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N O O N

C O N F E R E N C E
Yo u gotta e at lunch a n y wa y s, m ig h t a s wel l l e ar n how re duc e t he
number of patients you kill

ADVENTURES IN RENAL
IMAGING
JOEL M. TOPF, M.D.
Clinical Nephrologist

248.470.8163

22201 Moross Road, Detroit • telephone: 313.886.8787 •

f a x : 3 1 3 . 8 8 6 . 4 1 0 3 • w w w. p b f l u i d s . c o m
Introduction
The pattern of modern medical care:
The patient gets sick and presents with a set of symptoms.

Chest pain, shortness of breath

The physician determines a differential of possible diagnosis

Cardiac failure, cardiac ischemia, PE, pneumonia

The physician orders and performs a slate of diagnostic studies

Stress test, CT angio, Chest x-ray, troponins, D-dimers, cultures

After establishing a diagnosis drugs are administered and procedures performed


to cure or alleviate symptoms

antibiotics, thrombolytics, angiogram

A common calculation in determining the treatment is to weigh the risks inherent in


the therapy and compare them to the risks of the disease itself. The more severe the
disease the more toxicity we are wiling to accept in the therapy. Contemporary hospi-
talized patients are so ill that physicians routinely order therapies with huge degrees
of risk and associated morbidity: bypass surgery, chemotherapy, liver transplantation,
radiation therapy; there is nearly no limit to the amount of risk we will take to battle disease.

I believe that physicians have become so used to exposing patients to risk in the
treatment phase that they do not adjust the assessment of risk-benefit when exposing
patients to the risks inherent in diagnostic tests.

The benefit that patients receive from undergoing a diagnostic tests are more difficult
to pin-down than the benefit from treatment. What benefit does a patient gain from
accurately diagnosing a self-limited, spontaneously resolving condition like post-
strep GN? What benefit does a patient gain from accurately diagnosing a fatal and
untreatable condition like metastatic pancreatic cancer? Obviously patients have little

to gain from these procedures when they are successful. So, we should accept
very little risk in the diagnostic work-up of these conditions.
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When determining acceptable risk to patients in the diagnostic phase, you need to
have less tolerance for risk than in the treatment phase.

There are three different diagnostic situations where renal issues figure prominently:

1. The risk of contrast nephropathy with iodinated contrast agents

2. The risk of nephrogenic systemic sclerosis with gadolinium containing


paramagnetics for MRI/MRA
3. The risk of acute renal failure with sodium phosphate for bowel prep prior
to colonoscopy.

Acute phosphate nephropathy! 4


Sodium phosphorous and nephrocalcinosis! 4
Epidemiology! 6
Conclusion! 10
Key teaching points! 11
Gadolinium and Nephrogenic Fibrosing Dermopathy! 12
Nephrogenic Fibrosing Dermopathy! 13
Gadolinium! 13
Epidemiology! 15
Treatment! 16
Conclusion! 17
Key teaching points! 18
Strategies to Avoid Contrast Nephropathy: Case report! 19
Definition of contrast nephropathy! 20
Epidemiology! 20
Consequences of contrast nephropathy! 22
Preventing contrast nephropathy! 24
The Contrast Agents! 24
Hydration Strategies! 25
Acetylcysteine! 29
Key Teaching points! 31

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Acute phosphate nephropathy
CC: I’m still on dialysis

A 61 y.o. Caucasian female presented to my office after being told that she needed temporary
dialysis for acute renal failure. After 6 weeks of peritoneal dialysis there are no signs that her
kidneys are healing. Four months prior, she had started feeling tired and losing weight. Her
primary care doctor did some tests and told her that she had renal failure and sent her to a
nephrologist. This nephrologist performed a kidney biopsy (See below) and told her that she
had acute tubular necrosis, with calcium deposits in her kidneys, but that the glomeruli looked
great and he expected full recovery.

Past Medical History

No history of hypertension, diabetes or heart disease. No history of primary hyperparathyroid-


ism or renal tubular acidosis. Patient has a recto-vaginal fistula from Crohn’s disease that was
surgically repaired 4 months ago.

Patients who receive phosphate containing cathartics occasionally develop severe


acute renal failure. As the biopsy shows, unlike most renal disease the glomeruli are
spared with calcified debris in the tubules.

H & E Stain: Strange intratubular Van Kossa Stain: Deposits are Hanging out on peritoneal dialysis

deposits calcium deposits waiting for my kidneys to get


better.

SODIUM PHOSPHOROUS AND NEPHROCALCINOSIS


Colonoscopy for cancer screening is increasing in the United States. In 2002 over 14
million colonoscopies were performed for cancer screening. Two prep agents are used
in almost all of these procedures: polyethylene glycol (PEG, Golytely) and oral so-
dium phosphate solution (OSPS, Fleet EZ-Prep). Sodium phosphate produces the
superior prep with better patient tolerance according to most analysis. An inadequite
prep increases the likelihood of aborting the procedure or missing a neoplasm.

