Somatic genomic mosaicism in chronic kidney disease progression: A graded appraisal of renal epithelial injury, cellular senescence, and therapeutic implications.

AIMS: To appraise, and grade by strength of evidence, whether somatic genomic mosaicism contributes to chronic kidney disease (CKD) progression, and to separate mosaicism arising within kidney tissue from clonal alterations arising in blood. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science and Scopus from database inception to 28 July 2026. Terms covered somatic mosaicism, mosaic loss of chromosome Y (LOY), mosaic chromosomal alterations, clonal hematopoiesis of indeterminate potential (CHIP), and injured proximal tubule states in kidney disease. Each proposed mechanistic link was assigned to one of three prespecified evidence tiers: direct human kidney-tissue evidence (Tier A), systemic or indirect human evidence (Tier B), or model-based inference (Tier C). KEY FINDINGS: Tier A evidence rests on a single human kidney dataset in which LOY was enriched in injured proximal tubule cells (odds ratio 1.37 to 2.28 across injured proximal tubule states). Because this enrichment is approximately two-fold, LOY carries roughly 20% sensitivity and 40% positive predictive value for the injured state and therefore cannot identify it. Blood CHIP shows discordant kidney associations across cohorts, including two null studies. No study has shown that mosaic renal epithelial cells preferentially survive, become senescent, or drive immune and fibroblast signaling. Every proposed therapeutic node targets injury or senescence generally, not mosaic cells. SIGNIFICANCE: Somatic mosaicism is currently a graded marker of cumulative genomic stress in the kidney, not an established driver of CKD progression. We state falsifiable predictions and the experiments that would discriminate marker from mediator.