Acute Renal Failure

An Update

Jai Radhakrishnan, MD, MS, FASN, FACC

Associate Professor of Clinical Medicine
Columbia University
Objectives

„Epidemiology of ARF
„Diagnostic workup

„Specific syndromes of ARF

„Treatment and Prevention

ARF-Definitions
Second International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group Crit Care. 2004 Aug;8(4):R204
Changes in mortality in patients with
acute renal failure over 47 years

Ympa YP Am J Med. 2005 Aug;118(8):827-32.

Etiology of ARF

„ Pre-renal
(hemodynamic)
„ Intra-Renal
(parenchymal)
„ Post-renal
(obstructive)
 ARF: Pre-renal

„ Volume Depletion Prostaglandins Angiotensin-II

„ Cardiac
„ Redistribution
„ Hepatorenal
syndrome

„ NSAIDS
„ ACE-inhibitors
Hepatorenal Syndrome:
Diagnostic Criteria
„ MAJOR CRITERIA:
„Chronic/Acute liver disease with advanced hepatic failure and
portal hypertension
„ Low GFR (Creatinine>1.5mg/dL or CrCl<40ml/min)
„ Absence of shock, bacterial infection, nephrotoxin, GI /renal fluid
losses
„ No sustained renal improvement after withdrawing diuretics and
volume expansion (1.5 L NS)
„ Proteinuria<500mg/d and renal usg without obstruction or
parenchymal abnormality
„ MINOR CRITERIA
„ Urine Volume <500ml/day
„ Urine Na <10meq/L
„ Urine RBC<50/HPF
„ Serum Na <130meq/L

Hepatology. 1996 Jan;23(1):164-76

 Efferent and Afferent Arterioles of
Rabbit
100 100
AVP AVP
% Reduction in Lumen Diameter

90 90
NE NE
80 80

70 70

60 60

50 50

40 40

30 30

20 20

10 10

0 0
-14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5

Agonist (Log M) Agonist (Log M)

Efferent Afferent
Edwards AJP 1989
 Terlipressin +/- Albumin In HRS

Hepatology 36 (2002), pp. 941–948

 Hepatorenal Syndrome Type I: Vasopressin in One
Patient
AVP
SPA
120 120

SBP 100 100

SBP
(mm Hg)
(mm Hg)
80 80

60 60

UO 40 40
UO
(cc/h) (cc/h)
20 20

0 0
-6 -4 -2 0 2 4 6 8

Time (hrs)
 Diclofenac Residues as the
Cause of Vulture population
Decline in Pakistan

Nature. 2004 Feb 12;427(6975):

ARF: Post-renal

„ Consider obstruction in every patient with ARF.

„ Sites of obstruction leading to ARF:
„ Bladder neck obstruction
„ Bilateral ureters
„ Urine volume variable.
„ Renal USG or
Bladder catheterization.
ARF: Intra-Renal
„ VASCULAR „ GLOMERULAR
„ Vascular occlusion „ Acute/Rapidly
progressive
„ Atheroembolic
glomerulonephritis
disease
„ Thrombotic
microangiopathy
„ TUBULAR
„ Crystal
„ INTERSTITIAL
„ ATN
„ Interstitial nephritis
Atheroembolic disease

„ ARF precipitated by
angiography
„ Often eosinophilia and
low complement
„ Multi-organ dysfunction,
livedo reticularis, blue
toes
„ Generally irreversible
 Acute Interstitial Nephritis

„ Triad of fever, skin rash

and eosinophilia
„ Eosinophiluria
„ Drugs: penicillin,
cephalosporins, diuretics,
NSAIDS, dilantin
„ Usually completely
reversible upon
withdrawing drug
„ ?Glucocorticoids
 Rapidly Progressive Glomerulonephritis

„ ETIOLOGY
„ Immune complex GN:
-post infectious,SLE, IgAN, SBE,
cryoglobulinemia
„ Anti GBM antibody disease
„ Vasculitis:
-Wegener’s, microscopic PAN,
idiopathic crescentic GN

„ DIAGNOSTIC CLUES
„ Systemic findings
„ Significant proteinuria, RBC,
RBC casts
Crystal-induced ARF

„ Uric acid (tumor-lysis)

„ Oxalate (ethylene glycol)
„ Methotrexate
„ Acyclovir
„ Sulfonamides
Oxalate
„ Indinavir
„ Phospho Soda

Uric Acid
Indinavir- Urine Crystals

Gagnon RF.. Am J Kidney Dis 2000 Sep;36(3):507-515

Osmotic Nephrosis
„ Sucrose
„ Mannitol
„ Intravenous
immunoglobulin
„ Radiocontrast agents
„ Dextran
„ Hydroxyethyl starch

Ebcioglu Z.. Kidney International (2006) 70, 1873–1876.

J Am Soc Nephrol. 2005 Nov;16(11):3389-96.
Etiology of ATN

„ Ischemic
„ All pre-renal causes

„ Endogenous „ Exogenous Toxins

Toxins „ Antibiotics
„ Hemoglobin „ Contrast
„ Myoglobin „ Chemotherapy
„ Light chains „ Org. solvents,
Heavy metals
Radiocontrast Nephropathy
„ Clinical Course:
„ Onset of oliguria within 24 hours
„ Peak creatinine in 4-5 days followed by
recovery in the majority
„ Differential diagnosis: atheroembolic disease
„ Risk factors:
„ Age
„ Chronic kidney disease esp. diabetes
„ Pre-renal azotemia (e.g. cirrhosis, CHF)
„ Volume of contrast
Contrast Nephropathy Risk
S Creatinine> 0.5 mg/dl or > 25%at 48-72 h

Mehran R.. J Am Coll Cardiol. 2004 Oct 6;44(7):1393-9.

