Risk factors, histopathological features, and graft outcome of transplant glomerulopathy in the absence of donor-specific HLA antibodies

Abstract

Transplant glomerulopathy is established as a hallmark of chronic antibody-mediated rejection in kidney transplant patients with donor-specific HLA antibodies (HLA-DSA). The clinical importance of transplant glomerulopathy in the absence of HLA-DSA is not well established. To help define this, 954 patients (encompassing 3744 biopsies) who underwent kidney transplantation 2004-2013 were studied with retrospective high-resolution HLA genotyping of both donors and recipients. The risk factors, histopathological appearance and prognosis of cases with transplant glomerulopathy in the absence of HLA-DSA were compared to those cases with HLA-DSA, and the impact of the PIRCHE-II score and eplet mismatches on development of transplant glomerulopathy evaluated. In this cohort, 10.3% developed transplant glomerulopathy, on average 3.2 years post-transplant. At the time of glomerulopathy, 23.5% had persistent pre-transplant or de novo HLA-DSA, while 76.5% were HLA-DSA negative. Only HLA-DSA was identified as a risk factor for glomerulopathy development as eplet mismatches and the PIRCHE-II score did not associate. HLA-DSA negative biopsies with glomerulopathy had less interstitial inflammation, less glomerulitis, and less C4d deposition in the peritubular capillaries compared to the HLA-DSA positive biopsies with glomerulopathy. While graft function was comparable between the two groups, HLA-DSA positive glomerulopathy was associated with a significantly higher risk of graft failure compared to HLA-DSA negative glomerulopathy (Hazard Ratio 3.84; 95% confidence interval 1.94-7.59). Landmark analysis threeyears post-transplant showed that HLA-DSA negative patients with glomerulopathy still had a significant increased risk of graft failure compared to patients negative for glomerulopathy (2.62; 1.46-4.72). Thus, transplant glomerulopathy often occurs in the absence of HLA-DSA, independent of HLA molecular mismatches, and represents a different phenotype with less concomitant inflammation and better graft survival compared to that developed in the presence of HLA-DSA.

Poor Outcomes in Patients With Transplant Glomerulopathy Independent of Banff Categorization or Therapeutic Interventions

“…A retrospective analysis of TG in 954 kidney transplant recipients (3,744 biopsies including protocol biopsies) observed TG in 10% of patients independent of HLA mismatches, and >75% of TG cases had no HLA-DSA. They concluded that iTG represents a different phenotype that had lower levels of concomitant inflammation and graft loss compared with HLA-DSA+ TG ( 52 ). In our study iTG was observed in 47.5% of indication biopsies without signs for AMR, and we could not detect significant differences in outcomes among iTG, cAMR and cAAMR during a 5-year follow-up.…”

The evolution of histological changes suggestive of antibody‐mediated injury, in the presence and absence of donor‐specific anti‐HLA antibodies

“…Currently, it remains unclear which of these potential pathophysiologic processes are transient and do not progress to chronic irreversible injury, and which processes are deleterious, ultimately culminating in graft failure. In multiple studies on this same cohort, we showed that HLA-DSA negative ABMR/cg does not differ from ABMR/cg with HLA-DSA regarding histology or gene expression, but nonetheless has better outcome [11,19,42,43]. There is evidence supporting that the HLA-DSA negative cases represent a distinct entity, with a more transient histology of ABMR and less C4d deposition [19].…”

The Proteome of Antibody-Mediated Rejection: From Glomerulitis to Transplant Glomerulopathy

“…The observed multilayering of basement membranes, assessed in the first place by ultrastructural analysis, is considered to be induced by repeated, prolonged and/or sublytic endothelial damages, that are known to promote proinflammatory, procoagulant and proliferative-restorative changes of the endothelial cells and their environment [7]. While transplant glomerulopathy is not uncommon, with a cumulative incidence estimated of approximately 20% at 5 years of transplantation, and is associated with proteinuria and declining allograft function [8,9], the literature lacks an in-depth exploration of the deregulated proteins observed in this severe entity [10,11]. Changes in the extracellular matrix have been recently described by proteomics during active ABMR [12].…”