Contrast-Induced Nephropathy May Be Linked to Long-Term Adverse Events

Laurie Barclay, MD

June 26, 2009

June 26, 2009 ( UPDATED June 30, 2009 ) — Contrast-induced nephropathy (CIN) is linked to long-term adverse events, according to the results of a study reported in the June 25 Online First issue of the Clinical Journal of the American Society of Nephrology. However, an accompanying editorial disagrees with these findings.

"The relationship of...CIN to long-term adverse events (AEs) is controversial," write Dr. Richard J. Solomon, from Fletcher Allen Health Care in Burlington, Vermont, and colleagues. "Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs."

In a randomized, double-blind trial comparing iopamidol vs iodixanol as prevention strategies for CIN, long-term (≥ 1 year) follow-up was available for 294 participants. Using a χ2 test and Poisson regression analysis, the investigators determined the difference in the incidence of adverse events between patients who went on to have CIN and those who did not, as well as the difference in the incidence of adverse events between patients who received iopamidol or iodixanol. To strengthen and validate the findings and conclusions, the investigators performed the analysis using multiple definitions of CIN.

For all definitions of CIN, participants with CIN had a higher rate of long-term adverse events vs those without CIN. The incidence rate ratio for adverse events was twice as high in those with CIN, after adjustment for baseline comorbidities and risk factors. Participants who were randomly assigned to iopamidol had a lower incidence both of CIN and adverse events.

"The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN," the study authors write. "The specific pathophysiologic connection between CIN and long-term AEs is unclear."

Limitations of this study include inability to determine a dose-response effect and loss to follow-up of 120 patients of the original cohort.

"CIN after exposure to contrast media and defined by changes in SCr [serum creatinine] of ≥0.3 mg/dl and cystatin C increases of 15, 20, and 25% are associated with long-term AEs," the study authors conclude. "This validates the use of these definitions of CIN....These more sensitive definitions should be included as primary outcomes in future randomized clinical trials for CIN prevention."

In an accompanying editorial, Paul M. Palevsky, MD, from VA Pittsburgh Healthcare System and University of Pittsburgh School of Medicine in Pennsylvania, notes that the definitions of CIN used in this analysis differ from those specified a priori for the primary analysis. In particular, the present analysis used even smaller absolute increases in serum creatinine (>0.3 mg/dL vs. >0.5 mg/dL) and smaller relative increases (>15% to >25%) in serum cystatin C.

"Using these definitions, they have converted a 'negative' study to a 'positive' one, reporting higher rates of CIN associated with iodixanol administration as compared with iopamidol," Dr. Palevsky writes. "The authors conclude that the parallel decrease in the incidence of both CIN and adverse clinical outcomes associated with iopamidol as compared with iodixanol supports a causal role for CIN in the development of these outcomes, but have they truly demonstrated causality? Although in this analysis they report lower rates of both CIN and adverse outcomes in the iopamidol group as compared with iodixanol group, this association did not exist in their primary analysis."

Dr. Palevsky also points out that 1-year outcomes were determined in just more than 70% of the original study cohort and that the rates of CIN were similar with both contrast agents when a more conventional definition was used.

"Although results of this analysis do not negate a causal relationship, they are insufficient to support one," Dr. Palevsky concludes. "Rigorous validation of small changes in kidney function as meaningful surrogate end points for CIN will require larger trials—not smaller ones—designed with the statistical power to detect differences in clinically relevant end points. Only then will we be able to sort out the tangled relationship of cause and effect."

Bracco Diagnostics, Inc, supported this study and the underlying Cardiac Angiography in Renally Impaired Patients (CARE) trial and provided research funding to the study authors.

Dr. Palevsky has disclosed no relevant financial relationships.

Clin J Am Soc Nephrol. Published online June 25, 2009.