhibits both Ca
2+
and bicarbonate
excretion
Milk-alkali syndrome
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266
The most likely diagnosis in this patient is:
(A) Vomiting-induced metabolic alkalosis
(B) Hyporeninemic hypoaldosteronism
(C) Primary hyperparathyroidism
(D) Milk-alkali syndrome
(E) Acute pancreatitis
Case A18
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267
A 54-year-old smoker with chronic obstructive pulmonary disease,
diabetes and chronic renal failure is admitted with pneumonia.
Overnight he becomes progressively more obtunded; arterial blood gas
shows a PCO
2
of 78 mm Hg and he is intubatedand mechanically
ventilated. A renal consult is called 3 days later because of persistent
alkalemiaand failure to wean from the ventilator.
Serum sodium 135 mEq/L
Serum potassium 4.6 mEq/L
Serum chloride 82 mEq/L
Serum bicarbonate 43 mEq/L
Blood urea nitrogen 38 mg/dL
Serum creatinine 2.4 mg/dL
Arterial pH 7.64
Arterial PCO
2
41 mm Hg
Case A19
All of the following would correct the metabolic alkalosis in
this patient EXCEPT:
(A) Acetazolamide
(B) Intravenous saline
(C) Decreasing the tidal volume
(D) Hemodialysis
(E) Argininehydrochloride
Case A19
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268
Post-hypercapnic alkalosis
Chronic CO
2
retention
Compensatory renal HCO
3
-
retention
Mechanical ventilation
Normalization of PCO
2
Excretion of excess HCO
3
-
if.....
Sufficient time
Adequate renal function
Euvolemia
Case A19
All of the following would correct the metabolic alkalosis
in this patient EXCEPT:
(A) Acetazolamide
(B) Intravenous saline
(C) Decreasing the tidal volume
(D) Hemodialysis
(E) Argininehydrochloride
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269
Financial disclosures
No conflict of interest to disclose.
Alan S. L. Yu, M.B., B. Chir.
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270
Take Home Messages
David B. Mount, MD
Renal Division, BWH
Renal Division,
VA Boston Healthcare System
Disclosures
• Consultant (hyponatremia) – Salix, Otsuka
• Speaker bureau, 2005-2008 – Astellas
(conivaptan)
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271
OVERVIEW
• Key concepts in acid-base and electrolyte
disorders – will not cover alkalosis and
hypernatremia
• Key recent papers
• Newly described disorders
• The weird and wonderful – hereditary
disorders that appear on the boards
Hyponatremia
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272
4
8
12
280 290 300 310 270 260
0
Hypovolemic
Euvolemic
Hypervolemic
Plasma osmolality (mOsm/Kg)
P
l
a
s
m
a

A
V
P

(
p
g
/
m
L
)
Volume Status and Vasopressin Release
What About Thirst??
Thirst is stimulated
over same range of
osmolalityas AVP,
via activation of
central osmoreceptors
Typically need intake
of H
2
O to generate
hyponatremia
4
8
12
280 290 300 310 270 260
0
Plasma osmolality (mOsm/Kg)
P
l
a
s
m
a

A
V
P

(
p
g
/
m
L
)
Increasing Thirst
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273
Leftward Shift of the Thirst Response
in SIADH, i.e. Thirst Also Abnormal
A-H: SIADH pts
Grey: Controls
Smith et al, AJP Endocrinol, 2004
Diagnostic Algorithm
Kumar and Berl, Atlas of Diseases of the Kidney, 1999
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274
Spot Urinary Na
+
and the D
x
of
Hypovolemic Hyponatremia
Urine Na
+
in “ non-
edematous” patients with
hyponatremia, who do or
do not respond to saline
infusion with  serum Na
+
.
Na
+
-avid patients have 
vasopressin due to
hypovolemia 
suppressed by normal
saline infusion.
Am J Med 83: 905-908, 1987
Malignancy
SIADH
Carcinoma
Lung - ,
mesothelioma
Oropharynx
GI tract - stomach,
duodenum, pancreas
GU tract - ureter,
bladder, prostate
Endocrine thymoma
Lymphomas
Sarcomas
small cell CA
Central Nervous System
Infections
Encephalitis
Meningitis
Abscess
Bleeding, masses
Subdural hematoma
Subarachnoid bleed
Traumatic brain injury
Cavernous sinus thromb
Other
Multiple sclerosis
Guillain-Barre syndrome
Drugs
Ifosmamide
Cyclophosphamide
[NSAIDS]
[Chlorpopramide]
AVP analogs
DDAVP
Vasopressin
Ocytocin
SSRIs
Tricyclic antidepressants
Clofibrate
Carbamazepine
Vincristine
Nicotine
Narcotics
Anti-psychotics
Pulmonary Disorders
Infections
Bacterial pneumonia
Viral pneumonia
Pulmonary abscess
Tuberculosis
Aspergillosis
Asthma
Cystic fibrosis
Respiratory failure
with positive pressure ventilation
Miscellaneous
Pain
Postoperative state
Nausea
Endurance excercise
Hereditary (NSIAD)
Idiopathic
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275
Patterns of AVP Release in SIADH
A) Unregulated, erratic
B) Baseline increase,
normal osmotic response
C) “Reset osmostat”
D) Suppressed AVP
Robertson, Am J Med. 2006;119(7 Suppl 1):S36-42
Question #1 – Two Boys with
Hyponatremia
Characteristic Patient 1 Patient 2 Controls
Age 3.0 2.5 -
BP 80-120/34-92 93-118/37-57
MRI brain Normal Normal -
Serum: Na 123 118 134-43
K 4.6 4.7 3.4-4.9
Osm 252 247 285-293
BUN/creat 5/0.3 3/0.3
Aldosterone 10 24 6-68
Vasopressin <1 <1 1-13.3
TSH 0.77 4.58 1.7-9.1
Free thyroxine 1.09 0.97 0.8-1.8
Cortisol 13.3 10.3 4-20
Urine: Na 35 75
Osm 284 390

Feldman et al, NEJM, 2005
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276
How Would You Characterize
Their Clinical Syndrome?
A) SIADH with increased circulating oxytocin
B) Mineralocorticoid resistance and hypovolemic
hyponatremia
C) Co-existent central DI and renal salt-wasting
D) Normotonic hyponatremia – vasopressin levels
are appropriately suppressed
E) Increased renal sensitivity to vasopressin –
vasopressin levels are appropriately
suppressed
How Would You Characterize
Their Clinical Syndrome?
E) Increased renal sensitivity to vasopressin –
vasopressin levels are appropriately
suppressed
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277
The Patients Have Different Mutations
in the V2 Vasopressin Receptor (V2R)
Fel dman et al , N Engl J Med. 2005 May 5;352(18):1884-90
R137 C137 R137L
Gain of Function in the V2R in “ Nephrogeni c
Syndrome of Inappropriate Antidiuresi s”
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278
NSAID Mutations Target a Critical Residue in
the V2 Receptor, Also Invol ved in
Hereditary Nephrogenic DI
Patterns of AVP Release in SIADH
A) Unregulated, erratic
B) Baseline increase,
normal osmotic response
C) “Reset osmostat”
D) Suppressed AVP
Robertson, Am J Med. 2006;119(7 Suppl 1):S36-42
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279
Question #2
A 56 year-old male veteran is seen in Renal consultation for recurrent
hyponatremia, during multiple admissions to the local VA hospital.
PMH includes atrial flutter, chronic alcoholism (beer), cocaine abuse,
depression, and bipolar disorder. Current medications include
bupropion, lamotrigine, and quetiapine
ROS is negative. He lives alone.
BP is 100/60, HR 72 without orthostatic change.
Physical exam is unremarkable.
Laboratory Studies:
Na
+
124 BUN 6 mg/dL
K
+
4.0 creat 0.9 mg/dL
S Osm 264 mOsm/kg Uosm 161 mOsm/Kg
Urine Na <20 TSH 1.7 iU/ml (.3-5.5)
Cortisol 18.50 µg/dL
A. Bupropion
B. Primary adrenal failure
C. Secondary adrenal failure
D. Hypovolemic hyponatremia
E. Low dietary solute intake
Which of the following is the most likely
cause of his hyponatremia?
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280
E. Low dietary solute intake
“Beer potomania” – 6-8 beers/day
Which of the following is the most likely
cause of his hyponatremia?
Beer Potomania
• Due to marked  in urinary solutes, limiting
urinary free water excretion.
• Beer, typically the sole nutrient in these pts, is
very low in protein and salt content, containing
only 1-2 millimole per liter of Na
+
.
• Thought to have very high risk of overcorrection
and osmotic demyelination.
• Urine Na <20, urine Osms usually 100-200
mOsm/kg, rather than <100
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281
Free Water Clearance and Solute Excretion
Thaler et al, Am J Kidney Dis 1998;31(6):1028-1031
Causes of Acute Hyponatremia
• Iatrogenic
– Postoperative – premenopausal women
– Hypotonic fluids with cause of ↑ vasopressin
– Glycine irrigant – TURP, uterine surgery
– Colonoscopy preparation
– Recent institution of thiazides
• Polydipsia
• Ecstasy ingestion
• Exercise induced
• Multifactorial, e.g. thiazide and polydipsia
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282
Pulmonary Edema After Ecstasy Ingestion
Nguyen et al, Nature ClinPrac Nephrology, 2006
20 year-old female
college student
[Na
+
] 117 mM
Is Chronic Hyponatremia
Really That Asymptomatic?
• Case-control series of 122 consecutive
asymptomatic hyponatremia patients.
• Na ranged from 115-135
• Prevalence of falls was 21.3% versus 5.4
% in case controls (p < 0.001).
• Fall was often reason for admission.
• Subtle gait and attention defects in a
separate cohort of hypoNa patients.
Renneboog, et al, Am J Med, 2006
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283
Falls and the Magnitude of Hyponatremia:
Occurrence at All Levels
Renneboog, et al, Am J Med, 2006
Are Falls and Other Symptoms
Common in Chronic Hyponatremia?
• 223 cases of thiazide-associated
hyponatremia, 1996-2002
• Symptoms included malaise and lethargy
(49%), dizzy spells (47%), vomiting (35%),
confusion or obtundation(17%), and falls
(17%).
• Confusion or vomiting much more likely at
Na </= 115.
Chow et al, J Nat’l Med Assoc, 2004
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284
J Bone Miner Res. 2010 Mar;25(3):554-63.
Treatment of Hyponatremia
• Management of acute, symptomatic
hyponatremia
• Management of chronic hyponatremia
– Fluid restriction
– Lasix and salt tabs -  countercurrent
mechanism and repletion of excreted NaCl
– Democlocycline -  V
2
R response
– Vasopressin antagonists
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285
We Hopefully Agree……
• Treatment of acute, symptomatic
hyponatremiacan be life-saving
• Management should include:
– hypertonic saline
– ABG, CXR, and CNS imaging (if available –
but do NOT delay therapy)
– supplemental O
2
prn
– loop diuretic (R
x
of pulmonary edema and 
countercurrent mechanism)
Rate of Correction
• Acute (<48 hr) symptomatic hyponatremia
– 1-2 mEq/l per hour, correcting by 4-6 mEqu/L and/or
until correction of severe symptoms, then chronic
criteria
– hypertonic saline, plus furosemide (particularly if in
pulmonary edema)
– Close attention to oxygenation
• Chronic hyponatremia (>48 hr)
– 0.5 mEq/l per hour,  10 mEqu/first 24 hours, and 
18/first 48 hours
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286
David Ellison and Tom Berl, NEJM, 356, 2064-2072, 2007
Formulas For Calculating
Initial Saline Infusion Rates
****MAJOR CAVEAT*****
No matter how “precise” a given formula for
estimating ΔNa
+
after treatment, it cannot
predict changes in the underlying
physiology
  risk of over-shooting R
x
goal
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287
The Adrogue/Madi as Formula Underestimates
∆Na
+
After Hypertoni c Saline
Mohmand et al, CJASN, 2007
What If You “ Over-Correct” :
Treatment of Osmotic Demyelination
• DDAVP and D5W to re-induce
hyponatremia– animal and human data
• Myo-inositol supplementation during
correction – animal data
• Dexamethasoneto restore blood brain
barrier function – animal data
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288
Re-Induction of Hyponatremia
With DDAVP + Free H
2
O
Sterns et al, CJASN, 2008
Course of
one case
Hyponatremic Causes Associated
With “ Overcorrection”
• Hypovolemic hyponatremia, after volume
resuscitation with saline and ↓ AVP (half-life of
AVP is 10-20 minutes)
• Hypopituitarismwith 2º adrenal failure, after
treatment with cortisol and and ↓ AVP
• Thiazide-associated hyponatremia, after
discontinuation and saline hydration
• Rapid spontaneous resolution of SIADH or of a
“non-osmotic” increase in AVP, e.g. post-
operative nausea/pain
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289
Tolvaptan in Hyponatremia:
The SALT Trials
Schrier et al, NEJM, 2006
Rapid Correction with IV Conivaptan
Zeltser et al, Am J Nephrol, 2007
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290
Pros and Cons of the Vaptans
• What are the indications for these drugs in clinical
practice?
• Expensive – but so is democlocycline
• Risk of overcorrection – minimize by frequent
monitoring of serum Na during the first 48 hours
• Tolvaptan can be used in liver disease
(conivaptan should NOT)
• Conivaptan is IV but not PO; tolvaptan is PO but
not IV…..
Potassium
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291
Na
+
, K
+
and H
2
O
Transport in
Principal Cells
ENaC – epithelial Na channel
ROMK – secretory K channel
Maxi-K – flow-activated K
channel
Question #3
You are asked to evaluate moderate, variable
hyperkalemia in a 26 yo woman with Type I
diabetes since age 10. She has hypertension
and proteinuria, with Uprot:creat of 1.
Medications include lisinopril 40mg daily, insulin,
prn NSAIDs (for H/A), oral contraceptive
Laboratory Studies:
Na
+
134 BUN 30
K
+
5.2 creatinine 1.5
Cl
-
110 TTKG 5
HCO
3
-
20
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292
A. Underlying renal artery stenosis
B. Excessive dietary intake of potassium
C. Subclinical adrenal insufficiency
D. Hyporeninemic hypoaldosteronism
E. Her oral contraceptive
Which of the following factors is most
likelyto have contributed to her risk of
hyperkalemia?
E. Her oral contraceptive
Which of the following factors is most
likelyto have contributed to her risk of
hyperkalemia?
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293
Drospirenone and Hyperkalemia
• Drospirenone3 mg is the progestin component of
several oral contraceptives (Ocs), including “Yaz”,
“Yasmin”, and “Yasminelle”.
• Drospirenonealso inhibits the mineralocorticoidreceptor
– 3 mg is equivalent to ~25 mg of spironolactone.
• OCs containing 3 mg drospirenonecan reduce bp, but
do not cause hyperkalemia in healthy women.
•  Risk of hyperkalemia in patients with underlying
predispositions, +/- other RAS-active meds.
Direct and Indirect Inhibition of the
Amiloride-Sensi ti ve Sodium Channel (ENaC)
MLR – mineralocorticoidreceptor
CAP – channel-activating protease
ENaC– epithelial sodium channel
+
-
-
+
+
CAP
ENaC
MLR
Aldosterone
Nafamostat
Ami loride
Tri methopri m
Tri amterene
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294
Question #4
You are asked to evaluate a female patient with
intestinal pseudo-obstruction (Ogilvie’s syndrome),
with diarrhea and profound hypokalemia.
Meds include metoprolol, risperidone, insulin
Exam and imaging notable for signs of colonic
distension.
Laboratory Studies:
Na
+
151 BUN 30
K
+
2.5 creatinine 1.5
Cl
-
115 TTKG 3
HCO
3
-
15 stool K
+
100 mEqu/kg
stool Na
+
10 mEqu/kg
Which of the following is the most likely
cause of this patient’s hypokalemia?
A. Ischemic bowel
B. C diff colitis
C. Activation of intestinal K
+
secretion
D. Osmotic diarrhea
E. Sympathetic activation with
redistributive hypokalemia
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295
Which of the following is the most likely
cause of this patient’s hypokalemia?
C. Activation of intestinal K
+
secretion
Ogilvie’s Syndrome and Hypokalemia
• Hypokalemiadue to massive upregulation
of colonic BK channels, leading to K
+
-rich
diarrhea
• BK channels are the major secretoryK
+
channel in colon, responsible for increased
K
+
secretion in ESRD and in response to
sympathetic activation; ? link between
sympathetic activation after intestinal
pseudo-obstruction
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296
Colonic BK Channels in Ogilvie’s
Syndrome
Patient ESRD control patient
Nephrology Dialysis Transplantation 2008 23(10):3350-3352
Treatment of Hyperkalemia
Mechanism Therapy Dose Onset Duration
Stabilize membrane
potential
Calcium 10% Ca-gluconate,
10 ml over 10 min.
1-3 min. 30-60
min
Cellular K
+
uptake Insulin


β
2
-agonist

10 U R with 50 ml
of D50, if BS<250

nebulized albuterol,
10 mg
30 min.


30 min.
4-6 h


2-4 h

K
+
removal Kayexalate


Hemodialysis
30-60 g PO

?


Immediate
?

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297
Caveats/Concerns re Kayexalate/SPS
• Slow onset of effect ? makes SPS
unnecessary and inappropriate in most patients
with acute hyperkalemia.
• Intestinal necrosis due to SPS in sorbitol is often
a fatal complication, NOT restricted to post-op
setting.
• New FDA advisory September, 2009 – do NOT
administer SPS with sorbitol.
• Yet SPS with sorbitol remains a very popular
“reflex” mechanism of therapy for hyperkalemia,
often the only formulation of SPS available.
Question #5
40 yo man with a h/o depression, back pain, HTN, and asthma,
presents with dyspnea, abdominal pain, and vomiting.
Meds include paracetamol (hydrocodone/acetaminophen) metoprolol,
candesartan, and rabeprazole.
He denies alcohol or drug use, antifreeze ingestion, etc.
Physical exam remarkable only for tachypnea (36 bpm)
Laboratory Studies:
ABG 6.98/6/145/3 acetone negative
Na
+
144 ethanol <5
K
+
4 tylenol 7.5(10-30)
Cl
-
109 lactate 4.3(0.5-2.2)
Glucose 209 AG 32
BUN 6
Osmolality 312(gap ~10)
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298
Which of the following is the most
likely cause of this acidosis?
A. Alcoholic ketoacidosis
B. Ethylene glycol toxicity
C. D-Lactic acidosis
D. Pyroglutamic aciduria
E. Toluene ingestion
Which of the following is the most
likely cause of this acidosis?
D. Pyroglutamic aciduria,
also known as 5-oxoprolinuria
Acetaminophen therapy, AG-acidosis
Urinary 5-oxoproline
20.7 mmol/mmol creatinine(<.06)
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299
5-Oxoprolinuria and Acidosis
• Classically due to errors of metabolism in
the -glutamyl cycle.
• Acquired cases increasingly reported,
almost always in association with
acetaminophen use.
• Variable presentations, but all have
metabolic acidosis with increased anion
gap.
Acetaminophen and the Anion Gap in a
Patient with 5-Oxoprolinuria
Humphreys et al, AJ KD; 2006, 46, 143-146
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300
The -Glutamyl Cycle and 5-Oxoprolinuria
* Involved in hereditary forms
Glutathione
reduction by
acetaminophen
reduces
feedback
inhibition
→ ↑5-oxoproline
Anion Gap Acidoses
• Keto-acidosis
– Diabetic (DKA) – Type I and Type II DM
– Alcoholic (AKA)
• Lactic Acidosis, including D-Lactic Acidosis
• Methanol poisoning
• Ethylene glycol poisoning
• Propylene glycol – IV drug infusions
• Salicylate toxicity
• Congenital organic acidoses
• Pyroglutamic acidemia (5-oxoprolinuria)
– Genetic
– Acetaminophen, flucloxacillin, vigabratin
• Uremia
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301
Utility of the ∆AG/∆HCO
3
-
Ratio
AG – 8
24 – HCO
3
-
∆AG/∆HCO
3
-
=
∆AG/∆HCO
3
-
Diagnosi s
1 Pure AG acidosis
<1 Concomitant non-AG
acidosis
>1 Concomitant metabolic
alkalosis

Classically:
Caveats for the ∆AG/∆HCO
3
-
Ratio
• Assumes sensitivity/accuracy of the anion gap; 
albumin etc. can  measured anion gap
• Assumes an equivalent volume of distribution of
the offending anions and H
+
not always the
case, e.g. in lactic acidosis
• Many anions are rapidly excreted   AG
Examples:
D-lactate – not reabsorbed by proximal tubule
Ketoacids in DKA – variable excretion, dependent on
volume status, etc.
Rastegar, JASN, 18, 2007
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302
Classification of Renal Tubular
Acidosis (RTA)
• Type I, “classic” hypokalemic distal RTA
–  K+, unable to decrease urine pH <5.5 despite
acidemia
• Type II, proximal RTA
– typically  K+,  threshold for HCO
3
-
reabsorptionby
proximal tubule urine pH can  to 5.5 only once
serum HCO
3
-
<15
• Type IV, “hyperkalemic” distal RTA
–  K+, urine pH usually <5.5
– either generalized  in aldosterone or renal
resistance
NHE
NBC
Na
+
V-ATP
H
+
Blood
Tubular
fluid
filtered
HCO
3
-
CA-4
CO
2
+
H
2
O
CO
2
+H
2
O
CA-2
Na
+
nHCO
3
-
H
+
HCO
3
-
80-90%
Proximal Tubule HCO
3
-
Absorption
Dr. M. F. Romero, CWRU, 2002
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303
Cause of Proximal RTA (pRTA)
• Isolated pRTA
– Primary – hereditary (Na-HCO
3
transporter), sporadic
(often transient)
– Carbonic anhydrase deficit – hereditary, CA inhibitors
• Generalized proximal tubular dysfunction –
associated glycosuria, phosphaturia, etc.
– Primary – hereditary Fanconi’s syndrome
– Genetic disease – cystinosis, Wilson’s disease
– Acquired – Sjoegren’s, paraproteinemias, vitamin D
deficiency, etc.
– Drugs/toxins – ifosfamide, FK-506/tacrolimus,
cyclosporine, toluene, outdated tetracycline, lead,
mercury, etc.
Pathophysiology of Proximal RTA
• Reduced proximal HCO
3
-
reabsorption
overwhelms distal nephron
– ↑ Cl- reabsorption hyperchloremic acidosis
– ↓ filtered load of HCO
3
-
distal reabsorption
↓ urine pH
• At steady state, [HCO
3
-
] = 15-18 mEq/L,
with urine pH <5.5
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304
Diagnosis of Proximal RTA
• Typically need to distinguish from
hypokalemic distal RTA
•  Plasma bicarbonate concentration
toward normal (18 to 20 meq/L) with IV
bicarbat 0.5 to 1.0 meq/kg per hour
• In proximal RTA, urine pH should ↑ to >7.5
with FeHCO
3
of 15-20%; in hypokalemic
distal RTA will see minimal change in
urine pH, FeHCO3 should be <3%
2K
+
NH /K
4
+ +
NH
3
NH
3
NH
4
+
NH
4
+
NH + H
3
+
2K
+
ATP
ATP
ATP
ATP
K
+
H
+
H
+
K
+
K
+
ROMK
kAE1
KCC4
ENaC
Aquapori n-2
Lumen
3Na
+
3Na
+
Na
+
Cl
-
Cl
-
Cl
-
Cl
-
HC0
3
-
(-) (+)
NH
4
+
Excretion,
Renal Collecting
Duct
Take-home point:
Principal
cells generate a
lumen-negative
potential difference,
which drives K
+
and
H
+
excretion
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305
Functional Classification of Distal RTA
• Defective H-ATPase “ secretory”
defect
• Unfavorable electrical gradient for H
+
secretion “ voltage” defect
• Back diffusion of H
+
“ permeability”
defect
• Insufficient delivery of NH
3
to the distal
nephronNH
3
defect, e.g. in
hyperkalemia
Causes of Hypokalemic dRTA
• Primary – hereditary
– H
+
-ATPase subunit genes
– type II carbonic anhydrase (proximal and distal RTA)
– AE1 Cl-HCO
3
exchanger (SLC4A1)
• Genetic causes – sickle-cell, Fabry’s, Wilson’s,
elliptocytosis, MCDK
• Auto-immune disorders – SLE, etc.
• Nephrocalcinosis/hypercalciuria
• Amyloidosis
• Drugs/toxins – amphotericin
• Tubulo-interstitial disease – reflux nephropathy,
obstructive uropathy
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306
Mutations in the B-subunit of H-ATPase
Cause Autosomal Recessive Distal RTA With
Deafness
Karet et al, Nature Genetics, 21, 1999
Index
case
Age
at Dx
pH HCO
3
-
K
+
Urine
pH
Urine Ca
2+

(mg/kg/d)
RTA18 3 mo 7.26 13 2.2 6.9 8.5 (high)
RTA59 2 mo 7.10 8.7 2.9 7.5 6.0
RTA35 3 yrs 7.19 8.9 2.8 6.0 5.0
RTA29 6 mo 7.12 11 3.2 7.0 8.5

H
+
, NH
3
, and HCO
3
-
Transport in
Intercalated Cells
2K
+
NH /K
4
+ +
ATP
ATP
ATP
K
+
H
+
H
+
H
+
AE1
CA-II
KCC4
H -ATPase
+
H /K -ATPase
+ +
Lumen
Interstitium
3Na
+
Cl
-
Cl
-
Cl
-
HC0
3
-
C0
2
H 0
2
NH
3
NH
4
+
NH
3
RhCG
RhBG NH
3
(-) (+)
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307
“Hyperkalemic Distal RTA”
• Type IV RTA (hyporeninemic hypoaldo)
– Diabetic nephropathy, SLE, acute post-Strep GN
– Type II Pseudohypoaldosteronism (Gordon’s
syndrome)
• Adrenal insufficiency
– Addison’s, AIDS, isolated hypoaldo, CAH, etc.
• Mineralocorticoid resistance
– Type I Pseudohypoaldosteronism
– Interstitial disease, e.g. AIN, obstructive uropathy
• Drug-induced
– Various mechanisms; K
+
redistribution, ENaC
inhibition, RAS inhibition, etc.
Disclosures
• Consultant (hyponatremia) Salix Otsuka • Consultant (hyponatremia) – Salix, Otsuka
• Speaker bureau, 2005-2008 – Astellas
(conivaptan)
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308
PATHOLOGY AND
MECHANISMS OF
GLOMERULAR DISEASES
Helmut G. Rennke, M.D.
Disclosures
• NONE • NONE
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309
PT
DT
a
PT
DT
e
MD PT
DT
BC
CL
US
Ep
End
Ep
CL
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310
Ep
FP
US
CL
End
THE CLINICAL SYNDROMES
1. The Nephrotic Syndrome
2. The Acute Nephritic Syndrome
3. Rapidly Progressive Glomerulonephritis
4. Asymptomatic Hematuria / Proteinuria
5. The Chronic Nephritic Syndrome
(Chronic Renal Failure)
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311
1.- Epithelial Cell Disease (Minimal Change
Disease)
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing 7. Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
MECHANISMS OF KIDNEY INJURY
Genetic and congenital
abnormalities
M t b li b liti
Paraproteins
Thrombosis and
b liti f th Metabolic abnormalities
Immune mechanisms
Types II, III, and IV
Cytokines
Abnormalities in
complement-regulatory
proteins
abnormalities of the
coagulation/fibrinolysis
system
Physical factors: radiation
Obstruction of the
excretory system
Infections: bacteria fungi proteins
Ischemic injury
Toxic damage:
environmental, dietary,
iatrogenic toxins
Infections: bacteria, fungi,
viruses, parasites
Functional and structural
adaptations
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312
IMMUNE-MEDIATED DISORDERS
TYPE MECHANISM OF TISSUE INJURY
I. Immediate
Hypersensitivity
IgE antibodies – immediate release of vasoactive
amines, lipid mediators, cytokines from mast cells -
it t f i fl t ll
II. Antibody-
mediated
III Immune
recruitment of inflammatory cells.
IgG, IgM antibodies; binding to target molecule, cell, or
matrix component:
A. loss or enhancement of cell/protein function
B. lysis of target cell via complement activation
C. antibody-dependent cell cytotoxicity
Antigen-antibody complexes in circulation – Complement III. Immune
Complex-
mediated
IV. T Cell-mediated
Antigen antibody complexes in circulation Complement
and Fc receptor-mediated recruitment of neutrophils -
release of lysosomal enzymes and other toxic mediators
CD4
+
T cells – macrophage activation – cytokines -
inflammation
CD8
+
T cells - direct cytotoxicity – cytokines - inflammation
Proteinuria (>3.5g/day)
THE NEPHROTIC SYNDROME
Hypoalbuminemia
Hyperlipidemia
Lipiduria
Edema
Bland urine sediment
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1.- Epithelial Cell Disease (Minimal Change Disease)
2 F l S l Gl l l i
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing g
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
THE NEPHROTIC SYNDROME
The structural abnormality y
shared by all nephrotic
conditions or diseases with
heavy proteinuria is diffuse
i lifi ti “f i ” f th simplification or “fusion” of the
foot processes of the glomerular
visceral epithelial cells.
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MOLECULAR ORGANIZATION OF THE
FOOT PROCESS OF THE GLOMERULAR
VISCERAL EPITHELIAL CELL
C t t i N=NHERF2 Cat=catenins
CD-CD2AP
Cas=p130Cas
Ez=ezrin
FAK=focal adhesion kinase
TPV=talin-paxilin-vinculin
ILK-integrin-linked kinase
M=myosin
N=NHERF2
NSCC=non-selective Ca
chanel
PC=podocalyxin
S=synaptopodin
U=utrophin
Z=ZO-1
Endlich. 2001 Curr Opin
Nephrol Hypertens
10:331,
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315
THE PHENOTYPIC EXPRESSION
OF GENETIC DEFECTS OF THE
PODOCYTE - THE FAMILIAL
PODOCYTOPATHIES
Diffuse Simplification (“ fusion” )
of Foot Processes
Diffuse Mesangial Sclerosis
Focal and Segmental
Glomerulosclerosis
Diffuse Simplification (“ fusion” ) of
Foot Processes
Diffuse Mesangial Sclerosis
Focal and Segmental
Glomerulosclerosis
Genetic Abnormalities of the Podocyte
The Diffuse Familial Podocytopathies
Nephrin; NPHS1; 19q13.1; the congenital
nephrotic syndrome (CNS); diffuse lesion, AR nephrotic syndrome (CNS); diffuse lesion, AR
Podocin ; NPHS2; 1q25-q31; familial and
sporadic SRNS and FSGS; diffuse lesion, AR
CD2-associated protein, p130
CAS
–associated;
NS; Chr 6; AR; truncated protein; diffuse
mesangial sclerosis and collapsing lesions; AR
Wilms Tumor gene; WT-1; 11p13; Diffuse
Mesangial Sclerosis, AD
- WAGR (Wilms tumor, Aniridia, Gonadal, Renal abn)
- Denys-Drash syndrome (Renal dis, mPsH, WT)
- Frasier syndrome (FSGS, mPsH, Gblast)
- WT-1 splice mutation in 46XX female
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Genetic Abnormalities of the Podocyte
The Focal Familial Podocytopathies
α-actinin-4; ACTN4; 19q13; progressive
proteinuria and familial FSGS; age-related
penetrance; AD
Canonical Transient Receptor Potential 6;
TRPC6; 11q; progressive proteinuria and
familial FSGS; age-related penetrance; AD
Member of the formin family of actin-
regulating proteins; IFN2; 14q; progressive
proteinuria and familial FSGS; age-related
penetrance; AD
α-galactosidase deficiency (Fabry; Xq24-24)
Sialidase deficiency (4q21 23)
OTHER GENETIC DISEASES WITH FSGS,
PROTEINURIA, OR RENAL FAILURE
Sialidase deficiency (4q21-23)
Familial form of unilateral renal agenesis
Charcot-Marie-Tooth Disease (FSGS)
Mitochondrial disease, mDNA-A3243G; Myopathies and FSGS
b4-Integrin mutation: epidermolysis bullosa and congenital
FSGS
Inherited basement membrane defects:
- X-linked Alport syndrome (COL4A5)
- autosomal recessive hereditary nephritis
(COL4A3; COL4A4)
- Thin basement membrane disease (COL4A4)
Nail-patella syndrome (LMX1B; 9q34)
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317
DIFFUSE EPITHELIAL CELL
DISEASE
MINIMAL CHANGE DISEASE
DIFFUSE EPITHELIAL CELL
DISEASE
•Hereditary “ Podocytopathies” Hereditary Podocytopathies
Congenital nephrotic syndrome (Finish type)
Defect in Nephrin; NPHS1; 19q13.1; AR
Denys-Drash syndrome (mesagial sclerosis)
Defect in WT1;
Steroid-resistant nephrotic syndrome
Defect in Podocin; NPHS2; Defect in Podocin; NPHS2;
•Acquired Epithelial Cell Disease
Minimal Change Disease and Associated Lesions
Idiopathic Focal and Segmental Glomerulosclerosis
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319
IgG
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320
CLINICAL CONDITIONS ASSOCIATED
WITH MINIMAL CHANGE DISEASE
Idiopathic minimal change disease
(lipoid nephrosis, nil disease) ( p p )
subgroup with acute renal failure
Secondary forms of diffuse epithelial cell disease:
- associated with drug use, with or without AIN
- early stage of HIV-associated nephropathy,
collapsing glomerulopathy, and heroin
nephropathy
- associated with Hodgkin's disease and other
lymphoproliferative disorders
- associated with insect bites, immunizations, etc.
- associated with IgA nephropathy, diabetes
mellitus, SLE, and other glomerulopathies
ACUTE RENAL FAILURE IN ADULT
MINIMAL CHANGE DISEASE
MCD + ARF MCD
Serum Creat. (mg/dl) 2.2-15.2 0.6 – 1.4
Age (years) 59.6 40.3
Systolic BP (mmHg) 158 138
Proteinuria (g/day) 13 5 7 9 Proteinuria (g/day) 13.5 7.9
Arteriosclerosis Index (0-4) 1.7 0.7
Evidence of ATN 71% 0%
J C J ennette, RJ Falk. Am J Kidney Dis 16:432-437, 1990.
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321
NSAID-ASSOCIATED NEPHROTIC SYNDROME
24 cases of the NS associated with use of NSAID
17 biopsies: all showed minimal disease
Average 24-hour urine protein was 11.2g
Peak plasma creatinine 0.8 to 14.8 mg/dl
The NS remitted or improved in 23/24
Course of remission: Course of remission:
19/24 < 2 months
4/24 > 2 months
Feinfeld, Olesniky, Pirani, Appel. Nephron 37:174, 1984.
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322
FOCAL AND SEGMENTAL
GLOMERULOSCLEROSIS (FSGS)
1. IDIOPATHIC OR PRIMARY FSGS
2. SECONDARY (ADAPTIVE) FSGS
3. SEGMENTAL GLOMERULAR SCARRING 3. SEGMENTAL GLOMERULAR SCARRING
4. FAMILIAL FSGS
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323
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324
IgM
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325
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326
IMMUNE-MEDIATED DISORDERS
TYPE MECHANISM OF TISSUE INJURY
I. Immediate
Hypersensitivity
IgE antibodies – immediate release of vasoactive
amines, lipid mediators, cytokines from mast cells -
it t f i fl t ll
II. Antibody-
mediated
III Immune
recruitment of inflammatory cells.
IgG, IgM antibodies; binding to target molecule, cell, or
matrix component:
A. loss or enhancement of cell/protein function
B. lysis of target cell via complement activation
C. antibody-dependent cell cytotoxicity
Antigen-antibody complexes in circulation – Complement III. Immune
Complex-
mediated
IV. T Cell-mediated
Antigen antibody complexes in circulation Complement
and Fc receptor-mediated recruitment of neutrophils -
release of lysosomal enzymes and other toxic mediators
CD4
+
T cells – macrophage activation – cytokines -
inflammation
CD8
+
T cells - direct cytotoxicity – cytokines - inflammation
FOCAL AND SEGMENTAL
GLOMERULOSCLEROSIS (FSGS)
1. IDIOPATHIC OR PRIMARY FSGS
2. FAMILIAL FSGS
3. SECONDARY OR ADAPTIVE FSGS
4. SEGMENTAL GLOMERULAR SCARRING
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327
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328
FOCAL AND SEGMENTAL
GLOMERULOSCLEROSIS (FSGS)
1. IDIOPATHIC OR PRIMARY FSGS
2. FAMILIAL FSGS
3. SECONDARY OR ADAPTIVE FSGS
4. SEGMENTAL GLOMERULAR SCARRING
Unilateral renal agenesis and compensatory hypertrophy
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329
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330
METABOLIC SYNDROME
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331
IDIOPATHIC vs. ADAPTIVE FSGS
Sudden onset
nephrotic syndrome
(edema)
Slowly progressive
proteinuria without edema
(edema)
No history of prior
kidney disease
Normal size glomeruli
Diffuse effacement of
History of prior kidney
disease (pregnancy) or
vascular conditions
Glomerular hypertrophy
Foot processes largely
foot processes
No significant
parenchymal atrophy
preserved
Pre-existing kidney injury
COLLAPSING
GLOMERULOPATHY
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333
Albumin
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334
MEMBRANOUS GLOMERULOPATHY
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335
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336
IgG
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337
IMMUNE-MEDIATED DISORDERS
TYPE MECHANISM OF TISSUE INJURY
I. Immediate
Hypersensitivity
IgE antibodies – immediate release of vasoactive
amines, lipid mediators, cytokines from mast cells -
it t f i fl t ll
II. Antibody-
mediated
III Immune
recruitment of inflammatory cells.
IgG, IgM antibodies; binding to target molecule, cell, or
matrix component:
A. loss or enhancement of cell/protein function
B. lysis of target cell via complement activation
C. antibody-dependent cell cytotoxicity
Antigen-antibody complexes in circulation – Complement III. Immune
Complex-
mediated
IV. T Cell-mediated
Antigen antibody complexes in circulation Complement
and Fc receptor-mediated recruitment of neutrophils -
release of lysosomal enzymes and other toxic mediators
CD4
+
T cells – macrophage activation – cytokines -
inflammation
CD8
+
T cells - direct cytotoxicity – cytokines - inflammation
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338
TYPE II, ANTIBODY-MEDIATED
A. Antibody-dependent and complement-mediated:
Autoimmune hemolytic anemia
Agranulocytosis
Autoimmune thrombocytopenia
Erythroblastosis fetalis (Rh)
Idiopathic Membranous Glomerulopathy (M type
phospholipase A2 receptor, α enolase)
Congenital Membranous GN (neutral endopeptidase) g ( p p )
Bullous pemphigoid ? (hemidesmosomes; PA 1 and 2)
Rheumatic fever ? (cross-reactive antibodies to M proteins)
Antibody-mediated allograft rejection, vasculitis (HLA)
PATHOGENESIS OF MEMBRANOUS
NEPHROPATHY
In situ formation of immune complexes: endogenous
epithelial cell antigen and circulating
t tib di autoantibodies
Complement activation
Epithelial cell injury (MAC)
Permeability defect due cell damage, retraction of foot
processes, and loss of filtration slit diaphragms
Proteinuria
Active inflammation does not occur; a gradient of
chemotactic agents is not established against the
ultrafiltration flux; lack of endothelial cell injury
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339
CONDITIONS ASSOCIATED WITH
MEMBRANOUS NEPHROPATHY
1.- Idiopathic Membranous Nephropathy
Congenital Membranous Nephropathy
2.- Autoimmune Diseases
SLE and RA
Hashimoto's disease, Grave's disease,
MCTD Sjögren's syndrome MCTD, Sjögren s syndrome,
primary biliary cirrhosis,
bullous pemphigoid, dermatitis
herpetiformis, ankylosing spondylitis,
small bowel enteropathies
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340
CONDITIONS ASSOCIATED WITH
MEMBRANOUS NEPHROPATHY
3.- Infectious or Parasitic Diseases
H titi B d C Hepatitis B and C
Syphilis
Filariasis, hydatidic cyst, schistosomiasis,
malaria, leprosy, enterococcal endocarditis
4 D 4.- Drugs
Au, Hg, Penicillamine, Captopril,
NSAIDs, Hydrochlorothiazide, Hydralazine,
Trimethadione, Chlormethiazole
WHY DO PATIENTS WITH DIFFUSE
EPITHELIAL CELL DISEASE TEND TO
HAVE EDEMA (NEPHROTIC SYNDROME),
WHILE PATIENTS WITH ONLY FOCAL
DAMAGE TO THE PODOCYTES USUALLY
LACK EDEMA?
The theory of the low serum albumin
concentration as the driving force for salt
retention (the under-fill theory)
The notion of the proteinuric nephron as the
immediate cause of sodium retention; the
reset volume-sensing mechanism in the
proteinuric tubule
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341
STARLING FORCES OPERATING IN
THE PERIPHERAL CAPILLARIES
Na
+
DELIVERY AND REABSORPTION IN
PROTEINURIC AND NON-PROTEINURIC
NEPHRONS IN UNILATERAL PAN-INDUCED
NEPHROTIC SYNDROME NEPHROTIC SYNDROME
J Clin Invest 71:91-103, 1983
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342
Klisic J , Zhang J , Nief V, Reyes L,
Moe OW, Ambuhl PM. 2003.
Albumin regulates the Na+/H+
exchanger 3 in OKP cells. J Am
Soc Nephrol 14:3008-3016
THE ACUTE NEPHRITIC
SYNDROME
Hematuria
(red cell casts, dysmorphic RBCs)
Oliguria
Azotemia Azotemia
Hypertension
Edema
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343
THE ACUTE NEPHRITIC
SYNDROME
Di h t i d b th t Diseases characterized by the acute
nephritic syndrome are associated
invariably with deposition of immune
complexes in the more proximal layers
of the glomerular capillary wall in close of the glomerular capillary wall, in close
proximity to the endothelial cell surfaces
or in the lamina rara interna.
MECHANISMS OF IMMUNE COMPLEX
FORMATION WITHIN THE PERIPHERAL
CAPILLARY WALL
Subepithelial IC Subendothelial IC
Endogenous epithelial
cell antigens
(membranous GN,
membranous lupus
Entrapment of circulating
immune complexes
(lupus nephritis, post-
infectious GN)
Subepithelial IC Subendothelial IC
membranous lupus
nephritis)
Planted exogenous
antigens
(post-infectious GN)
)
Planted exogenous or
endogenous antigens
(DNA in lupus nephritis)
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344
24 hours
2 days
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345
2 weeks
14 days
4 weeks
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346
5 minutes
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347
30 minutes
4 hours
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348
24 hours
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349
MODELS OF DISEASES WITH IMMUNE
COMPLEXES PLANTED WITHIN THE
CAPILLARY WALL
SUBEPITHELIAL IC
SUBENDOTHELIAL IC
SUBEPITHELIAL IC
Epithelial cell injury
Proteinuria
No endothelial injury
SUBENDOTHELIAL IC
No epithelial cell injury
No proteinuria
Endothelial injury
No inflammation
Evolves over month
Acute inflammation
Evolves over hours or
few days
1.- Epithelial Cell Disease (Minimal Change Disease)
2 F l S l Gl l l i
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing g
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
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350
HepC-associated acute GN
IgM
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351
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352
IgG
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353
RB
US
RB
C
US
RBC
Plt
CL
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354
CONDITIONS ASSOCIATED WITH DIFFUSE
PROLIFERATIVE GLOMERULONEPHRITIS
Acute Postinfectious Glomerulonephritis:
bacterial: streptococcal, staphylococcal,
pneumococcal, and typhoid fever
viral: varicella, mumps, ECHO and Coxsackie,
infectious mononucleosis, hepatitis B,
hepatitis C with cryoglobulins, measles
Other: syphilis, leptospirosis, toxoplasmosis,
falciparummalaria parasitic diseases falciparum malaria, parasitic diseases
Diffuse proliferative lupus nephritis
Dense Deposit Diseases (MPGN type II), early phase
Essential mixed cryoglobulinemia, early phase
THE MEMBRANOPROLIFERATIVE
PATTERN OF INJURY
STRUCTURAL CHANGES:
HYPERCELLULARITY HYPERCELLULARITY
CAPILLARY WALL THICKENING (double contours)
CONDITIONS ASSOCIATED WITH THE
MPGN PATTERN:
IMMUNE COMPLEX DISEASES IMMUNE COMPLEX DISEASES
ABNORMALITIES OF COMPLEMENT-
REGULATORY PROTEINS
THROMBOTIC ANGIOPATHIES
DEPOSITION DISEASE
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355
THE MEMBRANOPROLIFERATIVE
PATTERN OF INJURY
STRUCTURAL CHANGES:
HYPERCELLULARITY
CAPILLARY WALL THICKENING (double contours)
CONDITIONS ASSOCIATED WITH THE
MPGN PATTERN:
IMMUNE COMPLEX DISEASES IMMUNE COMPLEX DISEASES
ABNORMALITIES OF COMPLEMENT-
REGULATORY PROTEINS
THROMBOTIC ANGIOPATHIES
DEPOSITION DISEASE
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356
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357
CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF INJURY
1. IMMUNE COMPLEX-MEDIATED DISEASES
Chronic infections:
Vi l h titi B h titi C d ti l i d Viral: hepatitis B, hepatitis C and essential mixed
cryoglobulinemia
Bacterial: endocarditis, infected ventriculo-atrial (or
jugular) shunt, multiple visceral abscesses,
leprosy, meningococcal meningitis
Protozoa: malaria, schistosomiasis
Other infections: mycoplasma ?Borreliosis Other infections: mycoplasma, ?Borreliosis,
Leishmaniasis
Miscellaneous:
Chronic liver disease (cirrhosis and alpha1-antitrypsin
deficiency)
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358
1. IMMUNE COMPLEX-MEDIATED DISEASES:
Autoimmune diseases:
SLE
CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF INJURY
SLE
Sjögren syndrome
Rheumatoid arthritis
Inherited complement deficiencies, in
particular C2 deficiency
Idiopathic forms of MPGN (unknown association):
MPGN type I yp
MPGN type II or dense deposit disease and
partial lipodystrophy
MPGN type III (Strife and Anders variant,
Burkholder variant)
IMMUNE-MEDIATED DISORDERS
TYPE MECHANISM OF TISSUE INJURY
I. Immediate
Hypersensitivity
IgE antibodies – immediate release of vasoactive
amines, lipid mediators, cytokines from mast cells -
it t f i fl t ll
II. Antibody-
mediated
III Immune
recruitment of inflammatory cells.
IgG, IgM antibodies; binding to target molecule, cell, or
matrix component:
A. loss or enhancement of cell/protein function
B. lysis of target cell via complement activation
C. antibody-dependent cell cytotoxicity
Antigen-antibody complexes in circulation – Complement III. Immune
Complex-
mediated
IV. T Cell-mediated
Antigen antibody complexes in circulation Complement
and Fc receptor-mediated recruitment of neutrophils -
release of lysosomal enzymes and other toxic mediators
CD4
+
T cells – macrophage activation – cytokines -
inflammation
CD8
+
T cells - direct cytotoxicity – cytokines - inflammation
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359
2 DEFECTS IN COMPLEMENT REGULATORY
CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF
INJURY
2. DEFECTS IN COMPLEMENT-REGULATORY
PROTEINS:
Dense Deposit Disease (MPGN type II),
- C3 nephritic factor
- genetic defects in factor H, factor I,
d MCP CD46 and MCP or CD46
- partial lipodystrophy
Glomerulonephritis C3
Atypical HUS (d-HUS)
DENSE DEPOSIT DISEASE
MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS TYPE II
Affects predominantly children or young Affects predominantly children or young
adults
Nephritic syndrome, often acute in onset
Chronic or subacute clinical course;
progressive proteinuria
P i h l i Persistent hypocomplementemia
Associated with familial lipodystrophy
Nephritic factor; autoantibody against C3
convertase of the alternative pathway
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360
US
Cap
C3
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361
PATHOGENESIS OF DENSE DEPOSIT
DISEASE
Mechanisms of complement
dysregulation that result in DDD:
Homozygous factor H deficiency (factor
H dissociates the C3bBb complex)
Deletion of a single AA in regulatory
domain 4 of factor H
dysregulation that result in DDD:
Inactivation of factor H by a circulating
inhibitor (monoclonal paraproteins)
The autoantibody C3 nephritic factor
(stabilizes the C3bBb complex)
ACTIVATION OF THE COMPLEMENT SYSTEM
CLASSICAL LECTIN ALTERNATIVE
Ag-Ab SUGARS Agg. Ig; Endotoxin
Activated C1 Mg; D C3b; B g; ;
C4a
C4b2b
C3 CONVERTASE
C3
C3bBb
C3b
feedback
pathway
Properdin
C3 CONVERTASE
C3bBbP
C3b C3a
C4b2b
C5b67 C5b
C5
C5a
C5b-9
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362
GLOMERULONEPHRITIS C3
OR
Primary glomerulonephritis with
isolated C3 deposits
Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J,
Knebelmann B, Grunfeld JP, Lesavre P, Noel LH, Fakhouri F. Primary
glomerulonephritis with isolated C3 deposits: a new entity which shares
common genetic risk factors with haemolytic uraemic syndrome. J Med
Genet 2007 44:193-9. Epub 2006 Oct 3.
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363
C
3
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364
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365
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366
C3
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367
MEMBRANOPROLIFERATIVE
GLOMERULONEPHRITIS TYPE III
Strife and Anders variant; with defects of
the lamina densa
unknown pathogenesis; ? thrombotic
angiopathy
B kh ld i t ith b ith li l Burkholder variant; with subepithelial
deposits
? post-infectious GN
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368
CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF INJURY
3. CHRONIC AND HEALED THROMBOTIC
MICROANGIOPATHIES:
H li h f HUS/TTP Healing phase of HUS/TTP
The syndrome of circulating anti-phospholipid
(anti-cardiolipin) antibodies
POEMS syndrome
Radiation nephritis
Nephropathy associated with bone marrow
transplantation
Drug-associated thrombotic angiopathies
Sickle cell anemia and polycythemia
Dysfibrinogenemia and other pro-thrombotic states
Transplant glomerulopathy
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369
Fibrin
US
End
*
CL
Mes
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370
Mes Mes
End
*
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371
CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF
INJURY
4. PARAPROTEIN DEPOSITION DISEASES:
Gl l thi i t d ith Glomerulopathies associated with
cryoglobulinemia type I
Waldenström macroglobulinemia
Immunotactoid glomerulopathy
Immunoglobulin light chain or
heavy chain deposition diseases
POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy,
m-protein, skin change)
Fibrillary glomerulonephritis
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372
Fibrillary GN
IgG
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373
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374
Fibrillary GN Amyloidosis
IgG/kappa Paraprotein deposition disease
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375
IgG Kappa Lambda
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376
CONDITIONS ASSOCIATED WITH A
MEMBRANOPROLIFERATIVE PATTERN OF
INJURY
3. PARAPROTEIN DEPOSITION DISEASES:
Gl l thi i t d ith Glomerulopathies associated with
cryoglobulinemia type I
Waldenström macroglobulinemia
Immunotactoid glomerulopathy
Immunoglobulin light chain or
heavy chain deposition diseases
POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy,
m-protein, skin change)
Fibrillary glomerulonephritis
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377
RAPIDLY PROGRESSIVE
GLOMERULONEPHRITIS
Rapid decline in renal function
(over several days or few weeks)
Active urine sediment
Usually no edema and no hypertension
1.- Epithelial Cell Disease (Minimal Change Dis.)
2 F l S l Gl l l i
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Focal Proliferative and Necrotizing
Glomerulonephritis p
7.- Crescentic Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
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378
CLINICAL CONDITIONS ASSOCIATED WITH
CRESCENTIC GLOMERULONEPHRITIS
Type I, anti-GBM disease
Type II, immune complex-mediated
Other primary glomerulonephritides:
post-infectious GN, IgA nephropathy, MPG
Systemic diseases (SLE, RA, H-S purpura)
Type III, pauci immune (ANCA-associated):
Idiopathic pauci-immune crescentic GN
Polyangiitis or SVV (ANCA-associated):
microscopic form of polyarteritis nodosa,
Wegener's granulomatosis
Churg-Strauss syndrome
Drug-induced vasculitides
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379
Fibrin
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380
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381
IgG
α3-IV COLLAGEN AS TARGET
OF IMMUNE INJURY OF IMMUNE INJURY
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382
IMMUNE MECHANISMS OF FOCAL
NECROTIZING AND CRESCENT FORMATION
Linear staining for IgG Granular staining for IgG No staining for IgG
Anti-GBM disease Immune-complex pauci-immune
Goodpasture syndr. disease (SLE) disease
(ANCA)
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383
IgG
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384
IMMUNE MECHANISMS OF FOCAL
NECROTIZING AND CRESCENT FORMATION
Linear staining for IgG Granular staining for IgG No staining for IgG
Anti-GBM disease Immune-complex pauci-immune
Goodpasture syndr. disease (SLE) disease
(ANCA)
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385
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386
c-ANCA p-ANCA
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387
IMMUNE-MEDIATED DISORDERS
TYPE MECHANISM OF TISSUE INJURY
I. Immediate
Hypersensitivity
IgE antibodies – immediate release of vasoactive
amines, lipid mediators, cytokines from mast cells -
it t f i fl t ll
II. Antibody-
mediated
III Immune
recruitment of inflammatory cells.
IgG, IgM antibodies; binding to target molecule, cell, or
matrix component:
A. loss or enhancement of cell/protein function
B. lysis of target cell via complement activation
C. antibody-dependent cell cytotoxicity
Antigen-antibody complexes in circulation – Complement III. Immune
Complex-
mediated
IV. T Cell-mediated
Antigen antibody complexes in circulation Complement
and Fc receptor-mediated recruitment of neutrophils -
release of lysosomal enzymes and other toxic mediators
CD4
+
T cells – macrophage activation – cytokines -
inflammation
CD8
+
T cells - direct cytotoxicity – cytokines - inflammation
TYPE II, ANTIBODY-MEDIATED
B. Antibody-dependent and cell-mediated (NK and
ADCC)
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388
ASYMPTOMATIC
HEMATURIA/PROTEINURIA
These conditions are characterized
morphologically either by focal
necrotizing and/or inflammatory lesions
of the glomeruli or by basement g y
membrane anomalies that result in
greater capillary fragility.
1.- Epithelial Cell Disease (Minimal Change Dis)
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Focal Proliferative and Necrotizing
Glomerulonephritis Glomerulonephritis
7.- Crescentic Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
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389
MESANGIOPROLIFERATIVE
GLOMERULONEPHRITIS
IgA Nephropathy IgA Nephropathy
Recovery phase of a postinfectious
glomerulonephritis
SLE WHO Class II, mesangial form, and
other IC mediated diseases other IC-mediated diseases
Idiopathic Mesangioproliferative GN
Some of the deposition diseases
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390
IgA
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391
Asymptomatic
Hematuria and/or
Proteinuria
Acute
Nephritis
Rapidly
Progressive
Nephritis
Chronic
Nephritis
or ESKD
CLINICAL AND MORPHOLOGICAL EXPRESSION
OF IgA NEPHROPATHY AND HSP
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392
Unusual Presentations in IgA
Nephropathy
IgA Nephropathy with gross hematuria and
Acute Renal Failure Acute Renal Failure
IgA Nephropathy with superimposed
Nephrotic Syndrome and Minimal
Change-like lesions
IgA Nephropathy with Proteinuria and g y
Membranous Nephropathy
IgA Nephropathy with ANCA serology and
Necrotizing and Crescentic
Glomerulonephritis
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393
PATHOGENESIS OF IgA NEPHROPATHY
AND HSP
A glycosylation defect of the O-linked glycans in the
hinge region of IgA1 molecules is believed to: hinge region of IgA1 molecules is believed to:
reduced clearance from the circulation because of
lack of receptor engagement by the abnormal
IgA
increased aggregation of IgA in the circulation
resulting in mesangial trapping
development of immune complex-forming development of immune complex-forming
autoantibodies directed against the abnormal
IgA
increased affinity of the abnormal IgA for mesangial
matrix
CLINICAL CONDITIONS ASSOCIATED WITH
GLOMERULAR BASEMENT MEMBRANE
ABNORMALITIES
Hereditary nephritis (Collagen type IV): Hereditary nephritis (Collagen type IV):
Classical Alport syndrome
Autosomal recessive hereditary nephritis
Autosomal dominant hereditary nephritis
Thin basement membrane disease (TBMD)
Epstein and Fechtner syndromes (myosin HC IIA)
Pierson Syndrome (laminin β2) (CNS+eye abn.)
Nail-patella syndrome or hereditary osteo- p y y
onychodysplasia (LMX1B, LIM homeodomain
transcription factor)
Collagen III glomerulopathy, Fibronectin glomerulopathy
Lecithin-cholesterol acyltranferase deficiency
(Resolving immune complex mediated GN)
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394
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395
BASEMENT MEMBRANE COLLAGENS
COLLAGEN TYPE IV
GENE/CHR CHAIN EXPRESSION DISEASE
COL4A1/c13 α1(IV) All BM, Mes Porencephaly and
COL4A2/ 13 2(IV) All BM M HANAC COL4A2/c13 α2(IV) All BM, Mes HANAC
COL4A3/c2 α3(IV) GBM, BC, dTBM arAS; adAS;TBM
COL4A4/c2 α4(IV) GBM, BC, dTBM arAS; adAS;TBM
COL4A5/cX α5(IV) GBM, BC, dTBM X-AS
COL4A6/cX α6(IV) BC, dTBM X-AS +
Kashtan CE: Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol
9:1736-1750, 1998.
Gubler MC: Inherited disease of the glomerular basement membrane. Nature Clin Prac Nephrol 4:24-
37, 2008.
leiomyomatosis
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396
GENETICS OF HEREDITARY NEPHRITIS
DISEASE MUTATIONS
X linked HN COL4A5 (only 50%of cases): X-linked HN COL4A5 (only 50% of cases):
large deletions, missense mutations,
splice-site mutations, small deletions
Sporadic AS de novo mutation of COL4A5 or germ
line mutation of COL4A5 in mother
ar HN COL4A3 COL4A4 ar HN COL4A3, COL4A4
ad HN COL4A3, COL4A4
TBM COL4A4, COL4A3
1.- Epithelial Cell Disease (Minimal Change Disease)
2 Focal Segmental Glomerulosclerosis
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
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397
CHRONIC RENAL FAILURE
CHRONIC NEPHRITIC SYNDROME
Th t t l i l t f thi d i The structural equivalent of this syndrome is
end-stage renal disease, with widespread
global glomerular obsolescence (sclerosis),
tubular atrophy, interstitial fibrosis, and
variable degree of arterial and arteriolar variable degree of arterial and arteriolar
sclerosis. A more precise diagnosis can often
be established by immunohistochemical and
ultrastructural studies.
Fabry
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398
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399
1.- Epithelial Cell Disease (Minimal Change
THE BASIC STRUCTURAL PATTERNS
OF GLOMERULAR INJURY
Disease)
2.- Focal Segmental Glomerulosclerosis
3.- Membranous Nephropathy
4.- Diffuse Proliferative Glomerulonephritis
5.- Membranoproliferative Glomerulonephritis
6.- Crescentic Glomerulonephritis
7 Focal Proliferati e and Necroti ing 7.- Focal Proliferative and Necrotizing
Glomerulonephritis
8.- Mesangial Proliferative Glomerulonephritis
9.- Basement Membrane Abnormalities
10.- Focal Global Glomerulosclerosis
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400
Disclosures
• NONE • NONE
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401
Cur r ent and Fut ur e
Ther apy of Lupus
Nephr i t i s
GERALD APPEL, MD
Professor of Clinical Medicine
Columbia University –College of
Physicians and Surgeons Physicians and Surgeons
NY-Presbyterian Hospital
New York, New York
Financial Disclosures Financial Disclosures
Dr. Appel has research grants, consultanships
and served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer,
Bristol-Myers Squibb, Takeda, Roche,
Aspreva, Genentech, Amgen, OrthoBiotech
and QuestCor.
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402
Prognostic Features in LN Prognostic Features in LN
Histological Predictors Histological Predictors
•• Histologic Histologic Class IV (diffuse proliferative LN) Class IV (diffuse proliferative LN)
•• High Activity and High Activity and Chronicity Chronicity on Biopsy on Biopsy
Crescents and Interstitial fibrosis Crescents and Interstitial fibrosis •• Crescents and Interstitial fibrosis Crescents and Interstitial fibrosis
•• Segmental necrotizing lesions Segmental necrotizing lesions
Clinical Predictors Clinical Predictors
•• Hypertension Hypertension
•• Anemia Anemia
•• High baseline serum High baseline serum creatinine creatinine
•• Higher baseline Higher baseline proteinuria proteinuria
•• Delay in therapy Delay in therapy
Epidemiologic Predictors Epidemiologic Predictors
•• African American Race African American Race
•• Low socioeconomic status. Low socioeconomic status.
Appel G, Cameron JS in Comprehensive Clinical Nephrology 2007. Comprehensive Clinical Nephrology 2007.
Ancestry and Lupus Nephritis:
Poverty and Ancestry prediction of
progression
( Barr RG, et al. NDT 18:2039- 2046, 2003)
1
2
3
4
5
6
7
RR of
Progressio
n
0
Poverty
unadjusted for
Ancestry
Poverty
Adjusted for
Ancestry
Ancestry
unadjusted for
Poverty
Ancestry
Adjusted for
Poverty
Poverty unadjusted for Ancestry Poverty Adjusted for Ancestry
Ancestry unadjusted for Poverty Ancestry Adjusted for Poverty
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403
Outcomes in African Americans
and Hispanics with LN
• 213 LN patients
• 93 African American 100 Hispanic 20 • 93 African American, 100 Hispanic, 20
Caucasian
• WHO II ( 9%) III(13%) IV ( 52%) V(26%)
• AA had higher BP and Screat , and lower
household income.
• Screat X2, ESRD higher in AA and Hispanic Screat X2, ESRD higher in AA and Hispanic
than Caucasians.
• Both biologic and low income a factor.
Contreras et al KI 69:1846, 2006
Outcomes in African Americans and
Hispanics with LN
Contreras et al KI 69:1846, 2006
Free of doubling Screat, ESRD, death
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404
Long-term Follow-up of Protocol
Completers in WHO Class IV LN
50
Doubling SCr
Dialysis
P
a
t
i
e
n
t
s

(
%
)
40
30
20
10
50% Rise SCr
Doubling SCr
MP + CY
(n = 20)
MP alone
(n = 24*)
CY alone
(n = 21)
*14 of 24 patients received CY after study completion
Illei GG, et al. Ann Intern Med. 2001;135:248-257.
0
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405
Event Cy Therapy
(n =21)
Combination Therapy
(n =20)
n/n n/n
Hypertension 10/20 10/20 yp
Ischemic heart disease 1/19 4/19
Hyperlipidemia 7/20 8/19
Valvular heart disease 9/19 7/21
Avascular necrosis 6/21 6/20
Osteoporosis 4/18 3/19
Premat re menopa se 9/16 10/18 Premature menopause 9/16 10/18
Major infections 7/21 9/20
Herpes zoster infection 6/21 5/20
The Euro-Lupus Nephritis Trial
• Multicenter prospecitive trial of 90 LN pts
with Proliferative LN ( WHO III IV Vc d ) with Proliferative LN ( WHO III,IV,Vc-d )
• High dose IVCYT ( 6 mo IVP + 2 quarterly
pulses ) vs Low dose IV CYT ( IVP q 2
wks x 6 followed by AZA )
• Follow 41 months
Houssiau et al. Arthritis & Rheumatisms 46: 2121-2131,
2002
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406
Euro Lupus Trial Euro Lupus Trial Treatment failure
)
LD
90
100
F
r
e
e

o
f

F
a
i
l
u
r
e

(
%
)
50
60
70
80
HD
HD
0 12 24 36 48 60
Follow-up (months)
50
0
LD
Houssiau Houssiau et al et al., Arthritis Rheum, 2002 ., Arthritis Rheum, 2002
Euro Lupus Trial Euro Lupus Trial - - Remission Remission
0.8
1
s
s
i
o
n
LD
HD
0.2
0.4
0.6
LD
P
r
o
b
a
b
i
l
i
t
y

o
f

r
e
m
i
s
HD
HD
Remission: < 10 RBC/hpf, 24-h proteinuria < 1g, no DSC
0
0 12 24 36 48 60
Follow-up (months)
Houssiau Houssiau et al et al., ., Arthritis Arthritis Rheum Rheum, 2002 , 2002
UCL UCL
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407
Euro Lupus Trial Renal Findings
3 0
3.5
4.0
r
i
a

(
g
)
LD
HD
1.3
1.4
(
m
g
/
d
l
)
HD
LD
0.5
1.0
1.5
2.0
2.5
3.0
2
4
-
h
o
u
r

P
r
o
t
e
i
n
u
r
0.8
0.9
1.0
1.1
1.2
S
e
r
u
m

C
r
e
a
t
i
n
i
n
e

p < 0.005 for « repeated measures » analyses (ANOVA)
p > 0.05 for « between groups » comparisons
0 3 12 6 0 3 6 12
Months Months
0 0
Houssiau Houssiau et al et al., ., Arthritis Arthritis Rheum Rheum, 2002 , 2002 UCL UCL
Euro Lupus Trial Euro Lupus Trial - - Renal Renal flares flares
100 LD
HD
LD
HD
80
60
40
20
F
r
e
e

o
f

r
e
n
a
l
f
l
a
r
e

(
%
)
Houssiau Houssiau et al et al., ., Arthritis Arthritis Rheum Rheum, 2002 , 2002
0 12 24 36 48 60
0
Follow-up (months)
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408
Euro Lupus Trial Euro Lupus Trial - Severe infection
o
n

(
%
)
LD
90
100
r
e
e

o
f

s
e
v
e
r
e

i
n
f
e
c
t
i
o
HD
50
60
70
80
  HD
F
r
0 12 24 36 48 60
Follow-up (months)
50
0
LD
HD
Houssiau et al., Arthritis Rheum, 2002
UCL UCL
ELNT ELNT - - Baseline data Baseline data
Parameter Parameter All All
(n = 90) (n = 90)
HD HD
IV CPM IV CPM
(n = 46) (n = 46)
LD LD
IV CPM IV CPM
(n = 44) (n = 44)
Age (years) Age (years) 31 31 ±± 11 11 30 30 ±± 11 11 33 33 ± ± 12 12
Females/Males (n) Females/Males (n) 84/6 84/6 43/3 43/3 41/3 41/3
Race Race
Caucasians (n) Caucasians (n)
Asians (n) Asians (n)
Afro Afro--Car./Blacks (n) Car./Blacks (n)
76 76
66
88
37 37
44
55
39 39
22
33
Past history Past history
Houssiau Houssiau et al et al., ., Arthritis Arthritis Rheum Rheum, 2002 , 2002
UCL UCL
yy
Past renal disease (n) Past renal disease (n)
Past GC treatment (n) Past GC treatment (n)
Past IS treatment (n) Past IS treatment (n)
21 21
55 55
77
11 11
27 27
44
10 10
28 28
33
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409
ELNT - 10 year FU - ESRD
HoussiauFA et al. Ann Rheum Dis 2009,
ELNT - 10 year FU
HoussiauFA et al. Ann Rheum Dis 2009, J an 20 (Epubaheadof print)
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410
• Euro-Lupus Regimen achieves good
ELNT - 10 year FU - Conclusions
Euro Lupus Regimen achieves good
clinical results in the very long-term
• Death and ESRD rates are low
• mainly Caucasians
• moderately severe LN moderately severe LN
• longterm IS (GC and other IS)
• anti-proteinuric therapy
• referral centers
Efficacy of MMF vs sequential POCY-AZA
in 42 patients with DPLN
76%
81%
Compl ete
remi ssi on
Group 1: MMF
(2 g x 6 mo,
then 1 g x 6 mo)
33%
11%
14%
19%
15%
14%
Infecti on
Rel apse
Parti al
remi ssi on
then 1 g x 6 mo)
+ prednisone
(0.8 mg/kg)
Group 2: POCY
(2.5 mg/kg/d
x 6 mo), then
AZA (1.5-2.0
mg/kg/d) +
prednisone
10%
0%
0 20 40 60 80 100
Death
Chan TM et al. New Engl J Med 2000; 343:1156-62.
Pts (%)
p
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411
Long-Term Study of MMF as Continuous Induction and
Maintenance (n=32) Treatment for DPLN compared to
Sequential POCY-AZA (n=30)
10
13
Chroni c renal
fai l ure
Group 1: MMF
induction
(2 g x 6 mo, 1 g or
1 5 g x 6 mo then
36%
40%
30%
4%
13%
34%
Amenorrhea
Infecti ons
Rel apse
P=0.013
P=0.004
1.5 g x 6 mo, then
1 g x 12 mo or
followed by AZA
(1-1.5 mg/kg/d)
Group 2: POCY
(2.5 mg/kg/d
x 6 mo), then
AZA (1.5-2
/k /d 6
Chan TM et al. JASN 2005; April
7%
0%
0 10 20 30 40 50
Mortal i ty
Patients (%)
mg/kg/d x 6 mo,
then 1-1.5
mg/kg/d). Both
groups received
corticosteroids
Sequential Therapy for Proliferative LN IV Cy
Induction – IV Cy vs. AZA vs. MMF
Maintenance
N = 59 93% F 33 yo 46% AA N 59 93% F 33 yo 46% AA
WHO III = 12 WHO IV = 46 Vb = 1
AI > 8 / 24 CI 1.9 - 3.6
HBP > 95% Active Serology
Neph Synd 64% Palb 2 7 g/dl Up/Ucr > 5 Neph Synd 64% Palb 2.7 g/dl Up/Ucr > 5
Pcreat 1.6 g/dl
U. Miami G. Contreras et al. NEJM 2004
Copyright Harvard Medical School, 2010. All Rights Reserved.
412
t
y
Patient survival
1.00
u
m
u
l
a
t
i
v
e

p
r
o
b
a
b
i
l
i
t
p = 0.11, MMF vs IVCY
p = 0.02, AZA vs IVCY
p = 0.33, MMF vs AZA
0.50
0.75
19 19 15 10 9 4 2 AZA
20 19 12 6 3 2 1 IVCY
20 20 14 11 6 2 2 MMF
Time (months)
C
u
0.00
0.25
0 12 24 36 48 60 72
Free of clinical event (death or CRF)
t
y
1.00
p = 0.049, MMF vs IVCY
p = 0.009, AZA vs IVCY
p = 0.503, MMF vs AZA
u
m
u
l
a
t
i
v
e

p
r
o
b
a
b
i
l
i
t
0.50
0.75
19 19 15 10 9 4 2 AZA
20 19 12 6 3 2 1 IVCY
20 20 14 11 6 2 2 MMF
C
u
Time (months)
0.00
0.25
0 12 24 36 48 60 72
Copyright Harvard Medical School, 2010. All Rights Reserved.
413
Relapse during maintenance phase –
Free of Relapse
p = 0.021, MMF vs IVCY
p = 0.124, AZA vs IVCY
p = 0.222, MMF vs AZA
y
1.00
m
u
l
a
t
i
v
e

p
r
o
b
a
b
i
l
i
t
y
0 25
0.50
0.75
C
u
m
19 15 10 6 4 3 1 AZA
17 10 4 2 2 1 1 IVCY
19 17 12 8 3 2 1 MMF
0.00
0.25
0 12 24 36 48 60 72
Time (months)
Sequential LN Rx: IV CY vs AZA vs
MMF Maintenance Therapy
Side Effects of Therapy
Hospital Days
Per Patient
Year Amenorrhea Infection Major
(%) (%) (%)
IV CY 13 32 68 12
AZA 1* 7* 28* 3
MMF 1* 6* 21* 3 MMF 1 6 21 3
Contreras G, et al. NEJ M 2004
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414
Multicenter Trial of MMF vs IVCyc for
Induction Therapy of Severe LN
MMF (n=71) IVC (n=69)
Ginzler E. … Appel G N Eng J Med Nov. 2005
( ) ( )
Age ( yrs) 32.5 ± 10.0 31.0 ± 9.0
Female 61 (86%) 65 (94%)
Black 43 (61%) 36 (52%)
Duration of SLE, mo. 43.72 ± 66.88 58.70 ± 80.64
Screatinine, mg/dL 1.06 ± 0.52 1.08 ± 0.49
Urine protein g/24 hr 4 06 ± 3 14 4 41 ± 3 51 Urine protein, g/24 hr 4.06 ± 3.14 4.41 ± 3.51
Urine sediment
RBC/hpf
WBC/hpf
24.1 ± 50.3
12.6 ± 23.5
33.2 ± 115.5
10.3 ± 17.3
Salbumin, g/L 2.81 ± 0.95 2.69 ± 0.56
Remission Rates: MMF vs. IVC
Intent to treat analysis
60
P=0.009
22.5
29.6
52.1
4
24.5
30.4
10
20
30
40
50
60
P=NS P=0.005
e
r
c
e
n
t

R
e
s
p
o
n
d
i
n
g
0
Complete Remission Partial Remission Complete +Partial
Remission
MMF IVC
P
e
Ginzler E. … Appel G N Eng J Med Nov. 2005
Copyright Harvard Medical School, 2010. All Rights Reserved.
415
Change in Serum Creatinine and
Urine Protein Excretion
Serum
Creatinine
Urine
Protein
1
2
3
4
5
0.9
1
1.1
1.2
Creatinine
Protein
u
m

C
r
e
a
t
i
n
i
n
e

(
m
g
/
d
L
)
U
r
i
n
e

P
r
o
t
e
i
n

(
m
g
/
d
L
)
0
1
0 4 8 12 16 20 24
Weeks
0.8
0 4 8 12 16 20 24
Weeks
MMF IV CYC
S
e
r
u
NEJM 11/05 Study – Last Outcomes
MMF IVC
• Renal Flare 8 8
• Renal Failure 4 7
• Death 4 8
• All p = NS at Mean follow-up 36 and 37
months
Ginzler E. … Appel G N Eng J Med Nov. 2005
Copyright Harvard Medical School, 2010. All Rights Reserved.
416
Randomized (n = 370)
Open-label treatment
MMF
IVC
ALMS TRIAL – RCT MMF vs IVC in Severe LN
Appel , Contreras, Dooley et al JASN 2009
Allocated to MMF
(n = 185)
Received MMF (n = 184)
Withdrawals (n = 35)
Due to adverse event (n = 24)
Consent withdrawn (n = 6)
Other reason (n = 5)
Allocated to IVC
(n = 185)
Received IVC (n = 180)
Withdrawals (n = 29)
Due to adverse event (n = 13)
Consent withdrawn (n = 5)
Other reason (n = 11)
Maintenance phase
Double-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years
Primary endpoint: responders in randomized population (n = 370)
Responders
ALMS TRIAL Primary Endpoint:
Responders at Month 6
100
Response judged by
blinded Clinical Endpoint
56.2%
53.0%
20
40
60
80
100
p
o
r
t
i
o
n

o
f

p
a
t
i
e
n
t
s

r
e
p
o
n
d
i
n
g

(
%
)
p
Committee:
Decrease in proteinuria
to <3g if baseline
nephrotic (≥3g/d) ,
or by ≥50% in patients ith
subnephrotic (<3g/d)
proteinuria
d
0
20
P
r
o
pr
and
Stabilization of serum
creatinine level (24-week
level ± 25% of baseline),
or improvement
MMF was not superior to IVC
(p = 0.575)
MMF IVC
Appel , Contreras, Dooley et al JASN 2009
Copyright Harvard Medical School, 2010. All Rights Reserved.
417
100
120
140
160

(
μ
m
o
l
/
L
,

S
D
)
IVC
ALMS Trial - Renal Variables
0
20
40
60
80
S
e
r
u
m

c
r
e
a
t
i
n
i
n
e

MMF
7
8
9
g
/
d
a
y
,

S
D
)
Serum creatinine
and urine protein
0
1
2
3
4
5
6
Baseline 4 8 12 16 20 24 Endpoint
Week
2
4

h
o
u
r

u
r
i
n
e

p
r
o
t
e
i
n

(
g
and urine protein
levels improved
in both the MMF
and IVC groups
ALMS - Key Non-Renal Variables
MMF
MMF
IVC
Appel , Contreras, Dooley et al JASN 2009
40
60
80
100
120
a

c
o
n
c
e
n
t
r
a
t
i
o
n

(
U
/
m
L
,

S
D
)
MMF
IVC
20
30
40
50
u
m

a
l
b
u
m
i
n

(
g
/
L
,

S
D
)
IVC
0
20
Baseline Endpoint Baseline Endpoint Baseline Endpoint
Anti-dsDNA Complement C3 Complement C4
M
e
a
n

p
l
a
s
m
a
0
10
Baseline Endpoint
Albumin
S
e
r
u
Copyright Harvard Medical School, 2010. All Rights Reserved.
418
ALMS Trial - Adverse Events (AEs)
Occurring in ≥10% of Patients
MMF (n = 184)
AE n (%)
Diarrhea 52 (28)
IVC (n = 180)
AE n (%)
Nausea 82 (45)
Diarrhea 52 (28)
Headache 38 (20)
Peripheral edema 35 (19)
Arthralgia 29 (15)
Nausea 27 (14)
Hypertension 26 (14)
Nasopharyngitis 25 (13)
Vomiting 25 (13)
( )
Vomiting 68 (37)
Alopecia 64 (35)
Headache 47 (26)
Arthralgia 43 (23)
Leukopenia 38 (21)
Pyrexia 30 (16)
Edema peripheral 30 (16)
o t g 5 ( 3)
Cough 24 (13)
Anemia 23 (12)
Alopecia 20 (10)
Deaths 9(4.9)
Edema, peripheral 30 (16)
Nasopharyngitis 29 (16)
URI 28 (15)
Hypertension 25 (13)
Diarrhea 23 (12)
Deaths 5(3)
ALMS Trial - Summary
• Study did not show that MMF was
superior to IVC
• Overall response rates similar with MMF • Overall response rates similar with MMF
and IVC in all renal and non-renal
parameters
• Adverse Events for MMF and IVC were
broadly similar over 24 weeks, and
consistent with previous reports
• Ongoing maintenance phase compares
MMF with azathioprine for up to 3 years
Appel , Contreras, Dooley et al JASN 2009
Copyright Harvard Medical School, 2010. All Rights Reserved.
419
MMF in LN with Poor Renal Function:
Analysis of the ALMS Data
29 Pts (18 MMF, 11 IVC).
Baseline: MMF vs IVC similar in age proteinuria ( 5 1 Baseline: MMF vs IVC similar in age, proteinuria ( 5.1
and 4.6 g/day ), chronicity on bx, and GFR ( 21 vs
24 ml/min).
No difference in composite outcome of response to
proteinuria and Scr;
GFR increased 20 ml/min more with MMF ;
Proteinuria decreased (0.8g/d) more with MMF.
25% of both groups had treatment limiting adverse 25% of both groups had treatment limiting adverse
events.
Conclusion: No evidence that IVC is more effective
than MMF in pts with severe LN.
Walsh M, Solomons N, Jayne D, for the ALMS group JASN 19: 780A, 2008.
Lupus Nephritis Class V
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420
Lupus Membranous Nephropathy:
I VC vs. MMF
84 –pure Class V LN
in Ginzler Trial +
ALMS Trial
MMF group
N=42
IVC group
N=42
MMF for 24 wks
N=33
IVC for 24wks
N=32
Discontinued
N=9
Discontinued
N=10
CR: N=6
PR: N=17
NR: N=10
N 32
CR: N=2
PR: N=19
NR: N=11
Radhakrishnan J, Moutzouris D, Ginzler G, and Appel G J
Kidney Int. 77:152-160, 2009.
Absolute partial and Complete Remission
Rates
Membranous LN
21
23
25
19
21
6
17
10
15
20
N
u
m
b
e
r

o
f

p
a
t
i
e
n
t
s
IVC
MMF
Radhakrishnan J, Moutzouris D, Ginzler E, and Appel G
Kidney Int 77:152-160, 2009.
2
0
5
CR PR CR+PR
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421
ALMS Maintenance Trial: One of the Largest
Trials Ever Conducted in Lupus Nephritis –
Vancouver 2010
24-wk induction phase 36-mo maintenance phase
MMF
1.5 g BID
Response
or
Remission Yes
Re-
randomization
IVC 0.5–1
g/m
2
Monthly
p 36 mo maintenance phase
MMF
1 g BID
AZA 2
mg/kg/d
*Oral corticosteroids administered in induction and maintenance phases
AZA, azathioprine; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil
No further treatment
(exit study)
No
ALMS Maintenance Trial 2010
Kaplan-Meier Curve
Time to Treatment Failure ITT, N=227
1
e
e
Time to treatment failure MMF Time to treatment failure AZA MMF AZA
0.4
0.6
0.8
1
t
y

o
f

b
e
i
n
g
e
v
e
n
t

f
r
e
p = 0.003
0
0.2
month 3 month 6 month 9 month 12month 15month 18month 21month 24month 27month 30month 33month 36
P
r
o
b
a
b
i
l
i
t
3 6 9 12 15 18 21 24 27 30 33 36
Month
Copyright Harvard Medical School, 2010. All Rights Reserved.
422
ALMS Maintenance Trial
Subjects Achieving Primary and Key
Secondary Endpoints
100
%
)
MMF AZA
40
60
80

w
i
t
h

T
x

F
a
i
l
u
r
e

(
%MMF AZA
1° end-
point
2° endpoints
0
20
Tx failure ESRD Renal
flare
Creat
doubled
Rescue
meds
Broad
definition
P
a
t
i
e
n
t
s

