Fibrosis as the Engine of Kidney Functional Decline

Tubulointerstitial fibrosis is a defining histopathological hallmark of chronic kidney disease (CKD) and develops in response to diverse acute and chronic insults to the kidney. Converging evidence has established interstitial fibrosis as a direct causal driver of kidney function decline. Following injury, tubular epithelial cells can initiate fibrotic remodeling by promoting immune cell recruitment and myofibroblast activation. Myofibroblasts, predominantly derived from tissue-resident fibroblasts and pericytes to a lesser extent, are the principal effector cells of kidney interstitial fibrosis, producing the majority of extracellular matrix (ECM). During their differentiation, perivascular myofibroblast progenitors detach from the microvasculature and invade the interstitium, which destabilizes capillaries and promotes capillary rarefaction. Capillary rarefaction, together with excessive ECM deposition that impairs oxygen diffusion, induces sustained tubular hypoxia and perpetuates epithelial injury. This establishes a self-reinforcing cycle of fibrotic remodeling that becomes largely independent of the initiating insult. Over the past decade, technological advances have markedly refined our understanding of this pathogenic cascade. Single-cell and spatial transcriptomics have resolved cellular heterogeneity, defined fibro-inflammatory niches, and delineated intercellular communication networks that sustain fibrotic remodeling. In parallel, human pluripotent stem cell–derived kidney organoids have emerged as scalable, multicellular model systems that recapitulate key features of tubular injury, inflammation, and myofibroblast activation, enabling functional validation of candidate targets in a human context. In this review, we synthesize current mechanistic insights into kidney fibrotic remodeling and discuss how high-resolution transcriptomics and increasingly mature organoid platforms accelerate antifibrotic drug discovery.