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While generally safe, OSPS has some theoretical disadvantages compared to PEG.
OSPS causes fluid shifts, allows phosphorous absorption, and has numerous contra-
indications for use in various populations.

In June 2004 Markowitz et al described 5 patients who developed serious renal com-
plications from the OSPS and ushered in a new era of caution regarding colonic prep.
(Markowitz GS, Nasr SH, Klein P, Anderson H, Et al. Hum Pathol 35: 675-684; 2004.)

1 2 3 4 5

demo- 69 white 82 African 55 hispanic 64 African 76 white


male American female American female
graphics
male female

HTN, Pros- HTN HTN HTN HTN


tate Ca COPD DM DM spastic colon
PMH
1° Hyperpara colon perf. CAD/MI obesity
Rad. proctitis

ARB ARB ACEi ARB


HCTZ HCTZ ASA
Meds
glitazone, glitazone
ASA ASA

Cr (GFR) 1.2 mg/dl (64 0.9 (104 mL/ 0.6 (110 mL/ 0.9 (81 mL/ 0.9 (65 mL/
before Na- mL/min) min) min) min) min)
Phos 2 weeks 1 day before 3.5 months 4 months 1 year
before before before before

Cr 6.7 5.2 4.5 2.3 6


after Na- 1 month after 1 week after 2 weeks after 8 weeks later 3 days after
Phos

Cr at Bi- 6.3 4.9 4.0 3.0 8.0


opsy 7 weeks 4 weeks 16 weeks 28 weeks 1 week

Final Cr 8.5 (7 mL/ 4.3 (17 mL/ 3.5 (14 mL/ 3.3 (18 mL/ 3.7 (15 mL/
min) min) min) min) min)
6 weeks after 3 months 5 weeks after 3 weeks after 3 wks after
the bx after bx bx bx bx

All the patients were biopsied and had normal glomeruli (except patient 4 who had
concurrent nodular diabetic glomerulopathy) but significant acute and chronic
changes to the tubules. There were prominent tubule lesions of calcium phosphate.
Patients also had variable amounts of interstitial inflammation.

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OSPS have been used as a cathartic since the 1893. In the early 90’s their use as a
bowel prep agent was recognized. Prior to Markowitz, Fleets was thought of as a be-
nign agent as recognized in its other-the-counter status. The company quotes a rate of
serious adverse events of 1 per 1.4
million doses. Most adverse events
Considerable caution should be ad- are related to inappropriate doses
vised before OsmoPrep Tablets are used or use in inappropriate patients.
in patients with the following illnesses: Despite this enviable safety record
severe renal insufficiency (creatinine there were some warning signals
clearance less than 30 mL/minute), that there maybe problems with
congestive heart failure, ascites, unsta- OSPS.
ble angina, gastric retention, ileus,
Transient hyperphosphatemia is
acute bowel obstruction, pseudo-
ubiquitous and, previously, had
obstruction of the bowel, severe chronic
been thought to be without clinical
constipation, bowel perforation, acute
significance. It is likely that in pa-
colitis, toxic megacolon, gastric bypass
tients with volume depletion and
or stapling surgery, or hypomotility
decreased nephron mass (i.e.
syndrome.
chronic kidney disease) the in-
creased phosphorous load com-

pre-OSPS
2 hr after 2nd dose
8
Serum Phos (mg/dL)

0
Vanner, 1990 Cohen, 1994

bined with increased water reabsorption in the proximal tubules causes a pathologi-
cally elevated intratubular phosphorous concentration. This results in a spontaneous
precipitation of calcium phosphate and permanently damages the tubule and causes
loss of the nephron.

EPIDEMIOLOGY

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Markowitz’s paper
C O N T R A I N D I C AT I O N S T O N A P H O S
resulted in a wave of
SOLUTIONS FOR COLONOSCOPY PREP
case reports and
small case series Renal failure
showing similar find- Hyperparathyroidism
ings. Markowitz
Congestive heart failure
himself published a
definitive article with Liver failure
21 cases. (Markowitz Intestinal obstruction
GS et al. J Am Soc
Nephrol 2005; 16:3389.) The proposed risk factors of
decreased renal function, ACEi/ARB and diuretics were all verified. Case
reports and case-control studies are incapable of estimating the incidence of this prob-
lem. There have been numerous studies that tried to retrospectively determine if this
was a common but unrecognized cause of renal failure or was rare.

Most use a similar methodology of combing a database of colonoscopies and looking


for patients who incidentally had pre- and post-procedure creatinines.