Heme Pigment Induced ATN
„ Rhabdomyolysis: traumatic or non-traumatic
„ Intravascular hemolysis
„ Mechanism uncertain: Vasoconstriction,
precipitation/obstruction, toxicity of other
breakdown products
„ Concomitant volume depletion
 Aminoglycoside Nephrotoxicity
„ Non-oliguric renal
failure
„ Onset several days
after treatment
„ Recovery is usually
complete within 3
weeks

Mingeot-Leclercq MP… Antimicrob Agents Chemother. 1999 May;43(5):1003-12.

Top 5 Causes of ARF

„Am J Kidney Dis. 2002 May;39(5):930-6

Urinary Indices in Oliguric ARF

Urinary Index Pre-renal ATN

Osmolality >500 <400

(mOsom/kg)
Sodium (meq/L) <20 >40

Fractional ex of Na <1 % >2%

*UNa / PNa ÷ UCr / PCr

Urine Microscopy

Red Cell Cast WBC Cast

Muddy (granular) Cast Broad Cast

 Workup of Renal Failure
RENAL FAILURE

Acute or Chronic

Post-Renal Renal Pre-Renal

Glomerular Vascular Interstitial Tubular

History, Physical, Urine analysis, USG
Treatment of ATN-2005

SUPPORTIVE CARE
• Acid-base/electrolyte balance
• Fluid balance
• Nutrition
• Review of drugs
• Dialysis:
• PD, HD, Continuous modalities
 Intensity of Renal Support in Critically Ill
Patients with Acute Kidney Injury.

35 ml/kg/h

20 ml/kg/h

N Engl J Med. 2008 May 20. [Epub ahead of print]

Course and Outcome of ATN

„Am J Kidney Dis. 2002 May;39(5):930-6

Pathogenesis of ATN

Bruce A. Molitoris & Robert Bacallao

Tubuloglomerular feedback

„ Endothelin
„ Adenosine

„ Nitric Oxide
„ Prostacyclin
 Pathogenesis of ATN:
Reactive Oxygen Species
„ Source of ROS:
„ Xanthine
Dehydrogenase
„ NADH Oxidase
QUESTION: What preventive strategies
have been consistently shown to be effective
against ATN?
„ Maintaining euvolemia ?
„ N-acetyl cysteine ?
„ Dopamine ?
„ Iso-osmolar contrast ?
Preventive Strategies
„ POSITIVE:
„ Hydration

„ EQUIVOCAL:
„ Bicarbonate

„ N-Acetyl Cysteine

„ Theophylline

„ Isoosmolar Contrast

„ CRRT/Dialysis

„ NEGATIVE:
„ Atrial natriuretic peptide

„ Anti-endothelin

antagonist
„ Fenoldopam
 The Data
Effect on Mortality Friedrich JO; Adhikari N; Herridge MS; Beyene J.
Meta-analysis: low-dose dopamine increases urine output but does not prevent
renal dysfunction or death.
Ann Intern Med 2005 Apr 5;142(7):510-24.

Effect on need for Renal

Replacement Therapy
 High-dose Furosemide for
Established ARF
„ 338 pts with ARF on dialysis
„ Furosemide (25mg/kg IV or 35mg/kg PO, or
matched placebo) daily.
„ No difference in :
„ Survival
„ Renal recovery
„ Shorter time to 2L/day diuresis

Am J Kidney Dis. 2004 Sep;44(3):402-9

Course and Outcome of ATN

„Am J Kidney Dis. 2002 May;39(5):930-6

 ARF Outcomes after Discharge:
Survival
„ 979 pts who
received CRRT
„ 69% in-hospital
mortality
„ Post discharge
survival:
„ 6M: 89%
„ 5 Y: 50%

Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279

ARF: Outcomes after Discharge
Quality of Life

„ 77% assessed health as “Good to excellent”

„ 69% resumed working
„ 57% self-sustaining
„ Most Common Complaints:
„ Loss of energy
„ Difficulty with heavy housework
„ Limited physical mobility

Morgera, S. American Journal of Kidney Disease 2002; 40(2):275-279

Korkeila, M. Nephrology, Dialysis, and Transplantation 2000
Future Developments
„ Biomarkers:
„ Cell-based therapy
 Current Status of Biomarkers

„ Neutrophil Gelatinase-associated Lipocalcin

(NGAL)
„ Kidney Injury Molecule-1
„ Interleukin 18

Nickolas T.. Curr Opin Nephrol Hypertens. 2008 Mar;17(2):127-132

 225

200
Serum Creat Rise
175
Urine NGAL (ng/ml)

150

125

100

75
ARF
50 (n=20)

25

No ARF
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

(n=51)
2 4 6 8 12 24 36 48 60 72 84 96 108 120

Post CPB Time (hours)

Urine NGAL is upregulated 15-fold within 2 hours after CPB in patients who later develop ARF

Lancet. 2005Apr;365(9466):1231-8.
 Urinary NGAL at 2 Hours Post CPB
600

Sensitivity: 100%
500
Specificity: 98%
Urine NGAL (ng/ml) 2 hr post CPB

400
PPV: 95%
NPV: 100%
300

200

100

50
0 0 1 2

ARF No ARF
(n=20) (n=51)

The 2-hour urine NGAL was 50 ng/ml or higher in all patients who subsequently developed ARF

Lancet. 2005Apr;365(9466):1231-8.
Ann Intern Med. 2008 Jun 3;148(11):810-9.
Conclusions
„ ARF is common in hospitalized patients & has a
high mortality
„ A significant number of patients recover
„ The best (and least expensive) preventive
strategy is to maintain euvolumia