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Introduction Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc), characterized by acute hypertension and rapid renal function decline, with 50% of cases manifesting thrombotic microangiopathy (TMA). Despite early Angiotensin-Converting Enzyme inhibitor (ACEi) intervention and glucocorticoid avoidance in high-risk SSc patients, the rate of end-stage kidney disease and mortality remains extremely high. This study aims to investigate the cellular and microenvironment heterogeneity in kidneys affected by SRC through the integration of spatial transcriptomics and proteomics.Material and Methods We included kidney biopsies from 5 patients with SRC, 4 patients with type IV lupus nephritis (LN) as disease controls. Additionally, we included 3 normal kidney tissues adjacent to benign kidney tumors as normal controls. Initially, the routine pathological evaluation and spatial transcriptomic analysis using the 10x Genomics Visium platform were sequentially performed. Subsequently, we validated these identification through tyramide-based multiplexed immunofluorences.Results Principal Component Analysis (PCA) exhibited distinct cellular signature based on the cell composition within compartment across SRC, LN and normal kidney. We observed the enrichment of fibroblasts in SRC kidney and the enrichment of immune cells (T cells and B cell) in LN kidney. In addition, tubulointerstitial compartments also manifested changes in prominent cells across these three groups. For instance, we found the reduced frequency in subsets of proximal tubules (PT) and thick ascending loop of Henle (TAL) in SRC and particularly in LN, in comparison to normal kidney. Differential gene-expression analysis revealed widespread up-regulation of complement-associated genes (C3, C7, C1Q), extracellular-matrix genes (COL1A1, COL4A1, COL3A1), and the known injury markers (SPP1, CST3, CLU and IGFBP7) across multiple cell types, suggesting the overwhelming injury that shape the pathological landscape of SRC. Tyramide signal amplification (TSA) staining further confirmed the expansion of FAP+ fibroblast in SRC kidney, while predominant CD45+ immune cell infiltration was observed in LN, consistent of our transcriptomic findings.Conclusions The current study may reveal the molecular and cellular changes using comprehensive and unsupervised spatial technologies, which may provide up-to-date insights that could inform future treatment approaches.