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Treatment-Resistant Recurrent Membranoproliferative Glomerulonephritis in Renal Allograft Responding to Rituximab: Case Report
Treatment-Resistant Recurrent Membranoproliferative Glomerulonephritis in Renal Allograft Responding to Rituximab: Case Report M. Farooquia,*, K. Alsaadb, N. Aloudahc, and H. Alhamdanc a Division of Nephrology, King Abdulaziz Medical City, Riyadh, Saudi Arabia; bDepartment of Pathology and Laboratory Medicine, King Abdullah International Medical Research Center and College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia; and cDepartment of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia
ABSTRACT We report a case of idiopathic membranoproliferative glomerulonephritis (MPGN) recurring 2 years after a living-unrelated kidney transplantation. The disease was refractory to intravenous immunoglobulin and plasmapheresis. Treatment with 2 doses of rituximab resulted in remission of the disease. The disease relapsed 18 months later after an episode of cytomegalovirus pneumonitis. After treatment of the pneumonitis, a lung biopsy was performed owing to persistent chest symptoms, which revealed bronchiolitis obliterans with organizing pneumonia. Bone marrow examination and culture revealed presence of acid-fast bacilli, and culture grew Mycobacterium tuberculosis. A repeated course of rituximab was withheld because of infection with tuberculosis, the patient’s chest symptoms, and rare reports of noninfectious lung disease after the use of rituximab. The patient continues to have proteinuria with impaired kidney function.
M
EMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) is a disorder with reported frequency varying from 4.8% to 28% of kidney biopsies [1e4]. In general, the patients are treated with immunosuppressive medications including steroids and cyclophosphamide or antiproliferative agents. The response to treatment is variable, and significant proportion of patients reach end-stage kidney disease despite treatment. The disease is well known to recur in kidney allografts, 27% in 1st transplants and up to 80% in 2nd transplants [5,6]. CASE REPORT A 58-year-old man with history of diabetes mellitus and hypertension presented with development of recent onset generalized body swelling, uncontrolled blood pressure, and serum creatinine rising from 142 mmol/L in May 2009 to 321 mmol/L in December 2009. He also developed heavy proteinuria of 16 g/d. There was no history of recent infections or systemic or urinary symptoms. His physical examination was remarkable for presence of nonproliferative diabetic retinopathy and generalized edema. Urine microscopic examination revealed few red blood cells but no casts. Serology including hepatitis B, hepatitis C, antineutrophil cytoplasmic antibody (ANCA), and antinuclear antibody (ANA) were negative. His serum C3 and C4 levels were normal. He tested negative for human immunodeficiency ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 823e826 (2015)
virus (HIV), and his serum and urine protein electrophoreses were negative for monoclonal proteins. The patient underwent ultrasound-guided kidney biopsy. Histologic examination demonstrated features compatible with a membranoproliferative pattern of glomerular injury. The specimen contained 29 glomeruli, of which 11 were globally sclerosed. The remaining glomeruli exhibited lobular accentuation of the glomerular tufts and showed moderate increase in mesangial matrix and segmental mild increase in mesangial cellularity. Segmental glomerular scarring in the form of obliteration of the glomerular capillaries and adhesion of the glomerular tufts to the Bowman capsule was identified in 5 glomeruli. The glomerular capillaries showed diffuse increase in thickness and double contouring in periodic acid Schiff and methenamine silver special stains. Proliferative features in the form of segmental endocapillary hypercellularity and subendothelial deposits were evident. These were associated with cellular crescents in 5 glomeruli (Fig 1A). There was moderate interstitial fibrosis and tubular atrophy, accompanied by moderate chronic, predominantly lymphocytic, interstitial inflammation. Severe arteriolar hyalinosis and moderate arterial sclerosis were
*Address correspondence to Mahfooz Farooqui, MD, FACP, FASN, Division of Nephrology, Department of Medicine, King Abdulaziz Medical City, PO Box 22490, Mail Code 1443, Riyadh 11426, Saudi Arabia. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.02.003
