Cases & Commentaries

Compare and Contrast

Spotlight Case
Commentary By Kerry C. Cho, MD; Glenn M. Chertow, MD, MPH

Case Objectives

  • Define contrast nephropathy (CN)
  • List risk factors for CN
  • Implement pharmacologic strategies for
    CN prophylaxis
  • Follow an algorithm for CN risk
    reduction and prevention

Case & Commentary: Part 1

A 76-year-old woman came to the emergency
department (ED) complaining of vomiting, dehydration, and abdominal
pain. An abdominal x-ray revealed a pattern consistent with a
partial small bowel obstruction. She was admitted to the hospital.
Her blood urea nitrogen (BUN) was 32 mg/dL and her creatinine was
1.4 mg/dL. The patient underwent a contrast-enhanced abdominal CT
to look for a lead point in the bowel obstruction. She received no
therapies designed to decrease the risk of contrast
nephropathy.

In this case, we do not know the patient’s
baseline serum creatinine concentration and whether her kidney
function was stable or acutely deteriorating. Given the small bowel
obstruction, she may have been volume depleted due to vomiting and
poor oral intake. If we assume that she has chronic kidney disease
(CKD), and the creatinine of 1.4 mg/dL reflected her baseline, we
can use the MDRD (Modification of Diet in Renal Disease Study
Group) formula (1) (go to related site) to estimate the glomerular
filtration rate (GFR). This formula adjusts for body surface area,
which is necessary when comparing a patient’s estimated GFR
to normal values, or to the levels defining the stages of CKD. Body
surface area of 1.73 m2 is the normal mean value for
young adults. Thus, using the MDRD formula, her GFR would be 37
mL/min/1.73 m2, a rate that would be classified as stage
III (moderate) chronic kidney disease by the National Kidney
Foundation guidelines.(2) However,
since her weight was not provided, we cannot calculate an estimated
creatinine clearance using the Cockcroft-Gault formula.

Administration of contrast in patients with
baseline renal dysfunction can result in contrast nephropathy (CN),
most commonly defined as an increase of ≥ 0.5 mg/dL or
≥ 25% in the serum creatinine concentration within 48 hours
following contrast exposure. Patients with normal kidney function
and no risk factors (Table 1 [3]) have a very
low incidence of CN. In one study of older patients receiving
coronary angiography, the incidence of CN was only 1.2% in patients
without risk factors but increased to 11.2% with one risk factor
and more than 20% with two risk factors.(5) The
incidence of dialysis-requiring CN is much lower, less than 1% in a
large study of 1,826 patients undergoing coronary
intervention.(6)

In addition to the risk factors listed in
Table 1, other
possible risk factors for CN include older age (with normal kidney
function), concomitant use of selected drugs (amphotericin B,
cyclosporin A, tacrolimus, diuretics, and non-steroidal
anti-inflammatory drugs), proteinuria of any cause, and
peri-procedural complications and hypotension. Thus, some risk
factors for CN are modifiable (volume of contrast, type of
contrast, reduced renal perfusion), whereas others are
non-modifiable (ie, patient-related factors such as age, chronic
kidney disease, diabetes, and heart failure).(4)
But whether they are or are not modifiable, it is important to
consider the patient’s level of risk before choosing whether
to perform a contrast study and, if so, whether to employ
strategies that may modify the risk of CN.

Case & Commentary: Part 2

By hospital day number 3, the patient’s
urine output was minimal and the BUN and creatinine had risen to 70
mg/dL and 3.5 mg/dL, respectively. Her small bowel obstruction
continued to improve and no surgical intervention was
necessary.

The timing of this patient’s renal
decompensation is consistent with CN. Unfortunately, there are no
effective therapies for established CN. Thus, physicians should
focus efforts on prevention. Avoiding contrast entirely is the
safest and simplest option. Consultation with a radiologist may
direct the clinician to non-nephrotoxic imaging modalities, such as
ultrasound, magnetic resonance, and nuclear medicine studies.
Computed tomography without contrast may also yield satisfactory
results, depending on the type of clinical situation. Angiography
can be performed with non-nephrotoxic CO2 contrast.
Consultation with a radiologist is often quite helpful in
determining whether alternative studies can provide the needed
imaging without the risk of CN. If contrast cannot be avoided, the
total volume should be minimized. Physicians should avoid other
nephrotoxic drugs if at all possible.

