Re-Evaluating the Transplant Glomerulopathy Lesion-Beyond Donor-Specific Antibodies

Abstract

There have been significant advances in short-term outcomes in renal transplantation. However, longer-term graft survival has improved only minimally. After the first post-transplant year, it has been estimated that chronic allograft damage is responsible for 5% of graft loss per year. Transplant glomerulopathy (TG), a unique morphologic lesion, is reported to accompany progressive chronic allograft dysfunction in many cases. While not constituting a specific etiologic diagnosis, TG is primarily considered as a histologic manifestation of ongoing allo-immune damage from donor-specific anti-HLA alloantibodies (DSA). In this review article, we re-evaluate the existing literature on TG, with particular emphasis on the role of non-HLA-antibodies and complement-mediated injury, cell-mediated immune mechanisms, and early podocyte stress in the pathogenesis of Transplant Glomerulopathy.

Keywords: C4d; anti HLA antibodies; banff criteria; podocyte; transplant glomerulopathy (TG).

FIGURE 1

Light microscopic and ultrastructural findings in allograft biopsies demonstrating C4d staining and transplant glomerulopathy. (A) Hematoxylin and eosin stain of allograft biopsy with glomerulus showing global wall thickening and increase in mesangial cellularity, suspicious for transplant glomerulopathy, 200x. (B) PAS stain of glomerulus demonstrating reduplication of the capillary basement membranes (see inset, black arrows), 200x. (C) Transmission electron photomicrograph showing expansion of the lamina rara interna by grungy variably electron-dense material, as well as areas of original (red arrows) and de novo (black arrows) basement membrane formation, indicative of transplant glomerulopathy, TEM, 13,900x. (D) Immunofluorescent staining for C4d showing diffuse circumferential positive staining in peritubular capillaries in a patient with concurrent transplant glomerulopathy on biopsy (patient developed positive Class II donor-specific antibodies ∼2 years after diagnosis; 100x). (E) immunohistochemical staining for C4d showing diffuse positive staining in peritubular capillaries in a patient demonstrating early transplant glomerulopathy and findings indicative of chronic antibody-mediated rejection on biopsy, 100x.

FIGURE 2

Schematic of potential pathogenetic mechanisms related to TG. TG defined by basement membrane multilayering on the lamina rara densa side is likely initiated by immunologically mediated endothelial injury. While the role of DSA is frequently reported, selected anti-donor antibodies directed against non-HLA proteins have been incriminated. Accompanying complement mediated injury likely plays a role, along with anti-donor antibodies. A proportion of TG is unassociated with DSA and is now attributable to innate and adaptive cell-mediated mechanisms. Activated NK cells seem to be associated with TG in combination with DSA, while T-cell infiltration/activation has been observed without DSA. An understudied contributor to TG is the role played by podocyte stress from obligate glomerular hypertrophy, compounded by donor-recipient weight mismatch and metabolic or immunologic injury. Whether podocyte loss is causal in TG remains a hypothesis in need of testing. Endothelial injury from other sources (cTMA, viral injury, or medications) can cause/compound endothelial injury and multilayering.