Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults of European ancestry. A better understanding of the pathophysiology has emerged in recent years identifying the PLA₂R antigen and anti-PLA₂R antibodies as associated with disease in the majority of primary MN cases. Further evidence for an immunologic mechanism of disease is the association of certain HLA types, HLA-DR3 and HLA-DQ2, with MN. Up to 50% of primary MN patients experience recurrence of MN post kidney transplantation. There is limited evidence that donor HLA type can also influence the chances of MN recurrence post transplantation. These findings led the Batal et al to study the impact of different donor and recipient HLA types on post-transplant MN recurrence.

This study was a multicenter, international, retrospective case series of 77 patients with biopsy proven post-transplant MN (de novo or recurrent) and 43 control patients (primary MN without recurrence). Controls were matched for transplantation era and follow-up time. The primary outcome was death-censored graft failure, defined as reinitiation of dialysis or retransplantation. The authors sought to identify risk factors for MN with a focus on donor and recipient HLA type.

De novo MN occurred in younger recipients (40 vs 56 years old) and was more likely to be associated with donor-specific antibodies (60% vs 5%) and antibody-mediated rejection (33% vs 4%) when compared to recurrent MN. With regards to HLA type, recurrent MN was more common in recipients with HLA-DQ2 antigen (P = 0.02) and HLA-DR17 antigen (P= 0.006) when compared with de novo MN but not when compared with non-recurrent controls. Similarly, donor HLA-DQ2 (P = 0.03) and HLA-DR17 antigens (P = 0.03) were more common in patients with recurrent MN than those with de novo MN but not when compared with non-recurrent controls. Recipient HLA-A3 antigen was more commonly found in patients with recurrent MN when compared to de novo MN (P = 0.01) and nominally when compared to non-recurrent controls (P = 0.09). Donor HLA-A3 antigen was not associated with any recurrent, de novo or non-recurrent MN.

Table 1 from Batal et al, AJKD © National Kidney Foundation

Recipient age (HR 1.04, P = 0.006), allograft from living related donor (HR, 1.86; P =  0.07), steroid-free regimen (HR 2.66, P = 0.001), and recipient HLA-A3 (HR, 2.89; P = 0.001) were all associated with recurrent MN post transplantation in the multivariable model. Multivariable analysis revealed no clinical or histologic variables were associated with graft survival in de novo MN. Unsurprisingly, proteinuria (HR, 1.32; P = 0.019) and transplant glomerulitis (HR, 2.00; P = 0.017) were associated with inferior graft survival post recurrent MN. Finally, graft failure was greater with de novo MN when compared to recurrent MN (HR, 3.2).

Allograft survival in de novo and recurrent membranous nephropathy (MN). Kaplan-Meier curves for postbiopsy cumulative kidney allograft survival in patients with de novo versus recurrent MN.

Allograft survival in de novo and recurrent membranous nephropathy (MN). Kaplan-Meier curves for postbiopsy cumulative kidney allograft survival in patients with de novo versus recurrent MN. Figure 2 from Batal et al, AJKD © National Kidney Foundation

The two main questions Batal et al set out to clarify were 1) the association of HLA types and 2) the role of alloimmunity in posttransplant MN. The most interesting finding with regard to the first question is that recipient HLA-A3 was predictive of recurrence of MN. None of the other HLA types assessed (donor or recipient) were predictive of recurrent or de novo MN. Recurrent MN (like native MN) is usually PLA₂R-positive whereas de novo MN is usually PLA₂R-negative. Concurrent antibody mediated rejection was also found to be more common with de novo MN.  These findings suggest that despite similar histologic findings (subepithelial deposits) the disease mechanism behind de nova and recurrent MN is different. Finally, graft survival was worse for de novo disease compared to recurrent disease.

This study is a large study of post-transplantation MN, a rare disease, which makes this work important. A limitation identified by the authors is the possibility that the HLA-A3 association is confounded by variations in HLA-A3 frequencies in different populations. The study adds weight to importance of both autoimmunity and alloimunity in the pathogenesis of post-transplantation MN. These results might also suggest that the clinician be more vigilant when monitoring a recipient with the HLA-A3 genotype for recurrent MN.

– Post prepared by Andrew Malone, AJKDBlog Contributor. Follow him @AndrewFMalone.

To view Batal et al (subscription required), please visit AJKD.org. 

Title: Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series
Authors: I. Batal, E.-R. Vasilescu, D.M. Dadhania, A. Abderrahmane Adel, S. Ali Husain, R. Avasare, G.Serban, D. Santoriello, P. Khairallah, A. Patel, M.J. Moritz, E. Latulippe, J. Riopel, K. Khallout, S.J. Swanson, A.S. Bomback, S. Mohan, L. Ratner, J. Radhakrishnan, D.J. Cohen, G.B. Appel, M.B. Stokes, G.S. Markowitz, S.V. Seshan, S.A. De Serres, N. Andeen, A. Loupy, K. Kiryluk, and V.D. D’Agati
DOI: https://doi.org/10.1053/j.ajkd.2020.01.009