#1228 MOTS-c improves CV and mortality risk prediction in chronic hemodialysis patients: a prospective, multicenter cohort study

Abstract

Abstract Background and Aims Cardiovascular disease (CVD) is the leading cause of death in patients with end stage kidney disease (ESKD), especially in those undergoing chronic hemodialysis (HD), but correct risk prediction in this setting is often complicated. The mitochondrial open reading frame of 12S rRNA type-C (MOTS-s) is a peptide encoded by mitochondrial DNA, mainly expressed by cardiac and skeletal muscle tissues, which may prevent CVD thanks to its remarkable anti-oxidant capacities. From a clinical point of view, altered circulating MOTS-c levels predict worsen CV outcomes, particularly among diabetic individuals or post-AMI patients. Mitochondrial dysfunction is highly pervasive in HD patients. Starting from this background, we aimed at evaluating the clinical significance and predictive usefulness of measuring circulating MOTS-c in a multicenter cohort of chronic HD patients, beyond common cohort-related risk factors. Method We conducted a prospective, observational study on 94 chronic HD patients. The study endpoint was a composite of all-cause/CV mortality and non-fatal CV events. We identified the cohort-related predictors of the endpoint by logistic and Cox-regression analyses and built prognostic models based on such variables. Performance of such models was tested before and after the inclusion of MOTS-c. 31 healthy patients were employed as controls. MOTS-c was measured in serum using a commercially available ELISA kit. Results MOTS-c levels were more elevated in HD patients than in controls (36.7 [24.9-49.9] vs. 13.8 [10.4-28.7] ng/mL; p < 0.001; Fig. 1) and independently correlated with a history of ischemic heart disease (β = 0.213; p = 0.03), LVMi (β = 0.185; p = 0.05) and phosphate plasma concentration (β = −0.201; p = 0.05). Of note, MOTS-c levels were even more increased in the 53 individuals experiencing the endpoint during a median 26.5. months follow-up (p = 0.01; Fig. 2). MOTS-c predicted 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 peptide to multivariate models including the other, cohort-related risk factors (age, LVMi, E/e’, diabetes, pulse pressure) remarkably improved the calibration, risk variability explanation (+3%), 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). Conclusion Circulating MOTS-c balance is altered in chronic HD patients. In these individuals, MOTS-c may add significant information to improve CV and mortality risk prediction, on top of traditional and uremia-specific, cohort-related risk variables. Future investigations are needed to extend this preliminary observation in wider HD cohorts.