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Fig 1. Native renal biopsy. (A) Glomeruli showed features of proliferative, crescent-forming, immune-mediated glomerulonephritis compatible with membranoproliferative glomerulonephritis (periodic acideSchiff, 200). Segmental double contouring of the glomerular capillaries was evident (inset; methenamine silver stain, 400). (B) Ultrastructural photograph showing subendothelial immune-type dense deposits (transmission electron microscopy, urinyl acetate and lead citrate stain, 10,000). present. There was no evidence of microthrombi in the interstitial blood vessels or of vasculitis. Immunofluorescence and electron microscopy studies confirmed the immune-mediated nature of the glomerular disease. There was diffuse coarse granular and pseudolinear capillary and mesangial staining for IgG (3þ/3þ), C3 (3þ), C1q (2þ) and kappa (2þ) light chain. Weak staining for IgM (1þ) and lambda light chain was also seen. There was no staining for IgA and albumin. Ultrastructural examination demonstrated variably sized subendothelial and mesangial immune-type dense deposits, thickened glomerular basement membranes with segmental replication, and diffuse effacement of the foot processes (Fig 1B). Therapeutic options were discussed with the patient, who chose not to be treated with cyclophosphamide, and treatment was initiated with intravenous methylprednisolone pulse therapy of 1,000 mg for 3 days followed by oral steroids at 1 mg/kg/day. The patient did not respond to this therapy and became dialysis-dependent within 2 months. He underwent living-unrelated kidney transplant 2 months after starting dialysis. His maintenance immunosuppression comprised of prednisone, mycophenolate mofetil, and tacrolimus. He had undetectable proteinuria and serum creatinine at baseline of 120 mmol/L until July 2011. His diabetes remained poorly controlled, and he developed trace proteinuria on dipstick in October 2011. He presented in February 2012 with generalized body swelling, proteinuria of 12 g/d, and rise in serum creatinine from baseline of 120 mmol/L to 175 mmol/L. Again, his serology for hepatitis B, hepatitis C, ANCA, and ANA were negative. His C3 and C4 were normal. He tested negative for HIV, and his serum and urine electrophoreses revealed no abnormal monoclonal proteins. The patient again underwent ultrasound-guided percutaneous biopsy of the kidney allograft, which showed histologic, immunohistochemical, and ultrastructural findings similar to those seen in the native renal biopsy and compatible with recurrent crescentforming MPGN. However, there was mild interstitial fibrosis and tubular atrophy, more exuberant glomerular hypercellularity, and less degree of crescent formation (Fig 2). No significant global glomerular sclerosis was seen. There was no evidence of viral cytopathic effect or cellular or humoral renal allograft rejection. Immunohistochemical stains for polyomavirus (dilution 1:200, clone Pab416; Abcam, Cambridge, United Kingdom) and C4d (1:40, polyclonal; Abcam) were negative. The patient was again treated with intravenous pulses of methylprednisolone, plasmapheresis, and intravenous immunoglobulin. His anasarca was resistant to diuretic therapy, and he required
intermittent ultrafiltration for 2 months for episodes of pulmonary edema. He was eventually given rituximab at 375 mg/m2 of body surface area: 2 doses 2 weeks apart. The patient improved gradually over 4 months with resolution of edema, stabilization of serum creatinine (175 mmol/L), reduction of proteinuria to 0.66 g/d, and normalization of serum albumin. The patient remained edema free with minimal proteinuria until October 2013, when he was admitted to a local hospital because of edema and shortness of breath and was diagnosed with cytomegalovirus pneumonitis. He was treated with diuretics, empiric antibiotics, and intravenous ganciclovir. His persisting cough and difficulty in breathing on exertion required lung biopsy which revealed bronchiolitis obliterans with organizing pneumonia. He presented to the transplant clinic in February 2014 with generalized edema, shortness of breath, hypoalbuminemia, and proteinuria of 7 g/d. Repeated kidney biopsy revealed MPGN with moderate interstitial fibrosis and tubular atrophy. The patient continued to have chest symptoms after treatment of the cytomegalovirus infection. Bronchoscopy, lung biopsy, and bronchoalveolar lavage for cytology and cultures (including Mycobacterium tuberculosis) were nondiagnostic. Eventually, diagnosis of tuberculosis was made on bone marrow examination. Further immunosuppression with rituximab was withheld owing to tuberculosis and reports of noninfectious lung complications associated with the use of rituximab. He continues to have proteinuria and impaired kidney function with serum creatinine of 170 mmol/L.
