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 kidney failure patients is not well understood. Methods To evaluate serum oxalate concentrations and risk of all-cause mortality and cardiovascular events in a cohort of kidney failure patients requiring chronic dialysis, we performed a post-hoc analysis of the randomized German Diabetes Dialysis Study (4D Study); this study included 1255 European hemodialysis patients 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 cohort and validated in a separate cohort of 104 US dialysis patients 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 died, including 139 (25.4%) from sudden cardiac death. A total of 413 patients reached the primary composite cardiovascular endpoint (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 dialysis patients. Further studies are warranted to test whether oxalate-lowering strategies improve cardiovascular mortality in dialysis patients.

Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association

“…In the German diabetes dialysis (4D) study, patients in the highest oxalate quartile had an increased risk of cardiovascular events (HR, 1.40 [95% CI, 1.08–1.81]) and SCD (HR, 1.62 [95% CI, 1.03–2.56]). 55…”

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

“…Furthermore, it should be noted that turmeric contains a high percentage of water-soluble oxalate, and turmeric doses comparable to those used in some of the studies (~3 g/d) result in a significantly increased urinary oxalate excretion in healthy subjects [ 180 ]. This should raise some caution, as oxalate accumulates in CKD5-HD and high oxalate concentrations in those patients were associated with cardiovascular events [ 181 ]. Table 3 summarizes the molecular responses to pharmacological Nrf2 activation reported in human CKD.…”

Secondary oxalate nephropathy and kidney transplantation

“…Whether CaOx deposition contributes to DGF or reduced allograft function leads to CaOx deposition cannot be determined from these studies. Furthermore, elevated oxalate levels have been associated with an increased risk of sudden cardiac death in dialysis patients [22 ▪▪ ].…”

“…A study of 212 kidney transplant recipients showed that the median plasma oxalate concentration at the time of transplantation was 35.0 μmol/l, and 98% of the patients had levels above normal limits (2.6–11.0 μmol/l) [48]. Another study of over 1100 dialysis patients documented a median level of 42.4 μmol/l [22 ▪▪ ]. Since most patients have high oxalate levels at the time of transplant due to advance kidney disease, there are no particular oxalate levels where intervention is recommended.…”