Tubulointerstitial inflammation driving interstitial fibrosis and tubular atrophy predicts poor renal outcome in refractory lupus nephritis.

Abstract

Interstitial fibrosis and tubular atrophy (IF/TA) predicts end-stage kidney disease (ESKD) in lupus nephritis (LN). Repeat kidney biopsies were evaluated to identify variables driving progression of IF/TA and ESKD. LN patients with ≥2 biopsies from 1994 to 2018 were identified. Biopsies were interpreted by nephropathologists and classified according to ISN/RPS criteria. Clinical outcomes were ascertained through 2023. Multiplex immunohistochemistry was used to characterize the tubulointerstitial inflammation (TII). One hundred and four LN patients [84% female, age 25 (+/-12) years at diagnosis, 14% White, 40% Black, 35% Hispanic] with a median follow-up of 11 (6-16) years were identified. On initial biopsy, 90% had class III or IV proliferative LN with or without class V. Forty-seven patients developed ESKD. We identified proteinuria, the presence of cellular and fibrocellular crescents, and IF/TA ≥ 25% at the first biopsy to be associated with the composite outcome of ESKD, chronic kidney disease (CKD) or death. In the absence of chronicity, persistent TII ≥ 25% was the only histological predictor of ESKD (OR 4.13; 95% CI: 1.06, 16.06). The severity of TII on one biopsy predicted the extent of IF/TA on the subsequent biopsy. The increase in TII between the first and second biopsies was particularly high in the subgroup of patients that progressed rapidly to advanced IF/TA and ESKD. Multiplex immunohistochemistry revealed that TII could occur as tubulitis mediated by CD8 T cells or as organized T and B cell rich infiltrates reminiscent of tertiary lymphoid structures. TII predicts the development of IF/TA in LN and independently from glomerulosclerosis is associated with progression to ESKD.