DISCUSSION
Idiopathic MPGN is a challenging form of renal injury for which there are few controlled trials of treatment, particularly in adult patients. Additionally, the disease pattern and prognosis may differ according to age of presentation and geographic location studied [7e9]. MPGN with crescents represents an aggressive disease and over time many patients, despite therapy, progress to end-stage kidney disease. Clinical prognostic factors include increased serum creatinine, proteinuria 1 g/d, systolic blood pressure (BP) 160 mm Hg, diastolic BP 90 mm Hg, serum albumin <35 g/L, presence of urinary granular casts, and age 60 years [10]. Histologic features suggestive of poor outcome include presence of
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Fig 2. Renal allograft biopsy. (A) Glomeruli showed hypersegmentation of the tufts, endocapillary hypercellularity, segmental subendothelial deposits, and replication of the glomerular capillaries (periodic acideSchiff, 200). (B) Immunofluorescence staining demonstrated intense glomerular staining for IgG and C3.
crescents, fibrosis of the interstitium, and mesangial proliferation. MPGN has a tendency to recur after kidney transplantation, with a rate of 20%e50% in 1st transplants. The reported risk of graft loss is variable in different studies. A group from Italy described 63 patients with MPGN type I with 68 renal transplants. They compared these patients with a matched group of control subjects. They reported no difference in patient survival or 15-year graft survival in the 2 groups. In their study 16 patients (23.5%) developed a recurrence of MPGN after transplantation. The group with recurrence of MPGN had a lower 15-year graft survival: 40.4% compared with 73.5% in the group with no recurrence of the disease [11]. An earlier study from the Netherlands reported on 31 cases of MPGN type I. They reported recurrence of disease to be 48% at 4 years. Five patients with recurrent MPGN received 2nd transplants, and 4 of those retransplanted patients (80%) had recurrence of MPGN [12]. MPGN type II has a higher recurrence rate of 80%e100% with 15%e30% of the affected patients losing their graft within 5 years [13]. Hariharan et al reported 66% graft failure with MPGN after kidney transplantation in a multicenter registry in the United States [14]. Treatment of MPGN
It is essential to identify the presence of a primary disease, such as lupus erythematosus, hepatitis C, cryoglobulinemia, paraproteinemias, and malignancy, leading to MPGN. The secondary MPGN treatment requires treatment of the primary disease, often in combination with immunosuppression. Idiopathic MPGN type I (which is characterized by subendothelial and mesangial immune deposits) differs from MPGN type II (characterized by intramembranous dense deposits) in etiology and clinical course. MPGN type II, also called dense deposit disease, is more common in pediatric populations. In the pediatric population, use of steroids, particularly with intravenous pulse therapy, is associated with better renal survival [15,16]. When protein restriction and antihypertensive therapy was compared with addition of aspirin
and dipyridamole, reduction in proteinuria was seen with no change in serum creatinine after 24e36 months [17,18]. Some studies have failed to demonstrate short- to mediumterm benefits of the use of cyclophosphamide, yet the use of cyclophosphamide, in combination with steroids, may be of benefit when there is severe, crescent-forming disease [19,20]. Likewise, there are case series reporting improved outcome with the use of mycophenolate mofetil in idiopathic MPGN resistant to steroids [21,22]. Rituximab has previously been described for treatment of resistant forms of MPGN as well as MPGN occurring after kidney transplantation [23,24]. Our case had a slow improvement over 4 months which lasted for 16 months, when his disease relapsed. It could be argued that we should have monitored CD19 and should have administered further cycles of rituximab if a rising count of CD19þ lymphocyte was observed [25]. We were further limited by patient’s persistent chest symptoms and the association of progressive noninfectious lung disease with the use of rituximab. Patients who develop recurrence of idiopathic MPGN in the kidney allograft probably represent the group with a resistant form of the disease, because these patients are usually on immunosuppressive therapy with a combination of agents, such as steroids, calcineurin inhibitor, and antiproliferative agent (either azathioprine or mycophenolate mofetil). There is no clear consensus regarding a 1st-line therapeutic agent in recurrent MPGN after transplantation. Because the number of these cases is small, it is unlikely that a controlled trial of treatment will become available to guide therapy. There are plenty of cases of post-transplantation focal segmental glomerulosclerosis and IgA nephropathy and their treatment, because these forms of glomerulonephritis are common. Treatment of post-transplantation MPGN, being relatively rare, is reported by only a few. Dillon et al described a series of patients with MPGN type I with reduction of proteinuria after treatment with rituximab [26]. We report that case to suggest that rituximab remains a therapeutic option for the treatment of idiopathic type I MPGN resistant to other forms of treatment. Infectious as well as