ALMS Maintenance Trial 2010
• MMF was superior to AZA in maintaining
renal response and preventing relapse in
subjects with active LN who responded to subjects with active LN who responded to
induction therapy with either MMF or IVC
• Failure rate was 32% in the AZA group vs
16% in MMF group (p=0.005); completion
rate at 3 years was 63% for MMF vs 49% for
AZA
• Superiority of MMF was consistent regardless
of induction treatment, race or region
• Superiority of MMF was confirmed by
consistent results in key secondary endpoints
Copyright Harvard Medical School, 2010. All Rights Reserved.
423
ALMS Maintenance Trial
• The pattern and frequency of AEs was
consistent with reported previously
for MMF and AZA for MMF and AZA
• Serious AEs, and withdrawals due to
AEs, were more common in the AZA
group
• This trial demonstrated improved
clinical benefit for MMF over AZA as
maintenance therapy for lupus
nephritis
LUNAR – Rituximab Study Design
Rituximab + MMF (n=72)
Treatment Period
Screening
Follow-up Period Placebo + MMF (n=72)
Prednisone taper
Weeks
1 and 2
(Days 1 and 15)
Week
16
Weeks
24 and 26
(Days 168 and 182)
Week
52
Week
78
(Days 1 and 15) (Days 168 and 182)
=Study drug infusion.
=Corticosteroids:
•1000 mg IV methlyprednisolone given at days 1 and then days 2, 3, or 4
•Oral prednisone initiated at 0.75 mg/kg/day after IV steroids and then tapered to
10 mg/day by day 112
Copyright Harvard Medical School, 2010. All Rights Reserved.
424
Patient Disposition
Patients
Randomized 1:1
(N=144)
Placebo
(n=72)
Rituximab
(n=72)
9 Withdrawals Total
5 Lost to Follow-up
3 Patients’ Decision
5 Withdrawals Total
2 Lost to Follow-up
2 Deaths
Completed Week 52
(n=63)
88%
Completed Week 52
(n=67)
93%
1 Physician’s Decision 1 Patient’s Decision
Primary Endpoint:
Renal Response at Week 52
54.1
60
Placebo (N=72) Rituximab (N=72)
30.6
15.3
26.4
30.6
43.0
10
20
30
40
50
P
r
o
p
o
r
t
i
o
n

o
f

P
a
t
i
e
n
t
s
P=0.55* P=0.55*
0
Complete Renal
Response (CRR)
Partial Renal
Response (PRR)
No Response (NR)
Mean MMF dose: Placebo: 2.4±0.62 g; Rituximab: 2.7±0.41 g
Furie R et al ACR 2009
Copyright Harvard Medical School, 2010. All Rights Reserved.
425
Conclusions
•LUNAR is the largest randomized, placebo-controlled
trial to evaluate rituximab in LN
•Although there were more responders with rituximab
(57% vs. 46%), there was no statistically significant
difference in primary or clinical secondary endpoints at
week 52
•Rituximab had a statistically significant effect on levels of Rituximab had a statistically significant effect on levels of
anti-dsDNA and complement at week 52
•Adverse and serious adverse events were similar in
frequency , with no new or unexpected safety signals
Remission rates in the multitarget therapy and IVCY
groups after 6 and 9 months (intention-to-treat )
Bao, H. et al. J Am Soc Nephrol 2008;19:2001-2010
Copyright Harvard Medical School, 2010. All Rights Reserved.
426
Probability of achieving complete remission for
patients treated with multitarget therapy or IVCY
Bao, H. et al. J Am Soc Nephrol 2008;19:2001-2010
The Future
• More use of new drugs ( MMF, Rituximab, co-
stimulatory blockers ) stimulatory blockers ).
• More use of combination therapies for
induction treatment.
• Longer maintenance therapy.
• Development of entirely new drugs (
t l l l bl k f t ki tolerance molecules, blockers of cytokines ,
etc )
• Need for creativity – not one regimen for all.
Copyright Harvard Medical School, 2010. All Rights Reserved.
427
Financial Disclosures
Dr. Appel has research grants, consultanships
and served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer,
Bristol-Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
Copyright Harvard Medical School, 2010. All Rights Reserved.
428
Board Review Questions
Glomerular and
Parenchymal Disease
Brigham Hospital Boston August 2010 Brigham Hospital Boston August 2010
GERALD APPEL, MD
Professor of Clinical Medicine
Columbia University –College of
Physicians and Surgeons
NY-Presbyterian Hospital
New York, New York
Financial Disclosures
Dr. Appel has research grants, consultanships and
served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer, Bristol-
Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
Copyright Harvard Medical School, 2010. All Rights Reserved.
429
Question 1
Which patient is least likely to have
minimal change disease?
1) 65 year old WM with ARF-AKI and 4+
proteinuria
2) 32 year old WF with 2.1 g proteinuria
daily
3) 45 ld BM ith 9 t i i 3) 45 year old BM with 9 g proteinuria
daily
4) 28 year old WM with High BP,
microhematuria and 4+ proteinuria.
Question 1
Which patient is least likely to have
minimal change disease?
1) 65 year old WM with ARF-AKI and 4+
proteinuria
2) 32 year old WF with 2.1 g proteinuria
daily
3) 45 ld BM ith 9 t i i 3) 45 year old BM with 9 g proteinuria
daily
4) 28 year old WM with High BP,
microhematuria and 4+ proteinuria.
Copyright Harvard Medical School, 2010. All Rights Reserved.
430
Minimal Change Disease Minimal Change Disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
431
Adult Minimal Change Disease:
Daily vs Alternate Day Steroids
• 95 Nephrotic adults with MCD
• 80% white, 7% black, 5% Hispanic p
• Age: 45yo, Male: 61%
• SCr: 1.4 mg/dl, SAlb: 2.2 g/dl, UPro: 10 g/d
• Treatment:
– Daily steroids (1 mg/kg/d for 26 wks): 65 pts
– Alternate day steroids (2 mg/kg/qod for 26 wks):
23 pts
Remission: • Remission:
– CR= UPro <0.3 g/d
– PR= >50% reduction in UPro from baseline
• Baseline features similar among the 2 groups
Waldman M… Appel G CJASN 2007
Steroids
Adult MCD:
Daily vs Alternate Day Steroids
Daily QOD p value
N 65 23
Duration (wks) 26 29 NS
Remission 76% 74% NS
CR 64% 77% NS
Relapse 75% 62% NS
Waldman M… Appel G CJASN 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
432
TIME TO REMISSION
100
Adult MCD – Time to Remission
Waldman …Appel CJASN 2007
40
50
60
70
80
90
R
E
M
I
S
S
I
O
N

(
%
)
TIME TO REMISSION (ALL)
TIME TO REMISISION (QD)
TIME TO REMISISON (QOD) p =NS
0
10
20
30
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
TIME (WEEKS)
RELAPSE FREE SURVIVAL
100
Adult MCD – Relapse Free Survival
Waldman …Appel CJASN 2007
70
80
90
R
E
L
A
P
S
E

F
R
E
E

(
%
)
RELAPSE FREE SURVIVAL (ALL)
RELAPSE FREE SURVIVAL (QD)
RELAPSE FREE SURVIVAL (QOD)
p =NS
50
60
1 7 13 19 25
TIME (WEEKS)
Copyright Harvard Medical School, 2010. All Rights Reserved.
433
Question 2
A 38 year old WF has the nephrotic syndrome due to
biospy proven MCD. She has responded to a course py p p
of prednisone with a complete remission but has
relapsed x 3 whenever she discontinues the
prednisone. Which therapy will give the highest
remission rate for treatment at this time?
1) cyclosporine
2) l h h id 2) cyclophosphamide
3) tacrolimus
4) mycophenolate mofetil
5) All above are equivalent
Question 2
A 38 year old WF has the nephrotic syndrome due to
biospy proven MCD. She has responded to a course py p p
of prednisone with a complete remission but has
relapsed x 3 whenever she discontinues the
prednisone. Which therapy will give the highest
remission rate for treatment at this time?
1) cyclosporine
2) l h h id 2) cyclophosphamide
3) tacrolimus
4) mycophenolate mofetil
5) All above are equivalent
Copyright Harvard Medical School, 2010. All Rights Reserved.
434
Steroid-Dependent Adult MCD:
Response to Second Line Agents is Similar
80
10
20
30
40
50
60
70
P
e
r
c
e
n
t

P
t
s
0
10
CyT CyA Tac MMF ALL
CR PR
Waldman, Appel et al, CJ ASN 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
435
Question 3
Which clinical and laboratory features
t b h ti ti t i suggest an obese nephrotic patient is
more likely to have secondaryrather
than primary FSGS.
1) Black race and 9 g proteinuria/day
2) White race and 3 5g proteinuria/day 2) White race and 3.5g proteinuria/day
3) BMI >40 and absence of hematuria
4) BMI > 40 and plasma albumin < 2 g/dl
Question 3
Which clinical and laboratory features
t b h ti ti t i suggest an obese nephrotic patient is
more likely to have secondaryrather
than primary FSGS.
1) Black race and 9 g proteinuria/day
2) White race and 3 5g proteinuria/day 2) White race and 3.5g proteinuria/day
3) BMI >40 and absence of hematuria
4) BMI > 40 and plasma albumin < 2 g/dl
Copyright Harvard Medical School, 2010. All Rights Reserved.
436
Obesity Related Glomerulomegaly and
FSGS
Copyright Harvard Medical School, 2010. All Rights Reserved.
437
Obesity-related Glomerulopathy: An Emerging
Epidemic
• Review >6800 Bxs 1986-2000
• ORG 0.2% (1986-1990) 2.0% (1996-2000)
ORG (71) FSGS (50) ORG (71) FSGS (50)
Age /Race 43 yo /75% W 32 yo/52% W p<.01
NS 5.6% 54% p<.01
Salb 3.9 g/dl 2.9 g/dl p<.001
FSGS 18% 39%
Glomerulomeg 100% 10%
FPE 40% 75%
Double Pcreat 14% 50%
ESRD 3.6% 42%
Kambham, Markowitz, Valeri et al. Kidney Int 59:1498-1509. 2001.
Copyright Harvard Medical School, 2010. All Rights Reserved.
438
Kambham N, Markowitz G, Valeri A, et al. Kidney Int 59:1498-1509, 2001
Question 4
Which genetic defect of FSGS is not
i t d ith t l d i t associated with an autosomal dominant
inheritance?
1) alpha actinen 4
2) Inverted formin 2
3) Podocin 3) Podocin
4) TRPC6 channel
Copyright Harvard Medical School, 2010. All Rights Reserved.
439
Question 4
Which genetic defect of FSGS is not
i t d ith t l d i t associated with an autosomal dominant
inheritance?
1) alpha actinen 4
2) Inverted formin 2
3) Podocin 3) Podocin
4) TRPC6 channel
Copyright Harvard Medical School, 2010. All Rights Reserved.
440
Genetic Podocyte Mutations
• Alpha actinin 4 familial autosomal
d i t FSGS dominant FSGS.
• Podocin ( NPHS2 ) autosomal recessive
steroid resistant nephrotic syndrome
• TRPC6 channel defect – autosomal
dominant FSGS ( Nature Genetics 2005) dominant FSGS ( Nature Genetics 2005)
• Formin INF2 gene – autosomal dominant
(Nature Genetics 42:72, 2010)
Question 5
Which statement is NOT true about the
incidence of FSGS.
1) The incidence of FSGS is increasing in the
US and it is the most common pattern of
idiopathic nephrotic syndrome in Blacks.
2) The incidence of FSGS is increasing in
Caucasians in the US.
3) The incidence of FSGS in most other 3) The incidence of FSGS in most other
countries is as high as the US.
4) FSGS is the most frequent form of
idiopathic nephrotic syndrome to lead to
ESRD.
Copyright Harvard Medical School, 2010. All Rights Reserved.
441
Question 5
Which statement is NOT true about the
incidence of FSGS.
1) The incidence of FSGS is increasing in the
US and it is the most common pattern of
idiopathic nephrotic syndrome in Blacks.
2) The incidence of FSGS is increasing in
Caucasians in the US.
3) The incidence of FSGS in most other 3) The incidence of FSGS in most other
countries is as high as the US.
4) FSGS is the most frequent form of
idiopathic nephrotic syndrome to lead to
ESRD.
Copyright Harvard Medical School, 2010. All Rights Reserved.
442
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443
Nephrotic Syndrome: Main pathologies (%)
Span Italy
1
Dnmark
6
Japan
7
Korea
9
UA Emerits
19
MCD 17.1 12 23.5 37.7 59.4 26.2
FGS 14.1 12.3 8 9 11.1 15.4
MN 22.9 32.9 22.4 23.3 15.9 28.3
IgAN 4.5 2.4 17.5 19.2 3.3 3.2
RIVERA F, LÓPEZ-GÓMEZ JM, PÉREZ-GARCÍA R Kidney Int 66:898; 2004
Primary Glomerulonephritis in China
Type 1979-1999 2000-2008
IgAN 45% 45%
MsPGN 25% 25%
MN 10% 11%
FSGS 6% 9%
MPGN 3% 1% MPGN 3% 1%
CrGn 2% 1%
Lei-Shi LI, Zhi-Hong Liu KI 2004
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444
Trends in the progressive G.N*
1975 - 2005
N= 9256
’75-’79 ’80-’84 ’85-’89 ’90-’94 ’95-’99 ’00-’04 Total
MGN 134 172 171 164 129 143 920
MPGN 90 67 33 46 37 31 304
FSGS 141 164 163 239 311 271 1289
IGA 129 215 227 262 309 356 1498
LUPUS 170 191 143 174 136 100 921
Vasculitis 29 66 76 93 76 68 411
* Toronto GN Registry
FSGS: Incidence in Olmstead MN
• A retrospective study of 195 native renal
biopsies from 1974-2003.
• All adult patients residing in Olmstead
County, MN
• >90% Caucasian Pts.
1974-1983 1984-1993 1994-2003
5.7 % 17.9% 20.2%
Swaminathan S, Leung N, Lager DJ et al Clin JASN 1: 483, 22006.
Copyright Harvard Medical School, 2010. All Rights Reserved.
445
Question 6
Which therapy has been studied in a
t ll d d i d f hi i controlled randomized fashion in
adults with FSGS.
1) Mycophenolate mofetil
2) Cyclopsorine 2) Cyclopsorine
3) Rituximab
4) IV cyclophosphamide
Question 6
Which therapy has been studied in a
t ll d d i d f hi i controlled randomized fashion in
adults with FSGS.
1) Mycophenolate mofetil
2) Cyclopsorine 2) Cyclopsorine
3) Rituximab
4) IV cyclophosphamide
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446
Randomized Trial of Cyclosporine for
Steroid Resistant FSGS
Placebo (23) CyA (26)
Age 40 yo 38 yo • Age 40 yo 38 yo
• %Male 74% 65%
• %W 87% 88%
• BP 134/85 130/87
• Salb(g/dl) 3.0 3.1
• Screat(mg/dl) 1.4 1.3 Screat(mg/dl) 1.4 1.3
• Urine prot (g/d) 8.7 6.9
D.Cattran, G.Appel, …M.Pohl et al - N. Amer. N. Syn Study Group
Kidney Int 56:2220-2226, 1999
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447
Cyclosporin in FSGS: Remission
CSA: 26 pts
Pbo: 23 pts
p <0.001
Pbo: 23 pts
p <0.05
Cattran, Appel, Hebert et al, N Amer Nephrotic Synd Study Group
Kidney Int 56:2220-2226, 1999
Cyclosporine in SR-FSGS
52%
Placebo
p <0.05
25%
p <0 05
CSA
Cattran, Appel, Hebert et al, N Amer Neph Syn Study Group
Kidney Int 56:2220-2226, 1999
p <0.05
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448
Question 7
Which is a common feature of idiopathic
b h th ? membranous nephropathy?
1) Calcium oxalate stones
2) Uric acid stones
3) Renal vein thrombosis
4) Exudative pleural effusions
Question 7
Which is a common feature of idiopathic
b h th ? membranous nephropathy?
1) Calcium oxalate stones
2) Uric acid stones
3) Renal vein thrombosis
4) Exudative pleural effusions
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449
Thrombotic Abnormalities in the
Nephrotic Syndrome
Increased coagulation tendency
( plat. hyperaggregability, high fibrinogen and ( plat. hyperaggregability, high fibrinogen and
fibrinogen-fibrin transfer, decreased
fibrinolysis, low anti-thrombin III )
DVT, RVT, pulmonary emboli
Membranous NS greatest risk (up to 35% ) Membranous NS greatest risk (up to 35% )
Most RVT asymptomatic , but flank pain,
microhematuria, low GFR
Copyright Harvard Medical School, 2010. All Rights Reserved.
450
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451
Question 8
Which features on the biopsy of a patient
with membranous nephropathy y
suggest a secondary form of the
disease rather than primary?
1) Segmental scarring
2) Mesangial deposits 2) Mesangial deposits
3) Global glomeruloslcerosis
4) Subepithelial deposits without
“ spike” formation
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452
Question 8
Which features on the biopsy of a patient
with membranous nephropathy y
suggest a secondary form of the
disease rather than primary?
1) Segmental scarring
2) Mesangial deposits 2) Mesangial deposits
3) Global glomeruloslcerosis
4) Subepithelial deposits without
“ spike” formation
Copyright Harvard Medical School, 2010. All Rights Reserved.
453
Question 9
Recent evidence strongly suggests the
di f th ti i idi thi discovery of the antigen in idiopathic
membranous nephropathy. It is felt to
be which protein?
1) Thrombospondin 2
2) Beta glycoprotein 1 2) Beta glycoprotein 1
3) Beta catenin 4
4) Phospholipase A 2 receptor
Question 9
Recent evidence strongly suggests the
di f th ti i idi thi discovery of the antigen in idiopathic
membranous nephropathy. It is felt to
be which protein?
1) Thrombospondin 2
2) Beta glycoprotein 1 2) Beta glycoprotein 1
3) Beta catenin 4
4) Phospholipase A 2 receptor
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454
Phospholipase A2 Receptor
D. Salant et al NEJM 2009
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455
PLA2R and IgG4 Co-Localize in
Human iMGN
Modified from Beck et al, NEJM 2009
Anti-PLA
2
R: sensitivity and
specificity
Beck et al, ASN 09
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456
Anti-PLA2R antibodies in MN sera
parallels clinical course of disease
16
serum albumin (g/dl) urine protein:creatinine
6
8
10
12
14
16
0
2
4
J an 07 Apr 07 Oct 07 Dec 07 Mar 08 Apr 08
Modified from Beck et al, NEJM 2009
Question 10
Which therapy has NOT proven effective in
producing remissions of the nephrotic producing remissions of the nephrotic
syndrome in a randomized controlled trial
in idiopathic membranous nephropathy?
1) Tacrolimus
2) Alteranting months of corticosteroids and
cyclophosphamide cyclophosphamide
3) ACTH
4) Rituximab
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457
Question 10
Which therapy has NOT proven effective in
producing remissions of the nephrotic producing remissions of the nephrotic
syndrome in a randomized controlled trial
in idiopathic membranous nephropathy?
1) Tacrolimus
2) Alteranting months of corticosteroids and
cyclophosphamide cyclophosphamide
3) ACTH
4) Rituximab
Copyright Harvard Medical School, 2010. All Rights Reserved.
458
Changes in Daily Protein Excretion in 42 Treated
Pts and 39 Controls During 2 Years Follow-up
*
*
* *
P = 0.00001
Control
group
Treatment
group
7
6
5
4
3
2
1
Months
B 6 12 18 24
*P <0.01 vs basal value.
Ponticelli C et al. N Engl J Med. 1989;320:8-13.
Changes in Reciprocals of Creatinine in 30
Treated and 25 Control Pts Followed for >5 Years
*
*
P = 0.0041
Control
group
Treatment
group
0.014
0.013
0.012
0.011
0.010
0.009
0.008
0 007
*
Plasma Creatinine
(μmol/L)
1
*P <0.0002 vs basal value.
Ponticelli C et al. N Engl J Med. 1989;320:8-13.
Months
B 12 24
0.007
0.006
36 48 60
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459
Cumulative Probability of PR or CR, or CR Alone of Neph.
Syn. in Pts w Methylprednisolone plus Chlorambucil (- - -)
or Methylprednisolone plus Cyclophosphamide (–––)
100
Partial or complete remission
20
40
60
80
Complete remission
Percent
0
20
0 6 12 18 24 30 36 42 48 54 60
Months
Ponticelli C et al. J Am Soc Nephrol. 1998;9:444-450.
Cyc l ospor i ne i n Pat i ent s w i t h St er oi d-
r esi st ant Membr anous Nephr opat hy: A
Randomi zed Tr i al .
n=51 RX for 26 wks
Cattran …Appel Kidney I nt. 59:1484-90, 2001.
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460
Tacrolimus Monotherapy in Membranous
Nephropathy: A randomized controlled trial
Praga M, Barrio G, Juarez GF, et al. Kidney Int 71:924-930,2007
Rituximab in Idiopathic Memb. Nephropathy:
Time Course of Proteinuria and S Creatinine.
J Am Soc Nephrol 14:1851-1857, 2003
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461
Rituximab Therapy of Idiopathic
Membranous Nephropathy
Fervenza FC, …Cattran D Kidney Int. 73:117-126 ,2008
Steroids + Cyclophosphamide vs ACTH in
Membranous NS
Ponticelli et al. 2006 AJKD
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462
Controlled Trial in MN – Ponticelli et al. AJKD 2006
32 pts with idiopathic MN ( mean proteinuria 5-7 g/day)
randomized to steroids plus cyclohosphamide (A) vs ACTH (B)
MethylPred + cyclophosphamide ACTH
16000
ACTHAR: 1
st
ten American patients with
iMN treated with ACTH
2000
4000
6000
8000
10000
12000
14000
P
r
o
t
e
i
n
u
r
i
a

(
m
g
/
d
a
y
)
Pre-treatment proteinuria
Last Proteinuria
0
1 2 3 4 5 6 7 8 9 10
Pati ents wi th membranous
nephropathy
Copyright Harvard Medical School, 2010. All Rights Reserved.
463
Question 14
A 22 yo WM with a 2 yr
history of proteinuria and
hematuria has this biopsy. hematuria has this biopsy.
Which is NOT likely to be
found with this lesion?
1) Low C4 level
2) C3Neph
3) Low factor H level
4) Low C3 level
Question 14
A 22 yo WM with a 2 yr
history of proteinuria and
hematuria has this biopsy. hematuria has this biopsy.
Which is NOT likely to be
found with this lesion?
1) Low C4 level
2) C3Neph
3) Low factor H level
4) Low C3 level
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464
MPGN Type II DDD
• Rare disease w deposition of electron dense
material w/i GBM and Bruch’s memb. of eye.
M t 5 15 t d • Most 5-15 yo at dx.
• Within 10 yr 50% ESRD.
• Uncontrolled activation of alternate pathway
of complement cascade.
• Loss of complement regulation by C3
Nephritic Factor, an autoantibody directed
i t C3 t against C3 convertase.
• Some patients mutation of H gene ( plasma
replacement may help ).
• Recurs in most allografts associated with
renal failure.
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465
Concept of pathogenesis of
complement-mediated renal diseases
Endothelial
cells
Glomerular
capillary loop
CFH deficiency/defect
C3NeF
Impaired C Alt Path control
in fluid phase
CFH, IF, MCP
mutations
aHUS
Impaired C Alt Path control
on surfaces
GBM
DDD
GN C3 +MPGN
Servais et al, J Med Genet 2007
Question 15
A 32 year WM ex IV drug abuser presents with edema.
He has a normal BP and physical exam is negative
t f 2/6 t li t th d except for 2/6 systolic murmur at the apex and a non
blanching purpuric rash on his legs.
• He has a serum creatinine of 1.8 mg/dl , U/A with
dysmorphic rbcs and 3.6 g proteinuria daily
• The following tests are negative ANA,ANCA, ASLO,
SPEP. Serum total complement is markedly reduced
with a normal C3 and a low C4 level. with a normal C3 and a low C4 level.
• USG reveal normal sized kidneys with increased
echogenicity.
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466
Question 15
Which diagnosis is most likely?
1) HIVAN
2) MPGN due to HCV
3) Proliferative GN due to SBE
4) AA amyloidosis
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467
Question 15
Which diagnosis is most likely?
1) HIVAN
2) MPGN due to HCV
3) Proliferative GN due to SBE
4) AA amyloidosis
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468
Question 16
27 yo F stock analyst has had 3 spontaneous abortions, and
Raynaud’s phenomenon. 2 years ago she developed a DVT of Raynaud s phenomenon. 2 years ago she developed a DVT of
the calf after a long auto trip. She develops arthralgias, low
temps, and malaise.
Px BP 152/92, P 84, malar flush, 2/6 SEM, swollen MCP and PIP
joints, livedo reticularis of legs and 2+ ankle edema.
Lab: WBC 3.6 K, Hct 24%, plts 89K
U/A 4+ prot, 3+ heme, 8-15 rbc, + rbc casts
BUN 43 mg/dl, Pcreat 2.6 mg/dl, 24 hr UV prot 1.2g/d , PT 14.6,
PTT 85. ANA + 1:160, anti-dsDNA negative, C3 and C4 borderline
low
Question 16
Renal biopsy is most likely to show
hi h f th f ll i ? which of the following ?
1) Diffuse proliferative GN
2) Focal proliferative GN
3) Thrombotic microangiopathy
4) Membranous lupus nephropathy
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469
Question 16
Renal biopsy is most likely to show
hi h f th f ll i ? which of the following ?
1) Diffuse proliferative GN
2) Focal proliferative GN
3) Thrombotic microangiopathy
4) Membranous lupus nephropathy
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470
Antiphospholipid Antibodies
• Family of autoantibodies ( IgG, IgM,IgA ) against
negatively charged phospholipids negatively charged phospholipids
• Lupus Anticoagulant – prolongs lipid dependent
coagulation tests, interferes with phospholipid of
the prothrombin activator complex.
• Anticardiolipin Antibodies- bind to cardiolipin -
the antigen used in VDRL syphilis assay (+VDRL) the antigen used in VDRL syphilis assay (+VDRL)
• APL Antibodies have a procoagulant effect!
The Euro-phospholipid study:
Presenting Manifestation
DVT (32%)
Hemolysis
DVT (32%)
Thrombocytopenia (22%)
Livedo (20%)
Stroke
Superficial thrombophlebitis
Pulmonary embolism
Fetal loss
Hemolysis
Skin ulcers
Seizures
Vasculitic skin lesions
Myocardial infarction
Amaurosis Fugax
Fetal loss
TIA
Renal manifestations 2.2%
g
Digital Gangrene
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471
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472
Question 17
A 75 year old white male presents with a
three week lowgrade fever malaise and a three week low grade fever, malaise and a
petechial skin rash. Bx of the rash shows
leukocytoclastic vasculitis.
His creatinine is 4.8 mg/dl and he has 2.4 g
proteinuria daily with red cells and rbc
casts on U/A MPO ANCA is strongly casts on U/A. MPO ANCA is strongly
positive. Bx shows a crescentic GN.
Question 17
Which statement is true about treatment of this
patient’s disease? p
1) PO cyclophosphamide is superior to IV
cyclophosphamide in inducing remissions.
2) IV rituximab and IV cyclophosphamide are
equally effective at inducing remissions.
3) IV rituximab is superior to IV 3) IV rituximab is superior to IV
cyclophosphamide at inducing a remission.
4) If effectively treated he will have low
morbidity and mortaliy from therapy.
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473
Question 17
Which statement is true about treatment of this
patient’s disease? p
1) PO cyclophosphamide is superior to IV
cyclophosphamide in inducing remissions.
2) IV rituximab and IV cyclophosphamide are
equally effective at inducing remissions.
3) IV rituximab is superior to IV 3) IV rituximab is superior to IV
cyclophosphamide at inducing a remission.
4) If effectively treated he will have low
morbidity and mortaliy from therapy.
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474
RITUXIVAS STUDY
RITUXIVAS STUDY
1
.
0
0
o
n
RTX CYC
0
.
2
5
0
.
5
0
0
.
7
5
P
r
o
p
o
r
t
i
o
n

A
c
h
i
e
v
i
n
g

R
e
m
i
s
s
i
o
Sustained
remission
25/33
(76%)
9/11
(82%)
No
sustained
2
incomplete
1
incomplete
0
.
0
0
P
0 100 200 300 400
Time (days)
Cyclophosphamide Rituximab
remission
p
response
p
response
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475
Survival in Renal Vasculitis
Trial GFR (ml/min) Age(yrs) Mortality
CYCAZAREM NEJM, 2003 49 58 5%
CYCLOPS ASN, 2006 38 57 9.5%
RITUXVAS NEJM2010 17 68 18%
MEPEX JASN, 2007 <10 66 25%
Question 18
A 4 yo WF goes to a petting zoo with her parents .
She cuddles the sheep, calves, and other baby
animals She does not wash her hands immediately animals. She does not wash her hands immediately
afterwards.
• 3 d later she develops abdominal cramps, diarrhea,
and bloody stools. N/V, fever. She is given
antibiotics by her pediatrician.
• Day 6 later there are echymoses of extremities and
lips, thrombocytopenia, oliguria, and seizures. p , y p , g ,
• Stool is + for E.coli O157:H7.
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476
Question 18
Which therapy has proven effective for this
di ? disease?
1) IV quinolone antibiotics
2) Plasma exchange therapy
3) Synsorb –shiga toxin binding agent
4) None of the above
Question 18
Which therapy has proven effective for this
di ? disease?
1) IV quinolone antibiotics
2) Plasma exchange therapy
3) Synsorb –shiga toxin binding agent
4) None of the above
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477
DANGER! Petting Zoo!
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478
Glomerulus with thrombus
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479
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480
Therapy of STx-HUS D+
?Antibiotics – Yes if sepsis, Yes w Shigella dysenteria ?Antibiotics Yes if sepsis, Yes w Shigella dysenteria
Type I disease, others No
Supportive care – Dialysis, ACE –ARBs , BP Control
Lack of efficacy
Heparin, fibrinolytic agents, platelet txs, PTE –
plasma infusion, IVIG, antioxidants, Steroids, anti-plt
agents, vincristine, splnx.
SYNSORB Pk ( STx binding agent ) failed in acute
trials.
Transplant effective and safe.
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481
Question 19
A 36 year old previously healthy AA female develops
fever and bruising . She goes to her LMD and CBC
shows plats 15 K, Hct 28%, normal PT and PTT.
Smear microangiopathic hemolytic anemia. Over Smear microangiopathic hemolytic anemia. Over
next few days her urine output declines and she
develops sudden blindness followed by decreased
mental status.
What should be done next for this patient?
1) Send for an assay for the metalloprotease
ADAMTS 13.
2) Institute immediate plasma exchange and
corticosteroid therapy.
3) Institute immediate heparin and start coumadin
anticoagulation.
4) Start rituximab and corticosteroids.
Question 19
A 36 year old previously healthy AA female develops
fever and bruising . She goes to her LMD and CBC
shows plats 15 K, Hct 28%, normal PT and PTT.
Smear microangiopathic hemolytic anemia. Over Smear microangiopathic hemolytic anemia. Over
next few days her urine output declines and she
develops sudden blindness followed by decreased
mental status.
What should be done next for this patient?
1) Send for an assay for the metalloprotease
ADAMTS 13.
2) Institute immediate plasma exchange and
corticosteroid therapy.
3) Institute immediate heparin and start coumadin
anticoagulation.
4) Start rituximab and corticosteroids.
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482
Question 20
• A 62 yo W M plumber with mild HBP is
l t df t i i d d evaluated for proteinuria and edema.
• Px BP 142/84, Cor S1S2 S4 G, Chest clr,
Abd no LKKS, ext 2-3+ pedal edema
• Lab. BUN 32, Pcreat 1.2, U/A 4+ prot, 24
hr UV prot 4 2 g/d hr UV prot 4.2 g/d,
• ANA , complement , Hep B-C, neg
• Spep 1.8 g IgG kappa, Palb 2.8 g/dl
Copyright Harvard Medical School, 2010. All Rights Reserved.
483
Question 20
His Biopsy might show all EXCEPT which
of the Following?
1
22
3
4
3
4
Question 20
His Biopsy might show all EXCEPT which
of the Following?
1
22
3
4
3
4
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484
Financial Disclosures
Dr. Appel has research grants, consultanships and
served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer, Bristol-
Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
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485
The Challenging
Biopsy – Boston
August 2010 August 2010
Jerry Appel, MD FASN
Helmut Rennke MD FACP
Financial Disclosures
Dr. Appel has research grants, consultanships
and served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer,
Bristol-Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
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486
CASE 1
• An 82 yo WM presents with ARF.
P ti t h h f HBP 8 • Patient has a hx of HBP x 8 yrs, once
told high BS – diet only, gout, s/p small
MI 4 yrs ago. Meds: Toprol XL,
lisinopril, allopurinol.
• 4 mo PTA BUN 28 mg/dl Pcreat 1.4
/dl O 2 3 t d mg/dl. Over 2-3 mo noted some
increase in “ normal” mild ankle
swelling.
CASE 1
• 3 wks PTA developed >15 # weight gain and
progressive edema of feet ankles and legs progressive edema of feet, ankles, and legs.
• 2-3 days PTA developed Nausea/vomiting
and abdominal cramps. To cardiologist who
ordered labs. BUN 115 mg/dl Pcreat. 7.4
mg/dl.
• 24 hr urine protein 18 g/day • 24 hr urine protein 18 g/day.
• U/A 4+ prot. 5-10 rbc, 0-5 wbc, 0 casts.
• ANA , CH50, HBV-HCV neg.
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487
Case 1
1) What other serologic tests should be
d h ? done here?
2) Should renal Biopsy be done now?
vs Wait and follow Pcreatinine?
3) Is there data on biopsies in pts > 80
years old? years old?
4) What is likely Dx?
Kidney Biopsy
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488
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489
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490
Renal biopsy in patients aged >80 yo
•Nephropathology Associates, Little Rock, AR
•Files examined from 2001- 2003 to identify biopsies in
>80
•100 patients out of 3,227 native biopsies (3.1%)
•Comparisons made with group aged 65 79 years
Nair et al AJ KD 2004 44;4: 618-626
•Comparisons made with group aged 65-79 years
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491
Presentation by renal syndromes
40
45
0
15
20
25
30
35
%

o
f

p
a
t
i
e
n
t
s
>80 years
65-79 years
Nair et al AJ KD 2004 44;4: 618-626
0
5
10
NS Nephr RPGN Prot/Hem ARF CRF
Idiopathic nephrotic syndrome
45
50
15
20
25
30
35
40
%

o
f

p
a
t
i
e
n
t
s
> 80 years
65 - 79 years
Nair et al AJ KD 2004 44;4: 618-626
0
5
10
MCD FSGS MN
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492
Most common diagnoses
18
20
> 80 years65 - 79 ye
4
6
8
10
12
14
16
%

o
f

p
a
t
i
e
n
t
s
0
2
Crescentic GNFSGS MCD IgA Amyloid MN MPGN SLE
Nair et al AJ KD 2004 44;4: 618-626
Renal biopsy in patients > 80 years
•Renal Pathology Registry at Laboratory at
Columbia University Medical Center NY Columbia University Medical Center, NY
•Files examined from 2005 - 2008 to identify
biopsies in patients aged >80 years old
•235 patients identified - the largest series for
Moutsakis D-A, Herlitz L, Appel GB, et al.. Renal Biopsy in the
Very Elderly. Clinical J Amer Soc Nephrol. 4: 1073-1082, 2009.
patients >80
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493
Clinical Presentation
46.4
45
50
23.8
13.2
9.4
5.5
5
10
15
20
25
30
35
40
%

o
f

p
a
t
i
e
n
t
s
0.4 1.3
0
5
AKI CRF NS AKI
and
NS
Prot Prot
and
Hem
Hem
…Moutsakis D-A, Herlitz L, Appel GB, et al.. Renal Biopsy in the Very
Elderly. Clinical J Amer Soc Nephrol. 4: 1073-1082, 2009.
Nephrotic Syndrome in >80
20
25
5
10
15
20
%

o
f

p
a
t
i
e
n
t
s
0
MN Amyloid MCD IgA DM MPGN pi - GN
……Moutsakis Moutsakis D D--A, A, Herlitz Herlitz L, L, Appel Appel GB, et al.. Renal Biopsy in the Very GB, et al.. Renal Biopsy in the Very
Elderly. Clinical J Elderly. Clinical J Amer Amer Soc Soc Nephrol Nephrol. 4: 1073 . 4: 1073- -1082, 2009. 1082, 2009.
Copyright Harvard Medical School, 2010. All Rights Reserved.
494
Clinical Presentation per diagnosis
120
ARF CRF NS ARF/NSProt Prot&He
20
40
60
80
100
%

o
f

p
a
t
i
e
n
t
s
0
pauci GN2o FSGS
HTN
HTN NS IgA MN Amyl MCD Myel Cast
……Moutsakis Moutsakis D D--A, A, Herlitz Herlitz L, L, Appel Appel GB, et al.. Renal Biopsy in the Very GB, et al.. Renal Biopsy in the Very
Elderly. Clinical J Elderly. Clinical J Amer Amer Soc Soc Nephrol Nephrol. 4: 1073 . 4: 1073- -1082, 2009. 1082, 2009.
Primary Diagnosis # of Cases % of Cases
Most Common Renal Biopsy Diagnoses in 259 Adults >60 Years
Old Presenting with Acute Renal Insufficiency
AJKD 35: 433-447, 2000
Primary Diagnosis # of Cases % of Cases
Pauci-immune crescentic GN 79 31
Acute interstitial nephritis 47 19
ATN + nephrotic syndrome 19* 8
Atheroemboli 18 7
ATN 17 7
Light chain cast nephropathy 15 6 Light chain cast nephropathy 15 6
Post-infectious GN 14 6
Anti-GBM nephritis 10 4
*15 of 19 patients had minimal change disease, 3 FSGS, 1
membranous
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495
Etiologies of ARF with MCD
• Ischemic tubular injury
• Interstitial edema
• Volume depletion secondary diuretics
• Reduced intraglomerular pressure w/
ACEi/ARB’s
• NSAID’s
Serum Creatinine
<1.5 mg/dl >2.0 mg/dl
Number of patients 50 21
Adult minimal change glomerulopathy with
acute renal failure
Number of patients 50 21
Serum creatinine 1.0 + 0.2 5.5 + 3.3*
Age 40 + 16 60 + 16*
Systolic BP 138 + 27 158 + 24*
Diastolic BP 85 + 13 89 + 7
Serum albumin (g/dl) 2.7 + 1.0 2.1 + 0.8** Serum albumin (g/dl) 2.7 + 1.0 2.1 + 0.8
Proteinuria (g/24h) 7.9 + 5.6 13.5 + 9.4*
Arteriosclerosis (0-4 scale) 0.7 + 0.9 1.7 + 1.4*
**p <0.01 **p <0.05
Falk RJ, Jennette JC. Adult minimal change glomerulopathy with acute renal failure. Am J Kidney Dis 16: 432-
437, 1990
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496
Features,Treatment, and Outcome of
Adult MCD
• 95 Bx MCD at CUMC from 1990-2005
• 61%F 45yo 81%W • 61%F 45yo 81%W
• GFR 72 cc/min Pcreat 1.4 mg/dl Palb 2.2 g/dl
24hProt 9.93 g/d hematuria 20% HBP 43%
• ARF 17% (eventual 24%)
• 88 Rx stds 65 Daily v 23 QOD 76v74% response
• No Dfference QD vsQOD or in time to response ( 11 v No Dfference QD vsQOD or in time to response ( 11 v
16 wks ) or percent relapse ( 75 v 63% )
• Of responders 60% relapse , most respond again
• 54% Rx w cyA, cytoxan, MMF, or Tacrolimus
• Waldman M…Appel GB Clin JASN 2:445-454 2007
Case 2
• 54yo WF w DM x15 yrs and Nephrotic Syndrome.
• DM x 15 yrs, HBP x15yrs, obesity, GERD y y y
• 1 yr ago 2-3+proteinuria on dipstick; Pcreat 0.8 mg/dl
• Over 4 months increasing edema, Pcreat. Increased
from 1.0 to 1.9 mg/dl and proteinuria increased from
0.8 g/day to 20 g/day.
• Saw opthalmologist 1 month ago no clear -
retinopathy.
• Meds: ramipril 10 mg, furosemide 40mg, glyburide 5 Meds: ramipril 10 mg, furosemide 40mg, glyburide 5
mg/d
• Px BP 140/92, P64, Wt 232# Ht 5’5”
• HENT, Cor, Chest, Abd all neg. Ext 2+pedal and
pretibial edema
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497
Case 2
Laboratory:
BUN 28 /dl PC t 1 9 /dl • BUN 28 mg/dl, PCreat. 1.9 mg/dl
• U/A 4+ prot. 2+heme 5-10 rbc 0-4 wbc 0
casts
• BS 132 mg/dl HgA1C 6.5
• Palb 3.2 g/dl Pcholesterol 235 mg/dl Palb 3.2 g/dl Pcholesterol 235 mg/dl
• USG 12-13 cm non-echogenic kidneys
• ANA, serum complement, Spep-Upep,
ANCA, all negative or wnl
Case 2
• Is this most likely to be isolated DM
h th ? Wh h t? nephropathy? Why or why not?
• What physical exam finding might help
you?
• If there is another dx what is it likely to be?
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498
Kidney Biopsy
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499
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500
Bx 168 TypeII DM w R.Disease
All documented DM.
All some indication for BX.
Eye fundoscopy of NO Predictive Value
Predictors another disease w or w/o DM
changes.
1) ARF
2) Very active urine sediment
3) Sudden onset nephrotic proteinuria
Bx findings in DM with other RD
DN/NDRDn=32, NDRDn=43 /168 DN/NDRD n 32, NDRD n 43 /168
Glomerular Diseases
Fsgs (14 ), MN ( 6 ), IgA ( 3), HSP ( 3 ),
MPGN ( 4 ), other (5 )
T b l i t titi l di ( 28) ( AIN 10 ) Tubulointerstitial dis ( n=28) ( AIN = 10 )
Vascular disease ( n = 15 )
Atheroemboli ( n = 8 )
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501
Case 3
48 yo WF interior designer w asymptomatic proteinuria
• Pt in excellent health w no significant med Hx; Fam Pt in excellent health w no significant med Hx; Fam
Hx neg.; denies drug use or meds.
• Routine exec. Px. Wnl BP 132/84 mm Hg
Noted proteinuria and refer for eval.
• Lab: CBC wnl, CXry and EKG wnl, BUN 18 mg/dl,
Pcreat 1.0 mg/dl, U/A 4+ prot 3-5 rbc, 0 wbc 0 casts
24 hr UV prot. 1.8 g/d, Palb 3.9 g/dl, Pcholest 204 24 hr UV prot. 1.8 g/d, Palb 3.9 g/dl, Pcholest 204
mg/dl
ANA, CH50, HBSAg-Ab, HCV neg.
CASE 3
1) Should pt receive an ACEinhib.-ARB to
reduce proteinuria? reduce proteinuria?
2) Should Bx be done now or after ACEi-ARB?
3) If proteinuria decreases to < 1g/ day w ACEi
– ARB should Bx be done?
4) Should other lab.-serologic tests be done
i t B ? Whi h ? prior to Bx? Which ones?
5) What are likely dxs for asympt. proteinuria
of 1.8 g/day in 48 yo WF
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502
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503
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504
Boston University Eight-Year Experience
Amyloid SCT
701 patients evaluated
309 underwent HDM/SCT
Median Survival 4.6 years
L. Dember. Bone Marrow Transplantation for the Treatment of Primary Amyloidosis.
Clinical Nephrology Conference: New Therapies for Old Diseases. ASN 2006
Overall Survival According to
Randomization Arm (intent to treat)
80
100
%
)
OS = 56 months
M D
0
20
40
60
80
O
v
e
r
a
l
l
S
u
r
v
i
v
a
l
(
%
OS = 56 months
OS = 22 months
M -Dex
ASCT
20
deaths
31
deaths
p <0.05
Median survival of entire cohort : 48.5 months
Median follow-up for living patients : 3 years
0
0 10 20 30 40 50 60 70 80
Months
P Ronco. Free Communications: Non-Traditional Variables and Outcomes, ASN 2006. SA-FC141
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505
Conclusions
• This first randomized trial shows a survival
advantage of M-Dex-based oral regimen over
HDM ith ASCT i th t t t f t i AL HDM with ASCT in the treatment of systemic AL
amyloidosis
• HDM with ASCT is associated with shorter
survival in patients with kidney involvement
• These results confirm the efficacy and tolerance
of M-Dex in Al amyloidosis
Th l d t d M D i fi t li d • They lead to recommend M-Dex in first line and
to propose ASCT only for refractory patients
P Ronco et al. ASN 2006
Case 4
• A 23 yo WF student presents with ARF.
• Past hx neg, No meds, Neg Fam Hx.
• 6 mo PTA pain in right eye and blurry
vision. Opth Dx uveitis. Steroid drops with
resolution.
• Vague joint aches, no arthritis, no rash ,
no Fever/chills no visual sx took several no Fever/chills, no visual sx, took several
doses of motrin. No other meds.
• Check up by LMD BP 122/74 mHg Afeb,
nl HENT, Cor, Chest, Abd, no edema.
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506
Case 4
• U/A tr prot 2+heme 4-10 rbc 6-10 wbc • U/A tr prot 2+heme 4-10 rbc 6-10 wbc
• BUN 38 Pcreat 2.3 mg/dl
• Urine culture no Growth
• USG large echogenic kidneys
• WBC 6.8K 3% eos , Hct 34%, plts 325K
• Palb 3.6 g/dl, ESR 43, ANA – neg, CH50 nl,
HBV neg, HCV neg, HIV neg, Chest Xray-.
• BX peformed
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507
TINU Syndrome
• Over 150 cases
• Pathogenesis unclear – T cell proliferation – cell
mediated immunity defect mediated immunity defect.
• Most young Females, median age 15, 3:1 F:M,
no genetic or familial tendency,
• Uveitis ( typical bilateral ) + Interstitial Nephritis ( up
to months before or months after uveitis )
• +/- fever, wt loss, fatigue, malaise, anorexia,
arthralgias, myalgias, H/A.
Renal findings: sterile pyuria flank pain hematuria • Renal findings: sterile pyuria, flank pain, hematuria,
renal insufficiency, and ARF.
• Lab: nonspecific, some eosinophilia, high ESR,
• Therapy: spontaneous resolution, steroids.
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508
Sarcoid and the Kidney
• Hypercalcemia yp
• Hypercalciuria
• Nephrolithiasis
• Interstial Infiltrates with granulomas
• Glomerular Lesions ( may be coincidental) Glomerular Lesions ( may be coincidental)
Sarcoid and the Kidney
• Renal histologic prevalence very variable g p y
– post mortem 20% , Bx series 35-50%.
• Clinical disease clearly less than histologic
disease
• Hypercalcemia common, hypercalciuira
2.5-20%some stones, nephrocalcinosis 2.5 20% some stones, nephrocalcinosis
and renal insuffic/
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509
Sjogren’s Syndrome and the Kidney
• Sjogren’s assoc w a lymphocytic and plasmacytic
infiltrate in salivary, parotid, and lacrimal glands.
• Same proces in kidney causes interstitial nephritis and p y p
tubular defects.
• Renal involvement very variable ( 2-67%)
• Acute interstitial infiltrates, tubular damage and with
chronicity interstitial fibrosis. Glomerular lesions are rare.
• Benign U/A, mild proteinuria, occas Fanconi’s-Type I
distal RTA, Nephrogenic DI.
• Usually responds to corticosteroids.
• Pertovaara M. et al Clin Neph 56:10, 2001
• Bessini N. et al NDT 16:2328, 2001
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510
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511
Case 5
A 20 y.o. BM college student presents with a
3-4 week hx of progressive ankle and leg
edema and an 18 # wt gain.
On Px BP 120/74 mm HG. Weight 274# Ht
5’6’’ Cor chest abd WNL ext 2 3+ pedal and 5 6 Cor-chest-abd WNL, ext 2-3+ pedal and
pretibial edema.
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512
Case 5
Laboratory evaluation:
CBC normal
BUN 18 mg/dl, Pcreatinine 1.0 mg/dl,
Palbumin 2.1 g/dl, Cholesterol 284 mg/dl
U/A 4+ protein, 0 rbc, 0-2 wbc, 0 casts
24 hour proteinuria 16.2 g/Day
ANA complement Hep B and C serology HIV ANA, complement, Hep B and C serology, HIV,
all negative or WNL.
USG large echogenic kidneys.
Case 5
• What is the Bx most likely to show
(MCD, FSGS, MN, IgA Nephropathy ?)
• What Dx if patient were Caucasian ?
• What Dx if Asian Descent?
• What if patient weighed 154 #?
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513
Obesity-related Glomerulopathy: An Emerging
Epidemic
• Review >6800 Bxs 1986-2000
• ORG 0.2% (1986-1990) 2.0% (1996-2000)
ORG (71) FSGS (50)
Age /Race 43 yo /75% W 32 yo/52% W p<.01
NS 5.6% 54% p<.01
Salb 3.9 g/dl 2.9 g/dl p<.001
FSGS 18% 39%
Glomerulomeg 100% 10% Glomerulomeg 100% 10%
FPE 40% 75%
Double Pcreat 14% 50%
ESRD 3.6% 42%
Kambham, Markowitz, Valeri et al. Kidney Int 59:1498-1509. 2001.
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514
Kambham N, Markowitz G, Valeri A, et al. Kidney Int 59:1498-1509, 2001
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515
26
25
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516
Focal cystic dilation of tubules and prominent
tubulointerstitial inflammation are frequent in
collapsing FSGS
Course Patient 5
• Could not use cyclosporine – away at
h l school
• Prednisone 120 QOD x 2 months then
taper over 6 months
• Returned in complete remission
Follow x 4 yrs U/A 0 tr protein normal • Follow x 4 yrs U/A 0-tr protein, normal
BUN/creatinine
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517
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518
Injured podocytes may take
different pathways
Podocyte injury
FSGS CG
Proliferation
Cell hypertrophy
Cell death/Detachment
De-differentiation
Collapse
Sclerosis
Collapsing FSGS –
Laurenivicius…Rennke Kidney Int 1999
Collapsing FSGS –
Laurenivicius…Rennke Kidney Int 1999
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519
Collapsing Glomerulopathy:
Clinicopathological Findings
• 74 cases in 10 years period (1995-2005)
• mean age 42 years 41 M(56%) 33 F (44%) • mean age 42 years. 41 M (56%) 33 F (44%).
• 18/74 AA (24.4%)
• Clinical associations: 39 idiopathic
10 viral infection
8 autoimmune disease
9 post-transplant
4 pamidronate
4 b 4 obese
• Conclusion: diverse group of disorders are associated with collapsing
glomerulopathy, most have in common an altered immune status.
ASN 2005 Sandra M. Soares, Sanjeev Sethi - Mayo Clinic, Rochester, MN.
Copyright Harvard Medical School, 2010. All Rights Reserved.
520
Renal Survival Curve: Collapsing vs Control FSGS
(Valeri…D’Agati, Kidney Int 50: 1734, 1996)
Renal Survival Curve: Collapsing vs Control FSGS
(Valeri…D’Agati, Kidney Int 50: 1734, 1996)
100
90
80
e
n
a
l

S
u
r
v
i
v
a
l

(
%
)
Control FSGS
P < 0.001
Collapsing FSGS
80
70
60
50
40
30
Time (months)
R
e
p g
20
10
0
0 12 24 36 48 60 72
Glomerular Disease Collaborative Netwok
Outcomes of FSGS Variants:
UNC Chapel Hill
20
30
40
50
60
70
80
P
e
r
c
e
n
t
Remission
ESRD at 3 years
0
10
A
l
l
F
S
G
S
C
o
l
la
p
s
i
n
g
T
i
p

L
e
s
i
o
n
P
e
r
i
h
i
l
a
r
N
O
S
Kidney International (2006) 69, 920-926
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521
Outcomes of FSGS Variants:
Columbia University
80
REMI SSI ON ESRD
20
30
40
50
60
70
80
0
10
ALL FSGS CELL COLL TI P
LESI ON
NOS
Kidney International (2006) 70, 1783–1792.
Financial Disclosures
Dr. Appel has research grants, consultanships
and served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer,
Bristol-Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
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522
David J. Salant
Boston University Medical Center
Approach to the Diagnosis
and Management of Rapidly
Progressive
Glomerulonephritis
Disclosures:
Consulting:
• Questcor
• Taligen
Grant support:
• Questcor
Patent pending:
• Diagnostics for Membranous Nephropathy
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523
Rapidly Progressive
Glomerulonephritis
(RPGN)
• Rapidly progressi ve renal failure
• Hematuria ± rbc casts; RBC dysmorphi a
• Oliguria - variable
• Hypertensi on - unusual
• Proteinuria - variable
Immunofluorescence in RPGN
l i near IgG on GBM pauci-i mmune
granul ar IgG on capi l l ary wal l
granul ar IgA i n mesangi um
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524
Renal Biopsy
Necrotizing and/or Crescentic GN
Linear GBM deposits
11%
(anti-GBM antibody disease)
Granular immune deposits
8%
(immune complex disease)
No immune deposits
81%
(ANCA-associated disease)
With pulmonary hemorrhage
•Goodpasture syndrome
Renal limited
•Anti-GBM GN
Systemic symptoms
•SLE
•HSP
•Postinfectious
•Cryoglobulinemia
Renal limited
•IgA nephropathy
•MPGN
Systemic symptoms
•Wegener granulomatosis
•Microscopic PAN
•Churg-Strauss syndrome
Renal limited
•Pauci-immune GN
Percentages from Jennette, 1993; n = 65
A 25 year old man presents to the ER with cough and
minor hemoptysis, microscopic hematuria and Screat - 1.3 mg/dL. A
“viral syndrome” is diagnosed and he is sent home.
Two weeks later he represents with more severe hemoptysis, oliguria
and Screat - 6.8 mg/dL.
Treatment: Pulse methylprednisolone; ventilation; cyclophosphamide;
plasmapheresis
Chest Xray:
Renal biopsy:
Case 1
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525
IgG IgG
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526
Which of the following serological tests is most
likely to be positive?
A. Anti-proteinase 3
B. Low C3 and C4
C. Anti-dsDNA
D. Anti-GBM
What is the target antigen?
The NC1 domain of the 3 (and
5) chains of type IV collagen
Pedchenko et al. NEJM July 22, 2010
Salant NEJM July, 22, 2010
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527
















GBM
Mesangium
NC1
Goodpasture epi tope
Chromosome 13
Chromosome 2
Chromosome X
Location of the Goodpasture Antigen
Type IV col l agen
His pulmonary symptoms resolve within 72 hours but he
remains oliguric and dialysis dependent after 10 days.
Which of the following treatment options should you
pursue?
A. Discontinue plasmapheresis and taper off
immunosuppressives
B. Continue plasmapheresis and immunosuppressives
C. Add IVIG
D. Add rituximab
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528
Anti-GBM Antibody Disease
Risk factors for pulmonary hemorrhage
(Goodpasture syndrome):
• Young males
• Smoking, volatile solvents, viral respiratory infection
Recurrence of Anti-GBM Nephritis after
Renal Transplantation
•Nephritis is likely to recur if there is circulating antibody at
the time of transplantation
•Delay transplantation until anti-GBM is undetectable by
ELISA for anti-GBM
•A weakly positive western blot is not a contraindication to
transplantation if the ELISA is negative.
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529
Case 2
A 35-year old man presents with crampy
abdominal pain, painful joints, swollen ankles and
a rash on his legs.
BP is 150/90, the abdomen is diffusely tender and
stool occult blood test is positive.
Urinalysis - 3+blood, 3+albumin, numerous
dysmorphic RBCs and occasional RBC casts
Se Cr 2.2 mg/dL, Urine prot/Cr 3.3, C3 and C4
normal, serology pending
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530
Which of the following is the
most likely diagnosis?
A. Polyarteritis nodosa
B. Microscopic polyangiitis
C. Mixed cryoglobulinemia
D. Henoch Schonlein purpura
IgA IgA
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531
Case 3:
A 25-year old woman presents with malaise and pleuriticchest pain of
one week’s duration. Her BP is 145/100 and she has 2+bilateral leg
edema. There is no rash or arthritis. Urinalysis shows 3+protein and 3+
blood and there are numerous red cells, 5-10 leukocytes and occasional
red cell casts on microscopy.
Serum creatinineis newly elevated at 2.3 mg/dL and serum albumin is
3.3 g/dL. Hb 11.5, wbc 3,300, platelets 120,000. Serological tests for
ANA, ANCA and anti-GBM are pending but serum complement levels
return with C3 60 mg/dL and C4 10 mg/dL (both low).
Urine protein:Cr 4.5
A renal biopsy is obtained.
Case 3:
A 25-year old woman presents with malaise and pleuriticchest pain of
one week’s duration. Her BP is 145/100 and she has 2+bilateral leg
edema. There is no rash or arthritis. Urinalysis shows 3+protein and 3+
blood and there are numerous red cells, 5-10 leukocytes and occasional
red cell casts on microscopy.
•Serum creatinineis newly elevated at 2.3 mg/dL
•Serum albumin is 3.3 g/dL
•Hb11.5, wbc 3,300, platelets 120,000
•Serological tests for ANA, ANCA and anti-GBM are pending
•Serum complement - C3 60 mg/dL and C4 10 mg/dL (both low)
•Urine protein:Cr 4.5
A renal biopsy is obtained.
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532
Which of the following immunofluorescent patterns would
you expect in this case?
IgG
IgA
IgG
IgG
A
B
C
D
C3 C4
Poststrep GN low normal
Other postinfectious (e.g. endocarditis) low low
SLE nephritis III/IV low low
MPGN 1 (Hepatitis C-associated) low v. low
Dense deposit disease low normal
Mixed cryoglobulinemia low v. low
IgAN/HSP normal normal
Anti-GBM normal normal
ANCA-associated (pauci-immune) GN normal normal
Serum complement levels in RPGN
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533
Disease Pulmonary
disease
Cutaneous
vasculitis
Goodpasture syndrome present absent
Wegener’s granulomatosis present present
Microscopic polyangiitis present present
Churg-Strauss allergic
granulomatosis
present present
Mixed cryoglobulinemia rare present
Henoch-Schönlein purpura rare present
Systemic lupus
erythematosus
rare unusual
Case 4
• A 56-year old man presented with 6-week history
cough productive of small amounts of bloody
sputum.
• Apart from fatigue he had no other complaints.
• Physical exam - BP 125/80; afebrile; O
2
sat 93%
RA; no edema, rash or joint abnormalities
• Urinalysis - 1+albumin, microscopic hematuria
with RBC casts
• Serum Cr 2.5 mg/dL; Hb 11.1 g/dL
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534
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535
IgG
Which of the following serological
tests is most likely to be positive in
this case?
A. Anti-myeloperoxidase
B. Anti-GBM
C. RPR
D. Anti-proteinase 3
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536
pANCA Control
ANCA
Desi gnation: c-ANCA p-ANCA
Staining
pattern:
diffuse
cytoplasmic

perinuclear
Antigen: proteinase 3
(29 kD PMN
serine
proteinase)

myeloperoxidase;
other
Disease
association
WG > MPA MPA > WG

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537
Clinical presentation of
patient
Prevalence of
PI-CGN
PPV for
PI-CGN
NPV for
PI-CGN
Rapidly progressive
glomerulonephritis
47%
(106/224)
98% 80%
Hematuria, proteinuria,
and creatinine 1.5-3 mg/dl
21%
(181/862)
92% 93%

Hematuria, proteinuria,
and creatinine <1.5 mg/dl
7%
(51/685)
77% 98%


Estimated positive and negative predictive values of
ANCA tests for pauci-immune crescentic GN (PI- CGN)
Patients: adults (>18 years old) with different clinical presentations
Assay has a 72.5% sensitivity and a 98.4% specificity
From: Jennette JC, Wilkman AS, Falk RJ. Kidney Int 1998;53:796-798
Does a rise in ANCA titer predict a
relapse of vasculitis or GN?
• Patients with WG who had a rise in ANCA titer
experienced fewer relapses if they were treated
expectantly - Cohen Tervaert et al. Lancet 1990.
• Meta-analysis showed only 48% specificity and 52%
sensitivity - Cohen Tervaert et al. 1995.
• Relapse occurs more frequently in the presence of a
positive ANCA (80% vs 20%) but a rise in titer is a poor
predictor of relapse - Kyndt et al. Am J Med 1999.
PPV: cANCA 28%; anti-PR3 12%; anti-MPO 43%
Copyright Harvard Medical School, 2010. All Rights Reserved.
538
Drug-Associated ANCA-Positive
Necrotizing Vasculitis
•Hydralazine
•Propylthiouracil
•Minocycline - HLA-DR4 or -DR2 linked
•Penicillamine
•Cimetidine
•Allopurinol
•Silicon ??
Case 5
A 43-year old man with end-stage kidney failure from pANCA-
associated pauci-immune crescentic glomerulonephritis is being
considered for renal transplantation. He presented with RPGN and
acute renal failure 8 years ago and responded well to
immunosuppressive therapy, however over the past 18 months his renal
function has declined slowly but progressively. He has no symptoms or
signs of systemic vasculitis and has been off all immunosuppressive
agents for 6 years. His urinalysis is benign except for 2+proteinuria.
Repeat renal biopsy six months ago showed extensive
glomerulosclerosis with fibrous crescents in 20% of glomeruli, tubular
atrophy and interstitial fibrosis. ELISA for myeloperoxidaseis positive
15 units (normal <2.8).
Copyright Harvard Medical School, 2010. All Rights Reserved.
539
Which of the following statements is correct regarding this
patient’s candidacy for renal transplantation?
A. Renal transplantation is contraindicated because of
the high rate of recurrent disease.
B. Transplantation should be delayed until ANCA
becomes undetectable by ELISA.
C. Renal transplantation can proceed using standard
immunosuppression.
D. Renal transplantation can proceed but the
immunosuppressive regimen should include
cyclophosphamide.
•Relapse rate: ~10-20% - not all renal
•Relapse is not correlated with ANCA positivity at the time
of transplant, duration on dialysis, nature of the vasculitis
(WG or MPA), or type of ANCA
•Most respond to cyclophosphamide
•5 year overall and death-censored graft survivals were 94
and 100%, respectively (Gera et al)
•No clear risk factors identified for relapse
Recurrence of ANCA-associated Renal Vasculitis
and Pauci-Immune GN after Renal Transplantation
• Allan et al: J ASN 1998 - 22 cases
• Nachmanet al: Kidney Int 1999 - 127 cases
• Schmitt et al: Lancet 1993 - 20 cases of WG
• Gera et al: Kidney Int 2007 - 35 cases (20 MPA, 15 WG)
Copyright Harvard Medical School, 2010. All Rights Reserved.
540
Conclusion: Renal transplantation is a safe and effective
treatment for end-stage ANCA-associated vasculitis with a
low recurrence rate
Case 6
• A 63-year old woman presents with RPGN
and is found to have renal limited
vasculitis with pauci-immune crescentic
GN on biopsy, positive pANCA and anti-
MPO.
• Serum creatinine falls from 3.8 mg/dL and
stabilizes at 1.5 mg/dL after pulse
methylprednisoloneand initiation of oral
prednisone and cyclophosphamide.
Copyright Harvard Medical School, 2010. All Rights Reserved.
541
Which of the following maintenance
therapies should you prescribe?
A. Taper prednisone and continue
cyclophosphamide until the patient has been in
clinical remission for 12 months
B. Taper prednisone and switch
cyclophosphamide to azathioprine after 6
months if the patient is in clinical remission
C. Taper prednisone and switch
cyclophosphamide to TMP/sulfa after 6 months
if the patient is in clinical remission
A Randomized Trial of Maintenance Therapy
for Vasculitis Associ ated with Antineutrophil
Cytoplasmic Autoanti bodies
Jayne et al for the European Vasculitis Study Group
N Engl J Med 349:36-44, 2003
About 30% of patients with ANCA-associated
vasculitis that enter remission will relapse!
Copyright Harvard Medical School, 2010. All Rights Reserved.
542
0 6 9 12 15 18
Months after randomization
1.0
0.9
0.8
0.7
0.6
Induction therapy
Cyclophosphamide + prednisone
3 mnths
or
3-6 mnths
Randomization
Remission
Cyclophosphamide
N = 79
Azathioprine
N = 76
12 mnths
Azathioprine
End follow up 18 mnths after entry Jayne et al N Engl J Med 349:36, 2003
Comments
1. Open label adequately powered prospective
randomized controlled study
2. The relapse rate with maintenance azathioprine
was the same as with cyclophosphamide
3. Serious adverse events over 18 months were
not substantially different in the two groups
Copyright Harvard Medical School, 2010. All Rights Reserved.
543
Case 7
• A previously healthy 35-year old man presents
with malaise and is found to be oliguric and
serum creatinine is 6.8 mg/dl (1.0 on routine
exam 6 months ago).
• Urinalysis shows microscopic hematuria with
mostly dysmorhic RBCs.
• pANCA is strongly positive.
• Renal biopsy shows cellular crescents in 75% of
glomeruli with periglomerular inflammation and
moderate interstitial fibrosis.
He remains oliguric despite prednisone
started by the referring nephrologist. In
addition to supportive care with dialysis,
which of the following is the most
appropriate treatment for this patient?
A. No further treatment is indicated
B. Pulse methylprednisolonefollowed by
oral prednisone and cyclophosphamide
C. Plasma exchange and oral prednisone
and cyclophosphamide
Copyright Harvard Medical School, 2010. All Rights Reserved.
544
Randomized Trial of Plasma Exchange or High-
Dosage Methylprednisolone as Adjunctive Therapy
for Severe Renal Vasculitis
David R.W. J ayne*, Gill Gaskin, Niels Rasmussen, Daniel Abramowicz, Franco Ferrario||, Loic
Guillevin¶, Eduardo Mirapeix**, Caroline O.S. Savage, Renato A. Sinico||, Coen A. Stegeman, Kerstin
W. Westman, Fokko J . van der Woude||||, Robert A.F. de Lind van Wijngaarden¶¶, Charles D. Pusey on
behalf of the European Vasculitis Study Group
J Am Soc Nephrol 18: 2180-2188, 2007
MEPEX n=151 (Courtesy David Jayne)
Entry
WG/MPA/RLV
Creatinine >500/L (5.8mg/dL)
Renal Biopsy cellular crescents
Methyl Predni sol one
IV 1g/day x 3
Pl asma exchange
60ml/kg x 7 over 2 weeks
Pri mary end poi nt
Renal recovery
at 3 months:
Patient survival
Dialysis independence
Creatinine <500/L
CYC p.o. 6/12, AZA
Predp.o. taper
Copyright Harvard Medical School, 2010. All Rights Reserved.
545
Modified from Jayne, D. R.W. et al. J Am Soc Nephrol 2007;18:2180-2188
51 evaluated for
Secondary end-points
29 dialysis independent
22 ESRD
56 evaluated for primary
end-point
33 dialysis independent
23 ESRD
59 evaluated for primary
end-point
48 dialysis independent
11 ESRD
151
Screened
137
randomized
14 excluded
67
IV methylprednisolone
70
Plasma Exchange
11 deaths
23 ESRD
8 deaths
2 ESRD
11 deaths
11 ESRD
5 deaths
2 ESRD
51 evaluated for
Secondary end-points
41 dialysis independent
10 ESRD
Entry
3 months
12 months
Enrollment, Patient Survival and Renal Outcome
Comments
1. Open label adequately powered prospective randomized
controlled study.
2. Plasma exchange significantly improved the chances of
renal recovery at 3 and 12 months.
3. Serious adverse events were common and the mortality
rate was high (23% in MP group and 27% in PE group).
4. The results apply only to patients with severe, active
renal disease without life-threatening extra-renal
manifestations or chronic kidney damage.
Copyright Harvard Medical School, 2010. All Rights Reserved.
546
NOVEL IMMUNOTHERAPIES
TNF inhibition therapies:
• Encouraging small studies with Infliximab(humanized anti-TNF)
suggested efficacy.
• Soluble TNF receptor:Fc fusion protein - Etanercept did not reduce
the rate of relapses in a prospective randomized study (NEJ M
2005).
Anti-CD20 (Rituximab):
• RAVE was a phase II/III double-blind, placebo-controlled trial of
rituximabin WG, MPA and ANCA-associated GN.
• Rituximabwas as effective as cyclophosphamide (both in
combination with glucocorticoids) in inducing remission.
• The adverse event rates were similar.
• (NEJ M J uly 15, 2010)
ANCA-associated GN - Summary
• ANCA is an excellent marker of pauci-immune crescentic GN.
• c-ANCA tends to occur more often in patients with features of
classical Wegener’s granulomatosis and p-ANCA in patients with
renal limited disease but there is much overlap.
• MPO (p-ANCA)- and PR3 (c-ANCA)-associated GN and vasculitis
have a similar prognosis and response to treatment.
• The titer of ANCA does not correlate well with disease activity but
disappearance of ANCA is associated with remission.
• The value of ANCA in predicting relapse is controversial.
• Azathioprineis effective maintenance therapy.
• Plasmapheresis is indicated for AAGN vasculitis with ARF.
• Rituximabmay be an alternative to cyclophosphamide for induction
of remission.
Copyright Harvard Medical School, 2010. All Rights Reserved.
547
Disclosures:
Consulting:
• Questcor • Questcor
• Taligen
Grant support:
• Questcor
Patent pending:
• Diagnostics for Membranous Nephropathy
Copyright Harvard Medical School, 2010. All Rights Reserved.
548
Genetics of Renal Disease Genetics of Renal Disease
Martin Pollak, M.D.
NephrologyDivision, BIDMC Nephrology Division, BIDMC
Associate Professor of Medicine, HMS
Financial Disclosures
Dr. Pollakhas no conflicts of interest to disclose.
Copyright Harvard Medical School, 2010. All Rights Reserved.
549
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture
• Quantitatively important hereditary disorders
– Cystic disease
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephrotic syndrome, proteinuria p y p
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture ,
• Quantitatively important hereditary disorders
– Cystic disease
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephroticsyndrome, proteinuria FSGS, nephrotic syndrome, proteinuria
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Copyright Harvard Medical School, 2010. All Rights Reserved.
550
Copyright Harvard Medical School, 2010. All Rights Reserved.
551
a
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a
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e
l
e
 
c
o
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f
e
r
r
e
d
 
b
y
 
v
a
Disease frequency 
R
i
s
k
 
c
Copyright Harvard Medical School, 2010. All Rights Reserved.
552
rs12917707: The rare allele (T vs G)
confers 80% of normal CKD risk
(from OMIM):
FAMILIAL J UVENILE HYPERURICEMIC NEPHROPATHY ; FJHN
Phenotypes caused by UMOD mutations
UMOD: encodes uromodulin, aka Tamm-Horsfall protein
• Alternative titles: HYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE ; HNFJ
NEPHROPATHY, FAMILIAL, WITH GOUT
GOUTY NEPHROPATHY, FAMILIAL JUVENILE
• AD inheritance. Low FeUrea.
GLOMERULOCYSTIC KIDNEY DISEASE WITH HYPERURICEMIA AND
ISOSTHENURIA
• cyst dilatation and collapse of glomeruli with hyperuricemia and isosthenuria, Electron y p g yp
microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic
reticulum. Patient urine samples consistently showed a severe reduction of excreted
uromodulin.
MEDULLARY CYSTIC KIDNEY DISEASE 2; MCKD2
• Alternative titles: CYSTIC KIDNEY DISEASE 2, AUTOSOMAL DOMINANT; ADMCKD2
Copyright Harvard Medical School, 2010. All Rights Reserved.
553
Familial interstitial disease
11 11
Copyright Harvard Medical School, 2010. All Rights Reserved.
554
Admixture mapping
From Kopp, 2008
Copyright Harvard Medical School, 2010. All Rights Reserved.
555
FSGS association
Results of association of 180
African American FSGS cases and
205 African American controls were
genotyped. (A) Fisher's exact test,
(B) Logistic regression controlling
for rs73885319, (C) Logistic
regression controlling for
rs73885319 and rs71785313.
Copyright Harvard Medical School, 2010. All Rights Reserved.
556
APOL1 background
ApoL1 travels in the blood
in HDL3 complexes. p
Hungry Trypanosomes eat
HDL3 and the complex
goes in the Trypanosome
stomach (the lysosome).
ApoL1 causesthe Trypanosome to lyse. SRA (serum response
associated protein) in T.b.rhodiense inactivates ApoL1
Haplotype homozygosity in Yoruba
The 230 genotyped
chromosomes from the 167
Yoruba samples, a mix of
trios, pairs, and unrelated p
samples, were divided in three
groups according to the
presence of the core alleles
G1 (n=88), G2 (n=17), or the
absence of either (n=125).
Haplotypes were colored in
such a way that chromosomes
with the same color at a given
iti h th position have the same
haplotype from that position
up to the position of the C-
terminal part of APOL1, and
their colors are different when
this is not the case.
Copyright Harvard Medical School, 2010. All Rights Reserved.
557
19
Summary: ApoL1
• CodingvariantsinAPOL1geneexplainthe • Coding variants in APOL1 gene explain the
increased risk of kidney disease in African
Americans under a recessive inheritance
model
• These variants make the encoded protein
able to kill Trypanosome b. rhodiense
• These variants are recent (~3000 years old)
and are an example of balancing selection
Copyright Harvard Medical School, 2010. All Rights Reserved.
558
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture
• Quantitatively important hereditary disorders
– Cystic disease
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephrotic syndrome, proteinuria , p y , p
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Autosomal Dominant Polycystic Kidney
Disease (ADPKD)
• PKD1, chromosome 16, 85% of cases
– Polycystin-1 protein (PC1), 4302 amino
acids
• PKD2, chromosome 4, 15% of cases
– Polycystin-2 protein (PC-2), 968 amino
acids
Cystogenesis requires a “second hit”,
either in the remaining normal allele of the
germline inherited gene, or in the other
PKD gene (“trans-heterozygous” mechanism)
Copyright Harvard Medical School, 2010. All Rights Reserved.
559
ADPKD: Clinical features
• Renal cysts • Renal cysts
• Liver cysts
• Intracranial aneuryms
• Cardiac valve abnormalities
• Abdominal inguinal hernias • Abdominal, inguinal hernias
• Kidney stones
Domain Structure of Human “Cystogenic”
Proteins
Fibrocystin
ARPKD gene
Igarashi and Somlo, JASN, 2002
Copyright Harvard Medical School, 2010. All Rights Reserved.
560
Renal Disease in ADPKD – the Role of
Genotype
• Medianageof ESRDis54inPKD1 74inPKD2 • Median age of ESRD is 54 in PKD1, 74 in PKD2
• Less hypertension, UTIs, and hematuria in PKD2-
associated disease
Hateboer et al, Lancet, 1999
Genetic Testing in PKD
• Mutational analysisversuslinkage • Mutational analysis versus linkage
• Clinical utility
– Kidney transplant donor evaluation (does
potential living related donor have
presymptomatic PKD?)
– Earlier treatment????
•ACE-I, antioxidants, K+supplementation,…
Copyright Harvard Medical School, 2010. All Rights Reserved.
561
Genotyping: PKD1
• Genotype family members at flanking polymorphic markers and
intragenic markers (typically several)
1 2 3
• Define haplotypes in family (groups of marker alleles inherited
together)
1 3 2
2 4 3
Example: Linkage analysis
Near ESRD
?
Family with ADPKD: 22 y.o. wants to donate kidney
to dad approaching ESRD. No cysts on CT scan.
Copyright Harvard Medical School, 2010. All Rights Reserved.
562
Eaxample 1: Linkage analysis
12 36
45 23 13 26 23 24
? 24
43 25
Step 1: Is disease in this family linked to PKD1 locus?
This example: Yes - Lod score ~ 2.0, or 1 in 100 odds of seeing
this cosegregation pattern by chance (disease is segregating
with the “ 2” haplotype).
Linkage analysis
23
24 24
Variation: Only 1 affected available
Copyright Harvard Medical School, 2010. All Rights Reserved.
563
Direct mutational analysis:
Screen for sequence variants by PCR amplification of PKD1, PKD2
exons from patient’s genomic DNA
Problems: Sensitivity? Decision as to whether nucleotide change is
disease causing?
Copyright Harvard Medical School, 2010. All Rights Reserved.
564
Other renal cystic diseases
• ARPKD
• Von Hippel Lindau
• Tuberous Sclerosis
• MCKD/nephronophthisis complex p p p
• Multiple simple cysts
Nephronophthisis (NPHP)
• Nephronophthisis (NPHP) is an autosomal recessive kidney disease leading to end-
stage renal failure
• Key histological findings: tubulointerstitial fibrosis, tubular dilatation and cyst
formation and tubular atrophy.
• NPHP is often a feature of a multisystem disease that may include retinal dystrophy
(Senior–Loken Syndrome) and cerebello-ocular-renal syndromes (Joubert syndrome
and related diseases (JSRD)).
• NPHP may present with an early decrease in urinary concentration
• End-stage renal failure (ESRF) typically occurs during early teenage years, with the
exception of the rare infantile forms, where there is ESRF before 5 years of age.
• Molecular genetics allows detection of the most common mutations (involving NPHP1 o ecu a ge et cs a o s detect o o t e ost co o utat o s ( o g
and accounting for 25% of all cases).
• Evidence to date implicates the primary renal cilium and basal body apparatus in the
pathogenesis of NPHP.
• Patients need regular monitoring of renal and liver function, eye examinations and
preparation for renal transplantation, which is the treatment of choice for the renal
failure that invariably ensues.
Copyright Harvard Medical School, 2010. All Rights Reserved.
565
EJ HG, Simms et al 2008
EJ HG, Simms et al 2008
Copyright Harvard Medical School, 2010. All Rights Reserved.
566
Nephrocystin proteins and their protein domains. Domain structure of the nephrocystin proteins. Nephrocystin
proteins contain a diverse variety of protein domains and no common pattern can be identified.
EJ HG, Simms et al 2008
Subcellular localization of nephrocystins to primary cilia, basal bodies, the mitotic spindle, focal adhesions and
adherens junctions, and functional interaction with other proteins mutated in renal " ciliopathies
Hildebrandt, F. et al. J Am Soc Nephrol 2009;20:23-35
Copyright Harvard Medical School, 2010. All Rights Reserved.
567
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture
• Quantitatively important hereditary disorders
– Cystic disease
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephrotic syndrome, proteinuria , p y , p
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Alport Syndrome and Other Disorders
of Type IV Collagen
Hudson, et al, NEJM, 2003
Copyright Harvard Medical School, 2010. All Rights Reserved.
568
Alport syndrome
• Most commonform: X linked • Most common form: X-linked
– Defects in COL4A5
• Renal disease: always
• Deafness: often
• Ocular disease: sometimes • Ocular disease: sometimes
Alport syndrome and related disorders
Hudson, NEJM, 2003
Copyright Harvard Medical School, 2010. All Rights Reserved.
569
Alport Syndrome
Atlas of Renal Pathology, AJKD, 2000
The Thin Basement Membrane Lesion
Atlas of Renal Pathology, AJKD, 2000
Copyright Harvard Medical School, 2010. All Rights Reserved.
570
Alport GBM is More Susceptible to
in vitro Proteolysis
Kalluri et al, J Clin Invest, 1996
Post-Transplant Anti-GBM Disease
• Occurs in 3-4% of patients with Alport’s, both
autosomal and X-linked
the possibility of anti-GBM disease does not
preclude transplantation
• X-linked, auto-antibodies 5 chain, but also
against 〈3 and 〈4
• Clinical anti-GBM disease typically occurs within
thefirst year post transplant the first year post-transplant
• Clinical disease may be more common in those
with large deletions
Copyright Harvard Medical School, 2010. All Rights Reserved.
571
Evaluation of hematuria
• Consider familial basement membrane syndromes
P f f il hi d/ i i l • Presence of family history and/or proteinuria strongly
suggests glomerular rather than lower tract
(“urologic”) problem
• Definitive dx of Alport syndrome: Renal biopsy
(genetic testing is not widely available)
• Consider other diseasesaswell: Consider other diseases as well:
– Familial IgA nephropathy
– Nail patella sydrome
– Fabry disease
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture
• Quantitatively important hereditary disorders
– ADPKD
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephrotic syndrome, proteinuria , p y , p
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Copyright Harvard Medical School, 2010. All Rights Reserved.
572
38 y.o. man with renal insuffuciency
Molecular anatomy of the podocyte foot process cytoskeleton
MAGI-1
Podocalyxin
NHERF2
Ezrin
FAT
NEPH-1?
V
T
P
SGS Dominant FSGS:
〈-actinin-4
TRPC6
CD2AP(?)
Recessive FSGS/NS
NPHS1
NPHS2
LAMB2
PLCE1
Copyright Harvard Medical School, 2010. All Rights Reserved.
573
Podocyte molecules in context
From Tryggvason
NPHS2: Podocin
NH2
COOH
Schwarz, JCI
Copyright Harvard Medical School, 2010. All Rights Reserved.
574
Familial FSGS
• 1/3of pediatricsteroid resistant nephrotic • 1/3 of pediatric steroid-resistant nephrotic
syndrome or FSGS is due to mutations in
the podocin gene NPHS2
• Recessive: absence of FH does not rule out
“familial” form of disease
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture
• Quantitatively important hereditary disorders
– ADPKD
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephrotic syndrome, proteinuria , p y , p
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Copyright Harvard Medical School, 2010. All Rights Reserved.
575
Fabry Disease
• X-linked deficiency of lysosomal 〈-galactosidase
accumulation of neutral sphingolipids, mostly
globotriasylceramide (GL3) g y ( )
• Classically, symptoms begin ~10 years of age
– Characteristic angiokeratomas, groin, hips, umbilical region
– Characteristic corneal opacity, which does not affect vision
– Peripheral neuropathy with severe acroparasthesias
– Mixed glomerular and tubular renal disease, typically
ESRDby3 4
th
decade ESRD by 3-4
th
decade
– Cardiac involvement – LVH, conduction abnormalities,
arrhythmias
– Vascular disease (endotheliopathy)
Angiokeratomas in Fabry Disease
Desnick et al, Ann Int Med, 2003
Copyright Harvard Medical School, 2010. All Rights Reserved.
576
Corneal Opacity in Fabry Disease
Desnick et al, Ann Int Med, 2003
Lamellated Lysosomal Inclusions of GL3 in
Podocytes of a Patient with Fabry Disease
Atlas of Renal Pathology, AJKD, 2001
Copyright Harvard Medical School, 2010. All Rights Reserved.
577
Diagnosis
• Affected males 〈-galactosidase activity in peripheral WBC.
Atypical variants may have residual activity.
• Female carriers may have normal enzyme activity DNA y y y
analysis
• Female carriers may have significant disease burden, due to
random X-inactivation
Treatment
• Enzyme replacement therapy, with Replagal or Fabrazyme
• Reduces plasma GL3 to undetectable, in addition to reduced
tissue accumulation
• Indications, dosage, endpoints, and cost-effectiveness are as yet
unclear
Reduced Glomerular Endothelial GL3 After
Enzyme Replacement
5 mos. treatment Pre-treatment
Thurberg et al, KI, 2002 – GL3 deposits
Copyright Harvard Medical School, 2010. All Rights Reserved.
578
Topics
• Common genetic variations and kidney disease
– GWAS studies, admixture
• Quantitatively important hereditary disorders
– ADPKD
– Alport syndrome/Hereditary nephritis
• Novel pathogenetic mechanisms
– FSGS, nephrotic syndrome, proteinuria , p y , p
• Novel molecular treatment
– Fabry disease
• Tubular disorders
Copyright Harvard Medical School, 2010. All Rights Reserved.
579
NEJM, 1999
NEJM, 1999
Copyright Harvard Medical School, 2010. All Rights Reserved.
580
Chronic metabolic
alkalosis/hypokalemia
• Diuretic abuse
• Bulemia
• Hyperaldosteronism
• Bartter/Gitelman syndromes
– Dx: Urinary chloride
– Family history
– Molecular genetics
Bartter’s vs Gitelman’s syndromes
BARTTER’s GITELMAN’s
Location of defect Ascending limb of Henle Distal tubule
Age of presentation Prenatal, infancy, early
childhood
Late childhood or
adulthood
Biochemical differences Serum Mg sometimes low
Increased urine Ca
excretion
Serum MG low
Decreased urine Ca
excretion
Molecular etiology Na-K-2Cl cotransporter,
apical K channel (ROMK),
basolateral Cl channel
(CLCNKB)
Henle
Na-Cl cotransporter in
distal tubule
Copyright Harvard Medical School, 2010. All Rights Reserved.
581
Familial Hypertension and the
WNK (With-no-Lysine)
Protein Kinases
Pseudohypoaldosteronism Type II
• Also known as Gordon’s syndrome or the
“chloride-shunt” disorder
• The“mirror image” of Gitelman’ssyndrome: The mirror image of Gitelman s syndrome:
- hypertension
- hyperkalemic acidosis
- suppression of plasma renin, aldosterone
- hypercalciuria
• Responsive to thiazides, suggesting defect in p , gg g
the DCT
• Autosomal dominant transmission, linked to
chromosomes 1q32-42, 12p13, and 17p11-
q21
Copyright Harvard Medical School, 2010. All Rights Reserved.
582
Financial Disclosures
Dr. Pollakhas no conflicts of interest to disclose.
Copyright Harvard Medical School, 2010. All Rights Reserved.
583
Pediatric Kidney Disease: A Board
Primer
J ulie R. Ingelfinger, M.D.
Professor of Pediatrics, Harvard Medical School
Senior Consultant, Pediatric Nephrology,
MassGeneral Hospital for Children at MGH
Pediatric Kidney Disease: A Board
Primer
J ulie R. Ingelfinger, M.D.
DISCLOSURE: I am a deputy editor at the
New England J ournal of Medicine, a paid
position
Copyright Harvard Medical School, 2010. All Rights Reserved.
584
Pediatric Kidney Disease:
*Issues of growth and development
*Congenital diseases
*Differences in presentation, evaluation,
treatment and implication of diseases
EXAMPLES:
Hematuria
Hypertension
Nephrotic Syndrome
Renal Functional Development: GFR
m
l
/
m
i
n
/
1
.
7
3
m
2

