Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis

BACKGROUND: In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to end-stage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts. METHODS: Data were acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep-learning models and other computer vision techniques. RESULTS: High B cell densities were associated with protection from ESRD. In contrast, high densities of CD8(+), γδ, and other CD4(–)CD8(–) T cells were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with Tfh cells, while CD4(–) T cells formed small neighborhoods in the tubulointerstitium, with frequency that predicted progression to ESRD. CONCLUSION: These data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease. FUNDING: This study was funded by the NIH Autoimmunity Centers of Excellence (AI082724), Department of Defense (LRI180083), Alliance for Lupus Research, and NIH awards (S10-OD025081, S10-RR021039, and P30-CA14599).