The Bronx VA

Singal et. al. reviewed 311 patients who underwent colonoscopy at the Peters Veter-
ans Hospital in the Bronx New York who incidentally had a creatinine in the 12
months preceding the procedure and the 12 months after the procedure. They found a
tiny difference in the change in the average serum creatinine (0.09 mg/dL lower with
PEG, p=0.005) and a large difference in the number of patients with a 25% increase in
serum creatinine. However, none of the patients had severe irreversible renal failure.
In the three patients
whose creatinines
20%
rose over 2, all re-
20%
25% increase in Cr

turned to pre- 15% p<0.002


colonoscopy levels
within 6 months. No 10%
cases of irreversible 8%
5%
severe renal failure in
OSPS PEG
150+ administrations 0%
of OSPS. Singal AK, Rosman AS, Post AB, Bauman WA, Et
al. Aliment Pharmacol Ther 2008 27, 41-47.

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Henry Ford Hospital

Researchers at Henry Ford Hospital looked at colonoscopies done from 1999-2005.


They excluded pre-existing renal disease, patients without at least one creatinine
within 12 months prior and 6 months after the procedure. This lead to a study popu-
lation of 2,352 patients. OSPS was used in 2,083 and PEG in 269. Eighty-eight of these
patients dropped their GFR below 60 cc/min in the 6 months after the colonoscopy
without an obvious explanation following chart review. There was no association be-
tween using OSPS and developing renal failure (RR 1.14 95% CI: 0.55-2.39). They did find
some general risk factors for developing renal insufficiency after a colonoscopy. See
table.

FA C T O R RR 95% CI What is 13,175 mg/


Age > 65 3.23 2.08-5.03 dL?

African American Race 1.70 1.02-2.83 The concentration


Baseline GFR 60-90 mL/min 5.60 3.18-9.86 of phosphate in a
bottle of Fleets.
Hypertension 2.99 1.73-5.19

ACEi 1.90 1.23-2.95

ARB 2.69 1.43-5.05

Thiazide diuretics 2.26 1.47-3.45

Russmann S, Lamerato L, Marfatia A, Motsko SP. Am J Gastroenterol 2007; 102: 2655-


2663.

University of Pennsylvania Health System

Bruneli performed a case control study of 141 cases of incident ARF following endo-
scopy (25% or 0.5 mg/dL increase in creatinine) and found no association with OSPS.
(Brunelli SM, Lewis JD, Gupta M, et al. J Am Soc Nephrol 18: 3199-3205, 2007)

Archives of Internal Medicine

Case control study of 286 patients with normal kidney function who underwent out-
patient colonoscopy with OSPS compared to 125 age and sex matched controls. Un-
fortunately since nearly everyone who underwent colonoscopy at this institution
used OSPS the investigators had to use control patients who did not get colonosco-

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pies. The control group does allow one to look at the affect of the prep without being
confused by natural age-related loss of renal function.

OSPS Control
80

78
GFR (mL/min)
p=0.20
76
p=0.002
74
p<0.001
72

70
Baseline 6 mo 12 mo

There was a modest but undeniable loss of renal function with use of OSPS. The
authors pointed out that many patients receive multiple colonoscopies over their life-
time and if the damage is additive this could become a real source of significant mor-
bidity. (Khurana A. Arch Intern Med. 2008;168(6):593-597.)

Largest study on the incidence of OSPS associated AKI

The department of defense uses an EMR for all of its beneficiaries around Washington
D.C. This was used to look for prescriptions for PEG or OSPS followed by a proce-
dure code of a lower GI endoscopy. From January 2002 to May 2006 they found 16,826
patients; 9,799 of them had a creatinine in the 12 months prior to the procedure (mean
87±77 days) and the 12 months after the procedure (mean 126±101 days). They state
they tried to restrict the analysis to patients receiving screening colonoscopies. 65% of
the cohort received OSPS, 35% received PEG. The PEG population was older, had
more CKD, more doctor visits, more CHF and were more likely to be on ACEi/ARB.
1.3% of the cohort had a 50% increase in creatinine. On univariate analysis there was
no difference with OSPS and PEG but on multivariate analysis adjusting for a host of
variables (age, DM, blood pressure, CVD, ACEi/ARB, diuretic use, CHF, NSAID,
CKD, proteinuria) use of OSPS was found to have an OR of 2.35 for developing AKI.
No patient required dialysis. Follow-up creatinine were found on 99 of the 114 cases
of AKI. The creatinine returned to baseline in only 16 patients. The authors found an un-
adjusted number needed to harm (NNH) of 263 and an adjusted NNH of 81. (Hurst
FP, Bohen EM, et al. J Am Soc Nephrol 18: 3192-3198, 2007)

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CONCLUSION
In December 2008, the FDA required a boxed warning for OSPS regarding phosphate
nephropathy and identified the following risk groups:

Individuals who appear to have an increased risk of acute phosphate neph-


ropathy following the use of OSPs include persons: who are over age 55;
who are hypovolemic or have decreased intravascular volume; who have
baseline kidney disease, bowel obstruction, or active colitis; and
who are using medications that affect renal perfusion or function (such as
diuretics, angiotensin converting enzyme inhibitors, angiotensin
receptor blockers, and possibly nonsteroidal anti-inflammatory
drugs).