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noninfectious pulmonary side effects may limit long-term use of this agent [27e29]. REFERENCES [1] Alatif T, Maoujoud O, Montasser I, et al. Glomerular disease in military hospital of Morocco: review of single center renal biopsy database on adults. Indian J Nephrol 2012;22:257e63. [2] Rabbani M, Memon G, Ahmad B, et al. Percutaneous renal biopsy results: a retrospective analysis of 511 consecutive cases. Saudi J Kidney Dis Transpl 2012;23:614e8. [3] Wu Y, Wang Z, Xu H, et al. Frequency of primary glomerular disease in northeastern China. Braz J Med Biol Res 2011;44: 810e3. [4] Das U, Dakshinamurthy K, Prayaga A. Pattern of biopsy proven renal disease in a single center of South India: 19 years experience. Indian J Nephrol 2011;21:250e7. [5] Ponticelli C, Glassock R. Post transplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol 2010;5:2363e72. [6] Lorenz EC, Sethi S, Leung N, Dispenzieri A, Feryenza F, Cosio FG. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int 2010;77:721e8. [7] Salwa-Zurawska W, Bortkiewicz E, Wozniak A, Dworacki G, Maciejewski J. Morphological and clinical aspects of membranoproliferative glomerulonephritis in children. Pol J Pathol 1996;47: 215e24. [8] Abdurrahman MB, Elidrissy AT, Shipkey FH, al Rasheed S, al Mugeiren M. Clinicopathological features of childhood nephrotic syndrome in Saudi Arabia. Ann Trop Paediatr 1990;10:125e32. [9] Cameron JS, Turner DR, Heaton J, et al. Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med 1983;74:175e92. [10] Vikse BE, Bostad L, Aasarød K, Lysebo DE, Iversen BM. Prognostic factors in mesangioproliferative glomerulonephritis. Nephrol Dial Transplant 2002;17:1603e13. [11] Moroni G, Casati C, Quaglini S, et al. Membranoproliferative glomerulonephritis type I in renal transplantation patients: a single-center study of a cohort of 68 renal transplants followed up for 11 years. Transplantation 2011;91:1233e9. [12] Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene RA, Wetzels JF. Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation: analysis of the incidence, risk factors, and impact on graft survival. Transplantation 1997;63:1628e33. [13] Braun MC, Stablein DM, Hamiwka LA, Bell L, Bartosh SM, Strife CF. Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience. J Am Soc Nephrol 2005;16: 2225e33. [14] Hariharan S, Adams MB, Brennan DC, et al. Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR). Transplantation 1999;68:635e41. [15] Damodar A, Mustafa R, Bhatnagar J, et al. Use of anti-CD20 antibody in the treatment of post-transplant glomerulonephritis. Clin Transplant 2011;25:375e9.
FAROOQUI, ALSAAD, ALOUDAH ET AL [16] Sellier-Leclerc AL, Baudouin V, Kwon T, et al. Rituximab in steroid-dependent idiopathic nephrotic syndrome in childhooddfollow-up after CD19 recovery. Nephrol Dial Transplant 2012;27:1083e9. [17] Emre S, Sirin A, Alpay H, Tanman F, Uysal V, Nayir A, et al. Pulse methylprednisolone therapy in children with membranoproliferative glomerulonephritis. Acta Paediatr Jpn 1995;37: 626e9. [18] Bergstein JM, Andreoli SP. Response of type I membranoproliferative glomerulonephritis to pulse methylprednisolone and alternate-day prednisone therapy. Pediatr Nephrol 1995;9: 268e71. [19] Zäuner I, Böhler J, Braun N, Grupp C, Heering P, Schollmeyer P. Collaborative Glomerulonephritis Therapy Study Group (CGTS). Effect of aspirin and dipyridamole on proteinuria in idiopathic membranoproliferative glomerulonephritis: a multicentre prospective clinical trial. Nephrol Dial Transplant 1994;9:619e22. Erratum: Nephrol Dial Transplant 1994;9:1526. [20] Harmankaya O, Bas¸türk T, Oztürk Y, Karabiber N, Obek A. Effect of acetylsalicylic acid and dipyridamole in primary membranoproliferative glomerulonephritis type I. Int Urol Nephrol 2001;33:583e7. [21] Cattran DC, Cardella CJ, Roscoe JM, et al. Results of a controlled drug trial in membranoproliferative glomerulonephritis. Kidney Int 1985;27:436e41. [22] Töz H, Ok E, Unsal A, As¸çi G, Bas¸demir G, Bas¸çi A. Effectiveness of pulse cyclophosphamide plus oral steroid therapy in idiopathic membranoproliferative glomerulonephritis. Nephrol Dial Transplant 1997;12:1081e2. [23] Yuan M, Zou J, Zhang X, Liu H, Teng J, Zhong Y, et al. Combination therapy with mycophenolate mofetil and prednisone in steroid-resistant idiopathic membranoproliferative glomerulonephritis. Clin Nephrol 2010;73:354e9. [24] De