Data from Schwartz and Furth. PediatrNephrol 22:1839, 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
585
Renal Functional Development: GFR
P
e
r
c
e
n
t

o
f

A
d
u
l
t

F
u
n
c
t
i
o
n
Data from Rhodin et al. Human renal function maturation: a quantitative description
using weight and postmenstrual age. Pediatr Nephrol 2009; 24: 67-76
Renal Functional Development: Uosm
U
r
i
n
e

O
s
m
o
l
a
l
i
t
y
Data from Polaceket al. The osmotic concentrating ability in healthy infants and
children AJDC 1965; 40: 291-295
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586
Renal Functional Development
*FENadrops over first weeks of life
*Proximal tubular function continues to mature
*Renal blood flow continues to mature
*Medication handling must be considered
in terms of age
QED: Think of the AGE of the CHILD
Three Examples of Nephrology Issues
Different in Children cf. Adults
*HEMATURIA
*HYPERTENSION
*NEPHROTIC SYNDROME
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587
#1-Hematuria in Children
*Isolated hematuriain child: malignancy RARE
*Evaluation differs from that in adults
*Gross hematuriaestimated at 1/1000 visits—
Invasive radiographic modalities and
cystoscopy are not always indicated but
sometimes prove necessary and useful
Hematuria in Children
*J immy goes to the pediatrician for a well-
child check. His pediatrician decides to do
a screening urinalysis. J immy is found to
have isolated microhematuria. What should
be done?
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588
Hematuria in Children
*Don’t miss something serious
*Avoid unnecessary and invasive testing
*Careful history and physical helpful
*Reassure family
Screening Detection
Isolated hematuria: Screening
*7 million school children screened by urinalysis.
*1044 - abnormal urinalysis
*719 (60.1%) - isolated hematuria.
*52 – biopsy
-33 thin basement membrane disease
-16 definable pathology, mainly IgAN
Data from: Park YH, Choi JY, Chung HS, et al.
Hematuriaand proteinuriain a mass school urine
screening test. Pediatr Nephrol 2005; 20:1126–1130.
Copyright Harvard Medical School, 2010. All Rights Reserved.
589
Screening Detection
* School screening of all children in South Korea
*461 children –persistently abnormal urinalysis
*289 – isolated hematuria
*Renal biopsy- almost half (47.1%) had normal
findings
*The most common pathologic diagnosis
-thin basement membrane disease
-IgAN
Data from: Lee YM, BaekSY, Kim JH, et al. Analysis of renal
biopsies performed in children with abnormal findings in
urinary mass screening. ActaPaediatr 2006; 95:849–853.
Hematuria in Children
•Define type of hematuria:
•Define hematuria as macro or microscopic
•Define whether evidence of glomerular or
non-glomerular hematuria.
•Radiologic Examination
•Microscopic: not always needed; consider US
•Macroscopic: depends on whether trauma or
not
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590
ACR Guidelines: Hematuria in Children
* CAREFUL HISTORY:
Urinary tract infection
Strenuous activity
Tropical exposure
Recent strep throat
Recent trauma,
Menstruation,
Bleeding tendency
Bloody diarrhea
Pain: joint pain, rash, flank pain dysuria and frequency
Search for h/o trauma, foreign body
FH: stone, sickle cell, stone
Coley BD, GundermanR, Blatt ER, Fordham L, PodbereskyDJ, Prince JS,
Expert Panel on Pediatric Imaging. Hematuria- child. Reston (VA):
American College of Radiology (ACR); 2006
ACR Guidelines: Hematuria in Children
* PHYSICAL EXAMINATION
height and weight
Fevers
arthritis
Rashes
Edema
Abdominal examination-- nephromegaly, abdominal masses
Genital exam
Rectal exam
CVA tenderness
Cranial nerves- look for obvious deafness
Coley BD, GundermanR, Blatt ER, Fordham L, PodbereskyDJ, Prince JS,
Expert Panel on Pediatric Imaging. Hematuria- child. Reston (VA):
American College of Radiology (ACR); 2006
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591
Gross Hematuria
• Most common: glomerulopathy, urinary
infection, hypercalciuria, stones,
congenital urologic conditions, and trauma
• Less common: malignancy, angiomatous
malformations of the collecting system, the
nutcracker syndrome, ADPKD, sickling
hemoglobinopathies, hyperoxaluria,
idiopathic thrombocytopenic purpura,
schistosomiasis, and factitious hematuria
Urological Series
• 342 patients with gross hematuria.
• 272 boys—52 (19%) had benign
urethrorrhagia
• Other findings: URI, trauma, stones
• 3 patients with low-grade transitional cell
carcinoma
• 1 patient with Wilms tumor.
Greenfield SP, Williot P, Kaplan D. Gross hematuriain children: a ten-year review. Urology 2007;
69:166–169.
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592
#2-Hypertension in Children
*Hypertension in child: etiology is age-
dependent
*Evaluation differs from that in adults
*Treatment varies, depending on dx.
Staged evaluation, age-dependent
evaluation
4th Report Updates
• Updated BP norms from NHANES 1999-
2000
• Redefined terminology
• BP percentiles- 50
th
, 90
th
, 95
th
, 99
th
www.nhlbi.nih.gov/guidelines/
hypertension/child_tbl.htm
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593
Manual Reading is Standard
• Auscultatory(manual) and Oscillometric
(automated) BP measurements are not
interchangeable
• Park et al, Arch Pediatr Adolesc Med, 2001;155
• Podoll et al, Pediatrics, 2007;119:e538-43
• Oscillometric machines are not
interchangeable
• Kaufmann et al, Anesth Analg, 1996;82:377–381
Underdiagnosis of HTN in Children
• Review of electronic medical record from Ohio of
14,187 pts, 3-18 years
• 507 (3.6%) with HTN
• 131 (26% of those) identified as HTN
• 485 (3.4%) with Pre-HTN
• 55 (11% of those) identified as Pre-HTN
Data from: Hansen et al, JAMA, 2007 Aug;298:874-9
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594
Rising Rates of HTN
• School based BP screening in 5102
adolescents
• 20% overweight (BMI ≥95
th
percentile)
• Prevalence of HTN after 3 readings 4.5%
• All ethnic variability was accounted for by
BMI
Sorof et al, Pediatrics 2004;113:475-482
Measurement of Blood
Pressure in Children
• Children >3 years old should have their BP
measured
• Auscultation is the preferred method of BP
measurement
• Correct measurement requires a cuff that is
appropriate to the size of the child’s upper arm
• Elevated BP must be confirmed on repeated
measurement
• BP >90th percentile obtained by oscillometric
devices should be repeated by auscultation
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595
Conditions Under Which Children Under 3
Years Old Should Have BP Measured
• Solid organ transplant
• Malignancy or bone marrow transplant
• Treatment with drugs known to raise BP
• Other systemic illnesses associated with
hypertension
• Evidence of elevated intra-cranial pressure
Recommended Dimensions
for Blood Pressure Cuff Bladders
Maximum Arm
Age Range Width (cm) Length (cm) Circumference (cm)
*
Newborn 4 8 10
Infant 6 12 15
Child 9 18 21
Small adult 10 24 26
Adult 13 30 34
Large adult 16 38 44
Thigh 20 42 52
*Calculated so that the largest arm would still allow bladder to encircle arm by at
least 80%.
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596
BP Cuff Size
40%of arm
circumference
Technique
• Small cuff raises BP
– Converse less dramatic
• Leg BPs higher than arm measure
• Oscillometric measurement highly
sensitive to movement
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597
MARIANA
• Mariana is a 12 yo girl whose BP has been high
in her pediatrician’s office on three occasions.
She is at the 50
th
percentile for height and
weight.
• Her mom says the BP is lower at CVS, where
they measured it, because, she tells you, “we
were worried. Her grandfather died of a stroke.”
• You take Mariana’s BP, and it is 128/82 mmHg.
• You ask the school nurse to check the BP, and
the values jump around.
• What might you do next?
Systolic BP (mmHg) Diastolic BP (mmHg)
Age BP Percentile of Height Percentile of Height
(Year) Percentile 5th 10th25th50th75th90th95th 5th 10th25th50th75th90th95th
12 50th 101 102 104 106 108 109 110 59 60 61 62 63 63 64
90th 115 116 118 120 121 123 123 74 75 75 76 77 78 79
95th 119 120 122 123 125 127 127 78 79 80 81 82 82 83
99th 126 127 129 131 133 134 135 86 87 88 89 90 90 91
Blood Pressure Levels for Girls
by Age and Height Percentile
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598
Classification of HTN in Children &
Adolescents, With Measurement Frequency
and Therapy Recommendations
SBP or DBP Percentile
Normal <90th
Prehypertension 90th to <95th or if BP exceeds 120/80 even
if below 90th percentile up to <95th
percentile
Stage 1 hypertension 95th percentile to the 99th percentile plus 5
mmHg
Stage 2 hypertension >99th percentile plus 5 mmHg
Classification of HTN in Children &
Adolescents, With Measurement Frequency
and Therapy Recommendations
Frequency of BP Measurement
Normal Recheck at next scheduled physical
examination
Prehypertension Recheck in 6 months
Stage 1 hypertension Recheck in 1–2 weeks or sooner if the
patient is symptomatic; if persistently
elevated on 2 additional occasions, evaluate
or refer to source of care within 1 month
Stage 2 hypertension Evaluate or refer to source of care within 1
week or immediately if the patient is
symptomatic
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599
Ambulatory Blood
Pressure Monitoring
• Useful in the evaluation of
– White-coat hypertension
– Target organ injury risk
– Apparent drug resistance
– Drug-induced hypotension
• Provides additional BP information in
– Chronic kidney disease
– Diabetes
– Autonomic dysfunction
• ABPM should be performed by clinicians
experienced in its use and interpretation.
Treating Mariana
• You find that most of Mariana’s BPs are
between Prehypertensive and Stage 1.
• Would you start medication?
• Especially in view of her grandfather’s
history?
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600
Classification of HTN in Children &
Adolescents, With Measurement Frequency
and Therapy Recommendations
Therapeutic Lifestyle Changes
Normal Encourage healthy diet, sleep, and physical
activity
Prehypertension Weight management counseling if
overweight, introduce physical activity and
diet management
Stage 1 hypertension Weight management counseling if
overweight, introduce physical activity and
diet management
Stage 2 hypertension Weight management counseling if
overweight, introduce physical activity and
diet management
Indications for
Antihypertensive Drug
Therapy in Children
• Symptomatic hypertension
• Secondary hypertension
• Hypertensive target-organ damage
• Diabetes (Types 1 and 2)
• Persistent hypertension despite
nonpharmacologicmeasures
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601
MARIANA, CONTINUED
• HOW MUCH “WORK UP” SHOULD
MARIANA UNDERGO?
• SHE AND HER FAMILY TELL YOU THAT
THEY DO NOT WANT HER TO HAVE
TOO MANY TESTS.
Clinical Evaluation of
Confirmed Hypertension
Study or Procedure Purpose Target Population
Evaluation for identifiable causes
History, physical
examination, including sleep
history, family history, risk
factors, and habits such as
smoking, alcohol, eating
habits
History and physical
examination help focus
subsequent evaluation
All children with persistent
BP >95th percentile
BUN, creatinine, electrolytes,
urinalysis, urine culture
R/O renal disease and
chronic pyelonephritis
All children with persistent
BP >95th percentile
CBC R/O anemia, consistent with
chronic renal disease
All children with persistent
BP >95th percentile
Renal U/S R/O renal scar, congenital
anomaly or disparate renal
size
All children with persistent
BP >95th percentile
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602
Clinical Evaluation of
Confirmed Hypertension
Study or Procedure Purpose Target Population
Evaluation for comorbidity
Fasting lipid panel, fasting
glucose
Identify hyperlipidemia,
identify metabolic
abnormalities
Overweight patients with BP
at 90th–94th percentile; all
patients with BP >95th
percentile. Family history of
hypertension or
cardiovascular disease.
Child with chronic renal
disease
Drug screen Identify substances that
might cause hypertension
History suggestive of
possible contribution by
substances or drugs.
Polysomnography Identify sleep disorder in
association with
hypertension
History of loud, frequent
snoring
Clinical Evaluation of
Confirmed Hypertension
Study or Procedure Purpose Target Population
Evaluation for target-organ damage
Echocardiogram Identify LVH and other
indications of cardiac
involvement
Patients with comorbid risk
factors* and BP 90th–94th
percentile; all patients with
BP >95th percentile
Retinal exam Identify retinal vascular
changes
Patients with comorbid risk
factors and BP 90th–94th
percentile; all patients with
BP >95th percentile
Further evaluation as indicated
Ambulatory BP monitoring Identify white-coat
hypertension, abnormal
diurnal BP pattern, BP load
Patients in whom white-coat
hypertension is suspected,
and when other information
on BP pattern is needed
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603
Clinical Evaluation of
Confirmed Hypertension
Study or Procedure Purpose Target Population
Plasma renin determination Identify low renin, suggesting
mineralocorticoid-related
disease
Young children with Stage 1
hypertension and any child
or adolescent with Stage 2
hypertension
Positive family history of
severe hypertension
Renovascular imaging· Isotopic scintigraphy (renal
scan)
Magnetic resonance
angiography
Plasma and urine steroid
levels
Identify steroid-mediated
hypertension
Young children with Stage 1
hypertension and any child
or adolescent with Stage 2
hypertension
Plasma and urine
catecholamines
Identify catecholamine-
mediated hypertension
Young children with Stage 1
hypertension and any child
or adolescent with Stage 2
hypertension
Primary Hypertension and
Evaluation for Comorbidities
• Primary hypertension is identifiable in
children and adolescents
• Hypertension and prehypertension are
significant health issues in the young due
to the marked increase in the prevalence
of overweight children
• The evaluation of hypertensive children
should include assessment for additional
risk factors
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604
Management Algorithm
Measure BP and Height and Calculate BMI
DetermineBP categoryfor sex, age, andheight*
Educateon
Heart Healthy
Lifestyle

For the family
RxSpecific
for Cause
DrugRx

Monitor
Q6Mo
>95%
Prehypertensive
DiagnosticWorkupInclude Evaluationfor Target-
OrganDamage

Secondary
Hypertension
Overweight
Normal
BMI
Overweight
90–<95%
<90%
>95%
Normotensive
Therapeutic
Lifestyle
Changes

Repeat BP
In 6 months
Consider DiagnosticWorkupandEvaluation
for Target-OrganDamage

If overweight or comorbidity exists
Weight
Reduction
Primary
Hypertension
Normal
BMI
Consider Referral
To provider with expertise
in pediatric hypertension
DrugRx Weight Reduction
andDrugRx
Overweight
Stage 2 Hypertension Stage 1 Hypertension
Repeat BP
Over 3 visits
Weight
Reduction
Still >95%
90–<95% or 120/80mmHg
or 120/80
mmHg
Normal
BMI
DiagnosticWorkupInclude Evaluationfor Target-
OrganDamage

Therapeutic
Lifestyle
Changes

Secondary
Hypertension
or Primary
Hypertension
Classification of HTN in Children &
Adolescents, With Measurement Frequency
and Therapy Recommendations
Pharmacologic Therapy
Normal —
Prehypertension None unless compelling indications such as
CKD, diabetes mellitus, heart failure, LVH
Stage 1 hypertension Initiate therapy based on compelling
indications
Stage 2 hypertension Initiate therapy
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605
Ambulatory BP Monitoring
• ABPM
• White Coat HTN
• Efficacy of therapy
• Can differentiate between Primary and
Secondary HTN
– Flynn, Pediatrics, 2002;110:89-93
• Better relationship with markers of end
organ damage then casual BP readings
#3-Nephrotic Syndrome in Children
*Nephrotic syndrome in child: etiology
varies with age
*Evaluation differs from that in adults
*Treatment varies, depending on dx.
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606
Nephrotic Syndrome Definition
• Massive proteinuria
– urinary protein loss of >50 mg/kg per 24 hours or protein/creat ratio
>2g/g or 50 mg/kg/day, or 3-4+on dipstick
• Hypoproteinemia
– (<2 -2.5 g/dL [20 g/L )
• Hyperlipidemia
• Edema
• This is a SYNDROME with multiple causes
Nephrotic Syndrome Definitions- 2
• Remission
– Urinary protein excretion <4 mg/m2/hour or 0-trace on dipstick
or protein/creatinine ratio <0.2 g/g for 3 consecutive days
• Initial responder
– Attains complete remission within initial 8 wks of steroids
• Initial nonresponder/steroid resistance
– Failure to achieve remission during the initial 8 wks of steroids
• Relapse
– protein loss of >40mg/m2/hour or protein/creat ratio >2g/g or
50 mg/kg/day, or 2+on dipstick for 3 consecutive days
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607
Nephrotic Syndrome Definitions-3
• Infrequent relapse
– 1 relapse within 6 months of initial response or 1-3 relapses in
12 months.
• Frequent relapse
– 2 or more relpases within 6 months of initial response; 4 or more
per 12 months.
• Steroid dependence
– Two consecutive relapses during steroid therapy or within 14
days of ceasing therapySteroid dependence
• Late nonresponder
– Proteinuria for >8 weeks following one or more remissions
Incidence and Prevalence
• US, UK, AU and NZ:
– Incidence ~1-2/ 100,000 population .
– Prevalence ~ 16-19/ 100, 000 population.
• China- may be higher
• South Asia- appears higher
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608
Primary Glomerulopathies Underlying
Nephrotic Syndrome in Children and
Adults
ENTITY CHILDREN ADULT <60 Y ADULT >60 Y
Minimal lesion 76 20 20
FSGS 8 15 2
Membranous 7 40 39
Membranoproliferative 4 7 0
OTHER 5 18 39
Data from Lewis EJ. Management of the nephroticsyndrome in adults. In: Cameron
JS, GlassockRJ, eds. The nephroticsyndrome. New York: Marcel
Dekker, 1988:461-521. and from OrthS and Ritz Engl J Med 1998; 338:1202-1211
Typical Course and Response
• Most children with idiopathic nephrotic
syndrome (INS) respond to corticosteroids
and have minimal change disease (MCD) .
• Response to steroids is associated with a
good long-term prognosis for disease
resolution.
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609
ISKDC and Nephrotic Syndrome
• The International Study of Kidney Disease in
Childhood [ISKDC]-- 1967 to 1974
– Enrolled over 500 children aged 12 weeks to 16 years
• Diagnoses % % remission
– Minimal change 76.4% 93
– FSGS 6.9 50
– MesProlif 2.3 25
• Response highly predictive of renal histology
Glomerulus in Minimal Lesion Nephrotic Syndrome
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610
Normal Podocytes
Podocytes in NS
X 2125 Scanning EM
Renal Biopsy/NS
X 6000 Transmission EM
Steroid Responsiveness
•Steroid Responsive ~80%
– Urinary remission: ~50% by ~1 week; ~80%
by 2-2.5 weeks; ~98% by 28 days
– Complete remission: ~50% by 3 weeks; ~80%
by 30 days; ~90% by 5 weeks; ~100% by 8
weeks
•Steroid-dependent during 1-year
follow-up, 57% of children.
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611
Initial Treatment
• Corticosteroids since the mid-1950s.
• 1956 Dr. Gavin Arneil treated 4 children
with 60 mg daily.
• ISKDC -- 60 mg/m2/day for 4 weeks
followed by 40 mg/m2/day 3 days of 7 for
4 weeks.
• APN -- alternate days after remission.
Length of Initial Treatment
• Studies comparing 2 months vs. 3 or
more:
– Meta-analysis favors longer Rx
• Studies comparing 3 months vs. 6 months:
– Meta-analysis favors longer Rx
From: HodsonEM, Knight JF, Willis NS, Craig JC. Update of Cochrane Database Syst Rev:
CD001533, 2004; PMID: 15106158 [Review]. Cochrane Database of SystRev CD001533,
2005.
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612
Prednisone +/- AlkylatingAgent
LattaK, von SchnakenburgC, EhrichJH. A meta-analysis of cytotoxictreatment of
Frequently relapsing nephroticsyndrome in children. PediatrNephrol 2001; 16:
271-82.
Meta-analysis of steroids plus either placebo or alkylatingagent.
Overall: 5 trials: relative risk favored alkylatingagent: 0.32 (0.16, 0.63)
Drugs: either cyclophosphamideor chlorambucil.
BUT: Issues to consider: toxicity of these agents: In these studies:
N assessed
Death 7 (1.1%) 625
Malignancies 3 (0.6%) 534
Seizures 9 (3.4%) 266
Infections 35 (6.3%) 552
Hemorrhagic cystitis 0 552
Leukopenia 151 (33%) 456
Thrombocytopenia 24 ((5.9%) 408
Hair loss 5 (2.1%) 237
Other Therapy
At Presentation:
-Prednisone or Prednisone plus Cyclosporine. Sustained remission longer
In children receiving both. Hoyer, PF et al. J AmerSoc Nephrol 2006; 17: 1151-1157.
Frequent RelapsingNephroticSyndrome:
-Cyclophosphamide
-Chlorambucil
-Cyclosporine A
-Mycophenolate
-Levamisole
-Azathioprine–no reduction in relapse rate
-Mizoribine-relapse rates fell by up to 50%
-Tacrolimus
-Vincristine
-Monoclonal antibodies
-ACEi, ARB, etc.
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613
Other Therapy
Cyclosporine cf. Cyclophosphamide: Study in children and adults:
cyclophosphamide(2.5 mg/kg/day) for 8 weeks or
CsA(5 mg/kg/day in adults, 6 mg/kg/day in children) for
9 months, tapered off by 25%every month until
complete discontinuation at month 12.
- Almost 90%on both meds in remission for 6 months.
- By one year, about 65%in remission.
- Cyclophosphamidepatients stayed at ~65%fpr 2 years.
-Cyclosporine patients fell to 25% in remission by early
part of second year.
Data from Ponticelli C, Cyclosporinversus cyclophosphamidefor patients
with steroid-dependent and frequently relapsing idiopathic nephrotic
syndrome: a multicentre randomized controlled trial. Nephrol Dial Transplant
1993; 8: 1326-1332.
Probability of Minimal Lesion in Early Biopsy
of Idiopathic Nephrotic Syndrome in a Child
FEATURE PROBABILITY
No adverse findings 90-95%
Random case 90
Female child 70
Child >6 years old 65
Hypertension alone 60
Hematuriaalone 50
Infant (>3 months to 1 year) 20
Postpubertal 20
Steroid resistant 20
Hematuriaplus HTN 10
Infant (<3 months) 0-5%
Tune B, Mendoza S. Treatment of the idiopathic nephroticsyndrome: regimens
and outcomes in children and adults. JASN, 1997 May;8(5):824-32.
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614
Focal Segmental Glomerulosclerosis
(FSGS)
• In childhood, usually steroid-resistant and
difficult to treat.
– There is evidence that FSGS in Children is
increasing in frequency. (Eddy and Symons.
Lancet 2003; 362: 629-39).
Slide: courtesyC. Jennette
Approach to FSGS
• Current strategies for control of FSGS use
a stepwise approach
• Goals
– Normalization of urinary protein excretion and
– Prevention of kidney failure.
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615
Approach to FSGS
• Steroids initially declare self steroid-
resistant.
• Cytotoxic medications.
• Ancillary care– control of nephrotic state.
Steroid-resistant FSGS
Consider genetic testing, Rule out other underlying
Syndromic FSGS? diseases leadingto FSGS
Positive for mutation in podocin, Not done, not available or negative
WT1, CD2AP, TRPC6, etc.
Careful watching, anti-
proteinuric Rx with
ACE inhibitors or
ARBs
No response
Response
Trial with CyA, and Pred.
for at least 6 months
Continue CyA as
Long-term treatment
APPROACH TO STEROID-RESISTANT FSGS
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616
Board Review Question 1
A 3 year old boy presents with nephroticsyndrome. He has no
hypertension, no hematuriaand no family history of renal
disease. If you were to do a renal biopsy , what is the
probability that he will have minimal lesion nephroticsyndrome?
1)20%
2)40%
3)65%
4)90%
Board Review Question 1
A 3 year old boy presents with nephroticsyndrome. He has no
hypertension, no hematuriaand no family history of renal
disease. If you were to do a renal biopsy , what is the
probability that he will have minimal lesion nephroticsyndrome?
1)20%
2)40%
3)65%
4)90%
In a male child of this age with no adverse correlates, early
biopsies have shown a 90-95% probability of minimal lesion
disease.
Copyright Harvard Medical School, 2010. All Rights Reserved.
617
Board Review Question 2
Indications for initiating pharmacotherapy in a child with stage I
Hypertension include all of the following except.
1) Hypertensive target-organ damage
2) Type 2 diabetes
3) Renal transplant
4) Obesity
Board Review Question 2
Indications for initiating pharmacotherapy in a child with stage I
Hypertension include all of the following except.
1)Hypertensive target-organ damage
2)Type 2 diabetes
3)Renal transplant
4)Obesity
In a child with stage I hypertension, non-pharmacologic therapy
is indicated, unless there are other findings, which include
symptomatic hypertension, secondary hypertension, hypertensive
target-organ damage, type 1 diabetes or type 2 diabetes, and
persistent hypertension, despite use of non-pharmacologic measures.
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618
Pediatric Kidney Disease: A Board
Primer
Julie R. Ingelfinger, M.D.
DISCLOSURE: I am a deputy editor at the DISCLOSURE: I am a deputy editor at the
New England Journal of Medicine, a paid
position
Copyright Harvard Medical School, 2010. All Rights Reserved.
619
Membranous Nephropathy
and FSGS
August 11, 2010
J ohannes Schlondorff
Instructor in Medicine
Division of Nephrology
Beth Israel Deaconess Medical Center
Brigham Renal Board Review Course
Disclosures
• None
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620
Membranous Nephropathy
• Clinical Presentation
• Pathology
• Etiology
• Epidemiology
• Natural History / Prognosis
• Management and Therapeutic Options
Question 1:
A 54 year old woman developed nephrotic syndrome 2 months
ago. Renal biopsy at that time revealed membranous nephropathy,
~10% tubular atrophy and interstitial fibrosis. She is currently taking
Lisinopril 40mg qhs, Furosemide 40mg bid. On exam, BP 130/80, P
80. Lungs clear, 3+pitting edema. Na 133, K 4.2, Cr 0.9mg/dl;
albumin 2.9g/dl. Urine protein/Cr ratio 6.
All of the following are reasonable therapeutic interventions to
begin today, except:
A. Irbesartan 150mg qd.
B. Increase Furosemide to 80mg bid.
C. Simvastatin 10mg qhs.
D. Protein restricted diet.
E. Alternating steroid/cyclophosphamide modified Ponticelli protocol.
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621
• 60-80% with nephrotic syndrome (NS)
• remainder with subnephrotic proteinuria
detected incidentally
• ~60% of those with subnephrotic range
proteinuria progress to NS within 1-2 years
of presentation
• 30-40% with microscopic hematuria
• Only 10-20% with HTN
• <20% with significantly impaired renal
function
Clinical Presentation
• Uniform thickening of glomerular capillary
wall by PAS / light microscopy.
• Craters and spikes in glomerular
basement membrane on silver stain
• IF with diffuse, granular deposits of IgG
(predominantly IgG4) along basement
membrane
• Subepithelial electron dense deposits on
EM (stages described by Ehrenreich&
Churg)
Pathology
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622
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623
IgG
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624
• Stage I:
– Subepithelial deposits only
located on the surface of the
GBM.
• Stage II:
– Deposits are partially
surrounded by new basement
membrane. Classic spike
pattern on silver stain.
• Stage III:
– Incorporation of deposits into
basement membrane.
• Stage IV:
– Electo-lucent remnants of
deposits within the basement
membrane.
• Stage V:
– Capillary walls diffusely
thickened. No increase in
mesangial cells or matrix.
Pathology
History on MN
1957: David Jones identifies the unique glomerularpathologic findings of
MN, distinguishing it from other causes of “nephrotic
glomerulonephritis”:
“Striking granular aggregations of IgGand electron-dense deposits
along the subepithelial aspect of the GBM, believed to represent
immune complexes arising from the circulation”
1959: Heymann et al. describe a rat model of MN, induced by active
immunization of Lewis rats with preparations of renal brush border
proteins (“Heymannnephritis model”).
Hypothesis: Subepithelial deposits result from glomerular“trapping” of
circulating immune complexes formed by circulating BB antigens and
corresponding antibodies.
1978: Van Damme et al. and Couser et al.: Injection of anti-BB antibodies in
live rats and in ex vivo kidneys can bind glomeruli in the absence of
BB antigen.
Hypothesis: The immune complex formation occurs in situ (“fixed
antigen”)
Copyright Harvard Medical School, 2010. All Rights Reserved.
625
Glassock(2009) NEJM 361:81
Several candidate antigens in idiopathic
membranous nephropathy have recently
been identified:
•M-type phospholipase A
2
receptor (PLA
2
R)
– Beck et al (2009) NEJM
•neutral endopeptidase
– Debiec et al (2002) NEJM; Ronco & Debiec (in press) Arch Med Sci
•a-enolase (?)
– Wakui et al (1999) Clin Exp Immunol
Pathophysiology
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626
Pathophysiology
• Reported sensitivity and specificity for PLA2R antibodies for IMN are 75%
and 100%, respectively.
• Unclear if 25% of patients with MN and no PLA2R antibody have antibodies
to another antigen, have secondary MN, or represent those with a lag
between loss of PLA2R antibodies and resolution of proteinuria.
• Preliminary data (Beck et al, 8
th
International Podocyte Conference, 2010)
suggest that PLA2R antibody titers and proteinuria have a linear correlation,
though residual proteinuria may remain for some time after no PLA2R
antibody is detected.
• 2/3 of cases are primary or idiopathic
Etiology
Ponticelli (2007) J Nephrol 20:268
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627
• Idiopathic MN until recently the leading cause of
NS in Caucasian adults. Still remains 2
nd
or 3
rd
cause.
• Peak incidence commonly quoted to be between
30-50 years of age, but more recent studies shift
peak to 60-79.
• Incidence of MN equal in men and women, but
patients with ESRD due to MN have a M:F ratio
of 2-3:1.
• In USA and Europe, MN is second or third
leading cause of ESRD in patients with a
primary glomerulonephritis.
Epidemiology
• Rule of thirds – 30% spontaneous
remission; 30% progression to ESRD;
30% variable proteinuria but stable
renal function; 10% death from non-
renal causes.
• BUT, rate of progression to ESRD
within 5 years appears to correlate with
prevalence of nephrotic syndrome.
Natural History
Schieppati et al (1993) NEJM
du Buf-Vereijke et al (2005) AJKD
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628
• Little role for pathology in predicting
prognosis independently of clinical data.
• Predictive risk model developed by
Cattran et al (1997) KI
Prognostic Factors
Ponticelli (2007) J Nephrol 20:268
Risk Stratification - Cattran(2005) J ASN 16:1188
• Requires a minimum of a 6 month observation
period.
• Utilizes (1) lowest sustained degree of
proteinuria over the observation period, (2) initial
CrCl, and (3) DCrCl over 6 month period.
Risk Group Low Moderate High
Proteinuria <4g/day 4-8g/day >8g/day
Renal fxn Normal Normal Impaired GFR
CRI / 5yrs 5% ~50% 75%
Copyright Harvard Medical School, 2010. All Rights Reserved.
629
Value of Remission - Troyanovet al (2004)KI
• 348 nephrotic iMN patients in Toronto GN Registry with
>12mo follow-up
• CR: <0.3g protein/d
• PR: <3.5g protein/d & >50% reduction in proteinuria
•Substantial relapse rates
for both CR (23%) and PR
(47%); many experienced
a 2
nd
remission.
•Relapses affected rate of
decline of CrCl, but not
risk of ESRD.
Management
• If secondary MN, treat the cause if possible.
• Conservative therapy:
– Maintain BP<125/75mm Hg
– Dietary protein restriction (Giordano et al (2001) KI)
– ACE-I ±ARB for proteinuria reduction (?) and BP
– Statin for hyperlipidemia and proteinuria reduction
• Prophylactic anticoagulation controversial.
– Variable reported incidence of renal vein thrombosis
and thromboembolic events (20-50% in severe
nephrotics)
– Thromboembolic mortality 14%/4.5yrs; 42% in high
risk patients (Bellomo et al (1993) Nephron)
– Decision analysis model favors anticoagulation (Sarasin
& Schifferli (1994) KI)
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630
Management
Cattran(2005) JASN 16:1188
Evidence for Therapies
• Alternate day prednisone ineffective
– 3 RCT (Collaborative (1979) NEJ M 201:1301; Cameron et al (1990)
QJ M 274:133; Cattran et al (1989) NEJ M 320:210)
• Cytoxic agent (chlorambucil or cyclophosphamide) +
prednisone effective
– Three 2-month cycles: Methylpred 1g IV x 3 days, then
prednisone 0.5mg/kg/d x 27 days; then d/c prednisone,
chlorambucil 0.2mg/kd/d x 1 month (Ponticelli (1995) KI)
– Similar protocol using cyclophosphamide 2.5mg/kg/d rather than
chlorambucil similarly effective, but with fewer side effects
(Ponticelli (1998) J ASN)
– Cyclophosphamide 1.5-2mg/kd/d x 12 months, Methylpred 1g x3
days months 1,3,5 and Prednisone 0.5mg/kd qod x6 months (du
Buf-Vereijken et al (2004) NDT; pts with impaired renal fxn)
Copyright Harvard Medical School, 2010. All Rights Reserved.
631
Chlorambucil Protocol
Ponticelli et al (1995) KI 48:1600
Survival without dialysis
Probability of Response (CR or PR)
Chlorambucil vs. Cyclophosphamide
Ponticelli et al (1998) J ASN 9:444
Probability of Response Probability of Relapse
Cyclophosphamide
Chlorambucil
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632
Patients with renal insufficiency
du Buf-Kereijken et al (2004) NDT
Probability of Response Probability of Relapse
•Oral cyclophosphamide +steroids x12 months
•Renal survival 86% @ 5yrs, 74% @ 7yrs
•Historical control renal survival 32%
Cyclosporine
Cattranet al (1999) KI
•Multi-center, single blind
•49 pts, steroid-resistant MN, NS
•CsA 3.5mg/kg/d divided bid +
Pred0.15mg/kg/d x26 weeks,
then tapered off vs. pred alone
•CR/PR at 26wks: 75% vs 22%
•At 78wks, 39% vs 13%
•Renal fxnunchanged.
Cattranet al (1995) KI
•17 pts, progressive MN
•CsA 3.5mg/kd/d vs placebo
•CsA reduced rate of renal
decline, reduced proteinuria;
effect persisted in 6/8pts
Alexopoulos et al (2006) NDT
•51 pts, MN, NS, Cr<2mg/dl
•CsA vs CsA +prednisolone x12 mo
•CsA 2-3mg/kd/d divided bid; goal
trough 100-200ng/ml
•Prednisolone 0.6mg/kg/d, tapered
to 10-15mg/d by 6mo
•Responders at 12mo maintained on
CsA 1-1.5mg/kd/d ±prednisolone
0.1mg/kd/d
•CR/PR at 12mo: 85% vs 83%
•Relapse rate: 47% vs 15%
(associated with trough<100ng/ml)
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633
Tacrolimus
Praga et al (2007) KI 71:924
• 48 pts, MN, NS, CrCl >50ml/min/1.73m
2
• Tacrolimus (0.05mg/kg/d) x12 mo then taper vs. placebo
• CR/PR @ 18mo: 94% vs. 35%
• 50% increase sCr: 4% vs 26%
• 47% of Tac group relapsed by month 30
Li et al (2008) J Neph21:584
• 25 Chinese pts, proteinuria>6g/24hr after 3-6mo
observation
• Tacrolimus vs. cyclophosphamide, all prednisone.
• Short follow-up (24wk), but higher response rate
(CR/PR) in tacrolimus group (92% vs 85%)
MMF – mixed results
Dussol et al (2008) AJ KD
•36 pts, MN, NS, Cr<2.26
•MMF 2g/d x 12 months vs
placebo
•CR/PR @ 12mo: 37 vs 41%
Branten et al (2007) AJ KD
•32 pts, NS, median Cr 1.8
•MMF 2g/d +steroids, compared
to historical cyclophosphamide
controls.
•CR/PR @ 12mo: 66 vs 72%
•No response: 16% vs 0%
•Relapse: 38 vs 13%
Chan et al (2007) Nephrology
•20 pts, MN, NS, mean Cr 1.1
•Treatment naïve
•MMF 2g/d +pred vs.
chlorambucil
•CR/PR @ 15mo: 64 vs 67%
2 non-controlled studies
evaluated patients with MN which
had failed multiple agents or had
steroid or CsA dependence, and
demonstrated response in terms
of proteinuria reduction ±ability to
withdraw steroids/CsA. (Miller et
al (2000) AJ KD 36:250; Choi et al
(2002) KI 61:1098.)
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634
Rituximab
Remuzzi et al (mult publications)
• 50pts treated with rituximab as
first line therapy.
• Rituximab 375mg/m
2
qweek x 4
weeks
• CR 20%; PR 36-50%
• Generally well tolerated (1
episode of laryngospasm)
Fervenza et al (2008) KI
• 15 pts, 7 failed other
immunosuppression
• Rituximab 1g days 1 and 15
• 2
nd
course at 6mo if
proteinuria>3g/d and B cell
count >15/ul (10 of 15 pts)
• CR 13%; PR 40%
• Generally well tolerated (1 pt
with lung neoplasm dx 3
months post therapy)
•No randomized control trials.
•2 large case series; systematic review by Bomback et al
(2009) CJ ASN
Rituximab
Segarra et al (2009) CJ ASN
• Single center; 13 pts, iMN, eGFR>60ml/min
• CNI dependence (4+relapses of NS on taper); 8
failed cyclophosphamide; 2 failed chlorambucil;
10 IgG infusion, 11 MMF to limit CNI dose
• Rituximab 375mg/m
2
qweek x4; 1 month later,
steroids/MMF discontinued, CNI weaned by 30%
qmonth
• All patients weaned from CNI, MMF, pred.
• At 12mo 4/13 CR, 9/13 PR.
• 3 relapses, all responded to single re-treatment
with PR.
• At 30mo, 13/13 PR.
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635
ACTH
Ponticelli et al (2007) AJ KD
• Single center, randomized control study
• 32 patients, iMN, NS, Cr<1.9
• Synthetic ACTH 1mg IM, increased from qoweek
to 2x/week x1 year vs. methylprednisone +
chlorambucil (9/16) or cyclophosphamide (7/16)
• CR/PR: 87% vs. 93%. 1 pt progressed to ESRD
in ACTH group
• Relapse: 3/14 vs. 7/15.
• Side effects mild, reversible.
Summary
Consider rituximabin patients with contraindication to cytotoxictherapy or CNI
dependence, or in a research setting.
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636
Question 1:
A 54 year old woman developed nephrotic syndrome 2 months
ago. Renal biopsy at that time revealed membranous nephropathy,
~10% tubular atrophy and interstitial fibrosis. She is currently taking
Lisinopril 40mg qhs, Furosemide 40mg bid. On exam, BP 130/80, P
80. Lungs clear, 3+pitting edema. Na 133, K 4.2, Cr 0.9mg/dl;
albumin 2.9g/dl. Urine protein/Cr ratio 6.
All of the following are reasonable therapeutic interventions to
begin today, except:
A. Irbesartan 150mg qd.
B. Increase Furosemide to 80mg bid.
C. Simvastatin 10mg qhs.
D. Protein restricted diet.
E. Alternating steroid/cyclophosphamide modified Ponticelli protocol.
Focal Segmental
Glomerulosclerosis
• Epidemiology
• Pathology
• Classification
• Clinical Presentation
• Prognosis
• Initial Treatment
• Treatment of Steroid-resistant and
dependent FSGS
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637
Question 2:
A 46 yo man with a history of hypertension, obesity and peptic ulcer
disease developed nephrotic syndrome. Renal biopsy revealed
secondary FSGS with glomerulomegaly. He returns today for follow-up
4 months after his biopsy. Current medications include Enalapril,
Valsartan, Furosemide, Atorvastatinand Pantoprazole.
On exam: BP 124/72, P 76. Weight 272lbs. Lungs are clear. Heart
exam unremarkable. Abdomen benign. Ankles with 2+edema. Labs
are notable for BUN 16, Cr 1.1mg/dl, Glc 104mg/dl, Alb 3.1g/dl. CBC
within normal limits. UA with 1+blood, 3+protein; urine protein/Cr ratio
4.2.
Based on his presentation, you recommend the following course of
action:
A. Continued conservative therapy and observation.
B. Treatment with Prednisone 80mg qd.
C.Treatment with Cyclosporine 100 mg bid and Prednisone 15mg qd.
D.Treatment with Tacrolimus 2mg bid.
E. Referral for bariatric surgery.
• Incidence of FSGS in biopsy series has
risen over the last 30 years.
• FSGS most common pathology in biopsies
for idiopathic NS in US; 35% in all cases,
50% in African-Americans
• FSGS most common primary glomerular
disease causing ESRD in US (USRDS)
Epidemiology
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638
• FSGS is a descriptive term for a
pathologic lesion, not a disease entity.
Pathology
Etiological Classification of FSGS
Primary (idiopathic) FSGS
• Permeability factor
mediated?
Secondary FSGS
1.Familial / genetic
•ApoL-I, a-actinin-4, TRPC6,
NPHS1&2, PLCE1, COQ2
2.Virus-associated
•HIV, ParvoB-19, CMV,
HTLV-1
3.Drug/toxin-mediated
•Interferon-a, Sirolimus,
Bisphosphonates, Lithium,
Heroin
4.Arising from adaptive
structural-functional
responses
•Reduced renal mass (e.g.
renal agenesis or dysplasia,
reflux nephropathy, cortical
necrosis, surgical ablation)
•Initially normal renal mass
(e.g. hypertension, obesity,
OSA, sickle cell anemia,
atheroembolicdisease)
Adapted from D’Agati et al (2004) AJ KD
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639
Histological Variants of FSGS
•5 variants:
1. Classic
2. Perihilar
• Frequently seen with secondary FSGS due to glomerular
hypertension
3. Tip lesion
• Abrupt onset, high degree of proteinuria; better response to
steroids, some spontaneous remissions reported; ? less
likely to progress to ESRD
4. Cellular
5. Collapsing
• More severe, poorer prognosis
Prognostic value of histological variants remains
debated.
Pathophysiology
Intact Foot Process
Effacement
Persistent Podocyte
Stress
Podocyte Loss
Apoptosis/Detachment
Decreased
Podocyte Density
Compensatory
Podocyte Hypertrophy
Glomerular
Hyperfiltration/
Hypertrophy
“Pathologic”
Podocyte Hypertrophy
Glomerulosclerosis
Podocyte
Injury
Sustained Injury
‘Second hit’
TRPC6
?
ACTN4
?
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640
FSGS and People of African Descent
• Cumulative lifetime risk for ESRD varies
by ancestry; e.g. ~2% for European
Americans, ~7.5% for African Americans
• African Americans have ~4x higher risk of
sporatic FSGS, 18-50x higher risk of
HIVAN
• The higher risk of FSGS in peoples of
African descent is not specific to US
FSGS and People of African Descent
• Higher risk of hypertensive ESKD, HIVAN and FSGS all link to
genetic variants in ApoL1 found in high frequency in West Africa,
and which confer protection against certain trypanosomal infections.
• A situation analogous to sickle cell disease/thalasemias?
• Odds ratios for recessive carriers: FSGS 10.5; H-ESRD 7.3
• Mechanism of disease, value of testing and therapeutic implications
are all still unknown, but stay tuned…
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641
Mean age 40-50; male:female ~1:1
Primary FSGS
• Nephrotic range proteinuria: 60-75%
• Microscopic hematuria: 30-50%
• Hypertension: 45-65%
• Impaired renal function: 25-50%
Secondary FSGS
• Slowly progressive proteinuria and renal insufficiency
• Peripheral edema and hypoalbuminemia uncommon
even with nephrotic range proteinuria.
• Heavy proteinuria uncommon.
Clinical Presentation
Clinical Presentation
Deegens et al (2008) Neth J Med
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642
Prognostic Factors
Proteinuria
• Nephrotic vs non-nephrotic renal survival of 76% vs. 92% at 5yrs, 57
vs 92% at 10yrs.
• Massive proteinuria (>10g/d) has renal survival of ~20% at 5 yrs.
Renal insufficiency
• 10-yr renal survival 27% if Cr>1.3; 100% if Cr<1.3.
Histology
• Interstitial fibrosis
• Collapsing variant worse; ?Better prognosis with tip lesion
Response to Therapy
• Single most important prognostic factor
• 10 yr renal survival in one series (Chun et al (2004) J ASN):
Classic Scar Tip Lesion Collapsing
Remission 100% 100% 80%
Non-responder 49% 25% 21%
Prognostic Factor – Response to
Therapy
Troyanovet al (2005) JASN 16:1061
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643
Treatment Options
• Unlike MN, spontaneous remissions in
FSGS are rare (<6%), therefore attempting
to obtain a treatment induced remission is
of importance for primary FSGS.
• Treatment of secondary FSGS is limited to
conservative management, and (if
possible) treatment of underlying cause
Treatment in Primary FSGS
•Conservative therapy (ACE-I/ARB, BP
control ≤125/75, ?statin) for all patients.
•Immunosuppressive therapy is generally
not suggested for patients with:
1. Preserved renal function and sub-nephrotic
range proteinuria (due to relatively good
prognosis)
2. Impaired renal function and sub-nephrotic
range proteinuria (due to poor prognosis even
with treatment, question of secondary FSGS)
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644
Treatment in Primary FSGS
• No RCT data for use of
steroids.
• Steroids remain first line
therapy.
• Current recommendation:
Prednisone 1mg/kg/d for 8-16
wks, or 2mg/kg/qod if high risk
for complications.
• Prolonged course may be
necessary! Median time to
remission reported in 3.5-5
month range; additional
responses up to 9 months into
therapy.
Korbet (1998) J ASN
Steroid Taper after Response
CR within 12 weeks:
• Continue full dose 1-2 weeks, then
• Taper dose (every 2-3 weeks) over 2-3 months.
• Consider switching to alt day dosing during taper.
PR by 12 weeks:
• Consider switch to alt day dosing.
• Slow taper (every 6 weeks) over 6-9 months.
• Halt taper if proteinuria rises, consider adding CsA or MMF.
Decreased proteinuria by 12-16 weeks, but no PR:
• Assess slope of proteinuria decline, risks/toxicity of continued high
dose prednisone.
• Consider continued therapy, alt day dosing, adding CsA or MMF.
No significant response by 12-16 weeks:
• Considered steroid resistant FSGS.
• Consider starting CsA, alternate day dosing, and tapering steroids.
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645
Treatment of Relapses
• >75% of patients who relapse will respond to
retreatment.
• If relapse occurs after >6-12 months off of
steroids, retreat with prednisone.
• If relapse occurs <6-12 months after
discontinuation of steroids, or during steroid
taper, consider patient steroid-dependent.
• If significant steroid toxicity, or repeated
relapses, treat with CsA (3.5mg/kg/d) and low
dose prednisone.
Treatment of steroid-dependent FSGS
• Response to CsA usually within 1 month, but
relapse rate of ~75% upon taper, leading to
need for prolonged low dose CsA therapy.
• Cytotoxic therapy (cyclophosphamide 2mg/kg/d
x2-3 months, high dose prednisone for 1 month)
Korbet (1998) J ASN
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646
Treatment of steroid-resistant FSGS
• Cyclosporine A
– Several RCT demonstrating benefit
• Tacrolimus
– Uncontrolled, open label trials
• Cytotoxic Agents
– Limit use to patients with limited response to prednisone alone,
and high risk of CsA toxicity.
– No benefit in prolonged treatment (>12 weeks)
• MMF
– One RCT comparing to prednisone alone in naïve patients
– Largely observational data; limit to those with contra-indication to
CsA, renal insufficiency
• Sirolimus
– Single prospective trial suggesting some efficacy, but reports of
adverse effects on renal function.
• Rituximab
– Case reports of response in children with FSGS, FSGS in tx.
CsA for steroid-resistant FSGS
Cattran et al (1999) KI
•Multicenter, RCT
•49 pts with SR FSGS
•CsA 3.5mg/kg/d divided
bid +Pred 0.15mg/kg/d
vs. Pred alone x 26 wks
•CR/PR at 26wks: 70% vs
4%
•Relapse rate: 40% at 52
wks, 60% at 78 wks
•≥50% decline in CrCl:
25% vs. 52% at 200 wks
Ponticelli et al (1993) KI
• Multicenter, adult & peds,
SR MCD & FSGS
• CsA 5mg/kg/d x 6mo,
then taper vs. supportive
care
• CR/PR: 57% vs 16%
• Relapse rate of 70%
Heering et al (2004) AJ KD
• 57 pts SR FSGS
• Pred 1.5mg/kg/d +CsA
5mg/kg/d vs. Pred +
Chlorambucil 0.1-
0.4mg/kg/d x 6-12 weeks,
followed by CsA
• CR/PR: 60 vs 65% (NS)
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647
Cattran et al (2007) KI 72:1429
CsAdosing goals:
CR/PR, stable GFR, CsA trough
125-175ng/ml
MMF for FSGS
Senthil Nayagam et al (2008) NDT
• Single center, RCT
• 33pts FSGS and NS
• MMF 1g bid +Pred 0.5mg/kg/d x 8-12 wks vs. Pred
1mg/kg/d x 12-24wks
• CR/PR: 70 vs 69%
• Relapse: 24 vs 19% (NS)
• Several observational studies have reported decreases
in proteinuria >50% in 40-50% of patients, occasional
remission, and stable Cr levels in patients with FSGS
resistant or dependent upon steroids, cyclosporine or
cytotoxic agents.
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648
Question 2:
A 46 yo man with a history of hypertension, obesity and peptic ulcer
disease developed nephrotic syndrome. Renal biopsy revealed
secondary FSGS with glomerulomegaly. He returns today for follow-up
4 months after his biopsy. Current medications include Enalapril,
Valsartan, Furosemide, Atorvastatin and Pantoprazole. , , p
On exam: BP 124/72, P 76. Weight 272lbs. Lungs are clear. Heart
exam unremarkable. Abdomen benign. Ankles with 2+ edema. Labs
are notable for BUN 16, Cr 1.1mg/dl, Glc 104mg/dl, Alb 3.1g/dl. CBC
within normal limits. UA with 1+ blood, 3+ protein; urine protein/Cr ratio
4.2.
Based on his presentation, you recommend the following course of
action:
A. Continued conservative therapy and observation.
B. Treatment with Prednisone 80mg qd.
C. Treatment with Cyclosporine 100 mg bid and Prednisone 15mg qd.
D. Treatment with Tacrolimus 2mg bid.
E. Referral for bariatric surgery. (?)
Disclosures
None • None
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649
Polycystic Kidney Disease: an
Update p
Theodore I. Steinman, M.D.
Clinical Professor of Medicine
Harvard Medical School Harvard Medical School
Beth Israel Deaconess Medical Ctr.
Brigham and Women’s Hospital
August 9, 2010
Disclosures
• None
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650
Autosomal Dominant
Polycystic Kidney Disease
• Mutation in ~70% located on short arm of
chromosome 16p 13.3 – p13.1 – (PKD1 locus)
• ~30% of mutation is located on chromosome
4q21-q23 milder phenotype with PKD2 locus. q q p yp
Later age of diagnosis and hypertension,
smaller kidney volume, fewer kidney cysts,
later age of ESRD system: disorder is kidney,
liver, pancreatic and vascular abnormalities.
Family History of Severity of Renal
Disease Predicts Mutated Gene in ADPK
Median Age of ESRD
PKD1 ~ 53 years PKD1 ~ 53 years
PKD2 ~ 73 years
Presence of at least one affected family member who developed
ESRD at age < 55 years was highly predictive of PKD1 mutation
(PPV 100%, sensitivity 72%)
If family member developed ESRD at age > 70 years, then highly
predictive of PKD 2 mutations (PPV 100%, Sensitivity 74%)
Barua et al JASN 20: 1833, 2009
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651
Sonographic Criteria for the Diagnosis of ADPKD
Age (yrs) Criteria PPV NPV
15-29
Original Ravine’s PKD1 diagnostic criteria
> 2 cysts unilateral or bilateral 99 2 87 7 15-29
30-39
40-59
> 60
> 2 cysts, unilateral or bilateral
> 2 cysts in each kidney
> 2 cysts in each kidney
> 4 cysts in each kidney
99.2
100
100
100
87.7
87.5
94.8
100
15-29
30-39
40-59
60
Revised unified diagnostic criteria
> 3 cysts, unilateral or bilateral
> 3 cysts, unilateral or bilateral
> 2 cysts in each kidney
2 t i h kid
100
100
100
100
85.5
96.4
94.8
100 > 60 > 2 cysts in each kidney 100 100
15-29
30-39
30-49
> 60
Revised criteria for exclusion of diagnosis
> 1 cyst
> 1 cyst
> 2 cysts
> 4 cysts in each kidney
96.6
94.0
96.7
100
90.8
98.3
100
100
Torres, KI 76:149-168, 2009
Cystogenesis
When cysts detach early from the tubule of origin, fluid
accumulates within the expanding cyst as a result of the
primary transepithelial transport of chloride through cyclic
AMP regulated channels in the apical lining cells.
CFTR (cystic fibrosis transmembrane conductance
regulator) present on apical surface of cyst epithelial cells.
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652
TwoTypesofCilia
• Motilecilia
– Beatrhythmically
– Foundprimarilyinthelungsandairways
– Helptomovefluidandsecretions
• Primarycilia
– Donotbeat
– Foundonalmostallcells
– Sensoryfunction
Cilia
• Tiny,hair-like
structures that Cilia structuresthat
projectfromthe
surfaceofthecell
Cilia
Cell
Nucleus
Copyright Harvard Medical School, 2010. All Rights Reserved.
653
PrimaryCiliaonKidneyCells
Wheatley,1995;Pan,2005
EvidencethatPKDisaDisorderofCilia
• TheproteinsthataremutatedinADPKD
andARPKDarelocatedinkidneycilia
– Polycystin-1
– Polycystin-2
– Fibrocystin
• Mice lacking kidney cilia develop PKD • MicelackingkidneyciliadevelopPKD
• Polycystin-1andpolycystin-2arerequired
forciliarysignaling
Copyright Harvard Medical School, 2010. All Rights Reserved.
654
Cilia in ADPKD
J Am Soc Nephrol 13:2384-2398, 2002
CiliaBendingProducesaRiseinCell
Calcium
Calcium
concentration
adaptedfromPraetorius,2001
Copyright Harvard Medical School, 2010. All Rights Reserved.
655
The calcium increases results
in K secretion
PolycystinsareRequiredfortheRisein
CellCalcium
e
Pkd1mutant
Normal
%

c
a
l
c
i
u
m

i
n
c
r
e
a
s
e
Nauli,2003
↑ calcium
cilia
bending
polycystin-1
polycystin-2
X
X
X
Copyright Harvard Medical School, 2010. All Rights Reserved.
656
Cilia
FLOW
RegulationofCellGrowth byCilia
Cell
inversin
β-catenin
Nocell
growth
Simons,2005
genes
Nucleus
LossofCiliaCausesAccumulationofβ-Catenin
Cell
X
Nucleus
β-catenin
Nucleus
Lin,2003
Cell
growth
genes
Copyright Harvard Medical School, 2010. All Rights Reserved.
657
Hypothesis About Role of
Angiogenesis in ADPKD
• Necessary for cyst cells to grow Necessary for cyst cells to grow
• Responsible for increased vascular
permeability facilitating fluid secretion
into cysts
• Neovascularization may result in
formation of aneurysms formation of aneurysms
– ? Brain – PC 1 & 2 expressed in smooth
muscle cells of cerebral arteries
– ? Renal bleeding
Copyright Harvard Medical School, 2010. All Rights Reserved.
658
CRISP RESULTS
• Total Kidney Volume (TKV) increased over the
three-year interval +204 ml+246 (n=214 P<.001)
and Total Cyst Volume (TCV) increase +218ml
+ 263 (n 210 P< 001) + 263 (n=210, P<.001).
• There was a direct correlation (r= 0.95, P<.001)
between the rate of change in TKV and the rate
of change in TCV.
• The change of volume in the left kidney
correlated directly with the change in the right
kidney (r=0.67, P<.001).
New England J. Of Medicine 354(20):2122-30
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659
Relation between Age and Total Kidney Volume in Patients with
Autosomal Dominant Polycystic Kidney Disease.
Total kidney volume (the sum of the volumes of the left and right kidneys) is shown in 232 women (blue
data points) and men (red data points) studied over a 3-year period. The total kidney volume increased
progressively in most patients but at widely differing rates. The two black lines superimposed on the data
points demarcate slow, moderate, and rapid rates of progression. The rate of disease progression in
individual adults at any age can be determined by measuring kidney length, width, and thickness on MRI,
CT, or ultrasound scans and estimating the kidney volume with the ellipsoid equation.
Grantham, JJ N Engl J Med 359:14
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660
Relationship between kidney
volume (US) and GFR
Fick-Brosnahan AJ KD: 112, 2002
Significant correlation between GFR and renal volume
in 229 patients with ADPKD
Schrier JASN 20:1888-1893, 2009
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661
Volume as an Endpoint in ADPKD
• Cysts are the disease, volume equals severity
• Cyst growth is distinctive and measurable
• Cyst volume strongly linked to functional decline
• Proliferation of promising treatments for ADPKD
Acquired Cystic Kidney Disease
• ACKD becomes a confounding variable –
goes on at a subliminal level for years in
patients with ADPKD preceding ESRD
(related to slow progression of CKD).
Copyright Harvard Medical School, 2010. All Rights Reserved.
662
Relationship between
hypertension and PKD
Across all age ranges
hypertension is noted when TKV
is ~ 1000 mL (~600 mL/cm height)
Progressive Loss of Kidney Function
• Rate of decline of GFR (data from MDRD study, starting
at GFR <55 ml/min)
Males 5 - 6 ml/min/year
Females 4 - 5 ml/min/year
• Pattern of GFR loss has recently been established by
CRISP study
– GFR stable for many years, despite progressive
increase in total kidney volume increase in total kidney volume
– GFR decrease not detected until total kidney
volume exceeds 1500 ml
Copyright Harvard Medical School, 2010. All Rights Reserved.
663
Loss of Kidney Function in ADPKD
80
100
%
)
20
40
60
R
e
n
a
l

f
u
n
c
t
i
o
n

(
%
Torres Mayo <aupCP1047707-9
0
0 10 20 30 40 50 60
Age (years)
Predictors of Disease Progression
(MR)
Hemodynamic
Anatomic
Hemodynamic
RBF
RVR
Anatomic
Total kidney
volume
RVR
GFR
Total cyst volume
% cyst volume
CRISP Study KI 2003; 64:2214-2221
Copyright Harvard Medical School, 2010. All Rights Reserved.
664
Principal Extrarenal Manifestations
Hepatic and pancreatic cysts
Asymptomatic in many patients, but can expand and
cause pain and infection; rarely massive PLD cause pain and infection; rarely massive PLD
Cardiac valvular abnormalities
Mitral, tricuspid and aortic valve prolapse and
regurgitation
Intracranial aneurysms
Risk of rupture; found in approximately 5% of patients s o uptu e; ou d app o ate y 5% o pat e ts
with no family history and about 22% of patients with
family history of ICA or SAH
Seminal vesicle cysts
Found in ~39-60% of men; undefined risk of infertility
Nephrolithiasis in ADPKD
• Occurs in ~20-36% of patients
• Uric acid (UA) (~50%); Ca Ox (~47%)
• Predisposing factors include
hypocitraturia, hyperoxaluria,
hypercalciuria, hypomagnesuria, possible
distal acidification defects
• S
UA
and renal urate handling normal
UA
g
• Expanding cysts compress the collecting
system producing urinary stasis, which
predisposes to stone formation and
infection
Copyright Harvard Medical School, 2010. All Rights Reserved.
665
Patient Characteristics in Stone
Formers
Old • Older
• Higher incidence of hypertension
• Hepatic cysts
• Impairment in submaximal Uosm
• History/Presence of UTIs
• Low urine volume
• LOW URINE pH (major factor)
ADDITIONAL FACTORS in Stone
Formation
• Activation of RAAS occurs early in ADPKD
• Type A acid secreting intercalated cells
(OMCD) express Type Ι angiotensin
receptors (AT
1
R)
• AΙΙ stimulates vacuolar H
+
-ATPase activity
in intercalated cells in intercalated cells
Copyright Harvard Medical School, 2010. All Rights Reserved.
666
Hypothesis
• In ADPKD upregulation of AΙΙ renal
i lt i ti l ti f H
+
i t expression results in stimulation of H
+
into
CD lumen
• Failure to adequately buffer increased H
+
results in urine acidification (UA stone risk
• ?Will Rx with ACEI &/or ARBs increase
urinary pH by downregulating H
+
-ATPase
• Pech et al JASN 19:84-91, 2008
Treatment of Nephrolithiasis in
ADPKD
With high incidence of h pocitrat ria K With high incidence of hypocitraturia, K
citrate might be useful to prevent uric acid
stones and reduce calcium oxalate super
saturation.
Alkalinization of urine
Copyright Harvard Medical School, 2010. All Rights Reserved.
667
ECSWL in ADPKD
• Can be performed safely, but residual
fragments in ~50% of patients (higher than
in the general population undergoing
lithotripsy).
Percutaneous Nephrolithotomy for
Large & Multiple Upper Tract
Calculi
• Can be done safely when stone >2 cm
• In minority of pts second stage endoscopic
ultrasonic lithotripsy procedure
• Percutaneous basket extraction (?) ( )
• Nishiuria et al CJASN 4:838-844, 2009
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668
Kidney Infection in ADPKD
• 30 to 50% of patients with ADPKD will have a
urinary tract infection either pyelonephritis or urinary tract infection, either pyelonephritis or
cyst infection, during their lifetime
• Urinary tract infections are more common in
women with ADPKD
• Fever and flank pain are the presenting
symptoms y
• Urine culture may be negative in cyst infection,
as cysts frequently don’t communicate with the
collecting system
Hematuria in ADPKD
• Cyst hemorrhage occurs in ~60% of individuals
– gross or microscopic hematuria if cyst connects to
collecting system g y
– intracyst or subcapsular hemorrhage without hematuria
– Correlation with increased TKV
• Excessive angiogenesis results in fragile blood
vessels stretched across walls of enlarging cysts;
susceptible to minor trauma with resultant p
hemorrhage
• Early onset of recurrent gross hematuria correlates
with kidney size and more rapid progression to
kidney failure
Copyright Harvard Medical School, 2010. All Rights Reserved.
669
Cyst Infection v. Intracystic
Hemorrhage in ADPKD:
CT & MR Imaging Criteria
Characteristics of infected c sts on MRI • Characteristics of infected cysts on MRI:
Intensity: higher on T1WI and DWI and
lower on T2WI than uninfected cysts
Fluid-level, cyst wall thickening and
increased density (on both MR & CT) increased density (on both MR & CT)
• Characteristics of hemorrhage on MRI:
Significantly higher T1WI, T2WI and DWI
Irregular higher density on CT
Evaluation of Infection
• PET (positron emission tomography) scan
is most useful in detecting infected cysts
(detects degree of inflammation).
Copyright Harvard Medical School, 2010. All Rights Reserved.
670
Treatment of Hematuria in ADPKD
• Appropriate diagnosis and treatment of
specific entity, such as infection or stone
• Correction of coagulopathy, if present
• Conservative management with hydration,
bed rest, and appropriate use of
analgesics
• Rarely, massive bleeding may require
transfusion, kidney embolization (TAE) or
nephrectomy
Treatment of Kidney Cyst Infection
in ADPKD
• Lipophilic antibiotics such as ciprofloxacin, Lipophilic antibiotics such as ciprofloxacin,
norfloxacin, trimethoprim, chloramphenicol
• Percutaneous or operative drainage is
rarely needed; only for refractory infection
• Resistant organisms
• Localization of infected cyst is difficult y
– Labeled WBC or gallium scan
– MRI with contrast
– PET scan
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671
Liver Cysts: Sx & Infection
• With marked hepatomegaly:
-- heaviness, dull ache
-- mechanical low back pain
-- early satiety
• If fever persists 1-2 wks after antibiotics in
infected cysts, drainage frequently needed
• Hepatic cyst infection more serious than
renal cyst infection. Do not delay drainage.
Carbohydrate Antigen (CA) 19-9:
Marker for Hepatic Cyst Infection
• CA 19-9 secreted by biliary epithelium CA 19 9 secreted by biliary epithelium
lining hepatic cysts and overproduction in
hepatic cyst infection
• Immunostaining for CA 19-9 showed
strong positivity in biliary tree epithelia and
in liver cysts. in liver cysts.
• Rise (active infection) / fall (improvement)
• Kanaan et al AJKD March, 2010
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672
Screening for cerebral aneurysm
Polycystin expression in VSMC and
endothelium vascular
malformation.
A d l t t l t d t Aneurysm development not related to
hypertension in ADPKD, but uncontrolled
BP can accelerate the process
Aneurysm (ICA) Formation
in ADPKD
General Population
ADPKD
Incidence
General Population
2.3 %
16.0 % *
* 2 first degree relatives with ICA,
smoking history, hypertension
ADPKD
~ 8 %
~ 17% ≠
≠With family history of ICA/SAH
90% of aneurysms in anterior circulation
10% of aneurysms in posterior circulation (greater risk of rupture)
Torres 2009
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673
Risk of ICA Rupture in ADPKD
%Yr
1.1
Aneurysm Size
2-6 mm
2.2
2.8
7-9 mm
10-26 mm
0.05% per year < 10 mm. No personal or family history of SAH
0.5% per year < 10 mm. With personal or family history of SAH % p y p y y
Betz KI 63: 2003
Gibbs KI 64: 2004
No Hx SAH
0
Hx SAH
1.5% per year
Risk Factors for ICA Rupture
1. Most aneurysms have a very low risk of
rupture and occurs without a family
history
2. With 2 PKD relatives with SAH the RR =
2.15
3 F > M and ICA > 8 mm 3. F > M and ICA > 8 mm
4. Pack years of smoking
5. Hypertension > 10 years
Torres 2009
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674
Risks of Intervention
Mortality 0.6 – 3.5%
Morbidity 4.1 – 25.4%
Follow up of ICA in ADPKD
< 7 mm Obser ation • < 7 mm Observation
• 7 – 12 mm Risk assessment
• > 12 mm Intervene
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675
Recommendations for ICA
Screening
1 Famil histor of ICA or SAH 1. Family history of ICA or SAH
2. Personal history of SAH
3. Prior to major elective surgery
(transplant)
4 High risk occupation 4. High risk occupation
5. Need for reassurance ?
(A and B) PRA (A) and aldosterone (B) are stimulated in
ADPKD as compared with patients with essential
hypertension.
Schrier JASN 20:1888-1893, 2009
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676
Pathogenetic role of RAAS in ADPKD. In addition to its vasoconstrictor
effect on BP, angiotensin II is known to increase cell proliferation,
angiogenesis, oxidant injury, and fibrosis, known renal components of
ADPKD P t ti l i di t ff t f i t i II i ADPKD. Potential indirect effects of angiotensin II on causing
hypertension include stimulation of the sympathetic nervous system,
endothelium, and aldosterone with sodium retention. Angiotensin II also
stimulates reactive oxygen species, which could account, at least in part,
for the observed endothelial dysfunction in ADPKD.
Schrier JASN 20:1888-1893, 2009
(A) Effect of BP control with
amlodipine versus enalapril on
LVMI in patients with ADPKD over
7 yr.
Effect of rigorous versus
standard BP control on LVMI in
patients with ADPKD over 7 yr
Schrier JASN 20:1888-1893, 2009
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677
Correlation between BP and LVMI in PKD
Schrier JASN 20:1888-1893, 2009
HALT-PKD
(Halt Progression of Autosomal
Dominant Polycystic Kidney Disease)
Objective: Two concurrent, randomized, double-blinded Objective: Two concurrent, randomized, double blinded
controlled trials to assess the effects of multi-level blockade
of the renin-angiotensin-aldosterone system (RAAS) and
aggressive blood pressure control on progression of early
(NKF Stage 1-2) and late (NKF Stage 3) ADPKD over a 5-
year period
H th Hypotheses:
1) Blockade of RAAS will significantly reduce renal
progression as compared to other antihypertensive therapy
2) Lower blood pressure will significantly reduce renal
progression as compared to standard BP targets
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678
Tolvaptan
Diagram depicting putative pathways up- or downregulated in
polycystic kidney disease and rationale for treatment with a V2
receptor antagonists, somatostatin, triptolide; tyrosine kinase,
src, MEK, TNFa, mTOR, or CKD inhibitors; metformin, and CFTR
or KCA3.1 inhibitors (green boxes)
Torres, Harris, KI 76:149-168, 2009
Copyright Harvard Medical School, 2010. All Rights Reserved.
679
Water in Treatment in PKD
Tubule cell proliferation – Transepithelial fluid secretion
cAMP stimulates growth
Enlarging Renal cysts
V2 receptor
AVP (ADH)
Renal dysfunction
Torres, Bankir, Grantham CJASN: 4: 1140-1150, 2009
Blocking action of AVP dramatically ameliorates the disease process
Cysts are the Disease
• Interference with primary cilia formation or its
resident PC1/PC2 complex leads to the resident PC1/PC2 complex leads to the
formation of cysts.
• High cystic burden destroys normal parenchyma
and ultimately results in ESRD for majority of
patients
• Goal is to target cyst growth before it
disconnects from parent nephron. Prevent initial
proliferative phase stemming from cilial defects
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680
Cyst Reduction with mTOR
Inhibitors
C sts de elop beca se of epithelial cell • Cysts develop because of epithelial cell
proliferation, in part mediated by mTOR
• In experimental animals, reduction of
kidney & liver cyst growth (and hence
increase in parenchymal volume) with p y )
mTOR inhibitors
• No change in pain pattern reported in early
limited clinical studies
mTOR Inhibitor Trials
• Everolimus slowed the rate of increased kidney
volume (decreased cell formation & volume (decreased cell formation &
proliferation), but did not alter the rate of decline
in eGFR.
• CRITIQUE: more than half of the volunteers had
Stage 3-4 CKD (“point of no return”). Also
CRISP data explanation. In PKD the GFR p
decline is a late phenomenon and may be
difficult to obtain therapeutic benefit with mTOR
inhibitors at a late stage.
• Walz et al NEJM, June 26, 2010
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681
Sirolimus
• Sirolimus had no effect on changes in kidney
d t l GFR A ti t d and cyst volume or eGFR. A negative study
except for showing side effects of sirolimus
(apthous stomatitis).
• CRITIQUE: Suboptimal dose of sirolimus (as
d t i l t di ) h compared to animal studies) may have
contributed to lack of effect.
• Serra et al, NEJM June 26, 2010
Somatastatin in ADPKD
• Octreotide: no change in kidney cyst
volume after 1 yr. of Rx. In placebo group
there was an ~8% increase in volume,
with improved perception of bodily pain
and physical activity.
• Lanreotide: 3-5% decrease in liver cyst Lanreotide: 3 5% decrease in liver cyst
volume, with improved health perception.
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682
Future Therapeutic Drugs
Act at site of primary cilium to re-establish calcium influx thru PC2 channel
directly or target downstream mediation
Or
Associated protein ssocated p ote
Cell Cycle Inhibition
TNF α inhibition
(Etanercept)
Cell cycle related
Kinase – Nek 8
100
Potential Therapies
HALT PKD
Study A
Tolvaptan
Somatostatin
water
Roscovitine,
Sirolimus,
Everolimus,
Triptolide
HALT PKD
Study B
20
40
60
80
n
a
l

f
u
n
c
t
i
o
n

(
%
)
0
20
0 10 20 30 40 50 60
R
e
n
Age (years)
Torres Mayo <aupCP1047707-9
Copyright Harvard Medical School, 2010. All Rights Reserved.
683
Disclosures
• None
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684
Updat e on
I gA Nephr opat hy
i 2010 i n 2010
GERALD APPEL, MD
Professor of Clinical Medicine Professor of Clinical Medicine
Columbia University –College of
Physicians and Surgeons
NY-Presbyterian Hospital
New York, New York
Financial Disclosures Financial Disclosures
Dr. Appel has research grants, consultanships and
served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer, Bristol-
Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
Copyright Harvard Medical School, 2010. All Rights Reserved.
685
I gA Nephr opat hy
• Most common idiopathic GN world
• Defined by IgA deposition in glomerular
mesangium
• Presents- Young – gross hematuria
Adults – Proteinuria + hematuria
• Not benign hematuria ( Berger’s Dis )
• ESRD in 15-20% by 10 yrs from onset and 30- • ESRD in 15-20% by 10 yrs from onset and 30-
40 % by 20 yrs.
• Risk Factors for Progression.
• Rx – Not one therapy fits all.
IgA Nephropathy IgA Nephropathy
IgA
Copyright Harvard Medical School, 2010. All Rights Reserved.
686
Pathogenesis of IgAN
• Abnormal immune response to mucosal
d i d i t l ti derived environmental antigens.
• Stimulation of IgA1 secreting B cells in
marrow and/or tonsils.
• Defective B1-3 galactosyl-transferase activity g y y
in B cells with excessive synthesis of
galactose-deficient IgA1
Pathogenesis of IgAN
• Auto-Antibody response to GD-IgA1 and Auto Antibody response to GD IgA1 and
formation of immune complexes or self
aggregating IgA ( with impaired clearance )
• Deposition of GD-IgA1 in mesangium - as immune
complexes or self-aggregated GD-IgA ).
M i l C ll lif ti d t i j • Mesangial Cell proliferation, podocyte injury,
capillary hypertension, altered permselectivity
• Glomerulosclerosis/Tubulointerstitial fibrosis.
Copyright Harvard Medical School, 2010. All Rights Reserved.
687
IgAN Pts have Increased Serum Galactose Deficient
IgA1 Levels
Z. Moldoveanu et al Kidney Int 71: 1148-1154, 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
688
IgAN:Δ GFR Prediction
(-ml/min/year)
14
Prediction of Progression in IgAN in 298 Pts
4
6
8
10
12
97mmHg
102mmHg
107mmHg
112mmHg
0
2
4
0.2g/d 0.5g/d 1g/d 2g/d 4g/d 6g/d
g
Bartosik, et al AJKD 38:728-735, 2001
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689
IgA Nephropathy:
Relative Risk of 2xScr after 5.6y
(Nishitani, et al KI 68:1078, 2005)
6
2
3
4
5
6
Male Sex
Age >60y
Scr
Upro
0
1
2
Clinical or Pathologic Features
p
HTN
IgA Nephropathy IgA Nephropathy
IgA
Copyright Harvard Medical School, 2010. All Rights Reserved.
690
IgA nephropathy is
morphologically heterogeneous
(Roberts, et al ASN CNC. 2008)
MEST-Oxford Classification System
• Mesangial Hypercellularity
0= <50%; 1=>50% glomeruli involved g
• Endocapillary proliferation
0= Absent; 1= Present
• Segmental glomerulosclerosis
0= Absent; 1=Present
• Tubulo-Interstitial Fibrosis
0= <25%; 1= 25-50%; 2= >50%
Preliminary Studies Show Good Correlation with Outcome
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691
Difficulties in Treatment Studies in
IgAN
• Slow progression in many – requires use Slow progression in many requires use
of surrogate markers of progression
• Variable rate of progression
• Heterogeneous population- phenotype
• Only a few RTC to define outcome of RX -
Recent meta analysis many “ of low y y
quality and poorly reported”
• Everyone knows how to treat some of the
pts – Nobody is certain how to treat others
IgA Nephropathy:Point of No Return
• “ Point of no Return” is the level of
renal function where no form of specfic p
treatment will improve renal function or
forestall eventual progression to ESRD
• Values vary between a Scr of 2.0 to
3.0mg/dL (eGFR=30-35ml/min-Stage 4
CKD) CKD)
D’Amico, 2001; Komatsu et al J Nephrol 18:690, 2005
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692
Therapy of IgA Nephropathy
• ACE inhibitors, ARB’s, Combinations
• Tonsillectomy
• Glucocorticoids (QD,QOD,Cyclic pulse)
• Fish Oils ( n-3 PUFA )
• Immunosuppressives
Azathioprine + steroids Azathioprine + steroids
Cyclophosphamide + steroids
Mycophenolate mofetil
ACE Inhibitors in IgA
Nephropathy:
A Controlled Trial
• A RCT comparing ACEi or ARB to non-ACEi A RCT comparing ACEi or ARB to non ACEi
therapy in IgA N
• SCr<1.2mg/dl UpV>500mg/d
• Follow-up=75±36mo.
• A 50% increase in SCr from baseline:
3/23 (13%) in ACEi or ARB
12/21 (57%) in PBO
(Praga M, et al. JASN 14:1578, 2003)
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693
Survival without the combined end point of 30%
reduction of baseline CrCl and/or increase in
proteinuria up to >3.5 g/d/ 1.73 m2
Coppo, R. et al. J Am Soc Nephrol 2007;18:1880-1888
Effects of Dietary Sodium and HCTZ on
the Antiproteinuric Efficacy of Losartan
Vogt et al J ASN 19:999-1007,2008
Copyright Harvard Medical School, 2010. All Rights Reserved.
694
RAAS Inhibition in IgA Nephropathy
• The goal of RAAS inhibition therapy
should be to reduce proteinuria to the
lowest value possible (preferably a
Up/Ucr <0.2g/g) without quality of life
interfering symptoms.
• Blood pressure should be maintained
at 110-120mm Hg Systolic at 110-120mm Hg Systolic
• Diuretics + Salt restriction should be
used to augment the anti-proteinuric
action of A-II inhibition
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695
The efficacy of tonsillectomy on
long-term survival in pts with IgAN
• 118 IgAN Bxed 1973-1980
48 / T il d 70 / T il f ll 192 • 48 s/p Tonsilx and 70 w/oTonsilx follow 192 mo.
• No dif in age, gender, Uprot, Screat, SIgA, BP,
histology, Rx.
• Renal survival 90% w Tonsx vs. 64% w/o Tonsx at
240 mo. By MVA tonsilx significant effect on
outcome.
• Tonsillectomy has a favorable effect on long-term
o tcome IF performed earl in the co rse outcome IF performed early in the course.
Xie Y, Nishi S, Ueno M et al. Kidney Int 63:1861-1867,
2003.
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696
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697
IgA Nephropathy:Fish Oils (Omacor)
(Donadio J , et al. Semin Nephrol, 2004)
90%
30%
40%
50%
60%
70%
80%
Fi sh Oi l
Pl acebo
0%
10%
20%
Survi val Free of
ESRD at 8 yrs
Survi val Free of
2XScr at 8 yrs
Multicenter Controlled Trial of QOD
Pred.vs QD Omega 3 FA vs PBO in IgAN
99 IgAN <40yo GFR > 50ml/min Up/Ucr >0.5
33 Pts Randomized to Pred 60mg/m2 QOD x3m with g
taper x 2yr
32 Pts OM-3 FA 4g/d ( 1.88g EPA, 1.48 g DHA ) x 2 yrs
31 Pts PBO x 2 yrs
Primary end-point GFR < 60% baseline;l HBP Rx ACEi
Neither Rx group showed a benefit over PBO g p
14 Rx failures 2 Pred, 8 FO, 4 PBO
Major factor associated w RF was higher baseline
Up/Ucr
Hogg RJ, LeeJ, Nardelli NA, et al. Clin JASN 2006
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698
Therapy of IgA Nephropathy
• ACE inhibitors, ARB’s, Combinations
• Tonsillectomy
• Fish Oils ( n-3 PUFA )
• Glucocorticoids ( QD,QOD,Cyclic
pulse )
• Immunosuppressives • Immunosuppressives
Azathioprine + steroids
Cyclophosphamide + steroids
Mycophenolate mofetil
IgAN: Controlled Trial of Steroids
Pozzi et al. JASN 15:157-163, 2004
Copyright Harvard Medical School, 2010. All Rights Reserved.
699
N = 63
Steroids plus ACEi versus ACEi alone in IgA
Nephropathy
A Prospective Randomized Controlled Trial
N 63
18 to 65 years old
Biopsy-proven IgAN within a one year period
Urine protein excretion of 1-5g/d
Estimated (eGFR) >30ml/min/1.73m
2
according to a
Modified MDRD equation for a Chinese population Modified MDRD equation for a Chinese population.
Jicheng L, … Haiyan Wang. AJKD 2008
Treated with Cilazapril or Combination of cilazapril +
prednisone: 0.8-1.0 mg/Kg/day X 8 weeks tapered by
5-10mg every two weeks
Steroids plus ACEi versus ACEi alone in IgA
Nephropathy
A Prospective Randomized Controlled Trial
A B
Jicheng L, … Haiyan Wang. AJKD 2008
Copyright Harvard Medical School, 2010. All Rights Reserved.
700
PROSPECTIVE RANDOMISED CONTROLLED TRIAL
OF STEROIDS PLUS RAMIPRIL IN
PROTEINURIC IgA NEPHROPATHY
n = 97
Proteinuria > 1g/24h - GFR > 50 ml/min Proteinuria 1g/24h GFR 50 ml/min
ALL PATIENTS
Ramipril
dose titrated to achieve
BP < 120/80 Proteinuria < 1g/24h
RANDOMISATION
Prednisolone 1 mg/kg/d for 2 months
Manno C et al. NDT 2009 Epub 23 July
g g
tapered by
0.2 mg/kg per month
PROSPECTIVE RANDOMISED CONTROLLED TRIAL
OF STEROIDS PLUS RAMIPRIL IN
PROTEINURIC IgA NEPHROPATHY
n = 97
Proteinuria > 1g/24h - GFR > 50 ml/min Proteinuria 1g/24h GFR 50 ml/min
STEROIDS CONTROL
1/48 ESRD 8/49
RAMIPRIL – mean dose 4.5 mg/day
Manno C et al. NDT 2009 Epub 23 July
98% 8 year renal survival 70% P = 0.006
Copyright Harvard Medical School, 2010. All Rights Reserved.
701
Steroids and Cytotoxic Agents in
Progressive IgA Nephropathy
Ballardie, F & Roberts, I. JASN 13:142, 2002
Therapy of IgA Nephropathy
• ACE inhibitors, ARB’s, Combinations , ,
• Tonsillectomy
• Glucocorticoids (QD,QOD,Cyclic pulse)
• Fish Oils ( n-3 PUFA )
• Azathioprine + steroids Azathioprine steroids
• Cyclophosphamide + steroids
• Mycophenolate mofetil
Copyright Harvard Medical School, 2010. All Rights Reserved.
702
ControlledTrial of MMF in IGA
Nephropathy
• 33 pts - Pcreat 1.4 mg/dl UV prot 1.6 g/d
• LowNa+ ACEi • Low Na+, ACEi
• MMF 2g/d vs. placebo x 2 yrs
MMF Placebo
Pcreat 1.48 - 1.71 1.40 – 1.53
UV t 1 79 1 80 1 30 0 75 UVprot 1.79 – 1.80 1.30 – 0.75
In IgA Nephrop. At mod risk no advantage to MMF
Maes BD et al. KI 65:1842-1849, 2004
MMF in IgA GN: A Controlled Trial
Maes R, et al KI 65:1842-9, 2004
2
0 6
0.8
1
1.2
1.4
1.6
1.8
2
MMF
Control
0
0.2
0.4
0.6
UpV Initial UpV 3 yr Scr initial Scr 3 yr
Copyright Harvard Medical School, 2010. All Rights Reserved.
703
MMF in IgA N: A Controlled Trial
(Tang et al, KI 68:802, 2005)
60%
70%
20%
30%
40%
50%
60%
MMF- % CR+PR
Control % CR+PR
0%
10%
20%
2 months 6 months 12 months
Mycophenolate Mofetil in IgA N:
Controlled Trials
Maes (n=34) Tang (n=40) Maes (n 34) Tang (n 40)
MMF- 2.0g/d x 3yr 1.5-2.0g/d x 6mo
eGFR- 71ml/min (Cin) 72ml/min (Ccr)
Scr- 1.43mg/dl 1.59mg/dl
UpV- 1.6g/d 1.8gm/d
SBP- 128mmHg 121mmHg
ACEi/ARB All All ACEi/ARB- All All
Histology- II-III (Churg/Sobin) 3.0 (Haas)
Ethnicity- N. European Oriental
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704
Mycophenolate Mofetil in IgA N:
A Controlled Trial
(Frisch G, et al NDT, 2005)
• A randomized controlled trial of • A randomized, controlled trial of
MMF 2.0gm/d X one year or placebo
in 40 patients* with “ severe, high-
risk” IgA N.
• Average Scr at entry= 2.4mg/dl UpV
> 1.0gm/d;
• All received A-II inhibition
• Follow-up 2 years
Mycophenolate Mofetil in IgA N: A
Controlled Trial
(Frisch G…Appel GB et al NDT 2005)
15.00%
20.00%
25.00%
30.00%
MMF
Control
0.00%
5.00%
10.00%
50% increase i n Scr 50% decrease i n UpV
Control
Copyright Harvard Medical School, 2010. All Rights Reserved.
705
MMF in IgA Nephropathy
• MMF might be more effective if used g
before a “ point of no return” (Scr <2.0-
3.0mg/dl)
• Dosage and duration of MMF required for
a beneficial effect on outcome is uncertain
• Are effects of MMF additive to AII
inhibition and/or Fish Oils?
• Ethnic/Racial associated differences in
pharmacokinetics/pharmacodynamics of
MMF may be important in response
Appel’s Therapy for IgAN in
2010
• All pts ACEi or ARB or ACEi/ARB. All pts ACEi or ARB or ACEi/ARB.
• All pts strongly consider Rx w statin.
• All pts consider low protein diet.
• All pts BP <130/80.
• Tonsillectomy for pts with frequent bad
URI d t illiti URI and tonsillitis.
• Fish Oils for those who want them –
Should not replace other therapies.
Copyright Harvard Medical School, 2010. All Rights Reserved.
706
Appel’s Therapy for IgAN in 2010
Mild Disease- ( nl GFR, < 0.5g Uprot/d, good Bx)
No other Rx. Must have follow to check for
increase in Uprot. And Pcreat.
Moderate or SevereDis. ( Abnl GFR, or > 1gUprot/d, or
Bx w signif activity or risk of progression ,
Crescentic GN)
- Steroids x 6mo
- Consider Cyt +Stds or MMF if other therapy not - Consider Cyt +Stds or MMF if other therapy not
acceptable
-High Pcreat. w Bx chronic damage GS-TIF – no
immunosuppressives
Financial Disclosures Financial Disclosures
Dr. Appel has research grants, consultanships and
served on speaker’s bureaus, adjudication
committees and scientific advisory boards y
of the following companies: Merck, Pfizer, Bristol-
Myers Squibb, Takeda, Roche, Aspreva,
Genentech, Amgen, OrthoBiotech and QuestCor.
Copyright Harvard Medical School, 2010. All Rights Reserved.
707
Amyloidosis
and
Light Chain Deposition Disease
Laura M. Dember, M.D.
Associate Professor of Medicine
Renal Section and Amyloid Treatment and
Research Program
Boston University School of Medicine
Disclosures
Research Support:
--Neurochem, Inc.
--FDA
--Boston University Amyloid Program
--NIDDK
Copyright Harvard Medical School, 2010. All Rights Reserved.
708
Amyloidosis
Group of diseases in which proteins that
are normally soluble deposit extracellularly
in tissues as insoluble fibrils with a
characteristic biochemical structure
Amyloidogenic Proteins Differ
Functionally and Structurally
Transthyretin Lysozyme Apolipoprotein A-I IgG Kappa
Beta 2M A-beta
Copyright Harvard Medical School, 2010. All Rights Reserved.
709
But Resulting Amyloid is Morphologically
Indistinguishable
Classification of the
Amyloidoses
• Amyloidogenic precursor protein
• Distribution of amyloid deposits
– systemic
– localized
Copyright Harvard Medical School, 2010. All Rights Reserved.
710
Systemic Amyloidosi s
Precursor Protein
AL (Primary) Ig Light Chain
AA (Secondary) Serum AA (SAA)
Hereditary
TTR, lysozyme,
ApoA1, ApoA2,
fibrinogen, gelsolin
Senile Systemic TTR
Dialysis-Related 2 microglobulin