OSPS can have devastating renal complications. Unfortunately we have no idea who
is at risk of developing those complications. The risk profile we develop from case
series (ACEi, diuretics, elderly) looks almost exactly like a population that regularly
receives OSPS without any complications.

Though the risk factors have not been conclusively determined it seems prudent to
avoid using OSPS in patients with any degree of renal insufficiency (even with a
normal creatinine) and to stop ACEi, ARB and diuretics prior to the prep.

The most important next step would be to perform high quality prospective studies
to help determine the true incidence and risk factors for this devastating but rare
complication.

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KEY TEACHING POINTS

Oral Sodium Phosphorous Bowel


Preps
Contraindicated in renal failure
In, apparently, low-risk patients
can cause permanent severe renal
failure
Causes transient hyperphos-
phatemia in all patients
Associated with a small but meas-
urable loss of kidney function in
unselected, low risk patients
Ask about colonoscopy prep in
your acute renal failure review of
systems

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Gadolinium and
Nephrogenic Fibrosing Dermopathy
Chief Complaint: My legs are made of wood.
38 year old dialysis patient complains
of lower extremity edema. The patient
is poorly compliant with fluid restric-
tions and regularly comes in for di-
alysis with 5 to 6 kg of weight gain
since last dialysis. Additionally the
patient has resistant hypertension
with systolic blood pressures running
from 180 to 200.

Past medical history


Diabetic nephropathy resulting in
ESRD, OSA with non-compliance
with CPAP, obesity and recent fever
associated with neck pain. The patient
had an MRI with gadolinium to rule
out a paraspinal abscess.

Physical exam
Remarkable for a pleasant, obese man.
His blood pressure is 180/79 with
lower extremities that have wood-like
skin changes, erythema, and indurated
plaque-like lesions.

Patient course:
The patient is aggressively ultra-filtered with additional treatments and prolonged nocturnal
dialysis. Unfortunately no improvement in the lower extremity edema or wood-like skin oc-
curs. He develops increased erythema resistant to IV antibiotics to treat a presumed cellulitis.
Vascular surgery and infectious diseases suspect inadequate lower extremity circulation. An-
giography shows adequate perfusion and no venous insufficiency.

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A skin biopsy is ultimately performed and shows:

The dermis demonstrates haphazardly arranged collagen bundles and a strikingly increased
number of spindled and plump fibroblast-like cells. There is a distinct absence of inflammatory
cells. The diagnosis is Nephrogenic Fibrosing Dermopathy.

NEPHROGENIC FIBROSING DERMOPATHY


Nephrogenic fibrosing dermopathy (NFD) is now more often referred by the more gen-
eral term nephrogenic systemic fibrosis (NSF) due to pathologic going beyond the skin.

In 2000, Cowper et al. published a case series of 14 hemodialysis patients who had
thickened, hardened skin, features suggestive of
scleromyxedema, however, none of the patients had Scleromyxedema
monoclonal gammopathy. In a later paper the same
group characterized the histology and suggested that A rare connective tis-
this was a new disease entity that had not previously sue disorder which
been recognized. (Lancet 2000;356: 1000-1) causes the skin to be-
come progressively
NFD is an acquired condition that usually occurs in
patients on dialysis. The condition is characterized by thick and hard. It is
swelling of the distal extremities (legs and arms) associated with para-
which then moves proximally (trunk), sparing the protein (usually IgG
face. Skin changes begin with swelling and progresses light chains) diseases
to induration and stiffening joints. Pruritis is a vari-
able complaint. The speed of progression varies from case to case.

GADOLINIUM
Numerous agents and factors were suspected of causing NSF including ACEi, epo-
etin, clotting abnormalities, antiphospholipid antibodies, and acidosis. In January
2006, a case series of 5 patients with NFD was reported in which every patient had
received gadodiamide 2-4 weeks before the initial skin changes. They noted that all
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the patients were acidotic and that 4 control patients that were on dialysis and ex-
posed to gadodiamide but were not acidotic did not develop NFD. The average dose
of contrast was 35 mL. (Grobner T. Nephro Dial Transplant 2006; 21: 1104-1108.)

This was substantiated by a second report of 13 hemodialysis patients who received


gadodiamide 2-75 days (mean 25 days) prior to development of skin changes. The
average dose was 38 mL. However; this group did not find any association with aci-
dosis. (Marckmann P, Skov L, Rossen K, et al. J Am Soc Nephrol 2006; 17: 2359-2362.)

Further corroborating the link between gadolinium and NFD were two reports that
demonstrated gadolinium deposition in the affected areas of the skin biopsies. (Boyd
A, Zic JA, Abraham JL. J Am Acad Dermotol 2007; 56: 27-30.)

Gadolinium contrast agents for MRI/ 98.7 99.5


100 95.6
MRA are rapidly cleared with a half
life of 1.3 hours in healthy volunteers.
78.2
Fraction of gadolinium cleared

In chronic kidney disease the half-life


can be extended from 30 to 120 hours. 75
Dialysis effectively clears gadolinium.
See graph. (study of 70 dialysis pa-
tients, each dialysis session was 4 50
hours long. Okada S, Katagiri K, Et al.
Acta Radiol 2001; 42: 339-341.)