S, Al-Nabhani D, Thorner P, Cattran D, Piscione TD, Licht C. Remission of resistant MPGN type I with mycophenolate mofetil and steroids. Pediatr Nephrol 2009;24:597e600. [25] Kong WY, Swaminathan R, Irish A. Our experience with rituximab therapy for adult-onset primary glomerulonephritis and review of literature. Int Urol Nephrol 2013;45:795e802. [26] Dillon JJ, Hladunewich M, Haley WE, Reich HN, Cattran DC, Fervenza FC. Rituximab therapy for type I membranoproliferative glomerulonephritis. Clin Nephrol 2012;77:290e5. [27] Hadjinicolaou AV, Nisar MK, Bhagat S, Parfrey H, Chilvers ER, Ostör AJ. Noninfectious pulmonary complications of newer biological agents for rheumatic diseasesda systematic literature review. Rheumatology (Oxford) 2011;50:2297e305. [28] Gottenberg JE, Ravaud P, Bardin T, et al. Autoimmunity and Rituximab Registry, French Society of Rheumatology. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the Autoimmunity and Rituximab Registry. Arthritis Rheum 2010;62:2625e32. [29] Liu X, Hong XN, Gu YJ, Wang BY, Luo ZG, Cao J. Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma. Leuk Lymphoma 2008;49: 1778e83.
ABSTRACT We report a case of idiopathic membranoproliferative glomerulonephritis (MPGN) recurring 2 years after a living-unrelated kidney transplantation. The disease was refractory to intravenous immunoglobulin and plasmapheresis. Treatment with 2 doses of rituximab resulted in remission of the disease. The disease relapsed 18 months later after an episode of cytomegalovirus pneumonitis. After treatment of the pneumonitis, a lung biopsy was performed owing to persistent chest symptoms, which revealed bronchiolitis obliterans with organizing pneumonia. Bone marrow examination and culture revealed presence of acid-fast bacilli, and culture grew Mycobacterium tuberculosis. A repeated course of rituximab was withheld because of infection with tuberculosis, the patient’s chest symptoms, and rare reports of noninfectious lung disease after the use of rituximab. The patient continues to have proteinuria with impaired kidney function.
M
EMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN) is a disorder with reported frequency varying from 4.8% to 28% of kidney biopsies [1e4]. In general, the patients are treated with immunosuppressive medications including steroids and cyclophosphamide or antiproliferative agents. The response to treatment is variable, and significant proportion of patients reach end-stage kidney disease despite treatment. The disease is well known to recur in kidney allografts, 27% in 1st transplants and up to 80% in 2nd transplants [5,6]. CASE REPORT A 58-year-old man with history of diabetes mellitus and hypertension presented with development of recent onset generalized body swelling, uncontrolled blood pressure, and serum creatinine rising from 142 mmol/L in May 2009 to 321 mmol/L in December 2009. He also developed heavy proteinuria of 16 g/d. There was no history of recent infections or systemic or urinary symptoms. His physical examination was remarkable for presence of nonproliferative diabetic retinopathy and generalized edema. Urine microscopic examination revealed few red blood cells but no casts. Serology including hepatitis B, hepatitis C, antineutrophil cytoplasmic antibody (ANCA), and antinuclear antibody (ANA) were negative. His serum C3 and C4 levels were normal. He tested negative for human immunodeficiency ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 823e826 (2015)
virus (HIV), and his serum and urine protein electrophoreses were negative for monoclonal proteins. The patient underwent ultrasound-guided kidney biopsy. Histologic examination demonstrated features compatible with a membranoproliferative pattern of glomerular injury. The specimen contained 29 glomeruli, of which 11 were globally sclerosed. The remaining glomeruli exhibited lobular accentuation of the glomerular tufts and showed moderate increase in mesangial matrix and segmental mild increase in mesangial cellularity. Segmental glomerular scarring in the form of obliteration of the glomerular capillaries and adhesion of the glomerular tufts to the Bowman capsule was identified in 5 glomeruli. The glomerular capillaries showed diffuse increase in thickness and double contouring in periodic acid Schiff and methenamine silver special stains. Proliferative features in the form of segmental endocapillary hypercellularity and subendothelial deposits were evident. These were associated with cellular crescents in 5 glomeruli (Fig 1A). There was moderate interstitial fibrosis and tubular atrophy, accompanied by moderate chronic, predominantly lymphocytic, interstitial inflammation. Severe arteriolar hyalinosis and moderate arterial sclerosis were
*Address correspondence to Mahfooz Farooqui, MD, FACP, FASN, Division of Nephrology, Department of Medicine, King Abdulaziz Medical City, PO Box 22490, Mail Code 1443, Riyadh 11426, Saudi Arabia. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.02.003