The type of contrast may be important in reducing
the risk of CN. Studies have shown that iso-osmolar and low-osmolar
contrast are less nephrotoxic than traditional, high-osmolar
contrast. A meta-analysis comparing low-osmolar contrast material
with traditional agents found a reduced risk of CN in patients with
chronic kidney disease.(7) A recent
randomized clinical trial found that iodixanol, an iso-osmolar
agent, was less nephrotoxic than low-osmolar iohexol in patients
with diabetes and an elevated serum creatinine concentration
undergoing coronary or aortofemoral angiography.(8)

Pharmacological interventions for CN prophylaxis
include N-acetylcysteine, hydration with saline or isotonic sodium
bicarbonate, and methylxanthines (theophylline and aminophylline).
Ineffective strategies include calcium channel blockers, mannitol,
furosemide, atrial natriuretic peptide, endothelin antagonists,
dopamine, fenoldopam, and hemodialysis. A recent review cogently
summarized the approach to pharmacological prophylaxis for
CN.(9) Given the
low incidence of CN in the general population, prophylactic
strategies should be limited to patients at high risk.

The original report of N-acetylcysteine
prophylaxis appeared in 2000 and garnered considerable
attention.(10) The regimen
includes four oral doses of acetylcysteine, 600 mg twice daily,
starting the day before the contrast study. N-Acetylcysteine
produced a relative risk of 0.1 in the incidence of CN (defined as
increase of 0.5 mg/dL in the serum creatinine concentration)
compared with placebo. Subsequent clinical trials produced
conflicting results, leading to dampening of enthusiasm for this
approach. However, several meta-analyses of acetylcysteine have
also been published, with the majority reporting an overall
benefit.(11)

In part because of the lingering questions
regarding N-acetylcysteine’s true benefits in preventing CN,
a recent trial of isotonic sodium bicarbonate generated significant
interest.(12) One hundred
and nineteen subjects with baseline serum creatinine greater than
1.1 mg/dL were randomized to volume expansion with either isotonic
sodium bicarbonate or normal (0.9%) saline. The infusion rates were
3 mL/kg/hour for 1 hour before, and 1 mL/kg/hour for 6 hours after,
radiocontrast exposure. These patients did not receive
N-acetylcysteine. The incidence of CN (defined as a 25% increase in
serum creatinine within 2 days of exposure) was 1.7% in the
bicarbonate group vs. 13.6% in the saline group. Low rates of CN
were subsequently confirmed in an open-label study of 191 patients
given a simplified isotonic sodium bicarbonate infusion with
radiocontrast exposure.

Hemodialysis and hemofiltration may remove a
fraction of administered radiocontrast, but the relatively low
incidence of CN, even among high-risk patients, does not warrant
their application. The largest hemodialysis trial randomized
subjects to a single hemodialysis session following contrast
exposure but failed to reduce the incidence of CN and other
complications.(13) Marenzi and
colleagues published a controversial study of prophylactic
continuous hemofiltration.(14) Subjects
received hemofiltration immediately before, and for 18 to 24 hours
after, coronary angiography. The hemofiltration group had a lower
incidence of CN (5% vs. 50%). However, because CN was defined as a
change in serum creatinine—and hemofiltration directly
decreases serum creatinine concentration—it is difficult to
interpret the results of this study.

A recent meta-analysis of theophylline and
aminophylline concluded that these agents reduce the rise in serum
creatinine following radiocontrast exposure.(15)
Unfortunately, most of the theophylline and aminophylline studies
did not report the fraction of subjects experiencing a discrete
risk (e.g., ≥ 0.5 mg/dL increase in serum creatinine). So
here, too, it is not entirely clear how best to interpret the value
of these prophylactic therapies.

Case & Commentary: Part 3

Due to continued oliguria and persistent
uremia, hemodialysis was started on hospital day number 5.

The role of CN in the development of end-stage
renal disease is undefined, and the vast majority of cases of CN
are reversible. However, severe or repeated episodes of acute
kidney injury may increase the risk of progressive chronic kidney
disease.

