The diversity of transplant glomerulitis and its relationship to alloantibody

Abstract Introduction While transplant glomerulitis often signifies antibody-mediated rejection (AMR), the pathophysiology of C4dptc and donor specific antibodies (DSA) negative cases is unclear. Methods We compared Banff 1997 defined glomerulitis (n=271, from 4300 biopsies) using serological and pathological dichotomization, against rejection without glomerulitis (g0REJ, n=612) and normal controls (NIL, n=1442). Results Epidemiological risk factors were female recipients, living donation, early T cell-mediated rejection (TCMR) or AMR, and prior corticosteroid rejection treatment. Glomerulitis associated with sensitization in 38.0%, ischemic endothelial injury in 20.7%, iatrogenic minimization in 30.3%, and non-adherence in 21.4%. Banff g score correlated with DSA+, C4dptc+, C4dglom+, Banff cg, i, t, ti scores, serum creatinine, and proteinuria. DSA+ glomerulitis was typified by inflammation, chronic scarring, C4d+, later presentation, treatment resistance, and functional deterioration (P<0.001 versus DSA−). DSA− glomerulitis from CD3+ TCMR (pure 43.3%, mixed 28.7% with AMR) presented earlier with excellent graft outcomes. C4dptc− glomerulitis was etiologically classified TCMR in 36.8%, pure AMR in 28.1%. and mixed AMR in 31.3%. Isolated glomerulitis in 20.3% was diagnosed by surveillance sampling in 70.9%, displayed CD3+ in 51.9% and a distinct but minimal spatial transcriptomic phenotype, with superior allograft outcomes compared with glomerulitis with inflammation. Kidneys with glomerulitis and g0REJ failed more frequently than NIL (P<0.001). Graft survival was independently determined by DSA+, C4dptc+, transplant glomerulopathy, and chronic interstitial fibrosis using multivariable Cox regression, but not by glomerulitis score. Conclusions Glomerulitis is a heterogenous biological lesion that frequently signifies AMR, however TCMR or innate cellular inflammation caused many DSA− and/or C4dptc− episodes.