Abstract

Introduction 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. Methods We performed a longitudinal cohort study of 672 adult KTR with a functioning graft for at least 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. Results 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 log2 ng/L; P<0.001), particularly among patients with abnormal liver enzyme levels (HR 2.62, 95% CI 1.73‒ 3.95 per log2 ng/L; P<0.001). A dose-response relationship was observed, with a HR of 2.67 (95% CI 1.36‒5.26 per log2 ng/L; P<0.001) and 4.31 (95% CI 2.25‒8.22 per log2 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. Conclusions In KTR, plasma cadmium is independently associated with increased risk of kidney function decline and late graft failure. Cadmium-targeted interventions may represent novel riskmanagement strategies to decrease the burden of late kidney graft failure.