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Anti-CD20 Monoclonal Antibody (Rituximab) for the Treatment of Membranous Nephropathy After Living-Unrelated Kidney Transplantation: A Case Report
Anti-CD20 Monoclonal Antibody (Rituximab) for the Treatment of Membranous Nephropathy After Living-Unrelated Kidney Transplantation: A Case Report T. Sirimongkolrat, N. Premasathian, A. Vongwiwatana, S. Limsrichamrern, B. Cheunsuchon, and S. Vasuvattakul ABSTRACT A 41-year-old Thai male with end-stage renal disease of uncertain etiology started chronic hemodialysis in November 2001. Two years later, he underwent a living unrelated, four HLA mismatched, kidney transplantation from his wife. Pretransplant class I panel reactive antibody was 80% and the cross-match was positive for immunoglobulin (Ig)M. There was no complication until 30 months after transplantation, when he developed frank nephrotic syndrome with 12.9 g/day of proteinuria. Serum creatinine was 1.5 mg/dL. Allograft biopsy showed membranous nephropathy and mild acute cellular rejection with plasma cell infiltration. In addition to enalapril, valsartan, and simvastatin, a single dose of rituximab (375 mg/m2) and a 3-day course of pulse methylprednisolone were prescribe for the acute rejection episode. The patient was maintained on the same immunosuppressive regimen: cyclosporine, azathioprine, and prednisolone. Five months after the therapy, proteinuria was reduced to 0.5 g/day with a normalized serum albumin level. At 4 years post transplantation, his renal function remains stable. His serum albumin is 4.5 g/dL and urine protein-to-creatinine ratio 0.2.
I
DIOPATHIC MEMBRANOUS nephropathy (IMN) is the common cause of nephrotic syndrome (NS) in adults. The course of IMN in renal transplant patients and the potential treatment options are even less clear than in nonrenal transplant patients with IMN. The mean time of onset of recurrent disease is approximately 10 months posttransplantation as compared with the more insidious and later onset of symptoms in de novo IMN, namely, at a mean of 18 to 21 months after transplantation.1,2 Recurrent IMN may have a more aggressive initial course; however, de novo disease shows poorer outcomes, with graft loss as high as 50%3 compared with 10% to 15% of recurrence cases after 10 years.4 De novo IMN is the second most common cause of NS among transplanted individuals (second only to chronic transplant glomerulopathy).5 Graft loss is higher when associated with acute rejection episodes. Recent reports have shown a potential therapeutic role of rituximab in both non-renal transplant IMN and recurrent IMN with a modest side effect prolife and no major adverse event.6,7 CASE REPORT We have described a 41-year-old Thai man with end-stage renal disease (ESRD) of unknown etiology without a clinical diagnosis of
NS. During routine follow-up at the renal transplant clinic at 30 months after receiving a four HLA mismatch living-unrelated kidney transplantation from his wife, he developed frank NS. His physical examination was unremarkable, except for leg edema with a blood pressure around 110/75 mmHg on diltiazem. His past medical history was positive for hypertension, ESRD of unknown etiology, and erythropoietin-induced pure red cell aplasia that resolved in the early post-renal transplant period with an hematocrit level of 44% at 2 months postsurgery. Pretransplant type I panel reactive antibody (PRA) was 80%; the cross-match was positive for immunoglobulin (Ig)M. His induction immunosuppressive therapy consisted of cyclosporine (Neoral) and methylprednisolone. His maintenance immunosuppressive therapy consisted of azathioprine (Imuran), prednisolone, and cyclosporine (Neoral). There was no complication until 30 months after transplantation, when he developed NS with 12.9 g/day of proteinuria. His serum From the Division of Nephrology, Department of Medicine (T.S., N.P., A.V., S.V.); the Department of Surgery (S.L.); and the Department of Pathology (B.C.), Siriraj Hospital, Bangkok, Thailand. Address reprint requests to Dr Nalinee Premasathian Renal Division, 2nd floor, Pa-ob Building Siriraj Hospital, Prannok, Bangkoknoi, Bangkok Thailand 10700. E-mail: nalinee2216@ gmail.com
