Elevated Serum Nardilysin Is Inversely Associated with Cardiovascular Disease in Kidney Transplant Recipients

BACKGROUND: Kidney transplant recipients (KTRs) suffer from enhanced cardiovascular (CV) and metabolic burden due to interplay between pro-inflammatory and metabolic risk factors. Nardilysin (NRDc) and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are circulating peptides that represent candidate markers of cardiometabolic pathobiology, though their relevance in KTRs is unknown. METHODS: We measured serum NRDc and MOTS-c concentrations in an observational cohort of 150 patients (118 KTRs and aged-matched controls-32 patients) using commercial ELISA kits. KTRs were followed for a median of 29.2 (25.3-31.9) months. Relationships with CV and metabolic parameters were assessed using Pearson's correlation and penalized logistic regression. Renal allograft loss with all-cause mortality as competing event was examined using Fine-Gray regression. RESULTS: Median serum NRDc (1.91 vs. 0.42 ng/mL, P<0.001) and MOTS-c (178 vs. 142 ng/mL, P=0.014) were significantly higher in KTRs, as compared with controls. NRDc showed a weak positive linear relationship with body-mass index (r=0.21, P=0.02). After adjusting for age and sex, higher standardized ln-NRDc was independently associated with lower odds of prevalent CV disease (OR 0.59, 95% CI 0.34-0.97, P=0.04). This CV disease association was stable after further adjustment for hsIL-6. We did not observed significant associations for MOTS-c and cardiometabolic features. In competing risks analysis, MOTS-c showed a consistent but non-significant trend toward lower risk of allograft loss (adj. sHR 0.50, 95% CI 0.22-1.10, P=0.08), while NRDc was not associated with allograft loss. Both serum NRDc and MOTS-c marker were not associated with all-cause mortality or follow-up eGFR decline. CONCLUSIONS: Elevated circulating serum NRDc and MOTS-c levels in KTRs may reflect altered metabolic and inflammatory pathways. The inverse association between NRDc and prevalent CV disease warrants further investigation in longitudinal studies with incident CV events.