Transplant Glomerulopathy
Authors: Mark Haas
Journal: Journal of the American Society of Nephrology (2014)

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 antibody-mediated 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 cell–mediated rejection (TCMR).3–5 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 ≥3+ by dipstick in 15 (42%). Proteinuria was not different in C4d-positive and C4d-negative cases, but levels of >1 g/d or ≥2+ 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 post-transplantation, 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 also found that although acute rejection (mainly TCMR), acute tubular injury, calcineurin inhibitor toxicity, and BK virus nephropathy were not associated with a significant increase in UPod/Cr above levels seen in transplant recipients with biopsies showing no histologic lesions, TG was associated with an additional 5- to 10-fold increase in UPod/Cr, signifying a marked acceleration of podocyte detachment from GBMs. What is especially interesting about these findings in patients with TG is that similar elevations in UPod/Cr were seen in patients who developed TG early in their post-transplant course (mean 0.9 years; range, 3–24 months) and those who developed late TG (mean 10.6 years post-transplantation). The glomerular parameters in these two groups of patients are very different, and suggest different mechanisms underlying the podocyte injury and detachment. In patients with late TG, mean glomerular volume had increased 2.2-fold since the time of implantation and 1.9-fold after the initial compensatory enlargement that occurred by 3 months post-transplantation, Thus, in these patients with late TG, the primary mechanism underlying the podocyte injury and detachment is likely to be similar to that observed in the 5/6 nephrectomy model, where glomerular enlargement exceeds the capability of podocytes to hypertrophy, leading to podocyte stress, injury, and ultimately detachment with resulting glomerulosclerosis.10 Notably, the marked glomerular hypertrophy seen in late TG is not simply a matter of time post-transplantation, because biopsies without TG or other glomerulopathy performed at similar times post-transplantation showed only modest glomerular enlargement (1.2-fold) compared with 3-month protocol biopsies.9 Whether this difference in late TG and late non-TG biopsies is the result of immunologic effects in the former is currently unclear. In contrast with biopsies showing late TG, glomeruli in biopsies with early TG were only mildly (1.2-fold) and not significantly enlarged compared with those on 3-month protocol biopsies, yet showed similar levels of podocyte depletion (as documented by both UPod/Cr and the mean number of podocytes per glomerulus) as with late TG. This strongly suggests that in early TG, active immunologic mechanisms of podocyte injury are in large part responsible for the podocyte depletion. Podocytes express MHC class I and class II molecules, and this increases under inflammatory conditions.11,12 Furthermore, podocytes can serve as antigen-presenting cells, and deleting MHC class II exclusively on podocytes markedly attenuates the severity of GN in a mouse model of anti-GBM nephritis.12 Yang et al.9 did not compare glomerulitis in their cases of early versus late TG, and they observed acute ABMR only infrequently before the development of early or late TG, although diagnosis was based on an older version of the Banff classification that did not recognize C4d-negative ABMR. However, 5 of 8 cases of early TG were associated with a history of TCMR (Banff 1A or above) compared with only 2 of 17 cases of late TG, suggesting that an inflammatory environment may have been present, at least transiently, in the majority of kidneys developing early TG, 6 of 8 of which were also exposed to DSAs.9 These findings suggest a scenario in which glomeruli exposed to an inflammatory environment due to the presence of TCMR, ABMR, or both show endothelial injury allowing for filtration of DSAs, which then binds to podocytes expressing HLA producing podocyte injury, increased glomerular permeability to DSAs and other proteins, and further podocyte DSA binding, injury, and detachment. According to this hypothesis, early TG and podocyte injury and detachment would be related but parallel events, with TG resulting from endothelial injury and the associated proteinuria due largely to podocyte injury and detachment. The presence of DSAs is crucial in this model, not only to development of endothelial injury and TG but also because acute rejection (mainly TCMR) alone was not found to be associated with levels of UPod/Cr above those seen in renal allograft recipients without rejection.9 This hypothesis should be testable in animal models, and a similar course of events (i.e., endothelial injury preceding podocyte injury) was demonstrated in a model of adriamycin-induced nephropathy.13 The apparent difference in the pathogenesis of early versus late TG also has important treatment implications. Late TG, particularly without evidence of active microvascular inflammation, would appear unlikely to respond to therapies designed to target B cells and reduce DSAs, and might best be treated by blockade of the renin-angiotensin system (RAS). In several animal models of glomerulosclerosis, RAS blockade prevents continuous podocyte loss and progression to ESRD.10 Furthermore, in a recent double-blind, randomized, placebo-controlled trial, RAS blockade with losartan appeared to reduce the risk of a composite outcome of doubling of interstitial volume or graft loss.14 By contrast, patients with early TG would appear more likely to respond to treatments targeting B cells and DSAs, particularly when there is concurrent microvascular inflammation. In a study of patients diagnosed with TG 3.2 years post-transplantation, Kahwaji et al.15 found that treatment with rituximab and intravenous Ig (IVIG) was associated with stabilization of proteinuria (with no difference in RAS blockade between rituximab/IVIG and no rituximab/IVIG groups), and stabilization of proteinuria was associated with significantly improved graft survival.15 These investigators also found that 11 of 17 patients with TG and moderate to severe peritubular capillaritis (Banff score≥2) who were treated with rituximab and IVIG had stable graft function, compared with 0 of 6 patients with similar histology not receiving this therapy. In their study, Yang et al.9 confirmed the overall poor prognosis of grafts with TG; 4 of 8 patients with early TG lost their grafts at a mean of 2.6 years post-transplantation, and 9 of 17 grafts with late TG were lost at a mean of 12.4 years post-transplantation. In both cases, this represents a relatively fast progression to graft loss, noting that early and late TG were diagnosed at a mean of 0.9 years and 10.6 years post-transplantation, respectively. This poor prognosis has led some transplant clinicians to believe that progression to graft loss is inevitable in patients with TG, and has discouraged clinicians from treating these patients. Clearly, in the case of TG, Benjamin Franklin's axiom that an ounce of prevention is worth a pound of cure holds true. However, as with other disease processes associated with poor outcomes, developing an increased understanding of pathogenic mechanisms underlying TG offers new hope for measures that can prolong graft survival. This may require thinking "outside the box," or in this case, outside of the GBM. Disclosures None. The author thanks Dr. Cynthia C. Nast for her comments on the manuscript.