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.