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.07.074
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2440
Transplantation Proceedings, 40, 2440 –2441 (2008)
RITUXIMAB FOR MEMBRANOUS NEPHROPATHY albumin was 2.2 g/dL. His lipid profile showed a total cholesterol of 398 mg/dL, triglyceride of 433 mg/dL and low-density lipoprotein (LDL) of 256 mg/dL. Serum creatinine was 1.8 mg/dL. Hepatitis profiles were negative. The patient had received enalapril at moderate dose 1 month before the kidney biopsy. An allograft kidney biopsy performed in August 2006 showed membranous nephropathy with Banff type IA acute cellular rejection with plasma cell infiltration. Staining for C4d deposition was negative. He was started on the treatment with simvastatin, a single dose of rituximab (375 mg/m2), and 3 daily doses of methylprednisolone (500 mg/day) for acute rejection. Serum creatinine, proteinuria, and other clinical parameters were measured at baseline, weekly during the first 2 months, and every 1 to 2 months thereafter. At 1 month after rituximab treatment, there was a significant reduction in urine protein-to-creatinine ratio from 12.9 to 3 with a corresponding increase in serum albumin, improvement in hypercholesterolemia, and stable serum creatinine. Five months after therapy, the urine protein-to-creatinine ratio was reduced to 0.5 with normalized serum albumin level. At 4 years posttransplantation, his renal function remains stable with the serum creatinine of 1.3 mg/dL; LDL, 75 mg/dL; serum albumin, 4.5 g/dL; and urine protein-to-creatinine ratio, 0.2.
DISCUSSION
Our patient was diagnosed with post-renal transplant membranous nephropathy with late-onset NS (30 months after transplantation). He was also diagnosed with concomitant acute cellular rejection with plasma cell infiltration. Some reports have shown the pathophysiology of de novo disease may be related to a secondary antibody response to a glomerular antigen exposed by rejection.3 We treated our patient with IMN and acute cellular rejection with 3 days of 500 mg of methylprednisolone for acute rejection and a single dose of 375 mg/m2 of rituximab intravenous infusion for IMN. The treatment resulted in complete remission with no adverse event. The speculative role of rituximab for treatment of IMN has been suggested by depleting the autoreactive B-cell clone committed to produce nephritogenic antibody.6 Recently, Gallon et al7 reported a 39-year-old man with recurrent IMN and NS treated with four weekly doses of rituximab (375 mg/m2) and followed for 3 years. Treatment
2441
resulted in a significant reduction in proteinuria from 18 g/day to 0.5 g/day, a corresponding increase in serum albumin, improvement in hypercholesterolemia, and stable renal function.7 Plasmacytic acute rejection is uncommon in allograft biopsies. Combined data from three studies have shown more severe graft dysfunction and graft loss among plasmacytic acute rejection episodes compared with episodes free of plasma cell infiltration.8 After activation, B cells produce cytokines, modify immunoglobulin production, process antigen for presentation to T cells, and proliferate and differentiate into plasma cells. Because Rituximab perturbs these processes it may help in the treatment of acute rejection episodes with plasma cell infiltration.9 In conclusion, Rituximab seemed to be effective to treat posttransplant IMN.
