Unbalanced Circulating Humanin Levels and Cardiovascular Risk in Chronic Hemodialysis Patients: a Pilot, Prospective Study

Mortality and cardiovascular (CV) risk prediction in individuals with end-stage kidney disease (ESKD) on chronic hemodialysis (HD) remains challenging due to the multitude of implicated factors. In a multicenter ESKD-HD cohort, we tested the prognostic yield of the assessment of circulating Humanin, a small mitochondrial-derived peptide involved in CV protection, on CV events and mortality. We conducted a prospective, observational, pilot study on 94 prevalent HD patients. The prognostic capacity of circulating Humanin levels was tested on a primary composite (all-cause mortality + non-fatal CV events) and a secondary exploratory endpoint (all-cause mortality alone). Baseline Humanin level was comparable in patients reaching the primary or secondary endpoint as compared to others (p = 0.69 and 0.76, respectively). Unadjusted followed by multivariable Cox regression analyses adjusted for age, left ventricular mass index (LVMi), E/e’, pulse pressure and diabetes mellitus indicated a non-linear relationship between Humanin levels and the composite outcome with the highest Hazard Ratio (HR) associated with very low (< 450.7 pg/mL; HR ranging from 4.25 to 2.49) and very high (> 759.5 pg/mL; HR ranging from 5.84 to 4.50) Humanin values. Restricted cubic splines fitting univariate and multivariate Cox regression analyses visually confirmed a curvilinear trend with an increasing risk observed for lower and higher Humanin values around the median, respectively. A similar, u-shaped association was also evidenced with the secondary endpoint. Altered Humanin levels may impart prognostic information in ESKD-HD patients at risk of death or CV events. Future investigations are needed to confirm whether Humanin measurement could improve CV and mortality risk prediction beyond traditional risk models.