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Fig 1. Native renal biopsy. (A) Glomeruli showed features of proliferative, crescent-forming, immune-mediated glomerulonephritis compatible with membranoproliferative glomerulonephritis (periodic acideSchiff, 200). Segmental double contouring of the glomerular capillaries was evident (inset; methenamine silver stain, 400). (B) Ultrastructural photograph showing subendothelial immune-type dense deposits (transmission electron microscopy, urinyl acetate and lead citrate stain, 10,000). present. There was no evidence of microthrombi in the interstitial blood vessels or of vasculitis. Immunofluorescence and electron microscopy studies confirmed the immune-mediated nature of the glomerular disease. There was diffuse coarse granular and pseudolinear capillary and mesangial staining for IgG (3þ/3þ), C3 (3þ), C1q (2þ) and kappa (2þ) light chain. Weak staining for IgM (1þ) and lambda light chain was also seen. There was no staining for IgA and albumin. Ultrastructural examination demonstrated variably sized subendothelial and mesangial immune-type dense deposits, thickened glomerular basement membranes with segmental replication, and diffuse effacement of the foot processes (Fig 1B). Therapeutic options were discussed with the patient, who chose not to be treated with cyclophosphamide, and treatment was initiated with intravenous methylprednisolone pulse therapy of 1,000 mg for 3 days followed by oral steroids at 1 mg/kg/day. The patient did not respond to this therapy and became dialysis-dependent within 2 months. He underwent living-unrelated kidney transplant 2 months after starting dialysis. His maintenance immunosuppression comprised of prednisone, mycophenolate mofetil, and tacrolimus. He had undetectable proteinuria and serum creatinine at baseline of 120 mmol/L until July 2011. His diabetes remained poorly controlled, and he developed trace proteinuria on dipstick in October 2011. He presented in February 2012 with generalized body swelling, proteinuria of 12 g/d, and rise in serum creatinine from baseline of 120 mmol/L to 175 mmol/L. Again, his serology for hepatitis B, hepatitis C, ANCA, and ANA were negative. His C3 and C4 were normal. He tested negative for HIV, and his serum and urine electrophoreses revealed no abnormal monoclonal proteins. The patient again underwent ultrasound-guided percutaneous biopsy of the kidney allograft, which showed histologic, immunohistochemical, and ultrastructural findings similar to those seen in the native renal biopsy and compatible with recurrent crescentforming MPGN. However, there was mild interstitial fibrosis and tubular atrophy, more exuberant glomerular hypercellularity, and less degree of crescent formation (Fig 2). No significant global glomerular sclerosis was seen. There was no evidence of viral cytopathic effect or cellular or humoral renal allograft rejection. Immunohistochemical stains for polyomavirus (dilution 1:200, clone Pab416; Abcam, Cambridge, United Kingdom) and C4d (1:40, polyclonal; Abcam) were negative. The patient was again treated with intravenous pulses of methylprednisolone, plasmapheresis, and intravenous immunoglobulin. His anasarca was resistant to diuretic therapy, and he required
intermittent ultrafiltration for 2 months for episodes of pulmonary edema. He was eventually given rituximab at 375 mg/m2 of body surface area: 2 doses 2 weeks apart. The patient improved gradually over 4 months with resolution of edema, stabilization of serum creatinine (175 mmol/L), reduction of proteinuria to 0.66 g/d, and normalization of serum albumin. The patient remained edema free with minimal proteinuria until October 2013, when he was admitted to a local hospital because of edema and shortness of breath and was diagnosed with cytomegalovirus pneumonitis. He was treated with diuretics, empiric antibiotics, and intravenous ganciclovir. His persisting cough and difficulty in breathing on exertion required lung biopsy which revealed bronchiolitis obliterans with organizing pneumonia. He presented to the transplant clinic in February 2014 with generalized edema, shortness of breath, hypoalbuminemia, and proteinuria of 7 g/d. Repeated kidney biopsy revealed MPGN with moderate interstitial fibrosis and tubular atrophy. The patient continued to have chest symptoms after treatment of the cytomegalovirus infection. Bronchoscopy, lung biopsy, and bronchoalveolar lavage for cytology and cultures (including Mycobacterium tuberculosis) were nondiagnostic. Eventually, diagnosis of tuberculosis was made on bone marrow examination. Further immunosuppression with rituximab was withheld owing to tuberculosis and reports of noninfectious lung complications associated with the use of rituximab. He continues to have proteinuria and impaired kidney function with serum creatinine of 170 mmol/L.
