Cellular and Molecular Determinants of Human Kidney Disease

Chronic kidney disease (CKD) is a global health challenge with limited therapies. We present a human kidney disease atlas integrating high-resolution spatial transcriptomics and single nucleus multi-omic with longitudinal outcomes in ~150 patients spanning glomerular and tubulointerstitial disorders and controls. Multicellular factor analysis revealed a unifying tubular injury program across patients, linked to kidney function and marked by proinflammatory pathways. This proinflammatory multicellular program mapped into spatial tubulo-interstitial profibrotic neighborhoods defined by immune cells and mesenchymal cells independent of the underlying kidney disease. Partitioned heritability of estimated glomerular filtration rate genome-wide association studies mapped genetic risk to tubular regulatory elements. Translating the tubular injury program into a circulating proteomic score yielded a mechanistically grounded biomarker set that predicts incident CKD in 44,250 UK Biobank participants. CRISPR perturbations in human proximal tubule cells and Gapmer silencing in kidney organoids identified RELA, the p65 subunit of nuclear factor kappa B (NF-κB), as a key transcriptional driver of the program. Spatial maps resolved disease-driving cell–cell networks and neighborhoods within the tubulointerstitial compartment and glomeruli, including signatures, cell-states and trajectories within crescents—a hallmark of aggressive glomerular injury. This atlas delineates an overarching mechanism of CKD and provides a molecular framework for precision therapeutics.