Anja Pfau1, Theresa Ermer2,3,4, Steven G Coca5, Maria Clarissa Tio6, Bernd Genser7,8, Martin Reichel1, Fredric O Finkelstein3, Winfried März9,10,11, Christoph Wanner12, Sushrut S Waikar13, Kai-Uwe Eckardt1, Peter S Aronson3, Christiane Drechsler12,14, Felix Knauf15,3. 1. Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany. 2. Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 3. Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut. 4. London School of Hygiene & Tropical Medicine, University of London, London, United Kingdom. 5. Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York. 6. Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 7. BGStats Consulting, Vienna, Austria. 8. Mannheim Institute of Public Health, Social and Preventive Medicine, University of Heidelberg, Heidelberg, Germany. 9. Medical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University of Heidelberg, Mannheim, Germany. 10. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. 11. Synlab Academy, Mannheim, Germany. 12. Division of Nephrology, Department of Internal Medicine 1 and Comprehensive Heart Failure Centre, University Hospital of Würzburg, Würzburg, Germany. 13. Section of Nephrology, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts. 14. KfH Kidney Center for Dialysis and Kidney Transplantation, Würzburg, Germany. 15. Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany Felix.Knauf@charite.de.
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.
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.
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