DISCUSSION
Idiopathic MPGN is a challenging form of renal injury for which there are few controlled trials of treatment, particularly in adult patients. Additionally, the disease pattern and prognosis may differ according to age of presentation and geographic location studied [7e9]. MPGN with crescents represents an aggressive disease and over time many patients, despite therapy, progress to end-stage kidney disease. Clinical prognostic factors include increased serum creatinine, proteinuria 1 g/d, systolic blood pressure (BP) 160 mm Hg, diastolic BP 90 mm Hg, serum albumin <35 g/L, presence of urinary granular casts, and age 60 years [10]. Histologic features suggestive of poor outcome include presence of
TREATMENT-RESISTANT RECURRENT MPGN
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Fig 2. Renal allograft biopsy. (A) Glomeruli showed hypersegmentation of the tufts, endocapillary hypercellularity, segmental subendothelial deposits, and replication of the glomerular capillaries (periodic acideSchiff, 200). (B) Immunofluorescence staining demonstrated intense glomerular staining for IgG and C3.
crescents, fibrosis of the interstitium, and mesangial proliferation. MPGN has a tendency to recur after kidney transplantation, with a rate of 20%e50% in 1st transplants. The reported risk of graft loss is variable in different studies. A group from Italy described 63 patients with MPGN type I with 68 renal transplants. They compared these patients with a matched group of control subjects. They reported no difference in patient survival or 15-year graft survival in the 2 groups. In their study 16 patients (23.5%) developed a recurrence of MPGN after transplantation. The group with recurrence of MPGN had a lower 15-year graft survival: 40.4% compared with 73.5% in the group with no recurrence of the disease [11]. An earlier study from the Netherlands reported on 31 cases of MPGN type I. They reported recurrence of disease to be 48% at 4 years. Five patients with recurrent MPGN received 2nd transplants, and 4 of those retransplanted patients (80%) had recurrence of MPGN [12]. MPGN type II has a higher recurrence rate of 80%e100% with 15%e30% of the affected patients losing their graft within 5 years [13]. Hariharan et al reported 66% graft failure with MPGN after kidney transplantation in a multicenter registry in the United States [14]. Treatment of MPGN
It is essential to identify the presence of a primary disease, such as lupus erythematosus, hepatitis C, cryoglobulinemia, paraproteinemias, and malignancy, leading to MPGN. The secondary MPGN treatment requires treatment of the primary disease, often in combination with immunosuppression. Idiopathic MPGN type I (which is characterized by subendothelial and mesangial immune deposits) differs from MPGN type II (characterized by intramembranous dense deposits) in etiology and clinical course. MPGN type II, also called dense deposit disease, is more common in pediatric populations. In the pediatric population, use of steroids, particularly with intravenous pulse therapy, is associated with better renal survival [15,16]. When protein restriction and antihypertensive therapy was compared with addition of aspirin
and dipyridamole, reduction in proteinuria was seen with no change in serum creatinine after 24e36 months [17,18]. Some studies have failed to demonstrate short- to mediumterm benefits of the use of cyclophosphamide, yet the use of cyclophosphamide, in combination with steroids, may be of benefit when there is severe, crescent-forming disease [19,20]. Likewise, there are case series reporting improved outcome with the use of mycophenolate mofetil in idiopathic MPGN resistant to steroids [21,22]. Rituximab has previously been described for treatment of resistant forms of MPGN as well as MPGN occurring after kidney transplantation [23,24]. Our case had a slow improvement over 4 months which lasted for 16 months, when his disease relapsed. It could be argued that we should have monitored CD19 and should have administered further cycles of rituximab if a rising