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

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

3. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol. 2000;11:177-82. [ go to PubMed ]

4. Gami AS, Garovic VD. Contrast nephropathy after coronary angiography. Mayo Clin Proc. 2004;79:211-9. [ 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 prospective study. Arch Intern Med. 1990;150:1237-42. [ go to PubMed ]

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8. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ, for the NEPHRIC Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003;348:491-9. [ go to PubMed ]

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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. 1996;275:1489-94. [ 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. 2004;44:1763-71. [ go to PubMed ]

19. Waybill MM, Waybill PN. Contrast media-induced nephrotoxicity: identification of patients at risk and algorithms for prevention. J Vasc Interv Radiol. 2001;12:3-9. [ 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

* 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