The mitochondrial-derived peptide MOTS-c may refine mortality and cardiovascular risk prediction in chronic hemodialysis patients: a multicenter cohort study.

Introduction Uremic patients exhibit remarkably increased rates of mortality and cardiovascular events, but risk prediction in this setting remains difficult. Systemic mitochondrial dysfunction is pervasive in ESKD and may contribute to CV complications. We tested the clinical significance of circulating MOTS-c, a small mitochondrial-derived peptide, as a biomarker for improving mortality and CV risk prediction in hemodialysis (HD) patients. Methods We conducted a prospective, observational, multicenter study on 94 prevalent HD patients. The study endpoint was a composite of all-cause mortality and non-fatal CV events. The diagnostic and prognostic capacity of predictive models based on cohort-related risk factors were tested before and after the inclusion of MOTS-c. Results MOTS-c levels were higher in HD patients than in controls (p<0.001) and even more elevated (p=0.01) in the 53 individuals experiencing the combined endpoint during follow-up (median duration: 26.5 mo.). MOTS-c was independently associated with the endpoint at either multivariate logistic (OR 1.020; 95%CI 1.011-1.109; p=0.03) or Cox-regression analyses (HR 1.004; 95%CI 1.000-1.025; p=0.05) and the addition of this biomarker to prognostic models including the other cohort-related risk predictors (age, LVMi, E/e', diabetes, pulse pressure) significantly improved the calibration, risk variability explanation, discrimination (ROC-AUC from 0.727 to 0.743; C-index from 0.658 to 0.700) and, particularly, the overall reclassification capacity (NRI 15.87%; p=0.01). Conclusions In HD patients, the mitochondrial-derived peptide MOTS-c may impart significant information to refine CV risk prediction, beyond cohort-related risk factors. Future investigations are needed to generalize these findings in larger and more heterogeneous cohorts.

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S. Karger AG, Basel.