Abstract / Summary
Peritoneal fibrosis is a major cause of progressive peritoneal membrane dysfunction and technique failure in patients receiving long-term peritoneal dialysis. Conventional models emphasize repeated chemical injury, sterile inflammation, angiogenesis, and transforming growth factor-β signaling, but they do not fully explain why apparently similar dialysis exposures produce different trajectories of membrane loss. Here, we develop a metabolism-centered framework in which glucose-rich dialysate, glucose degradation products, carbonyl stress, hypoxia, and inflammatory mediators may establish a maladaptive metabolic state during membrane remodeling. Available evidence supports an important and increasingly recognized metabolic dimension of PD-associated membrane injury, although direct human evidence for structural PF remains limited. Evidence from peritoneal dialysis models and patient effluent studies supports coordinated changes in glycolysis, mitochondrial oxidative metabolism, fatty-acid oxidation, lipid peroxidation, amino-acid anaplerosis, and immune-cell metabolism. These changes are associated with mesothelial-to-mesenchymal transition, macrophage plasticity, fibroblast activation, extracellular-vesicle signaling, and ferroptosis-related or inflammasome-associated injury. We summarize LC–MS-, GC–MS-, and NMR-based metabolomics, proteomics, and integrated multi-omics approaches for characterizing dialysate and plasma signatures, and we define a staged validation pathway from discovery to longitudinal clinical prediction. The study-level evidence tables are selected narrative evidence maps that separate human membrane-function or inflammatory signals from experimental structural fibrosis endpoints and report the model, exposure, quantitative result, and principal limitation for each cited study. Therapeutic opportunities include biocompatible dialysis-fluid design, glycolytic and mitochondrial modulation, restoration of redox and lipid homeostasis, ferroptosis control, immunometabolic interventions, and rational evaluation of bioactive compounds. The central translational hypothesis is that serial dialysate metabolomics may identify a reversible phase of membrane injury before fixed fibrosis; this hypothesis requires prospective validation against structural or clinically adjudicated peritoneal fibrosis outcomes.