25
With the current hypothesis that gado-
linium is the cause of NSF the FDA
recommends avoiding gadolinium in 0.0
any patient with a GFR < 30 mL/min, 0
any degree of acute renal failure, and Infusion 1 2 3 4
particularly with patients in hepatore- Hemodialysis Treatment
nal syndrome. The FDA also recom-
mends that if “at-risk” patients are exposed to gadolinium that they receive prompt
and repeated (up to 4) dialysis sessions.

There has been an interest (especially from the manufacturers at the number of cases
fractionated by the specific gadolinium compound used. The Dallas VA uses Pro-
Hance and in a retrospective analysis of 198 exposures in hemodialysis patients they
found no cases of NFD. (Clin J Am Soc Nephrol 3: 747-751, 2008). In an animal study,
only rats exposed to gadodiamide developed NFD like symptoms. (Eur Radiol. 2008;
18: 2164-73.)
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GENERIC BRAND D I S S O C I AT I O N NSF CASES: FDA
NAME NAME HALF-LIFE M E D WAT C H

Gadobenate-
MultiHance N/A 10
dimeglumine

Gadodiamide Omniscan 30 seconds 283

Gadopentate
Magnevist 10 minutes 125
dimeglumine

Gadoteridol ProHance 3 hours 9

Gadoverse-
Optimark N/A 20
tamide

EPIDEMIOLOGY
80% of reported cases have been in patients on dialysis and no patients have been
reported with CKD stages 1-3.

Two recent analysis have focused on patients with advanced CKD, not yet on dialysis.
Chrysochou looked at 2,278 Gd-MRI scans in patients not on dialysis and retrospec-
tively looked for evidence of subsequent
Number of scans by CKD stage
NFD over a ten year period in England.
(Clin J Am Soc Nephrol 5: 484-489, 2010) 1,000

They found no cases of NFD. One con- 750


cern is that 65% of the scans used Multi-
500
hance, a Gd compound with an appar-
ently lower rate of NFD and only 2% 250

0
CKD 1

CKD 2

CKD 3

CKD 4

CKD 5

Multihance
Magnevist
Omniscan
Dotarem
Gadovist
Vasovist

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used gadodiamide, a frequent offender.

A few studies have attempted to look at the rate of NFD when following exposure to
gadolinium. Collidge and colleagues found an attack rate of 3.1% when they looked
at a cohort of dialysis patients who underwent MRI with gadolinium. They also
found a tight relationship of gadolinium exposure and increasing diagnosis of NFD.
(Collidge TA,Thomson PC, et al. Radiology 2007: 245; 168.)

Deo and Cowper looked at NSF in and around Bridgeport, Connecticut. They found a
2.4% attack rate per MRI. (Deo A, Fogel M, Cowper SE. Clin J Am Soc Nephrol 2: 264
–267, 2007.)

TREATMENT
Unfortunately there are no proven therapies for NSF. Some attempted therapies in-
clude: oral and topical steroids, cytoxin, extracorporeal photopheresis (ECP), tacro-
limus, IV IG, plasmapheresis, alpha interferon.

In one series from Stanford 5 patients underwent ECP. ECP is an immune modulating
treatment.

1. The patient ingests or is infused with a light-activatable drug, called psoralen.

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2. Blood is temporarily removed from the patients. White blood cells are separated
out and then mixed outside the body with the patient's plasma, saline, heparin,
and 8-methoxyposoralen.

3. The preparation is then passed through a device where it is exposed to ultraviolet


light.

4. The treated mixture and untreated blood is combined and returned to the patient.
The procedure takes approximately 4 hours.

In the Stanford series 3 of the 5 patients reported marked improvement in self-


ambulation with the therapy (after 45 treatments, 6 and 20 weeks) A mean of 20
treatments were required to see an affect. Objective improvement in joint mobility
was modest in the three responders and 2 patients had no improvement. The 60%
response rate is greater than the 20% improvement rate found in most series. (Rich-
mond H, Zwerner J, et al. Arch Dermatol. 2007;143:1025-1030.)

CONCLUSION
NSF is a new disease entity that occurs in dialysis patients. It was first recognized in
2000. NSF is characterized by thickened skin that causes joint contractures. It can
cause fibrosis of the heart, diaphragm and skeletal muscle. It has been associated with
the use of gadolinium contrast used in MRI/MRA. There is no evidence that dialysis
reduces the risk of NSF after gadolinium exposure but since dialysis effectively re-
moves gadolium it is recommended that patients get dialysis immediatley after any
gadolinium exposure.
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KEY TEACHING POINTS

Key teaching points on Nephrogenic


systemic fibrosis
Almost exclusively occurs in pa-
tients on hemodialysis (acute or
chronic)
Exposure to gadolinium is com-
mon to most but not all patients
Gadolinium agents that are more
likely to ionize appear to be higher
risk
The condition is generally irre-
versible and progressive
Avoid gadolinium in all patients on
dialysis and in ARF. Use gadolin-
ium with caution in patients with
significant renal insufficiency

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Strategies to Avoid Contrast Nephropathy:
Case report

Chief Complaint: chest pain


70 year old African American presents to the ER with typi-
cal chest pain.

