High Oxalate Concentrations Correlate with Increased Risk for Sudden Cardiac Death in Dialysis Patients

Significance Statement Oxalate is a toxic end product of metabolism that is highly elevated in patients with kidney failure requiring chronic dialysis. Basic research has demonstrated that oxalate is a potential trigger of systemic inflammation, progression of CKD, and cardiovascular complications. The authors conducted a post-hoc analysis of the randomized German Diabetes Dialysis Study of 1255 European patients with diabetes on hemodialysis. In their analysis of 1108 patients, they found those with higher serum oxalate concentrations were more likely than those with lower levels of serum oxalate to experience cardiovascular mortality, particularly sudden cardiac death. These findings suggest oxalate-lowering therapeutic strategies might have potential for decreasing cardiovascular mortality in patients with kidney disease. Background The clinical significance of accumulating toxic terminal metabolites such as oxalate in patients with kidney failure is not well understood. Methods To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of patients with kidney failure requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis (4D) Study; this study included 1255 European patients on hemodialysis with diabetes followed-up for a median of 4 years. The results obtained via Cox proportional hazards models were confirmed by competing risk regression and restricted cubic spline modeling in the 4D Study cohort and validated in a separate cohort of 104 US patients on dialysis after a median follow-up of 2.5 years. Results A total of 1108 patients had baseline oxalate measurements, with a median oxalate concentration of 42.4 µM. During follow-up, 548 patients died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular end point (cardiac death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Patients in the highest oxalate quartile (≥59.7 µM) had a 40% increased risk for cardiovascular events (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [95% CI], 1.08 to 1.81) and a 62% increased risk of sudden cardiac death (aHR, 1.62; 95% CI, 1.03 to 2.56), compared with those in the lowest quartile (≤29.6 µM). The associations remained when accounting for competing risks and with oxalate as a continuous variable. Conclusions Elevated serum oxalate is a novel risk factor for cardiovascular events and sudden cardiac death in patients on dialysis. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in patients on dialysis.