AGEs-RAGE Axis and Mitochondrial-Derived Peptides in Advanced Chronic Kidney Disease: Interconnected Pathways Beyond Inflammation and Nutrition.

Background. Chronic kidney disease [CKD] is characterized by increased glycoxidative stress, inflammation, and mitochondrial dysfunction. Advanced glycation end-products [AGEs] and their receptor [RAGE] mediate glycoxidative stress, whereas mitochondrial-derived peptides [MDPs], including humanin [HN], MOTS-c, and humanin-like 1 [HN-L1], regulate mitochondrial stress responses. We investigated links between AGE-RAGE activation and mitochondrial signaling in CKD. Methods. Serum AGEs, soluble RAGE isoforms, and MDPs were measured by ELISA in 160 adults with kidney failure undergoing living-donor kidney transplantation and in 80 controls, Results. CKD patients showed higher AGEs and esRAGE, lower AGEs/sRAGE ratios, and reduced MDPs. AGEs correlated positively with sRAGE, cRAGE, and HN, while MOTS-c was inversely associated with AGEs and the AGEs/sRAGE ratio. In multivariable analyses, HN remained independently associated with AGEs, sRAGE, and the AGEs/sRAGE ratio, whereas MOTS-c showed an inverse association with the AGEs/sRAGE ratio. CRP was associated with the AGEs/sRAGE ratio while PEW showed no associations with AGEs-RAGE components or MDP. Conclusions. CKD is characterized by increased glycoxidative stress and reduced MDPs, reflecting altered mitochondrial stress signaling. AGEs-RAGE and MDPs are biologically linked, suggesting partially overlapping but distinct pathophysiological pathways.