Host-Shaped Microbial Metabolite Signaling in the AKI-to-CKDTransition: Mechanisms and Therapeutic Boundaries

Acute kidney injury (AKI) increases the subsequent risk of chronic kidney disease (CKD), but the transition is shaped by the quality of tubular repair rather than nephron loss alone. We frame the gut-kidney axis as a bidirectional host-microbial system in which AKI-related inflammation, impaired solute clearance, altered tubular transport, intestinal barrier dysfunction, medications, diet, and intestinal transit may redirect microbial metabolic output during recovery. Repair-disrupting candidates, including trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), p-cresyl sulfate (PCS), and broader aromatic solute burden, are evaluated alongside repair-permissive candidates such as short-chain fatty acids (SCFAs), selected indoles, and bile acids; polyamines are treated as bidirectional and stage-dependent. We connect these exposures to mitochondrial recovery, cell-cycle arrest, senescence, immune recruitment, endothelial stress, and fibroblast activation, while distinguishing microbial production from host transformation, renal clearance, and tubular uptake. Direct human AKI-to-CKD evidence remains limited, and antibiotic-depletion studies cannot isolate a single metabolite pathway. Translational studies should therefore combine longitudinal blood, urine, and fecal profiling with AKI etiology, treatment exposures, tubular injury markers, spatial kidney biology, and target-engagement endpoints.