SUN-309 PLASMA CADMIUM AND RISK OF LATE GRAFT FAILURE AND KIDNEY FUNCTION DECLINE IN KIDNEY TRANSPLANT RECIPIENTS

Abstract

The kidney is the most sensitive organ to cadmium-induced toxicity, particularly in conditions of long-term ongoing oxidative stress. We hypothesized that, in kidney transplant recipients (KTR), the nephrotoxic exposure to cadmium represents an overlooked hazard for preserved graft functioning. We performed a longitudinal cohort study of 672 adult KTR with a functioning graft ≥1 year, recruited at a university setting (2008-2011). A Kaplan-Meier curve, log-rank test, and multivariable-adjusted Cox proportional-hazards regression analyses were performed to assess the prospective association of plasma cadmium with the primary endpoint death-censored graft failure (defined as restart of dialysis or re-transplantation) and the secondary endpoint kidney function decline (defined as doubling of serum creatinine or graft failure). Subgroup prospective analyses were performed according to significant effect-modifiers. Median plasma cadmium was 58 (IQR, 43‒75) ng/L. During 4.9 (IQR, 3.4‒5.5) years of follow-up, 78 KTR developed graft failure (13, 26, and 39 events across tertiles of cadmium; P<0.001). Plasma cadmium associated with increased risk of graft failure (HR 1.96, 95% CI 1.56‒2.47 per 2log ng/L; P<0.001), particularly among patients with abnormal liver enzyme levels (HR 2.62, 95% CI 1.73‒3.95 per 2log ng/L; P<0.001). A dose-response relationship was observed, with a HR of 2.67 (95% CI 1.36‒5.26 per 2log ng/L; P<0.001) and 4.31 (95% CI 2.25‒8.22 per 2log ng/L; P<0.001) for patients in tertile 2 and 3 of plasma cadmium distribution, respectively. Our findings were independent of adjustment for donor, recipient, and transplant characteristics, robust in sensitivity analyses without outliers, and consistent over the secondary end-point kidney function decline. A seemingly significant association of cadmium with all-cause mortality was lost in graft failure-censored analyses.Table 1Association of plasma cadmium with risk of death-censored graft failure (nevents=78) and kidney function decline (nevents=95)ModelsCadmium per 2log (ng/L)HR (95% CI)P valueDeath-Censored Graft FailureCrude1.89 (1.47‒2.43)<0.001Model 11.96 (1.56‒2.47)<0.001Model 21.96 (1.40‒2.75)<0.001Model 31.96 (1.40‒2.76)<0.001Model 42.01 (1.45‒2.79)<0.001Kidney Function DeclineCrude1.66 (1.29‒2.15)<0.001Model 11.78 (1.41‒2.26)<0.001Model 21.77 (1.28‒2.44)0.001Model 31.75 (1.27‒2.42)0.001Model 41.75 (1.27‒2.42)<0.001 Open table in a new tab Multivariable model 1 was adjusted for age and sex. Subsequently, additive adjustment was performed for eGFR, proteinuria, primary kidney disease, transplant vintage, acute rejection, cold ischemia time, human leukocyte antigens mismatches, and deceased donor status (model 2); body mass index, systolic blood pressure, blood glucose, and presence of diabetes (model 3); and, smoking and alcohol use (model 4). View Large Image Figure ViewerDownload Hi-res image Download (PPT) In KTR, plasma cadmium is independently associated with increased risk of kidney function decline and late graft failure. Cadmium-targeted interventions may represent novel risk-management strategies to decrease the burden of late kidney graft failure.