T cell, M2 macrophage infiltration and collagen, fibronectin, VCAM-1 expression portend poor outcome in lupus nephritis.

INTRODUCTION: Despite advances in lupus nephritis (LN) management, its heterogenous nature poses challenges in predicting treatment response. Multiplexed spatial proteomics offers a potential solution to dissect the heterogeneity of treatment response in LN. METHODS: Renal response was assessed in 16 LN patients undergoing physician-directed induction therapy. Baseline biopsies from these patients were subjected to 34-plex spatial proteomics. A total of 53 glomerular and 49 tubulointerstitial regions of interest from these LN patients and renal cell carcinoma (RCC) controls were analyzed for spatial predictors of treatment response. RESULTS: There were increased glomerular and tubulointerstitial immune infiltrates in LN kidneys compared to RCC controls, including CD45RO, HLA-DR, and CD68-positive cells. Interestingly, there was increased glomerular and interstitial collagen I, collagen IV deposition, and fibronectin extracellular matrix (ECM) proteins in class V compared to class IV LN. Glomerular and tubulointerstitial immune infiltrates and fibrosis in pre-treatment biopsies predicted non-response (NR) to immunosuppressive therapy, including leukocytes expressing CD45RO, HLA-DR, CD4, CD14, and CD163 and collagen I, collagen IV, and fibronectin expression. Increased tubular and parietal epithelial cell expression of the activation/injury marker VCAM-1 also marked treatment NR. DISCUSSION: As defined by multiplexed spatial proteomics, increased infiltration of activated T cells and CD163+ M2 macrophages, glomerular and tubulointerstitial fibrosis, and heightened expression of the injury marker VCAM-1 portend poor response to immunosuppressive treatment in LN.