Erythritol and xylitol predict mortality, cardiovascular events, and kidney disease progression in chronic kidney disease: insights from the GCKD study

Background and Aims Erythritol and xylitol are widely used sugar substitutes that have been linked with adverse cardiovascular outcomes in recent observational studies and with a pro-thrombotic state in vivo. As both are predominantly cleared by the kidneys, circulating levels may accumulate in patients with chronic kidney disease (CKD). However, their prognostic relevance for kidney disease progression and long-term outcomes in patients with established CKD remains poorly characterized. Purpose To assess the association of circulating levels of erythritol and xylitol with mortality, cardiovascular events, and kidney disease progression in CKD patients. Methods Levels of erythritol and xylitol were assessed in 5,143 baseline plasma samples of participants from the German Chronic Kidney Disease (GCKD) study using untargeted metabolomics studies. Participants were assigned into quartiles for each sweetener and time-to-event analyses performed using Cox proportional hazards models. Outcomes were all-cause mortality, 4-point major adverse cardiovascular events (4P-MACE: myocardial infarction, stroke, death or vascular events), and a composite kidney endpoint (CKE: >40% estimated glomerular filtration rate(eGFR) decline, eGFR <15 mL/min/1.73 m², initiation of kidney replacement therapy, or renal death). The main model was adjusted for age, sex, diabetes, hypertension, current smoking, LDL cholesterol, HDL cholesterol, triglycerides, hsCRP, eGFR, and urine albumin-to-creatinine ratio (UACR). Incremental prognostic value was assessed using discrimination (Harrell’s C-statistic) and risk reclassification metrics (IDI and NRI) comparing the clinical risk model with versus without erythritol and xylitol. Results Median erythritol and xylitol levels were higher across higher CKD categories The median follow-up of the participants was 10.5 years. Higher baseline erythritol and xylitol levels were consistently associated with adverse outcomes. In fully adjusted models (quartile Q4 vs Q1), erythritol was associated with higher risk of all-cause mortality (hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.78–2.95), CKE (HR 1.70, CI 1.40–2.06) and 4P-MACE (HR 1.46, CI 1.15–1.85). Xylitol showed similar associations with all-cause mortality (HR 1.99, CI 1.57–2.52), CKE (HR 1.65, CI 1.36–1.99) and 4P-MACE (HR 1.34, CI 1.07–1.69). Adding erythritol and xylitol to the clinical risk model improved risk discrimination as assessed by Harrell’s C-statistic and improved risk reclassification as assessed by IDI and NRI. Conclusion In the GCKD study, elevated levels of circulating erythritol and xylitol independently associated with all-cause mortality, cardiovascular events, and kidney disease progression. These findings support erythritol and xylitol as promising biomarkers for risk stratification in CKD. They also suggest that consumption of both sweeteners in patients with CKD should be reevaluated for safety.