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

Aleksandar Senev,Elisabet Van Loon,Evelyne Lerut,Jasper Callemeyn,Maarten Coemans,Vicky Van Sandt,Dirk Kuypers,Marie-Paule Emonds,Maarten Naesens

doi:10.1016/j.kint.2021.01.029

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 three-years 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.

Highlights

Transplant glomerulopathy (TG), duplication or multilayering of the glomerular basement membrane, is considered to represent the morphologic reflection of chronic or repetitive injury to the glomerular endothelium of renal allografts.[1,2] While its pathogenesis is essentially unclear, and the clinical presentation is heterogeneous, the diagnosis of TG is associated with kidney graft functional deterioration and shortened allograft survival.[3,4,5] To date, no effective therapeutic approaches have been able to reverse the poor outcomes of kidney transplants with TG.[6]
We found no significant association between pretransplant non–HLA-DSA, HLA antigen mismatches, eplet mismatches, and PIRCHE-II score with the development of TG
In this single-center cohort study, with complete highresolution HLA genotyping and anti-HLA antibody followup, we described that TG in the absence of HLA-DSA is more frequent and represents a distinct phenotype with better outcome than TG developed in the presence of HLA-DSA

Summary

Introduction

Transplant glomerulopathy (TG), duplication or multilayering of the glomerular basement membrane, is considered to represent the morphologic reflection of chronic or repetitive injury to the glomerular endothelium of renal allografts.[1,2] While its pathogenesis is essentially unclear, and the clinical presentation is heterogeneous, the diagnosis of TG is associated with kidney graft functional deterioration and shortened allograft survival.[3,4,5] To date, no effective therapeutic approaches have been able to reverse the poor outcomes of kidney transplants with TG.[6]. TG is not specific for caABMR or cABMR and can be seen in other disease processes affecting the glomerular endothelium.[12,13] Several studies have suggested heterogeneity of these HLA-DSA–independent processes and reported an association among TG and hepatitis C virus infection, membranoproliferative glomerulonephritis, and chronic thrombotic microangiopathy.[4,14,15] The risk factors and clinical management of patients with HLA-DSA– negative TG remain largely unknown. We investigated the risk factors, histologic appearance, and impact of TG in a complete high-resolution HLA genotyped cohort and HLA antibody follow-up, with focus on the evaluation of TG in the absence of HLA-DSA, as this represents an ill-specified clinical phenotype

Methods

Results

Conclusion