count of CD19þ lymphocyte was observed [25]. We were further limited by patient’s persistent chest symptoms and the association of progressive noninfectious lung disease with the use of rituximab. Patients who develop recurrence of idiopathic MPGN in the kidney allograft probably represent the group with a resistant form of the disease, because these patients are usually on immunosuppressive therapy with a combination of agents, such as steroids, calcineurin inhibitor, and antiproliferative agent (either azathioprine or mycophenolate mofetil). There is no clear consensus regarding a 1st-line therapeutic agent in recurrent MPGN after transplantation. Because the number of these cases is small, it is unlikely that a controlled trial of treatment will become available to guide therapy. There are plenty of cases of post-transplantation focal segmental glomerulosclerosis and IgA nephropathy and their treatment, because these forms of glomerulonephritis are common. Treatment of post-transplantation MPGN, being relatively rare, is reported by only a few. Dillon et al described a series of patients with MPGN type I with reduction of proteinuria after treatment with rituximab [26]. We report that case to suggest that rituximab remains a therapeutic option for the treatment of idiopathic type I MPGN resistant to other forms of treatment. Infectious as well as
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noninfectious pulmonary side effects may limit long-term use of this agent [27e29]. REFERENCES [1] Alatif T, Maoujoud O, Montasser I, et al. Glomerular disease in military hospital of Morocco: review of single center renal biopsy database on adults. Indian J Nephrol 2012;22:257e63. [2] Rabbani M, Memon G, Ahmad B, et al. Percutaneous renal biopsy results: a retrospective analysis of 511 consecutive cases. Saudi J Kidney Dis Transpl 2012;23:614e8. [3] Wu Y, Wang Z, Xu H, et al. Frequency of primary glomerular disease in northeastern China. Braz J Med Biol Res 2011;44: 810e3. [4] Das U, Dakshinamurthy K, Prayaga A. Pattern of biopsy proven renal disease in a single center of South India: 19 years experience. Indian J Nephrol 2011;21:250e7. [5] Ponticelli C, Glassock R. Post transplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol 2010;5:2363e72. [6] Lorenz EC, Sethi S, Leung N, Dispenzieri A, Feryenza F, Cosio FG. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int 2010;77:721e8. [7] Salwa-Zurawska W, Bortkiewicz E, Wozniak A, Dworacki G, Maciejewski J. Morphological and clinical aspects of membranoproliferative glomerulonephritis in children. Pol J Pathol 1996;47: 215e24. [8] Abdurrahman MB, Elidrissy AT, Shipkey FH, al Rasheed S, al Mugeiren M. Clinicopathological features of childhood nephrotic syndrome in Saudi Arabia. Ann Trop Paediatr 1990;10:125e32. [9] Cameron JS, Turner DR, Heaton J, et al. Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med 1983;74:175e92. [10] Vikse BE, Bostad L, Aasarød K, Lysebo DE, Iversen BM. Prognostic factors in mesangioproliferative glomerulonephritis. Nephrol Dial Transplant 2002;17:1603e13. [11] Moroni G, Casati C, Quaglini S, et al. Membranoproliferative glomerulonephritis type I in renal transplantation patients: a single-center study of a cohort of 68 renal transplants followed up for 11 years. Transplantation 2011;91:1233e9. [12] Andresdottir MB, Assmann KJ, Hoitsma AJ, Koene RA, Wetzels JF. Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation: analysis of the incidence, risk factors, and impact on graft survival. Transplantation 1997;63:1628e33. [13] Braun MC, Stablein DM, Hamiwka LA, Bell L, Bartosh SM, Strife CF. Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience. J Am Soc Nephrol 2005;16: 2225e33. [14] Hariharan S, Adams MB, Brennan DC, et al. Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR). Transplantation 1999;68:635e41. [15] Damodar A, Mustafa R, Bhatnagar J, et al. Use of anti-CD20 antibody in the treatment of post-transplant glomerulonephritis. Clin Transplant 2011;25:375e9.
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