Radiocontrast Nephropathy: A Time for Affirmative Action

Contrast-induced nephropathy (CIN) is a well-recognized risk of coronary angiography and percutaneous coronary intervention (PCI), with an overall estimated incidence up to 15% and less than 1% incidence of severe CIN requiring dialysis.1 Although the pathogenesis of CIN is not entirely clear, several mechanisms for dye-induced renal injury have been proposed, including alterations in renal medullary perfusion,2 direct cytotoxicity,3 and oxygen-free radical generation.4 Despite major advances in catheter-based technology and adjunctive antithrombotic therapy, the risk of CIN has remained unchanged over the past decade. This is a disturbing fact, since even mild degrees of post-PCI renal dysfunction portend poor clinical outcomes.5,6 With ever-improving refinements in device technology, PCI has become the dominant form of coronary revascularization. This year 800,000 PCI procedures will be performed in the United States, more than double the number of coronary artery bypass (CABG) surgeries. A procedural volume of this magnitude emphasizes the need for vigilance, among interventional cardiologists, to identify predictors of radiocontrast nephropathy and prevent its occurrence. Recognizing the major predisposing risk factors for CIN is pivotal in its prevention. The single most important risk factor for CIN is baseline renal dysfunction.7 Other reported baseline characteristics and comorbidities that impart an increased risk include the volume of contrast administered,8 diabetes mellitus, congestive heart failure, volume depletion, and the concomitant administration of nephrotoxic drugs such as nonsteroidal anti-inflammatory agents. Not surprisingly, given the age-related decline in glomerular filtration rate (GFR), octogenarians have a three-fold increase in the occurrence of CIN.9 Whether the incidence and clinical outcome of contrast nephropathy have a particular gender predilection is not known, and is a question that Iakovou et al. address in this issue of the Journal. The study by Iakovou and colleagues is a retrospective single-center analysis of 8,628 consecutive patients who underwent PCI between 1994 and 1999. The occurrence of contrast nephropathy, defined as >= 25% increase in See Iakovou et al. on pages 18–25 serum creatinine concentration within 48 hours, was higher among female patients compared with males (23.6% vs. 17.4%; p = 1.5 mg/dl, was present in 3.2% of females and 2.9% of males. Among patients with no baseline renal impairment, there was a significantly higher incidence of hypertension and diabetes among female patients than among their male counterparts, and females in this group were significantly older. Further, females expectedly had a smaller body surface area (BSA) than males. A multivariate analysis model incorporating a number of established risk factors for the development of CIN identified baseline renal insufficiency, diabetes mellitus, female gender and hypertension as independent predictors of CIN. Among patients with normal baseline renal function, the volume of contrast used relative to BSA was significantly higher in females compared with males. In an analysis of outcomes of patients without baseline CRI who sustained CIN, females tended to have higher rates of in-hospital mortality and Q-wave myocardial infarction (MI) than males. There were no significant gender differences regarding in-hospital mortality or MI among patients with baseline CRI. In the overall cohort of patients with CIN, a Cox proportional hazards method revealed that CRI, diabetes, age, and class IV congestive heart failure predicted one-year mortality. Interestingly, one-year outcome analyses by gender showed a strong trend for higher mortality among females than males in the cohort of CIN patients with no baseline CRI (14 vs. 10%; p = 0.05), and for a higher incidence of adverse cardiac events in female patients (36 vs. 30%; p = 0.06). There were no gender differences in one-year outcomes among patients with baseline CRI. Results from this analysis reaffirm previously identified risk factors for the development of CIN, such as baseline CRI, diabetes and hypertension, but also suggest that female gender is an independent predictor of radiocontrast nephropathy. Moreover, the authors conclude that female gender is a marker of higher one-year mortality among CIN patients with normal baseline renal function. Several key questions are raised by this study. Is female gender really a risk factor for the development of CIN and a marker of worse outcomes among CIN patients? Are there confounding variables that may account for the findings in this study? Are there physiological and “hormonal” mechanisms that may justify these findings? How should we change our clinical approach based on these findings? Before concluding their findings as definitive, Iakovou et al. appropriately recognize several limitations to this study, including the definitions used for CIN and for baseline CRI, the lack of any creatinine clearance estimates, and the retrospective design per se. Females were older on average than their male counterparts, were administered higher volumes of contrast relative to their body habitus, had significantly higher rates of diabetes, hypertension, procedural vascular complications and blood transfusions (therefore, at least transient, hypovolemia), all of which are known risk factors for CIN and markers of poor long-term outcomes in PCI patients. It is conceivable that a combination of such factors could be, at least in part, responsible for the higher apparent mortality among females who develop contrast nephropathy. The mean serum creatinine between men and women identified with baseline renal insufficiency is also not reported. Further, these results must be cautiously interpreted given the potential for chance findings based on multiple comparisons. Although there is a scarcity of data regarding the effect of gender on the development of contrast nephropathy, the findings of Iakovou et al. contradict those of a previous randomized controlled trial of ionic vs. non-ionic contrast media, in which a multivariate analysis identified male gender as an independent risk factor for CIN.10 A wide spectrum of human diseases exhibit gender differences in risk factors, incidence, and outcomes. Several parameters of renal physiology have been shown to vary with changes in the hormonal milieu. Specifically, estrogen receptors have been identified in kidneys,11 although their physiologic role is not entirely clear. Ovarian hormones have been shown to modulate renal blood flow in multiple studies. Estrogens and progestins supplements significantly reduce renal blood flow and activate the renin-angiotensin system.12 Animal studies have shown that 17-beta-estradiol enhances nitric oxide-dependent relaxation in renal arteries.13 Estrogens have also been shown to modulate the activity of renal tubular cell lysosomal enzymes like cathepsin B, D, and L.14 Any of these renal vascular or cellular effects of ovarian hormones could potentially influence the nephrotoxicity of contrast agents. What lessons can we derive from the findings in the present study? The significant difference in BSA between female and male patients calls attention to the issue of whether creatinine clearance (CrCl), rather than absolute serum creatinine level, ought to be systematically used for risk assessment and decisions regarding prevention strategy. In this study, aggressive pre-hydration was reserved for patients with a baseline creatinine >= 1.5 mg/dl. Serum creatinine level is a crude indicator of true glomerular filtration rate, whereas CrCl, calculated using the Cockcroft-Gault formula,15 has been repeatedly shown to be a more reliable indicator of GFR.16 CrCl is computed using the following formula: CrCl (ml/minute) = ([140-age] x weight [kg])/(serum creatinine [mg/dl] x 72) CrCl Female = 0.85 x CrCl Accordingly, a 65-year-old, 65 kg female with a serum creatinine level of 1.2 mg/dl has a CrCl of 48 ml/minute. This represents a worse renal function than that of a 40-year-old, 90 kg, male with a serum creatinine of 2.2 mg/dl (CrCl of 57 ml/minute); yet, the latter patient would systematically be labeled as having “renal insufficiency” whereas the former may not. Randomized clinical trials of different strategies in the prevention of contrast nephropathy have often used a creatinine clearance

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