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Resolution of IgM Nephropathy After Rituximab Treatment
CASE REPORTS Resolution of IgM Nephropathy After Rituximab Treatment Michiel G.H. Betjes, MD, PhD, and Joke I. Roodnat, MD, PhD Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by mesangial deposits of IgM. IgM nephropathy presenting with proteinuria, especially nephrotic syndrome, frequently is steroid dependent or steroid resistant and associated with reaching end-stage renal disease after a 15-year follow-up. Because no long-term effective treatment is known for patients with IgM nephropathy, there is a clear need for therapeutic alternatives. We describe a patient who reached end-stage renal disease 20 years after IgM nephropathy was diagnosed at the age of 3 years. IgM nephropathy recurred after kidney transplantation, leading to microscopic hematuria and proteinuria. High-dose steroid therapy was not effective, and kidney function slowly decreased. Three years after transplantation, 2 doses of rituximab were administered, leading to complete remission of the IgM nephropathy. One year after rituximab treatment, the patient has stable kidney function, normal urinary sediment, and no proteinuria. Rituximab may be a valuable novel therapeutic drug for the treatment of patients with IgM nephropathy. Am J Kidney Dis 53:1059-1062. © 2009 by the National Kidney Foundation, Inc. INDEX WORDS: Immunoglobulin M (IgM) nephropathy; rituximab; anti-CD20; transplantation; nephrotic syndrome.
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mmunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by immunofluorescence IgM deposits within the mesangium, which can be recognized as electrondense deposits by using electron microscopy.1 IgM deposition often is associated with complement C3. Light microscopy shows variable features of normal glomeruli to mesangial hypercellularity and extracellular matrix accumulation with or without a varying degree of segmental or global sclerosis. This translates to a wide spectrum of clinical presentation, varying from isolated hematuria to overt nephrotic syndrome. The disease may affect both pediatric and adult patients, and the overall long-term prognosis is favorable for patients with isolated hematuria. Patients presenting with proteinuria and specifically nephrotic syndrome have an increased risk of developing end-stage renal disease.1 Although the proteinuria may respond to steroid treatment, steroid dependency is frequent.1-3 Long-term remission of proteinuria was achieved in only 14% of patients, indicating the need for a more effective treatment.1,2 We report the case of a 26-year-old man who presented with recurrence of IgM nephropathy after transplantation and responded with complete remission of proteinuria after rituximab treatment.
CASE REPORT Clinical History Severe nephrotic syndrome was first diagnosed in the patient at the age of 3 years. Complete remission of protein-
uria initially was achieved with steroid therapy. However, frequent relapses occurred during the years, leading to steroid-dependent and, in later years, steroid-resistant nephrotic syndrome. A kidney biopsy performed at age 14 years showed 20 glomeruli with similar histological changes. In all glomeruli, modest mesangial hypercellularity was observed (Fig 1A) without areas of sclerosis. The tubulointerstitial compartment showed no abnormalities. Immunofluorescence was negative for IgG, IgA, and complement, but deposits of IgM were present in a granular mesangial pattern (Fig 1D). Based on these findings, IgM nephropathy was diagnosed. Serum IgM levels were within normal range. As a consequence of prednisone treatment, the patient developed a short stature and aseptic osteonecrosis of the femur. Additional treatments with cyclophosphamide and cyclosporine were ineffective, and kidney function gradually decreased, reaching end-stage renal disease at the age of 22 years. After 2 years of peritoneal dialysis therapy (he became anuric after 1 year of dialysis), he received a kidney transplant from a living related donor with 2 HLA-AB mismatches and 1 HLA-DR mismatch. Panel-reactive antibodies were 0% before transplantation. Immunosuppressive
From the Department of Internal Medicine, Division of Nephrology, Erasmus Medical Center, Rotterdam, The Netherlands. Received June 23, 2008. Accepted in revised form October 29, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.10.038 on December 12, 2008. Address correspondence to Michiel G.H. Betjes, MD, PhD, Erasmus Medical Center, Department of Internal Medicine, Division of Nephrology, Dr Molewater plein 40, 3015 GD Rotterdam, The Netherlands. E-mail: m.g.h.betjes@ erasmusmc.nl © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5306-0020$36.00/0 doi:10.1053/j.ajkd.2008.10.038
American Journal of Kidney Diseases, Vol 53, No 6 (June), 2009: pp 1059-1062
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Betjes and Roodnat
Figure 1. Light microscopy of sections from kidney biopsies of the (A, D) native kidney and (B, C, E, F) transplant kidney (B, E) before and (C, F) after treatment with rituximab. (Top panel) Light microscopy of Jones silver-stained sections of glomeruli and (bottom panel) immunofluorescence of glomeruli stained with anti–immunoglobulin M (IgM) antibody. The glomerulus from the native kidney has (A) increased mesangial cellularity with (D) granular mesangial deposition of IgM, whereas the glomerulus from the transplant kidney before rituximab treatment shows (B) normal architecture with (E) diffuse to granular mesangial deposition of IgM. Six months after rituximab treatment, the kidney biopsy specimen showed many sclerosed glomeruli with thickened Bowman capsules in the viable glomeruli, but no mesangial deposition of IgM.
