Beyond solute clearance: the kidney–gut–immune–nutrition axis in hemodialysis and peritoneal dialysis and a proposed framework for integrated risk stratification

Abstract

Kidney disease affects approximately ~850 million people globally, with millions dependent on dialysis as life-sustaining renal replacement therapy. While dialysis corrects solute accumulation and fluid overload, it incompletely replicates normal renal physiology and introduces its own biological stressors, perpetuating a cycle of systemic dysfunction that extends well beyond the kidney. Central to this dysfunction is the kidney–gut–immune–nutrition (KGIN) axis: a bidirectional network linking renal clearance, intestinal microbial homeostasis, immune regulation, and nutritional metabolism. In end-stage renal disease, each component of this axis is simultaneously disrupted and becomes a driver of further deterioration. Uremic toxin accumulation remodels the gut microbiome toward a dysbiotic state, characterized by depletion of short-chain fatty acid-producing organisms and expansion of pathobionts. The resulting compromise of intestinal barrier integrity permits systemic translocation of lipopolysaccharide and other microbial products, sustaining chronic low-grade inflammation and a paradoxical state of immune dysfunction marked by heightened inflammatory signaling alongside impaired pathogen defense. These perturbations converge on nutritional status, driving protein-energy wasting through catabolic cytokine signaling, anorexia, and suppression of anabolic pathways, with sarcopenia reported in several dialysis cohorts to progress at two to three fold faster than age related muscle loss. Hemodialysis and peritoneal dialysis produce distinct patterns of axis disruption: hemodialysis is characterized by intermittent toxin peaks, bioincompatible membrane-driven complement activation, and more severe dysbiosis, whereas peritoneal dialysis introduces continuous peritoneal glucose exposure and a unique local immune microenvironment, with generally slower decline in residual kidney function. These modality-specific differences translate into divergent cardiovascular, infectious, and nutritional risk profiles that are incompletely explained by traditional clinical variables. Emerging multi-omics approaches, including metagenomics, metabolomics, and high-throughput immune profiling, are beginning to characterize axis disruption with unprecedented resolution, enabling in-depth characterization of host-microbiome-immune identification of patient subgroups with distinct mechanistic signatures that cannot be captured by single domain analysis alone. To bridge this analytical capability with clinical practice, we propose the Microbiome–Immune–Nutrition (MIN) Index, a conceptual, hypothesis generating composite biomarker framework designed to synthesize data across all three axis domains and stratify patients by the severity of disruption to guide targeted, personalized interventions, which remain to be demonstrated through prospective validation studies. Therapeutic strategies targeting the axis, including dietary fiber and plant-based approaches, synbiotics, fecal microbiota transplantation, advanced dialysis modalities, and omega-3 and polyphenol supplementation, show mechanistic promise but require larger, better-designed trials with hard clinical endpoints before routine clinical adoption. Standardization of microbiome research methodology, investment in longitudinal multi-omics cohorts, and development of international collaborative consortia are research priorities that will be essential to translate mechanistic insights into improvements in survival and quality of life for patients on maintenance dialysis.