Localized Forms
Precursor Protein
Localized AL Ig Light Chain
Alzheimer’s disease A
Creutzfeldt-J akob APrP
Type II DM Amylin

Copyright Harvard Medical School, 2010. All Rights Reserved.
711
Clinical Presentation and
Diagnosis
Patient 1
• 58 yo man with new lower extremity edema
• On exam, hepatomegaly, orthostatic hypotension
• Urinary protein excretion 7.5 g/day, creatinine 1.7 mg/dl,
albumin 3.1 g/dl, cholesterol 340 mg/dl
• Alkaline phosphatase 380 U/L
• Echocardiography: diastolic dysfunction, wall thickening
• Kidney biopsy: Light microscopy - mesangial expansion
with early nodule formation, nodules very weakly PAS-
positive and stain orange-pink with Congo red dye
Copyright Harvard Medical School, 2010. All Rights Reserved.
712
What’s the Disease?
• Does he have amyloidosis?
• If so, what type?
What’s the Disease?
• Does he have amyloidosis?
Copyright Harvard Medical School, 2010. All Rights Reserved.
713
What’s the Disease?
• Does he have amyloidosis?
This is not enough
What’s the Disease?
• Does he have amyloidosis?
– Need polarized microscopy result to call this
Congo red-positive
This is not enough This clinches the diagnosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
714
What’s the Disease?
• Does he have amyloidosis? YES
• If so, what type?
– Can clinical presentation help?
– Can laboratory studies help?
– Can kidney biopsy help?
Clinical Manifestations
AL Amyloidosis
– Can involve any organ/tissue except brain
– Kidney and heart most common
– Liver, ANS, PNS, GI tract, soft tissue, thyroid,
adrenal glands
– Macroglossia is highly specific for AL disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
715
Clinical Manifestations
AA Amyloidosis
– Occurs in setting of longstanding inflammation
(RA, IBD, FMF, osteomyelitis, bronchiectasis)
– Most patients have kidney involvement
– Liver, autonomic nervous system, GI tract
involvement can occur
– Thyroid involvement is more common than in
other types of amyloidosis
– Heart involvement can occur but is unusual
Clinical Manifestations
Hereditary Amyloidoses
Amyl oidogenic Protein Organ Invol vement
Transthyretin Peripheral nervous system, heart, vitreous
opacities. Kidney involvement is not typical.
Fibrinogen Aα chain Kidney, liver, spleen. Hypertension is common.
Kidney involvement is predominantly glomerular.
Apolipoprotein AI Kidney (predominant medullary deposition), liver,
heart, skin, larynx.
Apolipoprotein AII Kidney
Lysozyme Kidney, liver, GI tract, spleen, lymph nodes, lung,
thyroid, salivary glands
Gelsolin Cranial nerves, lattice corneal dystrophy
Cystatin C Cerebral vessels

Copyright Harvard Medical School, 2010. All Rights Reserved.
716
Back to the Patient
• 58 yo man with new lower extremity edema
• Hepatomegaly, orthostatic hypotension
• Urinary protein excretion 7.5 g/day,
serum creatinine 1.7 mg/dl, albumin 3.1 g/dl
• Alkaline phosphatase 380 U/L
• Echocardiography – wall thickening, diastolic
dysfunction
Back to the Patient
• 58 yo man with new lower extremity edema
• Hepatomegaly, orthostatic hypotension
• Urinary protein excretion 7.5 g/day,
serum creatinine 1.7 mg/dl, albumin 3.1 g/dl
• Alkaline phosphatase 380 U/L
• Echocardiography – wall thickening, diastolic
dysfunction
Clinical manifestations suggest
AL disease but not sufficient to make
diagnosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
717
Can Laboratory Studies Help
Determine the Type of Amyloid?
• AL Disease: plasma cell disorder is usually
evident by:
– Serum IFE
– Urine IFE
– Quantitative free light chain assay
– Bone marrow biopsy
– SPEP and UPEP are not sensitive enough!
• AA Disease: No laboratory marker
• Hereditary forms: Isoelectric focusing, DNA
sequencing
• Dialysis-Related: No laboratory marker
Back to the Patient
• SIFE: monoclonal IgG lambda protein
• UIFE: monoclonal lambda light chain
evident by UIFE
• Serum free light chain kappa / lambda
ratio 0.08 (normal: 0.26-1.65)
• Bone marrow biopsy 6% plasma cells with
lambda predominance
Copyright Harvard Medical School, 2010. All Rights Reserved.
718
Does Kidney Biopsy Help Determine
the Type of Amyloid?
Determining Type of Amyloid from Kidney
Biopsy
• Amyloidogenic protein can be identified by
immunofluorescence or immunohistochemistry in some,
but not all, cases.
• Epitopes recognized by commercially available reagents
may be lost.
• Reagents are not available for several of the hereditary
forms.
Lambda LC Kappa LC
Copyright Harvard Medical School, 2010. All Rights Reserved.
719
Does Electron Microscopy Help?
• Amyloid fibrils
– 8 - 12 nm diameter
– non-branching
– random orientation
• Fibrillary GN fibrils
– 15 - 20 nm diameter
– non-branching
– random orientation
• Immunotactoid GN fibrils
– 30 - 60 nm diameter
– non-branching
– ordered orientation
Immunotactoid GN
Abdominal Fat Aspirate
• How sensitive is abdominal fat Congo red
staining?
– AL: sensitivity 80-90%
– AA: sensitivity 65-75%
– Hereditary: probably <65%
• How specific is Congo red staining (of any
tissue)?
– Operator-dependent
– Over-staining is common with inexperienced labs
Copyright Harvard Medical School, 2010. All Rights Reserved.
720
Our Patient has AL Disease
• Amyloid present in kidney
• Plasma cell dyscrasia evident by
hematologic studies
• Single light chain isotype (lambda) present
in kidney
Treatment of Amyloidosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
721
Disorder of Protein Misfolding
Soluble
Precursor
Unstable
Variant
Mutation
Proteolytic event
Environmental factors
Excessive concentration
Disorder of Protein Misfolding
Precursor
Unstable
Fragment
Folding
Intermediate
Self-Aggregation
Amyloid Fibril Degradation
Soluble
Precursor
Unstable
Variant
Folding
Intermediate
Self-Aggregation
Amyloid Fibril Degradation
Mutation
Proteolytic event
Environmental factors
Excessive concentration
Copyright Harvard Medical School, 2010. All Rights Reserved.
722
Treatment Targets
• Precursor Protein Production
• Fibril Formation
• Tissue Deposition
• Degradation
Treatment of AL Amyloidosi s
Copyright Harvard Medical School, 2010. All Rights Reserved.
723
AL Disease: Survival from
Diagnosis in Untreated Patients
Overall 13 mos
Cardiac 6 mos
Renal 21 mos
Peripheral Neuropathy 26 mos
Treatment Targets
• Precursor Protein Production
• Fibril Formation
• Tissue Deposition
• Degradation
Copyright Harvard Medical School, 2010. All Rights Reserved.
724
Reducing Precursor Protein in AL Disease:
Oral Melphalan and Prednisone
1. Skinner et al, Am J Med 1996 Median Survival
--Melphalan/Prednisone/Colchicine 12 months
--Colchicine 7 months
2. Kyle et al, NEJ M 1999 Median Survival
--Melphalan/Prednisone 18 months
--Melphalan/Prednisone/Colchicine 17 months
--Colchicine 8 months
High-Dose Melphalan with Autologous
Stem Cell Transplantation
G-CSF
Stem Cell
Collection
I.V. Melphalan Stem Cell Infusion
Copyright Harvard Medical School, 2010. All Rights Reserved.
725
BU Experience with HDM/SCT
1994-2008
497 Patients
Sanchorawalaet al, ASH 2008
Compl ete Response 40%
Med. Survi val 73 months S
u
r
v
i
v
a
l
Years
5-Year Survi val 55%
Skinner et al, Ann Intern Med 140:85-93, 2004
Non-Complete Response
N=108
Median 5.2 yrs
Impact of Hematologic Response
on Survival
Complete Response
N=73
Median >5 yrs
Yes 73 73 61 49 35 24 16 6 2
No 108 108 77 50 32 17 4 1 0
Copyright Harvard Medical School, 2010. All Rights Reserved.
726
Hematologic Response is Durable
• Relapse rate is low (8%)
• Longest follow-up is 16 years
Proteinuria Improves with Achievement
of Hematologic CR
0
25 25
50
75
100
0
Complete
Remission
Persistent
Disease
Complete
Remission
Persistent
Disease
Urine Protein Creatinine Clearance
2
4
6
8
10
g

/

2
4

h
r
m
l

/

m
i
n
Dember et al, Ann Intern Med 134:746-53, 2001
Baseline
12 Months
Copyright Harvard Medical School, 2010. All Rights Reserved.
727
Treatment Toxicities
• Arrhythmias
• Heart Failure
• Sepsis
• Gastrointestinal bleeding
• Splenic Rupture
• Mucositis
• Acute Kidney Injury
Toxicity
Treatment-Related Mortality at BU:
• 1994-2002 14%
• 2000-2005 9%
• 2004-2008 <5%
Copyright Harvard Medical School, 2010. All Rights Reserved.
728
Toxicity
Treatment-Related Mortality at BU:
• 1994-2002 14%
• 2000-2005 9%
• 2004-2008 <5%
Tolerability Improves with Experience
Skinner et al, Ann Intern Med 140:85-93, 2004
N=173
Median=6.8 yrs
N=136
Median=1.59 yrs
Impact of Cardiac Involvement
on Survival
Copyright Harvard Medical School, 2010. All Rights Reserved.
729
BU Eligibility Criteria for SCT
• Performance status <3 by SWOG criteria
• Left ventricular ejection fraction >40%
• Room air oxygen saturation >95%
• Supine systolic blood pressure greater
than 90 mm Hg
• Criteria are evolving with accumulating
experience
BU Eligibility Criteria for SCT
• Performance status <3 by SWOG criteria
• Left ventricular ejection fraction >40%
• Room air oxygen saturation >95%
• Supine systolic blood pressure greater
than 90 mm Hg
• Criteria are evolving with accumulating
experience AND with emergence of
effective alternatives
Copyright Harvard Medical School, 2010. All Rights Reserved.
730
Summary: Autologous Stem Cell
Transplant for AL Amyloidosis
• Can produce a complete hematologic remission
in a substantial proportion of patients.
• Complete hematologic remission is associated
with prolonged survival and with improvement in
organ function.
• The hematologic response appears to be
sustained.
• Treatment toxicity is prohibitive for many
patients.
Additional Approaches
• Melphalan / dexamethasone
• Modified-dose IV melphalanwith SCT
• Tandem HDM/SCT
• Thalidomide / dexamethasone
• Lenalidomide / dexamethasone
• Bortezomib / dexamethasone
Copyright Harvard Medical School, 2010. All Rights Reserved.
731
Melphalan / Dexamethasone?
80 of 100 Randomized Patients
Underwent Treatment
Copyright Harvard Medical School, 2010. All Rights Reserved.
732
Better Survival in Mel/Dex Group
AA Amyloidosi s
Copyright Harvard Medical School, 2010. All Rights Reserved.
733
AA Amyloidosi s Treatment
• Anti-inflammatory or immunosuppressive
therapy to suppress precursor protein production
(SAA)
– For FMF, colchicine can prevent disease
• Eprodisate – targets amyloid formation and
deposition
– Small molecule developed to interfere with interactions between
AA protein and GAGs and thereby reduce amyloid fibril
formation and tissue deposition
– Appears to reduce rate of decline of kidney function (NEJ M
2007)
– Not approved, not available
Orthotopic Liver Transplantation
for TTR Amyloidosis
• Used since 1991 and now considered the
definitive treatment
• Mutant form of TTR disappears from
circulation
• Issues:
– optimal timing difficult to determine
– wild-type TTR may deposit as amyloid at
sites with pre-existing amyloid.
Copyright Harvard Medical School, 2010. All Rights Reserved.
734
Strategy: Stabilize the Native
Conformation
Sacchettini J C & Kelly J W, Nat Rev Drug Discov 2002
NSAIDs Bind to TTR Tetramer and
Inhibit Dissociation into Monomers
• Multi-center trial using diflunisal as tetramer
stabilizer is underway.
• Could prevent development or progression
of disease.
• Stabilization of wild-type TTR could be of
value after liver transplantation.
• This strategy of “conformation stabilizers”
may be applicable to other amyloidogenic
precursor proteins.
Copyright Harvard Medical School, 2010. All Rights Reserved.
735
Dialysis-Related Amyloidosis
• Kidney transplantation is best treatment
– Symptoms improve even with persistence of
deposits
• Hemofiltration?
• Adsorption membranes?
• Super-flux membranes?
Light Chain Deposition
Disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
736
Monoclonal Immunoglobulin-Associated
Kidney Diseases
• AL amyloidosis
• Light (or heavy) chain deposition disease
• Cast nephropathy
• Waldenstrom’s macroglobulinemic GN
• Immunotactoid glomerulopathy (?)
• Type 1 cryoglobulinemia
• Proliferative GN with monoclonal IgG deposits
Patient 2
• 58 yo man with new lower extremity edema
• Hepatomegaly, orthostatic hypotension
• Urinary protein excretion 7.5 g/day,
serum creatinine1.7 mg/dl, albumin 3.1 g/dl, cholesterol
340 mg/dl
• Alkaline phosphatase 380 U/L
• Echocardiography: diastolic dysfunction, wall thickening
• Kidney biopsy: Light microscopy: mesangial expansion
with nodule formation; nodules very weakly strongly
PAS-positive; no staining with Congo red dye; marked
thickening of tubular basement membranes
Copyright Harvard Medical School, 2010. All Rights Reserved.
737
Patient 2
• Thickened basement
membranes
• Strongly PAS-positive
nodules
• Linear kappa staining of
tubular basement
membranes and periphery
of mesangial nodules
• Continuous glomerular
subendothelial electron
densities
• Electron densities are
granular (not fibrillar)
RoncoP et al. ClinJ Am Soc Nephrol 1: 1342, 2006
Patient 2
• Faint IgG kappa band by serum IFE
• Urine IFE unremarkable
• Serum free light chain kappa / lambda
ratio 287 (normal 0.26-1.65)
• Bone marrow biopsy 4% plasma cells;
kappa clonalityby flow cytometry
Copyright Harvard Medical School, 2010. All Rights Reserved.
738
AL Amyloidosis vs LCDD
• Both can occur with or without multiple myeloma
• Concentration of light chain in serum or urine
can be very low and barely detectable
(sometimes undetectable)
• Kappa or lambda light chain, but lambda more
common in AL amyloidosis and kappa more
common in LCDD
• Kidney manifestations similar: nephrotic
syndrome, progressive loss of GFR
• Extra-renal manifestations can occur in both
(more common in amyloidosis)
Treatment of LCDD
• Until recently, if myeloma was not present
LCDD was considered a form of MGUS
• Now recognized that the light chains are
pathogenic, kidney failure is typical, and
extra-renal manifestations occur
• LCDD starting to be approached in same
way as AL amyloidosis (chemotherapy)
Copyright Harvard Medical School, 2010. All Rights Reserved.
739
High-Dose Melphalan with
Autologous SCT for LCDD
• Royer et al, KI 2004 – 11 patients
• Weichman et al, BMT 2006 – 6 patients
• Lorenz et al, NDT 2008 – 6 patients
Question 1
A 65 year old man with recently diagnosed multiple
myeloma is found to have serum creatinine of 2 mg/dl. 24
hour protein excretion is 3.2 g per day. Urinalysis shows
3+protein, no blood, and no cells or casts in sediment.
Which of the following would you expect to find on kidney
biopsy?
A. Congo red-positivity, non-branching fibrils 10 nm in
diameter by EM
B. Nodular glomerulosclerosis, strong kappa staining of
glomeruli and tubular basement membranes by IF, and
non-fibrillary electron dense deposits by EM
C. Intra-tubular PAS-negative casts and peritubular
interstitial inflammation
D. A or B
Copyright Harvard Medical School, 2010. All Rights Reserved.
740
Question 1
A 65 year old man with recently diagnosed multiple
myeloma is found to have serum creatinineof 2 mg/dl. 24
hour protein excretion is 3.2 g per day. Urinalysis shows
3+protein, no blood, and no cells or casts in sediment.
Which of the following would you expect to find on kidney
biopsy?
A. Congo red-positivity, non-branching fibrils 10 nm in
diameter by EM
B. Nodular glomerulosclerosis, strong kappa staining of
glomeruli and tubular basement membranes by IF, and
non-fibrillaryelectron dense deposits by EM
C. Intra-tubular PAS-negative casts and peritubular
interstitial inflammation
D. A or B
Question 2
A 40 year old woman with LCDD (without multiple
myeloma) develops end-stage renal disease 6 months after
her initial presentation. She begins peritoneal dialysis. She
tells you she would like to undergo kidney transplantation.
What do you tell her?
A. Because she is clinically well without extra-renal
disease it is reasonable to undergo transplantation.
B. She should undergo aggressive treatment of the
plasma cell disorder and pursue kidney transplantation
if there is remission of the plasma cell disorder.
C. She is not a candidate for kidney transplantation
because of the plasma cell disorder, and she is not a
candidate for aggressive treatment of the plasma cell
disorder because she is dialysis-dependent.
Copyright Harvard Medical School, 2010. All Rights Reserved.
741
Question 2
A 40 year old woman with LCDD (without multiple
myeloma) develops end-stage renal disease 6 months after
her initial presentation. She begins peritoneal dialysis. She
tells you she would like to undergo kidney transplantation.
What do you tell her?
A. Because she is clinically well without extra-renal
disease it is reasonable to undergo transplantation.
B. She should undergo aggressive treatment of the
plasma cell disorder and pursue kidney transplantation
if there is remission of the plasma cell disorder.
C. She is not a candidate for kidney transplantation
because of the plasma cell disorder, and she is not a
candidate for aggressive treatment of the plasma cell
disorder because she is dialysis-dependent.
Key References
1. Merlini G and Bellotti V. Molecular mechanisms of amyloidosis.
N Engl J Med 2003; 349:583-596
2. Falk RH, Comenzo RL and Skinner M. The systemic amyloidoses.
N Engl J Med 1997; 337:898-909
3. Dember LM. Amyloidosis-associated kidney disease. J Amer Soc
Nephrol 2006; 17:3458-71
4. Skinner M, Sanchorawala V, Seldin et al. Survival and clinical
response to treatment with high-dose melphalan and autologous
stem cell transplantation in paitents with AL amyloidosis: an 8-
year study. Ann Intern Med 2004; 140:85-93
5. Ronco P, Plaisier E, Mougenot B, Aucouturier P. Immunoglobulin
light (heavy)-chain deposition: from molecular medicine to
pathophysiology-driven therapy. Clin J Am Soc Nephrol 2006;
1:1342-50
Copyright Harvard Medical School, 2010. All Rights Reserved.
742
Disclosures
Research Support:
--Neurochem, Inc.
--FDA
--Boston University Amyloid Program
--NIDDK
Copyright Harvard Medical School, 2010. All Rights Reserved.
743
Pregnancy and
Renal Disease Renal Disease
Robert A. Cohen M.D.
Beth Israel Deaconess Medical Center
Harvard Medical School
Disclosures
• None
Copyright Harvard Medical School, 2010. All Rights Reserved.
744
Case One
A 28 year-old G0,P0 consults you about risks
i l d i b i t Sh h I A involved in becoming pregnant. She has IgA
nephropathy diagnosed by renal biopsy at age
14. She complains of swelling in her ankles at
the end of the day. She has proteinuria;
creatinine has gradually increased. She is taking
lisinopril 20 mg daily but uses no NSAIDS Her lisinopril 20 mg daily but uses no NSAIDS. Her
blood pressure is 152/100 and she has 1+
pretibial edema.
Case One (cont.)
The urine dipstick reveals 3+ protein and 3+
heme; microscopically she has 5-12 RBC/HPF,
mostly acanthocytes.
BUN 31 mg/dl; creatinine 2.1 mg/dl; albumin 4.2
mg/dl, Hb 12.4
Urine protein/creatinine ratio 2.4
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745
Question #1:
Which statement(s) is(are) true?
A) IgA nephropathy with proteinuria portends > 50% risk of
l t d i f l f ti pregnancy-related worsening of renal function.
B) An increase in proteinuria and plasma creatinine is
expected in first half of pregnancy.
C) The risk of pregnancy-related decline in renal function
is < 10%.
D) The risk of pregnancy-related decline in renal function
may exceed 30% may exceed 30%.
E) A. and B.
F) B. and D.
G) None of the above.
Question #2:
Which statement(s) most accurately
describe(s) the risk to her pregnancy?
A) Sh i t i d i k f l i A) She is at increased risk for preeclampsia.
B) Fetal survival is reduced due to underlying
IgA nephropathy.
C) The fetus will be at increased risk for
prematurity and intrauterine growth restriction.
D) A and C D) A. and C.
E) B. and C.
F) A., B. and C.
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746
Fundamental Issues
• What is the impact of pregnancy on renal
function in patients with underlying renal disease
or impaired renal function?
• What is the impact of underlying renal disease or
impaired renal function on the fetus?
Data Are Limited
• No randomized clinical trials, no meta-anaylses
Difficult to identify appropriate controls • Difficult to identify appropriate controls
• Primarily small series
• Usually only one or a few collaborative centers
• Absence of uniform data points; limited # data points
• Variable, often limited, post-partum follow-up
• Difficulty distinguishing whether acceleration of
renal insufficiency during or right after renal insufficiency during or right after
pregnancy is due to pregnancy or natural history
of renal disease.
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747
Impact of Pregnancy on Renal
Disease/Renal Insufficiency
D d tl it f d l i l di • Depends mostly on severity of underlying renal disease
at onset of pregnancy
• Depends in part on whether hypertension controlled
during pregnancy
• Whether severe preeclampsia occurs
• Less dependant on type of renal disease
• Some small series suggest MPGN and FSGS important
• Diabetes may excacerbate proteinuria and hypertension
• Lupus nephritis—activity of disease affects pregnancy
Normal Renal Function at Baseline
(With or Without Renal Disease)
• Creatinine tends to decrease first half of
pregnancy (due to increased GFR)
• Baseline proteinuria (if present) tends to
increase
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748
Mild Renal Insufficiency
(Creatinine < 1.4 mg/dl)
• Data from several small series with mild
renal insufficiency at baseline: Minimal to
no impact of pregnancy in terms of
acceleration renal insufficiency.
Moderate to Severe Renal
Insufficiency Creatinine ≥ 1.4 mg/dl
• Largest Series: 82 pregnancies with creatinine ≥ 1 4 at • Largest Series: 82 pregnancies with creatinine ≥ 1.4 at
conception (mean creatinine = 1.9)
• Mean creatinine increased to 2.5 by 3
rd
trimester
• 20% had worse renal function during pregnancy
• 23% had worse renal function by 6 wks post-partum
• 8% recovered; 10% declined further
• 8 women (10%) → ESRD within year of pregnancy
• Creatinine >2.0 outset: Highest likelihood decline (33%
had accelerated decline renal function)
Jones DC, Hayslett JP. N Enl J Med 1996;335:225-32.
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749
Impact of Renal Disease on
Pregnancy Outcomes
• Fetal Survival Good (70 to 100%) • Fetal Survival Good (70 to 100%)
• Lower with uncontrolled hypertension
• Especially with MAB > 105 start of conception
• Risk of Prematurity estimated 45 -70%
• Risk of Intrauterine Growth Restriction estimated
20-50%
• Risk of Preeclampsia increased • Risk of Preeclampsia increased
• Greater risk of occurrence during late 2nd trimester
• Associated with both prematurity and intrauterine
growth restriction
Question #1:
Which statement(s) is(are) true?
A) IgA nephropathy with proteinuria portends > 50% risk of
pregnancy-related worsening of renal function. pregnancy related worsening of renal function.
B) An increase in proteinuria and plasma creatinine is
expected in first half of pregnancy.
C) The risk of pregnancy-related decline in renal function
is < 10%.
D) The risk of pregnancy-related decline in renal function
may exceed 30%. may exceed 30%.
E) A. and B.
F) B. and D.
G) None of the above.
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750
Question #2:
Which statement(s) most accurately
describe(s) the risk to her pregnancy?
A) Sh i t i d i k f l i A) She is at increased risk for preeclampsia.
B) Fetal survival is reduced due to underlying
IgA nephropathy.
C) The fetus will be at increased risk for
prematurity and intrauterine growth restriction.
D) A and C D) A. and C.
E) B. and C.
F) A., B. and C.
Case Two
A 32 year old G0P0 has diffuse proliferative lupus
nephritis diagnosed 19 months ago on renal biopsy. She nephritis diagnosed 19 months ago on renal biopsy. She
was treated with mycophenolate mofetil. Her labs at
diagnosis: creatinine 1.5 (0.7 previously); dsDNA titer
1:1280; C3 28 (90-180); C4 6 (10-40); urinalysis 4+
protein 3+ heme with many acanthocytes, wbcs and
mixed cellular casts; urine protein/creatine ratio 9.2.
She currently feels great. Exam is unremarkable. Labs:
creatinine 0 8 C3 65 and C4 9 normal dsDNA titer and creatinine 0.8, C3 65 and C4 9, normal dsDNA titer and
urine protein/creatinine ratio 0.6. Her urine sediment is
now unremarkable. Her anti-Ro and anti-La negative;
aPL negative. She inquires about becoming pregnant.
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751
Question # 1
Which statement is true?
A. Worsening proteinuria is an excellent indicator
of lupus relapse during pregnancy.
B. Her risk for fetal loss or preterm delivery is now
comparable to the general population
C. Azathioprine can be used to treat a lupus
relapse during pregnancy.
D. All of the above.
E. None of the above.
Lupus Nephritis and Pregnancy
• Mayo Clinic Cohort: 90 pregnancies in 58
women with SLE—retrospective analysis women with SLE retrospective analysis
• 47 SLE without LN at conception
• 23 active LN at conception
• Urine prot/creat ratio ≥ 0.5 and/or active urine sediement
• 20 quiescent LN
• Urine prot/creat ration < 0.5 and inactive sediment
• Identified maternal and fetal complications
• Maternal: preeclampsia, eclampsia, HELLP syndrome,
t k t l d th stroke, maternal death
• Fetal: preterm births, fetal loss
Wagner SJ et al. Lupus 2009;18:342-347.
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752
Lupus Nephritis and Pregnancy: Mayo
Clinic Cohort
Results:
Maternal complications in active LN much greater • Maternal complications in active LN much greater
compared to SLE without LN
• 57% versus 11% (P < 0.001)
• Higher preterm births active LN vs. SLE no LN
• 52% versus 19% (P < 0.001)
• Higher rate fetal loss active LN vs. SLE no LN
• 35% versus 9% (P < 0.03)
• Maternal and fetal outcomes better for SLE without
LN compared to quiescent LN
Wagener SJ et al. Lupus 2009; 18:342-347
Lupus Nephritis and Pregnancy
• Retrospective analysis: 118 pregnancies in 81
Italian women with LN Italian women with LN
• Biopsy proven prior to conception
• Hypocomplementemia at conception predicted poor
fetal outcome
• Low-dose aspirin appears to be protective
• Renal flare during or right after pregnancy predicted
by renal status at conception by renal status at conception
• Significantly higher likelihood in active LN compared with
remission or partial remission
Imbasciati E et al Nephrol Dial Transplant 2009;24:519-525
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753
• Active lupus nephritis associated with
increased fetal loss pre term delivery and
Lupus Nephritis and Pregnancy
increased fetal loss, pre-term delivery and
maternal complications
• Risk even higher if antiphospholipid Ab
positive
• Maternal risk: increased thrombosis and
preeclampsia
• Fetal risk: early and late miscarriage, prematurity
Andrade R et al Clin Exp Rhem 2008:28;268-274
Lupus Nephritis in Pregnancy
• Lupus nephritis flare or preeclampsia ?
H l t i d i d d DNA tit i l • Hypocomplementemia and increased dsDNA titers in lupus
nephritis; thrombocytopenia in either
• Active urine sediment and proteinuria in lupus nephritis
• Proteinuria alone seen with preeclampsia but can be seen
with lupus nephrits
• Treatment lupus nephritis
Glucocorticoids and azathioprine safe • Glucocorticoids and azathioprine safe
• Hydroxychloroquine also safe for extra-renal lupus
• Cyclophosphamide and mycophenolate mofetil not safe
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754
Question # 1
Which statement is true?
A Worsening proteinuria is an excellent indicator A. Worsening proteinuria is an excellent indicator
of lupus relapse during pregnancy.
B. Her risk for fetal loss or preterm delivery are
now comparable to the general population
C. Azathioprine can be used to treat a lupus
relapse during pregnancy relapse during pregnancy..
D. All of the above.
E. None of the above.
Case Three
A 41 y.o. nulliparous woman who underwent in-vitro
fertility is now pregnant with twins. She has enjoyed fertility is now pregnant with twins. She has enjoyed
good health but is obese and has a 20-year smoking
history. The first half of pregnancy has been
uneventful. At 32 ½ weeks she is hypertensive
(145/98) and has proteinuria (urine protein/creatinine
ratio 1.7). Five days later she complains of
persistent, severe headache and right upper
quadrant abdominal pain The blood pressure is quadrant abdominal pain. The blood pressure is
165/108. Platelet count is 70, creatinine 1.3, AST 94,
and ALT 92.
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755
Question #1:
Which statement(s) is(are) true?
A) Risk factors for preeclampsia include A) Risk factors for preeclampsia include
primagravida status, advanced maternal age,
mutiple gestation pregnancy, cigarette smoking,
and obesity.
B) Definitive treatment is delivery
C) Preeclampsia most likely would have been
averted with low-dose aspirin and calcium averted with low dose aspirin and calcium
supplementation during pregnancy.
D) A. and B.
E) B. and C.
Preeclampsia
• Systemic disorder unique to pregnancy
marked by new onset hypertension and
proteinuria after 20 weeks gestation
• Eclampsia: onset of seizures in
preeclampsia
Preeclampsia may be superimposed on • Preeclampsia may be superimposed on
chronic hypertension in pregnancy
• Incidence is 3-14% pregnancies worldwide
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756
Risk Factors
• First pregnancy, prior preeclampsia, family
history preeclampsia, multiple gestation,
obesity, pre-gestational diabetes, pre-
existing renal disease, pre-existing
hypertension, advanced maternal age,
antiphospholipid antibody syndrome (aPL). p p p y y ( )
• Cigarette smokers have lower risk preeclampsia v.
nonsmakers
Pathogenesis
• Disorder of placental hypopoxia/ischemia
• Due to impaired trophoblast invasion or
diff i i differentiation (impaired implantaton)
• Leads to generalized endothelial dysfunction
• Manifested by: hypertension, platelet activation, CNS changes,
seizures, glomerular endotheliosis, proteinuria, renal insufficiency,
hepatic ischemia/ necrosis, edema, hemolysis
• Marked by increased placental secretion/expression
ti i i f t ( Flt d l bl d li ) antiangiogenic factors (sFlt and soluble endoglin)
• Bind placental growth factor (PlGF) and VEGF
• Rising circulating levels sFlt1 may predict preeclampsia
Levine et al. N Engl J Med 2004;350:672.
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757
Severe Preeclampsia
Defined as preeclampsia accompanied
by at least one of following: by at least one of following:
cns dysfunction; liver capsule distension;
hepatocellular injury (transaminases > twice
normal); marked blood pressure elevation;
thrombocytopenia, marked proteinuria (≥ 5 g/24
hrs); oliguria; severe fetal growth restriction; hrs); oliguria; severe fetal growth restriction;
pulmonary edema; stroke
ACOG Practice Bulletin #33, January 2002
Preeclampsia: General
Management Principles
• Definitive teatment is delivery
• Prevents maternal or fetal complications
• Timing of delivery—depends on preeclampsia
severity, gestational age, maternal and fetal status
• Corticosteroids should be given at 24-34 weeks gestation in
l i preeclampsia
• Promotes fetal lung maturation
• Severe preeclampsia: delivery indicated regardless of
gestational age
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758
Preeclampsia:
Seizure prophylaxis
• Magnesium sulfate: drug of choice for Magnesium sulfate: drug of choice for
preventing eclampsia
• Evidence suggests use reduces incidence of
eclampsia
• But no effect on disease progression aside from seizure
prevention
• Dose for renal insufficiencyy
• Observe for toxicity (loss of deep tendon reflexes,
respiratory paralysis, cardiac arrest)
• Calcium gluconate---antidote for toxicity
Preeclampsia: Hypertension
Treatment
• Lack of data about level of blood pressure to treat • Lack of data about level of blood pressure to treat
• Does not alter the course of preeclampsia
• Concerns about deleterious effects of blood pressure
lowering on fetal growth need to be weighed with
concern for possible maternal vascular complications
(especially stroke)
• Usually treat systolic >150-160; diastolic > 100
• Medications for acute blood pressure lowering: IV
labetalol, hydralazine (less commonly diazoxide)
• Avoid sodium nitroprusside—possible fetal cyanide poisoning
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759
Mild Preeclampsia
Management
• Frequent monitoring, including labs
• Deliver by 36 to 38 weeks
• unless severe preeclampsia or abruption
placentae, marked fetal growth restriction, non-
reassuring fetal testing, or oligohydramnios
develop
Preeclampsia Prevention
• No clearly established preventive
measures
• Some data (very small studies) suggest
possible benefit of low-dose aspirin in
prevention in high risk groups p g g p
• But weight of evidence not strong
• No benefit from calcium supplementation
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760
Other Forms Hypertension in
Pregnancy
• Chronic hypertension: Antedates pregnancy
(systolic ≥ 140 and diastolic ≥ 90 mmHg)
• Limited data regarding degree of hypertension to treat
and target goals
• Expert opinion: treat bp > 150/95-100 mmHg
• Aim for lower levels if end-organ damage present g g p
• Gestational hypertension: mild hypertension
latter half pregnancy (but no proteinuria or other
signs preeclampsia)
Antihypertensive Drugs in
Pregnancy
D f h i • Drugs of choice:
• Methyldopa: 50 years experience; excellent long-term
safety profile
• No alteration of uteroplacental or fetal hemodynamics
• Labetalol: both alpha and beta-adrenergic blocking
properties; may have less impact on uterine/placental
blood flow than other beta blockers blood flow than other beta blockers
• Nifedipine (long-acting): appears safe
• Less data on diltiazem and verapamil but likely safe
• May worsen hypotension and neuromuscular blockade if
magnesium sulfate used for preeclampsis
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761
Antihypertensive Drugs in
Pregnancy
D t id • Drugs to avoid:
• ACE inhibitors and ARBs
• First trimester exposure: higher risk major congenital
malformations, esp. cardiovascular and cns malformations
• Later pregnancy exposure: oligohydramnios, hypocalvaria
• Drugs to use with caution:
Diuretics: avoid volume depletion • Diuretics: avoid volume depletion
• Beta blockers: may ↓ uterine/placental blood flow;
may be linked to intrauterine growth restriction and
fetal bradycardia
Question #1:
Which statement(s) is(are) true?
A) Risk factors for preeclampsia include A) Risk factors for preeclampsia include
primagravida status, advanced maternal age,
mutiple gestation pregnancy, cigarette smoking,
and obesity.
B) Definitive treatment is delivery
C) Preeclampsia most likely would have been
averted with low-dose aspirin and calcium averted with low dose aspirin and calcium
supplementation during pregnancy.
D) A. and B.
E) B. and C.
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762
Case Four
A 28 year-old woman who underwent a deceased
d l t l t 26 th i 6 donor renal transplant 26 months ago is now 6
weeks pregnant (unplanned pregnancy). She
has CKD due to focal segmental
glomerulosclerosis. Her immunosuppressive
medications include prednisone, tacrolimus and
mycophenolate mofetil She is not hypertensive mycophenolate mofetil. She is not hypertensive.
The creatinine is 1.2 mg/dl and the urine
protein/creatinine ratio is 0.4.
Question #1:
Which Statement is true?
Sh h ld ti h t i i A) She should continue her current immunosuppressive
medications.
B) Preeclampsia occurs in about two thirds of pregnant
recipients of renal grafts.
C) A. and B.
D) None of the Above
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763
Pregnancy in Recipients of Renal
Transplants
• ESKD associated with infertility ESKD associated with infertility
• Altered hypothalamic function
• Increased levels FSH, LH, prolactin
• Most anovulatory
• incidence pregnancy estimated 0.5% yearly
• Transplantation restores fertility in women
• Usually within months
• Some woman have no restoration of fertiliy • Some woman have no restoration of fertiliy
• ESKD can be associated with early menopause
• Average 4.5 years earler than general population
• Optimal contraception in place before transplantation
• Women have become pregnant in peri-transplant interval
Pregnancy in Recipients of Renal
Transplants
Timing of pregnancy individualized • Timing of pregnancy individualized
• Avoid in peri-transplant interval
• Highest potential exposure to fetotoxic and
teratogenic medications
• Highest doses of immunosuppressive
medications used
• Highest risk for rejection
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764
Pregnancy in Recipients of Renal
Transplants
• Previous advice: wait two years
• New AST Consensus: proceed when
• Graft function optimal (creatinine < 1.5 and proteinuria
< 500 mg/day)
• No fetotoxic infections
• No use of fetoxic or teratogenic medications
Immunosuppressive medication doses stable and at • Immunosuppressive medication doses stable and at
maintenance levels
• Usually about one year after transplant
McKay et al. Am J Transplantation;5:1-8,2005.
Pregnancy in Recipients of
Renal Transplants
• Risk of pregnancy-related renal function
decline
• Depends on renal function at outset of
pregnancy
• Generally, creatinine < 1.3 confers little risk
• Creatinine > 1.5 and proteinuria > 500 mg/24
hours confers increased risk irreversible graft loss
• Risk of preeclampsia about 32% (NTPR registry data)
Armenti et al. Clin Transpl 103-119, 2005.
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765
Pregnancy in Recipients of Renal
Transplants
• Risks of Pregnancy to fetus
• Preterm delivery rate 50 to 64%
• Mainly due to maternal and/or fetal compromise
• High risk premature rupture membranes
• Low birth weight rate about 50%
• Intrauterine growth restriction rate about 50%
Most cases thought due to hypertension and/or • Most cases thought due to hypertension and/or
preeclampsia or renal insufficiency
• High incidence (~20-26%) developmental delays
reported after age 5 (NTPR)
Stanley et al Transplant Proc 31:241-242, 1999
Pregnancy in Recipients of Renal
Transplants
• Safety of immunosuppressive drug use in pregnancy not
clearly established clearly established
• All pass through maternal-fetal circulation
• Some drugs appear safer than others
• FDA classifications not helpful—None labelled “A”
• Azathioprine and low-dose prednisone
• Minimal adverse effects on fetus
Fetal liver lacks enzyme to metabolize azathioprine • Fetal liver lacks enzyme to metabolize azathioprine
• Placenta metabolizes prednisone
• Calcineurin Inhibitors
• Monitor levels carefully to prevent toxicity
• Avoid sirolimus and mycophenolate mofetil
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766
Question #1:
Which Statement(s) is(are) true?
Sh h ld ti h t i i A) She should continue her current immunosuppressive
medications.
B) Preeclampsia occurs in about two thirds of pregnant
recipients of renal grafts.
C) A. and B.
D) None of the Above
Pregnancy and Renal Disease:
Conclusions
• Likelihood of pregnancy-related worsening of renal
function depends on degree of impairment at outset of p g p
pregnancy
• Fetal survival very good with renal disease but risk of
prematurity and intrauterine growth restriction increased
• Preeclampsia risk increased with renal disease
• Monitor closely for possible onset in 3
rd
trimester Monitor closely for possible onset in 3 trimester
• Fertility restored by transplantation
• Know which antihypertensives and immunosuppressive
medications to use or to avoid in pregnancy
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767
Disclosures
• None
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768
Treatment of Glomerulonephritis
J eremy S Duffield MD PhD
Laboratory of Inflammation Research, Renal Division,
Brigham & Women’s Hospital, & Harvard Medical School,
Boston, MA
http://duffieldlab.bwh.harvard.edu
Disclosures
• Scientific Advisory Board for Promedior
Inc and Regulus Therpeutics
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769
Rapidly Progressive Glomerulonephritis
Definition: Clinical syndrome characterized by rapid loss of renal
function (<3months)
• With features of glomerulonephritis:
o Dysmorphicred cells, red cell casts, leukocyturia, granular casts
o Glomerularproteinuriaoften >3g/d
• Often assoc with oliguria/anuria
• A renal biopsy will show >50% Crescents
• Also called crescentic GN
• Often referred to as nephritic syndrome (overlap)
• Most aggressive form of glomerularinjury
Pathol ogy:
a) fibrinoidnecrosis,
b) epithelial cell crescents,
c) destruction of glomerularcapillaries,
d) vasculitis in small vessels,
e) varying degrees of tubular injury (ATN)
RPGN differential
• Atheroembolic disease
• Acute thrombotic microangiopathy (TMA)
• ATN +/- underying chronic GN
• AIN
• Crystalopathies
• Acute myeloma kidney
• Obstruction
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770
Algorithm for diagnosing the causes of
RPGN
Rapidly progressive glomerulonephritis
Type I Type II Type III
What is severe glomerulonephritis?
Type II: Immune complex deposition triggers activation of
leukocytes (innate immunity) +/- autoimmunity against nuclear
proteins
Type I: Autoimmunity (cell mediated & humoral)
againstglomerularbasementmembrane
Type III: Pauci-immune with leukocyte activation triggered
in the glomerularcapillaries by anti-leukocyte antibodies &
anti-leukocyte cell mediated immunity
Glomerulus: highly specialized vasculature with
fenestrated endothelium unique CBM, high shear
stresses & specialized high density pericyte
(podocyte)
CD68
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771
Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
Disease Mechanisms
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Type II
RPGN
Type I
RPGN
PMN
Monocyte
CD8 T cell
Type III: Model of the role of ANCAs
in disease initiation
TNF
Secondary
inflammation
H
2
O
2
H
2
O
2
C5a
1. 2. 3.
Primed neutrophil
Primed monocyte
ANCA
Integrin
Integrin receptor
Fc gamma receptor
Granules or lysosomes
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772
Frequency of presentation RPGN by
glomerular pathology
Type I
Type II
Type III
Brenner’s The Kidney, 7th Ed, 2007
Characteristic glomerular pathology
• Focal necrosis
• Fibrinoidnecrosis
• Karryorrhexis (nuclear
fragmentation)
• Capillary rupture
• Crescent formation
• Endocapillaryinflammation
• Vasculitis
• Leukocyte infiltration
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773
Range of clinical presentations
by disease type
Remember RPGN may
be superimposed on
other common
glomerulardiseases
(ischemic vasculopathy
or diabetic nephropathy)
What tests should I order?
Immune panel:
CH50, C3, C4, ANA, dsDNA (Ro, La), CRP, RhF, cryoglobulins, IgE,
anti-GBM, ANCA IF, anti-PR3, anti-MPO, SPEP, UPEP
Infection panel:
HepB, HepC serology and viral load, ASOT, blood cultures, other anti-
sera
Other: eosinophils blood/ urine, FE Na
Urine: microscopy, Upr/UCr
US kidneys:
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774
Treatment objectives
• Prevent immune complex deposition and or
formation
• Prevent myeloid leukocyte activation in
response to immune complexes or
autoantibodies
• Prevent autoimmunity (antigen presentation,
autoreactive T cell and B cell clones)
• Prevent secondary inflammation
• Allow speedy repair of parenchymal cells
Treatment options
• Prednisone/methylprednisolone: Anti-inflammatory and leukocyte
cytotoxic
• Cytotoxic
– Cyclophosphamide
• Anti-T cell
– Tacrolimus/cyclosporin
• Antiproliferative
– Azathiaprine
– Mycophenolate
• Plasmapheresis
• Anti-viral
• Cytotoxicantibody therapies (eganti CD20, anti CD52, ATG
• Supportive therapies
• Treatment of infections where appropriate
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775
Pauci-immune GN / type III RPGN – only
seen in ANCA associated vasculitis (AAV)
• Common
• Initially thought to be adaptive cell-mediated autoimmunity
• ANCA identified in 1988 (Falk & J ennette,Niles, Goldschmeding
1989)
• 1993 antibodies first described to be potentially pathological
• Rat Model 1993
• Mouse model 2003
• Abs alone induce disease but probably require PMN and endothelial
cell activation
• However frequently no PMN seen in the glomerulus. Secondary (?)
inflammation with T cells and monocytes
RPGN manifestations of ANCA
associated Vasculitis (AAV)
Disease Clinical Characteristics %MPO %PR3
ChurgStrauss Syndrome Asthma, eosinophilia, neuopathy, nephritis 30-70 <10
Wegener’s Granulomatosis nose bleeds URT, nephritis, lung lesion 10-30 >70
Granulomas
Microscopic Polyangiitis Nephritis, alveolar hemorrhage, purpura 30-70 10-30
No granulomas
Renal Limited Vasculitis Nephritis only 30-70 10-30
BVAS (1994)-clinical activity score
Evidence of vasculitisin 10 organ systems: General (4), cutaneous(5), mucous
membranes/eyes (10), ENT (5), chest, (7) cardiovascular (6), abdominal (3),
renal (7), nervous system (9), other (4)
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776
Not all AAV is RPGN
• Natural History of Wegener’s
Granulomatosis
Hoffman et al, Ann Int Med 1992; 116:488-498
• Study of 158 patients
• 8% of patients: diagnosis made 5-16 yrs after symptoms began
• 90% of pts 1
st
sought med care due to upper or lower resp tract symptoms
• 18% with GN at presentation: in all cases renal disease was asymptomatic.
• 77% of patients eventually developed GN, usu. within 2 years.
• 11% developed ESRD.
• 88% C-ANCA; 5% P-ANCA
ANCAs: what are they and how to
interpret antibody results?
• Immunofluorescence
• pANCA or cANCA pattern
• Ethanol vs formalin fixation
• 1:20 cut off
• Exclude ANA
• Majority of targets are MPO and PR3
• Minority are lactoferrin, CathepsinG, elastase and others
• Also there are some IgA and IgM ANCAs
• Plasma concentrations of ANCAs (Especially anti-PR3)
correlate with disease activity
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777
ELISAs for MPO & PR3
• Csernocket al Rheumatology (2002)
41:1313
• IIF alone (1:20 cut off) sens 80% (WG)
70% (MPA) spec 100% (WG) 100 (MPA)
Better sens +spec for IIF than 7
commercial ELISAs.
• Meta-analysis: Choi et al J Rheum (2001)
28: 1584
• MPO sens 37% (CI: 27-47) spec 96% (CI
94-98). Combined with IIF 31% 99%
• PR3 +MPO +IIF sens 85% spec 98%
• Recommend IIF +ELISA
Anti PR3
Anti MPO
Bolton/Couser/Cameron 1970’s
Bolton and Couser, Am J Med 1979(66):495-502
Fauci 1983 Annals Int Med;98(1):76-85.
Pusey et al Kid Int (1991)
Mepex Trial (2007) J ayne et al J ASN 18: 2180
Euvas Trial NEJ M (2003) 349:36
Copyright Harvard Medical School, 2010. All Rights Reserved.
778
Anti-GBM disease/Goodpastures
syndrome: Type I RPGN
• Rare
• Either pulmonary renal or renal limited disease
• Linear deposition of antibody along GBM (>95%
IgG+C3, rarely IgMor IgA)
• Plasma concentrations correlated with disease
• Eluted antibodies transferred disease to Monkeys
• However there are patients with antibody
deposition and no disease
• If associated with lung hemorrhage, known as
Goodpasture’s syndrome
• Rapid access to anti-GBM antibody assay required
• Frequently associated with ANCA disease
Goodpasture’s: disease
mechanisms
• Disease susceptibility: HLA-DR2 (class II MHC)
• The antigen is non-collagenous domain of
Collagen IV of GBM
• 90% of Abs directed against alpha3(IV)NC1
(majority 7AA segment)
• Rarely against 1 or 4 collagen chains
• Although autoantibody is pathogenic there is
unequivocal evidence for T cell mediated
autoimmunity as well (Kalluri et al J CI 1997,
Reynolds et al NDT 2002)
Copyright Harvard Medical School, 2010. All Rights Reserved.
779
Demographics of anti-GBM
disease
Savage et al Brit Med J 1986. Study of 71pts
• Male: female. No preponderance. Broad range of ages
• Goodpasture’s syndrome in 30%
• Antibody Titres correlated with disease severity
• 2/3 presented dialysis dependent
• Hypertension rare.
• 10% had arthitis/myalgia/vasculiticrash (probably had
renal limited ANCA disease as well)
• Not all anti-GBM disease is RPGN
Presentation & outcome for anti-GBM
disease
Levy et al Ann Int Med (2001).
Single centre retrospective analysis 71 Pts. All treated with Pred, CYC and PEx
Proportion with
lung involvement
White bars =lung hemorrhage
Gray bars =no lung disease
%men
Copyright Harvard Medical School, 2010. All Rights Reserved.
780
Outcomes for patients with anti-GBM
disease
•Very small chance of renal recovery if dialysis dependent.
•If dialysis dependent and no lung hemorrhage consider not
using immunosuppression
Kaplan-Meier Plots
Outcome by %crescents and
presenting renal status
%

