The Nephron as a Diseased Unit: Tubular Epithelial Programmes and the Fibrotic Niche in CKD.

Abstract

Chronic kidney disease (CKD) has traditionally been conceptualized through a glomerular lens. However, extensive clinicopathological data show that tubulointerstitial fibrosis and tubular atrophy (IF/TA) are stronger predictors of long-term renal outcome than glomerular lesions, even in conditions historically labelled as "glomerular." Recent single-cell and spatial multiomic studies further reveal that tubular epithelial cells (TECs) in chronically diseased kidneys occupy distinct, tightly regulated states that orchestrate inflammation, metabolic reprogramming, and extracellular matrix remodelling within spatially organized fibrotic niches. In this Review, we propose a whole-nephron framework for CKD progression. We revisit the historical dominance of the glomerular paradigm and summarize evidence that tubulointerstitial damage is a principal structural determinant of renal function. We then outline how haemodynamic-hypoxic, metabolic-toxic, and immune-inflammatory insults converge on TECs and the peritubular microvasculature to trigger maladaptive epithelial programmes - including cell-cycle arrest and senescence, metabolic reprogramming and mitochondrial dysfunction, and sustained inflammatory and profibrotic activation. We describe the tubulointerstitium as a dynamic epithelial-stromal-vascular-immune network in which self-reinforcing fibrotic niches emerge. Finally, we discuss therapeutic and biomarker implications of an integrated, nephron-centric perspective, arguing that disease-modifying strategies will require targeting specific maladaptive tubular programmes and their crosstalk with the interstitium, alongside established glomerular-directed therapies.