Transplant Glomerulopathy

Abstract

Transplant glomerulopathy (TG) is a morphologic lesion of renal allografts that is characterized histologically by duplication and/or multilayering of the glomerular basement membrane (GBM). TG is well documented to be associated with the presence of donor-specific antibodies (DSAs), most notably against HLA class II antigens, and in the majority of cases is felt to represent a morphologic manifestation of chronic antibodymediated rejection (ABMR). 1,2 However, TG is not specific for chronic ABMR, and in one-fourth to one-third of cases appears to have a different etiology, including hepatitis C, thrombotic microangiopathy (TMA), and possibly T cellmediated rejection (TCMR). [3][4][5] For ABMR and TMA, the pathogenesis of TG clearly involves injury to the glomerular endothelium, and this may also be the case for TG secondary to hepatitis C, which has been shown in five cases to involve a lesion of TMA and anticardiolipin antibodies. 6 Indeed, the combination of moderate to severe margination of leukocytes in glomerular capillaries with associated endothelial cell swelling, GBM double contours, and the presence of DSAs is diagnostic for chronic, active ABMR according to the 2013 Banff classification. 7 TG is well documented to be an important predictor of poor allograft survival, and is also manifest by proteinuria that can be in the nephrotic range, particularly in advanced lesions. 2 In a study of graft outcomes in 36 patients with TG, John et al. 8 found a mean level of proteinuria of 2.1 g/d, with .3 g/d or $31 by dipstick in 15 (42%). Proteinuria was not different in C4d-positive and C4d-negative cases, but levels of .1 g/d or $21 by dipstick were associated with a trend toward worse graft survival. 8 In this context, the article in this issue of JASN by Yang et al. 9 from the laboratory of Roger Wiggins at the University of Michigan represents an interesting and unique approach to the study of TG. The authors examine podocyte density and related glomerular parameters in renal allograft biopsies taken at different times post-transplantation in patients with and without TG, and correlate these findings with urinary excretion of podocytes and of protein. Podocytes, with their complex structure that includes foot processes and slit diaphragms, are a vital element of the glomerular filtration barrier to protein. Not surprisingly, Yang et al. 9 found that transplantation of a single kidney resulted in an approximately 20% increase in glomerular volume and podocyte volume by 3 months posttransplantation, with a similar, corresponding decrease in podocyte nuclear density within glomeruli. However, somewhat surprisingly, they found that although the transplant patients had only a single functioning kidney, their urinary podocin/creatinine ratio (UPod/Cr; an estimate of podocyte excretion) at 3 months post-transplantation was on average approximately 6-fold higher than that of control patients with two kidneys and normal renal function, and this remained elevated beyond 5 years post-transplantation. Yang et al. 9 als...

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

“…A potential explanation for the strongest association of graft survival with the HLA-DSA status could relate to biopsy sampling error, due to the nature of the fluctuating injury process, or through the presence of subtle lesions that do not reach the Banff thresholds for phenotypic classification. 27 Therefore, even in the absence of the complete histopathologic caABMR phenotype on the current biopsy, the apparent association of HLA-DSA positivity with outcome in patients with TG suggests that these patients might still benefit from HLA-DSA removal therapies that can slow down the injury process initiated by HLA-DSA. On the other hand, in the patients with TG in the absence of HLA-DSA, diagnosing of ABMR h or MVI $ 2 was not independently associated with graft failure.…”

The time dependency of renal allograft histology

“…A greater severity of hyalinosis associated with increased glomerulosclerosis in sequential biopsy pairs irrespective of the CNI used, which suggests a hemodynamic cause (ischemic glomerulosclerosis) . Also other glomerular disease processes, such as transplant glomerulopathy and de novo or recurrent glomerular diseases, could ultimately lead to global glomerulosclerosis, as is also the case in native kidney diseases . Finally, further work is necessary to elucidate the potential involvement of other phenomena in progressive glomerulosclerosis, such as the concept of glomerulosclerosis due to tubular atrophy (a‐tubular glomeruli).…”

Increased CD16 expression on NK cells is indicative of antibody-dependent cell-mediated cytotoxicity in chronic-active antibody-mediated rejection

“…In combination with a variable degree of local complement activation, the activation of immune cells results in endothelial injury. The persistent endothelial injury leads to structural histomorphological changes of the glomeruli with loss of fenestration and duplication/multilamination of the basement membranes; more specifically known as transplant glomerulopathy (TG) [6,[15][16][17][18].…”