Chronic transplant glomerulopathy: New insights into pathogenesis

Abstract

There have been recent significant advances in short-term outcomes in renal transplantation, however, long-term allograft survival remains a challenge. With reported incidences as high of 74.5% of chronic graft loss in patients with biopsies showing transplant glomerulopathy (TG), this syndrome represents an important factor for chronic allograft complications. In this review we show an overview of the novel mechanistic insights into pathogenesis of TG, as well as a brief description of the pathology, diagnosis and newer prognostic indices within TG diagnosis. These data raise intriguing roles for cell-mediated immunity and podocyte stress in TG as well as reinforce previous associations of TG with ABMR. We also delve into management strategies for TG and report the paucity of existing clinical trial data for this prevalent condition in renal transplants.

Keywords: allograft failure; proteinuria; transplant glomerulopathy.

FIGURE 1

Proposed pathogenesis flow chart of Transplant Glomerulopathy. There are 3 main areas: Antibody-mediated injury, cell-mediated injury and “Two kidney to one Kidney Transition”, all leading to a common pathway which is endothelial injury

FIGURE 2

(A) Electron microscopy features of cg. Note multiple layers of new glomerular basement membrane formation (arrow head). The capillary wall has been insinuated by a mesangial cell and it cytoplasmic processes (so-called mesangial interposition). Since, electron microscopic changes precede histologic abnormalities, they have the potential to act as surrogate markers in clinical trials seeking to evaluate treatment regimens to prevent chronic ABMR. (B) Light microscopy: PAS image showing TG graded as cg1b in the Banff Schema. This finding is subtle and the earliest findings can be over-interpreted. Pathologist agreement between cg0 and cg1b is of the order of 45%. Accordingly, molecular classifiers developed by including biopsies graded as cg1b have the potential to generate false positive diagnoses of ABMR. (C) C4d staining in the glomerular basement membranes can be indicative of cg. However, as opposed to peritubular capillary staining glomerular basement membranes staining it is not a specific marker ABMR. It has been described in other forms of injury that lead to basement membrane remodeling such as ischemic glomerulopathy, membranoproliferative glomerulonephritis, thrombotic microangiopathy and eclampsia of pregnancy. Some non-specific linear C4d staining in the glomerular basement membranes is seen in virtually all biopsies, and follow up electron microscopy studies are performed only on tissues with distinctly granular staining