REFERENCES 1. Berger BE, Vincenti F, Biava C, et al: De novo and recurrent membranous glomerulopathy following kidney transplantation. Transplantation 35:315, 1983 2. Josephson MA, Spargo B, Hollandsworth D, et al: The recurrence of recurrent membranous glomerulopathy in a renaltransplant recipient— case-report and literature-review. Am J Kidney Dis 24:873, 1994 3. Truong L, Gelfand J, D’Agati V, et al: De novo membranous glomerulonephropathy in renal allografts: a report of ten cases and review of the literature. Am J Kidney Dis 14:131, 1989 4. Briganti EM, Russ GR, McNeil JJ, et al: Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med 347:103, 2002 5. Joshi K, Nada R, Minz M, et al: Recurrent glomerulopathy in the renal allograft. Transplant Proce 39:734, 2007 6. Ruggenenti P, Chiurchiu C, Brusegan V, et al: Rituximab in idiopathic membranous nephropathy: a one year prospective study. J Am Soc Nephrol 14:1851, 2003 7. Gallona L, Chhabra D: Anti-CD20 monoclonal antibody (Rituximab) for the treatment of recurrent idiopathic membranous nephropathy in a renal transplant patient. Am J Transplant 6:3017, 2006 8. Douglas A, Tibor N, Racusen LC: Plasma cell-rich acute renal allograft rejection. Transplantation 68:791, 1999 9. Salama AD, Pusey CD: Drug insight: rituximab in renal disease and transplantation. Nat Clin Pract Nephrol 2:221, 2006
I
DIOPATHIC MEMBRANOUS nephropathy (IMN) is the common cause of nephrotic syndrome (NS) in adults. The course of IMN in renal transplant patients and the potential treatment options are even less clear than in nonrenal transplant patients with IMN. The mean time of onset of recurrent disease is approximately 10 months posttransplantation as compared with the more insidious and later onset of symptoms in de novo IMN, namely, at a mean of 18 to 21 months after transplantation.1,2 Recurrent IMN may have a more aggressive initial course; however, de novo disease shows poorer outcomes, with graft loss as high as 50%3 compared with 10% to 15% of recurrence cases after 10 years.4 De novo IMN is the second most common cause of NS among transplanted individuals (second only to chronic transplant glomerulopathy).5 Graft loss is higher when associated with acute rejection episodes. Recent reports have shown a potential therapeutic role of rituximab in both non-renal transplant IMN and recurrent IMN with a modest side effect prolife and no major adverse event.6,7 CASE REPORT We have described a 41-year-old Thai man with end-stage renal disease (ESRD) of unknown etiology without a clinical diagnosis of
NS. During routine follow-up at the renal transplant clinic at 30 months after receiving a four HLA mismatch living-unrelated kidney transplantation from his wife, he developed frank NS. His physical examination was unremarkable, except for leg edema with a blood pressure around 110/75 mmHg on diltiazem. His past medical history was positive for hypertension, ESRD of unknown etiology, and erythropoietin-induced pure red cell aplasia that resolved in the early post-renal transplant period with an hematocrit level of 44% at 2 months postsurgery. Pretransplant type I panel reactive antibody (PRA) was 80%; the cross-match was positive for immunoglobulin (Ig)M. His induction immunosuppressive therapy consisted of cyclosporine (Neoral) and methylprednisolone. His maintenance immunosuppressive therapy consisted of azathioprine (Imuran), prednisolone, and cyclosporine (Neoral). There was no complication until 30 months after transplantation, when he developed NS with 12.9 g/day of proteinuria. His serum From the Division of Nephrology, Department of Medicine (T.S., N.P., A.V., S.V.); the Department of Surgery (S.L.); and the Department of Pathology (B.C.), Siriraj Hospital, Bangkok, Thailand. Address reprint requests to Dr Nalinee Premasathian Renal Division, 2nd floor, Pa-ob Building Siriraj Hospital, Prannok, Bangkoknoi, Bangkok Thailand 10700. E-mail: nalinee2216@ gmail.com
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.07.074
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2440
Transplantation Proceedings, 40, 2440 –2441 (2008)
RITUXIMAB FOR MEMBRANOUS NEPHROPATHY albumin was 2.2 g/dL. His lipid profile showed a total cholesterol of 398 mg/dL, triglyceride of 433 mg/dL and low-density lipoprotein (LDL) of 256 mg/dL. Serum creatinine was 1.8 mg/dL. Hepatitis profiles were negative. The patient had received enalapril at moderate dose 1 month before the kidney biopsy. An allograft kidney biopsy performed in August 2006 showed membranous nephropathy with Banff type IA acute cellular rejection with plasma cell infiltration. Staining for C4d deposition was negative. He was started on the treatment with simvastatin, a single dose of rituximab (375 mg/m2), and 3 daily doses of methylprednisolone (500 mg/day) for acute rejection. Serum creatinine, proteinuria, and other clinical parameters were measured at baseline, weekly during the first 2 months, and every 1 to 2 months thereafter. At 1 month after rituximab treatment, there was a significant reduction in urine protein-to-creatinine ratio from 12.9 to 3 with a corresponding increase in serum albumin, improvement in hypercholesterolemia, and stable serum creatinine. Five months after therapy, the urine protein-to-creatinine ratio was reduced to 0.5 with normalized serum albumin level. At 4 years posttransplantation, his renal function remains stable with the serum creatinine of 1.3 mg/dL; LDL, 75 mg/dL; serum albumin, 4.5 g/dL; and urine protein-to-creatinine ratio, 0.2.
