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

Abstract

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.

Keywords: cardiovascular disease; chronic hemodialysis; chronic kidney failure; oxalate; sudden cardiac death; uremic toxins.

Graphical abstract

Figure 1.

Oxalate concentrations and the risk of mortality/cardiovascular events in 1108 patients (4D Study cohort) with kidney failure requiring chronic HD (Forest plot). Multivariable-adjusted HRs and 95% CIs (error bars) for all-cause mortality, combined cardiovascular events, sudden cardiac death, death due to heart failure, myocardial infarction, and stroke in the 4D Study cohort stratified by oxalate concentrations at baseline (quartiles). Models are adjusted for age, sex, use of atorvastatin, time on HD, use of diuretics, C-reactive protein, body mass index, hemoglobin, albumin, and previous coronary artery disease (core model).

Figure 2.

Risk of (A) combined cardiovascular events and (B) sudden cardiac death as a function of continuous oxalate exposure in the 4D Study (restricted splines). Risk was assessed using restricted cubic spline modeling, and adjusted for age, sex, use of atorvastation, time on dialysis, use of diuretics, C-reactive protein, body mass index, hemoglobin, albumin, and previous coronary artery disease (n=1108). The black line represents the HR, the grey lines indicate the upper and lower 95% CIs. The pink dashed line marks an HR of 1.0.