Association of prognostic nutritional index with the risk of all-cause mortality and cardiovascular events in patients with diabetes-related foot ulcers: a non-linear relationship mediated by eGFR.

Abstract

Diabetes-related foot ulcers (DFU), a severe complication of diabetes, is strongly associated with high mortality. Although the prognostic nutritional index (PNI) has been validated for predicting clinical outcomes, its precise relationship with mortality risk in patients with DFU remains unclear. This study aimed to investigate the association between PNI and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) in patients with DFU, and to elucidate the underlying non-linear mechanisms. This retrospective cohort study consecutively enrolled 1,225 patients with DFU admitted to Air Force Medical Center from January 2015 to December 2022. Cox proportional hazards models were used to calculate HR with 95% CI for evaluating the association of PNI with all endpoints and Kaplan-Meier survival curves were generated. Restricted cubic spline (RCS) evaluated non-linear associations, and piecewise regression identified risk thresholds. Causal mediation analysis quantified the mediating effect of eGFR. During a median follow-up of 3.6 years, 378 (30.9%) all-cause deaths, 230 (18.8%) cardiovascular deaths, and 323 (26.4%) MACEs occurred. Multivariable-adjusted Cox proportional hazards models revealed significant inverse associations between PNI and all endpoints. In the fully adjusted model, each 1-unit increase in PNI was associated with a 5% reduction in all-cause mortality risk (HR: 0.95, 95%CI: 0.94-0.97, p < 0.001), a 4% reduction in cardiovascular mortality risk (HR: 0.96, 95%CI: 0.94-0.98, p < 0.001), and a 3% reduction in MACE risk (HR: 0.97, 95%CI: 0.95-0.98, p < 0.001). Quartile analysis revealed progressively decreasing risks across Q2 to Q4 groups versus Q1 (lowest quartile) for all endpoints. Kaplan-Meier survival curves corroborated the Cox regression results. RCS analysis demonstrated significant non-linear relationships between PNI and all endpoints, with exploratory, cohort-specific thresholds identified near 39.29-39.37 (non-linear p < 0.05). Causal mediation analysis revealed that eGFR mediated 11.5 and 11.9% of the effects of PNI on the risks of all-cause mortality and cardiovascular mortality, respectively ( p < 0.05). Prognostic nutritional index is an independent protective factor associated with lower risks of all-cause mortality, cardiovascular mortality, and MACE in patients with DFU. Elevated PNI is associated with significantly reduced risks of all-cause mortality and cardiovascular events, with eGFR partially mediating this association.