Transplant Glomerulopathy: Subclinical Incidence and Association with Alloantibody

Abstract

Transplant glomerulopathy (TG) usually has been described as part of a constellation of late chronic histologic abnormalities associated with proteinuria and declining function. The current study used both protocol and clinically-indicated biopsies to investigate clinical and subclinical TG, their prognosis and possible association with alloantibody. We retrospectively studied 582 renal transplants with a negative pretransplant T-cell complement dependent cytotoxicity crossmatch. TG was diagnosed in 55 patients, 27 (49%) based on protocol biopsy in well-functioning grafts. The cumulative incidence of TG increased over time to 20% at 5 years. The prognosis of subclinical TG was equally as poor as TG diagnosed with graft dysfunction, with progressive worsening of histopathologic changes and function. Although TG was associated with both acute and chronic histologic abnormalities, 14.5% of TG biopsies showed no interstitial fibrosis or tubular atrophy, while 58% (7/12) of biopsies with severe TG showed only minimal abnormalities. TG was associated with acute rejection, pretransplant hepatitis C antibody positivity and anti-HLA antibodies (especially anti-Class II), with the risk increasing if the antibodies were donor specific. We suggest that subclinical TG is an under-recognized cause of antibody-mediated, chronic renal allograft injury which may be mechanistically distinct from other causes of nephropathy.

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

“…The term ''TG'' is sometimes used as a synonym for ''chronic ABMR'' but at other times is used to imply that the biopsy does not meet the criteria for ABMR (20)(21)(22)(23). Once a term such as TG develops such ambiguity, its use cannot be effectively disciplined.…”

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

“…TG is a morphologic pattern of chronic kidney allograft injury, which is characterized by duplication/multilamination of capillary basement membranes in the absence of immune-complex deposits (8). TG is present in 20% of kidney allograft surveillance biopsies by 5 years following transplantation (9,10). Its prevalence in indication biopsies varies from 1.6% to 7% (5,6,(11)(12)(13).…”

“…TG develops as a consequence of overt and covert episodes of antibody-mediated rejection (5,(18)(19)(20)(21)(22)(23)(24), typically, due to HLA class II anti-HLA antibodies (5,10,(25)(26)(27)(28)(29)(30). Antibodies against HLA develop when antibody-accessible polymorphic residues on HLA antigens are recognized as ''nonself.''…”

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

“…[2][3][4][5][6][7] The prevalence of TxG increases over time after transplantation from 5% at 1 year to 20% at 5 years. 8 Early, subdiagnostic findings include an "activated" aspect of glomerular endothelial cells (GECs), with accumulation of mitochondria, Golgi apparati, and ribosomes, and a transition from fenestrated to continuous endothelium. 9 Diagnostic findings are double contours of the glomerular basement membrane, visible by light microscopy, involving 10% or more of at least one glomerulus with mesangial proliferation.…”

“…This chronic endothelial damage is thought to be due to alloantibody fixation. 8,[12][13][14] Whereas the primary insult in TxG seems to be directed against GECs, other features of TxG, such as proteinuria 8 and focal and segmental glomerulosclerosis 15 are typical indicators of podocyte damage. Proteinuria suggests podocyte damage, because podocytes are considered to be the most important component of the glomerular filter.…”