Partial therapeutic response to Rituximab for the treatment of chronic alloantibody mediated rejection of kidney allografts☆
Highlights
► Chronic alloantibody kidney allograft rejection markedly shortens renal allograft survival. ► Rituximab and standard maintenance therapy increases renal allograft survival time. ► The increased renal survival time was only observed in a subset of those patients. ► Clinical and pathological factors were not identified.
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.
Section snippets
Subjects
Subjects diagnosed with CAMR at the Massachusetts General Hospital (MGH) had kidney allograft biopsies from 1997 to 2007 were retrospectively reviewed under an institutional investigational review board approval and. All biopsies were for cause, elevated creatinine with or without proteinuria. Criteria for this diagnosis included transplant glomerulopathy (glomerular basement duplication), C4d staining of the peritubular capillaries by immunofluorescence, and presence of DSA (Table 1).
All subjects
The 31 subjects identified in this study were diagnosed with CAMR (Tables 1 and 2). Biopsies were for cause, either an increase in creatinine or proteinuria. The median time of diagnosis after transplant was 7.0 years (range 1.7 to 21.6 years). The mean creatinine at diagnosis was 2.9 +/− 1.1 mg/dl (range 1.6 to 6.1). Native kidney disease and other demographics are listed in Tables 1 and 2 along with baseline immunosuppression at the time of biopsy. Control subjects were receiving maintenance
Discussion
Previous studies have shown decreased kidney allograft survival in patients with CAMR (6–9). This study confirms those findings with control and Rituximab non-responder group having a median allograft survival post diagnosis of 439 days and 431 days, respectively. In the Rituximab responder group, median kidney survival is 1180 days. The variable response in kidney allograft survival between the Rituximab treated responder and Rituximab treated non-responder groups is striking, and quite
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Cited by (0)
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R.N.S., F.M., N.G., A.B.F., E.Z., S.S., N.T.-R., S.P., and W.W. participated in data collection. R.N.S., F.M., N.G., and N.T.-R. participated in the research design. R.N.S., F.M., N.G.,A.B.F., N.T.-R., E.Z. and W.W. participated in preparation of the manuscript. F.M., N.G., and N.T.-R. participated in clinical care. R.N.S. performed statistical analyses.