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number of patients you kill
ADVENTURES IN RENAL
IMAGING
JOEL M. TOPF, M.D.
Clinical Nephrologist
248.470.8163
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.
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:
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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.
H & E Stain: Strange intratubular Van Kossa Stain: Deposits are Hanging out on peritoneal dialysis
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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
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
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.
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
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Henry Ford Hospital
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)
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.)
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:
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
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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.
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.
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.)
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.)
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
Gadopentate
Magnevist 10 minutes 125
dimeglumine
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
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.
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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.
4. The treated mixture and untreated blood is combined and returned to the patient.
The procedure takes approximately 4 hours.
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
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Strategies to Avoid Contrast Nephropathy:
Case report
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
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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-
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?
11-25%
26-50%
>50%
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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.)
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.
8% 24%
6% 18%
4% 12%
2% 6%
0% 0%
.
E
t
t
or
or
or
C
lm
m
A
M
M
h
ta
ay
t
on
pi
-D
os
m
30
12
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.
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
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
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.
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.
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
Cr rise 25%
Cr rise 50%
Anuric ARF
326) that also supported the use of isotonic
bicarbonate.
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Zoungas in the Annals of Internal Medicine analyzed 23 trials of 3,563 patients and
concluded:
• 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.
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.
J o e l M . To p f , M . D .! Noon Conference
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KEY TEACHING POINTS
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Joel M. Topf, MD
Nephrology
248.470.8163
http://pbfluids.com/
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