Partial therapeutic response to Rituximab for the treatment of chronic alloantibody mediated rejection of kidney allografts

Abstract

Background and Objectives

Chronic rejection leads to kidney allograft failure and develops in many kidney transplant recipients. One cause of chronic rejection, chronic antibody mediated rejection (CAMR), is attributed to alloantibodies. Maintenance immunosuppression including prednisone, mycophenolate mofetil (MMF) and calcineurin inhibitors may limit alloantibody production in some patients, but many maintain or develop alloantibody production, leading to CAMR. Therefore, no efficacious therapy to treat CAMR is presently available to prevent the progression of CAMR to kidney allograft failure.

Design, Setting, Participants, and Measurements

We performed a retrospective review of 31 subjects with CAMR, of which 14 received Rituximab and 17 subjects did not. Response to Rituximab was defined as decline or stabilization of serum creatinine for at least one year. Data reviewed included demographic, clinical, allograft, post-transplant, and pathological variables. Pathological variables in the diagnostic allograft biopsy were scored according to Banff criteria.

Results

The median survival time (MST) for allografts in the control group was 439 days, and for the Rituximab treated group was 685 days. The Rituximab group was dichotomous with 8 subjects showing a medial survival time of 1180 days, and 6 subjects having a median survival time of 431 days. The MST for the responders was statistically significant from the non-responders and controls. No pathological parameter distinguished any subset of subjects.

Conclusions

These data show that Rituximab followed by standard maintenance immunosuppression shows a therapeutic effect in the treatment of CAMR, which is confined to a subset of treated subjects, not identifiable a priori.

Introduction

Although short term survival of kidney allografts has improved, chronic rejection leading to kidney allograft failure develops in a significant number of kidney transplant recipients [4], [5] and accounts for kidney failure in 50 to 80% of subjects [2]. Chronic antibody mediated rejection (CAMR), one cause of chronic rejection, is characterized by chronic glomerular and capillary endothelial injury [1], [2], [3], is usually associated with proteinuria [6], [7], [8], [9] and pathological hallmarks including transplant glomerulopathy (duplication and laminations of the glomerular basement membrane) plus excess laminations of the peritubular capillaries. CAMR correlates with alloantibodies [2], [9], [10], [11], [12], [13], [14]. The presence of donor specific de novo anti-HLA antibodies (DSA) also associates with a poorer kidney graft survival as compared to subjects without de novo anti-HLA antibodies [15], [16], [17], [18], [19]. In animal studies, monkeys with kidney allografts and alloantibodies but off immunosuppression have identical pathology to humans and universally progress to kidney allograft failure [20], [21]. Although mycophenolate mofetil (MMF) and calcineurin inhibitors are common in maintenance immunosuppression and may limit alloantibody production in some transplant patients, many maintain or develop alloantibodies.

Rituximab, a monoclonal anti-CD20 antibody, a possible drug to treat CAMR, depletes B cells, which later can develop into alloantibody secreting plasma cells. The potential efficacy of Rituximab is demonstrated in other antibody mediated conditions, e.g., acute humoral rejection in kidney transplant recipients [22], ANCA-associated vasculitis [23], idiopathic membranous glomerulonephritis [24], and resistant cases of rheumatoid arthritis [25].

Currently, no data exist standardizing a successful treatment for kidney allografts with CAMR. Therefore, we performed a retrospective analysis of subjects diagnosed with CAMR at Massachusetts General Hospital (MGH) between 1997 and 2007 and compared the outcomes of those who received Rituximab. Our goal is to determine if combined therapy of Rituximab followed by maintenance MMF and tacrolimus improves long term kidney allograft function.