medication consisted of tacrolimus, prednisone, and mycophenolate mofetil. Excellent kidney function was acquired initially, with an estimated glomerular filtration rate (according to the Cockcroft-Gault formula4) of 122 mL/min and protein-creatinine ratio of 0.12 (Fig 2). However, persistent microscopic hematu-
ria was detected within the first week after transplantation, which was soon followed by progressive proteinuria and decreasing estimated glomerular filtration rate. The kidney biopsy specimen showed 32 glomeruli, with 2 globally sclerosed. Glomeruli showed normal architecture
Figure 2. Estimated glomerular filtration rate (eGFR; left y-axis, red line) according to the Cockcroft-Gault formula,4 serum albumin concentration (g/dL; right y-axis, blue line), and urine protein-creatinine ratio (right y-axis, black line) after kidney transplantation. On the x-axis, time after transplantation in months is shown.
Immunoglobulin M Nephropathy and Rituximab without mesangial hypercellularity or sclerotic lesions. Tubules and arteries showed no abnormalities, specifically no infiltration with lymphocytes or granulocytes. Immunofluorescence was negative for complement C3, C4d, IgG, and IgA; however, IgM was present in a diffuse mesangial pattern (Fig 1E). Based on these findings, recurrence of IgM nephropathy in the kidney transplant was diagnosed. Pulse treatment with high-dose methylprednisolone (1,000 mg intravenously 3 times) did not affect kidney function or proteinuria. No further attempts were undertaken to treat the IgM nephropathy, and he was administered an angiotensinconverting enzyme inhibitor, which was continued for the entire follow-up described. He remained proteinuric, with serum albumin level of 22 to 28 g/L, and kidney function slowly decreased (Fig 2). Three years after transplantation, rituximab was administered (2 doses of 375 mg/m2 intravenously, with an interval of 4 weeks), resulting in rapid depletion of circulating CD20-positive B cells to less than 0.01 ⫻ 109 CD20-positive cells/L. Proteinuria decreased 4 weeks after the first dose and resolved completely within several months, with disappearance of the microscopic hematuria. A kidney biopsy was performed 6 months after the first dose of rituximab. Fourteen glomeruli were identified, of which 10 were globally sclerosed. The nonsclerosed glomeruli showed wrinkling of the basal membrane and thickening of Bowman capsule (Fig 1C). Areas of atrophic tubules with interstitial fibrosis and lymphocytes were observed. Arteriolar hyalinosis was present. Immunofluorescence showed no deposits of mesangial IgM and was negative for C4d (Fig 1F). At present, 1 year after rituximab treatment, the patient’s kidney function is stable without proteinuria and with normal urinary sediment. The number of circulating B cells was completely restored to 0.15 ⫻ 109 CD20positive cells /L 6 months after anti-CD20 therapy.