c
r
e
s
c
e
n
t
s
Final dialysis dependent
Final dialysis independent
Anti-GBM disease (based on case series data)
Prednisone 1mg/kg (≤ 80mg) 3mo then
taper
CYC2.5mg/kg/d 3mo then taper.
Titrate against lymphocyte count
Plasma exchange 4L qd for 14 days
MONITOR ANTI-GBM LEVELS
Consider IV methylprednisolone 1gX2-3 for
veryactive disease
Consider AZA 1mg/kg/d
Maintenance Induction
Prednisone & AZA
(Prednisone taper over 3-6mo to
maintenance 0.1mg/kg/d
AZA initially2.0 mg/kg6mo then
taper over 6mo to 1mg/kg/d)
MONITOR ANTI-GBM LEVELS
Evidence of Pulmonary Hemorrhage?
Consider: IV MP, IVIG, ATG, anti-CD52 Ab
Consider:
Prednisone & MMF
Prednisone & Leflunamide
Or continued Rituximabtherapy(q6-12mo)
YES
Dialysis Dependent?
Evidence of PulmonaryHemorrhage? ANCA?
YES NO
NO
SUPPORTIVETREATMENT
ONLY
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781
RPGN: Type II disease (with immune
complexes)
• Lupus nephritis
• Sjogren’s Syndrome
• Hepatitis virus mediated nephritis
• IgA nephropathy
• Henoch Schonlein Purpura
• MPGN due to cryoglobulins
• Post-streptococcal glomerulonphritis
• Other post-infectious e.g. subacute endocarditis
Lupus Nephritis - RPGN
• No RCT specifically studying clinical presentation in LN. Therefore
no study only looking at RPGN. All studies use histology +
Proteinurialevels
• Many recent studies exclude RPGN e.g. MMF Hong Kong study
excluded pts with Cr>3.5 to try to exclude chronic disease.
• However very good supportive evidence from lupus studies for
Prednisone and CYC regimes in RPGN
• Consistent data support role for MMF in maintenance therapy and
show MMF for induction therapy in mild-to moderate disease
• Small open label studies support the role for rituximabin resistant
disease
• No role for PExin addition to steroids and CYC in severe LN (Lewis
et al NEJ M 1992 326 1373)
Copyright Harvard Medical School, 2010. All Rights Reserved.
782
Interpretation of clinical trials
in Lupus Nephritis
• Ethnicity
• Disease severity
• Number of patients
• Time to see a difference over and
above steroids alone (5 years)
Meta-analysis of MMF in Lupus
Nephritis
MMF for Induction Therapy of LN:
• A Systematic Review and Meta-analysis 268 pts in 4 RCTs MMF vs Cytoxan for
induction in LN.
• RR of failure to induce remit w MMF vs Cyt 0.7 ( p=.005) ; RR for death or ESRD for
• MMF vs Cyt 0.44 ( p=.02).
• Adverse events similar except more leukopenia, amenorrhea in Cyt pts.
Conclusion:
• MMF compared to Cyt reduces the risk of treatment failure during induction and may
reduce death and ESRD.
• MMF recommended as first line therapy for LN in pts w/o severe renal
dysfunction.
Walsh M, James M, Jayne D, et al. Clin J Am Soc Neph 2:968, 2007
Accepted practice for the management of Lupus nephritis has changed
Chan TM,.J AmSoc Nephrol. 2005 1076-84.
Chan TM, et al . N Engl J Med. (2000);343:1156-62.
Contreras et al NEJM
Copyright Harvard Medical School, 2010. All Rights Reserved.
783
CASE of LN with RPGN
• 22-year-ol d man with l upus and nephri ti s, al ong wi th edema,
hypertension and nephroti c range protei nuri a (12g/d) active uri ne
sediment and a rapi d ri se i n Creati ni ne over 2 weeks from 1.0 (eGFR
70) to 4.0 (eGFR 15) dsDNA >4000 whil e on IV cycl ophosphami de (4/6)
and Predni sone. Had previ ous course of Predni sone and MMF. He
was previ ousl y bi opsi ed 2 years ago and had Class III l upus nephriti s.
Never been i n compl ete remi ssi on
Renal Biopsy showed severe diffuse proliferative GN (Class IV) with >50%
crescents andsevere interstitial inflammation
Management of case
• In addition to supportive therapy and prophylaxis
• MP 1g x3. No response over 4 days
• ATG 5mg/kg/d X4 followed by rituximab 1g X1
• Cr improved slowly from peak of 4.6 to <1.0 over 4
weeks.
• Transitioned to 60mg pred/d, Cellcept 3g/d and
tacrolimus 1mg bid (level of 5-8)
• 2 months later persistent 5g prot/d (nephrotic
syndrome), active urine sediment, but normal
complement, dsDNA and normal eGFR
Copyright Harvard Medical School, 2010. All Rights Reserved.
784
What is supportive therapy?
• ACEI +/- ARB
• BP <130/80 with
antihypertensives/diuretics
• GI ulceration prophylaxis
• Anti PCP prophylaxis, antiviral prophylaxis
• Osteoporosis prophylaxis
• Edema control
• Glycemic control
LUPUS NEPHRITIS
Consider: IVIG, ATG, anti-
CD52 Ab(Campath) and/or
Rituximab
Consider plasmapheresis
Prednisone 1mg/kg (≤ 80mg) 3mo
then taper +MMF 3g/d for
12mths
If GFR  and/ or concurrent Class
V with Class IV disease consider:
a) Induction with IV MP
500mg/1g q24h X3 and CYC
500-750mg/m
2
q mo 6mo
b) Also consider 250mg/m
2
CYC
q14d for 3mo
c) MMF +/-tacrolimus
Titrate CYCagainst lymphocyte
count
(If CYCis not tolerated consider:
prednisone & Rituximab
[375mg/m
2
X4 or 1gX2-4])
Maintenance Induction Relapse
No clear role for Plasmapheresis
Prednisone & MMF
(Prednisone taper over 3-
6mo to maintenance
0.1mg/kg/d
MMF initially3g/d, taper
over 24mths)
Consider:
Prednisone & Azathiaprine
Prednisone & Leflunamide
Or continued Rituximab
therapy(q6-12mo)
Continueat least 2years
Even if complete remission
asrelapserateishigh
Prednisone & IV CYC
or Prednisone &
Rituximab +/- IV CYC
1g/m
2
x2-4
Alternatives:
Prednisone & MMF
+/- tacrolimus
Consider anti-CD52
antibodies or ATG
Partial Remission
Prednisone & IV CYC
or Prednisone &
Rituximab +/- IV CYC
1g/m
2
x1
Alternatives:
Prednisone & MMF +
tacrolimus
RPGN (>50%Crescents & risingCr) No RPGN
Induction
NO TRIALS--EMPIRICAL
InductionwithIV MP
500mg/1gq24hX3 CYC
500-750mg/m
2
qmonth
6mo
Titrate against lymphocyte
count
Consider transitioningto
+MMF3g/d+/-tacrolimus
No response
Pulmhemorr or cerebritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
785
Rituximab-humanized anti-CD20 antibodies
effective therapy in RPGN
Antigen presenting cells Costimulatory cells
Roles for B cells in more than Abproduction
CD8
AG
CD4
cytotoxicity
AG
cytokines
cytokines
cytokines
B
Current view of B cells in
adaptive immune
response
CD8
CD4
primed
plasma
AG
AG
B AG
Traditional view of B cells
in adaptive immune
response
Plasma cells
Short lived
Copyright Harvard Medical School, 2010. All Rights Reserved.
786
• Keogh et al (2006) Mayo: 10pts
with severe active WG or
treatment resistant. All went
into remission with RIT
375mg/m
2
X4) +oral Pred. 4
had a relapse which responded
to repeat RIT
Smith, Jayne et al J Rheumatology 2007
Prospective open label studies
show efficacy in relapse
RCTs in AAV and Lupus nephritis awaited
Rituximab- anti B cell therapy
• Effective in reducing remission in patients
who have relapsed with
– AAV with nephritis
– Lupus nephritis
• Effective primary therapy in hepatitis virus
associated glomerulonephritis and RPGN
• Excellent safety profile
• RCTs still needed
Copyright Harvard Medical School, 2010. All Rights Reserved.
787
Question 1
Randomized controlled trials in AAV:
1. Support a role for methotrexate
2. Show that MMF is superior to azathioprine
3. Indicate that it is safe to replace cyclophosphamide
after 6 months
4. Indicate the plasma exchange does not improve
outcome
5. Show a clear role for cyclophosphamide over
azathioprinein induction
Question 2
Concerning antibody therapies in the management of AAV:
1. There are RCTs supporting the use of antibody
therapies in AAV
2. Anti-TNF antibodies have been used effectively in the
management of resistant AAV
3. Anti-B cell therapy appears to be effective in many
patients resistant to conventional therapy
4. Antibody therapies have few side effects
5. CD54 and CD20 have the same cell expression profile
Copyright Harvard Medical School, 2010. All Rights Reserved.
788
Question 3
The following may be useful in the management of RPGN
due to cryogobulins
A. Prednisone
B. Plasma exchange
C. Rituximab
D. Bactrim
E. Cyclophospamide
Question 4
The following statements about the role of prednisone and
cyclophosphamide in the treatment of AAV are true
A. The use of methylprednisone or prednisone has been
subjected to RCT
B. The use of CYC has been subjected to an RCT
C. CYC is accepted first-line therapy for AAV with
crescentic GN
D. CYC causes thrombocyosis
E. Prednisone is used alone if there is pulmonary disease
as well as renal disease
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789
Disclosures
• Scientific AdvisoryBoard for Promedior • Scientific Advisory Board for Promedior
Inc and Regulus Therpeutics
Copyright Harvard Medical School, 2010. All Rights Reserved.
790
Brigham Board Review Course
Aug 10, 2010
Q&A
Dana Miskulin, MD
Tufts Medical Center
Disclosures
None
Copyright Harvard Medical School, 2010. All Rights Reserved.
791
Case #1
• 44yo male with developmental delay, deaf HIV on
HAART (undetectable viral load but CD4 counts
consistently <100), HCV 2/2 IVDA, DM, lipodystrophy,
CAD s/p PCIX3, presents to ID clinic with increasing leg
edema, 10 kg weight gain, dyspnea, fatigue over last few
weeks;
• admitted to hospital for diuresis and work-up; responds
to lasix/metolozone
• 24h urine shows 10g proteinuria
• sCr 2.33 mg/dl up from 1.0 mg/dl two months earlier
• U/A spgrav 1.015, ph 6, 2+blood, 3+protein, leuk
esterase negative
• Microscopy- 40 dysmorphic RBC/hpf, no RBC casts,
numerous lipid laden casts and oval fat bodies
• After holding ASA for one week, a kidney biopsy is
performed
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792
Immuno fluorescent examination could not be performed
on this formalin fixed specimen.
Copyright Harvard Medical School, 2010. All Rights Reserved.
793
Question 1
How would you treat this patient?
A. Pegylated interferon a + plasmapheresis
B. Corticosteroids
C. Pegylated interferon a
D. Pegylated interferon a + ribavirin
E. Pegylated interferon a + rituximab
DIAGNOSIS
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
(MPGN)
OF IMMUNE COMPLES ETIOLOGY
MOST LIKELY HEPATITIS C ASSOCIATED.
OVERLAPPING DIABETIC NEPHROPATHY
VASCULOPATHY, MODERATE
TUBULAR ATROPHY AND INTERSTITIAL FIBROSIS,
MILD
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794
Answer to Question 1
The correct answer is C.
The amount of blood on the urine sediment was more suggestive of
MPGN than HIVAN and indeed the biopsy demonstrates characteristic
findings of MPGN. Cryoglobulins were not present on EM. A review of
the evidence for treatment of HCV in CKD is found in the KDIGO HCV
guidelines published in 2009. A 12 month course of pegylated
interferon plus ribavirinis recommended in patients with moderate
proteinuriaand slowly declining kidney function. If CrCl<50 mls/min,
ribavirinshould be avoided due to high risk for hemolytic anemia and
red cell aplasia. A meta-analysis of trials comparing antiviral versus
immunosuppressive therapy (corticosteroids alone or in combination
with cyclophosphamide) in patients with HCV associated
glomerulonephritis, showed proteinuriadecreased more with IFN
therapy although there was no difference on long term renal function
[Alric, KI 2004]. The guidelines suggest adding Rituxamib,
cyclophosphamideor plasmapharesis to anti-viral therapy in patients
with nephrotic range proteinuria, rapidly progressive GN, or in an acute
flare of cryoglobulinemia.
Copyright Harvard Medical School, 2010. All Rights Reserved.
795
Case #2
20 yo female recently diagnosed with ADPKD
History:
12/15- dysuria, frequency and foul smelling urine
12/25-left sided flank pain and fevers to 105
12/27-at outside hospital diagnosed with pyelonephritis and started on
Bactrim
12/30-seen in clinic with temperature 102, nausea, ongoing left sided
flank pain
• Labs reveal sCr 0.70, WBC 15.3 with 87% PMNs and 1% bands
• U/A specific gravity 1.004, pH 5.5, nitrites negative, leuk esterase
negative, blood negative, 1 WBC, 1 RBC and a few bacteria
• -CT: Both kidneys are enlarged with innumerable heterogeneous
appearing cystic lesions, some hypodense, some hyperdense, of
differing sizes. There is a dominant 4.8 X 3.8 cm cyst at the upper
pole of the left kidney with fat stranding in the perinephric fat.
Question #2a (con’t)
Which Abx is least likely to be effective for
this condition:
A. Trimethoprim
B. Ciprofloxacin
C. Gentamycin
D. Chloramphenicol
Copyright Harvard Medical School, 2010. All Rights Reserved.
796
Answer to 2A
• The answer is C, gentamycin
Urinary tract infections in the ADPKD may consist of cystitis,
pyelonephritis, or cyst infection. Females are more likely than
males to be affected, in keeping with infection developing via
the ascending route. E coli and other gram negatives are the
most common organisms identified. The urine culture may be
negative if the infected cyst(s) is detached from the collecting
system. Cyst infection and pyelonephritis may be difficult to
distinguish as both present with flank pain and fevers and
imaging may not reveal an infected/inflamed cyst. The usual
treatment is fat soluble antibiotics which are able to penetrate
cyst walls. Even then, Abxmay need to be given for a
prolonged course if several cysts are involved. All of the
antibiotics shown, except gentamycinare fat soluble and
reach high concentrations in cyst fluid. A prolonged (E.g. 4-6
week course of Abxmay be needed in severe infections in
which the initial response to Abxis delayed.
Copyright Harvard Medical School, 2010. All Rights Reserved.
797
Case #2 Continued
Urine culture reveals >10,000 cfu/ml E Coli
sensitive to all but ampicillin
12/30 She is started on IV Ciprofloxacin
1/3 The urine has cleared but she continues
to spike temperatures and the WBC
remains elevated with a left shift
Question 2B
How would you manage this patient?
A. Add IV trimethoprim
B. Increase the ciprofloxacin to 400 mg IV
Q8 hours
C. Continue ciprofloxacin at 400 mg IV Q12
hours
D. Obtain a gallium scan
E. Arrange a CT guided percutaneous drain
of the left upper pole kidney cyst
Copyright Harvard Medical School, 2010. All Rights Reserved.
798
Answer to #2B
The correct answer is E.
• The CT scan (non-enhanced) shows a large inflamed cyst in
the left upper pole, corresponding to the patient’s symptoms.
The patient remains febrile despite 4 days of an antibiotic that
penetrates the cyst wall and to which the organism is
sensitive. It thus, would not make sense to switch antibiotics.
A gallium scan would confirm that the left upper pole cyst is
infected / inflamed, although we already know this from the
CT. A trial of higher dose ciprofloxacin could be attempted
but the better treatment would be to drain the infected cyst
(i.e. abscess). The cyst was aspirated for creamy fluid that
was growing E-Coli (sensitive to ciprofloxacin) and the patient
rapidly defervesced. A pigtail drain was placed and kept in
place until the cyst stopped draining. The patient continued a
6 week course of ciprofloxacin. Partial or complete
nephrectomymay be required for persistent infection, despite
antibiotic therapy/ percutaneous cyst drainage.
Copyright Harvard Medical School, 2010. All Rights Reserved.
799
Case #3
• 36 yo presents to the ER room with blurred vision and is
found to have a BP of 230/130 mm Hg
• He has had high BP for ‘years’. He has not seen a
physician in one year. He has been taking Chinese
herbal medications for headaches
• Retinal exam reveals Grade III hypertensive retinopathy
• Labs: serum creatinine 2.3 mg/dL, BUN 30
• U/A: 4+protein, 3+blood
• UACR: 1.94
• Started on labetalol 200 mg BID and lisinopril 20 mg per
day and discharged with follow-up in renal clinic
• In renal clinic, BP 140/100
• Urine sediment shows dysmorphic RBCs,
RBC casts, lipid-laden casts
• A serum creatinine from a year ago is 1.2
mg/dl
• A renal biopsy is performed
Case 3 (Con’t)
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800
Copyright Harvard Medical School, 2010. All Rights Reserved.
801
23
IgA
IgG
Question 3A
What is the diagnosis?
A. FSGS
B. MPGN
C. IgA nephropathy
D. ANCA vasculitis
E. Membranous nephropathy
Copyright Harvard Medical School, 2010. All Rights Reserved.
802
Answer to Question 3A
The correct answer is C.
• There is increased mesangium, mesangial
proliferation, and electron dense deposits
in the mesangium consistent with IgAN.
Immunofluoresence was 3+ positive for
IgA, 1+ for IgG, others were negative.
Copyright Harvard Medical School, 2010. All Rights Reserved.
803
Biopsy
• Renal biopsy – 28 of 36 glomeruli are 28 globally
sclerosed. The viable glomeruli show
mesangioproliferative changes, segmental to global
membranoproliferative changes, 1 glomerulus shows
active crescent. The interstitium show patchy tubular
atrophy and cortical fibrosis. There is moderate
interstitial nephritis. The arterial blood vessels show
severe vasculopathic changes. IF is 3+for mesangial
deposits of IgA.
• Serum creatinine remains 2.9 mg/dl
• How would you manage this patient?
Question 3B
In addition to controlling BP, how would
you treat this patient?
A.ACE inhibitors/ARB
B.ACE inhibitors/ARB + MMF
C.ACE inhibitors/ARB + Steroids
D.ACE-inhibitors/ARB + Steroids +
cyclophosphamide
Copyright Harvard Medical School, 2010. All Rights Reserved.
804
Answer to Case #3
The correct answer is A, maximize RAAs blockade.
Proteinuria is the most prognostic factor for renal outcomes in IgAN. The exact
threshold (0.5g vs. 1g/d) above which risk of renal progression is increased, is
uncertain but a reduction in proteinuria to <1 g/d has been associated with a better
prognosis. Several trials have shown a benefit of ACEI or ARBs in reducing
proteinuria and improving kidney function. The first step in managing this patient
should be to aggressively lower BP and maximize RAAS blockade, both of which may
significantly reduce proteinuria and slow GFR decline. The role of corticosteroids has
been assessed in patients with >1 g/d proteinuria and GFR >50 mls’min [Manno C
NDT 2001; Manno C NDT 2009; Lu J et al AJ KD 2009, Pozzi C J ASN 2004]. Three
of 4 RCTs used corticosteroids (different regimens but 0.5-1.0 mg/kg/d) in
combination with ACE inhibitors compared to ACE inhibitors alone. 4/4 studies
showed reduced proteinuria and 3 out of 4 showed a slower decline in kidney function
and /or a smaller number with a 50% decline in GFR with prednisone treatment. No
trials have examined prednisone treatment in patients with GFR<50 mls/min but if
proteinuria remains elevated after optimizing BP and RAAS blockade, it could be
considered. Cyclophosphamide and steroids are reserved for patients with
deteriorating kidney function and severe proteinuria, in the absence of extensive
scarring (a problem in this case) or in the setting of extensive crescents and rapidly
declining GFR. RCTs of MMF in IgAN have shown conflicting results. More studies
with MMF are needed.
Copyright Harvard Medical School, 2010. All Rights Reserved.
805
Case #4
• 26 yo with a history of antiphospholipid Ab syndrome
(presented with PE), SLE (mainly joint involvement)
treated with low dose steroids X 5 years (discontinued 2
years ago) and plaquenil, which he still takes
• Referred by rheumatologist for 4+proteinuria on dipstick
and a 24 h collection found to have 7.6 g/ day of
proteinuria. Prior dipsticks 6 months ago were negative
for protein
• P/E BP 144/88; lungs clear, trace peripheral edema
• U/A pH 5; specific gravity 1.015; +3 protein; trace blood;
no leukocytes; no nitrites; no other findings
• Microscopy- 2-3 RBC/hpf, no casts
• A kidney biopsy is performed
Copyright Harvard Medical School, 2010. All Rights Reserved.
806
Copyright Harvard Medical School, 2010. All Rights Reserved.
807
IF
Diffuse
global
Granular
IgG, IgA, IgM
C3, C4
C1q
4A. What is the diagnosis?
A. Thrombotic microangiopathy
B. WHO Class IV lupus nephritis
C. WHO Class III lupus nephritis
D. WHO Class V lupus nephritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
808
Answer to Question #4A
• The correct answer is D.
• The biopsy shows markedly thickened capillary
basement membranes with ‘spikes’ on silver stain. There
are diffuse subepithelial electron dense deposits with
"spikes" and "domes" present. The epithelial cell foot
processes are fused. Immunofluorescent studies reveal
granular deposits of IgG, IgA, IgM, and complement
along the glomerular basement membranes.
These findings are diagnostic of membranous
glomerulonephropathy, or Class V lupus nephritis.
Copyright Harvard Medical School, 2010. All Rights Reserved.
809
Question #4B
Which of the following statements about Class V
(membranous) lupus is correct:
A. 50% of patients with nephrotic range proteinuria have
a spontanous remission
B. Treatment of patients with Class III and Class V lupus,
should be directed towards treatment of the Class V
lupus
C. Cyclosporine or MMF are first line treatments for Class
V lupus
D. Patients with subnephrotic range proteinuria do not
need treatment
E. ESRD occurs in about 10% of patients with Class V
lupus after ~10 years
Answer to #4b
• The preferred treatment for Class V lupus are cyclophosphamide or
cyclosporine. There is only 1 small RCT (n=15 per am) comparing
cyclophosphamide or cyclosporine against prednisone in patients
with nephrotic range proteinuria. Those treated with either CYC or
CSA were more likely to achieve a complete remission but those
treated with cyclosporine relapsed after therapy was discontinued
(40% within a year). The toxicities of cyclophosphamide need to be
weighed against the harm, especially in young women of
childbearing age. MMF has only been tested in small, observational
studies of a short duration. The complete remission rate is in the
order of 40-60% at 6 months. RCTs are needed before MMF can be
recommended. In patients with Class 3 and 5 lupus, the treatment
should be directed at the more severe, Class 3 disease. The risk of
ESRD is ~10% at 10 years and is more likely in patients with non-
remitting, heavy proteinuria. Spontaneous remissions of nephrotic
range proteinuria are rare.
Copyright Harvard Medical School, 2010. All Rights Reserved.
810
Disclosures
None
Copyright Harvard Medical School, 2010. All Rights Reserved.
811
Glomerulonephritis
take home messages
Ajay K. Singh MD
asingh@partners.org
Disclosures
• Consulting • Consulting
– Amgen, Johnson and Johnson, Sandoz, Fibrogen
• Grant Support
– Amgen, Johnson and Johnson, Roche
• Advisory Boards
Rockwell – Rockwell
Copyright Harvard Medical School, 2010. All Rights Reserved.
812
ISN/RPS Classification 2004
Class-I Minimal mesangial LGN
Class-II Mesangial proliferative LGN
Class-III Focal GN (<50% glom. involved) (a/cor a-c)
Class-IV Diffuse GN (a/c or a-c)
( >50% glom. involved)
IV S and IV G
Weening et al Kidney International,65: 521-30,2004
IV-S and IV-G
Class-V Membranous LGN
Class-VI Advanced sclerotic LGN
( ≥ 90% sclerosed )
Prognostic Features in LN
Histological Predictors
• WHO – ISN Histologic Class IV
• Activity and Chronicity Index
• Crescents and Interstitial fibrosis
• Segmental necrotizing lesions
Clinical Predictors
• Hypertension
• Anemia
• High baseline serum creatinine
• Higher baseline proteinuria
• Delay in therapy Delay in therapy
Epidemiologic Predictors
• African American Race
• Low socioeconomic status.
Appel Appel G, Cameron JS in Comprehensive Clinical Nephrology 2007. G, Cameron JS in Comprehensive Clinical Nephrology 2007.
Copyright Harvard Medical School, 2010. All Rights Reserved.
813
Treatment
I NDUCTI ON
MAI NTENANCE
Cycl ophosphami de
Azat hi apr i ne
Myc ophenal at e mof et i l
Cycl ophosphami de
Azat hi opr i ne
Myc ophenal at e mof et i l
Pr edni sone
Met hyl pr edni sone
Pr edni sone
Met hyl pr edni sone
FSGS
CP1177455-5
Copyright Harvard Medical School, 2010. All Rights Reserved.
814
FSGS
• FSGS is a lesion, not a disease
• Incidence of FSGS in biopsy series has risen
Epidemiology
Brigham Renal Board Review Course
Incidence of FSGS in biopsy series has risen
over the last 30 years.
• FSGS most common pathology in biopsies for
idiopathic NS in US; 35% in all cases, 50% in
African-Americans
• FSGS most common primary glomerular disease FSGS most common primary glomerular disease
causing ESRD in US (USRDS)
Copyright Harvard Medical School, 2010. All Rights Reserved.
815
• FSGS is a descriptive term for a pathologic
Pathology
Brigham Renal Board Review Course
FSGS is a descriptive term for a pathologic
lesion, not a disease entity.
Etiological Classification of FSGS
Primary (idiopathic) FSGS
• Permeability factor mediated?
S d FSGS
Brigham Renal Board Review Course
Secondary FSGS
1. Familial / genetic
• MYH9, α-actinin-4, TRPC6,
NPHS1&2, PLCE1, COQ2
2. Virus-associated
• HIV, Parvo B-19, CMV, HTLV-1
3. Drug/toxin-mediated
• Interferon-α Sirolimus
4. Arising from adaptive
structural-functional responses
• Reduced renal mass (e.g. renal
agenesis or dysplasia, reflux
nephropathy, cortical necrosis,
surgical ablation) Interferon α, Sirolimus,
Bisphosphonates, Lithium,
Heroin
surgical ablation)
• Initially normal renal mass (e.g.
hypertension, obesity, OSA,
sickle cell anemia,
atheroembolic disease)
Adapted from D’Agati et al (2004) AJKD
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816
Histological Variants of FSGS
• 5 variants:
1 Classic
Brigham Renal Board Review Course
1. Classic
2. Perihilar
• Frequently seen with secondary FSGS due to glomerular
hypertension
3. Tip lesion
• Abrupt onset, high degree of proteinuria; better response to
steroids, some spontaneous remissions reported; ? less likely to
progress to ESRD
4. Cellular
5. Collapsing
• More severe, poorer prognosis
Prognostic value of histological variants remains debated.
Mean age 40-50; male:female ~1:1
Primary FSGS
Clinical Presentation
Brigham Renal Board Review Course
Primary FSGS
• Nephrotic range proteinuria: 60-75%
• Microscopic hematuria: 30-50%
• Hypertension: 45-65%
• Impaired renal function: 25-50%
Secondary FSGS
• Slowly progressive proteinuria and renal insufficiency
Peripheral edema and hypoalbuminemia uncommon even with • Peripheral edema and hypoalbuminemia uncommon even with
nephrotic range proteinuria.
• Heavy proteinuria uncommon.
Copyright Harvard Medical School, 2010. All Rights Reserved.
817
Presenting Features in FSGS
Children Adults
No. 459 665 No. 459 665
Nephrotic (%) 90 70
Male (%) 55 60
Hypertensive (%) 30 45
CP1177455-3
Hematuria (%) 55 45
Renal insufficiency (%) 20 30
“Pathogenic” Classification of FSGS
• Primary alterations of GEC
Primary FSGS
HIV-associated nephropathy
Heroin-associated nephropathy Heroin associated nephropathy
Pamidronate
Familial FSGS
Sporadic genetic mutations
• Reduced nephron mass/glomerular adaptation
Unilateral renal agenesis
Obesity-related glomerulopathy (+/- OSA)
CP1177455-4
Obesity-related glomerulopathy (+/- OSA)
• Secondary to basement membrane defects
• Secondary to focal proliferative glomerulonephritis
• Aging kidney
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818
80
100
Kidney Survival on the Basis of Degree of
Proteinuria at Time of Renal Biopsy
(13)
(9)
(10)
(7) (3) (5)
20
40
60
80
P
A vs B 0.038
P
A vs B 0.038
% with
functioning
kidneys
(A) Asymptomatic proteinuria
<3.5 gm/24 hr
n=15
(B) Nephrotic proteinuria
3.5-14 0 gm/24 hr
n=38
(C) Massive
proteinuria
>14 gm/24 hr
n=10
(29)
(7) (3) (5)
(1)
(20)
(14)
(9) (5)
0
20
0 2 4 6 8 10 12 14
A vs C <0.001
B vs C 0.014
A vs C <0.001
B vs C 0.014
Time from biopsy (yr)
Velosa et al: Mayo Clinic Proc 58, 1983 CP1044973-1
( )
Renal Survival in Nephrotic Adults with FSGS
Based on Remission Status
100
Remission Remission
25
50
75
Survival
(%)
Survival
(%)
No remission No remission
CP1177455-7
Banfi, 1991; Cattran, 1998;
Schwartz & Korbet, 1999
Banfi, 1991; Cattran, 1998;
Schwartz & Korbet, 1999
0
0 2 4 6 8 10 12
Years Years
Copyright Harvard Medical School, 2010. All Rights Reserved.
819
Spontaneous remissions Spontaneous remissions Spontaneous remissions
are rare (<5%) and are most
often partial remissions
Spontaneous remissions
are rare (<5%) and are most
often partial remissions
CP1151810-4
Treatment in Primary FSGS
Proteinuric patient with primary FSGS
ACEi/ARB & BP control (≤125/75)
Non-nephrotic Nephrotic
CP1151810-5
Follow Begin
immunosuppressive
therapy
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820
Persistence of the
Steroid Resistance in Adults
Persistence of the
nephrotic syndrome after
4 months of prednisone
t d f 1 /k /d
CP1151810-19
at a dose of 1 mg/kg/day
Meyrier et al: Kidney Int, 1994
Membranous Nephropathy
CP1195760-12
Copyright Harvard Medical School, 2010. All Rights Reserved.
821
• 60-80% with nephrotic syndrome (NS)
• remainder with subnephrotic proteinuria
Clinical Presentation
Brigham Renal Board Review Course
• remainder with subnephrotic proteinuria
detected incidentally
• ~60% of those with subnephrotic range
proteinuria progress to NS within 1-2 years of
presentation
• 30-40% with microscopic hematuria p
• Only 10-20% with HTN
• <20% with significantly impaired renal function
• Uniform thickening of glomerular capillary wall
b PAS / li ht i
Pathology
Brigham Renal Board Review Course
by PAS / light microscopy.
• Craters and spikes in glomerular basement
membrane on silver stain
• IF with diffuse, granular deposits of IgG
(predominantly IgG4) along basement
membrane membrane
• Subepithelial electron dense deposits on EM
(stages described by Ehrenreich & Churg)
Copyright Harvard Medical School, 2010. All Rights Reserved.
822
Risk of Progression Categories
Low risk
Laboratory
Normal Function Normal Function
Proteinuria < 4 g/d
Medium risk
Normal function
Persistent proteinuria
> 4<8 g/d
High risk
Abnormal function and/or Abnormal function and/or
Persistent proteinuria
> 8 g/d
Specific Treatment
Low Risk - Normal renal function and Low Risk Normal renal function and
proteinuria < 4g/24h
~ 5% risk of progression
Treatment
i) reduce proteinuria
ii) idealize blood pressure ii) idealize blood pressure
iii) use ACEi-ARB
Continue to monitor
Copyright Harvard Medical School, 2010. All Rights Reserved.
823
Specific Treatment
Medium Risk - Normal renal function and
persistent proteinuria (4-
8g/24h) over 6 months
Corticosteroids alone
- ineffective
Corticosteroids + cytotoxic
effective - effective
Cyclosporine - effective
Specific Treatment
High Risk (10-15%) - >8g/24h High Risk (10 15%) >8g/24h
Proteinuria
Corticosteroids - ineffective
Progression
Cyclosporine - effective
C ti t id + t t i Corticosteroids + cytotoxic
- effective
Copyright Harvard Medical School, 2010. All Rights Reserved.
824
IgA Definition
• Dominant or
CCo-dominant IgA deposition in glomeruli
Epidemiology (aka Berger’s disease)
• Most common cause of nephritis in the world (15 • Most common cause of nephritis in the world (15
to 40% of primary GN in world, 20% of primary GN in
USA)
• Males > Females (2:1)
• Peak occurrence in 2nd & 3rd decades
• Asian predominance (up to 40% of biopsies
compared with 20% in European/U S registries) compared with 20% in European/U.S. registries)
– ?screening bias
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825
Clinical Presentation
• Synpharyngitic (24 to 48 hrs after URI or GI infection -- Synpharyngitic (24 to 48 hrs after URI or GI infection
in contrast with post-infectious nephritis 1 to 3 weeks)
• Low grade fever, loin pain
• Serum IgA levels elevated in ~50%
• Spectrum of microscopic hematuria + low levels of
albuminuria to RPGN picture
• Can be with or w/o Henoch-Schonlein Purpura (HSP)
Children: gross hematuria after URI – Children: gross hematuria after URI
– Adults: microscopic hematuria and/or proteinuria
Definition of IgA Phenotypes for
Treatment Purposes
• Asymptomatic hematuria y p
• Recurrent gross hematuria
• Significant Proteinuria (“>1g”) and/or renal
insufficiency
• Rapidly progressive glomerulonephritis
• Nephrotic syndrome with minimal lesions
• Acute Renal Failure
• Henoch Schonlein Purpura
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826
Acute Renal Failure in IgAN
• 3% of 865 IgAN patients
• 25% of 32 pts had SCr >25%
• Associated with macroscopic
hematuria and red blood
cells in tubules
• 4% patient developing
chronic renal failure after a
mean follow-up of 65
months.
p
of baseline
• Duration of Macroscopic
Hematuria > 15 d
[OR 12.3; 1.06 to 143.5; P = 0.04]
Packham D…Clin Nephrol. 1994 Dec;42(6):349-53 Gutierrez E. Clin J Am Soc Nephrol. 2007 Jan;2(1):51-7.
Secondary IgA Nephropathy
• HIV infection
T l i L Toxoplasmosis Leprosy
• Celiac disease
Dermatitis herpetiformis
Crohn disease
• Liver disease
Alcoholic cirrhosis
• Ankylosing spondylitis
Reiter syndrome Reiter syndrome
• Neoplasia Mycosis fungoides
Lung CA
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827
LEE Classification
From: Lee SM, Rao VM, Franklin WA, et al: IgA nephropathy: morphologic predictors of progressive
renal disease. Hum Pathol 13(4):314-322, 1982
Histologic grade Histopathologic features
I Minimal or no mesangial hypercellularity, without g yp y,
glomerular sclerosis, proliferative endocapillary or
extracapillary changes.
II Less than 50% of glomeruli show localized mesangial
proliferation and sclerosis. Rarely, small crescents.
III Diffuse mesangial proliferation with focal and
segmental variation. Occasional small crescents and
adhesions. adhesions.
IV Marked diffuse mesangial proliferation and sclerosis.
Crescents in 45% or less of glomeruli.
V Similar to IV, but more severe changes. Crescents in
more than 45% of glomeruli
Subclass Histopathologic features
HAAS Classification
From: Haas M.: Histologic subclassification of IgA nephropathy: a
clinicopathologic study of 244 cases. Am J Kidney Dis 29(6):829-842, 1997
I Minimal or no mesangial hypercellularity, without
glomerular sclerosis, proliferative endocapillary or
extracapillary changes
II Focal and segmental glomerular sclerosis, minimal
mesangial hypercellularity, no crescents or necrosis
III Focal proliferative GN; 50% or less of glomeruli show
mesangial or endocapillary hypercellularity, crescents,
or necrosis
IV M th 50% f l d l li IV More than 50% of non-sclerosed glomeruli are
hypercellular (mesangial hypercellularity, endocapillary
hypercellularity, crescents, or necrosis)
V 40% or more of glomeruli are globally sclerotic and/or
40% or more of estimated cortical tubular atrophy or
loss
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828
Key features that should be reported in pathology reports
for patients with IgAN
Eitner, F. and Floege, J. (2009) The Oxford classification—predicting progression of IgAN
Nat. Rev. Nephrol. doi:10.1038/nrneph.2009.150
Difficulties in Treatment Studies in IgAN
• Slow progression in many – requires use of Slow progression in many requires use of
surrogate markers of progression
• Variable rate of progression
• Heterogeneous population- phenotype
• Only a few RTC to define outcome of RX - Recent
meta analysis many “ of low quality and poorly
reported”
• Everyone knows how to treat some of the pts –
Nobody is certain how to treat others
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829
Therapeutic Options
• Blockade of the Blockade of the
Renin/Angiotensin/Aldosterone axis
• Tonsillectomy
• Glucocorticoids
• Fish Oils
• Immunosuppressives
– Azathioprine + steroids
– Cyclophosphamide + steroids
– Mycophenolate mofetil
Specific Recommendations
Based on Phenotype
• Asymptomatic microhematuria y p
– Close monitoring
• Recurrent gross hematuria
– Tonsillectomy if documented tonsillitis
• Significant Proteinuria (“>1g”) and/or renal
insufficiency
– ACEi (+ ARB if tolerated)
– Consider
• Steroids alone • Steroids alone
• Cytotoxic + steroids
• Mycophenolate + Steroids
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830
Specific Recommendations
Based on Phenotype
• Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis
– Cytotoxic + Steroids
• Nephrotic syndrome with minimal lesions
– Steroids
• Acute Renal Failure
– Steroids if persistent gross hematuria
H h S h l i P • Henoch Schonlein Purpura
– Steroids +/- cytotoxics in “high risk”
ADPKD
• Most common genetic disease
– Incidence 1:500 – 1:1000 live births
• Clinical Manifestations
– abdominal mass
– chronic flank or back pain
– gross hematuria
– recurrent UTI
– nephrolithiasis (uric acid stones)
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831
Autosomal Dominant Polycystic
Kidney Disease
• Mutation in ~70% located on short arm of
chromosome 16p 13.3 – p13.1 – (PKD1 locus)
• ~30% of mutation is located on chromosome 4q21-
q23 milder phenotype with PKD2 locus. Later age of
diagnosis and hypertension, smaller kidney volume,
fewer kidney cysts later age of ESRD system: fewer kidney cysts, later age of ESRD system:
disorder is kidney, liver, pancreatic and vascular
abnormalities.
Ultrasound Criteria for Diagnosis of PKD1 in
At-Risk Individuals
Positive and negative predictive values 97-100% Positive and negative predictive values 97 100%
Ravine et al, Lancet 343:824, 1994
• Age < 30: at least 2 cysts (unilateral or bilateral)
• Age 30-59: at least 2 cysts/kidney
• Age > 60: at least 4 cysts/kidney
• For PKD2 age 30 59 use 4 or more cysts in both • For PKD2 age 30-59, use 4 or more cysts in both
kidneys for sensitivity of 96%
Pei et al, JASN 14:107A, 2003
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832
Progressive Loss of Kidney Function
• Rate of decline of GFR (data from MDRD study,
starting at GFR <55 ml/min) starting at GFR <55 ml/min)
Males 5 - 6 ml/min/year
Females 4 - 5 ml/min/year
• Pattern of GFR loss has recently been
established by CRISP study
– GFR stable for many years, despite progressive
increase in total kidney volume
– GFR decrease not detected until total kidney
volume exceeds 1500 ml
Hateboer et al, THE LANCET 353:103, 1999
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833
Consortium for Radiologic Imaging Studies of
Polycystic Kidney Disease (CRISP)
Study Completed
• Observational trial (no intervention) to
determine how to assess changes in
polycystic kidneys over a relatively short
period of time (3 years)
• 232 subjects with ‘normal’ kidney function 232 subjects with normal kidney function
• Emory; U. of Alabama; Kansas University;
Mayo
Kidney International, 64: 1035–1045, 2003
Kidney International, 64: 2214–2221, 2003
Principal Extrarenal Manifestations
Hepatic and pancreatic cysts
Asymptomatic in many patients, but can expand and cause pain and Asymptomatic in many patients, but can expand and cause pain and
infection; rarely massive PLD
Cardiac valvular abnormalities
Mitral, tricuspid and aortic valve prolapse and regurgitation
Intracranial aneurysms
Risk of rupture; found in approximately 5% of patients with no family
history and about 22% of patients with family history of ICA or SAH
Seminal vesicle cysts
Found in ~39-60% of men; undefined risk of infertility
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834
Treatment of ADPKD (1)
• There is no specific therapy
• Pain
Diff ti l di i bl d i f ti – Differential diagnosis: bleed vs. infection vs.
obstruction vs. stone
– Analgesics
– Percutaneous drainage; laparoscopic or
surgical unroofing of individual cysts
• Infection: lipophilic antibiotics p p
• Hypertension
– ACE inhibitors thought to be beneficial
Treatment of ADPKD (2)
• Progressive kidney insufficiency • Progressive kidney insufficiency
– Lack of proven benefit of low protein diets or ACE-I
– Cyst decompression does not alter progression
– Renal replacement therapy
• Extrarenal manifestations
– Intervene as needed for symptoms
Screen for cerebral aneurysms with + family history; – Screen for cerebral aneurysms with + family history;
antibiotic prophylaxis for valvular regurgitation
– Avoid estrogen/progesterone in women (effect on liver cyst
disease)
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835
Nephrolithiasis in ADPKD
• Occurs in ~20% of patients
• Uric acid and/or calcium oxalate
• Predisposing factors include hypocitraturia,
hyperoxaluria, hyperuricosuria, hyperuricemia,
hypercalciuria, possible distal acidification
defects
• Expanding cysts compress the collecting
system producing urinary stasis which system producing urinary stasis, which
predisposes to stone formation and infection
Treatment of Kidney Cyst Infection in
ADPKD
• Lipophilic antibiotics such as ciprofloxacin Lipophilic antibiotics such as ciprofloxacin,
norfloxacin, trimethoprim, chloramphenicol
• Percutaneous or operative drainage is rarely
needed; only for refractory infection
• Resistant organisms
• Localization of infected cyst is difficult
Labeled WBC or gallium scan – Labeled WBC or gallium scan
– MRI with contrast
– PET scan
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836
Kidney Infection in ADPKD
• 30 to 50% of patients with ADPKD will have a urinary 30 to 50% of patients with ADPKD will have a urinary
tract infection, either pyelonephritis or cyst infection,
during their lifetime
• Urinary tract infections are more common in women
with ADPKD
• Fever and flank pain are the presenting symptoms
• Urine culture may be negative in cyst infection, as
cysts frequently don’t communicate with the
collecting system
Hematuria in ADPKD
• Cyst hemorrhage occurs in ~60% of individuals
– gross or microscopic hematuria if cyst connects to
collecting system
– intracyst or subcapsular hemorrhage without
hematuria
• Excessive angiogenesis results in fragile blood
vessels stretched across walls of enlarging
cysts; susceptible to minor trauma with resultant
h h hemorrhage
• Patients with recurrent episodes of gross
hematuria have the largest kidneys and
progress more quickly to kidney failure
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837
Treatment of Hematuria in ADPKD
• Appropriate diagnosis and treatment of specific • Appropriate diagnosis and treatment of specific
entity, such as infection or stone
• Correction of coagulopathy, if present
• Conservative management with hydration, bed
rest, and appropriate use of analgesics
R l i bl di i • Rarely, massive bleeding may require
transfusion, or kidney embolization or
nephrectomy
Pregnancy and Renal Disease
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838
Mild Renal Insufficiency
(Creatinine ≤ 1.4 mg/dl)
• Data from several small series with mild renal
insufficiency at baseline: Minimal to no impact
of pregnancy in terms of acceleration renal
insufficiency.
Moderate to Severe Renal Insufficiency
Creatinine ≥ 1.4 mg/dl
• Largest Series: 82 pregnancies in 67 women with creatinine ≥ 1.4 at
conception (mean creatinine 1.9)
– Mean creatinine increased to 2.5 by 3
rd
trimester
– 20% had worse renal function during pregnancy
– 23% had worse renal function by 6 wks post-partum
• 8% recovered; 10% declined further
• 8 women (10%) →ESRD within year of pregnancy • 8 women (10%) → ESRD within year of pregnancy
• Creatinine >2.0 outset: Highest likelihood decline (33% had
accelerated decline renal function)
Jones DC, Hayslett JP. N Enl J Med 1996;335:226-32.
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839
Impact of Renal Disease on Pregnancy
Outcomes
• Fetal Survival Good (70 to 100%)
– Lower with uncontrolled hypertension
• Especially with MAB > 105 start of conception
• Risk of Prematurity estimated 45 -70%
• Risk of Intrauterine Growth Restriction estimated 20-50%
• Risk of Preeclampsia increased
– Greater risk of occurrence during second trimester g
– Associated with both prematurity and intrauterine growth
restriction
Preeclampsia
• Systemic disorder unique to pregnancy marked by new Systemic disorder unique to pregnancy marked by new
onset hypertension and proteinuria after 20 weeks
gestation
• Eclampsia: onset of seizures in preeclampsia
• Preeclampsia may be superimposed on chronic
hypertension in pregnancy
I id i 3 14% i ld id • Incidence is 3-14% pregnancies worldwide
Copyright Harvard Medical School, 2010. All Rights Reserved.
840
Risk Factors
• First pregnancy past history preeclampsia family history First pregnancy, past history preeclampsia, family history
preeclampsia, multiple gestation, obesity, pre-gestational
diabetes, pre-existing renal disease, pre-existing
hypertension, advanced maternal age, antiphospholipid
antibody syndrome.
• Cigarette smokers have lower risk preeclampsia v. nonsmakers
Severe Preeclampsia
Defined as preeclampsia accompanied by at Defined as preeclampsia accompanied by at
least one of following:
cns dysfunction; liver capsule distension; hepatocellular
injury (transaminases > twice normal); marked blood
pressure elevation; thrombocytopenia, marked
proteinuria (≥ 5 g/24 hrs); oliguria; severe fetal growth
restriction; pulmonary edema; stroke ; p y ;
ACOG Practice Bulletin #33, January 2002
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841
Preeclampsia: General Management
Principles
• Definitive treatment is delivery
• Prevents maternal or fetal complications
– Timing of delivery—depends on preeclampsia severity,
gestational age, maternal and fetal status
• Corticosteroids should be given at 24-34 weeks gestation in
preeclampsia
P t f t l l t ti – Promotes fetal lung maturation
– Severe preeclampsia: delivery indicated regardless of
gestational age
Preeclampsia:
Seizure prophylaxis
• Magnesium sulfate: drug of choice for preventing
eclampsia
– Evidence suggests use reduces incidence of eclampsia
• But no effect on disease progression aside from seizure
prevention
– Dose for renal insufficiency
Observe for toxicity (loss of deep tendon reflexes respiratory – Observe for toxicity (loss of deep tendon reflexes, respiratory
paralysis, cardiac arrest)
• Calcium gluconate---antidote for toxicity
Copyright Harvard Medical School, 2010. All Rights Reserved.
842
Preeclampsia: Hypertension Treatment
• Lack of data about level of blood pressure to treat
– Does not alter the course of preeclampsia
• Concerns about deleterious effects of blood pressure
lowering on fetal growth need to be weighed with
concern for possible maternal vascular complications
(especially stroke)
– Usually treat systolic >150-160; diastolic > 100-105
• Medications for acute blood pressure lowering: IV
labetalol, hydralazine (less commonly diazoxide)
– Avoid sodium nitroprusside—possible fetal cyanide poisoning
Mild Preeclampsia Management
• Frequent monitoring, including labs
• Deliver by 38 weeks
• unless severe preeclampsia or abruption
placentae, marked fetal growth restriction, non-
i f l i li h d i reassuring fetal testing, or oligohydramnios
develop
Copyright Harvard Medical School, 2010. All Rights Reserved.
843
Preeclampsia Prevention
• No clearly established preventive
measures
– Some data (very small studies) suggest
possible benefit of low-dose aspirin in
prevention in high risk groups
• But weight of evidence not strong
– No benefit from calcium supplementation
Other Forms Hypertension in
Pregnancy
• Chronic hypertension: Antedates pregnancy (systolic ≥
140 and diastolic ≥ 90 mmHg)
– Limited data regarding degree of hypertension to treat and target
goals
• Expert opinion: treat bp > 155-165/95-100 mmHg
• Aim for lower levels if end-organ damage present
• Gestational hypertension: mild hypertension latter half
pregnancy (but no proteinuria or other signs
preeclampsia)
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844
Antihypertensive Drugs in Pregnancy
• Drugs of choice:
– Methyldopa: nearly 50 years experience; excellent
long-term safety profile in pregancy
– Labetalol: both alpha and beta-adrenergic blocking
properties; may have less impact on uterine/placental
blood flow blood flow
– Nifedipine (long-acting): appears safe
– Less data on Diltiazem and Verapamil but likely safe
• May worsen hypotension and neuromuscular blockade if
magnesium sulfate used for preeclampsis
Antihypertensive Drugs in Pregnancy
• Drugs to avoid:
– ACE inhibitors and ARBs
• First trimester exposure: higher risk major congenital
malformations, esp. cardiovascular and cns malformations
• Later pregnancy exposure: oligohydramnios, hypocalvaria
• Drugs to use with caution:
– Diuretics: avoid volume depletion Diuretics: avoid volume depletion
– Beta blockers: may ↓ uterine/placental blood flow; may be linked
to intrauterine growth restriction and fetal bradycardia
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845
Disclosures
• Consulting • Consulting
– Amgen, Johnson and Johnson, Sandoz, Fibrogen
• Grant Support
– Amgen, Johnson and Johnson, Roche
• Advisory Boards
Rockwell – Rockwell
Copyright Harvard Medical School, 2010. All Rights Reserved.
846
Nephr ol ogy
Boar d Revi ew
Ajay K. Singh, M.D.
Associate Professor of Medicine, Harvard Medical
School
Physician, Brigham and Women’s Hospital
Di sc l osur es
• Consulting • Consulting
– Amgen, Johnson and Johnson, Sandoz,
Fibrogen
• Grant Support
– Amgen, Johnson and Johnson, Roche
• Advisory Boards
– Rockwell
Copyright Harvard Medical School, 2010. All Rights Reserved.
847
Quest i on 1
• 67 year old man - 1 week history of anorexia • 67 year old man - 1 week history of anorexia,
nausea, lassitude, and pedal edema.
• Longstanding hypertension, well controlled with
hydrochlorothiazide and amlodipine.
• Fenoprofen for osteoarthritis of the hip for the
past 3 months past 3 months.
Quest i on 1 c ont ’d
• Physical examination
– BP 142/68mm, HR 72 bpm, Temp of 97.8
O
F. p p
JVP 8 cm; normal cardiac and pulmonary
examinations; and 2+ pitting edema.
• Urinalysis showed a specific gravity of 1.017,
protein 4+, no blood, and negative for glucose.
Microscopic examination of the sediment was
bland.
Copyright Harvard Medical School, 2010. All Rights Reserved.
848
• BUN 18 mg/dL; Cr 0.8 mg/dL; Na 137, K
Quest i on 1 c ont ’d
4.4, Cl 95, C02 21, Ca 9.2, Phos 3.6, UA
4.6 mg/dL; Alb 2.9 g/dL; HCT 38%. anti-
dsDNA antibody level 0.
• 24 h protein excretion 7.7 g.
• Renal ultrasound showed normal sized
kidneys bilaterally without obstruction kidneys bilaterally without obstruction.
• The renal biopsy on light microscopy will most
Quest i on 1
The renal biopsy, on light microscopy, will most
probably show:
– A). Thickened loops with evidence of double
contours
– B). Swollen endothelial cells -- glomerular
endotheliosis
– C.) No changes
– D.) Focal segmental sclerosis
– E.) Mesangial proliferation
Copyright Harvard Medical School, 2010. All Rights Reserved.
849
PAS Stain x 400
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850
NSAI Ds and t he Ki dney
• Prerenal azotemia
• Ischemic acute tubular necrosis Ischemic acute tubular necrosis
• Allergic interstitial nephritis (AIN)
• AIN plus minimal change nephropathy
• ARF plus bilateral flank pain
• Sodium and water retention
• Hyperkalemia
• CRF and papillary necrosis
Whelton and Hamilton, J Clin Pharm 31: 588, 1991
Ac ut e I nt er st i t i al Nephr i t i s
Dr ugs
ANTIBIOTICS
Penicillins, cephasporins, others (quinolones, Bactrim)
DIURETICS
Thiazides, furosemide
ANALGESICS
NSAIDS
ANTICONVULSANTS
phenytoin, carbamazepine, phenobarbitol
OTHERS
allopurinol, cimetidine
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851
Cl i ni c al Syndr omes
• Drug Induced AIN • Drug Induced AIN
– Variable
– Full-blown hypersensitivity reaction to
asymptomatic increase in Scr
– Nephritic / Nephrotic / AIN Urine sediment
– Fanconi’s syndrome, hyperkalemeic
hyperchloremic metabolic acidosis,
Nephrogenic DI
Di agnost i c f eat ur es
• Urinalysis • Urinalysis
• Impaired concentrating ability (SG, low urine osmolality)
• Leukocytosis – eosinophilia (10-30%) common
• Increased IgE
• Urine eosinophiluria
• Gallium – high sensitivity, low specificity Gallium high sensitivity, low specificity
• Renal Biopsy
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852
Eosi nophi l ur i a
>1% of white cells in urine stained
Wright’s and Hansel’s Stain
Both use eosin-methylene blue combinations
CAUSES
•Acute Interstitial Nephritis
•UTI
pyelonephritis
Both use eosin methylene blue combinations
Hansel’s 4 fold more sensitive, less pH dependent
Sensitivity 67%, specificity 80%
pyelonephritis
prostatitis
Cystitis
•Glomerulonephritis
•Atheroembolic disease
Nolan et al, NEJM 1986
Hansel ’s st ai n
Hansel’s stain
Eos stain bright red
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853
Dr ug I nduc ed AI N
NSAID-induced AIN
+ Nephrotic Syndrome
Methicillin-induced AIN NSAID-induced AIN
Rossert et al KI 60: 804-817, 2001
NSAI D assoc i at ed AI N
• Heterogenous picture • Heterogenous picture
• Typically, no hypersensitivity reaction
• Usually middle-aged or elderly
• Majority: associated nephrotic syndrome (MCD)
• Pyuria, hematuria, eosinophiluria (less than
methicillin-associated)
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854
Nephr ot i c Syndr ome & AKI
• Characteristics: • Characteristics:
– Elderly
– HTN
– Severe Proteinuria
– Severe Hypoalbuminemia
– Severe Edema
– M>F
– Fenoprofen higher risk
Mi ni mal Change Di sease & AKI
• Reversible renal failure in MCD was first reported in the Reversible renal failure in MCD was first reported in the
1960’s by Chamberlain, Pringle and Wrong in QJM and
by Conolly, Wrong and Jones in Lancet.
– Reduced Oncotic Pressure
– Hypotension
– Hypovolemia
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855
Mi ni mal Change Di sease & AKI
• Etiologies Include: • Etiologies Include:
– ATN (60%-70%)
– AIN
– Renal Vein Thrombosis
– Interstitial edema
• Lowenstein, Schacht, Baldwin, AJM, 1981
R t ti i f 15 t / MCD&ARF • Retrospective review of 15 pts w/ MCD&ARF
• Postulated interstitial edema produced an in in
hydrostatic pressure in prox tubules and Bowman’s
space leading to dec GFR
Quest i on 2
• A 27 year old man with the acquired immunodeficiency syndrome
(AIDS) is hospitalized with a cough, fever, and a pulmonary infiltrate
on CXR Therapy is initiated with trimethoprim-sulfamethoxazole on CXR. Therapy is initiated with trimethoprim sulfamethoxazole.
On admission, the serum creatinine is 1.6 mg/dL and blood urea
nitrogen, 21 mg/dL; On re-examination 3 days later, the serum
creatinine is 2.2 mg/dL and blood urea nitrogen, 23 mg/dL. Results
of urinalysis both on admission and 3 days later are normal. Urine
output on day 3 is 1350 mL. The most likely cause of the increased
creatinine is:
– A.) AIDS glomerulopathy
B ) Trimethoprim-mediated decrease in creatinine secretion – B.) Trimethoprim-mediated decrease in creatinine secretion
– C.) Intratubular obstruction secondary to sulfonamide
– D.) AIN caused by trimethoprim-sulfamethoxazole therapy
– E.) Acute tubular necrosis secondary to sepsis
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856
Tr i met hopr i m-Sul f amet hox azol e
• Elevated creatinine, no change in BUN, no
evidence of ARF: inhibition of tubular secretion
• Allergic interstitial nephritis with fever, rash, and
eosinophilia induced by sulfa moiety
• Hyperkalemia with salt wasting due to amiloride-
like action of trimethoprim
• Rarely, crystallization of sulfamethoxazole
metabolite and renal stone formation
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857
Quest i on 3
• A previously healthy 26 year old Japanese-American
man becomes ill with fever (temperature, 38ºC [100.4º]),
malaise, myalgias, and a sore throat. Approximately 8
hours later, gross hematuria and flank pain begin. His
past medical history is notable for several prior episodes
of gross hematuria. Urinalysis shows protein, 3+ and
erythrocyte casts. His blood urea nitrogen (BUN) is 28
mg/dL, serum creatinine is 1.3 mg/dL. Electrolytes are
within normal limits. Serological testing reveals normal
complements, a normal IgA level, a 1:40 ANA, anti-DNA
ab level of 0 and negative ASLO and ANCA titers. His
anti-GBM titers are also negative. Which of the following
is the most likely diagnosis:
Quest i on 3
– A.) WHO class IV lupus nephritis
– B.) IgA nephropathy
– C.) Rapidly progressive glomerulonephritis
secondary to Wegener’s granulomatosis
– D.) Goodpasture’s syndrome ) p y
– E.) Post-streptococcal glomerulonephritis
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858
HSP and I gAN w i t h age
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859
I gAN c l i ni c al pr esent at i ons
Macroscopic Hematuria
• ≈ 80% pediatric pts, ≈ 40-55% adults
• synpharyngitic
30% fl k / l i i • ≈ 30% flank / loin pain
• recurrent gross hematuria
• varying levels of proteinuria
• slower progression
Microscopic Hematuria
• persistent
t i i • proteinuria
• ≈ 36% hypertension, ≈ 27-43% azotemic
• faster progression
RPGN
Nephrotic syndrome
Hi st ol ogi c Subc l asses of
I gAN (Haas, 1997)
• Class I Minimal Histologic lesion
Mi i l i l ll l it Minimal mesangial cellularity
• Class II FSGS-like
Minimal mesangial cellularity, no cresc
• Class III Focal proliferative GN
<50% glo’s hypercellular, +/- cresc
• Class IV Diffuse proliferative GN
>50% glo’s hypercellular, +/- cresc
• Class V Advanced chronic GN • Class V Advanced chronic GN
>40% global scl, >40% tubular atrophy
Copyright Harvard Medical School, 2010. All Rights Reserved.
860
Key features that should be reported in pathology reports for patients
with IgAN
Eitner, F. and Floege, J. (2009) The Oxford classification—predicting progression of IgAN
Nat. Rev. Nephrol. doi:10.1038/nrneph.2009.150
Renal Sur vi val by I gAN c l ass
0.8
1.0
I & II
0.2
0.4
0.6
V
III
All cases
20 40 60 80 100 120 140 160
Time from biopsy (mo)
0.2 V
IV
Copyright Harvard Medical School, 2010. All Rights Reserved.
861
Quest i on 4
– A 52 year old African-American female presents to the
emergency room with unstable angina. She is noted to
have a past medical history of mild chronic renal
insufficiency ( creatinine of 1 8 mg/dL) She is insufficiency ( creatinine of 1.8 mg/dL). She is
transferred to the coronary care unit and therapy for
her unstable angina is initiated. A cardiac
catheterization is planned for the next day. Risk factors
that would predispose this woman to contrast
nephrotoxicty include all of the following except:
– A.) Diabetes mellitus
– B.) Pre-existing renal insufficiency
– C.) The volume of IV contrast utilized in the procedure
– D.) Presence of extracellular volume contraction
– E.) A history of coronary artery disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
862
Quest i on 5
• Her cardiologist asks you to recommend a strategy to minimize the
risk of contrast nephrotoxicity All of the following would be risk of contrast nephrotoxicity. All of the following would be
reasonable strategies except:
• A.) Start the patient on 0.45% saline and order furosemide 40
mg IV and 10 g mannitol on call to the procedure
• B.) Start the patient on 0.9% saline at 1 ml/kg for 12 hours prior to
the procedure
• C.) Start the patient on N-acetyl cysteine 1200 mg in divided doses
and pre-hydrate the patient
• D.) Stop the ibuprofen the patient is taking for her arthritis
• E.) Start isotonic sodium bicarbonate solution IV at 1ml/kg for 12
hours prior to the procedure
• F.) Use low osmolality ionic contrast
Copyright Harvard Medical School, 2010. All Rights Reserved.
863
Cont r ast Nephr ot ox i c i t y
(ver sus at her oembol i )
• ARF and oliguria within 24-48 hours • ARF and oliguria within 24-48 hours
• Peak serum creatininine on days 3-5
• Low fractional excretion of sodium
• Benign sediment or granular casts
• Resolution usual within 1 week
• Risk factors: CRI, diabetic nephropathy,
dose>120 cc, multiple myeloma, volume
Cont r ast Nephr opat hy
• Incidence ARF: 6.4%
• Mortality: 30-70%
• Radiocontrast nephropathy (RCN)
3rd most common form of ARF 13%
mortality: 29%
• Potentially preventable
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864
Contrast Nephropathy Prophylaxis
Options:
1.Hydration – 0.45% or normal saline (Solomon,
NEJM 1994) NEJM 1994)
1.N-acetyl cysteine
1.Sodium bicarbonate
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The image cannot be displayed. Your computer may not have enough memory to open theimage or theimagemay havebeen
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The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. I f the red x still appears, you may have to delete the image and then insert it again.
corrupted. Restart your computer, and then open the file again. I f the red x still appears, you may have to delete the image and then insert it again.
The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. I f the red x still appears, you may have to delete the image and then insert it again.
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The image cannot be displayed. Your computer may not haveenough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. I …
enough memory to open theimage, or theimagemay havebeen corrupted. Restart your computer, and then open the file again. I f the red x still appears, you may have to delete the image and then insert it again.
The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. I f the red x still appears, you may have to delete the image and then insert it again.
Solomon et.al. NEJM 1994
Copyright Harvard Medical School, 2010. All Rights Reserved.
865
Pr event i on of Cont r ast -I nduc ed Nephr opat hy Wi t h
Sodi um Bi c ar bonat e: A Randomi zed Cont r ol l ed Tr i al
Study Objective: To determine whether intravenous infusion of
isotonic NaHCO3 solution is superior to 0.9% NS hydration
in the prevention of RCN
Study Design: Prospective randomized, controlled trial of 119
patients undergoing a non-emergent exposure to iodinated
contrast
Methods:
Patients received 154 mEq/L of NS or Na
+
HCO
3
at
bolus of 3 mL/kg per hour for 1 hour before contrast
1 mL/kg per hour for 6 hours post procedure.
Contrast Agent: Iopamidol (796 mOsm/L) Contrast Agent: Iopamidol (796 mOsm/L)
Entry Criteria: Serum Cr > 1.1 mg/dl
Exclusion: Patients receiving dopamine, FNP, N-AC,
or mannitol
Primary endpoint: Rise in serum Cr by 25% 48 hrs
Merten et.al JAMA 291 (19) 2328-2334, 2004
Pr event i on of Cont r ast -I nduc ed Nephr opat hy Wi t h
Sodi um Bi c ar bonat e: A Randomi zed Cont r ol l ed Tr i al
Sodium Chloride
Hydration
Cr=1.71 mg/dl
Sodium Bicarbonate
Hydration
Cr=1.89 mg/dl
Merten et.al JAMA 291 (19) 2328-2334, 2004
Copyright Harvard Medical School, 2010. All Rights Reserved.
866
Pr event i on of Cont r ast -I nduc ed Nephr opat hy Wi t h
Sodi um Bi c ar bonat e: A Randomi zed Cont r ol l ed Tr i al
R
P<0.02 -0.1 ml/min
%

C
h
a
n
g
e

i
n

G
F
R
P 0.02
+ 8.5
ml/min
0.1 ml/min
Merten et.al JAMA 291 (19) 2328-2334, 2004
Sodium Chloride
Hydratzion
Sodium Bicarbonate
Hydration
%
Ef f ec t of Ac et yl cyst ei ne on CN
Tepel et al , NEJ M: 343: 180-4, 2000
• RCT n=83 baseline CRI (Scr 2 4 + 1 3 mg/dL) • RCT, n=83, baseline CRI (Scr 2.4 + 1.3 mg/dL)
• antioxidant acetylcysteine (600 mg twice daily) or
placebo
• All patients hydrated with 0.45% saline before and after;
used non-ionic low osmolality agent
• Mean Scr at 48 h decreased in acetylcysteine group (2.5
+ 1.3 to 2.1 + 1.3 mg/dL, P<0.001) vs. increasing in
placebo group (2.4 + 1.3 to 2.6 + 1.5 mg/dL, P<0.001 CN
in Rx group 56% vs. placebo 29%, P=0.18)
Copyright Harvard Medical School, 2010. All Rights Reserved.
867
Ant i -Ox i dant Ther apy Reduc es I nc i denc e of
Radi oc ont r ast Nephr opat hy
21% RCN
2.4 2.6 2.5 2.1
2.0% RCN
1/2 NS Acetylcysteine
Tepel et.al. NEJM 2000
Saline
NAC
N-Ac et yl c yst ei ne f or t he Pr event i on of RCN:
A Revi ew of Pr ospec t i ve Cont r ol l ed Tr i al s
Presented Abstract ASN, San Diego, 2003
Copyright Harvard Medical School, 2010. All Rights Reserved.
868
Quest i on 6
• All of the following statements regarding aminoglycoside
nephrotoxicity are true, except:
– A ) Aminoglycosides cause a secondary A.) Aminoglycosides cause a secondary
phospholipidosis in lysosomes
– B.) Aminoglycosides are proximal tubule toxins
– C.) Hypokalemia increases the risk of aminoglycoside
nephrotoxicity
– D.) Hypokalemia and hypomagnesemia are
commonly observed in patients with aminolglycoside y p g y
nephrotoxicty
– E.) Multidose regimen is preferred to single dose
regimens in order to reduce aminoglycoside
nephrotoxicity.
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869
Ami nogl yc osi de Nephr ot ox i c i t y
• 25% incidence with “therapeutic” levels
l ti ith l ti d • some correlation with cumulative dose
• non-oliguric ARF after 5-10 days
• Toxicity correlates with cationic charge
• Pathology: membrane phospholipidosis
• Prevention: once daily dosing y g
Prine et al: Lancet 341: 335, 1993
Levinson Ann Intern Med 117: 694, 1992
• 48 year old male ESRD patient presents to the
ED with a K= 7 8 mEq/L HC03 of 22 His EKG
Quest i on 7
ED with a K= 7.8 mEq/L, HC03 of 22. His EKG
shows peaked T waves. Recommended initial
treatment include all of the following EXCEPT:
– A.) Calcium gluconate 10 mls, IV
– B.) Insulin 10 units and 1 amp of 50% dextrose
– C.) Albuterol nebulizer (10-20 mg)
– D.) IV bicarbonate 8.4%, 1 to 2 amps IV
– E.) Emergent dialysis
Copyright Harvard Medical School, 2010. All Rights Reserved.
870
Changes i n pl asma K
8.4% bi c ar b, epi nephr i ne, i nsul i n/dex t r ose, or HD
Blumberg et al
Am J. Med 88:507-512, 1988
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871
Changes i n pl asma K dur i ng I V i nf usi on
of bi c ar bonat e i n HD pat i ent s
Values= means + SE
*P<0.5, + P<0..01 vs. baseline
Blumberg et al KI, 41: 369-374, 1992
Quest i on 8
21yr female with 8 day Hx of fever, chills, malaise, nausea, dark urine.
She is initially treated for ‘UTI’ with ciprofloxacin. SCr 1.2 2.8 over 3
days; t/f to BWH Past History G1 P1; dental abscess drained 2 wks
previously Social history: 2 cigs/day; hairdresser 5 units Etoh/wk previously. Social history: 2 cigs/day; hairdresser, 5 units Etoh/wk
Review of systems: no rash, no arthralgia, no increased menstrual
blood loss; +mild SOB. Examination: P 94, BP 130/70, RR 18, afebrile,
O2 sat 97% (room air). Conjunctiva pale. Resp: BS normal - few bibasal
crackles. Cardiac, abdominal examination unremarkable; no leg edema.
Lab data: UA 3+blood, 2+protein. Used. multiple RBCs (some
dysmorphic), few WBCs, no casts. BUN 32, K 4
.
7, Cr 3
.
9. WBC 8
.
2, Hct
23, MCV 74, Plts 283. Normal complements, ANA negative. CXR:
bilateral lower zone “interstitial” infiltrates.
Th t lik l di i i The most likely diagnosis is:
A.) Churg Strauss syndrome
B.) Lupus nephritis
C.) Post-infectious GN
D.) Anti-GBM nephritis
E.) Mixed essential cryoglobulinemia
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872
Di f f er ent i al dx i n t hi s 21yr f emal e
w i t h ARF, ac t i ve ur i ne sedi ment ,
abnor mal CXR
1. Post-infectious GN (with pulmonary edema) os ec ous G ( pu o a y ede a)
2. Systemic vasculitis:
•Microscopic polyarteritis
•Wegener’s granulomatosis
•SLE
• Other systemic vasculitides (HSP, cryoglobulin
disease) disease)
3. Anti-GBM disease
4. Legionella / Mycoplasma sp. pneumonia
5. Other?
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873
Hypoc ompl ement emi a i n
Gl omer ul ar Di sease
Pathway Complement Disease
Classical Low C3, C4, CH50 Lupus Nephritis
Mixed essential
cryo
Alternate Low C3, Normal C4 Post-strep GN
Post-infect GN
SBE
Shunt
Hep B
MPGN type 2 MPGN type 2
Reduced synthesis Acquired Liver Disease
Hereditary (C2 def) Lupus
Ant i -GBM Nephr i t i s - Pat hol ogy
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874
I ni t i al Management
•1g of iv methyprednisolone
•12 hrs later, renal bx performed 12 hrs later, renal bx performed
Light microscopy: severe crescentic GN (90% of
glomeruli involved); marked inflammation of the
tubulo-interstitium. IF showed intense linear
staining of the glomerular basement membranes
for IgG.
•Cr now 5
.
2
•Serum aGBM titer by ELISA: 140 [ref 0-5]; ANCA
neg.
Fur t her Management
Started on Hammersmith protocol of Lockwood et al.
(Lancet 1976)
•Methylpred 1g iv x3days; then prednisone 1mg/kg/day •Methylpred 1g iv x3days; then prednisone 1mg/kg/day
•Cyclophosphamide 3mg/kg/day po
•Plasmapheresis daily x14days; 4L exchanges (albumin +
FFP).
Day 8 of hospital stay:
•Nausea, vomiting; urine output 800ml/24hrs; persistent
anemia despite RBC transfusions (Hct 23.9); BUN 122, Cr 7.6;
serum aGBM titer by ELISA: 20 [ref 0-5]
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875
Whi c h of t he f ol l ow i ng def i nes t he
best f ur t her t r eat ment st r at egy?
A St i i d l h i i k t A. Stop immunosuppression and plasmapheresis - risks to
patient (opportunistic infection, neoplasia, ovarian
damage) now outweigh potential benefits
B. Stop immunosuppression but continue plasmapheresis
until aGBM serology negative
C Continue immunosuppression and plasmapheresis C. Continue immunosuppression and plasmapheresis
D. Add rituximab
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876
I ndi c at i ons f or w i t hol di ng
i mmunosuppr essi on i n ant i -GBM di sease
Levy et al . Ann I nt er n Med, 2001
Renal limited disease with:
•Dialysis dependency (Cr > 7.0 approx.) and severe,
“irreversible” disease on biopsy (e.g. 100% crescents)
Exceptions:
Al l h h •Alveolar hemorrhage
•Very acute renal damage (based on Hx & histology)
•ANCA+ and antiGBM+
Fol l ow -up
•Anemia presumed multi-factorial in origin; further RBC
transfusions given g
•Pheresis continued until aGBM titre neg. by ELISA (total
19 exchanges); immunosuppression also contd.
•Pt was dialysed twice, then slowly recovered renal fn.
ACE-I prescribed due to ongoing proteinuria
Ad ised to stop smoking and a oid occ pational •Advised to stop smoking and avoid occupational
exposure to inhalants
•1 year later, off immunosuppression, pt was doing well:
Cr 0.9 and +1 protein on urine dipstick
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877
Causes of pul monar y-r enal syndr omes
(ac ut e r enal and r espi r at or y f ai l ur e)
•Goodpasture’s Disease p
•Systemic Vasculitis:
-Common’: WG, MPA, SLE
-‘Uncommon’: HSP, Churg Strauss syn., cryoglobulin
disease
•ARF (any etiology) with pulmonary edema (a y et o ogy) t pu o a y ede a
•Severe LVF / cardiogenic shock
•Severe pneumonia (esp. Legionella sp.)
•Renal vein / IVC thrombosis with pulmonary emboli
Quest i on 9
• A 22-year old white male is seen in the emergency
room for evaluation of acute renal failure. He explains
that he has just finished running the Boston marathon that he has just finished running the Boston marathon.
He complains of severe leg cramps. He tells you that
his urine is light pink. He has no significant past
medical history. He is not taking any medications. He
denies recent alcohol consumption. His physical
examination shows a white male. His BP is 120/80
mmHG, heart rate of 110 bpm, afebrile. His JVP is 2-3
cm He has clear lungs a normal cardiovascular and cm. He has clear lungs, a normal cardiovascular and
abdominal examination. He has no edema. His skin
turgor is reduced. Urinalysis reveals a SG of 1020, pH
5.0, 4+ blood, rest negative. His urine sediment shows
2-4 RBC’s but is otherwise negative.
Copyright Harvard Medical School, 2010. All Rights Reserved.
878
All of the following statements are correct
Quest i on 9
• All of the following statements are correct,
EXCEPT
– A.) His CPK level is likely to be elevated
– B.) His serum phosphorous is likely to be
normal
– C.) He should be rapidly volume repleted
– D.) His urine should be alkalinized
– E.) Orthotoludine positive urine is typical
Copyright Harvard Medical School, 2010. All Rights Reserved.
879
Feat ur es of Rhabdomyol ysi s
• Muscle pain and dark urine “Coca-Cola” color Muscle pain and dark urine Coca Cola color
• Orthotoludine-positive urine without RBCs
• Elevated CPK and myoglobin
• Increased K, Phos, urate, decreased Ca
• Rapid increase in serum creatinine
• Mechanism: free radicals ferrihemate reduced • Mechanism: free radicals, ferrihemate, reduced
nitric oxide
• Treatment: saline repletion, alkaline diuresis,
mannitol. Dialysis once ARF established
Causes of Rhabdomyol ysi s
• Excessive muscle activity
– seizures, delerium tremens, sport
• Direct of ischemic muscle injury
– trauma, compression syndrome, vascular
occlusion
• Metabolic disorders
– hypokalemia, hyponatremia,
hypophosphatemia
• Drugs or toxins
– ethanol, isopropyl alcohol, heroin, methadone
• Infections
– tetanus, legionaires, influenza
Copyright Harvard Medical School, 2010. All Rights Reserved.
880
Quest i on 10
• A 12-year-old boy consults his family physician • A 12-year-old boy consults his family physician
because of the recent onset of edema. He has
no other relevant history and the physical
examination is remarkable only for significant
pitting edema in the lower extremities. His blood
pressure is 135/80. His sediment shows the p
following:
The most appropriate treatment is:
Quest i on 10
a) Prednisone and cyclosporine
b) Prednisone and Rituximab
c) Prednisone
d) Prednisone and Cyclophosphamide
e) Prednsione and Cellcept
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881
Usedi ment
• BUN 15 mg/dL
Quest i on 10
g
• Creatinine 0.9 mg/dL
• Albumin 1.7 g/dL (normal = 3.5 to 5 g/dL)
• Glucose 92 mg/dL
• Urinalysis 4+ protein (by dipstick); no cells or casts
• The total protein to creatinine ratio is 10.8, 24 h protein
10 8 /d 10.8 g/day
Copyright Harvard Medical School, 2010. All Rights Reserved.
882
Quest i on 10
The most appropriate treatment is:
a) Prednisone and cyclosporine
b) Prednisone and Rituximab
c) Prednisone
d) Prednisone and Cyclophosphamide
e) Prednsione and Cellcept
Copyright Harvard Medical School, 2010. All Rights Reserved.
883
MCD
Prednisone 1 mg/kg/d
(max 80 mg/d)
Until complete remission or
6 wks of therapy
Prednisone 2 mg/Kg alt day
For 3 months
YES
Complete
NO
REMISSION?
p
Remission
Or relapse
CsA > 1 y
Cytoxan or
Chlorambucil
8-12 w
Steroid taper
Conservative
Rx
• 61 year old man
• Rheumatoid arthritis x 15 years & gold therapy X
Quest i on 11
• Rheumatoid arthritis x 15 years & gold therapy X
12 years, with excellent control of his symptoms.
• Six months prior he c/o of edema. Cr 1.0 mg/dl,
24-h protein 10 g, albumin 1.8 g/dl.
• UA: 4+ albuminuria, bland sediment.
• Gold salts D/C’d; proteinuria persists, 24h Gold salts D/C d; proteinuria persists, 24h
protein averaging 14 g/day.
Copyright Harvard Medical School, 2010. All Rights Reserved.
884
• On no medications other than lasix in particular
Quest i on 11
• On no medications other than lasix, in particular,
no NSAID in the recent past.
• Physical examination showed a well-developed
man in no acute distress. Blood pressure was
120/80. There was 4+ edema present.
• The most likely diagnosis is:
Quest i on 11
– A.) Membranous glomerulopathy secondary
to gold
– B.) Idiopathic membranous glomerulopathy
– C.) AA amyloidosis secondary to
rheumatoid arthritis
– D.) Primary focal segmental
glomerulosclerosis
– E.) Rheumatoid vasculitis
Copyright Harvard Medical School, 2010. All Rights Reserved.
885
Gl omer ul ar Di sease and RA
• Renal Disease with RA • Renal Disease with RA
– Membranous
– Mesangial proliferative GN +/- IgA deposits
– Diffuse proliferative GN
• Necrotizing and crescentic GN (rheumatoid
vasculitis)
– Amyloidosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
886
• Renal Disease with treatment of RA
Renal Di sease and RA
• Renal Disease with treatment of RA
– Gold: MN, MCD, ATN
– Penicillamine: MN, Crescentic GN, MCD
– NSAIDs: AIN, MN, MCD, ATN
– CsA: chronic vasculopathy and tubulopathy
– Methotrexate: ATN / crystal induced ARF
– Aza: AIN
Quest i on 12
• The following statements about Wegener’s
granulomatosus are all true EXCEPT: g
• A.) A small fraction of patients have anti-GBM
antibodies present.
• B.) C-ANCA pattern is observed on indirect
immunofluorescence.
• C.) Serial ANCA measurement has been proven to
predict relapse and should be utilized to intensify
th therapy.
• D.) Less than 15% of patients actually have
granulomas on renal biopsy.
• E.) Complement levels (C3, C4, CH50) in the serum
are in the normal range.
Copyright Harvard Medical School, 2010. All Rights Reserved.
887
WG
• Respiratory and kidney involvement
• Commonly presents with the syndrome rapidly
i l l h iti (RPGN) progressive glomerulonephritis (RPGN)
• Associated with ANCA
• Demographics
– Slight male predominance; may occur at any
age of life; peak incidence in the fourth to
sixth decade of life.
I d i ti ith HLA DR2 HLA B7 – Increased associations with HLA-DR2, HLA-B7,
and HLA-DR1 and DR1-DQW1.
– All sizes of arteries and veins may be affected
but there is a predilection for small and
medium sized vessels.
Copyright Harvard Medical School, 2010. All Rights Reserved.
888
WG
• Clinical Features
– Presentation may be indolent with progressive involvement of
the respiratory tract and mild renal findings or there may be a
fulminant presentation with acute glomerulonephritis or RPGN.
Predominantly affects respiratory tract but vasculitic – Predominantly affects respiratory tract, but vasculitic
multisystemic involvement is not uncommon.
– Upper respiratory involvement includes sinusitis, tinnitus, and
hearing loss with otic discharge and pain.
– Untreated, leads to tympanic membrane, deafness, chronic
sinusitis, and saddle-nose deformity.
– Lower respiratory tract symptoms include cough with dyspnea
progressing to hemoptysis and alveolar hemorrhage.
– Multisystemic disease may include skin (e g papules Multisystemic disease may include skin (e.g., papules,
purpura), joints (arthralgias, arthritis), eyes (conjunctivitis,
episcleritis,), nervous system, the liver, the thyroid, the
gallbladder, and the heart.
– Rapidly progressive glomerulonephritis and renal failure.
– Decline in GFR may be more gradual with non-nephrotic range
proteinuria, hematuria, and red cell casts.
WG
• Pathology
• Focal segmental necrotizing and crescentic
glomerulonephritis.
• Also intracapillary thrombosis with endothelial cell swelling
and polymorphonuclear leukocyte infiltration ± mural
necrosis in vessel wall, pyknosis or karyorrhexis (nuclear
dust) may be observed.
• Sites of active lesion often display non-specific crescents
and Bowman capsule destruction.
• Chronic changes include glomerulosclerosis and fibrous
crescents.
• Vasculitis may involve the small and medium size renal • Vasculitis may involve the small and medium size renal
arteries, veins and capillaries.
• Tubules show areas of focal tubular
degenerative/regenerative changes; cortical infarcts may
be observed.
• Immunofluorescence shows a pauci immune pattern with
little immunoglobulin deposition.
Copyright Harvard Medical School, 2010. All Rights Reserved.
889
c-ANCA p-ANCA
Quest i on 13
• All of the following drugs are removed • All of the following drugs are removed
completely or partly by dialysis except:
– A.) Cylcophosphamide
– B.) Vancomycin
– C.) Gentamicin
– D.) Metoprolol
– E.) Atenolol
Copyright Harvard Medical School, 2010. All Rights Reserved.
890
Removal of dr ugs by di al ysi s
• Cyclophosphamide: 30-60% • Cyclophosphamide: 30-60%
• Prednisone: negligible
• Captopril 35-40%
• Lisinopril: 50-60%
• Atenolol: 50%
• Metoprolol: negligible
Copyright Harvard Medical School, 2010. All Rights Reserved.
891
Quest i on 14
• All of the following drugs are contraindicated in • All of the following drugs are contraindicated in
pregnancy, except:
– A.) Cyclophosphamide
– B.) ACE inhibitors
– C.) Azathioprine
– D.) Methyl dopa
– E.) Cellcept
Copyright Harvard Medical School, 2010. All Rights Reserved.
892
FDA pr egnanc y
c at egor i es
• A – human studies (controlled) – no adverse risk
• B – animal studies no adverse risk; no anecdotal
human studies showing risk
• C – animal studies show risk; no human studies
• D – human risk but benefits outweigh D human risk but benefits outweigh
• X – human risk, no benefits outweigh risk
Ef f ec t of I mmunosuppr essi ve
Dr ugs i n Pr egnanc y
• Prednisone (category B)
– Neonatal lymphopenia
– Thymic hypoplasia
• Azathiaprine (category D)
– Crosses placenta, cannot be converted to active form
by fetal liver early in pregnancy (fetal liver lacks enzyme
inosinate pyrophosphorylase)
– No clear increase in congenital anomalies
– Neonatal leukopenia and thrombocytopenia
Copyright Harvard Medical School, 2010. All Rights Reserved.
893
ACEi and Di ur et i c s i n pr egnanc y
• ACEi are contraindicated in pregnancy
Associated with oligohydramnios – Associated with oligohydramnios
– Neonatal death from hypoplastic lungs or neonate
renal failure
– Higher risk of stillbirth
– Dysplastic kidneys, hypocalvaria, and contractures
– 2 studies -- no ill effects from 1st trimester exposure
Diuretics use with caution b/o increased risk of pre • Diuretics -- use with caution b/o increased risk of pre-
eclampsia
Ef f ec t of I mmunosuppr essi ve
Dr ugs i n Pr egnancy (c ont ’d)
• Cyclosporine (category C)
– Intrauterine growth retardation
• Cyclophsphamide (category D)
– Flattened nasal bridge
– Palate defect
Single coronary artery – Single coronary artery
– Imperforate anus
– Rectovaginal fistula
– Dysmorphic facies…… etc
Copyright Harvard Medical School, 2010. All Rights Reserved.
894
Ef f ec t of I mmunosuppr essi ve
Dr ugs i n Pr egnancy (c ont ’d)
• Tacrolimus
– Hyperkalemia
– Neonatal hyperkalemia
• MMF
– Embryocidal in animals
No human experience – No human experience
• Warfarin
– Teratogenic during 1
st
trimester
– Crosses placenta (fetal risk of bleeding)
Quest i on 15
• A 62-year old patient is admitted to the hospital
for evaluation of hemoptysis of 2 weeks for evaluation of hemoptysis of 2 weeks
duration. He gives a history of gradually worse
dyspnea over the past 10 years. He has a cough
productive of copious sputum during winter
months and several prior “lung infections” during
the winter months. He has noticed some general
malaise, loss of appetite, and tiredness, worse
recently.
Copyright Harvard Medical School, 2010. All Rights Reserved.
895
• Social history shows moderate beer intake -- 1-2
beers each night. Heavy smoking history 20-30
cigarettes/day x 40 years. He denies g y y
recreational drugs. Works as a janitor.
Medications: Atrovent inhaler and prn ventolin.
• Examination: mild dyspnea at rest. He is
confused and agitated. Not cooperative. Blood
pressure on admission is 168/92 mmHg without
orthostasis. HR 84 bpm. Lungs: he has
scattered rhonchi. Reduced right base air-entry
and dullness on percussion. He has no
peripheral edema.
• Urinalysis: SG 1010, pH 5.0. Rest negative.
• Urine sodium 42 mEq/L
• Urine osmolality 615 mOsm
• Electrolytes
– Na 100, K 3.5, C02 30, Cl 72, BUN 5.0,
Creatinine 0.6, Glucose 108 , Uric acid 2.6
Copyright Harvard Medical School, 2010. All Rights Reserved.
896
• All of the following statements are true except:
– A.) The patient’s total body sodium is normal
– B.) The calculated serum osmolality is approximately 208
mOs/Kg mOs/Kg
– C.) The patient has evidence of either inappropriate or
appropriate ADH secretion
– D.) The urine sodium value seen in this patient is atypical of
a patient with SIADH
– E.) Use of 3% hypertonic saline would be the best treatment at
this point in this patient
Copyright Harvard Medical School, 2010. All Rights Reserved.
897
Hypovelemia Euvolemia Hypervolemia
20% 35% 20%
Extrarenal Na losses
urine Na < 20
SIADH
Hypothyroidism
Extra-renal Disorders
CHF
urine Na < 20
Vomiting
Diarrhea
Renal Na losses
urine Na > 20
Diuretics
Osmotic diuretics
Hypothyroidism
Glucocorticoid def
Drugs
Pain
Respiratory failure
Positive pressure
breathing
CHF
Cirrhosis
Renal Disorders
NS
ARF
CRF
Cr i t er i a f or di agnosi ng SI ADH
• Euvolemia
• Uosm > 200 mOsm/Kg water)
• Normal renal, adrenal, thyroid function
• U Na > 20 mEq/L (usually 40 mEq/L)
• Hypouricemia (< 4 mg/dL) • Hypouricemia (< 4 mg/dL)
Copyright Harvard Medical School, 2010. All Rights Reserved.
898
Cl i ni c al Pr esent at i on of SI ADH
• High risk group
• young children
• elderly patients
• menstruating women
Na < 120
anorexia, lethargy, malaise, confusion, headaches
• Na < 100
Confusion, seizures, stupor, coma
Management of Hyponat r emi a
Acute Symptomatic
acute (< 48 hrs)
symptomatic symptomatic
<Na 120 mEq
Hypertonic saline (3%) via central line
Correct at 0.55 mEq/L/hr - 1.0 mEq/L/hr
< 20 mEq change in Na over 24 hrs
Asymptomatic Asymptomatic
acute or chronic
free water restriction
500 ml to 1 liter / day
Demeclocycline 300 mg BID to 300 mg QID
Copyright Harvard Medical School, 2010. All Rights Reserved.
899
Pr i c e f or r api d c or r ec t i on
• Rapid correction with acute severe
hyponatremia hyponatremia
• Price of too rapid correction is central pontine
myelinolysis
• Flaccid quadraplegia, dysphagia, dysarthria
• Predisposing factors unclear
• Experimental data support magnitude of • Experimental data support magnitude of
correction not rate of correction
– rate > 2 mEq/L/hr
– total > 20 mEq/L/24 hr
• A 42-year old white male 8 days post bone
marrow transplantation on treatment with FK506
Quest i on 16
marrow transplantation on treatment with FK506
(tacrolimus), among many other medications is
diagnosed with a type IV renal tubular acidosis.
All of the following features would be compatible
with this diagnosis except:
– A.) A urine pH of 5.0
– B.) The presence of hyperkalemia
– C.) A negative urine anion gap of -22
– D.) A serum bicarbonate of 18
– E.) A normal anion gap
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900
Ur i ne Ani on Gap
• Urine anion gap Urine anion gap
– =(Na+) + (K+) – (Cl-)
– = unmeasured anions – unmeasured cations
– Most cases of MA has negative value due to excretion of an
unmeasured anion NH4+
– Normal subjects, 20-40 meq NH4+ is excreted and anion gap = 0
– Metabolic acidosis, NH4+ excretion increases and UAG = -20 to
–50
– In CRF or type 1 and 4 RTA, impaired H+ and NH4 excretion,
UAG is positive
Copyright Harvard Medical School, 2010. All Rights Reserved.
901
Renal Tubul ar Ac i dosi s
• 3 types
• Type 1 (distal) RTA
R d d H+ ti b ll ti t b l – Reduced H+ secretion by collecting tubule
– Reduced NH4+ and titratable acid excretion
• Defective H+-ATPase pump
• Reduction in cortical Na+ resorption (voltage-dependent
defect)
• Increased membrane permeability, back diffusion of H+
(gradient defect)
Causes – Causes
• Idiopathic
• Autoimmune (SLE, RA etc), drugs and toxins (ampho B,
Toluene, lithium)
• Marked volume depletion
• Type 2 (proximal)
– Proximal NaHC03 reabsorption is reduced
– Self limiting disored, HC03 14-20 mEq/L
Renal Tubul ar Ac i dosi s
S g , C03 0 q/
– Etiology
• Idiopathic
• Hereditary (cystinosis, Wilson’s disease)
• Acquired (multiple myeloma, drugs (acetazolamide, outdated
tetracycline, lead etc), amyloidosis, Sjogren’s
– Diagnosis
• Normal AG metabolic acidosis G
• Moderate acidosis (14-20)
• Urine pH variable (> or < 5.3 depending on threshold)
• Plasma K normal
– Treatment
• Bicarb replacement
Copyright Harvard Medical School, 2010. All Rights Reserved.
902
Hyper k al emi c Di st al
RTA Type I V
• Disturbance of distal nephron function • Disturbance of distal nephron function
• Impaired excretion of H+ and K+
• Normal gap acidosis and hyperkalemia
Type 1 RTA
•Hypokalemia
•NL renal fxn
Type 4 RTA
•Hyperkalemia
•CRI
•U pH > 5.5
• Metabolic acidosis
severe HC03 < 15
• U pH <5.5
• Metabolic acidosis
mild HC03 > 15
Causes of Type I V RTA
Defect Causes
Mineralocorticoid Deficiency
Low renin low aldo -- Diabetes mellitus
-- Drugs: NSAIDS, CsA, ß-blockers
High renin low aldo -- Adrenal destruction
-- Congenital enzyme defects
-- Drugs: ACEi, ARBs, heparin
ketoconazole
Abnormal cortical collecting duct -- Absent or defective
mineralocorticoid receptor
D i i l t il id -- Drugs: spirinolactone, amiloride,
pentamidine, trimethoprim
-- Chronic tubulointerstitial disease
UTI, lupus nephritis, sickle cell neph
Copyright Harvard Medical School, 2010. All Rights Reserved.
903
RTA
Type 1
(distal)
Type 2
(proximal)
Type 4
Basic Defect distal
acidification
proximal
reabsorption
Aldo
deficiency or
resistance
Serum
bicarb
Plasma K
Urine pH
Maybe < 10
Low or NL
> 5 3
14-20
Low or NL
Variable
Usually > 15
Elevated
<5 3
Urine pH
Other
> 5.3 Variable <5.3
Serum aldo
level
Dose of
HC03
1-2 mEq/d 10-15 mEq/d 1-2 meq/d
Quest i on 17
• You are asked to consult on a 62 year old • You are asked to consult on a 62 year old
African-American male with acute on chronic
renal insufficiency secondary to diabetes
mellitus ascribed to contrast nephrotoxicity.
Routine chemistry labs show a potassium of 8.2
mg/dL. All of the following would be changes g g g
seen on the EKG compatible with hyperkalemia,
except:
Copyright Harvard Medical School, 2010. All Rights Reserved.
904
– A.) Peaked T waves
– B.) Prolonged QRS
– C.) Flattened p wave
– D.) Sine-wave appearing QRS complex D.) Sine wave appearing QRS complex
– E.) U wave
Copyright Harvard Medical School, 2010. All Rights Reserved.
905
EKG c hanges i n hyper k al emi a
• Early: tenting of T waves “pinch-bottomed T Early: tenting of T waves pinch bottomed T
waves”; precordial leads
• Prolonged P-R interval
• ST segment depression and lengthening of QRS
• P wave disappears, further widening of QRS
• Ventricular fibrillation Ventricular fibrillation
EKG c hanges i n Hyper k al emi a
Copyright Harvard Medical School, 2010. All Rights Reserved.
906
• The most common type of kidney stone
Quest i on 18
yp y
observed in the United States is:
– A.) Cystine stone
– B.) Triple phosphate stone
– C.) Struvite stone
D ) Calcium oxalate stone – D.) Calcium oxalate stone
– E.) Uric acid stone
Copyright Harvard Medical School, 2010. All Rights Reserved.
907
Nephr ol i t hi asi s
• 12% of US population affected
• Incidence rate (age 30-65)
– Male: 3/1000/yr
– Female: 1/1000/yr
• Calcium oxalate > 75%
– Hypercalciuria,hyperoxaluria, hypocitrituria,
hyperuricosuria
• Infection stone/Magnesium ammonium Infection stone/Magnesium ammonium
phosphate/struvite/triple phosphate 7-15%
• Uric acid 2%
• Calcium phosphate 2%
• Cystine <1%
Common Cr yst al s
Source: www:medstat.med.utah.edu/WebPath
Copyright Harvard Medical School, 2010. All Rights Reserved.
908
Di sc l osur es
• Consulting • Consulting
– Amgen, Johnson and Johnson, Sandoz,
Fibrogen
• Grant Support
– Amgen, Johnson and Johnson, Roche
• Advisory Boards
– Rockwell
Copyright Harvard Medical School, 2010. All Rights Reserved.
909
Kidney Stone Cases
Gary C. Curhan, MD, ScD
Associate Professor of Medicine
and Epidemiology
Disclosure
I have financial relationships or affiliation with:
Name of Organization Relationship
TAKEDA Consultant
ASTELLAS Grant Support
UP-TO-DATE Section Editor
American Society of Nephrology Editorial Board
Copyright Harvard Medical School, 2010. All Rights Reserved.
910
Type of Stones & Frequency in Adults
CaOx
CaOx
CaOx
Coe, 1983
Urinary Risk Factors
Increased risk
Calcium
Oxalate
Uric acid
Decreased risk
Citrate
Volume
But need to rethink our approach--these
are continuous variables, not dichotomous
Copyright Harvard Medical School, 2010. All Rights Reserved.
911
“Definitions”
• Hypercalciuria
– Males: >300 mg/d
– Females: >250 mg/d
– Either: >4 mg/kg/d
• Hyperoxaluria: >45 mg/d
• Hyperuricosuria
– Males: >800 mg/d
– Females: >750 mg/d
Case #1—Mr. G.O.
• 52 y.o. male with recurrent nephrolithiasis
• Passes a stone every two months
• PMH: chronic diarrhea
• Meds: Lomotil; allopurinol 300 mg/d
Copyright Harvard Medical School, 2010. All Rights Reserved.
912
Case #1—Evaluation
• Blood
– Bicarbonate 26 meq/L
– Uric acid 5.5 mg/dL
• KUB
– No stones seen
Case #1—24 hour urine
TV Ca Ox Cit UA Creat Na pH
2.4 290 56 141 503 2599 347 5.6
1.5 172 20 142 231 1528 237 5.3
Copyright Harvard Medical School, 2010. All Rights Reserved.
913
Questions
1. Metabolic abnormalities?
2. Stone type?
3. Next steps?
Question: Metabolic abnormalities?
Which urine is the correct one?
Second collection contains 40% less
creatinine than the first
Copyright Harvard Medical School, 2010. All Rights Reserved.
914
Case #1—24 hour urine
TV Ca Ox Cit UA Creat Na pH
2.4 290 56 141 503 2599 347 5.6
1.5 172 20 142 231 1528 237 5.3
Question: Metabolic abnormalities?
Assume first urine is the
correct one.
• High calcium,
oxalate, sodium
• Low citrate
• Normal uric acid
Assume second urine is
the correct one.
• High, sodium
• Low citrate
• Normal calcium,
oxalate, uric acid
Copyright Harvard Medical School, 2010. All Rights Reserved.
915
Question: Stone type?
1. Calcium oxalate
2. Calcium phosphate
3. Uric acid
4. Cystine
Uric acid 100%
Question: Next Steps?
• Imaging study
Spiral CT
• Repeat 24 hour urine
• Alkalinizationof urine
– Potassium citrate
– Patient follow urine pH (aim for ~6.5)
Copyright Harvard Medical School, 2010. All Rights Reserved.
916
Case #2—Ms. G.K.
• 45 y.o. female with recurrent nephrolithiasis
• Frequency: every 8-10 months
• Previous procedures:
– ESWL x 5
– Cystoscopyx 6
– PCNL x 1
• PMH—otherwise negative
Case #2—24 hour urine
TV Ca Ox Cit UA Creat Na pH
2.30 114 28 1102 396 972 168 7.30
Copyright Harvard Medical School, 2010. All Rights Reserved.
917
Question: Stone type?
1. Calcium oxalate
2. Calcium phosphate
3. Uric acid
4. Cystine
Cystine100%
Medications
• Potassium citrate 20 meqBID
– Occasionally checks urine pH
• Allergies
– Penicillaminerash
Copyright Harvard Medical School, 2010. All Rights Reserved.
918
CT Report
Right kidney is normal
Left kidney contains 4 mm and 2 mm upper
pole stones; 9 mm lower pole stone; 4 mm
at the left UVJ
Case #2—24 hour urine
TV Ca Ox Cit UA Creat Na pH
2.30 114 28 1102 396 972 168 7.30
Total cystine: 1877 mg/d (816 mg/L)
Copyright Harvard Medical School, 2010. All Rights Reserved.
919
Treatment
• Reduce [cystine] <250mg/L
• Increase fluid intake?
– Urine output >5 L/d
• Tiopronin (“Thiola”)
– Typically need at least 900 mg/d (300 mg TID)
• Continue alkalinization
Case #2—F/U 24 hour urine
First collection
Total cystine: 1877 mg/d
Second collection on tiopronin 900 mg/d
Total cystine: 2014 mg/d
Copyright Harvard Medical School, 2010. All Rights Reserved.
920
Why Was Urine CystineHigher?
• Day-to-day variability
• Lab variability
• Completeness of collection
• What does the lab actually measure?
– All existing assays seem to also measure the
cystine-tiopronincomplex
Case #2—6 Months Later…
• Calls with left renal colic
• Stopped medication because it clearly did
not work
• Is she correct?
Copyright Harvard Medical School, 2010. All Rights Reserved.
921
Case #3—Ms. J .B.
• 35 y.o. female nurse with recurrent stones
• Presented 5 years ago with colic and
bilateral renal stones
• PMH: unremarkable
Question: Stone type?
1. Calcium oxalate
2. Calcium phosphate
3. Uric acid
4. Cystine
Calcium oxalate 95%
Calcium phosphate 5%
Copyright Harvard Medical School, 2010. All Rights Reserved.
922
CT Report
Bilateral renal stones
3 mm stone at left UVJ
Question: Acute Management?
• Watchful waiting
– For how long?
• Pain
• Infection
• Hydronephrosis
• Medications
– Alpha blocker
• Cystoscopicremoval
• ESWL
Copyright Harvard Medical School, 2010. All Rights Reserved.
923
Case #3—24 hour urine
TV Ca Ox Cit UA Creat Na
1.73 210 26 845 493 1400 ---
1.10 209 32 943 447 1265 ---
Question: Treatment?
• Increase fluid intake
– How much to prescribe?
• If TV does not increase?
• Thiazide
Copyright Harvard Medical School, 2010. All Rights Reserved.
924
Curhan, Kidney Int, 2008
24 Hour Urine Calcium
Cases: 2237; Controls: 1113
Question: Follow-Up?
• Repeat 24 hour urine
– 4-6 weeks
• Adjust recommendations
• Repeat 24 hour urine
• Follow-up imaging
– Stone growth
– New stone formation
Copyright Harvard Medical School, 2010. All Rights Reserved.
925
Case #4—Mr. S.L.
• 49 y.o. male accountant with h/oCrohn’s
disease
• S/p partial ileal resection
• Recurrent intestinal obstruction
• Presented 6 months ago with abdominal pain
• Intestinal obstruction?
• Exploratory laparotomyplanned
Case #4—Mr. S.L.
• Pre-op evaluation: U/A-->100 RBC
• Underwent right hemi-colectomy
• POD #5—abdominal pain
– due to tapering of analgesics?
• Discharged home on Percocet
• Returned two days later to ER
• UVJ stone seen on CT
Copyright Harvard Medical School, 2010. All Rights Reserved.
926
Question: Stone type?
1. Calcium oxalate
2. Calcium phosphate
3. Uric acid
4. Cystine
Calcium oxalate 100%
Case #4—24 hour urine
TV Ca Ox Cit UA Creat Na
1.20 62 117 18 413 1350 ---
1.30 73 73 11 711 1412 ---
Copyright Harvard Medical School, 2010. All Rights Reserved.
927
Question: Treatment?
• Increase fluid intake
– How much to prescribe?
• Reduce oxalate
Increase dietary calcium intake
• Increase citrate
What formulation?
Case #5—Ms. E.J .
• 35 y.o. female neurology nurse
• Renal colic
• 9 x 5 mm stone right UVJ
• Cysto+laser lithotripsy
• Calcium oxalate 100%
• Patient reports she is “stone free”
Copyright Harvard Medical School, 2010. All Rights Reserved.
928
Case #5 —Ms. E.J .
• Diagnosed with recurrent UTIs
– U/A +for RBC, WBC
• Questionable relief from Abx
• KUB report “2 mm calcification at right
UVJ ”
Question: Next Steps?
• Urine cultures
Cultures are negative
• Imaging study
Spiral CT: UVJ stone
• Cystofor stone fragment removal
• 24 hr urine
Copyright Harvard Medical School, 2010. All Rights Reserved.
929
Case #5—24 hour urine
TV Ca Ox Cit UA Creat Na
1.97 477 42 437 978 1714 191
2.37 491 45 534 894 1510 196
Question: Metabolic abnormalities?
• Elevated in urine:
– calcium
– oxalate
– uric acid
– sodium
• Check PTH
Normal
Copyright Harvard Medical School, 2010. All Rights Reserved.
930
Question: Treatment?
• Maintain current fluid intake
• Diet
Reduce oxalate
Reduce sodium
Reduce animal protein
Increase dietary calcium intake?
• Check bone density
• Thiazide
Avoid if pregnancy planned
Case #5—24 hour urine
on HCTZ 25 mg/d
TV Ca Ox Cit UA Creat Na
3.99 465 44 1095 1005 1700 319
Compare with pre-treatment values
1.97 477 42 437 978 1714 191
2.37 491 45 534 894 1510 196
Copyright Harvard Medical School, 2010. All Rights Reserved.
931
Case #6 —Ms. P.T.
• 27 y.o. female with recurrent nephrolithiasis
• PMH: Recurrent UTIs
• Passes stones monthly
• KUB: bilateral renal calcifications
Question: Stone type?
1. Calcium oxalate
2. Calcium phosphate
3. Struvite
4. Cystine
Calcium phosphate 100%
Copyright Harvard Medical School, 2010. All Rights Reserved.
932
Case #6 —Ms. M.T.
• IVP
– Medullarysponge kidney
• CT
– Parenchymal calcifications
– Few stones in renal pelvis
• Serum HCO3 21
• Urine pH 6.6
Question: Next Steps?
• Urine cultures
Proteus
• Cystoand laser for stone fragment removal
3 unit bleed
required embolization
• 24 hr urine
Copyright Harvard Medical School, 2010. All Rights Reserved.
933
Case #6—24 hour urine
TV Ca Ox Cit UA Creat Na
0.93 251 18 225 437 978 132
0.87 275 21 189 334 1012 159
Question: Treatment?
• Increase fluid intake
• Diet
Reduce sodium
Increase dietary calcium intake?
• Check bone density
• Thiazide
• Alkali?
Copyright Harvard Medical School, 2010. All Rights Reserved.
934
Hypocitraturiaand Calcium
Phosphate Stones
• CaP form in more alkaline urine
• How to lower urine pH in patients with
RTA?
• How to raise urine citrate w/o raising urine
pH?
• Alkali may help or make the situation worse
Question: Next Steps?
• Screening urine cultures
aggressively treat UTIs
• Imaging study
Difficult to evaluate stone burden
• 24 hr urine
Copyright Harvard Medical School, 2010. All Rights Reserved.
935
Wisdom from Experience
• Always measure TWO 24 hour urines at
baseline
• Find out stone composition by analysis
• Repeat 24 hour urine after
recommendations
• Helical CT is the most reliable imaging
study
Wisdom from Experience
• Be careful when recommending a low
oxalate diet
• Explain to patient that a new episode of
colic does not always mean treatment
failure
• Not all chronic “kidney pain” is from stones
• Watch out for the addicted stone patient
• The urologist is your friend
Copyright Harvard Medical School, 2010. All Rights Reserved.
936
1. A 42 year old male suffered a severed spinal cord at
T10. He has a long history of recurrent urinary tract
infections. As part of the evaluation for abdominal pain,
he had a KUB that showed a staghorncalculus in his
right kidney. One of his urine infections most likely
included which of the following bacteria?
• a. E. coli
• b. MRSA
• c. Klebsiellapneumoniae
• d. proteusmirabilis
• (Correct answer is D)
2. A child whoseparents are first cousins was found to
have a kidney stone at age 7. The urinalysis showed
blood and many hexagonal crystals. The most likely
stone composition is:
• a. cystine
• b. struvite
• c. calcium oxalate
• d. uric acid
• (correct answer is A)
Copyright Harvard Medical School, 2010. All Rights Reserved.
937
References
• StamatelouKK, Francis ME, J ones CA, Nyberg LM, CurhanGC. Time trends in reported prevalence
of kidney stones in the United States: 1976-1994. Kidney Int 2003; 63:1817-23.
• CurhanGC, Willett WC, RimmEB, Stampfer MJ . A prospective study of dietary calciumand other
nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993; 328:833-8.
• Taylor EN, Stampfer MJ , Curhan, GC. Dietary factors and the risk of incident kidney stones in men:
new insights after 14 years of follow-up. J Am Soc Nephrol. 2004 Dec;15(12):3225-32.
• CurhanG, Willett W, Speizer F, SpiegelmanD, Stampfer M. Comparison of dietary calciumwith
supplemental calciumand other nutrients as factors affecting therisk for kidney stones in women.
Ann Intern Med 1997; 126:497-504.
• CurhanGC, Willett WC, Knight EL, Stampfer MJ . Dietary factors and the risk of incident kidney
stones in younger women (Nurses' Health Study II). Arch Intern Med 2004; 164:885-91.
• CurhanGC, Willett WC, Speizer FE, Stampfer MJ . Beverage use and risk for kidney stones in
women. Ann Intern Med 1998; 128:534-40.
• CurhanG, Taylor E. 24-h uric acid excretion and the risk of kidney stones. Kidney Int 2008;
Feb;73(4):489-496.
• Taylor EN, Stampfer MJ , Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA.
2005 J an 26;293(4):455-62.
• Taylor E, CurhanG. Oxalate intake and the risk for nephrolithiasis. J Am Soc Nephrol. 2007
J ul;18(7):2198-204.
• Evan AP, et al. Randall's plaque of patients with nephrolithiasisbegins in basement membranes of
thin loops of Henle. J Clin Invest. 2003 Mar;111(5):607-16.
• Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk of kidney stones. J
Am Soc Nephrol. 2009 Oct; 20(10):2253-9.
Disclosure
I have financial relationships or affiliation with:
Name of Organization Relationship
TAKEDA Consultant
ASTELLAS Grant Support
UP-TO-DATE Section Editor
American Society of Nephrology Editorial Board
Copyright Harvard Medical School, 2010. All Rights Reserved.
938
Hypertension Board Review
J ohn P. Forman, M.D., M.Sc.
Brigham and Women’s Hospital
Harvard Medical School
Disclosures
None
Copyright Harvard Medical School, 2010. All Rights Reserved.
939
Case 1
Case 1, question 1
A 78 year old woman with DM, CAD, and CKD (Cre=2.4 mg/dL), is
referred to you for persistent HTN, despite being treated with 5
medications (lisinopril 40 mg, amlodipine10 mg, furosemide40 mg
bid, metoprolol 50 mg, and losartan 50 mg). She is asymptomatic.
She tells you that she is often dizzy when she wakes up in the
morning. She checks her BP at home, and says it is typically 100 –
120 systolic. On exam, her BP is 164/70, non-orthostatic, HR 54,
but otherwise unremarkable. Her UA shows 2+albumin. BUN=42,
Cre=2.38, K=4.1.
- Which one of the following next steps is most appropriate?
A.) Increase the dose of her losartan to achieve better BP control
B.) Ask her to continue to do home BP measurements and see her
again in 3 months time.
C.) Do a screen for furosemidein her urine to see if she is being
adherent with her medications
D.) Set her up for ambulatory BP monitoring
E.) Start her on a clonidinepatch.
Copyright Harvard Medical School, 2010. All Rights Reserved.
940
135/85
Ambulatory Pressure
140/90
Clinic
Pressure
Sustained
Hypertension
White Coat
Hypertension
True
Normotension
Masked
Hypertension
10-40%
5-20%
Predictors of white coat HTN
• Older (age ≥ 60 years)
• Female
• Morning clinic visit
• BP meds taken in AM (vs. PM)
• Obesity
• Active smoking
• Diabetes
Banegas JR et al. Hypertension 2007; 49:62
Copyright Harvard Medical School, 2010. All Rights Reserved.
941
Recommendations for Clinical Use of ABPM:
J NC 7 & WHO-ISH
JNC 7 WHO-ISH
ABPM endorsed Yes Yes
Indications:
White Coat HTN Yes Yes
Labile BP Yes Yes
R/O hypotensive episodes Yes Yes
Resistant HTN Yes Yes
Autonomic dysfunction Yes No
A 78 year old woman with DM, CAD, and CKD (Cre=2.4 mg/dL), is
referred to you for persistent HTN, despite being treated with 5
medications (lisinopril 40 mg, amlodipine10 mg, furosemide40 mg
bid, metoprolol 50 mg, and losartan 50 mg). She is asymptomatic.
She tells you that she is often dizzy when she wakes up in the
morning. She checks her BP at home, and says it is typically 100 –
120 systolic. On exam, her BP is 164/70, non-orthostatic, HR 54,
but otherwise unremarkable. Her UA shows 2+albumin. BUN=42,
Cre=2.38, K=4.1.
- Which one of the following next steps is most appropriate?
A.) Increase the dose of her losartan to achieve better BP control
B.) Ask her to continue to do home BP measurements and see her
again in 3 months time.
C.) Do a screen for furosemidein her urine to see if she is being
adherent with her medications
 D.) Set her up for ambulatory BP monitoring
E.) Start her on a clonidinepatch.
Case 1, question 1
Copyright Harvard Medical School, 2010. All Rights Reserved.
942
Case 1, question 2
The patient returns for follow-up after completing the 24-
hour ABPM. Average daytime BP is 124/65 mmHg.
Mean nighttime BP is 110/50 mmHg. There is an 11%
drop in SBP from daytime to nighttime.
- Which of the following statements about 24-hour ABPM is
false?
A.) ABPM has prognostic value over and above clinic BP.
B.) Home BP monitoring is prognosticallyinferior to 24hr
mean BP.
C.) Nighttime BP is the strongest predictor of CV mortality.
D.) Non-dipping status is associated with greater declines in
GFR
E.) Non-dipping status is associated with a higher risk of CV
events.
Prognostic significance over and above
clinic BP
Clement DL. et al. NEJM 2003;348: 2407
Masked HTN = ↑ risk
Additional prognostic
information gained from
ABPM
Copyright Harvard Medical School, 2010. All Rights Reserved.
943
BP metric and risk of CV death
Dolan, E. et al. Hypertension 2005;46:156-161 N=5292
In fully adjusted models, including adjustment for clinic BP:
10 mmHg higher nighttime SBP 21% higher risk of CV death
5 mmHg higher nighttime DBP 9% higher risk of CV death
BP dipping and change in GFR
Davidson, M. B. et al. Arch Intern Med 2006;166:846-852.
329 adults w/o ESRD referred for 24hr ABPM
Copyright Harvard Medical School, 2010. All Rights Reserved.
944
Non-dipping and risk of CV events
Staessen, J. A. et al. JAMA 1999;282:539-546.
Each 10% higher night-
day ratio is associated
with a 41% higher risk
of CV events
Case 1, question 2
The patient returns for follow-up after completing the 24-
hour ABPM. Average daytime BP is 124/65 mmHg.
Mean nighttime BP is 110/50 mmHg. There is an 11%
drop in SBP from daytime to nighttime.
- Which of the following statements about 24-hour ABPM is
false?
A.) ABPM has prognostic value over and above clinic BP.
 B.) Home BP monitoring is prognostically inferior to
24hr mean BP.
C.) Nighttime BP is the strongest predictor of CV mortality.
D.) Non-dipping status is associated with greater declines in
GFR
E.) Non-dipping status is associated with a higher risk of CV
events.
Copyright Harvard Medical School, 2010. All Rights Reserved.
945
Case 2
Case 2: question 1
• A 37 year old white female referred to you for resistant hypertension.
• Occasional headaches, fatigue, and muscle cramps
• BP 170/100, BMI 27, exam is otherwise unremarkable.
• Enalapril 20 bid, HCTZ/triamterene25/37.5 qd, atenolol 50 qd.
• Potassium 2.6 meq/L, other labs normal
– Which of the following would most likely ESTABLISHthe correct
diagnosis?
A.) Fractionated plasma metanephrines
B.) Renal angiogram
C.) Plasma ratio of aldosterone to PRA (ARR)
D.) Low dose dexamethasone suppression test
E.) 24-hr urine aldosterone after oral sodium loading
F.) TSH
Copyright Harvard Medical School, 2010. All Rights Reserved.
946
Evaluate for endocrine causes
of secondary hypertension
Resistant hypertension
Eliminate “psuedoresistance”
Improper measurement
White coat syndrome
Non-adherence
Identify common non-endocrine causes
Obesity sleep apnea
Diabetes and/or kidney disease
Offending drugs or alcohol
Combination of poor lifestyle factors
Specific signs or symptoms
Adrenal incidentaloma
Primary aldosteronism:
the most common endocrine cause
• True prevalence is unclear
– Prevalence data come from referred
populations
– Prevalence data not always confirmed
– Lack of a widely accepted gold standard
Population Prevalence
Hypertension 5-13%
Resistant hypertension 17-23%
Hypertension with incidentaloma 1-10%
Copyright Harvard Medical School, 2010. All Rights Reserved.
947
Primary aldosteronism(PA): diagnosis*
Patient with possible PA
Patient with probable PA
Patient with confirmed PA
Screening test: ARR
Confirmatory test: choice of 4
*Endocrine society guidelines 2008
Patient with possible PHA
Patient with probable PHA
Patient with confirmed PHA
Screening test: ARR
Confirmatory test: choice of 4
*Endocrine society guidelines 2008
Problems
•Time of day?
•Sodium intake?
•Position?
•Ratio only or ratio plus aldo?
•Cutoff for ratio
•Do the patient’s meds matter?
•PRA assay sensitivity?
Primary aldosteronism(PA): diagnosis*
Copyright Harvard Medical School, 2010. All Rights Reserved.
948
Problems with the ARR
•Timing
– Mid-morning draw is recommended
•Diet
– Liberal sodium intake is recommended
•Position
– 15 minutes seated is recommended
•Specimen handling
– Maintain at room temperature is recommended
•In the real world…
– Not always convenient
•What is the appropriate cutoff?
– No guidance from the endocrine society
– Ratios used in various studies: 20-50
•Should the plasma aldosterone also be
considered?
– No guidance from the endocrine society
– From various studies: some do, some don’t
Problems with the ARR
Copyright Harvard Medical School, 2010. All Rights Reserved.
949
Medication Effect on ARR Effect on Decision
Β-blocker Lowers PRA (a lot) False positive
Diuretics Increases PRA False negative
ACEI/ARB Lowers aldo, increases PRA False negative
DHP Ca-blocker Increases PRA False negative
Central α2-blocker Lowers PRA False positive
Problems due to medications
Problems due to other factors
Factor Effect on ARR Effect on Decision
Hypokalemia Lowers also Falsenegative
Salt restricted Increases PRA False negative
CKD Lowers PRA False positive
Elderly Lowers PRA Falsepositive
Problems with the ARR
• What about medications?
– Endocrine society suggests washout of all meds
for 4 weeks, or…
– switching to combination of verapamil,
hydralazine, and α1-blockers
– Endocrine society may not live on a place I like
to call Earth
Problems with the ARR
Copyright Harvard Medical School, 2010. All Rights Reserved.
950
• Denominator dependence
– The PRA assay varies from lab to lab
– 0.2 to 2.0 ng/mL per hour
• Examples
– Patient with PA, no meds, aldo =16 ng/dL
(high), PRA suppressed at 2.0 ng/mL per hour
•Ratio =8 (false negative)
– Patient without PA, on β-blocker, aldo =6
ng/dL (normal), PRA suppressed at 0.2 ng/mL
per hour
•Ratio =30 (false positive)
Problems with the ARR
Patient with possible PHA
Patient with probable PHA
Patient with confirmed PHA
Screening test: ARR
Confirmatory test
*Endocrine society guidelines 2008
Options
•Outpatient salt suppression
•Saline infusion
•Fludrocortisone stimulation
•Captopril challenge
Primary aldosteronism(PA): diagnosis*
Copyright Harvard Medical School, 2010. All Rights Reserved.
951
Confirmatory tests for PHA
Test Issues
Outpatient salt suppression 3-day high salt diet and a 24 hour urine
collection
Saline infusion Requires at least 7 hours in either hospital or
infusion center
Fludrocortisone stimulation Usually requires a multi-day hospital admission
Captopril challenge 2-hour office-based test; some evidence of
inferiority compared to other tests
Case 2: question 1
• A 37 year old white female referred to you for resistant
hypertension.
• Occasional headaches, fatigue, and muscle cramps
• BP 170/100, BMI 27, exam is otherwise unremarkable.
• Enalapril 20 bid, HCTZ/triamterene 25/37.5 qd, atenolol 50
qd.
• Potassium 2.6 meq/L, other labs normal
– Which of the following would most likely ESTABLISHthe correct
diagnosis?
A.) Fractionated plasma metanephrines
B.) Renal angiogram
C.) Plasma ratio of aldosterone to PRA (ARR)
D.) Low dose dexamethasone suppression test
 E.) 24-hr urine aldosterone after oral sodium loading
F.) TSH
Copyright Harvard Medical School, 2010. All Rights Reserved.
952
• You intensify her BP meds and give KCL supplements
• She does the 24-hr urine with oral sodium loading
• Potassium 3.6 meq/L
• 24hr urine: 1.2 grams cre, 280 mmol of sodium, and 54
mcg aldosterone.
• No family history of hypertension.
• You’ve just diagnosed PHA. What are you going to do now?
a) Order an adrenal CT scan
b) Refer for adrenal vein sampling
c) Start spironolactone
Case 2: question 2
• Rare cause of PHA
– Only 26 cases between 1955-2002
• Usually >4cm and contrast enhancing
– Often metastatic at time of presentation
Adrenal carcinoma
Copyright Harvard Medical School, 2010. All Rights Reserved.
953
• You intensify her BP meds and give KCL supplements
• She does the 24-hr urine with oral sodium loading
• Potassium 3.6 meq/L
• 24hr urine: 1.2 grams cre, 280 mmol of sodium, and 54
mcg aldosterone.
• No family history of hypertension.
• You’ve just diagnosed PHA. What are you going to do now?
a) Order an adrenal CT scan
b) Refer for adrenal vein sampling
c) Start spironolactone
Case 2: question 2