Past medical history:


Hypertension, hyperlipidemia diabetes and chronic kidney
disease with a baseline Cr of 2.5 mg/dL.

Patient course:
He is admitted to the CCU for unstable angina and rules out
for an MI with serial negative enzymes. Has undergoes
stress test for risk stratification and this shows reversible
ischemia with intact ejection fraction.

He goes for a cardiac catheterization following NAC and generous hydration with isotonic
bicarbonate fluid. During the cath, a high grade lesion in the LAD is stented with a sirolimus
stent. Total dose of low osmolar, non-ionic dye is 220 cc.

On the second day after the catheterization his creatinine rises to 4.5 mg/dL. He remains non-
oliguric. The primary team consults neph- 5
rology. The next day the creatinine is 4.3
Serum Cr mg/dL

4
and nephrology clears the patient for dis-
charge with follow-up. 3
2
At the follow-up visit in one week the
creatine is 3.2 and 2 weeks after the cathe- 1
terization the creatinine is back baseline. 0
Admit
Cath
PCD 1
PCD 2
PCD 3
D/C

PCD 7

PCD 14

Summary

A patient at high risk for contrast


nephropathy gets exposed to contrast for a solid indication, gets sate of the art pro-
phylaxis, but develops contrast nephropathy anyways. Fortunately the patient gets
better without requiring dialysis.

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DEFINITION OF CONTRAST
NEPHROPATHY
The critical question is: Radio contrast nephropathy (RCN)
is one of the leading causes of hospi-
tal acquired acute renal failure (12-
Was there any harm to the 14% of ARF). It follows administra-
patient? tion of iodinated contrast for vascu-
lar visualization in CT scans, angi-
ography and venography. In pa-

No dialysis, no harm? tients who develop contrast nephro-


pathy the creatinine begins rising
immediately after exposure to the
contrast and typically peaks on the fourth day. The creatinine usually takes more than
a week to return to pre-hydration levels.

RCN typically causes non-oliguric acute renal failure.

While over two thirds of patients (68%) will manifest some increase in creatinine, only
increases in creatinine of 0.5 mg/dL or 25% are considered clinically significant and
labelled as contrast nephropathy.

The 0.5 mg/dL comes from a questionnaire sent to attending physicians which asked:

What is the smallest change in creatinine that would cause you to delay a follow-up pro-
cedure or discharge?

Eighty percent of the 84 respondents responded an increase of 0.5 mg/dL or lower.

The 25% increase in creatinine


40% comes from empiric data on 1
1 year mortality

year mortality data based on


30%
change in creatinine following
20% contrast.
10%
EPIDEMIOLOGY
0%
The incidence is generally about
0-10%

11-25%

26-50%

>50%

1-5% in unselected patients but


can rise to a much higher level in
rise in creatinine high risk patients. The numerous
risk factors have been identified

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A d v e n t u r e s i n R e n a l I m a g i n g! 20
in the proliferation of studies on RCN
but two risk factors have been significant Mayo Clinic cardiac cath data
in every study of sufficient power:
40%
chronic kidney disease and diabetes.

Frequency of RCN
(Rihal CS et al. Circulation 2002; 105: 30%
2259-2264.)
20%

10%
Risk factors for contrast
nephropathy 0%

0-1.1

1.2-1.9

2.0-2.9

≥3.0
Chronic kidney disease
Diabetes
Pre-Catheterization Cr
Dose of contrast
DM No DM
CHF
Balloon pump
Dehydration
Advanced age
Furosemide
Mannitol
Proteinuria
Multiple myeloma
Hyponatremia
Male gender
Female gender
Hypertension
Anemia

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CONSEQUENCES OF CONTRAST NEPHROPATHY
Retrospective studies have looked at
the consequences of these modest Levy, Horwitz, Et. al.
increases in creatinine and com-
75% 62%

Hospital Mortality
pared them to patients who did not
60%
develop contrast nephropathy. Levy
found nearly a 5-fold increase in 45% 34% 31%
death among patients with contrast 30%
nephropathy regtardless if they
15% 7%
needed dialysis. (Levy EM, Horwitz
RI, Et al. JAMA 1996; 0%

No CN

CN

CN, no HD

CN and HD
275(19):1489-1494.)

