In lupus nephritis, specificin situinflammatory states are associated with refractory disease and progression to renal failure

Abstract

In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end stage renal disease (ESRD). However, while approximately half of patients with moderate or severe TII develop ESRD, half do not. Therefore, we hypothesized that TII is heterogeneous with distinct inflammatory states each associated with different renal outcomes. We interrogated renal biopsies from LN longitudinal and cross-sectional cohorts using both conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed unique computational pipelines by training and implementing several deep learning models and other computer vision techniques. Surprisingly, across biopsies, high B cell densities were strongly associated with protection from ESRD. In contrast, CD4- T cell population densities, which included CD8, gamma-delta and double negative (CD4-CD8-TCRd-, DN) T cells, were associated with both acute refractory renal failure and progression to ESRD. Interestingly, inflammation was organized into different discrete clusters or neighborhoods each with unique characteristics including enrichment for specific cell populations. B cells were often organized into large neighborhoods with CD4+ T cells including T follicular helper-like cells. In contrast, the CD4- T cell populations formed small cellular neighborhoods whose frequency predicted subsequent progression to ESRD. These data reveal that in LN, specific in situ inflammatory states are associated with refractory disease and progression to ESRD.