A growing body of evidence indicates a strong relationship between inflammatory bowel disease (IBD) and a range of renal conditions, including chronic kidney disease, glomerulonephritis, tubulointerstitial disorders, nephrolithiasis, and secondary (AA) amyloidosis, which are rare yet severe systemic complications. In this review, we integrated clinical and epidemiological data to clarify the pathophysiological mechanisms underlying the gut–kidney axis. Existing evidence was critically appraised with the observation that, although associative data are plentiful, causal pathways in humans remain incompletely understood. We describe how dysbiosis of the gut microbiota, breakdown of the intestinal barrier, and altered microbial metabolites (e.g., trimethylamine N-oxide TMAO and short-chain fatty acids SCFAs) drive systemic inflammation and contribute to renal injury. Newer findings point to intestinal lymphatic dysfunction as a crucial intermediary. Injury to the proteinuric kidney triggers lymphangiogenesis within the gut and reshapes the composition of the lymph, thereby facilitating the systemic delivery of pro-inflammatory mediators, including IsoLG-modified apolipoprotein AI and Th17 cells, that worsen renal damage, thus establishing a self-reinforcing pathological loop. Nonetheless, evidence supporting the lymphatic pathway currently relies mainly on animal studies, with limited human validation. We also examined the contribution of conserved pathways such as IL-11-driven fibrosis, GSDMD-mediated pyroptosis, and free light chain toxicity. From a translational standpoint, these overlapping pathways represent promising therapeutic targets, although further testing is required to establish their clinical applicability. Such mechanistic insights underscore the importance of vigilant renal monitoring in individuals with IBD and careful management of drug-induced nephrotoxicity. Strategies that target these shared mechanisms, whether through restoration of the microbiota, modulation of lymphatic function, or precision immunomodulation, herald a new frontier for therapies aimed at dual-organ protection.
Zheng et al. (Wed,) studied this question.