Mayo Clinic Cath Registry


50%

40% 45%
Mortality

30%

20%

10% 15%
10% 12%
0% 4%
2%
6 mo 12 mo 60 mo
Contrast Nephropathy No Contrast Nephropathy
The Mayo clinic has a registry of all the
cardiac catheterizations done at that insti-
tution. (Rihal CS, Et al. Circulation 2002;
105: 2259-2264.) They tracked their pa-
tients for five years following the expo-
sure and looked at mortality based on the
development of contrast nephropathy.
The data is striking:

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The retrospective data is weak and few successful trials have been done with
intension-to-treat analysis. The few that have been done however have supported the
contention that contrast nephropathy itself is harmful and not just a marker of sus-
ceptible patients.

0.9% 0.45% Saline CVVH


10% 30%
Fraction of patients

8% 24%

6% 18%

4% 12%

2% 6%

0% 0%

.
E

t
t

or

or
or
C

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ta
ay

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-D

os

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30

12

Mueller C, Et al. Arch Intern Med Marenzi G, Marana I, Lauri G, et al. N


2002; 162: 329-336 Eng J Med 2003; 349: 1333-40.

contrast

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PREVENTING CONTRAST NEPHROPATHY
The Contrast Agents

While the dose of contrast is an important risk factor for RCN, the nature of the con-
trast agent itself is also a risk factor.

The first generation iodinated


contrast agents were high os- Blood 290
molar. These agents were tested
Iodixanol 290
in a large trial of over 1000 pa-
tients and found to have a low Ioxaglate 600
risk of contrast nephropathy, Iomeprol 620
approximately 2%. In the mid
loversol 702
90’s low osmolar agents
emerged with two advantages: iopromide 770
better quality imaging and pur- iohexol 780
ported lower incidence of RCN.
iopamidol 796
Randomized trials of unselected
patients showed no advantage iopentol 810
to low osmolar agents (RCN
iobitridol 915
2.8% with high osmolar vs.
2.7% with low osmolar agents, diatrizoate 2,000
P=0.85, Harris KG, et al Radiol- iothalamate 2,130
ogy 1991; 179:849-852.), how-
ever there was a trend to im- Osmolality
proved safety in patients at
higher inherent risk. Follow-up studies restricted to high risk patients confirmed this
trend. These low osmolar agents were only low osmolar compared to the first genera-
tion agents. Low osmolar agents were still hypertonic to plasma with an osmolarity of
600-915 mOsm/kg H2O.

There is one contrast agent which is isosmolar to blood, iodixanol. In a pair of well
done randomized controlled trials (one in CT scans and the other in cardiac caths)
iodixanol has been shown to be safer than iohexol in regards to RCN. (Chalmers N,
Jackson RW. Br J Radiol 1999; 72: 701-3. Aspelin P, Aubry P, Fransson SG, et al. N Eng
J Med 2003; 348: 491-9.)

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Iodixanol Iohexol

Aspelin data on Cardiac Cath


30%
Frequency of CN

20% 25%

10% 15%
3%

0%
Cr rise >0.5 Cr rise >1.0

Two subsequent studies (ICON by Mehran and CARE by Solomon) have challenged
this conclusion while the RECOVER trial by Jo support the use of isosmolar agents.

Hydration Strategies

Half normal saline

The traditional standard of care for preventing RCN is hydration with half normal
saline one mL per Kg for 12 hours before and 12 hours after exposure. The interesting
thing is this has never been tested in a RCT except as the control group in a negative
trial.

The Solomon trial (Solomon R, et al. N Engl J Med 1994; 331: 1416-20) looked at fu-
rosemide vs. manitol vs. placebo. All three groups received hydration with half nor-
mal saline.

The control group did less


bad than either of the ex-
perimental groups, thus
crowning half normal sa-
line as the champion and
standard of care.

Isotonic saline

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The best study on hydration is a German study by Christian Mueller who hypothe-
sized that “If half normal saline was good, then full normal normal saline should be
twice as good.” He randomized 1,620 patients undergoing coronary angioplasty to
either 0.9% Saline for 24-hours or 0.45% saline for 24-hours. The patient population
was relatively low risk: 20% CKD, 16% diabetes, 65% hypertension, 16% EF< 45%.

Despite the low risk profile there was less than half as much CN with the normal sa-
line (p=0.04). This advantage was extended in three prospectively determined sub-
groups: women, patients with diabetes and patients receiving high volumes of con-
trast (>250 mL). There was no advantage among patients with CKD (Cr > 1.3) P=0.36.

6%
Freq. of RCN

4%
0.9% Saline
0.45% Saline 2%

0%
Women

Diabetes

> 250 mL

CKD

Isotonic bicarbonate

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With isotonic saline crowned as superior to hypotonic fluids the question progressed
to whether chloride was the ideal anion to associate with sodium. In 2004 Merten, et
al published a randomized control trial of isotonic bicarbonate versus isotonic saline.
(Merten, Et al. JAMA 2004; 291: 2328-2334.) The study looked at 120 high risk popula-
tion: average creatinine 1.8, 48% diabetics and 95% cardiac catheterizations.

They found a 14% rate of CN with NaCl and 2% with Na Bicarbonate.

This study was criticized because the data safety monitoring board stopped the study
early and probably shouldn’t have.