• CT scan reveals a 1 cm adenoma in left
adrenal gland
• The right adrenal appears normal
• What are you going to do now?
a) Refer for surgical resection of left adrenal
b) Refer for adrenal vein sampling
c) Start spironolactone
d) Ask her if she would consider surgery
Case 2: question 3
Copyright Harvard Medical School, 2010. All Rights Reserved.
954
Surgery or MR antagonist for primary
aldosteronism?
• 54 patients with PA
• Treatment
– adrenalectomy(N=24)
– spironolactone (N=30)
• 7.4 year mean f/u
• Equivalent average BP
Copyrightrestrictions may apply.
Catena, C. et al. Arch Intern Med 2008;168:80-85.
P=0.71
Inci dence of composi te CV endpoi nt
• CT scan reveals a 1 cm adenoma in left
adrenal gland
• The right adrenal appears normal
• What are you going to do now?
a) Refer for surgical resection of left adrenal
b) Refer for adrenal vein sampling
c) Start spironolactone
 d) Ask her if she would consider surgery
Case 2: question 3
Copyright Harvard Medical School, 2010. All Rights Reserved.
955
• She would like to pursue surgery
• What are you going to do now?
a) Refer for surgical resection of left adrenal
b) Refer for adrenal vein sampling
c) Start spironolactone
Case 2: question 4
Is a unilateral adenoma sufficient?
• Systematic review of 38 studies (950 patients)
with PA, either CT or MRI, and AVS
• If we use CT or MRI alone to guide treatment
– Unilateral adenoma  surgery
– Bilateral or no adenoma spironolactone
• Inappropriate exclusion from adrenalectomy
– 19%
• Inappropriate adrenalectomy
– 19%
• Because disease was really bilateral: 15%
• Because disease was on the other side: 4%
Kempers M. et al. Ann Intern Med 2009;151:329-37.
Copyright Harvard Medical School, 2010. All Rights Reserved.
956
• She would like to pursue surgery
• What are you going to do now?
a) Refer for surgical resection of left adrenal
 b) Refer for adrenal vein sampling
c) Start spironolactone
Case 2: question 4
PA algorithm
Possible PA
Probable PA Confirmed PA
Screening test
Confirmatory test
*Endocrine society guidelines 2008
Adrenal CT scan
PA, no cancer
Surgery not desired
Treat medically
Surgery desired
Perform AVS
Unilateral PA
Bilateral PA
Operate
Copyright Harvard Medical School, 2010. All Rights Reserved.
957
Case 3
Case 3, question 1
• A 55 yo man is referred for chronic resistant hypertension, despite
taking lisinopril, chlorthalidone, amlodipine, and metoprolol. He
drinks 3-4 alcoholic beverages per week, and tries to restrict his salt
intake. He snores, but denies hypersomnolence or headaches, and
his wife is unaware of apneic episodes.
• His BP is 160/90, consistent with home readings. He is obese
(BMI=35), and has 1+pitting edema.
• Cre=1.0, K=3.8, and urinalysis is negative for albumin or cells.
– Which of the following is most correct?
A)His alcohol intake is likely contributing to his resistant
hypertension
B)His chlorthalidone should be replaced by furosemide
C)Polysomnography would most likely be positive for sleep apnea
D)Polysomnography is not indicated since he does not have
specific symptoms of sleep apnea
Copyright Harvard Medical School, 2010. All Rights Reserved.
958
Alcohol and hypertension
Alcohol intake, grams per day (10 grams  1 alcoholic beverage)
Clinical prediction of OSA
• Epidemiology
– 50-90% of obese patients with hypertension
• History/exam
– Best clinical predictors from the sleep
literature:
•Snoring
•Obesity
•Hypertension
•Witnessed gasping/choking
– “Physician impression” using the standard
questions (daytime somnolence, etc)
•50% sensitivity
Copyright Harvard Medical School, 2010. All Rights Reserved.
959
Prevalence of OSA in resistant hypertension
Two recent studies of overweight or obese individuals with confirmed
resistant hypertension
Logan AG, et al. J Hypertens 2001
Lozano L, et al. J Hypertens 2010
Case 3, question 1
• A 55 yo man is referred for chronic resistant hypertension, despite
taking lisinopril, chlorthalidone, amlodipine, and metoprolol. He
drinks 3-4 alcoholic beverages per week, and tries to restrict his salt
intake. He snores, but denies hypersomnolence or headaches, and
his wife is unaware of apneic episodes.
• His BP is 160/90, consistent with home readings. He is obese
(BMI=35), and has 1+pitting edema.
• Cre=1.0, K=3.8, and urinalysis is negative for albumin or cells.
– Which of the following is most correct?
A) His alcohol intake is likely contributing to his resistant hypertension
B) His chlorthalidone should be replaced by furosemide
 C) Pol ysomnography woul d most l i kel y be posi ti ve for sl eep
apnea
D) Polysomnography is not indicated since he does not have specific
symptoms of sleep apnea
Copyright Harvard Medical School, 2010. All Rights Reserved.
960
• You refer him for polysomnography, demonstrating an apnea-
hypopnea index (AHI) of 20 events per hour (moderate OSA). He
begins CPAP and is now seeing you 2 months later. He uses CPAP
nightly, sleeps well, and says that he feels more energetic. He still
takes lisinopril, chlorthalidone, amlodipine, and metoprolol. His
exam is unchanged and his BP is now 157/88 (instead of 160/90).
– Which one of the following is most likely to result in control of his
hypertension?
A) Spironolactone 25 mg/day titrating to 100 mg/day as needed.
B) An exercise program of walking, 20 minutes three times per week
C) Referral back to the sleep clinic to adjust his CPAP mask or prescription
since the therapy is not working
D) Referral to ENT for laser-assisted uvuloplasty
E) Long-acting diltiazem 120 mg/d titrating to 300 mg/day as needed
Case 3, question 2
Effect of CPAP on blood pressure
C
h
a
n
g
e

i
n

S
B
P

(
m
m
H
g
)
p=<0.05
p=<0.05 P=NS
(N=16) (N=12) (N=10)
Conclusion: effect of CPAP on blood
pressure is modest
Haentjens et al. Arch Intern Med 2007 Bazzano et al. Hypertens 2007 Alajmi et al. Lung 2007
Three meta-analyses published in 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
961
Relation between OSA and aldosterone
• Among 114 patients with resistant HTN
– 72 had “high probability” for OSA
– 42 had “low probability” for OSA
– On a high salt diet, 24hr urine aldosterone was
higher among those with a high probability for
OSA (13.6 vs. 9.8 µg, p<0.05)
» Calhoun et al. Chest 2004
• Among 60 patients with proven OSA and
resistant hypertension
– Plasma aldosterone was correlated with AHI
(r=0.44, p<0.01)
» Pratt-Ubanama et al. Chest 2007
Effect of Spironolactone in resistant hypertension:
Anglo-Scandinavian Cardiac Outcomes Trials (ASCOT)
ASCOT-BLPA (N=19,257)
Amlodipine & perindopril Atenolol & bendroflumethiazide
Doxazosin if needed
4
th
drug added if BP not at target
Doxazosin if needed
Spironolactone (N=1411)
Other drug
Chapman et al. Hypertension 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
962
Effect of Spironolactone in resistant hypertension:
Anglo-Scandinavian Cardiac Outcomes Trials (ASCOT)
Chapman et al. Hypertension 2007
• Mean BP fell from 157/85 to 135/76 with
spironolactone
•  BP =22/9 mmHg (other studies have found
similar effects in resistant hypertension)
• Effect on BP was similar in both treatment arms
(whether already on diuretic or not)
• Effect was somewhat larger if
– Age >60 years
– Female
– diabetic
• You refer him for polysomnography, demonstrating an apnea-
hypopnea index (AHI) of 20 events per hour (moderate OSA). He
begins CPAP and is now seeing you 2 months later. He uses CPAP
nightly, sleeps well, and says that he feels more energetic. He still
takes lisinopril, chlorthalidone, amlodipine, and metoprolol. His
exam is unchanged and his BP is now 157/88 (instead of 160/90).
– Which one of the following is most likely to result in control of his
hypertension?
 A) Spi ronol actone 25 mg/day ti trati ng to 100 mg/day as needed.
B) An exercise program of walking, 20 minutes three times per week
C) Referral back to the sleep clinic to adjust his CPAP mask or prescription
since the therapy is not working
D) Referral to ENT for laser-assisted uvuloplasty
E) Long-acting diltiazem 120 mg/d titrating to 300 mg/day as needed
Case 3, question 2
Copyright Harvard Medical School, 2010. All Rights Reserved.
963
Case 4
• An 85 yo F is seeking a second opinion because her PCP advised
her to take lisinopril-HCTZ to lower her BP. She only takes OTC
medications, specifically a multivitamin, fish oil, and vitamin D. Her
clinic and home BPs over the past 2 years have ranged from 158/60
to 180/72, consistent with isolated systolic hypertension (ISH). She
has no diabetes, MI, or stroke, but her mother died from a stroke at
age 77. She eats a healthy diet, walks for exercise 5 times/week,
and does not drink alcohol.
• She is a thin and fit elderly woman (BMI=22), BP is 172/65. She
has a 2/6 SEM, an S4, and no edema. Cre=0.8, UA is negative.
– You should advise her that:
A. She should have 24-hour ABPM because she likely has white-coat HTN
B. ISH is normal with ageing and requires no therapy
C. Although ISH should be treated in most, there are no data pertaining to women
of her age
D. Taking lisinopril-HCTZ may reduce her chances of dying and/or developing
congestive heart failure during the next 2 years
Case 4, question 1
Copyright Harvard Medical School, 2010. All Rights Reserved.
964
Systolic Hypertension in Europe (Syst-Eur)
Objective: To determine whether antihypertensive treatment reduces
cardiovascular complications in older patients with elevated
SBP
Patients: 4695 patients, 60 years of age, with SBP 160–219 mm Hg
and DBP <95 mm Hg
Treatments: Nitrendipine(10–40 mg/day) with possible addition or
substitution of:
Enalapril (5–20 mg/day)
Hydrochlorothiazide (12.5–25 mg/day)
Placebo
Follow-up: 2 years (median)
Endpoint: Total stroke
Myocardial infarction
Adapted from StaessenJ A et al. Lancet. 1997;350:757-764.
Syst-Eur: Outcomes
*P=.003;

P=.03;

P=.12;
§
P<.001.
Adapted from StaessenJ A et al. Lancet. 1997;350:757-764.
P
e
r
c
e
n
t

R
e
d
u
c
t
i
o
n

0
–5
–10
–15
–20
–25
–30
–35
–40
–45
–42*
CHF Stroke Al l CHD Total CVD MI
–26

–29

–30

–31
§
Risk Reduction
Copyright Harvard Medical School, 2010. All Rights Reserved.
965
Hypertension in the Very Elderly Trial: (HYVET)
Objective: To determine whether treatment of systolic hypertension in
patients  80 years old lowers the risk of stroke
Design: Multicenter, randomized, double-blind, placebo-controlled
Patients: 3845 men and women >80 y (mean, 84 y) with sustained
SBP >160 mmHg
Treatments: Step 1: thiazide
Step 2: ACEI
Goal: SBP <150 mmHg
Placebo
Follow-up: 1.8 years (stopped early)
Endpoint: Fatal and non-fatal stroke
Beckett NS, et al. NEJ M 2008; 358:1887
HYVET: Outcomes
Fatal and
non-fatal
stroke
-80
-60
-40
-20
0
- 30
P
e
r
c
e
n
t

r
e
d
u
c
t
i
o
n
- 39*
- 28
- 64
§
- 21*
*p<0.05
§
p<0.001
CHF
Fatal
stroke
Al l -cause
mortal ity
Fatal and
non-fatal MI
Beckett NS, et al. NEJ M 2008; 358:1887
Copyright Harvard Medical School, 2010. All Rights Reserved.
966
• An 85 yo F is seeking a second opinion because her PCP advised
her to take lisinopril-HCTZ to lower her BP. She only takes OTC
medications, specifically a multivitamin, fish oil, and vitamin D. Her
clinic and home BPs over the past 2 years have ranged from 158/60
to 180/72, consistent with isolated systolic hypertension (ISH). She
has no diabetes, MI, or stroke, but her mother died from a stroke at
age 77. She eats a healthy diet, walks for exercise 5 times/week,
and does not drink alcohol.
• She is a thin and fit elderly woman (BMI=22), BP is 172/65. She
has a 2/6 SEM, an S4, and no edema. Cre=0.8, UA is negative.
– You should advise her that:
A. She should have 24-hour ABPM because she likely has white-coat HTN
B. ISH is normal with ageing and requires no therapy
C. Although ISH should be treated in most, there are no data pertaining to women
of her age
 D. Taking lisinopril-HCTZ may reduce her chances of dying and/or
developing congestive heart failure during the next 2 years
Case 4, question 1
Case 5
Copyright Harvard Medical School, 2010. All Rights Reserved.
967
A 27 year old woman who is 30 weeks pregnant presents
for a routine OB visit and is found to have peripheral
edema but no other symptoms, a BP of 150/90
(previously normotensive) and 2+protein by dip, later
quantified as 1.3 g protein/g of creatinine(previously
normal). She is placed on bed rest; in addition, which
of the following best describes the next step to
address her high BP:
a. Begin triamterene-hydrochlorothiazide
b. Intravenous bolus of Mg-Sulfate, followed by oral
magnesium supplementation
c. Begin enalapril
d. Advise a low salt (<2000 mg) diet
e. Begin methyldopa
f. No anti-hypertensive medications can be used
Case 5, question 1
Fetopathic effects of AngiotensinBlockade
• 1
st
Trimester
– 3.7-fold increased risk of CV malformations (ASD, VSD, patent
ductus, pulmonic stenosis)
– 4.4-fold increased risk of neurologic malformations (spina bifida,
microcephaly)
– Risk not seen among infants exposed to other antihypertensive
medications during the 1
st
trimester
» WO Cooper et al. New Engl J Med 2006: 354:2443
• 2
nd
and 3
rd
Trimesters
– Renal failure
– Renal dysplasia
– Fetal hypotension
– Oligohydramnios
– Pulmonary hypoplasia
– IUGR
» A Quan. Early Hum Devel 2006; 82:23
Copyright Harvard Medical School, 2010. All Rights Reserved.
968
Drug Pregnancy class
Methyldopa
Amiloride
B
Labetalol
Metoprolol
Prazosin
Nifedipine
Hydralazine
HCTZ
Furosemide
C
ACE-inhibitors
Angiotensin receptor blockers
Spironolactone
Triamterene
Atenolol
D
Pregnancy risk categories of BP meds
Pregnancy class
A. Good human studies show no increase in risk
B. Animal studies show no increased risk without human data, or animal studies how harm but
human studies do not show harm
C. No human data combined with a lack of animal studies or studies showing harm
D. Human studies show possible harm, but benefit may outweigh the risk
X. Human studies show congenital abnormalities, and drug should not be used
A 27 year old woman who is 30 weeks pregnant presents
for a routine OB visit and is found to have peripheral
edema but no other symptoms, a BP of 150/90
(previously normotensive) and 2+protein by dip, later
quantified as 1.3 g protein/g of creatinine(previously
normal). She is placed on bed rest; in addition, which
of the following best describes the next step to
address her high BP:
a. Begin triamterene-hydrochlorothiazide
b. Intravenous bolus of Mg-Sulfate, followed by oral
magnesium supplementation
c. Begin enalapril
d. Advise a low salt (<2000 mg) diet
 e. Begin methyldopa
f. No anti-hypertensive medications can be used
Case 5, question 1
Copyright Harvard Medical School, 2010. All Rights Reserved.
969
Case 6
You are discussing the initiation of an ACEI with a 37 year old African
American man with hypertension and normal kidney function. He
asks you about potential side effects. All of the following are true
about side effects of ACEI except:
a. Cough and angioedema occur at rates of 5-20% and 0.7%,
respectively, depending on the survey.
b. Angioedemais less common in African Americans.
c. Angioedemaoccurs with both ACEI and ARB.
d. Cough results from inhibition of bradykininmetabolism.
e. Refractory hyperkalemiaoccurs with similar frequency
compared to other drugs among individuals with normal
kidney function.
f. Refractory hyperkalemiaoccurs with similar frequency
compared to other drugs among individuals with CKD.
g. Risk factors for hyperkalemiawhen starting an ACEI
include CKD, NSAIDs, and DM
Case 6, question 1
Copyright Harvard Medical School, 2010. All Rights Reserved.
970
Side effects of ACEI
• Cough
– Incidence is 5-20%, depending on survey
– Bradykininmediated
– More common in women
– Disappears when switched to ARB
» AH Israili et al. Ann Intern Med 1992; 117:234
• Angioedema
– Incidence is ~0.7%
– 3x higher risk in African Americans, 1.6x higher risk in elderly
– Can occur anytime, but usually within the first week
– Mechanism: bradykinin, complement system, autoantibodies
– May not be safe to switch to ARB
» J B Kostis et al. Arch Intern Med 2005; 165:1637
• Hyperkalemia
– In pooled analysis of 6 randomized trials of CKD patients,
withdrawal because of refractory hyperkalemiawas 1.4% (ACEI)
vs. 0.95% (non-ACEI)
» Lancet 2001; 357:1601
You are discussing the initiation of an ACEI with a 37 year old African
American man with hypertension and normal kidney function. He
asks you about potential side effects. All of the following are true
about side effects of ACEI except:
a. Cough and angioedema occur at rates of 5-20% and 0.7%,
respectively, depending on the survey.
 b. Angioedema is less common in African Americans.
c. Angioedemaoccurs with both ACEI and ARB.
d. Cough results from inhibition of bradykininmetabolism.
e. Refractory hyperkalemiaoccurs with similar frequency
compared to other drugs among individuals with normal
kidney function.
f. Refractory hyperkalemiaoccurs with similar frequency
compared to other drugs among individuals with CKD.
g. Risk factors for hyperkalemiawhen starting an ACEI
include CKD, NSAIDs, and DM
Case 6, question 1
Copyright Harvard Medical School, 2010. All Rights Reserved.
971
Final Question
An internal medicine colleague has read the recent
ACCORD trial and is wondering what the goal
blood pressure should be for the patients she
follows with chronic kidney disease.
You tell her that:
a. Because of consistent and convincing evidence from
multiple RCTs that aggressive BP control results in lower
mortality and CV events in in patients with CKD, the official
recommendation is a BP target of <130/80.
b. Although we lack consistent and convincing evidence
from multiple RCTs that aggressive BP control results
in lower mortality and CV events in in patients with
CKD, the official recommendation is a BP target of
<130/80.
c. Based upon the results of the ACCORD trial, and other
recent trials, the official recommendation for patients with
CKD has been changed to a target of <140/90.
Final question
Copyright Harvard Medical School, 2010. All Rights Reserved.
972
Disclosures
None
Copyright Harvard Medical School, 2010. All Rights Reserved.
973
Coronary Artery Disease and
Renal Disease
David Charytan, MD, MSc
Associate Staff Physician
Brigham & Women’s Hospital
Instructor in Medicine
Harvard Medical School
Disclosures
Dr Charytan receives funding from the
American Society of Nephrology, Paul
Teschan Research Fund (DCI), and the
American Heart Association.
Copyright Harvard Medical School, 2010. All Rights Reserved.
974
USRDS; 2005 ADR.
(A) Adjusted age-
specific MI rates
(B) Adjusted cause-
specific mortality rates
Go, A. S. et al. N Engl J Med 2004;351:1296-1305
Cardiovascular Event Rate in CKD
Copyright Harvard Medical School, 2010. All Rights Reserved.
975
Herzog CA. NEJM 1998; 339: 799-805
Estimated Cumulative Mortality Following First Myocardial
Infarction in Chronic Dialysis Patients
Anavekar NS. N Engl J Med 2004;351:1285-1295
Estimated Cardiovascular Death and Reinfarction Rates Three Years after MI in
Patients with Pre-ESRD CKD
Copyright Harvard Medical School, 2010. All Rights Reserved.
976
Relative Risk of ESRD vs. CV Death in
Elderly Patients with CKD
2 Year Incidence Rates
CV Death ESRD
CKD(+)/DM(+) 32.3% 6.1%
CKD(+)/DM(-) 29.5% 2.9%
CKD(-)/DM(-) 10.3% 0.1%
Collins AJ. KI 2003;64(S87):S24-31
Foley RN. JASN 2005;16:489-95
Summary: MI Risk in CKD
There is a high risk of a cardiovascular events in
patients with CKD that is directly proportional to
the degree of impairment in GFR and is 10-20
fold higher in patients with ESRD compared to
those with normal renal function
MI is a catastrophic event in patients with CKD
Risk of death from CVD markedly exceeds the
risk of progression to ESRD in elderly patients
with CKD
Copyright Harvard Medical School, 2010. All Rights Reserved.
977
Etiology of Increased Risk of CVD
Events CKD
High burden of fixed CAD
Inflammation
Oxidative stress
Coronary artery calcification
Traditional CV risk factors ( lipids,
diabetes, hypertension, age)
Poor performance of diagnostic tests
Underutilization of standard CV therapies
GFR
>60
GFR
45-
59
GFR
30-
44
GFR
<30
Nakano T. AJKD. 2010; 55:21-30
--
0.9
0.3
0.002
P value Calcification P Value Advanced
Atherosclerosis
eGFR
mL/min/1.73m
2
1.00 (Ref)
0.95 (0.46-1.94)
1.43 (0.69-2.95)
4.71 (1.78-12.50)
--
0.3
0.05
0.02
1.00 (Ref)
1.40 (0.76-2.55)
2.02 (0.99-4.15)
3.02 (1.22-7.49)
≥60
45-59
30-44
<30
Adjusted Odds Ratio for Advanced Atherosclerosis and
Calcified Lesions
Copyright Harvard Medical School, 2010. All Rights Reserved.
978
Incidence of Obstructive CAD in Advanced
CKD
60.2% incidence of obstructive CAD in new
dialysis patients (Joki, N. NDT. 1997;12:718-23)
Nearly ¾ with CAD have multi-vessel involvement
42% of transplant candidates have at least one-
vessel disease (Marwick, TH. Transplantation. 1990;49:100-103)
~50% incidence of CAD in asymptomatic
dialysis patients (Ohtake, T. JASN. 2005;16:1141-8. DeFilippi C. JAMA/ 2003;
290:353-9.)
Nearly ¾ with CAD have multi-vessel involvement
Inflammation, Oxidative Stress and CKD
All biomarkers of oxidative stress and
inflammation are elevated in patients with
stage 3-5 CKD (Payson BP. KI. 2004;65:1009-1016)
Not linearly correlated with eGFR but levels
generally higher in ESRD than pre-dialysis CKD
<0.001 0.61 0.29 Carbonyls nmol/
mg protein
Adapted from Oberg BP. KI 2004;65:1009-16
0.001 6.5 2.1 IL-6 pg/mL
<0.001 303 415 Thiols μmol/L
<0.001 0.046 0.036 F2-isoprostanes
ng/mL
0.02 3.9 1.8 CRP mg/L
P value CKD Patients Healthy Subjects
Inflammatory and Oxidative Stress Markers in Individuals with and without CKD
Copyright Harvard Medical School, 2010. All Rights Reserved.
979
Inflammation, Oxidative Stress and CKD
Both transient and persistent elevations in
inflammatory markers are associated with a
doubling in the risk of CV death in HD
patients
CRP persistently elevated to >10mg/L 20% and
transiently elevated in 26% (Wendy PJ. NDT. 2006;21:1588-1595,
Wanner C. NDT. 2002;17:29-32)
Elevated CRP associated with doubling of
mortality in stage 3-4 CKD patients (Menon V. KI.
2005;68:766-72)
Coronary Calcification ?
More common in patients with ESRD or CKD than
patients with normal renal function, particularly
among those with diabetes (Goodman WG. NEJM. 2000;18;1478-
83, Kramer H. JASN 2005;16:507-13)
Independently linked to risk of CV death in
patients with ESRD as well as in general
population (Matsuoka M. Clin Exp Neph 2004;8:54-58. Block GA. KI 2007;.
Block GA. KI 2007;78:438-41)
Moderately well correlated with presence of
coronary atherosclerosis
Sensitivity and specificity for detection of CAD vary
widely
Depending on cut point test performance may be poor
(Fujimoto N. Clin Chem Acta 2006;367:98-102. Sharple EJ. AJKD 2004;43:313-19)
Copyright Harvard Medical School, 2010. All Rights Reserved.
980
Coronary Calcification ?
No significant effect on mortality when patients randomized
to non-calcium containing binders compared with calcium
containing binders in long-term study (Kidney Int. 2007;72:1130-7. )
No significant relationship of eGFR or Cystatin C with CAC
score among patients with mild to moderate CKD in MESA
study of >6000 participants ( IX JH. JASN 2008;19:579-85)
Coronary calcification associated with other know CV risk
factors such as P04, serum calcium,PTH, fetuin A and FGF-
23 (Adeney KL. JASN 2009; 20:381-7, Guttierez OM. Circ, 2009;119:2545-52)
Coronary calcification is associated with calcification in large
conduit arteries
Resistant hypertension
Increased CV work load
Vascular Calcification Summary
Excellent marker of risk of all-cause and
cardiovascular mortality
Pathogenic role remains uncertain
Experimental studies suggest that calcification
stabilizes coronary plaque (H, Virmani R, Younis H, Burke AP, Kamm
RD, Lee RT. Circ 2001;103:1051-1056)
May be non-pathogenic or extra-coronary
calcification may be more important risk-factor
Copyright Harvard Medical School, 2010. All Rights Reserved.
981
Traditional Risk Factors and CKD
Most traditional
risk factors such
as advanced age,
hypertension,
hyperlipidemia are
common in
patients with CKD
Uhlig K. Sem in Dial 2003;16:118-127
0
10
20
30
40
50
60
70
80
90
T
o
ta
l C
h
o
le
s
t
e
r
o
l >
2
4
0
m
g
/d
L
T
r
ig
ly
c
e
r
id
e
s
>
2
0
0
m
g
/d
L
L
D
L
>
1
3
0

m
g
/
d
L
H
y
p
e
r
te
n
s
io
n
D
ia
b
e
t
e
s
S
m
o
k
in
g
HD
CKD 1-4
%

o
f

P
o
p
u
l
a
t
i
o
n
But Framingham risk
score is poorly predictive
in CKD (5 year-c statistic
only 0.62 in men) and
standard factors only
partly account for
elevated CV mortality
rates in CKD patients
Weiner D. JACC
2007;50:217-24
Fleishman EH. Clin Nephrol
200156:221-230.
Diagnosis of Ischemia in CKD
Differential symptoms of ischemia in CKD vs.
normal
Differential sensitivity and negative predictive
value of non-invasive testing compared with
general population
ECG may be difficult to interpret due to baseline
abnormalities (Zuber, et al. NDT 1989;4:632-4)
ST Elevation MI is ~50% less frequent in patients with CKD than in the
general population (Herzog CA. ASN 2004)
Dialysis-18.5% Moderate CKD-17.4% Normal Function-35.8%
Cardiac enzymes may be less sensitive/specific
in CKD
Copyright Harvard Medical School, 2010. All Rights Reserved.
982
Differential Symptoms of MI: CKD vs.
Normal Renal Function
Sosnov, J. AJKD. 2006;47:378-84
1.08 (0.86-1.37) Dizzyness/lightheadeness/syncope
1.35 (1.13-1.62) Cough, dsypnea
0.87 (0.66-1.13) Chest tightness
0.57 (0.46-0.70) Chest pain/pressure, diaphoresis
0.52 (0.42-0.64) Arm Pain/Shoulder Pain
Multivariate OR
(95% CI)
Symptoms
Stress Testing in ESRD
Maximal exercise stress test frequently non-diagnostic
due to limited functional capacity/mobility
Pharmacologic stress testing with contemporary tools
more frequently diagnostic
Accuracy in HD (Dahan M. AJKD 2002;40:737-44)
Dipyridamole/Stress-Thallium—Sensitivity
92%/Specificity-89%
Dipyridamole/Stress-Echo-Sensitivity 83%/Specificity 84%
Good utility as prognostic tools-6-fold increase in risk of MI
and 4-fold increase in risk of cardiac death in presence of
inducible ishemia (Rabbat DG. JASN 2003;14:431-9)
Negative predictive value may be low due to high pre-
test probability of CAD
Copyright Harvard Medical School, 2010. All Rights Reserved.
983
Cardiac Enzymes in CKD
CK and CK-MB
~88-100% of asymptomatic dialysis patients without
clinically suspected ischemia have intermittent
elevations in CK-MB (Green TR et al. Clin Neph 1986;25:22-7)
Troponin
ESRD
~20% of patients with ESRD have elevated Troponin
T (Apple FS. Circulation 2002;106:2941-1945, Illiou MC. AJKD 2003:42:513-23)
~7-18% have Troponin I elevation (Freda BJ. JACC 2002;40:2065-
71, Illiou MC. AJKD 2003:42:513-23)
CKD (Lamb EJ. AJKD 2007; 49:507-16)
Troponin I-elevated in 18% of pre-ESRD CKD patients
Troponin T-elevated in 43% of pre-ESRD CKD
patients
Summary: Dx of CAD
Diagnosis of CAD/MI can be challenging in
CKD patients
Standard non-invasive tests may have low
negative and positive predictive values
Maintenance of a high index of suspicion
is crucial
Copyright Harvard Medical School, 2010. All Rights Reserved.
984
Utilization of Cardiovascular Therapies
in CKD
___________________________________
CKD No CKD P
_______________________________________________
Angiography
All Patients 25.2% 46.8% <0.0001
Appropriate Candidates 29.6% 49.6% <0.0001
Revascularization After
Angiography 54.7% 62.0% <0.0001
_________________________________________________________
Chertow G. JASN 2005;15:2462-2468
Low Utilization of Invasive Diagnostic and Therapeutic Procedures
in Dialysis Patients after MI
Charytan D.
Am Heart J
2006;152:55
8-64
Copyright Harvard Medical School, 2010. All Rights Reserved.
985
Low Use of Medical Therapy in Patients with
ESRD
P
e
r
c
e
n
t

R
e
c
e
i
v
i
n
g

M
e
d
i
c
a
t
i
o
n

w
i
t
h
i
n

9
0

D
a
y
s

o
f

M
I
Winkelmayer W. AJKD. 2006
Treatment of Stable CAD in the
General Population
Standard of care derived from large,
randomized clinical trials
ASA/anti-platelet agents
Statins
ACE-I/ARB
Beta blocker
Percutaneous/surgical revascularization
Copyright Harvard Medical School, 2010. All Rights Reserved.
986
CKD ESRD HTN DM Smoking
Condition
Use of Baseline Conditions as Exclusion Criteria in Large
Cardiovascular Trials
F
r
e
q
u
e
n
c
y
Charytan D. KI 2006;70:2021-30
Anti-Platelet Agents
No randomized evidence for CAD endpoints in ESRD
population
2-fold increase of the risk of bleeding with Clopidogrel +
full dose ASA in ESRD but no change when with
Clopidogrel alone (Kauffman JS. JASN 2003;14:2313-2321, Dember, L. M. et al. JAMA
2008;299:2164-2171)
Risk of CV death/MI decreased in general population of
patients with hx of CVD administered Clopidogrel 75
mg/day + ASA (75-162 mg/day) vs. ASA alone, and
appears to be similar effective in patients with CKD (Bhatt,
DL. NEJM. 2006, Keltai M. Eur J Card Prev Rehab 2007;14:312-18 )
Retrospective analyses suggest that relative efficacy of
ASA is similar in patients with vs. without CKD(McCullough PA.
Am Heart J 2002;144:226-232, Berger AK. JACC 2003;42:201-8)
Recommendations:
ASA-all patients
Clopidogrel-consider with low dose ASA for patients with
documented CAD and low bleeding risk
Copyright Harvard Medical School, 2010. All Rights Reserved.
987
Statins
4D Trial (Wanner, C. NEJM 2005;353:238-248)
1297 Diabetic HD patients with LDL 80-190
mg/dL
Lipitor 20 mg/day vs. placebo
HR for CV events 0.92 (0.77-1.10)
AURORA Trial (Fellstrom BC. NEJM 2009;360:1395-1407)
2776 prevalent HD patients (40% with CAD)
Rosuvastatin 10 mg/day vs. placebo
HR for CV Death 1.0 (0.85-1.16)
No difference in non-fatal MI (2.1% vs. 2.5%)
Statins
Multiple trials/subgroup analyses demonstrating efficacy in
general population and moderate CKD population
Planet 1 and Planet 2 Study
Proteinuric renal disease from diabetic (Planet 1, n=325) or non-
diabetic CKD (Planet 2, n=220)
Atorvastatin 40 mg/daily vs. Rosuvastatin 10 mg or 40 mg/daily-1
year follow-up
Results
Atorvastatin significantly reduces proteinuria compared with baseline
No effect of Rosuvastatin on proteinuria
Greater loss of eGFR at 1 year in Rosuvastatin 10 mg (4 mL/min/1.73
m
2
) and 40 mg (8 mL/min/1.73 m
2
) groups than in Atorvastatin group (1-
2 mL/min/1.73 m
2
) in Planet 1 Study
Greater loss of eGFR in high dose Rosuvastatin group vs. Atorvastatin
group in Planet 2
Copyright Harvard Medical School, 2010. All Rights Reserved.
988
Statins
Recommendation:
Statins for most patients with CKD
May consider withholding in ESRD patients
with LDL ≤160
Atorvastatin may be preferable to
Rosuvastatin for individuals with pre-ESRD
ACE Inhibitors/ARB
Fosodial Trial (Zannad, F. KI. 2006;70:1318-24)
397 HD patients on HD > 6 months
Fosinopril vs. placebo
HR for CV events 0.93 (0.68-1.26) but underpowered due
lower than expected event rate
Open label trial of ARB vs. no therapy in 360 ESRD
patients (Suzuki, H. AJKD 2008;52:501-6)
HR for fatal and non-fatal CV events 0.51 (0.33-0.79)
HR for mortality 0.64 (0.39-1.06)
Recommendation:
ACE-I/ARB-consider for all patients with stage 3-5 CKD
Efficacy in ESRD uncertain but reasonable first line BP
agent
Copyright Harvard Medical School, 2010. All Rights Reserved.
989
Beta-Blockers
Carvedilol in ESRD (Cice, G. JACC.2003;41:1438-44)
114 HD patients with dilated cardiomyopathy, EF<35% &
NYHA class II or III CHF
Carvedilol ≤25 mg QD vs. Placebo for 24 months
HR for all-cause mortality 0.51 (0.32-0.82)
CV death HR 0.32 (0.18-0.57)
Non-fatal MI (11% vs. 12%)
Safety: side effects in < 10%
Recommendation
Administer to all patients with low EF (grade 1
recommendation)
Consider for all patients post-MI regardless of EF
CABG
CABG-No randomized evidence of efficacy in
the dialysis population
Surgical mortality in ESRD (Beckermann, J. J Throac Cardivasc Surg
2006;131:1261-6).
Off-pump-11.7% mortality at 30 days
On-pump-12.5% mortality at 30 days
Surgical mortality in general population-3-5%
Absolute 5-year mortality reduction of CABG vs.
medical therapy in general population is 5.6% (Yusuf, S.
Lancet. 1994;344:563-70)
Copyright Harvard Medical School, 2010. All Rights Reserved.
990
Percutaneous Revascularization
Percutaneous Angioplasty-No randomized
evidence of efficacy in the stage 3-5 CKD
population
In general population trials of patients with stable CAD
percutaneous therapy does not decrease mortality or risk
of MI vs. medical therapy in the general population
(Henderson, RA. JACC. 2003:42:1161-70)
May be inferior to CABG for treatment of multi-vessel
disease in general population (Hannan, EL. NEJM. 2006;352:2174-83)
2-Vessels-RR of death CABG vs. PTCA ~0.75
3-Vessels-RR of death CABG vs. PTCA ~0.64-0.74
Operative Mortality
1.7
3.5
7.5
9.8
0
1
2
3
4
5
6
7
8
9
10
N
o
r
m
a
l
/
E
a
r
l
y
C
K
D
S
t
a
g
e

3
S
t
a
g
e

4
S
t
a
g
e
5
/
E
S
R
D
Renal Function
I
n
-
h
o
s
p
i
t
a
l

M
o
r
t
a
l
i
t
y

(
%
)
Yeo K, et al Am J Card. 2008:101;1269-
74
19
7.6
13.2
18.5
8.3
12.3
0
4
8
12
16
20
Death and
Non-Fatal MI
Death Non-Fatal MI
Endpoint
P
e
r
e
c
e
n
t

w
i
t
h

O
u
t
c
o
m
e

a
t

4
.
6

Y
e
a
r
s
Pecutaneous
Intervention
Medical
Therapy
Boden WE. NEJM. 2007:356:1503-16
Copyright Harvard Medical School, 2010. All Rights Reserved.
991
Revascularization in CKD/ESRD
Percutaneous Angioplasty
? More effective than medical therapy
? Less effective than CABG
Post MI-1 year survival in ESRD (Chertow, GM. AJKD.
2000;35:1044-51)
Medical Tx-45%
PTCA-54%
CABG-69%
First Revascularization-RR of 2 year survival
CABG vs PCI -- 0.80 (0.76-0.84) (Herzog CA. Circ.
2002;106:2207-11)
Serruys PW et al. N Engl J Med 2009;360:961-972
Outcomes in Unprotected Left Main Stenting vs. CABG
Copyright Harvard Medical School, 2010. All Rights Reserved.
992
Randomization to Coronary Angiography vs.
Medical Therapy in patients with Acute
Coronary Syndromes and CKD
Hospitalization
Death
Charytan DM. CJASN 2009; 4:1032-43
Revascularization in CKD/ESRD
Recommendation
CABG
Risk benefit ratio must be considered carefully
Indicated for most patients with left main disease
or 3VD with proximal LAD, unless multiple
comorbidities
Percutaneous Interventions
Indicated for medically refractory angina
Role vs. medical therapy remains undefined
Left main PCI
Potentially treatment of choice for ESRD/advanced
CKD, but more data needed
Copyright Harvard Medical School, 2010. All Rights Reserved.
993
Summary: Therapy of CAD in CKD
Quality of available data is poor and further
studies needed
In general, evidence points towards benefits
from standard therapies
Increased risk of interventions and lack of
randomized evidence in CKD limit
recommendation for revascularization to
patients with high-risk anatomy or medically
refractory symptoms
Question #1
A 72 year-old peritoneal dialysis patient with type II diabetes,
elevated CRP and low albumin complains of occasional exertional
chest pain and shortness of breath. An exercise stress test is
ordered and is stopped after 3.5 minutes due to fatigue. EKG is
without ischemic changes. Which of the following statements is
most correct?
A) There is a low likelihood of obstructive coronary disease, no further
evaluation is needed
B) An echocardiogram should be ordered to evaluate ejection fraction
and rule out wall motion abnormalities.
C) Pharmacologic stress testing should be ordered to definitively rule
out obstructive coronary disease
D) Pharmacologic stress testing should be ordered. If non-invasive
testing is negative, consider proceeding to cardiac catheterization
Copyright Harvard Medical School, 2010. All Rights Reserved.
994
Question #1
A 72 year-old peritoneal dialysis patient with type II diabetes,
elevated CRP and low albumin complains of occasional exertional
chest pain and shortness of breath. An exercise stress test is
ordered and is stopped after 3.5 minutes due to fatigue. EKG is
without ischemic changes. Which of the following statements is
most correct?
A) There is a low likelihood of obstructive coronary disease, no further
evaluation is needed
B) An echocardiogram should be ordered to evaluate ejection fraction
and rule out wall motion abnormalities.
C) Pharmacologic stress testing should be ordered to definitively rule
out obstructive coronary disease
D) Pharmacologic stress testing should be ordered. If non-
invasive testing is negative, consider proceeding to cardiac
catheterization
Question #2
A 45 year-old previously stable male with an
estimated GFR of 30 cc/min/1.73m
2
develops
the new onset of diffuse, left-sided chest pain
described as “tightness” accompanied by
dyspnea. Physical exam is remarkable for blood
pressure of 140/80 and 1+ pitting edema with
clear lungs. EKG shows LVH but is otherwise
unremarkable. The patient is non-diabetic, has
normal cholesterol, and does not smoke. He has
otherwise been stable. Which one of the
following statements about the evaluation and
management is most correct?
Copyright Harvard Medical School, 2010. All Rights Reserved.
995
Question #2
A) Diuretics should be increased to treat
probable pulmonary congestion
B) Beta-adrenergic agonists should be
prescribed to treat asthma
C) Stress-testing and echo-cardiography shoud
be considered to rule out the presence of
structural heart disease
D) The atypical nature of the symptoms and lack
of traditional risk factors make coronary disease
unlikely. Stress testing can be safely deferred
References
Lentine K. Cardiovascular risk assessment among
potential kidney transplant recipients: Approaches and
controversies. AJKD 2010;55:152-67.
Patel T. Cardiovascular complications in diabetic kidney
disease. Sem Dial 2010:23:169-77.
Stenvinkel P. Emerging biomarkers for evaluating
cardiovascular risk in the chronic kidney disease patient:
how do new pieces fit into the uremic puzzle? CJASN
2008;3:505-21.
Fellsrom B. Cardiovascular disease in patients with renal
disease: the role of statins. Curr Med Res Opinion
2009;25:271-85
Copyright Harvard Medical School, 2010. All Rights Reserved.
996
Disclosures
Dr Charytan receives funding from the
American Society of Nephrology, Paul
Teschan Research Fund (DCI), and the
American Heart Association.
Copyright Harvard Medical School, 2010. All Rights Reserved.
997
Garasic 2010
Renovascular
Disease
Joseph M. Garasic, M.D.
Division of Cardiology
Massachusetts General Hospital
Boston, Massachusetts
Somethings Old, Somethings New,
& Lingering Questions
Garasic 2010
Presenter Disclosure
Information
The following relationships exist related to this
presentation:
Consultant / Equity Interest – Access Closure,
Inc.
Speaker’s Bureau – Sanofi-BMS Partnership
Copyright Harvard Medical School, 2010. All Rights Reserved.
998
Garasic 2010
Defining the Problem
RAS is an important cause of secondary
hypertension
Renovascular disease under-appreciated as
cause of CRF
23% of malignant hypertension is the result
of renovascular causes
Not all patients with RAS are hypertensive
as a result
Garasic 2010
Progress in Renovascular Disease
1) The disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Limiting restenosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
999
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Limiting restenosis
Garasic 2010
Etiology of Renal Artery Stenosis
Fibromuscular dysplasia
Atherosclerosis
Polyarteritis Nodosa
Radiation-induced
Takayasu’s arteritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1000
Garasic 2010
Renal Physiology
Garasic 2010
L. Gabriel Navar and L. Lee Hamm
Copyright Harvard Medical School, 2010. All Rights Reserved.
1001
Garasic 2010
Mark A. Pohl
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Limiting restenosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1002
Garasic 2010
Clinical Clues
Onset of diastolic hypertension after age 55
Refractory or malignant hypertension
Development of resistant hypertension in a
previously well-controlled patient
Progressive increase in Creatinine, even if still
“normal”
Presence of atherosclerotic macrovascular disease
elsewhere heightens suspicion
Left heart failure out-of-proportion to LV
dysfunction or ischemic burden
Clinically silent RAS
Garasic 2010
What is “medical therapy”for
renovascular disease?
Copyright Harvard Medical School, 2010. All Rights Reserved.
1003
Garasic 2010
Natural History of Renal Artery Stenosis
Caps et al. Circulation 1998; 98:2866-2872.
Role of lipid lowering and
Aggressive risk factor modification?
Garasic 2010
01/24/2002
Copyright Harvard Medical School, 2010. All Rights Reserved.
1004
Garasic 2010 09/05/2002
Garasic 2010
05/12/2006
Copyright Harvard Medical School, 2010. All Rights Reserved.
1005
Garasic 2010 02/06/2007
Garasic 2010
Trend of Serum Creatinine
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Creat
9/6/02 to 4/7/07
Copyright Harvard Medical School, 2010. All Rights Reserved.
1006
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Limiting restenosis
Garasic 2010
Clinical syndrome most important in patient
selection
Various diagnostic modalities:
Serologic markers
Duplex ultrasound - in experienced hands can predict
with great accuracy the presence or absence of
significant RAS
Captopril renal scan - 10-25% false negative
MR angiography - rare false negatives / common false
positives. Equipment/experience dependent
Contrast angiography
Screening for Renovascular Disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
1007
Garasic 2010
The Loss of MR Angiography
Nephrogenic Fibrosing Dermopathy
Mostly in HD Patients
Crippling skin thickening and contracture
Associated with Gadolinium exposure
90 Reported cases USA / 200 Wordwide
Garasic 2010
The Loss of MR Angiography The Loss of MR Angiography
Nephrogenic Fibrosing Dermopathy
Mostly in HD Patients
Crippling skin thickening and contracture
Associated with Gadolinium exposure
90 Reported cases USA / 200 Wordwide
What’s Old is New: Renal
Duplex
Copyright Harvard Medical School, 2010. All Rights Reserved.
1008
Garasic 2010
Duplex U/S for Renovascular Disease
Prospective Duplex U/S evaluation and Renal Angiography in 102 pts
Goal: Validate renal artery U/S as a viable non-invasive modality
Drawbacks:
Time and labor intensive
Technologist dependent
Not available
NPO
Requires a cooperative patient
Olin et al. Ann Intern Med. 1995; 122:833-838.
Degree Stenosis Renal PSV RAR
Normal < 180 cm/sec < 3.5
< 60% > 180 cm/sec < 3.5
> 60%
< or > 180 cm/sec
> 3.5
Occlusion No signal No signal
Garasic 2010
Screening Aortography
RN
LN
Copyright Harvard Medical School, 2010. All Rights Reserved.
1009
Garasic 2010
● Onset of hypertension at 30 years of age or severe hypertension at 55 years of
age* (Class I; LOE B)
● Accelerated, resistant, or malignant hypertension* (Class I: LOE C)
● Unexplained atrophic kidney or size discrepancy 1.5 cm between
kidneys† (Class I; LOE B)
● Sudden, unexplained pulmonary edema (Class I; LOE B)
● Unexplained renal dysfunction, including individuals starting renal
replacement therapy (Class IIa; LOE B)
● Development of new azotemia or worsening renal function after
administration of an ACE inhibitor or ARB agent (Class I; LOE B)
● Multivessel coronary artery disease or peripheral arterial disease (Class
IIb; LOE B)
● Unexplained congestive heart failure or refractory angina (Class IIb; LOE C)
New Recommendations
for RAS Screening: AHA Guidelines
Hirsch AT. Circ 2006; 113:e463
White et al. Circulation 2006;114;1892-1895
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Limiting restenosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1010
Garasic 2010
What Are the Goals of
Treatment for RAS?
Control hypertension
Aid in medical management
Prevent deterioration in renal function
Forestall need for dialysis
Defer death and disability
Garasic 2010
Hypertension and RAS
Among 152 patients with Unilateral or Bilateral RAS
undergoing surgical revascularization:
90% had improvement in BP control
Only 15% had “cure” of hypertension
Among 20 published series of PCI for atherosclerotic
renal artery disease:
54% had improvement in hypertension
9% had “cure” of hypertension
Hansen et al. J Vasc Surg 1992;16;319-31.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1011
Garasic 2010
Chronic Renal Insufficiency and RAS
Who Benefits From Revascularization?
Trial of 51 patients with Creat>2.0 before
revascularization with >75% Bilateral RAS:
67% had improvement in renal function
27% had stabilization in renal function
Only 6% had worsening in renal function
No demonstrated impact upon mortality
Novick et al. J Urol 1983; 129:907-12.
Garasic 2010
Experimental Data supporting Stenting for
Preservation of Renal Function
61 vessels in 31 patients with “global” obstructive
atherosclerotic renal disease
All with chronic renal insufficiency (Creat 1.5 – 4.0)
Stenting with non-articulated Palmaz stents
Follow-up Renal U/S, Serum Creat , BP measurements:
- Improvement in reciprocal slope of serum creatinine
- Improved BP control (SBP from 170±21 Pre-stent vs. 148
±15mmHg Post-stent; p<0.001)
- Restenosis (>50%) in only 1 of 61 vessels
- Stabilization of pole-to-pole renal dimension
Watson et al. Circulation. 2000; 102:1671-1677.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1012
Garasic 2010
Watson et al. Circulation. 2000; 102:1671-1677.
IMPROVED
STABLE
ALTERED
Garasic 2010
Dutch Renal Artery Stenosis Intervention Cooperative Study
Study Design:
• 106 hypertensive patients with RAS (>50%) and Creat<2.3 mg/dl
• PTA vs. Medical rx with follow-up of BP/meds/ renal fxn
at 3&12 mths
Results:
• BP same in both groups
• Fewer meds (2.1 vs. 3.2) in the PTA vs. Medical group
• Renal function similar between groups
Shortcomings:
• Crossover of patients from medical-to-PTA
• No stents
• Is 50% stenosis physiologically significant?
• Pts with elevated creatinine excluded
• Is the goal of renal artery revascularization improvement in BP control?
N Engl J Med 2000; 342:1007-14
Copyright Harvard Medical School, 2010. All Rights Reserved.
1013
Garasic 2010
ASTRAL Trial Schema
Diagnosis of significant ARVD
(Unilateral or Bilateral)
Revascularization not contraindicated
Uncertain whether to revascularize
Randomisation
No revascularization
Medical Treatment only
Revascularization
with angioplasty and/or
stent
(and medical treatment)
N Engl J Med 361;20, 19.
Garasic 2010
Eligibility
Any patient with atherosclerotic renovascular
disease (ARVD) and at least one ARVD lesion
that is suitable for balloon angioplasty and/or
stenting confirmed by angiogram.
No prior revascularisation procedure for ARVD.
No definite contraindication to revascularisation
and unlikely that revascularisation will become
indicated within the next 6 months.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1014
Garasic 2010
PATIENT CHARACTERISTICS –
GFR
Mean =40 ml/min (Range: 5.4 – 124.5)
0
50
100
150
200
250
300
<=20 20-30 30-40 40-50 >50
GFR (ml /mi n)
N
o
.

o
f

p
a
t
i
e
n
t
s
Garasic 2010
ANGIOGRAPHIC DATA BY
RANDOMISED TREATMENT
Revasc. Medical P-value
% Stenosis 76% (40 – 100%) 75% (20 – 100%) 0.3
Renal length 9.7cm (6 – 14) 9.7cm (6 – 20) 0.5
Location of ostial/distal ARVD lesion
Left kidney 24% 20% 0.2
Right kidney 18% 17%
Both 50% 57%
Missing data 8% 6%
Copyright Harvard Medical School, 2010. All Rights Reserved.
1015
Garasic 2010
PATIENT CHARACTERISTICS –
Percent Stenosis
Mean =76% (Range: 20% – 100%)
0
50
100
150
200
250
300
<50 50-59 60-69 70-79 80-89 >=90
Stenosis (%)
N
o
.

o
f

p
a
t
i
e
n
t
s
* 40% of Revascularization patients had no stenosis >70%.
Garasic 2010
COMPLIANCE WITH
RANDOMISED TREATMENT
N Revasc.
Successful
Attempted
but Failed
Not
Attempted
Revasc. 403 308 (82%)* 17 44
Medical 403 18 (4.4%) 1 1
Complications in Revasc Arm:
5 Renal Embolizations / 4 Renal Artery Occlusions / 4 Renal
Artery Perfs
Copyright Harvard Medical School, 2010. All Rights Reserved.
1016
Garasic 2010
REVASCULARIZATION PROCEDURE
Revasc. Medical
Intervention Performed N=308 N=13
Angioplasty plus stent 201 (65%) 8 (62%)
Stent only 86 (28%) 5 (38%)
Balloon angioplasty 21 (7%) 0 (-)
Unilateral 259 (84%) 11 (85%)
Bilateral 49 (16%) 2 (15%)
Garasic 2010
PLOT OF SCr OVER TIME
Copyright Harvard Medical School, 2010. All Rights Reserved.
1017
Garasic 2010
PLOT OF SYSTOLIC BP OVER TIME
Garasic 2010
PLOT OF DIASTOLIC BP OVER TIME
Copyright Harvard Medical School, 2010. All Rights Reserved.
1018
Garasic 2010
TIME TO FIRST RENAL EVENT
(ARF, Dialysis, Transplant, Nephrectomy, Renal Death)
HR=0.98, 95% CI=0.66 to 1.48
Garasic 2010
TIME TO FIRST OF MI, STROKE, VASCULAR DEATH
OR HOSPITALISATION FOR ANGINA, FLUID
OVERLOAD OR CARDIAC FAILURE
HR=0.90, 95% CI=0.66 to 1.15
Copyright Harvard Medical School, 2010. All Rights Reserved.
1019
Garasic 2010
All that said:
Garasic 2010
Copyright Harvard Medical School, 2010. All Rights Reserved.
1020
Garasic 2010
Study Design: Prospective, multi-center, two-arm randomized trial
Purpose: Medical therapy vs. Stenting for Systolic Htn + RAS
Enrollment: 1080 Patients
Patient Population: Systolic htn / >2 Htn Meds / >60% RAS with gradient or
>80% RAS with no gradient necessary
Endpoints:
Primary – Cardiovascular/ renal death, Stroke, MI, hospitalization for CHF,
progressive renal failure, need for permanent renal replacement
Seondary – Systolic BP response, Stent patency, Resistive index, all cause
mortality, subgroup analysis (DM vs non-DM), Longitudinal renal fxn
National PI: Christopher J. Cooper, M.D. Medical College of Ohio
U/S Core Lab: Michael Jaff, D.O. MGH
CORAL
Garasic 2010
Resistive
Index
Predicts
Fate of
Renal
Function
Radermacher et al. NEJM 2001 344: 410-17
PSV - MEDV
PSV
( )
=
Resistive
Index
Copyright Harvard Medical School, 2010. All Rights Reserved.
1021
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Renal artery restenosis
Garasic 2010
Options:
Contrast minimizing maneuvers
Use of low-osmolar, non-iodinated
contrast
CO2 Angiography
Gadolinium contrast
Mucomyst (Acetylcysteine)
Selective DA-1 agonists
HOCM may increase
cellular injury when
potentiated by hypoxemia
c/t LOCM
Useful for localization
> Anatomic definition
-Gadopentatate dimeglumine
-Renally cleared by GF
-Now has it’s own problems
-As a result, rarely used
AC and hydration
reduce Creatinine >
hydration alone in CT
with CRI (2% vs 21%)
May decrease incidence
of RCN vs. historical
controls (4.7% vs 18.8%)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1022
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Renal artery restenosis
Garasic 2010
Be Afraid….
Be Very Afraid!
Copyright Harvard Medical School, 2010. All Rights Reserved.
1023
Garasic 2010
Distal Atheroembolic Protection: The Ideal
Capture all debris
Continued renal perfusion during procedure
Limitless reservoir
Atraumatic to vessel wall
Technically easy to use
Low profile
Trackable
Garasic 2010
Pathology
of
Atheroembolism
• Plaque / cholesterol
• Endothelial cells
• Platelet-Fibrin Thrombi
• Calcified tissue
Copyright Harvard Medical School, 2010. All Rights Reserved.
1024
Garasic 2010
Evolution of Distal Protection Devices
Initially used in the treatment of patients with
coronary bypass graft disease
These interventions commonly plagued by
angiographic “No Reflow” phenomenon
Cardiac enzyme leak
Clinical myocardial infarction
Long attributed to RBC lysis and platelet
activation with resultant microvascular spasm
Garasic 2010
Initial Reports: Atheroembolic Protection
Percusurge Guardwire
47% of patients with SVG intervention had
gross, macroscopic evidence of red-yellow
debris
An additional 20% of patients had evidence of
microscopic debris
Carlino et al.Circulation 1999; 99: 3221-3223
Copyright Harvard Medical School, 2010. All Rights Reserved.
1025
Garasic 2010
Randomized comparison of SVG lesions
treated +/- PercuSurge Guardwire
Improved outcomes: 42% decrease MACE
Lower laboratory MI’s
Safe
High procedural success
SAFER Trial
Baim et al. Circulation 2002.
Garasic 2010
Distal Protection in Renovascular
Disease: An Opportunity
Most RAS caused by atheromatous disease
Ostial / proximal segments of disease are
common
Kidney will tolerate longer balloon occlusion
time than coronary / cerebral circulation
Atheroembolism has long been viewed as a
major risk / complication of percutaneous
intervention of the renal arteries.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1026
Garasic 2010
FILTER
DEVICES
OCCLUSION
DEVICES
Preserve flow
Limit Ischemic Time
More complete capture
Small debris
Vascular Injury
No antegrade flow
Prolonged Ischemic Time
Vascular Injury
Shoulder Regions
+
-
Garasic 2010
FILTER
DEVICES
Cordis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1027
Garasic 2010
Atheroembolization Protection
Percusurge Guardwire
A. Traverse
B. Inflate
C. Intervene
D. Embolectomize
Garasic 2010
Early Experience: Distal Protection
in Renovascular Intervention
28 patients with 32 renal arteries
29 Lesions ostial location
100% Technical success with GuardWire
Visible debris aspirated: 100% cases
Mean RA occlusion time: 6.55 min (2.29-13.21 min)
Creatinine post-procedure and at follow-up stable or
improved in all cases.
Conclusion: Distal protection against atheroembolism is feasible and safe
But is it effective?
Henry et al.J Endovasc Ther 2001; 8(3): 227-37.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1028
Garasic 2010
Non Randomized Data:
Distal Protection
in Renovascular Intervention
121 hypertensive patients / 148 renal arteries
Both occlusion balloons (n=46) and filters (n=95) used
Visible debris aspirated: 100% cases with Guardwire
Visible debris aspiration: 80% cases with filters
5X volume of particulate matter retrieved with FiberNet
6 mths: 99% of patients had stable or improved renal fxn
2 yrs: 95% of patients had stable or improved renal fxn
Conclusion: Distal protection against atheroembolism is feasible and safe
But is it effective?
Henry et al.J Cardiovasc Surg 2008; 8(3): 227-37.
Garasic 2010
Renal Artery Stent Revascularization with Embolic
Protection in Patients with Ischemic Nephropathy
RESULTS at 6 months
K-DOQI 3A K-DOQI 3B K-DOQI 4
Total
Improved
12(52%) 8(32%) 5(33%) 25(40%)
Stabilized
11(48%) 15(60%) 10(67%) 36(57%)
Unchanged
decline
0(0%) 2(8%) 0(0%) 2(3%)
Total 23 25 15 63
Level of pre-intervention CRI
97% of patients had renal function improved or stabilized at 6 months
94% of patient had renal function improved or stabilized at 16 months
Holden A, Hill A, Jaff M R, Pilmore H. Kid Int 2006;70:830-832.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1029
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients /
interventions
8) Renal artery restenosis
Garasic 2010
What are the benefits of PCI over
Surgical revascularization?
Shortened hospital stays
Reduced post-procedural morbidity / mortality
(J Vasc Surg 1994; 20: 76-87)
Early graft failure 5%
Peri-operative mortality 5.6%
43% of patients required aortic grafting
Comparable procedural success and improvement in renal function
(J Vasc Surg 1993; 18:841-52)
Procedural success: PTRA 83% vs. Surgery 97% (p=NS)
Improved or stable renal function: PTRA 83% vs. Surgery 72%
(p=NS)
Broadens pool of patients eligible for revascularization
Copyright Harvard Medical School, 2010. All Rights Reserved.
1030
Garasic 2010
Progress in Renovascular Disease
1) The Disease
2) Clinical diagnosis and “medical” management
3) Laboratory diagnosis / imaging modalities
4) Patient selection: who benefits from intervention?
5) Limiting contrast-induced nephropathy
6) Atheroembolic protection
7) Expanding the pool of eligible patients / interventions
8) Renal artery restenosis
Garasic 2010
P
a
t
h
o
b
i
o
l
o
g
y
o
f

I
n
-
s
t
e
n
t

R
e
s
t
e
n
o
s
i
s
Deep Arterial Injury: What Vascular Biology Tells Us
Copyright Harvard Medical School, 2010. All Rights Reserved.
1031
Garasic 2010
RA Stenting: Restenosis
van de Ven, 1999 52 50 ( 95%) 100 Pal maz angi o* 6 21%
Rocha-Si ngh, 1999 180 158 ( 88%) 43 Pal maz dupl ex + angi o 13 12%
Tuttl e, 1998 148 49 ( 33%) 100 Pal maz angi o 8 14%
Rundback, 1998 54 28 ( 52%) NA Pal maz angi o* + spi ral CT 12 26%
Whi te, 1997 133 80 ( 60%) 81 Pal maz angi o* 9 19%
Harden, 1997 32 24 ( 75%) 75 Pal maz angi o* 6 12%
Bl um, 1997 74 74 ( 100%) 100 Pal maz angi o* 24 11%
Henry, 1996 64 54 ( 84%) 53 Pal maz angi o* 14 9%
Iannone,1996 83 69 ( 85%) 78 Pal maz dupl ex 11 14%
Dorros, 1995 [ 30 ] 92 56 ( 61%) 100 Pal maz angi o* 7 25%
Hennequi n, 1994 21 20 ( 95%) 33 Wal l stent angi o* 29 20%
Rees, 1994 296 150 ( 51%) 100 Pal maz angi o* 7 33%
10 20%
Arteri es
eval uated
(%ori gi nal total
arteri es)
Stent type
angi o* = protocol -speci fi ed angi ographi c fol l ow-up
Study seri es
# of
Arteri es
wei ghted average
Osti al l esi on
(%)
Restenosi s (of
artery eval uated)
Average ti me to
eval uati on
(month)
Method of
eval uati on
~20%
Lim and Rosenfield, Curr Int Cardiol 2000,2:130-139.
Garasic 2010
Restenosis: Is it a problem in
the Renal Arteries?
Zeller et al. Catheter Cardiovasc Interv 2003; 60: 1-6.
0
2
4
6
8
10
12
14
16
18
3-4 5 6 7-9
Stent Size (mm)
R
e
s
t
e
n
o
s
i
s
R
a
t
e

(
%
)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1032
Garasic 2010
Curing ISR: The Molecular Approach
Garasic 2010
GREAT: 6-Month QA Data
Bare
Mean + SD
N=41 (79%)
SES
Mean + SD
N=45 (85%)
P-value
Reference vessel
diameter
5.58 ±0.81 mm 5.52 ±0.73 0.74
Diameter stenosis
(%DS)
23.9 ±22.89
(-2.3 - 96.8)
18.7 ±15.58
(0.7 – 66.6)
0.39
Minimum lumen
diameter (MLD)
4.33 ±1.44 mm
(0.2 - 6.8)
4.45 ±0.88 mm
(1.6 – 6.1)
0.88
In-stent restenosis
(> 50%)
6 (14.3%) 3 (6.7%) 0.30
Late loss 0.92 0.62 0.21
Zahringer et al. J Endovascular Therapy 2007;Vol. 14 (4): 460–468.
1 Year TLR: BMS 11.5% / SES 1.9% (P=0.21)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1033
Garasic 2010
Management of Renal Artery ISR:
DES
• Drug eluting (Sirolimus) coronary stents for renal re-
stenosis
• Renal Duplex: Mean PSV=445 +/- 131 cm/sec
• RAR 5.0 +/ - 1.6
• Clinical evidence of restenosis
• N=22 renal arteries
• 75% female
• 71.4% incidence of recurrent restenosis at median f/u
510 d
• Female gender an independent predictor of recurrent
ISR
Kiernan T et al. Vasc Med 2009; 15(1): 3-7.
Garasic 2010
The Utilization of PTFE-Covered Stents For The
Treatment of Renal Artery In-Stent Restenosis
Ten men and 16 women (mean age of 70 +/- 11 years).
Twelve (46%) of the patients had DM, 100% had HTN, 100% had
hypercholesterolemia, 16 (62%) were current or former smokers and all
had peripheral arterial disease.
Mean pre-procedure creatinine was 1.58 +/- 0.72 mg/dl (5 patients had a
solitary functioning kidney).
The average RA-ISR by angiography prior to intervention was 84 +/- 1.8 %.
There was 100% procedural success without any recorded procedural
complications.
Median stent diameter was 6 mm.
Median stent length was 16 mm.
Post-dilation was performed in all patients, median balloon diameter of 7 mm.
Mean follow-up of 10.2 +/- 4.7 months, 0% of patients who received a
PTFE-covered stent for RA-ISR had a severe enough renarrowing to
require repeat intervention.
Nicholas J . Ruggiero, II, J oseph Garasic, Michael R. J aff, Andrew B.
McCann, Thomas J . Kiernan, Brian G. Hynes, Douglas E. Drachman,
Robert Schainfeld, Kenneth Rosenfield, Gary M. Ansel. ACC 2010.
Pre
Post
Copyright Harvard Medical School, 2010. All Rights Reserved.
1034
Garasic 2010
In Summary
Renovascular disease is an often-unrecognized contributor to:
Uncontrolled hypertension
Volume overload / CHF
Chronic and progressive renal failure
Medical management of RAS involves avoidance of ACEI and use of
agents commonly used in the management of CAD
Existing literature allows data-driven decision making, helping clinicians
to properly manage their patients with renovascular disease. However,
the optimal treatment of patients with unilateral disease or “clinically
silent” disease is ill defined.
New technologies have expanded the pool of patients eligible for
percutaneous intervention, and help to limit procedural risk with renal
revascularization.
Atheroembolic distal protection devices are likely to be a mainstay of
therapy in the near future.
Vascular medicine allows cooperation and collaboration across
departmental boundaries.
Garasic 2010
Failure of renal function to improve after renal
intervention
may be predicted by:
A) Significant proteinuria
B) Recent onset or worsening of hypertension
C) Preserved renal span
D) Severe ostial stenosis
E) Creatinine clearance >40 ml/min
Copyright Harvard Medical School, 2010. All Rights Reserved.
1035
Garasic 2010
Which of the following statements regarding
Renovascular disease is false:
A) The rate of renal artery restenosis is ~20%
B) Renal intervention is curative of hypertension
in most cases of bilateral severe RAS
C) A low resistive index is associated with improved
outcomes
after renal intervention.
D) The majority of revascularized patients in the Astral
trial
had unilateral RAS
E) Fibromuscular dysplasia affecting the renal arteries
most typically does not result in a loss of renal span
Garasic 2010
Which is true of MR Angiography in evaluating
Renovascular disese:
A) MRA is the modality of choice in the HD patient
B) False negatives are common, but false positives are
rare
C) Renal duplex provides greater data for plotting
intervention
D) MRA is likely preferable to u/s in the obese patient
E) Pathology involving the mid renal artery such as
FMD is
diffficult to image by MRA
Copyright Harvard Medical School, 2010. All Rights Reserved.
1036
Garasic 2010
Presenter Disclosure
Information
The following relationships exist related to
this presentation:
Consultant / Equity Interest – Access Closure,
Inc.
Speaker’s Bureau – Sanofi-BMS Partnership
Copyright Harvard Medical School, 2010. All Rights Reserved.
1037
Acute Kidney Injury:
EPIDEMIOLOGY
Sushrut S. Waikar, MD, MPH
Renal Division
Brigham and Women’s Hospital
Disclosures
Investigator-initiated grant support from Pfizer,
Genzyme, Satellite HealthCare, NxStage;
DSMB member for Takeda
Copyright Harvard Medical School, 2010. All Rights Reserved.
1038
Board exam breakdown: ARF
19 to 21 questions total (10% of exam)
Differential diagnosis 3 – 5
Management 7 – 9
Prevention 0 – 2
Complications/Outcomes 4 – 6
ICU 1 – 3
Miscellaneous 0 – 1
From: http://www.abim.org/shared/pdf_blueprint/neph_cert.pdf
Overview
General epidemiologic characteristics of
acute kidney injury (AKI)
Definitions, incidence, mortality, prognostic
significance
Specific disease associations
Copyright Harvard Medical School, 2010. All Rights Reserved.
1039
Evolving terminology
ACUTE RENAL FAILURE
ACUTE KIDNEY INJURY
Experts from nephrology and
intensive care: Acute Kidney
Injury Network
Consensus that term “ARF”
needed updating in light of:
‘Failure’ denotes severe
dysfunction, fails to
capture spectrum of
condition
Injury short of failure (i.e.,
small increase in SCr) is
clinically important
Definitions of AKI
Over 35 distinct definitions in the literature
Early definitions emphasized severe kidney
injury: need for RRT, doubling of SCr
Newer definitions focus on smaller changes
in SCr (increase of >0.3 mg/dL or 50%),
incorporate urine output
Have not yet been validated: unlikely to be
asked about new definitions
Copyright Harvard Medical School, 2010. All Rights Reserved.
1040
New proposed stages of AKI
AKIN proposed criteria
Stage 1
SCr increase 0.3 or 50%
UO: <0.5ml/kg/h for >6h
Stage 2
SCr doubling
UO: <0.5ml/kg/h for >12h
Stage 3
SCr tripling, acute rise 0.5
UO: <0.3ml/kg/h for >24h
or anuria x 12h
Reviewed by Himmelfarb Kidney Int 2007 Molitoris JASN 2007
RIFLE criteria
“ RISK”
SCr increase by 50%
UO: <0.5ml/kg/h for >6h
“ INJURY”
SCr doubling
UO: <0.5ml/kg/h for >12h
“ FAILURE”
SCr tripling, acute rise 0.5
UO: <0.3ml/kg/h for >24h or
anuria x 12h
New proposed stages of AKI
Waikar & Bonventre
Stage 1
SCr increase of 0.3 in 24h OR 0.5 in 48h
Stage 2
SCr increase of 0.5 in 24h OR 1.0 in 48h
Stage 3
SCr increase of 1.0 in 24h OR 1.5 in 48h
Waikar & Bonventre JASN 2009
Copyright Harvard Medical School, 2010. All Rights Reserved.
1041
Question
The risk of acute kidney injury (>0.5 mg/dL
increase in SCr) in hospitalized patients is
approximately:
A) 0.5%
B) 1%
C) 3%
D) 13%
E) 25%
Incidence of AKI
Estimates depend entirely on definition, population
being studied
5 to 7%of hospital admissions (0.5, 1.0, or 1.5 mg/dL
increase in SCr depending on baseline)
13%of hospital admissions (0.5 mg/dL increase)
1%of admissions from community-acquired AKI
Following CABG:
15%of patients have a >25% increase in SCr
1-2%require renal replacement therapy
Sepsis:
Doubling of SCr in 9%with SIRS, 51%with shock
Copyright Harvard Medical School, 2010. All Rights Reserved.
1042
Rising incidence of AKI
Between 1988 and
2002: Four-fold
increase in AKI, six-
fold increase in AKI-D
(Waikar JASN 2006)
Community-based
estimate
1
: 522 AKI,
30 AKI-D per 100,000
A
K
I

i
n
c
i
d
e
n
c
e

(
/
1
0
0
,
0
0
0

p
y
)
1
Hsu Kidney Int 2007
322.7
388.3
453.6
522.4
0
100
200
300
400
500
600
1996-1997 1998-1999 2000-2001 2002-2003
Risk factors for AKI
Best studied in cardiac catheterization and
CABG
Cardiac catheterization:
Age, higher SCr, CHF, diabetes
contrast volume, intra-aortic balloon pump
CABG:
Age, higher SCr, CHF, diabetes, concomitant
valve surgery
urgency of operation, bypass time
Copyright Harvard Medical School, 2010. All Rights Reserved.
1043
Clinical features of AKI
BEST Kidney
Septic shock 48%
Major surgery 34%
Cardiogenic shock
27%
Hypovolemia 26%
Drug-induced 19%
Hepatorenal 6%
Obstructive uropathy
3%
Other 12%
PICARD
ATN (unspecified) 50%
Drug-induced 26%
Sepsis 19%
Cardiac disease 20%
Hypotension 20%
Pre-renal 20%
Liver disease 11%
Uchino JAMA 2005 Mehta Kidney Int 2004
Predictors of dialysis in AKI
PICARD
Age
Oliguria
High BUN
Liver failure
Copyright Harvard Medical School, 2010. All Rights Reserved.
1044
Small changes in SCr
1
Chertow JASN 2005
2
Brown Circulation 2006
Recent reports suggest that even small
increases in SCr increase risk of death
Among ~10,000 inpatients
1
: increase in SCr
of 0.3 or 0.4 mg/dL 70% higher adjusted
odds of death in hospital
Following CABG
2
: 50% to 99% increase in
SCr 6.6-fold higher adjusted risk of death
at 90d
Predictors of death in AKI
Results from multicenter observational studies
BEST Kidney Invest.
(Uchino J AMA 2005)
Overall mortality 60%
Age
Duration between
admission and AKI
Mechanical ventilation
Vasopressor use
Sepsis
Cardiogenic shock
Hepatorenal syndrome
PICARD
(ChertowKidney Int 2006)
Overall mortality 37%,
over 60% for AKI-RRT
Age
Higher BUN
Liver failure
Sepsis
CKD stage IV:
protective
Copyright Harvard Medical School, 2010. All Rights Reserved.
1045
Long-term outcomes of AKI
The kidneys possess a remarkable capacity to
recover after severe injury
Animal studies show permanent damage, however:
tubulointerstitial fibrosis, damage to microvasculature
Mortality
33% increased risk of death at 10y in survivors of AKI
following acute MI compared to non-AKI controls
1
Renal function decline
30% higher risk of ESRD with AKI on CKD
2
1
Parikh et al., Arch Int Med 2008
2
Hsu et al.,cJASN 2009
Costs associated with AKI
Markedly increased
60% increase in costs with AKI following
cardiac surgery (RIFLE “R”or 50% increase)
1
>0.3 mg/dL: Additional $5000 in general
hospitalized population
2
Annual costs in United States estimated at
$10 billion
2
1
Dasta et al., NDT 2008
2
Chertow et al.,JASN 2005
Copyright Harvard Medical School, 2010. All Rights Reserved.
1046
AKI in the developing world
Certain causes of AKI are region-specific
Malaria from P. falciparum: AKI in ~5% of
patients in endemic areas, up to 30% of
nonimmune travellers
Leptospirosis: widespread zoonosis, variable
clinical manifestations, AKI in up to 18%
Herbal toxins (e.g., Chinese herbal
nephropathy from Aristolochic acid)
Schistosomiasis: obstructive uropathy
Specific clinical scenarios
Copyright Harvard Medical School, 2010. All Rights Reserved.
1047
Community-acquired AKI
1% of hospital admissions
Differs greatly from hospital-acquired:
70% pre-renal azotemia
17% obstruction
11% intrinsic (mostly drug-induced, only 1 with
ATN)
Kaufman AJKD 1991
AKI following cardiac surgery
1 – 2% AKI requiring RRT
15% less severe AKI (25% increase SCr)
Major causes
Pre-renal azotemia (hypovolemia,
overdiuresis, cardiac failure)
Intrinsic (ATN, atheroemboli, contrast, AIN
from perioperative antibiotics)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1048
AKI in pregnancy
Marked reduction in incidence (industrialized world)
Causes
Early pregnancy: pre-renal azotemia from hyperemesis
gradivarum, ATN from septic abortion
Severe pre-eclampsia: usually preserved GFR unless
severe bleeding, DIC, etc
TTP-HUS
Mid-pregnancy, peripartum, or postpartum
Cortical necrosis: anuria, gross hematuria, flank pain
Abruption, placenta previa, fetal death, amniotic fluid
embolus
Acute fatty liver of pregnancy
Contrast nephropathy
Incidence
Negligible following radiologic procedures in patients
with normal SCr
50% in pts with advanced CKD
Following PCI
~3% overall (defined as 0.5 mg/dL increase)
25% in patients with SCr >2.0 mg/dL
Clear association with in-hospital and 5-yr mortality
Risk factors: age, higher SCr, CHF, diabetes,
contrast volume, intra-aortic balloon pump
Copyright Harvard Medical School, 2010. All Rights Reserved.
1049
AKI in bone marrow transplant
Incidence (defined as 50% increase SCr)
Myeloablative allo >non-myeloablative allo >
myeloablative auto (75% vs 40% vs 20%)
Common causes in first 3 weeks
ATN from sepsis
Hepatic veno-occlusive disease
Nephrotoxins
Other: tumor lysis, thrombotic
microangiopathy, CNI toxicity
Reviewed by Parikh Kidney Int 2006
AKI in cancer
Tumor lysis syndrome
Most commonly in poorly differentiated lymphoma
(e.g., Burkitt’s)
ALL >AML
Also described in other solid tumors
Multiple myeloma
Cast nephropathy
Hypercalcemia
Hyperuricemia
Contrast nephropathy
Obstruction
Prostate, bladder, uterus, cervix
Absence of hydronephrosis in retroperitoneal tumors
and retroperitoneal fibrosis
Reviewed by Humphreys JASN 2005
Copyright Harvard Medical School, 2010. All Rights Reserved.
1050
AKI in nephroticsyndrome
Minimal change disease
Risk factors: older age, higher BP, more
proteinuria
Collapsing glomerulopathy
Membranous nephropathy
Superimposed crescentic GN
Drug reaction
Vasoconstriction from NSAIDs
Allergic interstitial nephritis (NSAIDs, others)
AKI and NSAIDs
Hemodynamically mediated
Inhibition of prostaglandin synthesis afferent
arteriole vasoconstriction GFR decline
Risk factors: CHF, cirrhosis, volume depletion,
underlying CKD, diuretic therapy, age
COX-2 inhibitors have similar toxicity
Acute tubulointerstitial disease
Fenoprofen, but all NSAIDs
Absence of fever, rash, eosinophilia is common
Nephrotic syndrome
Mimimal change disease >>membranous nephropathy
Copyright Harvard Medical School, 2010. All Rights Reserved.
1051
AKI from other nephrotoxins
Aminoglycoside antibiotics
Nearly 50% of patients treated >14d; dose related
Proximal tubular injury
Typically nonoliguric AKI, slow onset
Recovery can take weeks, may be incomplete
Cisplatin
Cumulative dose-related
Tubulointerstitial pattern without heavy proteinuria
25% decline in GFR in 20-30% of patients
Incidence and severity increase with subsequent doses, may be
irreversible
Nonoliguric; hypomagnesemia common
Antivirals
Acyclovir: intratubular precipitation (U/A: needle shaped crystals)
Foscarnet: ATN
Tenofovir: ATN
Abdominal compartment syndrome
Increased intra-abdominal pressure can lead to
dysfunction of several organs
Cardiac, pulmonary, renal, GI, CNS
Abdominal pressure >25
Most common settings
Volume resuscitation for trauma
Post-laparotomy
Pancreatitis
Peritonitis
Increased renal venous pressure
Suspect in: tense abdomen, oliguria, azotemia
Copyright Harvard Medical School, 2010. All Rights Reserved.
1052
Question 1
26 year old G1P0 woman presents at 33 weeks gestation with lower
extremity edema and severe right upper quadrant pain. Physical
examination reveals BP 188/94, mild RUQ tenderness, and 3+lower
extremity edema. Labs notable for Hgb 8.6, platelet count 92,000/mm
3
,
INR 1.8, PTT 41, LDH 700, ALT 400, serum creatinine 1.4 mg/dL, 3+
albuminuria, and moderate schistocytes on peripheral blood smear.
Which of the following two are the MOST appropriate interventions:
A) Immediate delivery
B) Intravenous heparin
C) Plasma exchange
D) Activated protein C
E) Intravenous methylprednisolone
Question 2
A 76 year old man
developed a rise in serum
creatinine following cardiac
catheterization and
percutaneous coronary
intervention. His serum
creatinine trajectory was as
follows:
1
1.2
1.4
1.6
1.8
2
2.2
2.4
pre-
cath
24h 48h 72h 96h 120h 144h
S
C
r