CN has been linked to mortality, morbidity, and
prolonged length of stay. A cohort study of 16,248 inpatients
receiving a variety of diagnostic imaging studies found a mortality
rate of 34% in those with CN compared to only 7% in those without
CN; adjustment for differences in co-morbidities yielded a 5.5-fold
increase in the odds of death associated with CN.(16) Other
investigators reported that in-hospital mortality for patients with
acute renal failure requiring dialysis following coronary
intervention was 35.7%, with a 2-year survival of only
18.8%.(6) In another
study of 359 patients undergoing coronary stenting, CN was
associated with a median length of stay of 6 days, compared with
only 1 day without CN.(17)

How could this complication have been avoided in
this patient? An algorithm for radiocontrast use in high-risk
patients should include risk assessment, avoidance of contrast
exposure, determination of medical necessity, and prophylaxis
(Table
2
).(18,19) Low-risk
patients have a low incidence of nephropathy (1% or less) and need
not receive any prophylaxis. Among high-risk patients, chronic
kidney disease and other risk factors should be considered relative
(not absolute) contraindications to radiocontrast exposure.
Diagnostic information gained from computed tomography may yield
critical diagnostic information or allow an important therapeutic
intervention with potentially life-saving results. Therefore, if a
contrast study is what is required to appropriately manage a
patient at patient at high risk for CN, he or she should receive it
with appropriate prophylaxis and monitoring. In one study, elderly
patients with chronic kidney disease were half as likely to undergo
coronary angiography despite equivalently appropriate clinical
indications.(20)

In summary, CN is a possible complication of
radiographic studies, particularly in patients with baseline renal
dysfunction. The clinician considering the use of a contrast study
in an at-risk patient must consider first the possibility of using
alternative non-contrast–requiring imaging and next the
urgency of the clinical situation and the possibility of delaying
imaging to administer prophylactic modalities. However, urgent
diagnostic studies should not be delayed for fear of inducing
nephrotoxicity, as the delay-associated hazard frequently outweighs
the risk of CN. If contrast is to be administered, all efforts
should be made to avoid nephrotoxic medications before and after
radiocontrast exposure. In addition, the dose of the contrast
should be minimized, and iso-osmolar contrast material is
preferable. Finally, N-acetylcysteine and isotonic sodium
bicarbonate have been shown to decrease the risk of CN in at-risk
patients. However, the current literature does not allow for an
evidence-based choice between these two options, nor does it
support combining both prophylactic agents.

Kerry
C. Cho, MD
Assistant Clinical Professor
Division of Nephrology, Department of Medicine, University of
California, San Francisco

Glenn M. Chertow, MD,
MPH
Associate Professor in Residence
Division of Nephrology, Department of Medicine, University of
California, San Francisco

Faculty Disclosure: Dr. Cho and Dr.
Chertow have declared that neither they, nor any immediate members
of their families, have a financial arrangement or other
relationship with the manufacturers of any commercial products
discussed in this continuing medical education activity. In
addition, their commentary does not include information regarding
investigational or off-label use of pharmaceutical products or
medical devices.

References

1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers
N, Roth D. A more accurate method to estimate glomerular filtration
rate from serum creatinine: a new prediction equation. Modification
of Diet in Renal Disease Study Group. Ann Intern Med.
1999;130:461-70.
[ go to PubMed ]

2. Levey AS, Coresh J, Balk E, et al. National
Kidney Foundation practice guidelines for chronic kidney disease:
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2003;139:137-47.
[ go to PubMed ]

3. Murphy SW, Barrett BJ, Parfrey PS. Contrast
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[ go to PubMed ]

4. Gami AS, Garovic VD. Contrast nephropathy
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[ go to PubMed ]

5. Rich MW, Crecelius CA. Incidence, risk
factors, and clinical course of acute renal insufficiency after
cardiac catheterization in patients 70 years of age or older. A
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[ go to PubMed ]

6. McCullough PA, Wolyn R, Rocher LL, Levin RN,
O'Neill WW. Acute renal failure after coronary intervention:
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1997;103:368-75.
[ go to PubMed ]

7. Barrett BJ, Carlisle EJ. Metaanalysis of the
relative nephrotoxicity of high- and low-osmolality iodinated
contrast media. Radiology. 1993;188:171-8.
[ go to PubMed ]