The RENO trial randomized patients going for emergency PCI. (Recio-Mayoral A,
Chaparro M, Prado B, et al. J Am Coll Cardiol 2007; 49: 1283-8) Sodium bicarbonate
plus NAC versus isotonic salinie. Unfortunately this study had three variables which
varied between the control and experimental groups making it impossible to tease
out the relative contributions of the individual factors

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The study demonstrated a powerful treatment effect:

Experimental Control
CONTROL E X P E R I M E N TA L
RENO Trial
0.9% Saline Isotonic bicarbonate
32
1 mL/kg for 5mL/kg bolus over 1

Incidence of RCN (%)


12 hours after hour then 1.5 mL/kg
24
exposure for 12 hours

600 mg of 2400 mg of IV NAC


16
NAC q12h x2 with the initial bolus
following
exposure 8

Masuda, Ozcan and Briguori all performed 0


additional trials of various sizes (n=59, 264,

Cr rise > 0.5

Cr rise 25%

Cr rise 50%

Anuric ARF
326) that also supported the use of isotonic
bicarbonate.

• Masuda M, Yamada T, Mine T, et al.


Am J Cardiol 2007; 100: 781-6.

• Ozcan EE, Guneri S, Akdeniz A, et al. Am Heart J 2007; 154: 539-44.

• Briguori C, Airoldi F, D-Andrea D, et al. Circulation. 2007; 115: 1211-7.


In 2008, Maioli and Brar published two larger trials (n=502, 353) of isotonic bicarbon-
ate that showed no benefit.

• Maioli M, Toso A, Leoncini M, Et al. J Am Coll Cardiol, 2008; 52:599-604


• Brar SS, Yuh-Jer Shen A, Jorgensen MB, Et al. JAMA, 2008; 300:1038-1046
Further confusing the issue were two meta-analysis published in 2009 with conflict-
ing conclusions. Navaneethan published a meta-analysis in AJKD of 12 trials repre-
senting 1,854 patients but did not include Maioli’s data. He concluded:

Hydration with sodium bicarbonate decreases the incidence of contrast-


induced nephropathy in comparison to hydration with normal saline with-
out a significant difference in need for renal replacement therapy and in-
hospital mortality.

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Zoungas in the Annals of Internal Medicine analyzed 23 trials of 3,563 patients and
concluded:

The effectiveness of sodium bicarbonate treatment to prevent CIN in high-


risk patients remains uncertain. Earlier reports probably overestimated the
magnitude of any benefit, whereas larger, more recent trials have had neu-
tral results.

• Navaneethan SD, Singh S, Appasamy S, Et al. Am J Kidney Dis. 2009 53: 617-
27.

• Zoungas S, Ninomiya T, Huxley R, Et al. Ann Intern Med. 2009; 151: 631-8.

Acetylcysteine

In 2000 Mark Tepel published a small study on contrast nephropathy in the New Eng-
land Journal of Medicine. It was a small under powered study that had business be-
ing significant, except it was. He randomized 41 patients to acetylcysteine and 43 to
placebo. All patients underwent a contrasted CT scan and 10 developed contrast
nephropathy, 1 from the acetylcysteine group and 9 from the placebo group. Over-
night this changed our approach to contrast nephropathy.

N-acetylcysteine was previously used to restore glutathione levels in Tylenol toxicity


and to break up mucous when given by nebulizer. It is cheap and safe. In rats the
LD50 is 7,888 mg/kg.

Despite the immediate


and widespread adop-
tion of acetylcysteine
there was a deep level of
skepticism in the neph-
rology community.
Within a year and a half
the journals were awash
in acetylcysteine studies
and shortly after that, a
slew of meta-analysis
filled the land.

Despite variations in
technique the general

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consensus of the meta-analysis was that acetylcysteine worked. It appeared to reduce
the incidence of contrast nephropathy by roughly 60%. The problem was it didn’t
seem to prevent any patient oriented outcome. Acetylcysteine prevents the creatinine
from rising more than 25% or 0.5 mg/dL but it has not been able to prevent dialysis,
major adverse cardiovas-
cular events or death.

This maybe because ace-


tylcysteine alters creati-
nine handling in the
proximal tubule. Acetyl-
cysteine, actually accel-
erates the excretion of
creatinine resulting in
decreased serum creati-
nine.

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KEY TEACHING POINTS

Key teaching points on Contrast


Nephropathy
CN is rare (0-2%) in low risk
groups
Incidence can exceed 70% in
some high risk groups (CKD)
Even if it doesn’t progress to dialy-
sis, CN increazses hospital mortal-
ity
There is no treatment, only pre-
vention
Avoid or minimize contrast expo-
sure in high risk groups
Use isosmolar contrast
Use isotonic saline or bicarbonate
at the highest tolerable dose
Use acetylcysteine 600-1200 mg
bid for four doses but it may not
work.

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Joel M. Topf, MD
Nephrology
248.470.8163
http://pbfluids.com/

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