DISCUSSION This is the first case report of a patient with a diagnosis of IgM nephropathy who was treated with rituximab, resulting in complete remission with sustained response 1 year later. IgM nephropathy as a separate disease entity is controversial.5 In addition to mesangial IgM deposition, there are no specific features that distinguish this nephropathy from minimal change disease and focal segmental glomerulosclerosis (FSGS). IgM deposits can be visualized by using electron microscopy, but mesangial electron-dense deposits are not always visible, even in the same patient at different times.6 We observed recurrence of nephrotic syndrome with mesangial IgM deposits, but without FSGS lesions, in a transplant kidney, similar to the biopsy specimen of the native kidney when the patient was 3 years old. Such a clinical course is highly unlikely for minimal change disease and FSGS,
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but is in accordance with the slow progressive loss of renal function observed for IgM nephropathy1,2 and the possible recurrence in a transplant kidney.6,7 Only a few case reports have been published documenting the recurrence of biopsy-proven IgM nephropathy in a transplant kidney6,7 and/or treatment of patients with IgM nephropathy with rituximab.7,8 The best documented case, very similar to ours, was published by Salmon et al,6 who described IgM nephropathy in a 9-year-old boy leading to end-stage renal disease at age 22 years. Nephrotic syndrome reappeared within 3 months after kidney transplantation. Again, IgM nephropathy was diagnosed, incompletely responding to steroid therapy. The actual rate of recurrence of IgM nephropathy after kidney transplantation is not known because of a paucity of published data. In a recent long-term follow-up study, recurrence of IgM nephropathy was observed in 1 of 5 patients.1 In 2 published cases of IgM nephropathy, anti-CD20 therapy was given. However, the effect of B-cell depletion cannot be established from these case reports because rituximab was combined with plasmapheresis,7,8 immunoglobulin,7,8 and antithymocyte globulin.8 Several case reports have indicated a possible therapeutic effect of rituximab in patients with FSGS, although recurrence of FSGS after transplantation usually does not respond.9 However, the role of B cells in the pathogenesis of FSGS is unclear. It is possible, although speculative, that some cases of FSGS are actually cases of IgM nephropathy that have been diagnosed late in their clinical course when FSGS lesions have developed.1,2 The role of B cells in the pathogenesis of IgM nephropathy is not yet studied, but plausible because the presence of circulating IgM immune complexes has been postulated as a mechanism underlying the deposition of mesangial IgM.5,10 Although unproven, this deposition also may be caused by decreased or abnormal clearance of naturally occurring IgM immune complexes by mesangial cells. Potentially, autoimmune IgM antibodies may be involved in this process, the synthesis of which can be prevented efficiently by means of rituximab therapy.11 However, additional research clearly is needed to elucidate the pathogenesis of IgM nephropathy and establish the role of B cells in this disease.
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Betjes and Roodnat
Rituximab has a favorable safety profile, and there currently is no effective treatment for patients with IgM nephropathy. Therefore, in our opinion, the use of rituximab should be evaluated in patients presenting with IgM nephropathy– related nephrotic syndrome that does not respond to steroid therapy or becomes steroid dependent. In particular, the severe side effects of continuous prednisone treatment and progression to endstage renal disease, as observed in our patient, may be prevented.
ACKNOWLEDGEMENTS K. Hoogduin provided the photographs of the kidney biopsy sections.
REFERENCES 1. Myllymaki J, Saha H, Mustonen J, Helin H, Pasternack A: IgM nephropathy: Clinical picture and long-term prognosis. Am J Kidney Dis 41:343-350, 2003 2. Little MA, Dorman A, Gill D, Walshe JJ: Mesangioproliferative glomerulonephritis with IgM deposition: Clinical characteristics and outcome. Ren Fail 22:445-457, 2000 3. O’Donoghue DJ, Lawler W, Hunt LP, Acheson EJ, Mallick MP: IgM-associated primary diffuse mesangial glomerulonephritis: Natural history and prognostic indicators. Q J Med 79:333-350, 1991
4. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 5. Disciullo SO, Abuelo JG, Moalli K, Pezzullo JC: Circulating heavy IgM in IgM nephropathy. Clin Exp Immunol 73:395-400, 1988 6. Salmon AHJ, Kamel D, Mathieson PW: Recurrence of IgM nephropathy in a renal allograft. Nephrol Dial Transplant 19:2650-2652, 2004 7. Westphal S, Hansson S, Mjornstedt L, Molne J, Swerkersson S, Friman S: Early recurrence of nephrotic syndrome (immunoglobulin M nephropathy) after renal transplantation successfully treated with combinations of plasma exchanges, immunoglobulin, and rituximab. Transplant Proc 38:2659-2660, 2006 8. Ghiggeri GM, Musante L, Candiano G, et al: Protracted remission of proteinuria after combined therapy with plasmapheresis and anti-CD20 antibodies/cyclophosphamide in a child with oligoclonal IgM and glomerulosclerosis. Pediatr Nephrol 22:1953-1956, 2007 9. Yabu JM, Ho B, Scandling JD, Vincenti F: Rituximab failed to improve nephrotic syndrome in renal transplant patients with recurrent focal segmental glomerulosclerosis. Am J Transplant 8:222-227, 2008 10. Korpela M, Mustonen J, Teppa AM, Helin H, Pasternack A: Mesangial glomerulonephritis as an extraarticular manifestation of rheumatoid arthritis. Br J Rheumatol 36: 1189-1195, 1997 11. Korte MR, van Heerde MJ, de Man RA, Betjes MG: Rituximab for the treatment of glomerulonephritis in hepatitis C associated cryoglobulinaemia. Neth J Med 66:27-30, 2008
I
mmunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by immunofluorescence IgM deposits within the mesangium, which can be recognized as electrondense deposits by using electron microscopy.1 IgM deposition often is associated with complement C3. Light microscopy shows variable features of normal glomeruli to mesangial hypercellularity and extracellular matrix accumulation with or without a varying degree of segmental or global sclerosis. This translates to a wide spectrum of clinical presentation, varying from isolated hematuria to overt nephrotic syndrome. The disease may affect both pediatric and adult patients, and the overall long-term prognosis is favorable for patients with isolated hematuria. Patients presenting with proteinuria and specifically nephrotic syndrome have an increased risk of developing end-stage renal disease.1 Although the proteinuria may respond to steroid treatment, steroid dependency is frequent.1-3 Long-term remission of proteinuria was achieved in only 14% of patients, indicating the need for a more effective treatment.1,2 We report the case of a 26-year-old man who presented with recurrence of IgM nephropathy after transplantation and responded with complete remission of proteinuria after rituximab treatment.
CASE REPORT Clinical History Severe nephrotic syndrome was first diagnosed in the patient at the age of 3 years. Complete remission of protein-
uria initially was achieved with steroid therapy. However, frequent relapses occurred during the years, leading to steroid-dependent and, in later years, steroid-resistant nephrotic syndrome. A kidney biopsy performed at age 14 years showed 20 glomeruli with similar histological changes. In all glomeruli, modest mesangial hypercellularity was observed (Fig 1A) without areas of sclerosis. The tubulointerstitial compartment showed no abnormalities. Immunofluorescence was negative for IgG, IgA, and complement, but deposits of IgM were present in a granular mesangial pattern (Fig 1D). Based on these findings, IgM nephropathy was diagnosed. Serum IgM levels were within normal range. As a consequence of prednisone treatment, the patient developed a short stature and aseptic osteonecrosis of the femur. Additional treatments with cyclophosphamide and cyclosporine were ineffective, and kidney function gradually decreased, reaching end-stage renal disease at the age of 22 years. After 2 years of peritoneal dialysis therapy (he became anuric after 1 year of dialysis), he received a kidney transplant from a living related donor with 2 HLA-AB mismatches and 1 HLA-DR mismatch. Panel-reactive antibodies were 0% before transplantation. Immunosuppressive
From the Department of Internal Medicine, Division of Nephrology, Erasmus Medical Center, Rotterdam, The Netherlands. Received June 23, 2008. Accepted in revised form October 29, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.10.038 on December 12, 2008. Address correspondence to Michiel G.H. Betjes, MD, PhD, Erasmus Medical Center, Department of Internal Medicine, Division of Nephrology, Dr Molewater plein 40, 3015 GD Rotterdam, The Netherlands. E-mail: m.g.h.betjes@ erasmusmc.nl © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5306-0020$36.00/0 doi:10.1053/j.ajkd.2008.10.038
American Journal of Kidney Diseases, Vol 53, No 6 (June), 2009: pp 1059-1062
1059
1060
Betjes and Roodnat
Figure 1. Light microscopy of sections from kidney biopsies of the (A, D) native kidney and (B, C, E, F) transplant kidney (B, E) before and (C, F) after treatment with rituximab. (Top panel) Light microscopy of Jones silver-stained sections of glomeruli and (bottom panel) immunofluorescence of glomeruli stained with anti–immunoglobulin M (IgM) antibody. The glomerulus from the native kidney has (A) increased mesangial cellularity with (D) granular mesangial deposition of IgM, whereas the glomerulus from the transplant kidney before rituximab treatment shows (B) normal architecture with (E) diffuse to granular mesangial deposition of IgM. Six months after rituximab treatment, the kidney biopsy specimen showed many sclerosed glomeruli with thickened Bowman capsules in the viable glomeruli, but no mesangial deposition of IgM.
