Contrast-Induced Nephropathy: Back to Basics

Contrast-induced nephropathy (CIN) represents a significant clinical problem in the United States, where more than 1,000,000 patients undergo cardiac catheterization procedures every year. This makes catheterization the second most frequent in-hospital operative procedure performed, and also makes it the most common cause of in-hospital acute renal failure after surgical procedures and hypotension.1 The consequences in the short and long term for patients who develop CIN are well described and are serious in terms of prognosis, hospitalization length, cost, and problems of renal replacement therapy. Despite its importance, knowledge of the precise pathogenesis of CIN still is unclear and a matter of debate and active research. The problem has been lingering as an unresolved puzzle since the first case of CIN was described in 1942 by Pendergrass and colleagues.2 As a consequence of our insufficient understanding of this injurious process, many different strategies aimed at preventing and treating CIN have been generally unsuccessful in previous clinical studies. Hydration with intravenous fluids is the only universally accepted approach to prevent CIN. Pharmacological agents including theophyline, adenosine, natriuretic factors, calcium channel blockers, endothelin receptor antagonists, mannitol, diuretics, dopamine and other even more complex approaches have failed to provide much benefit uniformly. The favorable results recently obtained with the use of n-acetylcysteine and fenoldopam have rekindled interest in preventing CIN among many clinicians and in particular among interventional cardiologists. In 2000, an article by Tepel and colleagues in the New England Journal of Medicine3 reported a study performed in patients undergoing computed tomography. An older drug, oral n-acetylcysteine, a free-radical scavenger, was successful in preventing CIN when given before and after contrast administration. At the same time, other groups started to provide some promising evidence that fenoldopam, a selective dopamine-1 receptor agonist approved for the treatment of hypertension, was also useful in preventing CIN in patients at higher risk. Since then, over a hundred papers have been registered in the National Library of Medicine focusing on CIN. All of them provide evidence for or against some form of therapy, but without yet providing any definitive insight or final answer on how to prevent or help patients who develop CIN. In this current issue, two new communications are brought to the readers regarding this still-undecided topic. First, a review of the literature which summarizes most of the general knowledge regarding CIN by Gomes and colleagues; and secondly, a study by Tadros and colleagues, which addresses the use of n-acetylcysteine for the prevention of CIN. This second study focuses on the same question addressed by the study of Tepel et al.: does n-acetylcysteine help to prevent CIN or not? The answer is relevant, considering the limited options available to prevent CIN in the catheterization laboratory. Six studies recently published have addressed this same question. The results have been mixed: three were positive,4–6 and four7–10 were negative. Although there are several groups currently pooling the data of the published studies to attempt different meta-analyses, in reality the studies are difficult to compare because they enrolled small and differing ethnic populations with different baseline renal function, and used different regimens of hydration, methodology, and contrast media. Unfortunately, the study by Tadros et al. doesn’t help clarify the current conundrum. As pointed by its authors, the study involved a small number of patients without randomization. Different types of contrast media were used. Importantly, the comparison was based on historical controls without a pre-established regimen of intravenous fluids. This likely resulted in suboptimal hydration for today’s clinical practice for both the control and study groups. There were differences in the baseline weight between both groups, which influences the volume of distribution of the contrast agent, and importantly, there were differences in the creatinine values between the study and control groups at baseline. Also, the small number of patients severely limits the power of any sub-group analysis. The best evidence that we have so far regarding n-acetylcysteine probably is the study published by Kay and colleagues from Hong Kong.6 This particular study was positive in suggesting that n-acetylcysteine might be useful preventing CIN with cardiac catheterization procedures. Nevertheless, a well-designed and adequately powered, multicenter, randomized, placebo-controlled trial is urgently needed to help answer this important question regarding the use of n-acetylcysteine for cardiac catheterization procedures. The currently ongoing CONTRAST study is attempting this in trying to address all the same questions using fenoldopam. Contrast-induced nephropathy is a growing problem for the interventional cardiologist as the population grows older, with more complex medical problems, and with more cardiac catheterizations and percutaneous interventions being performed than ever. Perhaps we need to go back to basics and focus on the problem from a totally different point of view, trying to understand better the mechanisms involved in radiographic contrast renal injury. New successful strategies to prevent CIN are awaiting creative researchers to bring new solutions to the clinical arena based on a better understanding of the interactions between contrast media and renal function. Also, other approaches need to be welcomed, including new imaging modalities like magnetic resonance, which may be able to achieve contrast-enhanced angiography using a non-nephrotoxic agent like gadolinium. In the meantime, we seek the best evidence-based strategies to prevent CIN, all the while using abundant intravenous and oral hydration and as little contrast as possible.

1. D’Elia JA, Gleason RE, Alday M, et al. Nephrotoxicity from angiographic contrast material: A prospective study. Am J Med 1982;72:719–727. 2. Pendergrass EP, Chamberlin GW, Godfrey EW, Burdick ED. A survey of deaths and unfavorable sequelae following the administration of contrast media. Am J Radiol 1942;48:741–762. 3. Tepel N, Van der Giet N, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343: 180–184. 4. Diaz-Sandoval L, Kosowsky B, Losordo D. Acetylcysteine to prevent angiography-related renal tissue injury (APART trial). Am J Cardiol 2002;89:356–358. 5. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002;40:1383–1388. 6. Kay J, Chow WH, Chan TM, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA 2003;289:606–608. 7. Durham JD, Caputo C, Dokko J, et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int 2002 62:2202–2207. 8. Boccalandro F, Amhad M, Smalling RW, Sdringola S. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Cathet Cardiovasc Intervent 2003;58:336–341. 9. Allaqaband S, Tumuluri R, Malik AM, et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Cathet Cardiovasc Intervent 2002;57:279–283. 10. Briguori C, Manganelli F, Scarpato P, et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002;17;40:298–303.