(
m
g
/
d
L
)
Which of the following is LEAST LIKELY:
a) False-positive proteinuria at 12h
b) Hypocomplementemia
c) FeNa 0.3% at 24 hours
d) Normal urine output
Copyright Harvard Medical School, 2010. All Rights Reserved.
1053
Disclosures
Investigator-initiated grant support from Pfizer,
Genzyme, Satellite HealthCare, NxStage;
DSMB member for Takeda
Copyright Harvard Medical School, 2010. All Rights Reserved.
1054
Acute Kidney Injury
(aka: Acute Renal Failure)
It is more than just a change in name
J oseph V. BonventreMD PhD
Director, Renal Division
Brigham and Women’s Hospital
Harvard Medical School
Disclosure
Dr. Bonventre is co-inventor on KIM-1 patents , licensed to
Johnson and Johnson, Genzyme and BiogenIdec
Copyright Harvard Medical School, 2010. All Rights Reserved.
1055
Questions
1. What is the definition of acute renal failure/acute kidney
injury (AKI) ? What are the RIFLE criteria ?
2. How large do changes in creatininehave to be before
worrying about the effects of renal dysfunction on
mortality?
3. Is the incidence of AKI increasing or decreasing ?
4. Is mortality associated with AKI increasing or decreasing?
5. Does AKI contribute to Chronic Renal Failure?
6. Is dopamine appropriate for the treatment of AKI ?
Questions (2)
7. Does CRRT result in better outcome than IHD in AKI ?
8. Does increasing the dose of dialysis in AKI alter the
outcome?
9. Is serum creatininea good early marker for AKI?
10. What are some other potential biomarkers for early
diagnosis of AKI and prediction of outcome of AKI?
Copyright Harvard Medical School, 2010. All Rights Reserved.
1056
> Diagnosis and New terminology (AKI, RIFLE
Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
RIFLE criteria for diagnosis of acute kidney injury
Risk of renal injury
Injury to the kidney
Failure of kidney function
>0.3mg/dL increase
2.0 X baseline
3.0 X baseline
or
Serum creatinine>
4 mg/dL with an
absolute increase of
>0.5 mg/dL
<0.5 mL/kg/hr for >6 h
<0.5 mL/kg/hr for >12 h
<0.3 mL/kg/hr for >24 h
or
Anuriafor >12 h
Loss of kidney function
End-stage disease
Persistent renal failure for >4 weeks
Persistent renal failure for >3 months
Increase in serum
creatinine Urine output
Copyright Harvard Medical School, 2010. All Rights Reserved.
1057
Incidence of AKI depends on definition
• 1.0% if >2.0 mg/dL increase in SCr
• 12% if >0.5 mg/dl increase in SCr
Chertow
Burdick
Honour
Bonventre
Bates
J ASN 16:
3365-70, ‘05
Brigham and Womens: 9210 adults with
2 or more serum creatininedeterminations
during their hospitalization (of 19,982 admissions)
“AKI” and Mortality (Brigham and Womens, 9210 adults)
• “AKI” 6.5 (5.0 to 8.5) <0.0001
• Age(per 10 y) 1.7 (1.1 to 2.6) <0.0001
• CKD 2.5 (1.9 to 3.3) <0.0001
• DRG weight 1.2 (1.1 to 1.3) <0.0001
• CV 1.5 (1.0 to 2.2) <0.04
• Respiratory 3.0 (1.9 to 4.8) <0.0001
• GI 2.4 (1.4 to 4.1) <0.001
• Cancer 2.9 (1.9 to 4.4) <0.0001
• Infection 7.5 (4.2 to 13.6) <0.0001
Chertow
Burdick
Honour
Bonventre
Bates
J ASN 16:
3365-70, ‘05
Multivariable Odds Ratio for Death
AKI: Δ creatinine>+0.5 mg/dl
Copyright Harvard Medical School, 2010. All Rights Reserved.
1058
•>0.3 mg/dl 4.1 (3.1 to 5.5)
•>0.5 mg/dl 6.5 (5.0 to 8.5)
•>1.0 mg/dl 9.7 (7.1 to 13.2)
•>2.0 mg/dl 16.4 (10.3 to 26.0)
Chertow
Burdick
Honour
Bonventre
Bates
J ASN 16:
3365-70, ‘05
Multivariable Odds Ratio for Death
Δ serum creatinine
“AKI” and Mortality (Brigham and Womens, 9210 adults)
An abrupt (within 48 hours) reduction in kidney
function currently defined as an absolute
increase in serum creatinine of
either > 0.3 mg/dl or a percentage increase
of ≥50% or a reduction in urine output
(documented oliguria of < 0.5 ml/kg/hr for more
than 6 hours)*
Diagnostic Criteria for Acute Kidney Injury
(AKI)(current consensus - AKI Network)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1059
Waikar SS and Bonventre JV. J Am Soc Nephrol 2009;20:672-679
SCr concentrations after an abrupt 50% reduction in CrCl,
superimposed on four different levels of baseline kidney
function (no CKD and stages 2 through 4 CKD)
Solid squares show the point at which a 100% increase in SCr has occurred.
Open triangles show the point at which a 1.0 mg/dl increase in SCr has occurred.
> New terminology (AKI, Rifle Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
Copyright Harvard Medical School, 2010. All Rights Reserved.
1060
Number of cases of AKI per 1000 hospital discharges of US Medicare
beneficiaries (5,403,015 discharges)
Men
Women
White
By sex By race
By age Overall
Other
Black
85+ yr
75-84 yr
75-84 yr
< 64yr
50
45
40
35
30
25
20
15
10
5
50
45
40
35
30
25
20
15
10
5
40
35
30
25
20
15
10
50
45
40
35
30
25
20
15
10
Year
60
65
55
‘92‘93 ‘95 ‘94 ‘96‘97‘98‘99‘00‘01 ‘92‘93 ‘95 ‘94 ‘96‘97‘98‘99‘00‘01
Cases per
1000 discharges
Cases per
1000 discharges
Year
>84 yr
65-74 yr
Xueet al. J ASN
17:1135-42,
2006
Declining mortality in patients with AKI
Waikar,Curhan,Wald,McCarthyand Chertow, J ASN 17:1143-1150, 2006
Copyright Harvard Medical School, 2010. All Rights Reserved.
1061
Ishani, A. et al. J Am Soc Nephrol 2009;20:223-228
Estimated probability of initiating treatment of ESRD
Post-ischemic expression of α-smooth muscle actin
Ischemia
1 week
Ischemia
12 weeks
Ischemia
6 weeks
Sham
1 week
Copyright Harvard Medical School, 2010. All Rights Reserved.
1062
> New terminology (AKI, Rifle Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
MICROVASCULAR TUBULAR
Vasoconstriction
renal nerves, adenosine
angiotensinII, thromboxaneA
2
endothelin, leukotrienes
Vasodilation
acetylcholine, bradykinin
nitric oxide, PGE
2
Endothelial and vascular smooth
muscle cellular damage
Leukocyte-Endothelial adhesion
vascular obstruction,
leukocyte activation and
inflammation
Cytoskeletal breakdown
Loss of polarity
Apoptosis and Necrosis
Desquamation of viable
and necrotic cells
Tubular obstruction
Backleak
Glomerular Medullary
O
2
Inflammatory
Vasoactive
Mediators
Mechanisms of Kidney Injury and Repair
Copyright Harvard Medical School, 2010. All Rights Reserved.
1063
If arteriolar vasoconstriction is the cause of ARF
then a vasodilator should be therapeutic
Normal Arteriole Post-Ischemic
Renal Perfusion Pressure
Renal Perfusion Pressure
vasoconstrictors
unstimulated
vasodilators
•Dopamine
•Natriureticpeptides
•NO donors
•Calcium channel blockers
•Endothelinantagonists
•Adenosine antagonists
•ACE inhibitors
•ROS scavengers
•Prostaglandins agonists
and antagonists
•Platelet activating factor
•IGF-1 and basic FGF
Absence of Effect of Dopamine on Survival in Patients with Early
Renal Dysfunction
Bellamoet al. ANZICS Clinical Trial Group. Lancet 2000; 356: 2139-2143
Early Renal Dysfunctionis defined as either: <0.5 ml/kg/hr for 4 hr; or
an increase in serum creatinine>150 μmol/l; or
serum creatinine>150 μmol/l in absence of CRF
Copyright Harvard Medical School, 2010. All Rights Reserved.
1064
In-hospital mortality 1.68 (1.06-2.64)
Nonrecoveryof renal function 1.79 (1.19-2.68)
Death or nonrecovery 1.77 (1.14-2.76)
Covariant and Propensity
Score Adjusted Odds Ratio (95% CI)
Days from Consult to Dialysis/Death
100
75
50
25
00
0 10 20 30 40 50 60
% Survival
No Diuretics
Diuretic Responsive
Diuretic Nonresponsive
Diuretics, Mortality and Nonrecovery of Function in Acute
Kidney Injury
Mehta…Chertow,
PICARD
J AMA 288: 2547, 2002
> New terminology (AKI, Rifle Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
Copyright Harvard Medical School, 2010. All Rights Reserved.
1065
CD11b/
CD18
CD11c/
CD18
Ischemic Kidney
ICAMs
VCAM
selectins
Release of ROS,
proteases, elastases,
leukotrienes, PAF
Increased expression of adhesion
molecules on endothelial cells
Endothelial Cell
ICAMs
VCAM
selectins
iC3b
CD35
iC3b
Leukocyte Activation in Ischemic AKI
Local production of inflammatory mediators
- cytokines (TNFα, IL-1), chemokines(IL-8,
MCP-1)
- complement activation products
- platelet activating factor (PAF)
- metabolites of arachidonicacid
- reactive oxygen species (ROS)
Activated
Leukocytes
procoagulant
effects
Plasma proinflammatory cytokine levels
Himmelfarbet al.
J ASN 15: 2449,2004
PICARD
4.7 ± 1.7 2.9 ± 0.6 4.6 ± 0.7 10.6 ± 1.0
2.5 ± 0.4 290.2 ± 70.3* 32.4 ± 12.2* 23.5 ± 3.0*
2.8 ± 0.3 190.6 ± 32.4* 44.3 ± 13.1* 56.2 ± 5.3*
+
Healthy
Critically ill
ARF
IL-1β (pg/ml) TNF-α (pg/ml) IL-8(pg/ml) IL-6(pg/ml)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1066
Outer medullarycongestion in human ischemic acute kidney
injury
Oxygen tension is reduced in the outer medulla Oxygen tension is reduced in the outer medulla
Cortex
Outer Medulla
Inner Medulla
pO
2
≈ 50 mm Hg
≈ 10- 20 mm Hg
vasarecta
O
2
Copyright Harvard Medical School, 2010. All Rights Reserved.
1067
10
0
30 60 50 40
85
83
20
0.2
1.0
0.8
0.6
0.4
0
Survival (%)
Time (days)
184
175
68
62
58
57
Numbers at risk
IHD
CVVHDF
IHD
CVVHDF
Survival in patients treated with IHD vs CVVHDF in the ICU
Vinsonneauet al.
Lancet 368:379,2006
VA/NIH Acute Renal Failure Trial Network. NEJ M 359:7-20, 2008
Intensive (6X/Week) vsLess Intensive (3X/Week) Dialysis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1068
Meier et al. BMC Medicine 2009 7:23
Meta-analysis of Bicarbonate Therapy in Contrast Induced Nephropathy
> New terminology (AKI, Rifle Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
Copyright Harvard Medical School, 2010. All Rights Reserved.
1069
Ki67
    67                   at various times after ischemic in the mouse
Origin of Cells Involved in Tubular Epithelial Cell Repair
Loss of polarity Normal
Epithelium
Migration
Differentiation &
Reestablishment of polarity
Sloughing of viable and dead
cells with luminal obstruction
Ischemia/
Reperfusion
Apoptosis Necrosis
Cell death
Proliferation
Toxins
?
stem/progenitor
cell
Copyright Harvard Medical School, 2010. All Rights Reserved.
1070
Interstitial cells are not labeled with DsRed
(Macrophages labeled in green)
D
s
R
e
d
/
F
4
/
8
0
/
D
A
P
I
Inner Cortex Outer Medulla
Labeled epithelial cells proliferate
Serum Cr
(mg/dL)
2.0
1.0
0.5
1.5
Day 1 Day 15
Days post-IRI
Copyright Harvard Medical School, 2010. All Rights Reserved.
1071
Injection of MSCscultured on matrigel immediately post
I/R injury protected the kidney at 24 h without implantation
of cells in the kidney
0
0.5
1
1.5
2
2.5
PBS Mesenchymal
Stem Cells
Creatinine
(mg/dL)
**
Ischemic Kidney
BMSCsmay generated anti-inflammatory mediators in
AKI
Local production of inflammatory mediators Local production of inflammatory mediators
- - cytokines ( cytokines (TNF TNFα α, IL , IL- -1), 1), chemokines chemokines (IL (IL- -8, MCP 8, MCP- -1) 1)
- - complement activation products complement activation products
- - platelet activating factor (PAF) platelet activating factor (PAF)
- - metabolites of metabolites of arachidonic arachidonic acid acid
- - reactive oxygen species (ROS) reactive oxygen species (ROS)
ICAMs
VCAM
selectins
Release of ROS,
proteases, elastases,
leukotrienes, PAF
Increased expression of adhesion
molecules on endothelial cells
Endothelial Cell
ICAMs
VCAM
selectins
iC3b
iC3b
Activated
Leukocytes
BMSCs
(−)
  t -inflammatory
mediators
Copyright Harvard Medical School, 2010. All Rights Reserved.
1072
> New terminology (AKI, Rifle Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
Biomarkers of injury in kidney and heart
• Creatinine-based
– AKIN, RIFLE
– Stage dependent on absolute or
relative creatininerise
• Urine output-based
– AKIN, RIFLE
– Stage dependent on duration and
extent of oliguria
• Troponin, CPK, EKG
• Biomarkers of myocardial cell injury
often associated with
– Ischemic symptoms
Modified from SusWaikar
Copyright Harvard Medical School, 2010. All Rights Reserved.
1073
Damage Normal Epithelium
Toxic/ischemic
Injury
Apoptosis Necrosis
Cell death
Death
Death
Complications
Complications
Normal
Normal
Increased
risk
Increased
risk
Kidney
failure
Kidney
failure
Damage
Damage
↓ GFR
↓ GFR
Kidney Injury Molecule-1 (KIM-1)
Neutrophil Gelatinase Associated Lipocalin (NGAL)
N-acetyl-β-D-glucosaminidase (NAG)
Microalbuminuria
Cystatin C
Interleukin-18 (L-18)
Serum Creatinine
Blood Urea Nitrogen
Potential biomarkers for earl y diagnosis of AKI
AKIN Scheme,
2006
GFR
GFR
Delayed biomarkers for kidney
injury
Vaidya et al., Ann Rev Pharm Tox., 48, 2008
Copyright Harvard Medical School, 2010. All Rights Reserved.
1074
Nickolas, T. L. et. al. Ann Intern Med 2008;148:810-819
Study of Urine Biomarkers and Serum Creatinine in ER
on Admission
NGAL 0.948
Serum Creatinine 0.921
NAG 0.713
α1-Microglobulin 0.887
α1-Acid glycoprotein 0.832
Fract. Excret. Sodium 0.708
Nickolas et al. Ann Intern Med 2008;148:810-819
Test characteristics of Novel Biomarkers and Standard DiagnosticMarkers
in patients being admitted to the Columbia U. Hospital: ROC analysis
Urinary NGAL as determined by Western blot was equivalent
to serum creatininein predicting AKI
Biomarker AUC
Copyright Harvard Medical School, 2010. All Rights Reserved.
1075
Kim-1
BUN
SCr
AUC from ROC
ALL 0-3 0-2 0-1
A
Kim-1
BUN
SCr
Sensitivity
Histopathology Grade Subset
B
0.7
0.8
1.0
0.9
0.8
0.6
0.4
0.2
1.0
ALL 0-3 0-2 0-1
Comparison of Urinary KIM-1 to BUN or Creatinineas Predictors of
Pathology
Protective Safety
Testing
Consortium
(PSTC)
0.01
0.1
1
10
100
1000
KIM-1
Healthy AKI CKD UTI AAA CC ICU
0.0001
0.001
0.01
0.1
1
(n=50) (104) (50) (21) (13)
NAG
(70) (14)
NAG (U)
Creat (mg)
KIM-1 (ng)
Creat (mg)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1076
Healthy Volunteers AKI CKD UTI
0.1
1
10
100
1000
10000
(n=50) (100) (51) (20)
Healthy AKI CKD UTI AAA CC ICU
0.01
0.1
1
10
100
1000
10000
100000
1000000
(n=50) (103) (21) (50) (11) (70) (14)
NGAL
IL-18
NGAL(ng)
Creat (mg)
IL-18 (pg)
Creat (mg)
Heated Cisplatin
Urinary NAG (U/mg creat.)
Pre-op 2-8 24 48 72 96
0.0000
0.0025
0.0050
0.0075
0.0100
0.0125
0.0150
0.0175
0.0200
0.0225
0.0250
0.0275
0.0300
0.0325
0.0350
0.0375
0.0400
0.0425
AKI
No AKI
Time Point (hrs)
Urinary KIM-1 (ng/mg creat.)
Pre-op 2-8 24 48 72 96
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
3.25
3.50
3.75
4.00
Time Point (hrs)
Urinary Protein (mg/mg creat.)
Pre-op 2-8 24 48 72 96
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time Point (hrs.)
AKI
No AKI
AKI
No AKI
Copyright Harvard Medical School, 2010. All Rights Reserved.
1077
0
2
4
6
8
10
12
14
16
C
1
D
1
C
1
D
1
P
O
S
T
C
1
D
2
C
1
D
3
C
1
D
4
C
1
D
5
C
2
D
1
C
2
D
1
P
O
S
T
C
2
D
2
C
2
D
3
C
2
D
4
C
2
D
5
C
3
D
1
C
3
D
1
P
O
S
T
C
3
D
2
C
3
D
3
C
3
D
4
C
3
D
5
C
4
D
1
C
4
D
1
P
O
S
T
C
4
D
2
C
4
D
3
C
4
D
4
C
4
D
5
Cycle and Day
N
o
r
m
a
l
i
z
e
d

b
i
o
m
a
r
k
e
r

v
a
l
u
e
KIM-1/creat
NAG/creat
Mean Urinary KIM-1 and NAG Levels During CisplatinTreatments
In Patients with Testicular Cancer
5 4 3 2 1 0
1.0
0.9
0.8
0.7
0.6
0.5
T1 (0.01 -0.48)
Tertiles of
urinary KIM -1
excretion (ng/24h)
Follow -up (years)
T2 (0.49 -1.09)
T3 (1.15 -10.04)
5 4 3 2 1 0
1.0
0.9
0.8
0.7
0.6
0.5
T1 (0.01 -0.48)
Tertiles of
urinary KIM -1
excretion (ng/24h)
C
u
m
u
l
a
t
i
v
e

s
u
r
v
i
v
a
l

(
%
)
Follow -up (years)
T2 (0.49 -1.09)
T3 (1.15 -10.04)
(1)
(2)
(3)
Kaplan-Meier survival curve of tertiles of urinary KIM-1 excretion (in ng/24 hr)
at baseline for death-censored graft survival. P=0.001
Van Timmeran,VanGoor,Bonventre,
Bakker et al. Transplantation, 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
1078
Board Question (1)
The dialytictherapy which is most effective in
reducing mortality in patients in the ICU
with acute kidney injury is:
a. Continuous hemodialysis
b. Intermittent hemodialysis- 3 times per week
c. Intermittent hemodialysis- 6 times per week
d. Slow extended daily but intermittent
hemodialysis
e. None of the above
Board Question (2)
Which of the following has been associated with
increased risk for AKI:
1. Colonoscopy preps
2. Rice from fields located near battery factories
3. The chineseherb Aristolochia
4. Infant formula made in China
5. None of the above
a. 1 and 2 c. 1,2, and 4
d. 1,3, and 4 e. All of the above
Copyright Harvard Medical School, 2010. All Rights Reserved.
1079
Summary
1. The term “acute kidney injury” (AKI) is replacing
“acute renal failure” to reflect the importance of the
entire spectrum of kidney injury to outcome
2. The incidence of AKI is increasing
3. AKI contributes to Chronic Renal Failure?
4. Dopamine or diuretics do not affect outcome in
AKI but diuretics may be helpful prognostically.
5. Continousrenal replacement therapies have not
been shown to have a better outcome than
intermittent dialysis.
Summary (2)
6. Bone marrow derived cells have antiinflammatory
effects to enhance recovery from AKI but do not
replace dead epithelial cells.
7. Proximal epithelial cells are replaced by replication
of proximal cells that have survived the insult, not
by an interstitial stem cell.
8. New biomarkers of kidney injury will transform the
way that we diagnose kidney disease, monitor
patients with chronic kidney diseases, and make
clinical trials much more efficient.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1080
> New terminology (AKI, Rifle Criteria)
> Changing epidemiology
> Pathophysiologyand Implications for
Pharmacologic and DialyticTherapies
Vasoconstriction
Inflammation
> Repair (?Stem cells)
> Biomarkers
Acute Kidney Injury
Disclosure
Dr. Bonventre is co-inventor on KIM-1 patents , licensed to
Johnson and Johnson, Genzyme and BiogenIdec
Copyright Harvard Medical School, 2010. All Rights Reserved.
1081
Kenneth Christopher, MD, FASN, FCCP
Renal Division
ICU Nephrology Service
Brigham and Women’s Hospital
CVVH: An Overview
Disclosures
• I do not accept honorarium nor do consulting work
for the pharmaceutical or device industries.
• I do not serve as a member of a speaking bureau
for pharmaceutical or device companies.
• 2009 Awarded competitive Research Grant
support from NxStageMedical
Copyright Harvard Medical School, 2010. All Rights Reserved.
1082
Case
• 34 year old diabetic female on Lisinopril
• Witnessed PEA arrest
• Resuscitated
• Progressive volume overload (+15L)
• Oliguric, diuretic resistant
• BP 100/60 on moderate dose levophed
• Mechanically ventilated and sedated
• Na 129, K 5.7, CO
2
14, BUN 69, Cr 4.7
• Best Renal Replacement modality?
Case
• Best Renal Replacement modality?
• A. IHD
• B. CVVH
• C. CVVHD
• D. CVVHDF
• E. SLED
• F. All of the above
Copyright Harvard Medical School, 2010. All Rights Reserved.
1083
• Optimize hemodynamic and volume status 
• Minimize further renal injury 
• Correct metabolic abnormalities
• Removal of Uremic toxins 
• Permit adequate nutrition
Primary Therapeutic Goals in ARF
Luyckx VA Semin Dial. 2004;17(1):30‐6.
• Hypercatabolic state 
• Hemodynamic instability 
• Control of Volume status 
Limitations on Dialysis Delivery in ARF
Copyright Harvard Medical School, 2010. All Rights Reserved.
1084
CVVH       Continuous Veno‐Venous Hemofiltration
CVVHD   Continuous Veno‐Venous Hemodialysis
CVVHDF Continuous Veno‐Venous Hemodiafiltration
SCUF        Slow Continuous Ultra‐Filtration
SLED Slow Low Efficiency Dialysis
Continuous Renal Replacement 
Therapy (CRRT)
• Solute Removal
– Diffusion and Convection
• Solute Addition
– Replacement Fluid
• Fluid Removal
– Convection
• Detoxification
Primary Therapeutic Goals in CRRT
Copyright Harvard Medical School, 2010. All Rights Reserved.
1085
• Convection
– Ultrafiltration coefficient
– Sieving coefficient (Sc)
– Solvent Drag
• Diffusion
– Solvent gradient
• Effluent
• Secondary Membrane Formation
• Replacement Solution
• Clearance
Basic CRRT Concepts
• Fluid Removal and Solute Removal 
• Movement of fluid across the membrane via 
transmembrane pressure
• Water moves across the membrane and carries 
dissolved solutes with it via solvent drag 
– Ultrafiltration is fluid removal
– Hemofiltration involves partial or total replacement of fluid 
removed
Convection
LucianoA. Pedrini J Nephrol 2003; 16 (suppl 7): S57-S63
Copyright Harvard Medical School, 2010. All Rights Reserved.
1086
Convection
H2O
Transmembrane Pressure
Convection
Transmembrane Pressure
H2O
Glucose
Cr, BUN
Toxins
Na, Cl
K, PO4, Mg
Ca, HCO3
Copyright Harvard Medical School, 2010. All Rights Reserved.
1087
• Ultrafiltration plasma water
– Ultrafiltration coefficient of the membrane
– Potential to remove water adjusted for the transmembrane
pressure
• Solute removal from plasma
– Sieving coefficient for that solute
– Ratio between the solute concentration in the ultrafiltrate
and its average plasma concentration within the dialyzer 
– Inversely related to the solute molecular weight 
– ~1.0 with small solute and highly permeable membranes
Convection
LucianoA. Pedrini J Nephrol 2003; 16 (suppl 7): S57-S63
ChelamcharlaM, SeminNephrol. 2005;25(2):81-9
• Movement of solutes down a concentration gradient 
across a semipermeable membrane.
• Solutes cross the membrane from the blood to the 
dialysis fluid compartment. 
• Fluid in the dialysis compartment moves in a 
counter‐current direction, thereby maintaining a 
concentration gradient. 
Diffusion
Luciano A. Pedrini J Nephrol 2003; 16 (suppl 7): S57‐S63
Copyright Harvard Medical School, 2010. All Rights Reserved.
1088
• Diffusive clearance is determined by 
– Molecular weight of the solute 
– Concentration gradient across the membrane 
– Membrane surface area
– Thickness and pore size
Diffusion
• Represents the end product of the filtration process
• CVVH: Ultrafiltrate
• CVVHD: Dialysate plus variable ultrafiltrate
• CVVHDF: Dialysate plus ultrafiltrate
Effluent
Copyright Harvard Medical School, 2010. All Rights Reserved.
1089
CVVH
Continuous 
Veno‐Venous 
Hemofiltration
Access
Return
Effluent
Replacement
P
R
I
S
M
A
Prefilter
Postfilter
CVVHD
Continuous 
Veno‐Venous 
HemoDialysis
Access
Return
Effluent
P
R
I
S
M
A
Dialysate
Copyright Harvard Medical School, 2010. All Rights Reserved.
1090
CVVHDF
Continuous
Veno‐Venous
HemoDiaFiltration
Dialysate
Access
Return
Effluent
Replacement
P
R
I
S
M
A
Prefilter
Postfilter
SCUF CVVH
Hemofiltration
CVVHD
HemoDialysis
CVVHDF
HemoDiaFiltration
Blood filter
Middle Molecule
Clearance
Replacement Fluid
Dialysate
High
Permeability
+
None
None
High
Permeability
+++
RF
None
Low
Permeability
-
None
D
High
Permeability
+++
RF
D
Technical Aspects
Adapted from Johnson RJ, Feehally J, Comprehensive Clinical Nephrology  2
nd
Edition
Copyright Harvard Medical School, 2010. All Rights Reserved.
1091
• Replaces the ultrafiltrate removed by hemofiltration
and hemodiafiltration.
• Buffers: Lactate, bicarbonate or citrate  
• Lactate and Citrate metabolized by liver and muscle 
to bicarbonate. 
• Bicarbonate is most easily tolerated
– can be unstable in solution
• Lactate is more stable
– may contribute to an existing lactic acidosis in septic or liver
failure patients
• Citrate 
– Regional anticoagulation
Replacement Solution
P HeeringIntensiveCareMed 1999, 25:1244-1251
Tan HK Int J Artif Organs. 2003 J un;26(6):477-83.
Citrate Regional Anticoagulation
• Citrate causes anticoagulation by chelation of 
calcium in the extracorporeal system
• Systemic anticoagulation does not occur
• as ionized calcium level is restored when blood returning 
from the extracorporeal system is mixed with venous blood
• Rapid metabolism of citrate restores bicarbonate level 
and releases calcium
• Patients with severe liver failure and lactic acidosis 
may have difficulty metabolizing citrate and develop 
citrate toxicity
Copyright Harvard Medical School, 2010. All Rights Reserved.
1092
Citrate Replacement solution
• Sodium Citrate = 40 mEq/Liter,
• Dextrose = 2 gm/Liter,
• Sodium Chloride = 105 mEq/Liter,
• Magnesium Sulfate = 1.5 mEq/Liter.
• CVVH with maximum replacement of 2000 cc 
citrate/hour.
• CVVHDF add dialysate to improve clearance. 
• Calcium replacement scales adjusted depending on 
clearance 
Citrate Toxicity
• Low ionized Calcium despite repletion
• Elevated total serum Calcium in response to 
repletion
• Exacerbation of serum acidosis
• Elevation of anion gap
• Decrease Citrate replacement solution rate
• Switch replacement solutions
Copyright Harvard Medical School, 2010. All Rights Reserved.
1093
Pre‐ vs. post‐dilution
• Post‐dilution:
– High small solute 
clearance/ml
– UF rate limited by 
• Hematocrit
• QB
– Maximal UF is 25% plasma 
flow 
• Pre‐dilution:
– Less clearance/ml (diluted)
– Reduced efficiency by 10‐15%
– UF rate is not limited
Access
Return
Effluent
Replacement
P
R
I
S
M
A
Prefilter
Postfilter
• Replacement fluid infused at the proximal side
• Relatively low viscosity of the blood within the filter
• Efficiency of ultrafiltration is compromised
• Reduces net filtration fraction 
• Minimizes concentration of clotting factors 
• Prolongs filter lifespan
Pre‐Dilution
J oseph V. DiCarlo, MD ALL-NET Pediatric Critical Care Textbook
Copyright Harvard Medical School, 2010. All Rights Reserved.
1094
• Replacement fluid infused via distal side 
• Most efficient technique 
• Maximum clearances
• Maximally dehydrates the blood in the hemofilter
• Higher viscosity of the blood within the filter
• Clotting of filter
Post‐Dilution
• Hemofilters allow the passage of molecules with a 
molecular weight of less than 50,000 Daltons.
• Small molecules freely filtered 
– sodium, potassium, bicarbonate, glucose and ammonia. 
• Larger soluble substances filtered
– myoglobin, insulin, and interleukins
– medications (vancomycin, heparin) 
• Protein bound molecules are not filtered effectively
Ultrafiltration Membranes 
Copyright Harvard Medical School, 2010. All Rights Reserved.
1095
• Pressure exerted on the membrane during operation 
• Primary factor determining filtration rate
• Pressure difference between blood and fluid 
compartment
• Usual range 100 ‐ 500 mmHg
• Increased TMP associated with increased UF rate
• TMP= [(Filter Pressure + Return Pressure)/2] – Effluent Pressure
TMP TransMembrane Pressure
• Clearance is the rate at which solutes are cleared
– excretion rate of solute / blood concentration of solute
• Solute clearance in CVVH depends on UF Rate 
• Clearance in Predilution 10‐15% < Postdilution
• Predilution mode Clearance improved
– large hemofilters
– high UF Rate
Clearance
Copyright Harvard Medical School, 2010. All Rights Reserved.
1096
Strategies to Increase Solute Clearance
• Increase Transmembrane pressure
• Increase filter permeability to water
• Increase filter surface area
• Increase blood flow
• CVVHDF
– Add dialysis to convection 
J ohnson RJ , FeehallyJ , ComprehensiveClinical Nephrology 2
nd
Edition
• Protein layer formed over surface of dialyzer membrane with 
transmembrane pressure
• Reduces the effective solute and water permeability.
• Adsorption occurs in all membranes
• Magnified in CRRT
• Pre‐pump increases filter life
– Dilute blood going into the filter 
– Dilute protein and red cell concentration
Secondary Membrane Formation
ʺgel layerʺ or ʺprotein cakeʺ
Ronco C, Contrib Nephrol. 1991;93:175‐8
Mehta R, Atlas of Diseases of the Kidney 1999
Copyright Harvard Medical School, 2010. All Rights Reserved.
1097
• Patients with/ at risk for hypotension:
– severe hemodynamic instability
– hepatic failure
– CHF
– sepsis or multiple organ failure 
• Patients at risk of cerebral complications:
– hepatic failure, stroke or head trauma 
– high risk for cerebral edema
Indications for CRRT
• Increased metabolic needs
– massive burns
– sepsis 
– multiple organ failure
• Volume overload
– massive volume overload
– Patients receiving large amounts of fluids or blood products
– When volume management is critical
Indications for CRRT
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1098
Non‐renal Indications for CRRT
• Lactic acidosis
– Ongoing production
• Crush injury
– Myoglobin Removal
• Tumor lysis syndrome
• Temperature control 
– Relative hyper or relative hypothermia*
• Massive volume overload without ARF
• High NH
3
*Kopcke J. Anaesthesiol Reanim. 1996;21(6):159‐62.
Potential Advantages of CRRT
• Increased total solute clearance
• Gradual clearance may be better tolerated
– Decreases frequency of hypotension
– Decreases risk of cerebral edema
• Continuous clearance may help in removal of toxins 
with high intracellular concentrations
• Increased clearance of middle molecules
• Precise adaptable volume control
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1099
• Anticoagulation requirement
• Lack of rapid fluid and solute removal
• Limited role in overdose setting
• Relative Hypothermia 
• Electrolyte Depletion
– K, PO
4
, Ca 
Potential disadvantages of CRRT
Technical Complications of CRRT
• Vascular access malfunction
• Blood flow reduction and circuit clotting
• Loss of filter efficiency
• Line disconnection
• Air embolism
• Fluid and Electrolyte balance errors
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1100
Clinical Complications of CRRT
• Bleeding
• Thrombosis
• Line Infection and sepsis
• Relative Hypothermia masking low grade fever
• Nutrient losses
• Inadequate blood purification due to down time
– median 3 h per day down time
1
• Thrombocytopenia
– destruction or retention of platelets passing through hemofilter.
2
1. Uchino S,Intensive Care Med. 2003 Apr;29(4):575‐8.
2. Mulder J, Int J Artif Organs. 2003;26(10):906‐12., 
• Life‐threatening hyperkalemia
Contraindications of CRRT
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1101
• Minimal removal of protein bound drugs 
• Some may be removed via membrane adsorption
• Drug clearances increased with CVVHDF
• Higher doses may be needed with higher UF rates 
• GFR = 10 ml/min Low UF rate
• GFR = 30 ml/min Medium UF rate
• GFR = 50 ml/min High UF rate
Drug Dosage in CRRT
Mehta R, Atlas of Diseases of the Kidney 1999
Bugge JF.Acta Anaesthesiol Scand. 2001;45(8):929‐34.
• eGFR = Replacement Solution ml per hour
Ideal body weight
• eGFR = 3000 ml/hr
70 kg
• eGFR= 42
Estimate GFR in CRRT
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1102
• Increased azotemia induced by protein or amino 
acids in TPN
1
• Fluid overload caused by the administration of TPN
1
• Negative balances of selenium, copper, thiamine
2, 
• Loss of Magnesium and calcium
3
• High‐protein diet safe for patients with ARF on 
CRRT
4
• Protein intake of 2.5 g/kg/day 
– increases the likelihood of positive nitrogen balance
5
– corrects amino acid deficiencies.
6
Nutrition and CRRT
1. Bellomo R. Blood Purif. 2002;20(3):296‐303.   2. Berger MM. Am J Clin Nutr. 2004;80(2):410‐6.
3. Klein CJJPEN J Parenter Enteral Nutr. 2002;26(2):77‐92  4. Bellomo R. Ren Fail. 1997;19(1):111‐20.
5. Scheinkestel CD Nutrition. 2003;19(11‐12):909‐16.  6. Scheinkestel CD. Nutrition. 2003;19(9):733‐40.
• Many immune mediators are water soluble and fall 
into the middle‐molecular‐weight category 
– Theoretically removed via hemofiltration. 
– adsorption to the filter membrane
• CRRT in animal models of sepsis and have 
demonstrated some beneficial effects. 
– CVVH reduces plasma TNF, but not IL‐6, IL‐10. 
• Early isovolemic CVVH at 2 l/hour in established 
sepsis
– No reduction of several cytokines and anaphylatoxins
– Organ dysfunction not improved.
• CVVH has not been shown to benefit SIRS/Sepsis in 
the absence of ARF 
CRRT and Sepsis
Venkataraman R. Critical Care 2003, 7:139‐145 
Copyright Harvard Medical School, 2010. All Rights Reserved.
1103
• HVHF: ultrafiltration of more than > 35 ml/kg/hour 
• ʹsepsis dosesʹ of ultrafiltration 3.8–6 l/hour
– increased survival
– decreased vasopressor requirements
• animal studies 
– significant hemodynamic benefit 
– improvement in immune cell responsiveness 
– reduced mortality 
• More studies are needed to clarify the role of HVHF
– hyperdynamic septic shock 
• with or without acute renal failure 
– sepsis and SIRS.
High Volume HemoFiltration and Sepsis
Cole L. Intensive Care Med 2001, 27:978‐986
Oudemans‐van Straaten HM, Intensive Care Med 1999, 25:814‐821.
Honore PM Int J Artif Organs. 2004, 27(12):1077‐82.
• No consistent statistically significant difference in 
survival 
– Vinsonneauet al. Lancet 2006; 368: 379-85
• Both methods are complementary
• IHD  
– Faster Potassium elimination
– Faster Drug/ Toxin elimination
– Better for overdose
• CRRT 
– Regulation of higher calories requirements 
– Hemodynamically unstable patients
– Precise adaptable volume control
CRRT vs Hemodialysis
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1104
• All criteria for initiating CRRT are absent
• Urine output averages 1ml/kg/hr over a 24hr period
• Fluid balance can be kept approximately neutral with 
current urine output
• There is a complication related to CRRT
• When criteria are fulfilled begin a 12‐24 hour period 
without CRRT
• Reevaluate for indications for CRRT
• CRRT should be initiated early and ceased late
BellomoR, RoncoC. Intensive Care Med 1999;25:781-9
Cessation of CRRT 
In Continuous Veno Venous Hemodiafiltration
(CVVHDF) solutes are cleared by the following 
processes:
A. ultrafiltration
B. convection
C. diffusion
D. adsorbtion
E. A,B and C
F. B and C
Board Question 
1
Copyright Harvard Medical School, 2010. All Rights Reserved.
1105
In Continuous Veno Venous Hemodiafiltration
(CVVHDF) solutes are cleared by the following 
processes:
A. ultrafiltration
B. convection
C. diffusion
D. adsorbtion
E. A,B and C
F. B and C
Board Question 
1
Advantages of CVVH over Hemodialysis include (T/F)
A. Precise Adaptable Volume Control
B. Enhanced Middle Molecule clearance
C. Higher Filter Permeability
D. Enhanced Survival
E. Higher clearance per unit time
F. A, B and C
Board Question 
2
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1106
Advantages of CVVH over Hemodialysis include (T/F)
A. Precise Adaptable Volume Control T
B. Enhanced Middle Molecule clearance T
C. Higher Filter Permeability T
D. Enhanced Survival F
E. Higher clearance per unit time F
Board Question 
2
Sources
• Mehta R, Supportive Therapies Atlas of Diseases of the Kidney Chapter 19 Eds T Berl and 
JV Bonventre. Blackwell Science 1999
• Luciano A. Pedrini J Nephrol 2003; 16 (suppl 7): S57‐S63
• Chelamcharla M, Semin Nephrol. 2005;25(2):81‐9
• Johnson RJ, Feehally J, Comprehensive Clinical Nephrology  2nd Ed
• Venkataraman R. Critical Care 2003, 7:139‐145
• Cole L, Crit Care Med. 2002 Jan;30(1):100‐6. 
• Luyckx VA Semin Dial. 2004;17(1):30‐6.
• Humes HD. Kidney Int. 2004;66(4):1578‐88.
• Cole L. Intensive Care Med 2001, 27:978‐986
• Bugge JF.Acta Anaesthesiol Scand. 2001;45(8):929‐34
• Oudemans‐van Straaten HM, Intensive Care Med 1999, 25:814‐821.
• Honore PM Int J Artif Organs. 2004 Dec;27(12):1077‐82.
• Bellomo R. Blood Purif. 2002;20(3):296‐303.   
• Berger MM. Am J Clin Nutr. 2004;80(2):410‐6.
• Klein CJJPEN J Parenter Enteral Nutr. 2002;26(2):77‐92  
• Bellomo R. Ren Fail. 1997;19(1):111‐20.
• Scheinkestel CD Nutrition. 2003;19(11‐12):909‐16.  
• Scheinkestel CD. Nutrition. 2003;19(9):733‐40.
• Uchino S,Intensive Care Med. 2003 Apr;29(4):575‐8.
• Mulder J, Int J Artif Organs. 2003;26(10):906‐12., 
• Splendiani G. Artif Organs. 2000 Apr;24(4):305‐8
• van Bommel EF. Am J Nephrol. 2000;20(5):408‐11.
• Agostini M. Hum Exp Toxicol. 2003;22(3):165‐7.
• Kopcke J. Anaesthesiol Reanim. 1996;21(6):159‐62.
• Dicarlo JV. ALL‐NET Pediatric Critical Care Textbook 
Copyright Harvard Medical School, 2010. All Rights Reserved.
1107
Disclosures
• I do not accept honorarium nor do consulting work
for the pharmaceutical or device industries.
• I do not serve as a member of a speaking bureau
for pharmaceutical or device companies.
• 2009 Awarded competitive Research Grant
support from NxStageMedical
Copyright Harvard Medical School, 2010. All Rights Reserved.
1108
AKI Syndromes
Sushrut S. Waikar, MD, MPH
Assistant Professor, HMS
Associate Physician, Renal Division,
Brigham and Women’s Hospital
Disclosures
Investigator-initiated grant support from
Pfizer, Genzyme, Satellite HealthCare,
NxStage; DSMB member for Takeda
Copyright Harvard Medical School, 2010. All Rights Reserved.
1109
Case 1
A 65 year old man with known alcohol dependence
was found unconscious on his living room floor.
He was brought to the emergency department
where he was intubated for airway protection.
Vitals signs following intubation: T 98.3 BP
86/54 HR 116 O2 sat 99% on FI02 0.40
140 108 67 Calcium 7.6 Phos 8.5
6.3 15 4.6 Uric acid 4.3
Case 1 cont.
The urine was noted to be red. After
centrifugation, the sample remained red.
Centrifuged plasma sample was yellow.
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1110
Case 1 question
What is the most likely cause of his acute
kidney injury?
A. Hemolysis
B. Rhabdomyolysis
C. Acute intermittent porphyria
D. Paroxysmal nocturnal hemoglobinuria
Case 1 question
What is the most likely cause of his acute
kidney injury?
A. Hemolysis
B. Rhabdomyolysis
C. Acute intermittent porphyria
D. Paroxysmal nocturnal hemoglobinuria
Urine supernatant CLEAR in hematuria, but remains RED in rhabdomyolysis
and hemoglobinuria. Plasma supernatant may remain RED in hemoglobinuria
due ot hemoglobin’s large size compared to myoglobin (which is filtered and
cleared)
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1111
Rhabdomyolysis
• Dissolution of skeletal muscle leading to leakage of
contents into circulation
– Creatine kinase, aldolase, LDH, ALT, AST
• AKI in approximately 50% of cases
1
• Causes
– Crush syndrome, limb compression
– Strenuous exercise, seizures
– Disorders of glycolysis, glycogenolysis, lipid metabolism
– Infections (Influenza A and B), coxsackie-virus, HIV, EBV, Strep,
Staph
– Heat stroke, malignant hyperthermia, malignant neuroleptic
syndrome
– Hypokalemia, hypophosphatemia, hypocalcemia, DKA
– Drugs: fibrates, statins, alcohol, heroin, cocaine
1
Melli et al. Medicine 2005
Rhabdomyolysis pathogenesis
• Myoglobin
– 17.8 kDa protein freely filtered by glomerulus
– Appears in urine when renal threshold of 0.5 to 1.5
mg/dL is exceeded, usually when serum levels >100
mg/dL
• Intrarenal vasoconstriction
• Direct tubular injury
– Reactive oxygen species, free radicals
• Tubular obstruction
– Precipitates in tubules with Tamm-Horsfall protein,
especially in acidic urine
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1112
Rhabdomyolysis Dx
• Weak correlation between CK and AKI
– Rare to have AKI with admission CK <15,000
• Unless concomitant volume depletion, sepsis, etc
• Heme positive urine with absent RBCs
• Myoglobin
– True pathogenic factor but early peak, rapid
metabolism: low sensitivity for diagnosis
• Low FeNa is common!
– May reflect primacy of vasoconstriction and tubular
occlusion rather than tubular necrosis
Rhabdomyolysis Rx
• Early and aggressive volume repletion
• Lack of trials comparing different fluids
– Sodium bicarbonate
• Minimizes precipitation of myoglobin:TH protein
• Inhibits redox cycling of myoglobin, lipid peroxidation
• May minimize vasoconstriction
• BUT may worsen hypocalcemia
– Normal saline
• Disadvantage: hyperchloremic metabolic acidosis
• Diuretics (only after volume repletion)
– Mannitol: antioxidant, may relieve tubular obstruction, may help
improve hypovolemia due to osmotic gradient with injured muscle
cells
– Loop diuretics: not well studied, frequently used
Copyright Harvard Medical School, 2010. All Rights Reserved.
1113
Rhabdomyolysis treatment
guidelines
• Normal saline 400 ml/h
– If urine pH <6.5, alternate each NS liter with 1L of D5W / ½ NS plus 100
mmol bicarb
• Target urine output ~200 ml/h
• Frequent K checks
• Correct hypocalcemia only if tetany, seizures, or if severe
hyperkalemia occurs
• Consider mannitol up to 200 g/d, cumulative 800 g
– Discontinue if diuresis not established
– Check plasma osms and gap if used, stop >55 mosm/kg
• Hyperkalemia management (usual)
• Loop diuretics
• Hemodialyis for rising hyperkalemia, anuria, volume overload
Adapted from Bosch NEJ M 2009
Case 2
A 48 year old previously health man
presented to the ED complaining of
fatigue, anorexia, and weight loss. He took
no prescription or over the counter
medications. On exam, BP 168/94 HR 98
RR 16 O2 sat 95% RA
128 99 271 Calcium 7.1 Phos 5.3
8.4 7 24.6 Uric acid 4.3
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1114
Case 2 (cont.)
Moderate bilateral hydronephrosis, hydroureter, and
markedly distended bladder
Obstructive uropathy
Patient was admitted, underwent hemodialysis, and
received bilateral nephrostomy tubes and a suprapubic
catheter. Foley catheter placement was impossible due
to urethral stricture.
Urine output was brisk following relief of obstruction. HD
stopped after a single session.
Two weeks after presentation urine output was 6 liters per
day, reflective of severe postobstructive polyuria.
Discharged home with PICC for 2L normal saline/d plus
KCl, sodium bicarbonate supplementation. Required IVF
for 8 weeks.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1115
Case 2 question
Metabolic complications during post-
obstructive polyuria include impairment in:
A. Urinary concentrating ability
B. Urinary diluting ability
C. Sodium reabsorption
D. Urinary acidification
Post-renal
Stones, blood
clots, external
compression,
tumor, RP
fibrosis
BPH, blood
clots, cancer
Strictures
FOLEY
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1116
Obstructive uropathy
• Early phase
– Elevated intratubular pressure increases P
BS
, thereby reducing single
nephron GFR
– Compensatory hyperemia (afferent vasodilation) that serves to increase
GFR
• Later phase
– Vasoconstriction, reduced renal perfusion
– Reduction in Kf (ultrafiltration coefficient)
• Recovery after obstruction
– Dependent on duration, severity (partial/complete)
– Complete obstruction: relatively complete recovery even after 1 week;
little or no recovery after 12wks
1
• Tubular dysfunction during recovery
• Progressive interstitial fibrosis following severe obstruction
Better et al. Am J Med 1973
Case 3
• 65 yr old man admitted for atrial fibrillation with
rapid ventricular response, hospital course
complicated by catheter associated urosepsis
• Treated with ampicillin-sulbactam
• Seven days into course of antibiotics:
– diffuse erythematous rash across chest, arms, legs
– Rise in serum creatinine: 0.9 1.7 on day 7
– Progressive rise over next 5 days to BUN 96,
creatinine 6.8
Copyright Harvard Medical School, 2010. All Rights Reserved.
1117
Case 3 (cont.)
• PMHx: A fib, HTN, T2DM (oral
hypoglycemics), normal baseline kidney
function
• Meds: ASA, metoprolol, lisinopril,
ampicillin-sulbactam, glipizide, intermittent
dopamine during ICU stay for SBP’s ~ 90
• Allergies: none known
Case 3 (cont.)
• Exam:
– T 101.5, BP 88/50, HR 110, RR 22, O
2
93% 2L
– Notable findings:
•Diffuse erythematous rash over chest, arms, back
•Bilateral crackles on lung auscultation
•Tachycardic, no pericardial friction rub, J VP ~12
•2+dependent edema
• Labs: WBC 19, 12% eosinophils; BUN 96
and creatinine 6.8
Copyright Harvard Medical School, 2010. All Rights Reserved.
1118
Case 3 (cont.)
• Requests the following “biomarkers” to formulate
a differential diagnosis of acute kidney injury
– Fractional excretion of sodium
– Urinalysis and sediment
– Renal ultrasound
– Urine eosinophils
Case 3 (cont.)
• Requests the following “biomarkers” to formulate
a differential diagnosis of acute kidney injury
– Fractional excretion of sodium
– Urinalysis and sediment
– Renal ultrasound
– Urine eosinophils
1.6%
Positive: 10%
No hydro
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1119
Presumptive Dx, Rx
• Allergic interstitial nephritis due to
ampicillin
• Treatment recommended:
methylprednisolone 1gm IV x 1, then
prednisone 60mg per day
Presumptive Dx, Rx
• Allergic interstitial nephritis due to
ampicillin
• Treatment recommended:
methylprednisolone 1gm IV x 1, then
prednisone 60mg per day
• Creatinine continues to rise after 1 week of
steroids; dialysis initiated
• Kidney biopsy performed
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1120
Kidney biopsy
•Acute tubular necrosis
•No evidence of acute/chronic tubulointerstitial nephritis
Case summary
• Late recognition of acute kidney injury
• Reasonable interpretation of biomarkers
suggesting allergic interstitial nephritis
• No response to aggressive treatment for
presumed diagnosis; gold standard
diagnosis obtained (kidney biopsy)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1121
Acute interstitial nephritis
“Acute interstitial nephritis is found in the infectious
diseases of children, particularly in diptheria and scarlet
fever, but may be met with in other infectious diseases”
Acute interstitial nephritis
• Common cause of unexplained AKI
– Single series of 109 patients: 27% with AIN
1
• Drug related in >70%
– NSAIDs including COX-2 inhibitors
– Penicillins and cephalosporins
– Rifampin
– TMP-SMX, other sulfonamides
– Ciprofloxacin
– Cimetidine
– Allopurinol
– Proton pump inhibitors
– 5-aminosalicylates
1
Farrington et al. QJ Med 1989
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1122
Acute interstitial nephritis
• Infections
– Pneumonia with AIN: legionella
– Multisystem dysfunction, hemorrhage, confjunctival
suffusion: leptospirosis
– Cytomegalovirus
– Streptococcus
• Auto-immune disorders
– SLE
– SJ ogren’s
– TINU (tubulointerstitial nephritis +uveitis) syndrome
Acute interstitial nephritis
• Timing of onset is variable
– 3 to 5 days after second exposure, several weeks with first
exposure to drug
– 1 day following rifampin exposure
1
• Classic triad: fever, rash, eosinophilia
– Seen in only 10%
• Can see:
– WBCs, RBCs, WBC casts; rarely RBC casts
– Subnephrotic proteinuria
– Fanconi’s syndrome (glucosuria, aminoaciduria, phosphate
wasting), Type 2 RTA
• Gallium scan: conflicting reports regarding sens/spec
• Kidney biopsy: interstitial edema, infiltrate with T cells,
monocytes; also eosinophils, plasma cells, neutrophils
1
Ten et al. Mayo Clin Proc 1988
Copyright Harvard Medical School, 2010. All Rights Reserved.
1123
Acute interstitial nephritis
• Treatment approach
– Careful review of medication list, OTCs
– Discontinuation of offending agent
– +/- steroids
•No definitive study has ever been (perhaps never
will be) performed
•Some suggestion that early steroid therapy speeds
recovery
– Largest study to date:
1
retrospective, N =61 only 9 of
whom were not treated with steroids
1
Gonzalez et al. Kidney Int 2008
Steroids for AIN?
Delay (days) in steroid therapy
F
i
n
a
l

S
C
r
Gonzalez et al. Kidney Int 2008
PRO CON
Clarkson et al. NDT 2004
Months
F
i
n
a
l

S
C
r
Copyright Harvard Medical School, 2010. All Rights Reserved.
1124
Case 4
47 year old woman previously healthy, on no
medications developed recurrent uveitis
starting 6 months prior to a rise in SCr.
Both episodes of uveitis were treated with
topical steroids and improved rapidly.
SCr was 0.9 mg/dL in February and
increased to 2.5 mg/dL in November,
prompting nephrology consultation
Case 4 (cont.)
Exam: BP 155/93 HR 82 Weight 100 kg
HEENT: mild conjunctivitis bilaterally
Lungs: clear
CV: RRR nl s1 s2 no rub, no J VD
Abd: obese, soft, ND, NT
Ext: no pretibial edema
Skin: no rashes on trunk, legs, or arms
J oints: no active tenosynovitis or arthritis
Back: no CVAT
143
3.5
104 14
23 2.5
Ca 9.8 Phos 2.2 glucose 88
Urine pr:cr 0.8 u/a: +glucose +LE - nit
Urine sediment: WBCs no casts
Copyright Harvard Medical School, 2010. All Rights Reserved.
1125
Case 4 (cont.)
ANCA neg
Anti GBM neg
C3 C4 normal
SPEP / UPEP negative
Negative ANA, dsDNA, anti-Ro, anti-La
Renal ultrasound: normal size, echogenicity
CXR: no abnormalities
Case 4 question
The most likely diagnosis is:
A. Sarcoidosis
B. Bechet’s syndrome
C. Lupus nephritis
D. TINU syndrome
E. Sjogren’s disease
F. Wegener’s granulomatosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1126
Case 4 question
The most likely diagnosis is:
A. Sarcoidosis
B. Bechet’s syndrome
C. Lupus nephritis
D. TINU syndrome
E. Sjogren’s disease
F. Wegener’s granulomatosis
TINU syndrome
• Tubulointerstitial nephritis and uveitis: first described in
1975
• In addition to eye and kidney, may have:
– Fever, weight loss, fatigue, malaise, anorexia, abdominal pain,
arthralgias, headache, polyuria
• Uveitis: bilateral, usually anterior chamber, can precede
or follow nephritis
• Females >males; younger age predominance
• Treatment: steroids for severe cases. Many reports of
spontaneous resolution
– Uveitis can be chronic and relapsing whereas ATIN usually self-
limited
• Pathogenesis unknown: ? Common antigen in uveal and
tubular cells
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1127
Case 4 followup
0
0.5
1
1.5
2
2.5
3
0 14 56 63 77 84 105 133 203 259
Days from diagnosi s
S
C
r

(
m
g
/
d
L
)
Prednisone 60mg / day
…REFUSED
Case 5
31 year old woman with morbid obesity, bipolar disease on
chronic lithium therapy was brought to an outside
hospital with altered mental status and respiratory
failure. Her initial presentation was notable for tremors,
confusion, hypoxemic and hypercarbi respiratory failure
requiring intubation, and AKI. SCr was 2.5 mg/dL; lithium
level was 3.9 meq/L.
She was intubated and underwent hemodialysis, after
which lithium levels fell to below 1 meq/L. SCr recovered
to baseline (0.6 mg/dL). A 2 week ICU course was
notable for difficulty in weaning from mechanical
ventilation, catheter associated bacteremia with
vancomycin-sensitive enterococcus and persistent
fevers to 104. She was transferred to BWH for continued
care and the availability of a CT scan with adequate
capacity for her weight of ~500lbs.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1128
Case 5 (cont.)
She underwent contrast-enhanced CT of the
chest, abdomen, and pelvis for continued fevers
despite antibiotic therapy for enterococcal
bacteremia.
0
1
2
3
4
1 2 3 4 5 6 7 8
Day
S
C
r

(
m
g
/
d
L
)
CT +contrast
Case 5 (cont)
Relevant to her acute kidney injury:
• Meds on transfer: cefepime, diflucan, linezolid,
vancomycin
• Exam
– BP 100/60 (no pressors) HR 112 Temp 104, CVP 12 after 8+
liters volume in 72h
– Urine output 10 ml/hr
– Coarse breath sounds, tachycardic without rub, obese belly, ?
edema, no rashes, small decubitus ulcer on back
• Labs
– Na 140, K 4.5, Cl 108, Bicarb 16, BUN 49, SCr 3.3
– Ca 8.1, Ph 4.3, LFTs normal, CPK 370
– WBC 4.5, Hgb 7.7, Plt 86
– Vancomycin 58
– UNa <assay, UCr 350, Uosms 290, +++muddy brown casts
• CT imaging: no hydronephrosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1129
Case 5 (cont)
Relevant to her acute kidney injury:
• Meds on transfer: cefepime, diflucan, linezolid,
vancomycin
• Exam
– BP 100/60(no pressors) HR 112 Temp 104, CVP 12 after 8+
liters volume in 72h
– Urine output 10 ml/hr
– Coarse breath sounds, tachycardic without rub, obese belly, ?
edema, no rashes, small decubitus ulcer on back
• Labs
– Na 140, K 4.5, Cl 108, Bicarb 16, BUN 49, SCr 3.3
– Ca 8.1, Ph 4.3, LFTs normal, CPK 370
– WBC 4.5, Hgb 7.7, Plt 86
– Vancomycin 58
– UNa <assay, UCr 350, Uosms 290, +++muddy brown casts
• CT imaging: no hydronephrosis
Case 5: our formulation
Differential diagnosis
– Contrast nephropathy
– Sepsis +AKI
– TTP-HUS
– Vancomycin
nephrotoxicity
– Allergic interstitial
nephritis (cefepime)
– Abdominal
compartment
syndrome
Management issues
– Dialysis?
– Diuretics?
– Fluids?
Copyright Harvard Medical School, 2010. All Rights Reserved.
1130
Case 5 – teaching points
• Low FeNa = pre-renal azotemia (only)
• Vancomycin’s nephrotoxicity?
• Role of diuretics in management of oliguria
FeNa
• Percentage of filtered sodium that is
excreted
Copyright Harvard Medical School, 2010. All Rights Reserved.
1131
FeNa
• Percentage of filtered sodium that is
excreted
•What is your FeNa?
FeNa
• Percentage of filtered sodium that is
excreted
•What is your FeNa?
– Depends on sodium intake, GFR
Copyright Harvard Medical School, 2010. All Rights Reserved.
1132
FeNa
• Percentage of filtered sodium that is
excreted
•What is your FeNa?
– Depends on sodium intake, GFR
– Intake = 150 meq/d = Excreted
– Filtered = 140 meq/L * GFR (180L/d) = 25,200 meq
FeNa
• Percentage of filtered sodium that is
excreted
•What is your FeNa?
– Depends on sodium intake, GFR
– Intake = 150 meq/d = Excreted
– Filtered = 140 meq/L * GFR (180L/d) = 25,200 meq
•Ratio = 0.6%... you’re pre-renal!
Copyright Harvard Medical School, 2010. All Rights Reserved.
1133
What the FeNa tries to answer
• If your urine output is LOW, is it because:
– You’re dry as a bone, holding on to salt and
water?
OR
– Your tubules are dead, clogged up, low GFR:
cannot reabsorb sodium even if you wanted
to?
• It should not be used indiscriminately
• It should not alone guide volume management
• Can be helpful in: cardiorenal, hepatorenal
FeNa -- data
• “Urinary Diagnostic Indices in ARF”
Miller et al., Ann Int Med 1978
Copyright Harvard Medical School, 2010. All Rights Reserved.
1134
FeNa -- data
• “Urinary Diagnostic Indices in ARF”
Miller et al., Ann Int Med 1978
Pre-renal Oliguric ATN
U
osm
518 369
U
Na
18 68
FeNa 0.4% 7.0%
FeNa -- data
• “Urinary Diagnostic Indices in ARF”
Miller et al., Ann Int Med 1978
Pre-renal Oliguric ATN Acute GN
U
osm
518 369 385
U
Na
18 68 22
FeNa 0.4% 7.0% 0.6%
Copyright Harvard Medical School, 2010. All Rights Reserved.
1135
FeNa -- exceptions
• Low FeNa frequently seen in
– Early sepsis (“ATN”)
– Rhabdomyolysis (“ATN”)
– Contrast nephropathy (“ATN”)
– Urinary tract obstruction
• High FeNa despite being pre-renal
– Diuretic use (Fe
urea
… one study)
– Chronic kidney disease (=excreted/filtered)
Case 5 – teaching points
• Low FeNa = pre-renal azotemia (only)
• Role of diuretics in management of
oliguric AKI
Copyright Harvard Medical School, 2010. All Rights Reserved.
1136
Case 5 – teaching points
• Low FeNa = pre-renal azotemia (only)
• Role of diuretics in management of
oliguric AKI
Furosemide in oliguric AKI
• Pathophysiological rationale
– Sodium reabsorption =major energy-requiring
activitiy of the kidney
– Inhibition of Na/K/Cl pump in medullary thick
ascending limb
– Decrease renal tubular cell oxygen demand
• Popular!
– 70% of ICU patients with AKI given a diuretic at
enrollment (Uchino Crit Care Med 2004)
• Clinical equipoise with respect to efficacy
– Observational data suggest harm (Mehta JAMA 2002)
– Randomized controlled trials fail to show mortality
benefit (Cantarovich AJKD 2004)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1137
Ongoing RCT
Furosemide drip (titrated to urine output) vs. placebo
Target enrollment: 216 ICU pts with early SIRS, early AKI
Primary endpoint: progression to more severe AKI
(doubling of SCr)
Disclosures
Investigator-initiated grant support from
Pfizer, Genzyme, Satellite HealthCare,
NxStage; DSMB member for Takeda
Copyright Harvard Medical School, 2010. All Rights Reserved.
1138
AKI and Cancer
Benjamin D. Humphreys MD, PhD
Renal Division Renal Division
Brigham and Women’s Hospital /
Harvard Medical School
Disclosures
• None relevant to AKI and cancer • None relevant to AKI and cancer
Copyright Harvard Medical School, 2010. All Rights Reserved.
1139
Case 1: Myeloma
•50 yo previously healthy woman developed
fatigue and weight loss. Rejected for life
insurance due to new finding of S Cr 3.2
mg/dL.
•Delayed follow up 6 mo later, Cr 5.3, Hct 28.8,
free light chain 0.7 g/dL free kappa light chain.
Urine Pr:Cr =8 g/g, fine granular casts
•Renal biopsy
Micrographs courtesy of Helmut Rennke, MD
Copyright Harvard Medical School, 2010. All Rights Reserved.
1140
Lambda Kappa
Copyright Harvard Medical School, 2010. All Rights Reserved.
1141
Light Chain Deposition Disease
• Aka Monoclonal Ig Deposition Disease
• Monoclonal Ig deposition in glomeruli, tubular BM
and arteries (unlike Amyloid, also Congo Red
negative)
• Glomeruli: nodular glomerulosclerosis, nephrotic
proteinuria
• Tubules: BM thickening, dramatic interstitial
fibrosis
• Arterioles: PAS positive deposits, arteriolar
sclerosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1142
Multiple Myeloma
Kyle et al., 2003
1027 pts
1985-1998
0.2
0.4
1.0
F
r
a
c
t
i
o
n

A
l
i
v
e
2 4 6 8 10
Time (mo)
0.6
0.8
12 0
Survival after diagnosis
MGUS
No MGUS
Renal Involvement in MM
• 50% of pts have increased Cr at diagnosis
• 9% will require dialysis at some point
• 5,739 patients developed ESRD from MM in 2007,
representing 48% of patients with cancer-related
ESRD.
• 20% will develop progressive renal failure during course
of disease
• Patients with renal failure have poorer prognosis, and
are frequently excluded from aggressive or high dose
chemotherapy protocols due to expected toxicities
USRDS, 2007. Goldschmidt, H. et al. Nephrol. Dial. Transplant. 2000 15:301-304;
Copyright Harvard Medical School, 2010. All Rights Reserved.
1143
Bence J ones Protein
J ones, H. On a new substance occurring in the urine of a patient with mollities ossium. Phil Trans r Soc London
1848;138:55.
Saturday, November 1, 1845
Dear Dr. J ones,
This tube contains urine of a very high specific gravity. When boiled, it
becomes highly opake. On the addition of nitric acid it effervesces, assumes
a reddish hue, and becomes quite clear, but as it cools, assumes the
consistence and appearance which you see. Heat re-liquefies it. What is it?
Henry Bence J ones
AKI in Multiple Myeloma
• Cast Nephropathy
• Amyloidosis (AL)
• LCDD
• Interstitial nephritis
• Hypercalcemic AKI
• Urate nephropathy
• Plasma cell infiltration
• Hyperviscosity syndrome
• Other paraprotein diseases:
• Fanconi disease
Goldschmidt, H. et al. Nephrol. Dial. Transplant. 2000
15:301-304; doi:10.1093/ndt/15.3.301
↑Light
chains
↑Ca2+
Tubular
Injury
Casts
Dehydration
THP
↓GFR
Plasma Cell
Copyright Harvard Medical School, 2010. All Rights Reserved.
1144
Cast Nephropathy: Pheresis or Not?
• Standard therapy: Correct volume depletion, treat hypercalcemia,
discontinue NSAIDS, treat infection, etc…
• ??Renal Biopsy - usually not in acute setting
• Treat Myeloma: high dose Dex +/- melphalan, thalidomide
• ?Plasma exchange,
• Conflicting data
• How acute is renal insult?
• What was baseline renal function?
• What is the concentration of the circulating M-component?
• Treatment of choice in hyperviscosity syndromes
• Dialysis
Renal Failure in Hematopoietic
Stem Cell Transplantation
• In US in 2007, more HSCT were
performed (18,000) than renal transplants
(16,629)
• At least 5-15% of HCT recipients develop
ARF
• And 5-20% ultimately develop CKD
Copyright Harvard Medical School, 2010. All Rights Reserved.
1145
Organ Transplantation in US
0
2500
5000
7500
10000
12500
15000
17500
20000
25 60
750
2500
3700
18,000
Annual Numbers of
Blood and Marrow Transplantations,
1970-2006
- Worldwide -
N
u
m
b
e
r

o
f

T
r
a
n
s
p
l
a
n
t
s
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
40,000
1970 1975 1980 1985 1990 1995 2000 2005
Year
Allogeneic
Autologous
Source: IBMTR
Copyright Harvard Medical School, 2010. All Rights Reserved.
1146
“Typical HSCT”
W
B
C
Conditioning Engraftment
Time (days)
HCT infusion
GCSF
Neutropenia, thrombocytopenia
HSCT Basics
Myeloablative HSCT
Goal is to eradicate disease completely
This also ablates the marrow, requiring HCT rescue
Non-myeloablative HSCT
Less aggressive preparative regimens, does not ablate
marrow, allows mixed chimerism.
Uses the “graft vs. tumor effect”for disease eradication
Used for older patients, those with co-morbidities, or those
with indolent diseases such as CLL
Copyright Harvard Medical School, 2010. All Rights Reserved.
1147
HSCT Associated AKI and Mortality
Grade 1 ARF: >1.25 fold but <2-fold rise in serum Cr
Grade 2 ARF >2-fold rise in serum Cr but no HD
Grade 3 ARF =grade 2 parameters and requiring dialysis.
Parikh, CR Kid. Int, 2005
HSCT Associated AKI, Renal Replacement
and Mortality
HSCT Type
Mod-
severe
AKI
ARF
requiring
RRT
Mortality if
RRT
Myeloablative
Allogeneic 30-60% 20-30% 80%
Autologous 15-20% 5-10% 80%
Non-
myeloablative 40% 3-5% >70%
Copyright Harvard Medical School, 2010. All Rights Reserved.
1148
AKI after HSCT: Timeline
Adapted from Zager 1994
0
10
20
30
40
50
60
Time after HCT (days)
Tumor lysis
syndrome,
marrow
infusion
toxicity
TMA, CNI
toxicity
HRS/VOD,
ATN
AKI (no RRT)
AKI (RRT)
P
e
r
c
e
n
t

o
f

p
a
t
i
e
n
t
s
d
e
v
e
l
o
p
i
n
g
r
e
n
a
l

c
o
m
p
l
i
c
a
t
i
o
n

a
f
t
e
r

H
C
T
0 7 14 21 28 1 yr
Early AKI
•Hypovolemia / hypotension
(diarrhea, third space losses, sepsis)
•Functional pre-renal syndromes
•HRS (see below)
•CyA / tacrolimus, amphotericin
Copyright Harvard Medical School, 2010. All Rights Reserved.
1149
Case 2: VOD
•45 yo M undergoes myeloablative allo-BMT
for AML
•Between days +3 to +7 he gains 8 Kg with
dependent edema
•Beginning on day +7 bilirubin rises to 2.1
mg/dL and rose daily thereafter; he becomes
jaundiced and has RUQ tenderness and
ascites. Liver U/S showed reversal of flow.
•Creatinine rose slowly starting day +8, FeNa
0.05% despite IV lasix and sediment was bland
HRS/VOD: Pathogenesis
• 90% of HRS is due to VOD (other causes
include viral or drug-induced hepatitis)
• Conditioning-related toxicity (Radio-chemoRx)
• Hepatic endothelial and sinusoidal damage
cause sinusoidal obstruction, portal HTN and
intrahepatic porto-systemic shunting
Copyright Harvard Medical School, 2010. All Rights Reserved.
1150
HRS/VOD: Diagnosis
• Weight gain (edema, ascites), painful
hepatomegaly and jaundice precede renal failure
• Liver U/S often shows reversal of flow in the
portal vein.
• BP is often low-normal, FeNa is very low and
sediment bland initially, +/- muddy brown granular
casts later.
• Timing is helpful in diagnosis - VOD onset occurs
in days +3 to +30.
• Concurrent sepsis syndrome is often trigger for
ARF
HRS/VOD: Treatment
• Supportive care - reversible
• Volume mgmt: very high daily fluid intake
• Paracentesis often required, lactulose for
encephalopathy
• Diuretics, keep Hb
>
11, avoid SPA
• Dialysis: 50% will require; HD vs. CRRT
• tPA, Heparin, LMWH have been tried with
little success. Defibrotide appears very
promising.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1151
Late CKD: CNI toxicity
• Most HCT recipients are not on CNI long
term - discontinued after 6 months.
• A subset develop chronic GVHD and receive
longtermsteroids and CNI
• At risk for chronic CNI toxicity
Case 3: TMA
•45 yo M underwent myeloablative allo-BMT 10
months ago for CML
•Complicated by stage 4 hepatic GVHD
•Recently developed anemia, worsening HTN,
Cr ↑ from 1.6 to 2.8 mg/dL
•Sediment: hyaline casts, 500 mg proteinuria/
24 hrs
•1-2 schistocytes, occ. low haptoglobin, plt 130
(down from 320), LDH 550
Copyright Harvard Medical School, 2010. All Rights Reserved.
1152
Late AKI/CKD: TMA
•Also called “BMT Nephropathy,”
“radiation nephropathy”and
resembles HUS-TTP
•Hypertension, hypervolemia
common
•Disproportionate anemia, often
evidence of mild microangiopathic
hemolytic anemia (↑LDH, ↓ Hapto,
schistos, ↓Plt)
Putative pathogenesis of TMA
Chemotherapy
Radiation
Kidney
+
Renal endothelial damage and
inflammation
TMA syndrome
Loss of EC thromboresistance
Platelet and fibrin deposition
Microvascular obstruction
Microangiopathic
hemolytic anemia
Hypertension
Renal
failure
Glomerular
ischemia
Genetic
factors? CNI?
Pro-inflammatory
cytokines?
GVHD
Infection
+ +
+
Renal
shielding
-
Pro coagulant
state?
+
Adapted from Humphreys, Soiffer and Magee, J ASN, 2005
Copyright Harvard Medical School, 2010. All Rights Reserved.
1153
TMA: Treatment
• Goal is to limit further damage
• Aggressive BP control <130/80
• ACEI likely provide additional benefits
(hyperkalemia common)
• Reduce/discontinue CNI if possible
• 40% will ultimately progress to ESRD
TMA: Treatment
• Plasma exchange of unclear benefit, not used
unless florid Sx (eg TTP)
• The Oklahoma TTP-HUS Registry has had 23
patients with HCT-related TTP-HUS
12
• None of these had severe ADAMTS13 activity
deficiency
• None of them responded to plasma exchange
Copyright Harvard Medical School, 2010. All Rights Reserved.
1154
Case 4
•59 yo F underwent non-myeloablative
allo-BMT for relapsed AML
•Complicated by self-limited oral and
ocular GVHD (stage I)
•At 1 year post-BMT, she received HiB,
DPT and Pneumovax vaccines per
protocol. Cr =0.8.
•Beginning 5 days later she developed
fatigue and swelling
•She presented 14 days later with
anasarca, ARF (Cr =3.4) and 3+
proteinuria
Sediment
Copyright Harvard Medical School, 2010. All Rights Reserved.
1155
Copyright Harvard Medical School, 2010. All Rights Reserved.
1156
Response to steroids
Secondary causes of minimal
change nephropathy
Drugs
Nonsteroidal anti-inflammatory drugs
Ampicilli n
Gold
Allergens
Hymenoptera stings
Food
Pollen
Poison ivy and poison oak
Immunization
Infections
Viral
Cancer
HodgkinÕs disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
1157
Nephrotic Syndrome after BMT:
How frequent?
• Series of 163 consecutive non-myeloablative
HSCTs*
• Found seven cases of nephrotic syndrome
• Of these, 4 underwent renal Bx and all
showed membranous nephropathy
• ?Role of earlier withdrawal of
immunosuppression, marrow chimerismin
increased susceptibility to NS?
*Srinivasan R, BalowJ E, Sabnis S, et al., (2005) Nephrotic syndrome: an under-recognised
immune-mediated complication of non-myeloablative allogeneic haematopoietic cell
transplantation. Br J Haematol 131:74-79
Urate Nephropathy/TLS
Risk factors
Poorly differentiated lymphomas (Burkitts)
Acute lymphoblastic leukemia
Timing
Usually associated with induction chemotherapy
Occasionally spontaneous
Diagnosis
AKI +
Hyperkalemia
Hyperphosphatemia
Hypocalcemia
Hyperuricemia
Often high LDH
Urine uric acid : creatinine ratio is useful. If greater than 1, urate
nephropathy likely. If less than 0.6, unlikely.
Rhomboid crystals on sediment (absence does not rule out)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1158
TLS: Pathophysiology
Purines
Xanthine
Uric acid
Tumor Cell lysis
Allopurinol
Urate oxidase
(Rasburicase IV)
Allantoin
Rapid cell
turnover
Chemoradiotherapy
Crystal
nephropathy
K
+
release PO
4
2-
release
Volume
expansion
Urinary
excretion
ARF
Adapted from Humphreys, Soiffer and Magee, J ASN, 2005
Urate Nephropathy/TLS
Treatment
Prevention through volume expansion and allopurinol
Alkalinizing urine - controversial, as alkaline pH
decreases urate crystalization but increases Calcium
phosphate crystalization.
Hemodialysis
- for severe TLS and life-threatening electrolyte
disturbances
- Intermittent HD followed by CRRT may be effective
to avoid rebound
Rasburicase
- Increasing use in USA
Copyright Harvard Medical School, 2010. All Rights Reserved.
1159
Rasburicase for Hyperuricemia
-120 -80 -40 0 40 80 120 160
0
10
20
30
Uric acid (mg/dL)
S Cr (mg/dL)
1
2
3
4
5
IVF
Hours post rasburicase
6 mg Rasburicase
Thrombotic Microangiopathy and
Chemotherapy: Gemcitabine
Humphreys…Magee, Cancer, 2004
Cumulative incidence: 0.31 %
Most patients with
mild MAHA, sub
nephrotic
proteinuria and
bland sediment
Copyright Harvard Medical School, 2010. All Rights Reserved.
1160
Thrombotic Microangiopathy: Biopsy
Findings
Humphreys…Magee, Cancer, 2004
Gemcitabine-TMA: Summary
More common than appreciated
HTN is an early predictor of patients at risk
Discontinuation of drug usually results in improvement
in renal disease
Plasmapheresis likely of no benefit
ACE/ARB are beneficial when tolerated (fibrinolytic
effects)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1161
Case 5
• A 41-year-old woman with no history of hypertension (BP
108/74mmHg) was started on sunitinib for GIST in 2002.
• In 2005 she developed hypertension (BP 140/98mmHg
worsened to154/102mmHg) and required three
antihypertensives. Her S. Cr. rose from 0.8 to 2.0 mg/dl
and she was noted to have proteinuria (1.8gm/gm).
• The washout period for sunitinib was increased to 4 weeks
(instead of the usual 2 weeks) followed by reduction in
dose to 37.5mg alternating with 25mg every other day.
Over the course of twenty-four weeks, BP improved to
108/72mmHg, urine protein to 0.4 gm/gm and S. Cr. to
0.9mg/dl.
Hypertension on Sutent
Azizi M et al. N Engl J Med 2008;358:95-97
Diastolic
B
P