medication consisted of tacrolimus, prednisone, and mycophenolate mofetil. Excellent kidney function was acquired initially, with an estimated glomerular filtration rate (according to the Cockcroft-Gault formula4) of 122 mL/min and protein-creatinine ratio of 0.12 (Fig 2). However, persistent microscopic hematu-
ria was detected within the first week after transplantation, which was soon followed by progressive proteinuria and decreasing estimated glomerular filtration rate. The kidney biopsy specimen showed 32 glomeruli, with 2 globally sclerosed. Glomeruli showed normal architecture
Figure 2. Estimated glomerular filtration rate (eGFR; left y-axis, red line) according to the Cockcroft-Gault formula,4 serum albumin concentration (g/dL; right y-axis, blue line), and urine protein-creatinine ratio (right y-axis, black line) after kidney transplantation. On the x-axis, time after transplantation in months is shown.
Immunoglobulin M Nephropathy and Rituximab without mesangial hypercellularity or sclerotic lesions. Tubules and arteries showed no abnormalities, specifically no infiltration with lymphocytes or granulocytes. Immunofluorescence was negative for complement C3, C4d, IgG, and IgA; however, IgM was present in a diffuse mesangial pattern (Fig 1E). Based on these findings, recurrence of IgM nephropathy in the kidney transplant was diagnosed. Pulse treatment with high-dose methylprednisolone (1,000 mg intravenously 3 times) did not affect kidney function or proteinuria. No further attempts were undertaken to treat the IgM nephropathy, and he was administered an angiotensinconverting enzyme inhibitor, which was continued for the entire follow-up described. He remained proteinuric, with serum albumin level of 22 to 28 g/L, and kidney function slowly decreased (Fig 2). Three years after transplantation, rituximab was administered (2 doses of 375 mg/m2 intravenously, with an interval of 4 weeks), resulting in rapid depletion of circulating CD20-positive B cells to less than 0.01 ⫻ 109 CD20-positive cells/L. Proteinuria decreased 4 weeks after the first dose and resolved completely within several months, with disappearance of the microscopic hematuria. A kidney biopsy was performed 6 months after the first dose of rituximab. Fourteen glomeruli were identified, of which 10 were globally sclerosed. The nonsclerosed glomeruli showed wrinkling of the basal membrane and thickening of Bowman capsule (Fig 1C). Areas of atrophic tubules with interstitial fibrosis and lymphocytes were observed. Arteriolar hyalinosis was present. Immunofluorescence showed no deposits of mesangial IgM and was negative for C4d (Fig 1F). At present, 1 year after rituximab treatment, the patient’s kidney function is stable without proteinuria and with normal urinary sediment. The number of circulating B cells was completely restored to 0.15 ⫻ 109 CD20positive cells /L 6 months after anti-CD20 therapy.
DISCUSSION This is the first case report of a patient with a diagnosis of IgM nephropathy who was treated with rituximab, resulting in complete remission with sustained response 1 year later. IgM nephropathy as a separate disease entity is controversial.5 In addition to mesangial IgM deposition, there are no specific features that distinguish this nephropathy from minimal change disease and focal segmental glomerulosclerosis (FSGS). IgM deposits can be visualized by using electron microscopy, but mesangial electron-dense deposits are not always visible, even in the same patient at different times.6 We observed recurrence of nephrotic syndrome with mesangial IgM deposits, but without FSGS lesions, in a transplant kidney, similar to the biopsy specimen of the native kidney when the patient was 3 years old. Such a clinical course is highly unlikely for minimal change disease and FSGS,
1061
