Kidney spatial multiomics mapping decodes scleroderma renal crisis

Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis with incompletely understood pathogenesis, hindering therapeutics development and contributing to high rates of end-stage kidney disease and mortality. We aimed to construct a spatially resolved cellular and molecular atlas of SRC kidneys to identify disease-specific microenvironments and therapeutic targets.

Kidney biopsy samples from 12 patients with SRC manifesting histopathologically as thrombotic microangiopathy (TMA), 6 patients with lupus nephritis (LN), and 3 normal kidneys were analysed by spatial transcriptomics (discovery cohort), and the findings were validated in an expanded cohort by multiplexed imaging. Spatial organization and cellular phenotypes were analysed across histopathologically defined regions.

Multiplexed imaging demonstrated a pathological triad of TMA, immune infiltration, and fibrotic remodelling in SRC kidneys. SRC and LN shared activation of the complement cascade, type I interferon signalling, and fibrotic remodelling. However, SRC exhibited a distinct vascular-hypoxic axis. Spatial analyses revealed disease-specific glomerular niches at the interface between renal parenchymal cells and prominent myeloid immune cells. We demonstrated dynamic molecular signatures that progressed from mild lesions through overt SRC-associated pathological changes (glomerular TMA or arterial injury) to chronic lesions in each histopathologically defined region. Multiple pathological pathways were already upregulated in mild lesions, with selective enrichment in glomerular TMA and arterial injury, ultimately converging on injury and remodelling programmes in the chronic lesions.

This study advances our understanding of SRC beyond histopathology to the molecular and cellular landscape, providing an omics-driven framework to accelerate therapeutic target discovery in this rare, devastating disease.