8. Aspelin P, Aubry P, Fransson SG, Strasser R,
Willenbrock R, Berg KJ, for the NEPHRIC Study Investigators.
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Engl J Med. 2003;348:491-9.
[ go to PubMed ]

9. Ide JM, Lancelot E, Pines E, Corot C.
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pharmacological point of view. Invest Radiol. 2004;39:155-70.
[ go to PubMed ]

10. Tepel M, van der Giet M, Schwarzfeld C,
Laufer U, Liermann D, Zidek W. Prevention of
radiographic-contrast-agent-induced reductions in renal function by
acetylcysteine. N Engl J Med. 2000;343:180-4.
[ go to PubMed ]

11. Nallamothu BK, Shojania KG, Saint S, et al.
Is acetylcysteine effective in preventing contrast-related
nephropathy? A meta-analysis. Am J Med. 2004;117:938-47.
[ go to PubMed ]

12. Merten GJ, Burgess WP, Gray LV, et al.
Prevention of contrast-induced nephropathy with sodium bicarbonate:
a randomized controlled trial. JAMA. 2004;291:2328-34.
[ go to PubMed ]

13. Vogt B, Ferrari P, Schonholzer C, et al.
Prophylactic hemodialysis after radiocontrast media in patients
with renal insufficiency is potentially harmful. Am J Med.
2001;111:692-8.
[ go to PubMed ]

14. Marenzi G, Marana I, Lauri G, et al. The
prevention of radiocontrast-agent-induced nephropathy by
hemofiltration. N Engl J Med. 2003;349:1333-40.
[ go to PubMed ]

15. Ix JH, McCulloch CE, Chertow GM. Theophylline
for the prevention of radiocontrast nephropathy: a meta-analysis.
Nephrol Dial Transplant. 2004;19:2747-53.
[ go to PubMed ]

16. Levy EM, Viscoli CM, Horwitz RI. The effect
of acute renal failure on mortality. A cohort analysis. JAMA.
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[ go to PubMed ]

17. Aronow HD, Peyser PA, Eagle KA, et al.
Predictors of length of stay after coronary stenting. Am Heart J.
2001;142:799-805.
[ go to PubMed ]

18. Maeder M, Klein M, Fehr T, Rickli H. Contrast
nephropathy: review focusing on prevention. J Am Coll Cardiol.
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[ go to PubMed ]

19. Waybill MM, Waybill PN. Contrast
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[ go to PubMed ]

20. Chertow GM, Normand SL, McNeil BJ.
"Renalism": inappropriately low rates of coronary angiography in
elderly individuals with renal insufficiency. J Am Soc Nephrol.
2004;15:2462-8.
[ go to PubMed ]

Tables

Table 1. Risk factors for contrast
nephropathy

Pre-existing chronic kidney disease*

Diabetes mellitus with proteinuria

Multiple myeloma

Large volume of radiocontrast

Congestive heart failure

Decreased renal perfusion

* Most nephrologists would use as a cut-off an
estimated glomerular filtration rate or creatinine clearance less
than 60 mL/min/1.73 m2.

Table 2. Algorithm for reducing the risk of
contrast nephropathy

Kidney function – Estimate kidney
function with either the Cockcroft-Gault formula or the MDRD
formula.

Risk assessment – What risk factors
does the patient have?

Medical necessity – Is contrast
study absolutely necessary? Are there alternative imaging
modalities that can provide equivalent information?

Medical urgency – Is there time for
prophylactic measures and correction of volume status? Spread out
multiple contrast exposures over several days if possible.

Medications – Stop drugs that may
increase contrast nephrotoxicity: diuretics and non-steroidal
agents.

Prophylaxis (in high-risk patients only)
– Prescribe N-acetylcysteine if time permits (i.e., elective
studies). Isotonic sodium bicarbonate should be given to most
patients, except those with volume overload or metabolic alkalosis.
Consider aminophylline in selected high-risk patients requiring
urgent radiocontrast exposure who cannot tolerate volume
expansion.

Contrast material – Minimize the
volume of contrast administered. Use iso-osmolar, non-ionic
radiocontrast material if possible.

Consider nephrology consultation to
assist in risk assessment, patient education, and supportive
care.