but is in accordance with the slow progressive loss of renal function observed for IgM nephropathy1,2 and the possible recurrence in a transplant kidney.6,7 Only a few case reports have been published documenting the recurrence of biopsy-proven IgM nephropathy in a transplant kidney6,7 and/or treatment of patients with IgM nephropathy with rituximab.7,8 The best documented case, very similar to ours, was published by Salmon et al,6 who described IgM nephropathy in a 9-year-old boy leading to end-stage renal disease at age 22 years. Nephrotic syndrome reappeared within 3 months after kidney transplantation. Again, IgM nephropathy was diagnosed, incompletely responding to steroid therapy. The actual rate of recurrence of IgM nephropathy after kidney transplantation is not known because of a paucity of published data. In a recent long-term follow-up study, recurrence of IgM nephropathy was observed in 1 of 5 patients.1 In 2 published cases of IgM nephropathy, anti-CD20 therapy was given. However, the effect of B-cell depletion cannot be established from these case reports because rituximab was combined with plasmapheresis,7,8 immunoglobulin,7,8 and antithymocyte globulin.8 Several case reports have indicated a possible therapeutic effect of rituximab in patients with FSGS, although recurrence of FSGS after transplantation usually does not respond.9 However, the role of B cells in the pathogenesis of FSGS is unclear. It is possible, although speculative, that some cases of FSGS are actually cases of IgM nephropathy that have been diagnosed late in their clinical course when FSGS lesions have developed.1,2 The role of B cells in the pathogenesis of IgM nephropathy is not yet studied, but plausible because the presence of circulating IgM immune complexes has been postulated as a mechanism underlying the deposition of mesangial IgM.5,10 Although unproven, this deposition also may be caused by decreased or abnormal clearance of naturally occurring IgM immune complexes by mesangial cells. Potentially, autoimmune IgM antibodies may be involved in this process, the synthesis of which can be prevented efficiently by means of rituximab therapy.11 However, additional research clearly is needed to elucidate the pathogenesis of IgM nephropathy and establish the role of B cells in this disease.
1062
Betjes and Roodnat
Rituximab has a favorable safety profile, and there currently is no effective treatment for patients with IgM nephropathy. Therefore, in our opinion, the use of rituximab should be evaluated in patients presenting with IgM nephropathy– related nephrotic syndrome that does not respond to steroid therapy or becomes steroid dependent. In particular, the severe side effects of continuous prednisone treatment and progression to endstage renal disease, as observed in our patient, may be prevented.
ACKNOWLEDGEMENTS K. Hoogduin provided the photographs of the kidney biopsy sections.
REFERENCES 1. Myllymaki J, Saha H, Mustonen J, Helin H, Pasternack A: IgM nephropathy: Clinical picture and long-term prognosis. Am J Kidney Dis 41:343-350, 2003 2. Little MA, Dorman A, Gill D, Walshe JJ: Mesangioproliferative glomerulonephritis with IgM deposition: Clinical characteristics and outcome. Ren Fail 22:445-457, 2000 3. O’Donoghue DJ, Lawler W, Hunt LP, Acheson EJ, Mallick MP: IgM-associated primary diffuse mesangial glomerulonephritis: Natural history and prognostic indicators. Q J Med 79:333-350, 1991
4. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976 5. Disciullo SO, Abuelo JG, Moalli K, Pezzullo JC: Circulating heavy IgM in IgM nephropathy. Clin Exp Immunol 73:395-400, 1988 6. Salmon AHJ, Kamel D, Mathieson PW: Recurrence of IgM nephropathy in a renal allograft. Nephrol Dial Transplant 19:2650-2652, 2004 7. Westphal S, Hansson S, Mjornstedt L, Molne J, Swerkersson S, Friman S: Early recurrence of nephrotic syndrome (immunoglobulin M nephropathy) after renal transplantation successfully treated with combinations of plasma exchanges, immunoglobulin, and rituximab. Transplant Proc 38:2659-2660, 2006 8. Ghiggeri GM, Musante L, Candiano G, et al: Protracted remission of proteinuria after combined therapy with plasmapheresis and anti-CD20 antibodies/cyclophosphamide in a child with oligoclonal IgM and glomerulosclerosis. Pediatr Nephrol 22:1953-1956, 2007 9. Yabu JM, Ho B, Scandling JD, Vincenti F: Rituximab failed to improve nephrotic syndrome in renal transplant patients with recurrent focal segmental glomerulosclerosis. Am J Transplant 8:222-227, 2008 10. Korpela M, Mustonen J, Teppa AM, Helin H, Pasternack A: Mesangial glomerulonephritis as an extraarticular manifestation of rheumatoid arthritis. Br J Rheumatol 36: 1189-1195, 1997 11. Korte MR, van Heerde MJ, de Man RA, Betjes MG: Rituximab for the treatment of glomerulonephritis in hepatitis C associated cryoglobulinaemia. Neth J Med 66:27-30, 2008