DISCUSSION
Our patient was diagnosed with post-renal transplant membranous nephropathy with late-onset NS (30 months after transplantation). He was also diagnosed with concomitant acute cellular rejection with plasma cell infiltration. Some reports have shown the pathophysiology of de novo disease may be related to a secondary antibody response to a glomerular antigen exposed by rejection.3 We treated our patient with IMN and acute cellular rejection with 3 days of 500 mg of methylprednisolone for acute rejection and a single dose of 375 mg/m2 of rituximab intravenous infusion for IMN. The treatment resulted in complete remission with no adverse event. The speculative role of rituximab for treatment of IMN has been suggested by depleting the autoreactive B-cell clone committed to produce nephritogenic antibody.6 Recently, Gallon et al7 reported a 39-year-old man with recurrent IMN and NS treated with four weekly doses of rituximab (375 mg/m2) and followed for 3 years. Treatment
2441
resulted in a significant reduction in proteinuria from 18 g/day to 0.5 g/day, a corresponding increase in serum albumin, improvement in hypercholesterolemia, and stable renal function.7 Plasmacytic acute rejection is uncommon in allograft biopsies. Combined data from three studies have shown more severe graft dysfunction and graft loss among plasmacytic acute rejection episodes compared with episodes free of plasma cell infiltration.8 After activation, B cells produce cytokines, modify immunoglobulin production, process antigen for presentation to T cells, and proliferate and differentiate into plasma cells. Because Rituximab perturbs these processes it may help in the treatment of acute rejection episodes with plasma cell infiltration.9 In conclusion, Rituximab seemed to be effective to treat posttransplant IMN.
REFERENCES 1. Berger BE, Vincenti F, Biava C, et al: De novo and recurrent membranous glomerulopathy following kidney transplantation. Transplantation 35:315, 1983 2. Josephson MA, Spargo B, Hollandsworth D, et al: The recurrence of recurrent membranous glomerulopathy in a renaltransplant recipient— case-report and literature-review. Am J Kidney Dis 24:873, 1994 3. Truong L, Gelfand J, D’Agati V, et al: De novo membranous glomerulonephropathy in renal allografts: a report of ten cases and review of the literature. Am J Kidney Dis 14:131, 1989 4. Briganti EM, Russ GR, McNeil JJ, et al: Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med 347:103, 2002 5. Joshi K, Nada R, Minz M, et al: Recurrent glomerulopathy in the renal allograft. Transplant Proce 39:734, 2007 6. Ruggenenti P, Chiurchiu C, Brusegan V, et al: Rituximab in idiopathic membranous nephropathy: a one year prospective study. J Am Soc Nephrol 14:1851, 2003 7. Gallona L, Chhabra D: Anti-CD20 monoclonal antibody (Rituximab) for the treatment of recurrent idiopathic membranous nephropathy in a renal transplant patient. Am J Transplant 6:3017, 2006 8. Douglas A, Tibor N, Racusen LC: Plasma cell-rich acute renal allograft rejection. Transplantation 68:791, 1999 9. Salama AD, Pusey CD: Drug insight: rituximab in renal disease and transplantation. Nat Clin Pract Nephrol 2:221, 2006