Bernhard Dumoulin, Jonathan Levinsohn, Konstantin A. Klötzer, Chenyu Li, Liran Mao, Eunji Ha, Samer Mohandes, Thao Nguyen, Luca Paruzzo, Daigoro Hirohama, Victoria Fang, Vijay Bhoj, Hamideh Parhiz, Magaiver Andrade-Silva, Amin Abedini, Andi Bergeson, Daniel Traum, Michael J. May, Klaus H. Kaestner, Marco Ruella, Fiona E. McAllister, A Ari Hakimi, Mingyao Li, Matthew Palmer, E John Wherry, Christopher A Hunter, MP Cancro, Raymond Townsend, G Coppock, Manisha Singh, Michael Ross, James Tumlin, Kirk Campbell, Amy Mottl, Christos Argyropoulos, Tamara Isakova, Salem Almaani, Rupali S. Avasare, Richard Lafayette, Julia J. Scialla, Randy Luciano, Shweta Bansal, Frank Brosius, Ankit Mehta, Oliver Lenz, Nelson Kopyt, Piettro Canetta, Matthias Kretzler, Jeffrey Schelling, Alexis Hofherr, Steven S. Pullen, Andrew J. Thorley, Ching Shang, Erding Hu, Anil Karihaloo, Kishor Devalaraja-Narashimha, Katalin Susztak
Diabetic kidney disease (DKD), the leading cause of kidney failure, is marked by clinical and molecular heterogeneity, making therapeutic development exceedingly difficult1. Here we used Xenium and CosMx single-cell spatial transcriptomics, integrated with single-nucleus RNA sequencing, to build a cross-platform kidney atlas that makes tissue architecture computable for prognosis, non-invasive detection and patient selection. Using this atlas, we defined reproducible tissue niches and injury-linked microenvironments and uncovered a profibrotic context that expands with disease and tracks with worse kidney function. Within this architecture, we identified a B cell-predominant, tertiary lymphoid structure-like immune microenvironment that defines a distinct DKD subset with accelerated progression to renal end-points. We developed tissue biomarkers and a matched plasma protein panel that capture this biology, stratify patients in a population biobank and improve risk prediction beyond clinical models—supporting their potential for biomarker-guided selection in future B cell-targeted DKD trials. A single-cell spatial atlas identifies a B cell-predominant microenvironment within the profibrotic tubular niche that marks a subset of patients with diabetic kidney disease with rapid progression.