a
t

H
o
m
e

(
m
m
H
g
)
Sunit. Sunit.
Systolic
Normotensive patients
180
60
120
0 5 10
Copyright Harvard Medical School, 2010. All Rights Reserved.
1162
Rapid Development of HTN by anti-VEGF
chemo
A B
Robinson…Humphreys CJ ASN, 2010
Hypertension induced by anti-VEGF
agents
Copyright Harvard Medical School, 2010. All Rights Reserved.
1163
Case 6
• YS, a 79-year-old type 2 diabetic and
hypertensive woman, was started on sunitinib for
metastatic GIST.
• She had no proteinuria and her S. Cr. was
1.2mg/dl. She subsequently developed nephrotic
range proteinuria and AKI to 2.4mg/dl, both of
which resolved after discontinuing sutent.
• Two years later she was rechallenged with
Sorafenib, a different anti-angiogenic
chemotherapy, and proteinuria and renal failure
recurred.
Proteinuria on anti-Angiogenic Therapies
0 25 50 75 100 125 150
0
2
4
6
8
10
12
Weeks since starting protocol
Sunitinib
Sorafenib
SBP>200
Retaspimycin, erlotinib
nilotinib
SBP>200
Fatal MI
Imatinib
Copyright Harvard Medical School, 2010. All Rights Reserved.
1164
Maharaj et al., Am J Path 2006
VEGF
LacZ
Podocytes strongly express VEGF
Glomerulus
Arteriole lumen is
Completely occluded
J ust as seen in HUS/TTP
Copyright Harvard Medical School, 2010. All Rights Reserved.
1165
Almost all capillary lumens are obliterated by reactive
endothelium
Glomerular basement membrane is thickened
Called ‘double contours’ reflecting new bsmt
Membrane secreted by injured endothelial cells
Thickened endothelial cell cytoplasm
with new rim of
Bsmt membrane that it is secreting
The capillary lumen is very narrowed
Copyright Harvard Medical School, 2010. All Rights Reserved.
1166
Reversible Renal TMA – If Diagnosed in Time
Managing anti-VEGF renal toxiciteis
Control BP, use ACE/ARB first, followed by diuretics
and CCB
Monitor urine protein and kidney function monthly
If sub nephrotic proteinuria, may continue therapy
with aggressive BP and ACE/ARB
If renal failure, nephrotic proteinuria or hypertensive
emergency occurs, need dose reduction, washout or
discontinuation (in consultation with oncology)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1167
Review Question 1
All of the following are possible causes of AKI related
to multiple myeloma EXCEPT:
A. Hypercalcemia
B. Postrenal obstruction due to retroperitoneal
lymphadenopathy
C. Direct plasma cell infiltration of the kidney
D. Intratubular obstruction from crystal formation
E. Light chain deposition disease
Review Question 1
All of the following are possible causes of AKI related
to multiple myeloma EXCEPT:
A. Hypercalcemia
B. Postrenal obstruction due to retroperitoneal
lymphadenopathy
C. Direct plasma cell infiltration of the kidney
D. Intratubular obstruction from crystal formation
E. Light chain deposition disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
1168
Review Question 2
All of the following renal diseases are associated with
bone marrow transplantation EXCEPT:
A. Membranous nephropathy in the setting of GVHD
B. Hepatorenal syndrome due to veno-occlusive
disease
C. Chronic TMA syndrome
D. Interstitial nephritis
E. Tumor lysis syndrome
Review Question 2
All of the following renal diseases are associated with
bone marrow transplantation EXCEPT:
A. Membranous nephropathy in the setting of GVHD
B. Hepatorenal syndrome due to veno-occlusive
disease
C. Chronic TMA syndrome
D. Interstitial nephritis
E. Tumor lysis syndrome
Copyright Harvard Medical School, 2010. All Rights Reserved.
1169
References
1. S.M. Korbet and M.M. Schwartz. Multiple Myeloma. J ASN, 2006 17:2533-45.
2. Magee C, Pascual M. The growing problem of chronic renal failure after transplantation of a nonrenal organ. N Engl J
Med. 2003 Sep 4;349(10):994-6.
2. Griffiths M et al. Cyclosporin nephrotoxicity in heart and lung transplant patients. QJ M. 1996 Oct;89(10):751-63.
3. Broekroelofs J et al. Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal
function loss. Transplantation. 2000 Apr 27;69(8):1624-8.
4. Ojo A et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med. 2003 Sep 4;349(10):931-40.
5. Angermann C et al. Reduction of cyclosporine after introduction of mycophenolate mofetil improves chronic renal
dysfunction in heart transplant recipients--the IMPROVED multi-centre study. Eur Heart J . 2004 Sep;25(18):1626-34.
6. Cohen E. Renal failure after bone-marrow transplantation. Lancet. 2001 J an 6;357(9249):6-7.
7. Zager R. Acute renal failure in the setting of bone marrow transplantation. Kidney Int. 1994 Nov;46(5):1443-58.
8: Humphreys B, Soiffer R, Magee C. Renal failure associated with cancer and its treatment: an update. J Am Soc Nephrol.
2005 J an;16(1):151-61.
9. Cohen E. Radiation nephropathy after bone marrow transplantation. Kidney Int. 2000 Aug;58(2):903-18.
10. Parikh C et al. Acute renal failure after nonmyeloablative hematopoietic cell transplantation. J Am Soc Nephrol. 2004
J ul;15(7):1868-76.
11. Cohen E. ESRD after bone marrow transplantation: poor survival compared to other causes of ESRD. Nephron. 1998
Aug;79(4):408-12.
12 George J N Et al The OklahomaTTP-HUS registry: A communityperspective of patients with clinicallydiagnosedTTP- 12. George J N. Et al. The Oklahoma TTP-HUS registry: A community perspective of patients with clinically diagnosed TTP-
HUS. Sem Hematol.2004 J an;41(1):60-67.
13. E.S. Robinson…B.D. Humphreys. Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular
Endothelial Growth Factor Receptor Inhibitor. CJASN, 5(3):477-83, 2010.
14. V. Eremina…S.E. Quaggin. VEGF Inhibition and Renal Thrombotic Microangiopathy. NEJ M, 13;358(11), 2008.
15. Patel TV, J .A. Morgan, and B.D. Humphreys. A Preeclampsia-like Syndrome Characterized by Reversible Hypertension
and Proteinuria Induced by Multifunctional Tyrosine Kinase Inhibitors. Journal of the National Cancer Institute.
100:282-84, 2008.
16. Humphreys BD, … C.M. Magee. Gemcitabine-Associated Thrombotic Microangiopathy. Cancer 100: 2664-70, 2004.
Disclosures
• None relevant to AKI and cancer • None relevant to AKI and cancer
Copyright Harvard Medical School, 2010. All Rights Reserved.
1170
Nephrology
Board Review-3
Bradley M. Denker, M.D.
Associate Professor of Medicine, Harvard
Medical School
Physician, Brigham and Women’s Hospital
Chief Nephrology Harvard Vanguard Medical Chief Nephrology, Harvard Vanguard Medical
Associates
BWH Renal Board Review 8/11/2010
Disclosures
Dr Denker has reported no financial Dr. Denker has reported no financial
relationships with commercial entities
producing, marketing, re-selling, or
distributing health care goods or services
consumed by, or used on, patients.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1171
Question 1
• 67 year old man - 1 week history of anorexia • 67 year old man - 1 week history of anorexia,
nausea, lassitude, and pedal edema.
• Longstanding hypertension, well controlled
with hydrochlorothiazide and amlodipine.
• Fenoprofen for osteoarthritis of the hip for the
past 3 months past 3 months.
Question 1 cont’d
• Physical examination
• BP 157/93mm, HR 72 bpm, Temp of , p , p
97.8
O
F. JVP 8 cm; normal cardiac and
pulmonary examinations; and 2+ pitting
edema.
• Urinalysis showed a specific gravity of
1.017, protein 4+, 1+ blood, and
negative for glucose Microscopic negative for glucose. Microscopic
examination of the sediment showed 2-4
erythrocytes and 15-20 leukocytes/hpf,
and occasional granular casts.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1172
• BUN 93 mg/dL; Cr 7.8 mg/dL; Na 137, K 4.4, Cl
Question 1 cont’d
95, C02 21, Ca 9.2, Phos 7.8, UA 7.7 mg/dL;
Alb 2.9 g/dL; HCT 29%. ANCA (-) Antinuclear
(+) 1:40 titer, anti-dsDNA antibody level 0.
• 24 h protein excretion 7.7 g.
• Renal ultrasound showed normal sized kidneys
bilaterally without obstruction. y
• Three months previously his serum creatinine
was 1.7 mg/dL.
• The nephrotic-range proteinuria and renal
Question 1
The nephrotic range proteinuria and renal
failure are most likely the result of:
– A). Lupus nephritis
– B). Multiple myeloma
– C.) Systemic small vessel vasculitis
– D.) Fenoprofen-induced nephrotic D.) Fenoprofen induced nephrotic
syndrome and interstitial nephritis
– E.) Renal vein thrombosis secondary to
membranous nephropathy
Copyright Harvard Medical School, 2010. All Rights Reserved.
1173
• The nephrotic-range proteinuria and renal
Quest i on 1
• The nephrotic-range proteinuria and renal
failure are most likely the result of:
– A). Lupus nephritis
– B). Multiple myeloma
– C.) Systemic small vessel vasculitis
– D.) Fenoprofen-induced nephrotic
syndrome and interstitial nephritis
– E.) Renal vein thrombosis secondary to
membranous nephropathy
Copyright Harvard Medical School, 2010. All Rights Reserved.
1174
NSAIDs and the Kidney NSAIDs and the Kidney
• Prerenal azotemia • Prerenal azotemia
• Ischemic acute tubular necrosis
• Allergic interstitial nephritis (AIN)
• AIN plus minimal change nephropathy
• ARF plus bilateral flank pain
• Sodium and water retention
• Hyperkalemia
• CRF and papillary necrosis
Whelton and Hamilton, J Clin Pharm 31: 588, 1991
Question 2
• A 27 year old man with the acquired immunodeficiency
syndrome (AIDS) is hospitalized with a cough, fever, and a
pulmonary infiltrate on CXR. Therapy is initiated with
trimethoprim-sulfamethoxazole. On admission, the serum
ti i i 1 6 /dL d bl d it 21 /dL creatinine is 1.6 mg/dL and blood urea nitrogen, 21 mg/dL;
On re-examination 3 days later, the serum creatinine is 2.2
mg/dL and blood urea nitrogen, 23 mg/dL. Results of
urinalysis both on admission and 3 days later are normal.
Urine output on day 3 is 1350 mL. The most likely cause of
the increased creatinine is:
– A.) AIDS glomerulopathy
– B.) Trimethoprim-mediated decrease in creatinine
secretion
– C.) Intratubular obstruction secondary to sulfonamide
– D.) AIN caused by trimethoprim-sulfamethoxazole therapy
– E.) Acute tubular necrosis secondary to sepsis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1175
Quest i on 2
• A 27 year old man with the acquired immunodeficiency
syndrome (AIDS) is hospitalized with a cough, fever, and a
pulmonary infiltrate on CXR. Therapy is initiated with
trimethoprim-sulfamethoxazole. On admission, the serum
creatinine is 1 6 mg/dL and blood urea nitrogen 21 mg/dL; creatinine is 1.6 mg/dL and blood urea nitrogen, 21 mg/dL;
On re-examination 3 days later, the serum creatinine is 2.2
mg/dL and blood urea nitrogen, 23 mg/dL. Results of
urinalysis both on admission and 3 days later are normal.
Urine output on day 3 is 1350 mL. The most likely cause of
the increased creatinine is:
– A.) AIDS glomerulopathy
B ) Trimethoprim mediated decrease in creatinine – B.) Trimethoprim-mediated decrease in creatinine
secretion
– C.) Intratubular obstruction secondary to sulfonamide
– D.) AIN caused by trimethoprim-sulfamethoxazole
therapy
– E.) Acute tubular necrosis secondary to sepsis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1176
Trimethoprim-Sulfamethoxazole Trimethoprim-Sulfamethoxazole
• Elevated creatinine, no change in BUN, no g
evidence of ARF: inhibition of tubular secretion
• Allergic interstitial nephritis with fever, rash, and
eosinophilia induced by sulfa moiety
• Hyperkalemia with salt wasting due to amiloride-
like action of trimethoprim p
• Rarely, crystallization of sulfamethoxazole
metabolite and renal stone formation
43 yo white male is referred for evaluation of abnormal
renal function. The patient has fatigue, dry skin, and the
absence of sweating even in hot weather. He has severe
burning pain in the palm and soles during episodes of fever
Question 3
burning pain in the palm and soles during episodes of fever.
Medical history is otherwise neg. The patient’s mother has
skin lesions on lower trunk. Two male first cousins have
renal transplants for ESRD.
Exam-BP-130/90, P-76, Resp-16, Afebrile. Thumbnails are
normal There are many small dark purple-red papules on normal. There are many small, dark purple red papules on
the lower abdomen, genital area, hips and upper thighs
Labs: Bun-29, creat-1.9, CrCl-45cc/min with 1.0gms/24h
protein.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1177
Which of the following EM pictures would
be most likely on renal biopsy of this patient?
A
B C
Which of the following EM pictures would
be most likely on renal biopsy of this patient?
A-Amyloid
B-Fabrys C-Thin BM
Copyright Harvard Medical School, 2010. All Rights Reserved.
1178
This patient has Fabry’s disease and these are myeloid
bodies in the glomerular visceral epithelial cells.
Fabry’s Disease
X-linked deficiency of α-galactosidase A (1:40,000)
Substrate accumulates in endothelial, periendothelial
and smooth muscle cells of vascular system, renal
epithelial cell, myocardial cells, dorsal root ganglia and
cells of autonomic nervous system.
Clinical manifestations by age 10, ESRD by 30-40
Renal Manifestations: polyuria, polydipsia, Fanconi’s
syndrome, renal sinus cysts, proteinuria, unexplained
ckd, vacuolization of podocytes, distal tubules; (less
commonly proximal tubules) and vasculature
Copyright Harvard Medical School, 2010. All Rights Reserved.
1179
Question 4
– A 52 year old African-American female presents to the
emergency room with unstable angina. She is noted to
have a past medical history of mild chronic renal
insufficiency ( creatinine of 1 8 mg/dL) She is insufficiency ( creatinine of 1.8 mg/dL). She is
transferred to the coronary care unit and therapy for
her unstable angina is initiated. A cardiac
catheterization is planned for the next day. Risk factors
that would predispose this woman to contrast
nephrotoxicty include all of the following except:
– A.) Diabetes mellitus
– B.) Pre-existing renal insufficiency
– C.) The volume of IV contrast utilized in the procedure
– D.) Presence of extracellular volume contraction
– E.) A history of coronary artery disease
Quest i on 4
– A 52 year old African-American female presents to the
emergency room with unstable angina. She is noted to
have a past medical history of mild chronic renal
insufficiency ( creatinine of 1 8 mg/dL) She is insufficiency ( creatinine of 1.8 mg/dL). She is
transferred to the coronary care unit and therapy for
her unstable angina is initiated. A cardiac
catheterization is planned for the next day. Risk factors
that would predispose this woman to contrast
nephrotoxicty include all of the following except:
– A.) Diabetes mellitus
– B.) Pre-existing renal insufficiency
– C.) The volume of IV contrast utilized in the procedure
– D.) Presence of extracellular volume contraction
– E.) A history of coronary artery disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
1180
Question 4
Her cardiologist asks you to recommend a strategy to minimize
the risk of contrast nephrotoxicity. Which would be most
appropriate?
• A.) Start the patient on 0.45% saline and order furosemide
40 mg IV and 10 g mannitol on call to the procedure
• B.) Start the patient on 0.45% saline at 1 ml/kg for 12 hours
pre and post procedure and give N-acetyl cysteine 1200 mg
po bid, day before and day of procedure
• C.) Give N-acetyl cysteine 1200 mg po bid the day before
and day of the procedure and hydrate with isotonic sodium
bicarbonate at 3ml/kg for 1h pre and 1ml/kg for 6h post
procedure
• D.) Stop the ibuprofen the patient is taking for her arthritis
• E.) Use low osmolality ionic contrast
Copyright Harvard Medical School, 2010. All Rights Reserved.
1181
Question 4
Her cardiologist asks you to recommend a strategy to minimize
the risk of contrast nephrotoxicity. Which would be most
appropriate?
• A.) Start the patient on 0.45% saline and order furosemide
40 mg IV and 10 g mannitol on call to the procedure
• B.) Start the patient on 0.45% saline at 1 ml/kg for 12 hours
pre and post procedure and give N-acetyl cysteine 1200 mg
po bid, day before and day of procedure
• C.) Give N-acetyl cysteine 1200 mg po bid the day before
and day of the procedure and hydrate with isotonic sodium
bicarbonate at 3ml/kg for 1h pre and 1ml/kg for 6h post
procedure
• D.) Stop the ibuprofen the patient is taking for her arthritis
• E.) Use low osmolality ionic contrast
Copyright Harvard Medical School, 2010. All Rights Reserved.
1182
Contrast Nephrotoxicity
(versus atheroemboli)
Contrast Nephrotoxicity
(versus atheroemboli)
• ARF and oliguria within 24-48 hours ARF and oliguria within 24 48 hours
• Peak serum creatininine on days 3-5
• Low fractional excretion of sodium
• Benign sediment or granular casts
• Resolution usual within 1 week
• Risk factors: CRI diabetic nephropathy • Risk factors: CRI, diabetic nephropathy,
dose>120 cc, multiple myeloma, volume
• Prevention: hydration 75 cc 0.9% saline, non-
ionic for high risk patients or NaHCO3
Risk of CN
20
25
Probability
of CN %
5
10
15
20
Source: Davidson et al, Ann Intern Med: 110, 119-124, 1989
0
44.2 88.4 132.6 176.8
mcmol/L 1.2 mg/dL 2.0 mg/dL
Copyright Harvard Medical School, 2010. All Rights Reserved.
1183
Contrast Nephropathy
Risk Factors
• Pre-existing renal insufficiency Pre existing renal insufficiency
• Diabetes mellitus
• CHF
• Volume Depletion
• Dose/osmolality of Contrast agent
Question 5
What treatment resulted in the decreased risk of stone
formation in the following patient? 24 hour urine values
are given before and after therapy. Supersaturations are
given as SS Caox SSCaP and SSUA for calcium oxalate
Vol SSCAOX CA OX CIT SSCAP UpH SSUA UA
1.60 8.66 223 40 398 0.41 5.5 2.47 .876
2.45 3.93 205 39 1082 0.8 6.3 0.33 .767
< 6 0.5-2 0-1
given as SS Caox, SSCaP and SSUA for calcium oxalate,
calcium phosphate and uric acid.
A. Increased hydration alone
B. Na. Citrate
C. K. Citrate
D. Dietary Na Restriction
E. Allopurinol
Copyright Harvard Medical School, 2010. All Rights Reserved.
1184
Question 5
Vol SSCAOX CA OX CIT SSCAP UpH SSUA UA
1.60 8.66 223 40 398 0.41 5.5 2.47 .876
2.45 3.93 205 39 1082 0.8 6.3 0.33 .767
< 6 0 5 2 0 1 < 6 0.5-2 0-1
A. Increased hydration alone
B. Na. Citrate
C. K. Citrate
D. Dietary Na Restriction
E Allopurinol E. Allopurinol
Urinary citrate increased suggesting alkali therapy
K Citrate is preferred in most cases; Na increases Ca
+2
exchange and worsens hypercalciuria
SS CaP increased and SSUA decreased because of
increased U pH
Copyright Harvard Medical School, 2010. All Rights Reserved.
1185
Question 6
• All of the following statements regarding
aminoglycoside nephrotoxicity are true, except:
– A.) Aminoglycosides cause a secondary
phospholipidosis in lysosomes
– B.) Aminoglycosides are proximal tubule toxins
– C.) Hypokalemia increases the risk of
aminoglycoside nephrotoxicity
– D.) Hypokalemia and hypomagnesemia are
commonly observed in patients with commonly observed in patients with
aminolglycoside nephrotoxicty
– E.) Multidose regimen is preferred to single
dose regimens in order to reduce
aminoglycoside nephrotoxicity.
Quest i on 6
• All of the following statements regarding
aminoglycoside nephrotoxicity are true, except:
– A.) Aminoglycosides cause a secondary
phospholipidosis in lysosomes
– B.) Aminoglycosides are proximal tubule toxins
– C.) Hypokalemia increases the risk of
aminoglycoside nephrotoxicity
– D.) Hypokalemia and hypomagnesemia are
commonly observed in patients with commonly observed in patients with
aminolglycoside nephrotoxicty
– E.) Multidose regimen is preferred to single
dose regimens in order to reduce
aminoglycoside nephrotoxicity.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1186
Aminoglycoside Nephrotoxicity Aminoglycoside Nephrotoxicity
• 25% incidence with “therapeutic” levels 25% incidence with therapeutic levels
• some correlation with cumulative dose
• non-oliguric ARF after 5-10 days
• Toxicity correlates with cationic charge
• Pathology: membrane phospholipidosis
• Prevention: once daily dosing y g
Prine et al: Lancet 341: 335, 1993
Levinson Ann Intern Med 117: 694, 1992
Copyright Harvard Medical School, 2010. All Rights Reserved.
1187
Question 7
• A 69-year-old man without any past medical
history. Two months ago he developed mild
f joint pains and muscle aches for which he
took a non-steroidal anti-inflammatory drug
(Voltaren, or diclofenac). He developed
generalized edema which has persisted for
the last 2 weeks. His physical examination is
unremarkable except for 3+ pitting edema of unremarkable except for 3+ pitting edema of
the lower extremities. Blood pressure is
normal. No skin lesions are noted and his
joint and muscles are non-tender.
• His laboratory work-up reveals a 24 hour
Quest i on 7
• His laboratory work-up reveals a 24 hour
urinary protein excretion of 16g. The urinary
sediment is remarkable for 3-4 red blood
cells/hpf without casts. His BUN is 25mg/dl,
creatinine 1.2mg/dl, and his creatinine
clearance was measured at 80ml/min.
Serologic tests show an ANA of 1:160, an
anti-DNA ab level of 26, and borderline low
complements.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1188
Renal Biopsy is Performed:
IgG g
Th t lik l di i i
Question 7
• The most likely diagnosis is:
– A.) Class V (membranous) lupus nephritis
– B.) Idiopathic membranous glomerulopathy
– C.) Focal segmental glomerulonephritis
– D.) Class III lupus nephritis ) p p
– E.) Class IV lupus nephritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1189
Quest i on 7
• The most likely diagnosis is:
– A.) Class V (membranous) lupus nephritis
– B.) Idiopathic membranous glomerulopathy
– C.) Focal segmental glomeuonephritis
– D ) Call III lupus nephritis D.) Call III lupus nephritis
– E.) Class IV lupus nephritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1190
Renal Disease with SLE:
– Minimal Mesangial Lupus Nephritis (Class I)
– Mesangial Proliferative Lupus Nephritis
(Class II) (Class II)
– Focal Lupus Nephritis (Class III)
– Diffuse Lupus Nephritis (Class IV)
– Membranous Lupus Nephritis (Class V)
– Advanced Sclerosing Lupus Nephritis (Class
VI) VI)
– Tubulointerstitial and Vascular
Membranous (Class V)
Normal
Membranous LN (V): Subepithelial immune deposits, diffuse basement
membrane thickening. Similar to idiopathic MN but if tubuloreticular
structures, highly suggestive of SLE
LM findings of subendothelial deposits indicates V+ III or IV.
IgG
10-20% of patients; Nephrotic syndrome, may have some hematuria.
Pure Membranous may not require immunosuppression but if
associated with III or IV have a poorer prognosis.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1191
Question 8
• All of the following are true regarding
pentamidine nephropathy except: p p p y p
– A.) Often presents with a distal RTA
– B.) Hypomagnesemia is common
– C.) ECF volume contraction is a risk factor
– D.) Nebulized drug virtually never causes
acute renal failure
– E.) Acute renal failure is reversible on
discontinuation of the drug
Quest i on 8
• All of the following are true regarding
pentamidine nephropathy except: p p p y p
– A.) Often presents with a distal RTA
– B.) Hypomagnesemia is common
– C.) ECF volume contraction is a risk factor
– D.) Nebulized drug virtually never causes
acute renal failure
– E.) Acute renal failure is reversible on
discontinuation of the drug
Copyright Harvard Medical School, 2010. All Rights Reserved.
1192
Pentamidine Nephrotoxicity Pentamidine Nephrotoxicity
• Risk factors: hypovolemia and CRF yp
• 25-95% incidence of ARF after 7 to 10 days
• Several reports of ARF after nebulized drug
• Often pyuria, proteinuria, hematuria, casts
• Hypomagnesemia / Hypocalcemia, distal RTA
D t t b d d d t • Does not appear to be dose dependant
• Mechanism unknown
• Recovery usually within weeks
Copyright Harvard Medical School, 2010. All Rights Reserved.
1193
Question 9
• A 22-year old white male is seen in the emergency
room for evaluation of acute renal failure. He explains
that he has just finished running the Boston marathon. j g
He complains of severe leg cramps. He tells you that
his urine is light pink. He has no significant past
medical history. He is not taking any medications. He
denies recent alcohol consumption. His physical
examination shows a white male. His BP is 120/80
mmHG, heart rate of 110 bpm, afebrile. His JVP is 2-3
cm. He has clear lungs, a normal cardiovascular and g ,
abdominal examination. He has no edema. His skin
turgor is reduced. Urinalysis reveals a SG of 1020, pH
5.0, 4+ blood, rest negative. His urine sediment shows
2-4 RBC’s but is otherwise negative.
• All of the following statements are correct
Question 9
• All of the following statements are correct,
EXCEPT
– A.) His CPK level is likely to be elevated
– B.) His serum phosphorous is likely to be
normal
– C.) He should be rapidly volume repleted ) p y p
– D.) His urine should be alkalinized
– E.) Orthotoludine positive urine is typical
Copyright Harvard Medical School, 2010. All Rights Reserved.
1194
All of the following statements are correct
Quest i on 9
• All of the following statements are correct,
EXCEPT
– A.) His CPK level is likely to be elevated
– B.) His serum phosphorous is likely to be
normal
– C.) He should be rapidly volume repleted
– D.) His urine should be alkalinized
– E.) Orthotoludine positive urine is typical
Copyright Harvard Medical School, 2010. All Rights Reserved.
1195
Features of Rhabdomyolysis
• Muscle pain and dark urine “Coca-Cola” color Muscle pain and dark urine Coca Cola color
• Orthotoludine-positive urine without RBCs
• Elevated CPK and myoglobin
• Increased K, Phos, urate, decreased Ca
• Rapid increase in serum creatinine
• Mechanism: free radicals ferrihemate • Mechanism: free radicals, ferrihemate,
reduced nitric oxide
• Treatment: saline repletion, alkaline diuresis,
mannitol. Dialysis once ARF established
Causes of Rhabdomyolysis
• Excessive muscle activity
– seizures, delerium tremens, sport
• Direct of ischemic muscle injury Direct of ischemic muscle injury
– trauma, compression syndrome, vascular
occlusion
• Metabolic disorders
– hypokalemia, hyponatremia,
hypophosphatemia yp p p
• Drugs or toxins
– ethanol, isopropyl alcohol, heroin, methadone
• Infections
– tetanus, legionaires, influenza
Copyright Harvard Medical School, 2010. All Rights Reserved.
1196
Question 10
• 70 yo A M attorney develops pedal edema and foamy
urine. PMH-HTN, HypercholesPx BP 140/92, 1+ pedal
edema. Pt smokes 1 PPD and denies any medications
except rare ASA or tylenol.
• Lab: BUN 28 mg/dl, Pcreat 1.6 mg/dl, U/A 3+ protein 5-
10 rbc’s, P cholesterol 525 mg/dl, Palb 1.4 g/dl, 24 hr
UV prot10 g/d
• ANA, Complement, VDRL, HBV, HCV –
• Bx- Stage II-III MN w segmental sclerosis
• EM extensive subepithelial and some mesangial
deposits
Question 10
• What is the chance that this patient will be
found to have a malignancy underlying his
membranous nephropathy?
A) 2%
B) 12%
C) 18% )
D) 25%
E) 40%
Copyright Harvard Medical School, 2010. All Rights Reserved.
1197
Question 10
• What is the chance that this patient will be
found to have a malignancy underlying his
membranous nephropathy?
A) 2%
B) 12%
C) 18% )
D) 25%
E) 40%
Copyright Harvard Medical School, 2010. All Rights Reserved.
1198
Membranous Nephropathy and
Malignancy
• MN has been associated with malignancy,
but unclear how often. but unclear how often.
• Retrospective survey of 232 MN patients (148
M, 84 F) from 1994-2000.
• 24 pts (10.3%) had a known malignancy or
developed one within a year of diagnosis. In
pts > 65 years old, 25% had malignancy.
• Only difference between the Idiopathic and
the Malignancy associated MN was increase
in infiltrating leukocytes.
Lefaucheur C, et al Kidney Int 2006
27 year old male from the country of Cape Verde
who wishes to be a kidney donor for his aunt, who is an
ESRD patient from polycystic kidney disease on dialysis
for several years. The patient is healthy male with no
hi t f HTN di b t d i h it li ti
Question 11
history of HTN or diabetes, and no prior hospitalizations.
PMH: none All: NKDA, Current Medications: none,
denies NSAIDs.
SH: no tob, social EtOH use, no drugs. Works as
musician in Africa.
FH: +FH of ADPKD on father’s side of family FH: +FH of ADPKD on father s side of family.
His father has HTN but no known kidney disease.
He has two paternal aunts both with ADPKD, (one is
the potential recipient).
He has 6 sisters and 3 brothers none of whom have
known kidney disease (ages 24-36).
Copyright Harvard Medical School, 2010. All Rights Reserved.
1199
Physical Exam:
BP 112/66, P 58, BMI 21
Benign physical exam
Question 11
Benign physical exam.
Data:
Cr 0.72, normal lytes
T-bili 1.8, ALT 13, AST 15, ALKP
57
No microalbuminuria No microalbuminuria
HIV, hepatitis B, hepatitis C
negative
Question 11
Which of the following recommendations are
most appropriate?
• A. Obtain renal ultrasound and if no evidence of cystic
kidney disease, approve him as a donor
• B. Obtain renal ultrasound and if no evidence of cystic
kidney disease, advise him to have MRI, and if negative
approve him as a donor
pp p
• C. Advise against donation until he has a negative
ultrasound at age 40.
• D. Advise waiting until age 30 and if ultrasound and
MRI shows one or less cysts, then go ahead with
donation
Copyright Harvard Medical School, 2010. All Rights Reserved.
1200
Question 11
Which of the following recommendations are
most appropriate?
• A. Obtain renal ultrasound and if no evidence of cystic
kidney disease, approve him as a donor
• B. Obtain renal ultrasound and if no evidence of cystic
kidney disease, advise him to have MRI, and if negative
approve him as a donor
pp p
• C. Advise against donation until he has a negative
ultrasound at age 40.
• D. Advise waiting until age 30 and if ultrasound and
MRI shows one or less cysts, then go ahead with
donation
Copyright Harvard Medical School, 2010. All Rights Reserved.
1201
Recommended Screening for ADPKD:
• Ultrasound Criteria for Diagnosis of ADPKD:
– 15 to 39 years of age: at least three unilateral or
bilateral cysts bilateral cysts
– 40 to 59 years of age, two cysts in each kidney
– >60 years or older, four cysts in each kidney.
To Exclude ADPKD:
• >40, ultrasonographic evidence of zero or only one
renal cyst excludes the disease (negative PV=100%)
• 30-39 years of age, False negative rate of normal
ultrasound is ~2% (Normal CT or MRI would exclude
the disease.)
• <30 years of age, ultrasonographic imaging is limited
in its ability to help exclude the disease.
• 61 year old man
• Rheumatoid arthritis x 15 years & gold
therapy X 12 years with excellent control of
Question 12
therapy X 12 years, with excellent control of
his symptoms.
• Six months prior he c/o of edema. Cr 1.0
mg/dl, 24-h protein 10 g, albumin 1.8 g/dl.
• UA: 4+ albuminuria, bland sediment.
• Gold salts D/C’d; proteinuria persists, 24h Gold salts D/C d; proteinuria persists, 24h
protein averaging 14 g/day.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1202
• On no medications other than lasix in
Question 12
• On no medications other than lasix, in
particular, no NSAID in the recent past.
• Physical examination showed a well-
developed man in no acute distress. Blood
pressure was 120/80. There was 4+ edema
present. present.
• The most likely diagnosis is:
Question 12
– A.) Membranous glomerulopathy
secondary to gold
– B.) Idiopathic membranous glomerulopathy
– C.) AA amyloidosis secondary to
rheumatoid arthritis
– D.) Primary focal segmental
glomerulosclerosis
– E.) Rheumatoid vasculitis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1203
• The most likely diagnosis is:
Quest i on 12
– A.) Membranous glomerulopathy
secondary to gold
– B.) Idiopathic membranous glomerulopathy
– C.) AA amyloidosis secondary to
rheumatoid arthritis
– D.) Primary focal segmental
glomerulosclerosis
– E.) Rheumatoid vasculitis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1204
Glomerular Disease and RA
• Renal Disease with RA • Renal Disease with RA
– Membranous
– Mesangial proliferative GN +/- IgA deposits
– Diffuse proliferative GN
• Necrotizing and crescentic GN
(rheumatoid vasculitis)
– Amyloidosis
• Renal Disease with treatment of RA
Renal Di sease and RA
• Renal Disease with treatment of RA
– Gold: MN, MCD, ATN
– Penicillamine: MN, Crescentic GN, MCD
– NSAIDs: AIN, MN, MCD, ATN
– CsA: chronic vasculopathy and tubulopathy
– Methotrexate: ATN / crystal induced ARF
– Aza: AIN
Copyright Harvard Medical School, 2010. All Rights Reserved.
1205
• 65-year-old woman
Quest i on 13
• 65-year-old woman
• Adult onset diabetes mellitus for the last 2
years.
• Blood sugar levels have been controlled very
well on oral hypoglycemics.
2 th hi t f t h ti d • 2-month history of overt nephrotic syndrome.
• PMH: positive serology for hepatitis B.
Currently she is hepatitis B serum antigen
negative.
• Exam: moderately obese
Question 13
• Exam: moderately obese.
• Edema of the lower extremities (+++) & the
lumbosacral area.
• VS within normal limits, including a systemic
blood pressure of 140/85.
F d NL • Fundoscopy NL.
• Neurologic examination NL.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1206
• Labs
Quest i on 13
– BUN 18, Cr 1
– Ccr 90ml/min.
– 24 h urine 7.3g of protein
– UA benign sediment. Only rare hyaline casts are
seen.
– Lupus serology negative
– RF factor +. Cryo (-).
– Complements levels normal
– Coags normal parameters
• The most likely diagnosis is
Quest i on 13
y g
– A.) Stage 4 diabetic nephropathy
– B.) Minimal change disease with early
diabetic nephropathy
– C.) Class V lupus nephropathy
D ) Post infectious glomerulonephritis – D.) Post-infectious glomerulonephritis
– E.) Henoch-Schonlein nephritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1207
• The most likely diagnosis is
Quest i on 13
y g
– A.) Stage 4 diabetic nephropathy
– B.) Minimal change disease with early
diabetic nephropathy
– C.) Class V lupus nephropathy
D ) Post infectious glomerulonephritis – D.) Post-infectious glomerulonephritis
– E.) Henoch-Schonlein nephritis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1208
Natural History of Diabetic Nephropathy
ESRD
Stage 4
Stage 5
UAE
mg/d
3000
Overt
Nephropathy
Microalbuminuria
Stage 1 Stage 2
Stage 3
30
300
Early
DM
Structural
Changes
g g
0 2
5 12
25
years
30
Physiologic changes in DN
100-
50-
25-
75-
Copyright Harvard Medical School, 2010. All Rights Reserved.
1209
• 42 yo male with recurrent calcium oxalate stones. No
meds, No h/o of GI disease,UTI, or hypercalcemia
– Exam - mild obesity, 100kg, BP-130/70 otherwise WNL
– Urine - pH 5.0, trace blood,otherwise neg
– Chemistry: electrolytes-normal, Ca-9.8, PO4-2.7, Creat-
Question 14
Chemistry: electrolytes normal, Ca 9.8, PO4 2.7, Creat
0.9
• 24h Urine:
– Volume -1266mls (varies with intake)
– Sodium - 358meq/d (varies with intake)
– Potassium - 78meq/d (varies with intake)
– Calcium - 320mg/d (<250mg/d) g ( g )
– Oxalate - 42mg/d (<40mg/d)
– Citrate - 250mg/d (450-600mg/d)
– Urate - 870mg/d (<800mg/d)
– Urea - 14.4g/d;Estimate DPI (6.25(14.4)+0.03 Wt(kg)
~93gms
Question 14; Which of the following might
reduce new stone formation?
• A. HCTZ
• B. Low Calcium Diet
• C. Sodium Citrate
• D. Potassium Bicarbonate
• E Low Protein Diet E. Low Protein Diet
• F. Allopurinol
• H. Increased Fluid Intake
Copyright Harvard Medical School, 2010. All Rights Reserved.
1210
Answers/Pearls
• A. Yes - Hctz will lower urinary calcium excretion A. Yes Hctz will lower urinary calcium excretion
• B. NO - Low calcium diet (inc. oxalate absorb.)
• C. NO - Sodium citrate - Inc. Na will inc. Ca exc.
• D. Yes - K-bicarbonate - Inc. citrate exc, alk blood and
urine
• E. Yes - Low protein diet - Decrease Ca, urate
excretion; Increase citrate excretion ;
• F. Yes - Allopurinol - reduces urate excretion
• G. Yes - Increase Volume to >2L/d; reduces conc.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1211
• 42 yo WM referred for HTN, Renal
Insufficiency and crampy abdominal pain.
Question 15:
y py p
HTN diagnosed 2 years ago; on multiple
meds. PMH notable for gout involving right
knee and feet-last episode about 8 weeks ago
– PE notable for BP-168/100; otherwise WNL
• Laboratory Studies:
Hct 35 2% Hb 12 g/dl – Hct 35.2%, Hb-12 g/dl
– BUN/Creat - 42/2.9
– Electrolytes;Na-140, K-4.8, Cl-22, HCO3-22
– Uric acid - 9.4
– UA- pH 5.0,1+ protein, no cells, casts
Question 15: Which study is most likely to
reveal the diagnosis?
• A Urine porphobilinogen excretion • A. Urine porphobilinogen excretion
• B. 24h urine creatinine and beta2-
microglobulin excretion
• C. Urine lead excretion following
administration of EDTA
D R l Ult h • D. Renal Ultrasonography
• E. Renal Biopsy
Copyright Harvard Medical School, 2010. All Rights Reserved.
1212
Question 15: Which study is most likely to
reveal the diagnosis?
• A Urine porphobilinogen excretion • A. Urine porphobilinogen excretion
• B. 24h urine creatinine and beta2-
microglobulin excretion
• C. Urine lead excretion following
administration of EDTA
D R l Ult h • D. Renal Ultrasonography
• E. Renal Biopsy
Copyright Harvard Medical School, 2010. All Rights Reserved.
1213
Question 15 Answer
• C - Urine lead excretion following EDTA C Urine lead excretion following EDTA
– Classic Triad of Renal Insufficiency, HTN
and gout
– HTN duration too short to explain renal
insuff
– Porphyria - GI and Neuro Sx, no renal p y
– Without family history unlikely to have PKD
– Potentially large numbers of patients and
treatable with chelation therapy.
Question 16
A Family of Patients is determined to have
Autosomal Dominant FSGS
f f ? Which of the following is True?
A. They likely have a mutation in the nephrin gene
B. If they have a podocin genetic defect it is likely to be
steroid responsive
C They are likely to have a mutation in a actinin IV or C. They are likely to have a mutation in a-actinin IV or
TrpC6 ion channel
D. Almost 50% of adults with FSGS have been found to
have genetic mutation encoding for structural
proteins or transport channels of the visceral
epithelial cell.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1214
Question 16
A Family of Patients is determined to have
Autosomal Dominant FSGS
f f ? Which of the following is True?
A. They likely have a mutation in the nephrin gene
B. If they have a podocin genetic defect it is likely to be
steroid responsive
C They are likely to have a mutation in α actinin IV or C. They are likely to have a mutation in α-actinin IV or
TrpC6 ion channel
D. Almost 50% of adults with FSGS have been found to
have genetic mutation encoding for structural
proteins or transport channels of the visceral
epithelial cell.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1215
Classification of FSGS
D’Agati. 2008 Curr Opin Nephrol Hypertens 3;271
• Idiopathic - Mediated by permeability factor? p y p y
• Secondary:
– Familial/Genetic (next slide)
– Virus Associated: HIV, Parvovirus, SV40, CMV
– Drug Induced: Heroin, Interferon-α, Li, Pamidronate,
Sirolimus
– Hemodynamic/Structural:
• Reduced Renal Mass: agenesis, dysplasia, reflux, surgery,
chronic allograft nephropathy
• Normal Mass (Initially): HTN, atheroemboli, obesity, SSD
Genes Mutated in Familial FSGS
SD
Cyto
BM
D’Agati 2008 KI 73;399
Nuc
Copyright Harvard Medical School, 2010. All Rights Reserved.
1216
Molecular anatomy of the podocyte foot
process cytoskeleton
Podocalyxin
NHERF2
MAGI-1
NEPH-1?
Ezrin
V
T
P
ILK
PLCε1
Somlo and Mundel, Nature Genetics 2000
FAT
TRPC6
Question 17
• 57 yo black female with h/o mild hypertension,
presents to the ED with headache and BP-240/140.
The evening before she had consumed a “raw”
hamburger and she c/o non bloody bowel movements hamburger and she c/o non bloody bowel movements
the morning of admission. Her physical exam was
notable for T=100.4
o,
S4 gallop, petechiae but no
edema or other abnormalities.
• Labs notable Hct-22%, plts-95k, creat 4.5mg/dl
(3months prior 1.2mg/dl). Urinalysis - heme +, few ( p g ) y ,
rbcs, +1 protein, no casts. Admitted to ICU for IV
nipride.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1217
Question 17
Patient Normal
The Most Appropriate Next Step is:
• A Check ADAMTS-13 Level • A. Check ADAMTS-13 Level
• B. Obtain Stool Culture for E.Coli 01357
• C. Perform Kidney Biopsy
• D. Initiate Therapy with Steroids
• E. Initiate Therapy with Steroids and
Plasmapheresis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1218
Question 17: The Most Appropriate Next
Step is:
• A Check ADAMTS-13 Level • A. Check ADAMTS-13 Level
• B. Obtain Stool Culture for E.Coli 01357
• C. Perform a Kidney Biopsy
• D. Initiate Therapy with Steroids
• E. Initiate Therapy with Steroids and
Plasmapheresis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1219
Question 17
All of the following conditions can present with similar
findings: Scleroderma Crisis, Hemolytic uremic
syndrome Thrombotic Thrombocytopenia Purpura syndrome, Thrombotic Thrombocytopenia Purpura,
Malignant Hypertension, Disseminated Intravascular
Coagulation.
Kidney Biopsy will not distinguish these etiologies
Incubation time too short for Ecoli associated HUS
The presence of findings of neurologic symptoms,
h l ti i th b t i l f il hemolytic anemia, thrombocytopenia, renal failure
and low grade fever suggests TTP.
Summary of Indications for
Plasmapheresis in Renal Disease
Disease Category
Anti-GBM disease I
TTP I TTP I
Rapidly Progressive Glomerulonephritis II
Cryoglobulinemia II
Hemolytic Uremic Syndrome III
Desensitization for Renal II
transplantation
Recurrent FSGS III
Renal transplant rejection IV
Systemic Lupus Erythematosus III
Category I: Standard Primary Therapy; Category II: Supportive
Therapy; Category III: When the evidence of benefit is unclear;
Category IV: No current evidence of benefit or for research protocols
Copyright Harvard Medical School, 2010. All Rights Reserved.
1220
Question 18: For Which of the Following
Conditions is the use of Plasmapheresis
Least Indicated
• A Guillain-Barre Syndrome • A. Guillain-Barre Syndrome
• B. Myasthenia Gravis
• C. Multiple Myeloma with Cast Nephropathy
• D. Chronic inflammatory demyelinating
polyneuropathy
• E. Hyperviscosity in monoclonal
gammopathies (Waldeström
macroglobulinemia)
Question 18: For Which of the Following
Conditions is the use of Plasmapheresis
Least Indicated
• A Guillain-Barre Syndrome • A. Guillain-Barre Syndrome
• B. Myasthenia Gravis
• C. Multiple Myeloma with Cast Nephropathy
• D. Chronic inflammatory demyelinating
polyneuropathy
• E. Hyperviscosity in monoclonal
gammopathies (Waldeström
macroglobulinemia)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1221
Question 18
• All the other indications are CATEGORY I All the other indications are CATEGORY I
• Although early studies demonstrated improvement in
renal function and patient survival, the largest study
to date of 104 patients with multiple myeloma and
acute renal failure randomly assigned to conventional
therapy plus plasma exchanges or conventional
therapy alone did not show differences in composite therapy alone did not show differences in composite
outcome of death, dialysis dependence or severely
reduced renal function.
Clark WF, et al., Plasma exchange when myeloma presents as acute renal failure: a
randomized, controlled trial. Ann Intern Med 143:777-84. 2005.
Szczepiorkowski ZM, et al. Guidelines on the use of therapeutic apheresis in clinical
practice—Evidence-based approach from the Apheresis Applications
Committee of the American Society for Apheresis. J Clin Apher 22:106–175.
2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
1222
A 45-year-old woman is referred for recurrent oxalate
stone formation. The following is her 24-hr urine result.
Question 19
Vol SSCAOX CA OX CIT SSCAP UpH SSUA UA
1.52 10.04 40 143 23 0.09 5.5 0.53 .202
6-10 < 200 20-40 >550 0.5-2 0-1 <0.75
What is the likely cause of her disorder?
A. Renal tubular acidosis resulting in hypocitraturia
B. Dietary excess of nuts, chocolate, and berries
C. Hyperparathyroidism
D. Crohn’s disease
E. Oxalosis
A 45-year-old woman is referred for recurrent oxalate
stone formation. The following is her 24-hr urine result.
Question 19
Vol SSCAOX CA OX CIT SSCAP UpH SSUA UA
1.52 10.04 40 143 23 0.09 5.5 0.53 .202
6-10 < 200 20-40 >550 0.5-2 0-1 <0.75
What is the likely cause of her disorder?
A. Renal tubular acidosis resulting in hypocitraturia
B. Dietary excess of nuts, chocolate, and berries
C. Hyperparathyroidism
D. Crohn’s disease
E. Oxalosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1223
Answer: D
Vol SSCAOX CA OX CIT SSCAP UpH SSUA UA
1.52 10.04 40 143 23 0.09 5.5 0.53 .202
There is low citrate, high oxalate, and low volume in this
intestinal malabsorptive condition.
RTA does not explain increased U oxalate
6-10 < 200 20-40 >550 0.5-2 0-1 <0.75
Nuts etc do not explain degree of hyperoxaluria
Hyperparathyroidism only explains low U Ca
Oxalosis does lead to low U citrate, low U Calcium
Copyright Harvard Medical School, 2010. All Rights Reserved.
1224
A 55 yo woman is admitted to the hospital with 4 day h/o
tea colored urine and renal failure. 8 weeks prior she
received PCN for streptococcal pharyngitis and completed
10 days of therapy. Based upon UA showing rbcs, wbcs,
Question 20
she was given bactrim for 2 days prior to admission for
presumed UTI. Routine labs done 2 days ago return with
creat. 2.9. She denies any respiratory or sinus symptoms.
6 months ago renal function and UA were normal.
On admission she is afebrile, BP-146/96 with Pulse-90 and
R 20/ i Ad i i l b l t 4 2 d UA Resp-20/min. Admission labs reveal creat 4.2 and UA
shows many dysmorphic rbcs and rbc casts with 3+
protein. CXR is unremarkable.
Which of the following approaches is
most appropriate at this time?
A Obtain serologies for ANCA Anti-GBM ANA A. Obtain serologies for ANCA, Anti GBM, ANA,
ASLO, Hepatitis B, C, C3, C4 ESR and schedule
renal biopsy for the following morning.
B. Obtain serologies and initiate methylprednisolone
1 gm IV while awaiting renal biopsy.
C. Obtain emergent renal biopsy, serologies, and
wait for results before initiating therapy. g py
D. Obtain emergent renal biopsy, serologies, and
begin plasmapheresis and IV solumedrol while
awaiting test results.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1225
Which of the following approaches is
most appropriate at this time?
A Obtain serologies for ANCA Anti-GBM ANA A. Obtain serologies for ANCA, Anti GBM, ANA,
ASLO, Hepatitis B, C, C3, C4 ESR and schedule
renal biopsy for the following morning.
B. Obtain serologies and initiate methylprednisolone
1 gm IV while awaiting renal biopsy.
C. Obtain emergent renal biopsy, serologies, and
wait for results before initiating therapy. g py
D. Obtain emergent renal biopsy, serologies, and
begin plasmapheresis and IV solumedrol while
awaiting test results.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1226
H and E
Fibrin
Anti-glomerular basement membrane antibody
Copyright Harvard Medical School, 2010. All Rights Reserved.
1227
Correct Answer - D, begin therapy with
plasmapheresis and steroids.
Although the differential includes post-strept and g p p
bactrim mediated acute renal failure, this is too
long a latency period for post-strep and renal
failure already present prior to starting bactrim.
Therefore, this is a rapidly progressive
glomerulonephritis and a true emergency.
Literature supports poor prognosis if creat >4 and
very aggressive therapy indicated even before the
diagnosis is confirmed.
Question 21
Anterior Lenticonus is Pathognomonic for
Which of the Following Kidney Diseases?
A. Alports Syndrome
B. Meckel Gruber Syndrome
C. ARPKD
D Nephronophthisis (NPHP) D. Nephronophthisis (NPHP)
E. ADPKD with Mutations in Polycystin-2
Copyright Harvard Medical School, 2010. All Rights Reserved.
1228
Question 21
Anterior Lenticonus is Pathognomonic for
Which of the Following Kidney Diseases?
A.Alports Syndrome
B.Meckel Gruber Syndrome
C.ARPKD
D Nephronophthisis (NPHP) D.Nephronophthisis (NPHP)
E. ADPKD with Mutations in Polycystin-2
Copyright Harvard Medical School, 2010. All Rights Reserved.
1229
Nephronophthisis
Meckel Gruber: NPHP 6,8 and MKS Genes
ARPKD - Fibrocystin
Morphology of NPHP
Hildebrandt, F. et al. J Am Soc Nephrol 2007;18:1855-1871
Copyright Harvard Medical School, 2010. All Rights Reserved.
1230
Autosomal dominant polycystic kidney
disease: The genes
• PKD1
– Polycystin 1 Polycystin 1
• Huge Integral membrane
protein->400kDa-11 TM
Domains
• Cilia, Cell-cell interactions,
Cell Matrix: Regulates Cell
Cycle and Planar Cell
Polarity
• Expressed in many
tissues: kidney, brain, tissues: kidney, brain,
heart, bone, muscle
• PKD2
– Polycystin 2
• Interacts with polycystin 1
• Calcium Channel
Alport syndrome: The genes and
inheritance
• Mutations of type-IV collagen α chains
– X-linked
• X-Chromosome: COL4A5
• 85% of Alport Syndrome families
• New mutations in 10 to 15%
• X-linked Alport with leiomyomatosis COL4A5
and COL4A6
– Autosomal recessive
• Chromosome 2: either COL4A3 or COL4A4
• Majority of non-X-linked families
– Autosomal dominant
• Chromosome 2: COL4A3 and COL4A4?
• Rare
Copyright Harvard Medical School, 2010. All Rights Reserved.
1231
Alport syndrome
• Progressive glomerulonephritis: X-linked
• Severe in males
– 100% with hematuria from birth; 60-70% with
gross hematuria gross hematuria
– Proteinuria develops in all; nephrotic range in
30%
– ESRD in 90% by age 40yrs; <31 yrs in 75%
• Less symptomatic in females (carriers)
– 95% with hematuria, may be intermittent; 33%
gross hematuria
• Progressive sensorineural hearing loss
• Ocular abnormalities
gross hematuria
– Proteinuria develops in 2/3
– End Stage Renal Failure: 12% by age 40yrs;
30% by age 60yrs
Alport syndrome: Pathology
Normal
Alport syndrome
Copyright Harvard Medical School, 2010. All Rights Reserved.
1232
Alport syndrome: Ocular defects
• Ocular abnormalities in ~50%
– Anterior lenticonus -a regular
conical protrusion on the anterior
aspect of the lens due to thinning aspect of the lens due to thinning
of the lens capsule
• Never at birth; in 22% by 25 yrs
• Pathognomonic
• Associated with rapid
progression to End Stage
Renal Failure and hearing loss
M l fl k i 37% – Macular flecks in 37%
• May be only extra renal
manifestation
– Recurrent corneal erosions in
23%
• In severe AS
Fovea
A 50-year-old woman with recurrent mixed calcium oxalate
and calcium phosphate stones has the following serum
chemistries:
Question 22
Ca Phos Cr UA Mg Na K C02 Cl
10.86 2.74 1.11 6.8 1.9 137 3.8 20 110
Which of the following is least likely?
A Sh i h l i A. She is hypercalcuric
B. Elevated phosphate excretion is a risk factor for her
stones
C. She has a proximal renal tubular acidosis
D. Surgical management is required
E. Bone demineralization has occurred
Copyright Harvard Medical School, 2010. All Rights Reserved.
1233
A 50-year-old woman with recurrent mixed calcium oxalate
and calcium phosphate stones has the following serum
chemistries:
Question 22
Ca Phos Cr UA Mg Na K C02 Cl
10.86 2.74 1.11 6.8 1.9 137 3.8 20 110
Which of the following is least likely?
A Sh i h l i A. She is hypercalcuric
B. Elevated phosphate excretion is a risk factor for her
stones
C. She has a proximal renal tubular acidosis
D. Surgical management is required
E. Bone demineralization has occurred
Copyright Harvard Medical School, 2010. All Rights Reserved.
1234
Answer: B
The answer is B, elevated phosphate excretion.
Phosphate excretion is not a major risk factor for stone
disease.
This patient has primary hyperparathyroidism with its
associated renal t b lar acidosis and bone associated renal tubular acidosis and bone
demineralization.
Disclosures
Dr Denker has reported no financial Dr. Denker has reported no financial
relationships with commercial entities
producing, marketing, re-selling, or
distributing health care goods or services
consumed by, or used on, patients.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1235
Sushrut S. Waikar, MD, MPH
Renal Division
Brigham and Women’s Hospital /
Harvard Medical School
Take home messages:
ACUTE KIDNEY INJURY
Disclosures
Investigator-initiated grant support from Pfizer,
Genzyme, Satellite HealthCare, NxStage;
DSMB member for Takeda
Copyright Harvard Medical School, 2010. All Rights Reserved.
1236
New proposed definition of AKI
AKIN proposed criteria
Stage 1
SCr increase 0.3 or 50%
UO: <0.5ml/kg/h for >6h
Stage 2
SCr doubling
UO: <0.5ml/kg/h for >12h
Stage 3
SCr tripling, acute rise 0.5
UO: <0.3ml/kg/h for >24h
or anuria x 12h
Reviewed by Himmelfarb Kidney Int 2007 Molitoris JASN 2007
Rising incidence of AKI
• 4 to 6-fold increase from 1988 to 2002
Hsu CY KI 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
1237
Importance of small changes in SCr
• 70%increased odds of death with an
increase of just 0.3 to 0.4 mg/dL
• 6.6-fold increased risk of death after 50-99%
increase in SCr following CABG
Mortality after severe AKI-RRT
• 60% + in recent multicenter epidemiology
studies
Copyright Harvard Medical School, 2010. All Rights Reserved.
1238
Contrast nephropathy
• Incidence
– ~3% risk overall following PCI
– 25% risk if SCr >2.0 mg/dL
• Implications
– Increased in-hospital mortality
– Increased 5-year mortality
• Risk factors
– age, higher SCr, CHF, diabetes, contrast
volume, intra-aortic balloon pump
Atheroembolic renal disease
• Typical triad:
– Presenting event (catheterization, anticoagulation)
– Acute or subacute renal failure
– Signs of peripheral emboli
• Renal presenation: AKI, subacute AKI, proteinuria,
hematuria, renal infarction
• Non-renal signs: fever, myalgia, weight loss, neuro
smptoms, livedo reticularis, GI bleeding
• Lab findings: hyperamylasemia, elevated CPK,
decreased complements, eosinophilia/eosinophiluria
Copyright Harvard Medical School, 2010. All Rights Reserved.
1239
Secondary causes of minimal
change nephropathy
Drugs
Nonsteroidal anti-inflammatory drugs
Ampicilli n
Gold
Allergens
Hymenoptera stings
Food
Pollen
Poison ivy and poison oak
Immunization
Infections
Viral
Cancer
HodgkinÕs disease
AKI in cancer
Tumor lysis syndrome
– Most commonly in poorly differentiated lymphoma
(e.g., Burkitt’s)
– ALL >AML
– Also described in other solid tumors
Multiple myeloma
– Cast nephropathy
– Hypercalcemia
– Hyperuricemia
– Contrast nephropathy
Obstruction
– Prostate, bladder, uterus, cervix
– Absence of hydronephrosis in retroperitoneal
tumors and retroperitoneal fibrosis
Reviewed by Humphreys JASN 2005
Copyright Harvard Medical School, 2010. All Rights Reserved.
1240
AKI in Multiple Myeloma
• Cast Nephropathy
• Amyloidosis (AL)
• LCDD
• Interstitial nephritis
• Hypercalcemic AKI
• Urate nephropathy
• Plasma cell infiltration
• Hyperviscosity syndrome
• Other paraprotein diseases:
• Fanconi disease
Goldschmidt, H. et al. Nephrol. Dial. Transplant. 2000
15:301-304; doi:10.1093/ndt/15.3.301
↑Light
chains
↑Ca2+
Tubular
Injury
Casts Dehydration
THP
↓GFR
Plasma Cell
Light Chain Deposition Disease
• Aka Monoclonal Ig Deposition Disease
• Monoclonal Ig deposition in glomeruli, tubular BM
and arteries (unlike Amyloid, also Congo Red
negative)
• Glomeruli: nodular glomerulosclerosis, nephrotic
proteinuria
• Tubules: BM thickening, dramatic interstitial
fibrosis
• Arterioles: PAS positive deposits, arteriolar
sclerosis
Copyright Harvard Medical School, 2010. All Rights Reserved.
1241
AKI from other nephrotoxins
Aminoglycoside antibiotics
– Nearly 50% of patients treated >14d; dose related
– Proximal tubular injury
– Typically nonoliguric AKI, slow onset
– Recovery can take weeks, may be incomplete
Cisplatin
– Cumulative dose-related
– Tubulointerstitial pattern without heavy proteinuria
– 25% decline in GFR in 20-30% of patients
– Incidence and severity increase with subsequent doses, may be
irreversible
– Nonoliguric; hypomagnesemia common
Antivirals
– Acyclovir: intratubular precipitation (U/A: needle shaped crystals)
– Foscarnet: ATN
– Tenofovir: ATN
Aminoglycoside nephrotoxicity
• Non-oliguric, slow to recover
• Proximal tubule dysfunction
– Enzymuria, proteinuria, glucosuria, aminoaciduria
• Electrolyte abnormalities: hypoMg, hypoCa, hypoK
• Pathology
– Proximal tubule: myeloid bodies in lysosomes,
loss of microvilli of luminal surfaces
– Glomerular capillary: endothelial cell damage
Copyright Harvard Medical School, 2010. All Rights Reserved.
1242
Acute interstitial nephritis
• Antecedent illness or exposure
• Fever, rash [can be absent]
• Labs:
– Eosinophiia/-uria, hematuria, WBC casts, sub-
nephrotic proteinuria
• Biopsy: interstitial monocytic infiltrate with edema,
tubular damage, normal glomeruli
• Treatment: remove inciting agent, possible role for
steroids if no improvement after removal
– Prednisone 1 mg/kg x 1 mo, then taper
• Prognosis: up to 40% with permanent reduction in
GFR; interstitial fibrosis on biopsy may predict poor
outcome
Diffusive vs. convective clearance
• Diffusion: movement of solutes down concentration
gradient across semipermeable membrane
• Convection: solutes passively carried along with
water as it passes across a semipermeable
membrane
Hemodialysis -- Diffusive
CVVH -- Convective
CVVHD -- Diffusive
CVVHDF -- Both
Copyright Harvard Medical School, 2010. All Rights Reserved.
1243
Contraindication to CVVH
• Life threatening hyperkalemia
– On a per-minute basis, HD is ~10 times
more effective than CVVH in small solute
clearance
Patients with/ at risk for hypotension:
– severe hemodynamic instability
– hepatic failure
– CHF
– sepsis or multiple organ failure
Patients at risk of cerebral complications:
– hepatic failure, stroke or head trauma
– high risk for cerebral edema
Indications for CRRT
Copyright Harvard Medical School, 2010. All Rights Reserved.
1244
Increased metabolic needs
– massive burns
– sepsis
– multiple organ failure
Volume overload
– massive volume overload
– Patients receiving large amounts of fluids or blood products
– When volume management is critical
Indications for CRRT
Non-renal Indications for CRRT
Lactic acidosis
– Ongoing production
Crush injury
– Myoglobin Removal
Tumor lysis syndrome
Temperature control
– Relative hyper or relative hypothermia*
Massive volume overload without ARF
High NH
3
*Kopcke J. Anaesthesiol Reanim. 1996;21(6):159‐62.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1245
Disclosures
Investigator-initiated grant support from Pfizer,
Genzyme, Satellite HealthCare, NxStage;
DSMB member for Takeda
Copyright Harvard Medical School, 2010. All Rights Reserved.
1246
Board Preparation: ESRD
August 2010
Daniel W. Coyne, M.D.
Professor of Medicine
Director of Hemodialysis
Chromalloy American Kidney Center
Washington University School of Medicine, St. Louis, MO
Conflict of interest statement: consultant, advisor, and speaker for
Abbott; Consultant: INEOS, Watson; Consultant and Speaker, AMAG,
Pharmacosmos; PI in multicenter studies designed and funded by
Abbott, AMAG, Amgen, Genentech, Roche, and Watson
Copyright Harvard Medical School, 2010. All Rights Reserved.
1247
Question 1
The dialysis facility you supervise has an older water treatment
system, but has routinely achieved AAMI water quality
standards. Recently, a new water technician has been hired,
and the city has altered it water supply while performing
treatment plant upgrades.
You note that the mean Hgb is significantly lower in the unit, and
several patients have new severe anemia. Which of the
following water quality problems would not account for these
findings?
A. Chloramines
B. Copper
C. Fluoride
D. Nitrates
Copyright Harvard Medical School, 2010. All Rights Reserved.
1248
Water Delivery Circuits
Idealized Water Treatment System
Water Treatment Components
Prefilters
•particulate removal
Activated Carbon
•organic,chlorine removal
Ion Exchanger/Softener
•exchanges Na for Ca/Mg
Reverse Osmosis
• organic, non-organic removal
• clears bacteria, pyrogens, particulates
Deionizer
• H+ or OH- for other ions
UV light
Ultrafilter
•Kills, destroys or removes bacteria, endotoxin
Copyright Harvard Medical School, 2010. All Rights Reserved.
1249
Water Treatment
Reverse Osmosis
Water-Contamination Problems
Sign/Symptom Possible contaminant / Cause
Anemia Aluminum, chloramines, copper, zinc
Bone Disease Aluminum, Fluoride
Hemolysis Chloramines, copper, nitrates
Hypertension Calcium, sodium
Hypotension Bacteria, endotoxin, nitrates
Metabolic acidosis Low pH, sulfates
Encephalopathy Aluminum
Nausea/Vomiting Bacteria, endotoxin, low pH, nitrates, sulfates,
zinc
Copyright Harvard Medical School, 2010. All Rights Reserved.
1250
Question 2
Question 2: A 48 y.o. woman on hemodialysis for 2 years transfers
to your facility. During the first 10 minutes of her first treatment,
she develops cough, acute dyspnea, diffuse warmth, and
marked anxiety. She is hypotensive in the 70’s and tachycardic.
She denies any history of similar symptoms. Which action
would be most appropriate?
A. Administer NS, give epinephrine 1:1000 SQ, and provide
oxygen NC until transport arrives. Continue dialysis with no
ultrafiltration to remove possible toxin
B. Stop dialysis, and administer NS, consider use of
antihistamines, steroids, and epinephrine.
C. Stop dialysis, administer NS and NC 0
2
. Admit to hospital for
probable pulmonary embolus.
D. Clamp the lines, remove the patient from the machine without
returning the blood. Administer NS, O2, antihistamines,
epinephrine and steroids as needed.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1251
Types of Dialyzers
By Composition
Synthetic - PAN, AN-
69, polysulfone,
PMMA
Substituted Cellulose
–cellulose triacetate
Semi-synthetic –
Hemophan
Cellulose – cuprophan
By permeability
Low Flux
High Flux
Characteristics of Dialyzers
1. KoA: quantitative measure of a dialyzer's
efficiency of clearance
1. defined by membrane porosity and thickness, solute size
and flow rate of blood and dialysate
2. Ultrafiltration coefficient (KUf) - the volume of
fluid (in mL/h) that is transferred across the
membrane per mmHg of pressure gradient
3. Surface Area: Membrane surface within a class
of dialyzers corresponds to the clearance
Copyright Harvard Medical School, 2010. All Rights Reserved.
1252
Definitions: High-flux Hemodialysis
1. Used in most dialysis units
2. Dialyzers with K
uf
> 15 ml/mm Hg/hr
3. Enhanced middle molecule clearance, including beta-2
microglobulin
4. Can have more efficient drug removal
1. e.g. Vancomycin
Dialyzer Reactions
1. TYPE A REACTIONS
2. four of every 100,000 dialysis treatments
3. Begin in the first few minutes of dialysis, immediately after the
return of blood from the dialysis circuit to the patient
4. Occasionally onset is delayed
5. Symptoms
1. itching, burning sensation at the access site, urticaria, flushing, cough,
sneezing, wheezing, abdominal cramps, diarrhea, headache, back and
chest pain, nausea, vomiting, fever, and chills.
2. More severe reactions lead to dyspnea, a sense of impending doom,
and hypotension, potentially resulting in cardiac arrest and death.
6. Patients with an allergic history and eosinophilia appear to be
predisposed to this type of reaction
CAUSES
1. classic cause is ethylene oxide, via preformed IgE antibodies
2. Other leachable agents also can result in this type of reaction
Copyright Harvard Medical School, 2010. All Rights Reserved.
1253
Dialyzer Reactions
1. TYPE A – Anaphylactic type
Causes
1. Ethylene Oxide
2. AN69 (formerly negatively charged membranes)
3. Contaminated dialysate
4. Reuse problems
5. Heparin
6. Pre-existing eosinophilia
Treatment
1. Stop dialysis immediately
2. Do NOT return the blood to the patient
3. Use antihistamines, steroids, epinephrine,
bronchodilators, and pressors as needed based on
symptoms
Dialyzer Reactions
TYPE B Reactions
1. More common and less severe than type A reactions
2. Seen in 3 to 5 percent of patients dialyzed with new
cellulosic membranes
3. Much lower incidence with newer synthetic membranes
Symptoms
1. Delayed, begin within the first 15 to 30 minutes of the
dialysis treatment, occasionally later
2. Chest and back pain, dyspnea, nausea, vomiting, and
hypotension
3. Anaphylaxis is extremely rare.
4. There is generally an improvement in symptoms with
continuation of the dialysis treatment.
Cause: Thought to be complement mediated
Copyright Harvard Medical School, 2010. All Rights Reserved.
1254
Q3. A 28yo woman with bipolar disorder is admitted
with a lithium overdose. She took ~90 pills of LiCO3
300 mg. Her initial lithium level is 8.1 meq/L. Her BP is
100/60, R 98, RR 22. Cr is 0.8 mg/dL
Which is the appropriate definitive treatment?
1. Establish high urine flow of 200-300 ml/hr with
NS
2. Initiate HD of 6 hrs; Qb ~400, Qd ~700
3. Initiate CVVHDF with Qb 200, ~35ml/Kg/hr of
dialysate + replacement fluid
4. Initiate PD with exchanges every 2 hours
Copyright Harvard Medical School, 2010. All Rights Reserved.
1255
Common Poisons Amenable to removal by
Hemodialysis (HD) or Hemoperfusion (HP)
Drug General Conc. for intervention Method of Choice
mg/L mcmol/L (HD, HP)
Phenobarbitol 100 430 HP, HD
Glutethimide 40 180 HP
Methaqualone 40 160 HP
Salicylates 800 4.4 mmol.L HD
Theophylline 40 220 HP, HD
Paraquat 0.1 0.4 HP > HD
Methanol 500 16 mmol/L HD
Meprobamate 100 460 HP
From: Handbook of Dialysis, 4
th
edition, Ed: Daugirdas, Blake, and Ing
Modalities Recommended for Intoxications
Bayliss Hemodialysis International 2010; 14:158–167
Copyright Harvard Medical School, 2010. All Rights Reserved.
1256
General Rules Concerning Drug Removal
by Dialysis
1. Molecular weight
1. < 500 D – well cleared
2. 500 – 2000 D – somewhat cleared
2. Vd > 1 L/kg, very poorly removed
3. High protein binding, poorly cleared
4. Greater lipid solubility, poorly cleared
Q4. A 54yo man on HD for 5 years has undergone a
carpal tunnel release surgery. You prescribed a
narcotic for pain relief. Which of the following is
incorrect?
1. A dose reduction of at least 50% is required for
narcotics in dialysis patients
2. Metabolites of meperidine and propoxyphene
accumulate in renal failure and should be
avoided
3. Evidence of narcotic toxicity in ESRD include
nausea, myoclonic jerking, and delerium
4. Pain after carpal tunnel surgery should be
manageable by acetominephen alone
Copyright Harvard Medical School, 2010. All Rights Reserved.
1257
Question 5
A 48 y.o. man with Type I Diabetes has been on hemodialysis
for 7 years. He has a tunneled catheter, receives 3.5 hr
treatments TIW using a high flux 1.8m
2
polysulfone
dialyzer. A recent single pool Kt/V was 1.27. His typical
intradialytic weight gain is 2.7 kg. His predialysis BP is
142/64 and HR 88. Exam reveals no JVD, clear lungs, an
S4 gallop, and trace ankle edema. He has had recurrent
sudden mid-treatment hypotension despite 2 Kg increase
in his dry weight and a reduction in antihypertensives.
Which of the following actions you recommend to deal with
his intradialytic hypotension?
1. Increase in dry weight
2. Withhold antihypertensives prior to dialysis
3. Initiate sodium modeling with initial Na = 150 meq/L
4. Lower dialysate temperature to 35
o
C
Copyright Harvard Medical School, 2010. All Rights Reserved.
1258
Recurrent Intradialytic Hypotension
Causes
1. Easily corrected
1. Antihypertensives
2. Eating prior to dialysis
2. Dialyzer/Dialysate related
1. Dialyzer Reactions
2. Low sodium dialysate
3. High dialysate magnesium
4. Use of Acetate dialysate
3. Rapid fluid removal/excessive fluid gains
4. Autonomic neuropathy
5. Diminished cardiac reserve
6. Arrhythmias or pericardial effusion with tamponade
Copyright Harvard Medical School, 2010. All Rights Reserved.
1259
Intradialytic Hypotension Therapy
1. Acute Therapy
1. Trendelenburg position
2. Saline
3. Stop Ultrafiltration
4. Debatable: Reduce blood flow rate
2. Chronic Therapy
1. Dry Wgt adjustment
2. Adjust antiHTNives; hold short acting antiHTNives
3. Limit Wgt gains
4. Lengthen time; more treatments
5. Cool Dialysate (35.0 – 35.5
o
C)
6. Midodrine (10mg PO preHD)
7. ?Sertraline – an SSRI (50 to 100 mg QD)
Hemodialysis Induced Acute
Reduction in Cardiac Blood Flow
Dialysis reduced myocardial blood
flow
Reductions of >30% induced regional
wall motion abnormalities
McIntyre CJ ASN 2007
Copyright Harvard Medical School, 2010. All Rights Reserved.
1260
Hemodialysis Induced Cardiac
Stunning
Serial echoes show induction and resolution of
cardiac stunning due to hemodialysis
Note induction of regional wall motion abnormalities
Selby and McIntyre AJ KD 2007
Intradialytic Hypotension
Cool Temp. Dialysis and Midodrine
1. Prospective crossover study of 11
patients with symptomatic intradialytic
hypotension
1. Low temperature dialysis (35.5
o
)
2. Midodrine (10 mg preHD); α-1 adrenergic agonist
3. Combined therapy
2. Cool temperature dialysis
1. Significant increases in the lowest SBP during and after HD
2. Midodrine was equally effective
3. No increased benefits with combination therapy
Copyright Harvard Medical School, 2010. All Rights Reserved.
1261
Cool Temp Dialysate Ameliorates
Cardiac Stunning during HD
Selby et al. CJ ASN 2007
Question 6
1. Your dialysis patient has been scheduled for a
MRI with gadolinium contrast to assess a
suspicious renal mass seen on abdominal CT.
Which of the following is FALSE about
Nephrogenic Systemic Fibrosis?
1. No cases of NSF have been reported in patients with GFR
greater than 60ml/min
2. Radiologic societies recommend never using Gd as a
contrast agent for radiography, computed tomography, or
angiography as a method of avoiding Contrast-induced
nephropathy
3. The differences in incidence of NSF with different Gd
products is most likely due to variance in usage
4. Risk has not been shown to be lowered by prednisone
before and after the procedure
Copyright Harvard Medical School, 2010. All Rights Reserved.
1262
Clinical Characteristics of
Nephrogenic Fibrosing Dermopathy
(Nephrogenic Systemic Fibrosis )
AKA: Dialysis-associated or Nephrogenic
systemic fibrosis
Hardened papules/plaques
Symmetrical
Invol ve limbs and trunk
Advancing edge of lesions described as
“ amoeboid”
Gradual restriction of range of motion
Copyright Harvard Medical School, 2010. All Rights Reserved.
1263
NFD-Clinical Characteristics
Skin Findings
Hardened
papules/plaques
Symmetrical
Involve limbs and trunk
Advancing edge of
lesions described as
“ amoeboid”
Gradual restriction of
range of motion
Other common complaints
pruritis, burning pain,
restricted motion
No arthralgias, fever, or
myalgias
Often mistaken for cellulitis
Edema becomes difficult to
appreciate
Scleral Plaques have been
seen
Systemic Involvement of NFD
Ting et al. Reported fibrotic
infiltration of the psoas, rete
testes, and diaphragm in a
patient with NFD (A and B)
Jimenez et al., Cardiac (D) and
Lung involvement (E)
Ting et al. Arch Dermatol 139: 903-906 (2003) Jimenez et al. Arthritis&Rheumatism 50 (8): 2660-2666 (2004)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1264
NSF
Causes, Course, and Prognosis
1. Probably related to low affinity gadolinium complex
use with MRA
1. Three dialysis treatments removes about 95% of gadolinium
administered
2. Progressive induration, restricted range of motion,
flexion contractions
3. Chronology of visceral involvement is not clear
Q7. Urea blood concentrations rebound following
dialysis. Which of the following do not influence
urea rebound?
1. Urea generation rate of the individual
2. Dialysis access recirculation
3. Cardiopulmonary recirculation
4. Urea compartmentalization
Copyright Harvard Medical School, 2010. All Rights Reserved.
1265
Q8. Which of the following is incorrect about
obtaining a post-dialysis Urea for determination of
URR and Kt/V?
1. Obtain it from the arterial limb of the dialysis
tubing
2. Slow the blood pump to 50-100 ml/min for 30-60
seconds prior to sampling
3. Sampling from another access site provides
better URR accuracy than sampling from the
dialysis ciruit
4. It is minimally affected by the ultrafiltration
volume achieved during the dialysis session
Copyright Harvard Medical School, 2010. All Rights Reserved.
1266
Q9. Which of these factors is not a major influence
on the removal of urea during a dialysis session?
1. The generation rate of urea during the dialysis
session
2. The volume of distribution of urea
3. The treatment duration
4. The urea clearance of the dialyzer (K)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1267
Question 10
A 65 y.o. man with a left forearm graft for 17
months is noted to have a reduction in his
recent Kt/V from 1.4 to 1.2. Which of the
following statements about a change in Kt/V in
a hemodialysis patient is false?
1. It could indicate non-compliance with prescribed time
2. It could indicate a change in protein intake
3. It could indicate incorrect needle placement
4. It could indicate dialyzer dysfunction
5. It could indicate improper sample collection
Copyright Harvard Medical School, 2010. All Rights Reserved.
1268
Question 10
A 65 y.o. man with a left forearm graft for 17
months is noted to have a reduction in his
recent Kt/V from 1.4 to 1.2. Which of the
following statements about a change in Kt/V in
a hemodialysis patient is false?
1. It could indicate non-compliance with prescribed time
2. It could indicate a change in protein intake
3. It could indicate incorrect needle placement
4. It could indicate dialyzer dysfunction
5. It could indicate improper sample collection
Copyright Harvard Medical School, 2010. All Rights Reserved.
1269
Question 11
A 69 kg man in HD for 3 yrs has a left arm loop
graft of 13 months duration. He has had no
recent change in his dialysis prescription. The
last monthly Kt/V values are June 1.5; July 1.4;
August 1.3.
Which of these would be the next appropriate
action?
1. Fistulogram
2. Recirculation study
3. Review treatment flow sheets
4. No action; Kt/V remains acceptable
5. Repeat Kt/V
Causes for Fall in Dialysis Adequacy
Hemodialysis Patients
1. Purpose: determine relative frequencies of
causes of decreasing KT/V
2. Kinetic modeling and recirculation tested for 3
consecutive months
3. Baseline Kt/V = average Kt/V in prior 4 mon.
4. Clinically important fall in Kt/V:
1. decline of 0.2 if the baseline Kt/V was > 1.2
2. decline of 0.1 if the baseline Kt/V was <1.2.
Coyne, J ASN, 1996
Copyright Harvard Medical School, 2010. All Rights Reserved.
1270
Causes of Reduced Adequacy of Hemodialysis
No Cause
Found
32%
Reci rcul ati on
25%
Reduced
Bl ood
Processi ng
42%
Di al yzer
Dysfuncti on
1%
Coyne, J ASN, 1996
n=93/375 sessions
3 consecutive months
Outcomes of Patients With Elevated
Recirculation Results
Coyne, J ASN, 1996
n=22
Copyright Harvard Medical School, 2010. All Rights Reserved.
1271
Physical Examination Features of Vascular
Access Suggesting Dysfunction
1. Fistulas
1. Pulsatile vein
2. Multiple collaterals
2. Grafts
1. Pulsatile flow
2. Palpable transition from pulsatile to thrill
3. Auscultatory transition
Question 11
A 69 kg man in HD for 3 yrs has a left arm loop
graft of 13 months duration. He has had no
recent change in his dialysis prescription. The
last monthly Kt/V values are June 1.5; July 1.4;
August 1.3.
Which of these would be the next appropriate
action?
1. Fistulogram
2. Recirculation study
3. Review treatment flow sheets
4. No action; Kt/V remains acceptable
5. Repeat Kt/V
Copyright Harvard Medical School, 2010. All Rights Reserved.
1272
Question 12
A 62 y.o. man has been on hemodialysis for 3 years due to
ESRD from chronic GN. He recently had an episode of
chest pain, elevated troponin of 6.1, and 2 vessel cardiac
disease at catheterization.
Medical therapy is recommended. Lipid testing showed his
total cholesterol was 185 mg/dL, LDL 117 mg/dL, HDL 36
mg/dL, and TG 138. The Cardiologist recommends
atorvastatin at 20 mg per day, but the patient reports
some muscle soreness in the past with simvastatin.
Which of the following statements is NOT correct…
Copyright Harvard Medical School, 2010. All Rights Reserved.
1273
Question 12 (continued)
Which of the following statements is NOT correct
1. Statins have not been shown to reduce CV events or
deaths in HD patients
2. Use of statin in this patient is not indicated because of
the lack of proven efficacy in trials and the history of
rhabdomyolysis with statin in this patient
3. Uremic dyslipidemia is characterized by a shift in LDL
size to small dense LDL (dsLDL); statin therapy does
not alter LDL particle size
4. There is a higher incidence of dyslipidemia in PD
patients than HD patients
5. Combined statins and fibrates increase the risk of
myalgia and rhabdomyolysis in HD
Die Deutsche Diabetes Dialyse (4D)
Study population: 1255 type II diabetic
haemodialysis patients
Treatment: Atorvastatin 20 mg vs placebo
LDL-cholesterol difference: 1 mmol/l (40 mg/dl)
Follow-up: 4 years
Primary endpoint: Cardiac death, non-fatal MI
or stroke
Copyright Harvard Medical School, 2010. All Rights Reserved.
1274
4D Study Results
Atorvastatin
(619)
Placebo
(636)
Risk ratio
(95% CI)
Primary endpoint 226 243 0.92
(0.77 to 1.10)
P=0.37
Cardiac death 104 129
Non-fatal MI 69 76
Stroke 53 38
AURORA STUDY
Study population: 2776 patients
50 – 80 y.o, on ESRD for > 3
months (mean 3.5 yrs)
Treatment: Rosuvastatin vs placebo
LDL-cholesterol difference: 43%
Follow-up: 1296 patients died in follow up;
~1/2 from CV event
Primary endpoint: Cardiac death, non-fatal MI
or non-fatal stroke
Aurora Study, NEJ M, 2009
Copyright Harvard Medical School, 2010. All Rights Reserved.
1275
AURORA: Principal results
Rosuvastatin
(1389)
Placebo
(1384)
Risk ratio
(95% CI)
1
o
Endpoint
(cardiac death, non-
fatal MI or stroke)
396 408 0.96
(0.84 - 1.11)
P=0.59
All-cause
mortality
13.5 per
100/pt-yrs
14.0 per
100/pt-yrs
0.96;
(0.86 -1.07)
P = 0.51
Aurora Study, NEJ M, 2009
Question 12 (continued)
Which of the following statements is NOT correct
1. Statins have not been shown to reduce CV events or
deaths in HD patients
2. Use of statin in this patient is not indicated because of
the lack of proven efficacy in trials and the history of
rhabdomyolysis with statin in this patient
3. Uremic dyslipidemia is characterized by a shift in LDL
size to small dense LDL (dsLDL); statin therapy does
not alter LDL particle size
4. There is a higher incidence of dyslipidemia in PD
patients than HD patients
5. Combined statins and fibrates increase the risk of
myalgia and rhabdomyolysis in HD
Copyright Harvard Medical School, 2010. All Rights Reserved.
1276
Question 13
A. Which of the following bone result is most likely
with the this laboratory finding:
25D <10 ng/ml for the past 2 years
1. Osteitis Fibrosa
2. Osteomalacia
3. Adynamic Bone Disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
1277
Question 14
A. Which of the following bone results is most
likely with the this laboratory finding:
PTH < 100 ng/ml for 1 year
1. Osteitis Fibrosa
2. Osteomalacia
3. Adynamic Bone Disease
Copyright Harvard Medical School, 2010. All Rights Reserved.
1278
UpToDate ©2005
Adynamic Bone
Osteomalacia
Copyright Harvard Medical School, 2010. All Rights Reserved.
1279
Osteomalacia vs Normal Bone biopsy
http://www.endotext.org/parathyroid/parathyroid8/parathyroid8.html
The 3 figures on the left show
defective mineralization, irregularity
of mineralization fronts (Figure 5A)
high number of osteoid lamellae
(Figure 5C)
broad single tetracycline fluorescent
labels or no label at all, in contrast to
the normal double tetracycline
fluorescent labels (Figures 5E and
5F).
Osteitis Fibrosa
High Bone Turnover
Low Power showing
fibrosis and
disordered bone
formation and
mineralization
Fibrosis and marked
osteoclastic resorption
Fibrosis and
intratrabecular tunnels http://courses.washington.edu/bonephys/opgallery.html
Copyright Harvard Medical School, 2010. All Rights Reserved.
1280
Question 15
A 63-year-old diabetic man has been on hemodialysis for 5
years. He recently transferred to your unit, and you
review his labs (below) and find they are similar to his
previous facilities labs.
He denies bone pain, fractures, heart disease, or problems
with phosphorus control. He dialyzes on a 2.5 meq/L
Calcium bath, and recent Kt/V was 1.55.
Medications include calcium acetate 667 mg, two tabs with
each meal, and cholecalciferol 800 IU per day.
Laboratory studies: Serum: Sodium 140 meq/L, K+ 4.9
meq/L, Chloride 98 meq/L, HCO3 19 meq/L, Calcium 9.7
mg/dL, Phosphorus 4.8 mg/dL, Intact PTH 45 pg/mL,
25(OH)D 47 ng/ml. Which of the following statements
represents appropriate management of this patient?.
Question 15 (continued)
Which of the following statements represents
appropriate management of this patient?
1. The patient should continue on his present
medications. No changes are needed.
2. The patient should stop his cholecalciferol; Calcium
acetate should be stopped in 3 months if his PTH is <
100 pg/ml.
3. The patient should be started on a low dose of an
active vitamin D (such as paricalcitol) to reduce the
risk of a cardiovascular event or death. Cholecalciferol
can be stopped.
4. The patient should have calcium acetate stopped and
sevelamer 1600 mg TID started.
5. Both answer C and D.
Copyright Harvard Medical School, 2010. All Rights Reserved.
1281
Guideline 13C. Adynamic Bone Disease
13C.1 Adynamic bone disease in Stage 5 CKD (as
determined either by bone biopsy or intact PTH
<100 pg/mL [11.0 pmol/L]) should be treated by
allowing plasma levels of intact PTH to rise in order
to increase bone turnover. (Opinion)
13C.1a This can be accomplished by decreasing doses
of calcium-based phosphate binders and vitamin D
or eliminating such therapy. (Opinion)
Copyright Harvard Medical School, 2010. All Rights Reserved.
1282
Phosphate
retention
Low levels of
calcitriol
Hypocalcemia
Hyperparathyroidism
Chronic Renal Failure
1) Avoid Calcium-based Binders
(Use Sevelamer)
2) Avoid Vitamin D
3)? Use 1.0 to 2.0 Ca bath?
4)? Keep PO
4
near 5.5?
*Avoid Vitamin D
Supplementation
?Use Low Ca++
Bath (2.0 or 1.75)
*Use
Sevelamer
Low PTH and Adynamic Bone Disease
(iPTH <100; biPTH < 50-60)
Management of Low PTH in Dialysis
Patients: K/DOQI
Effect of Chronically low PTH: Adynamic Bone Disease
Management
1. Avoid Calcium-based Binders
1. Use Sevelamer (Renagel) or Lanthanum Carb