Spatiotemporal interaction of immune and renal cells controls glomerular crescent formation in autoimmune kidney disease

nature immunology Article https://doi.org/10.1038/s41590-025-02291-8 Spatiotemporal interaction of immune and renal cells controls glomerular crescent formation in autoimmune kidney disease Received: 18 December 2024 Accepted: 27 August 2025 Published online: xx xx xxxx Check for updates Zeba Sultana 1,2,3,4,10, Robin Khatri 2,3,4,5,10, Behnam Yousefi 2,3,4,5,6,10, Nikhat Shaikh 1,2,3, Saskia L. Jauch-Speer 2,7, Darius P. Schaub1,2,3,4,5, Jonas Engesser1,2,3, Malte Hellmig 1,2,3, Vincent Piegsa 1,2,3, Arthur Hube 1,2,3, Varshi Sivayoganathan1,2,3, Alina Borchers1,2,3, Anett Peters1,2,3, Anna Kaffke1,2,3, Stephanie Zielinski3,8, Hans-Joachim Paust1,2,3, Thiago Goldbeck-Strieder1,2,3, Ulrich O. Wenzel 1,2,3, Victor G. Puelles1,2,3, Elion Hoxha1,2,3, Thorsten Wiech 6,9, Catherine Meyer-Schwesinger3,8, Tobias B. Huber 1,2,3, Ulf Panzer 1,2,3,10 , Stefan Bonn 2,3,4,5,6,10 & Christian F. Krebs 1,2,3,10 Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney diseases and is characterized by glomerular crescent formation with proliferation of parietal epithelial cells (PECs). However, the underlying mechanisms of glomerular crescent formation are incompletely understood. Here we provide a high-resolution spatial kidney cell atlas of 57 samples from patients with RPGN (ANCA-associated GN, lupus nephritis and anti-glomerular basement membrane-GN) to characterize the cell signaling pathways in glomerular crescent development. Early platelet-derived growth factor (PDGF) signaling from epithelial and mesangial cells caused PEC activation and proliferation in glomerular crescents, whereas later transforming growth factor (TGF)-β signaling from macrophages, T cells and epithelial and mesangial cells triggered expression of extracellular matrix components in PECs associated with glomerulo sclerosis and disease progression. These findings were similar across the different GNs and were functionally validated in experimental GN by PDGF and TGFβ blockade. These results highlight a spatiotemporally conserved progression program into glomerular crescents and sclerosis and indicate new treatment options for autoimmune kidney disease. Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by a fast decline in kidney function accompanied by distinct histological features such as necrotizing glomerulonephritis and glomerular crescent formation. As a disease category, glomerulonephritis is among the most common causes for end-stage renal disease associated with a high morbidity and mortality. RPGN can develop in patients with systemic lupus erythematosus (SLE), ANCA-associated vasculitis (ANCA-GN) and anti-glomerular basement membrane A full list of affiliations appears at the end of the paper. Nature Immunology antibody disease (anti-GBM). Infiltrating immune cells and parietal epithelial cells (PECs) of the glomerulus are considered to be major cellular contributors to glomerular crescents1–7. Although PECs usually build the Bowman’s capsule, they proliferate in crescentic glomerulonephritis (cGN) and contribute to the glomerular crescent. Signaling between immune cells and renal cells has been proposed as crucial in the immunopathogenesis of glomerulonephritis; however, a comprehensive definition of infiltrating immune cells, their precise e-mail: ; ; Article https://doi.org/10.1038/s41590-025-02291-8 a b Modifications over time Cell-type annotation Niche composition Spatial cell–cell interactions d Glomerulonephritis (ANCA) n = 3.2 × 106 cells MNP PEC VSM/P UMAP2 MC 100 µm GPX-3 (tubules) COL1A1 (fibrosis) AQP2 (collecting duct) LYZ (Mono or MAC) PODXL (POD) CD163 (Mono or MAC) PDGFRB (MC) CD3 (T cells) EMCN (EC) CLDN1 (PEC) VSM ATL FIB PpE PC IC e Kidney cells (17 clusters) POD FIB 100 µm TAL DTL sy.de Glomerulus detection PEC Illustr ation : hega Slide ID Cell segmentation TAL POD PEC MC Fib. MC PpE VSM/P EC PT ATL CNT DCT DTL TAL Immune cells (13 clusters) EC Lymphocytes Tubular IC cells T cell NK/T cell B cell PL N MAC MDC Mono MAST cDC pDC cycMNP cycNK/T cell FIB IC NEU PC 100 Cluster contribution (%) Control kidney EC Inner a medull c Panel design • Common cellular markers • Intracellular signaling molecules (KEGG/Reactome) • Spatial transcriptomic from 34 RPGN POD MC r Oute ulla med Single-nuclear mRNA sequencing • 4 controls and 11 ANCA-GN samples Combined multiplex mRNA and protein Patient cohort • Cantrol (bx = 6) • ANCA-GN (bx = 32) • SLE (bx = 19) • anti-GBM (bx = 6) DCT x Corte Kidney biopsies PT In situ multiplex mRNA detection • 480 gene panel • Parallel H&E • 63 kidney bx • ~3 million cells 80 60 40 20 0 Control SLE ANCA aGBM DCT Glomerulus PC UMAP1 f Glomerulonephritis (ANCA) Control kidney Overview Glomerulus Overview 100 µm 100 µm Overview 100 µm Tubulointerstitium 1,000 µm Glomerulus 100 µm Overview 100 µm Tubulointerstitium 1,000 µm Glomerulus 100 µm Tubulointerstitium 1,000 µm 100 µm Glomerulus Tubulointerstitium 1,000 µm 100 µm Fig. 1 | Major cell types in the human renal cortex in health and inflammation. a, Overview of the patient cohort from the Hamburg Glomerulonephritis Registry and the analysis performed. b, Schematic showing the cross-section of a human kidney tissue with the localization of various cell types in different regions. Inset: cross-section of a glomerulus (top) and tubulointerstitial region (bottom) and the cell types therein. c, DAPI-stained images from kidney biopsies of control (left) and a patient with ANCA-GN (right). The images show glomeruli and surrounding regions overlaid with cell boundaries determined using a cell segmentation algorithm. Localization of specific marker genes is indicated, with glomerular boundaries highlighted for clarity. d, Uniform Manifold Approximation and Projection (UMAP) of ~3.2 million cells retained after QC filtering. Cells are colored based on their annotated cell type. e, Stacked bar plot showing the proportions of different cell types from the complete biopsy tissues across the four disease conditions. f, images from control (left four images) and ANCA-GN (right four images) kidney biopsies showing a glomerulus and tubulointerstitial region. For each region, the adjoining plots show the segmented cells color coded according to their cell-type annotation, illustrating cellular composition differences between conditions in different regions of the tissue. aGBM, anti-GBM antibodies; ATL, ascending thin limb of loop of Henle; bx, biopsies; cDC, conventional dendritic cell; CNT, connecting tubule; cycNKC/T, cycling NK cytotoxic T cell; DCT, distal convoluted tubule; DTL, descending thin limb of loop of Henle; FIB, fibroblast; Fib. MC, fibrotic mesangial cell; IC, intercalated cell of collecting duct; KEGG, Kyoto Encyclopedia of Genes and Genomes; MAC, macrophage; MC, mesangial cell; MDC, monocyte-derived cell; Mono, monocyte; N, neutro (...truncated)