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Rituximab Treatment of Dysproteinemias Affecting the Kidney: A Review of Three Cases
CASE REPORTS Rituximab Treatment of Dysproteinemias Affecting the Kidney: A Review of Three Cases Premila Bhat, MD, Stacey Weiss, MD, Gerald B. Appel, MD, and Jai Radhakrishnan, MD The renal diseases associated with monoclonal immunoglobulin deposits constitute a diverse range of clinical and pathological entities. Renal prognosis is variable, and there currently are no standard treatment regimens. We describe the effect of rituximab treatment on 3 patients with renal insufficiency and proteinuria with monoclonal immunoglobulin deposits associated with glomerulonephritis on renal biopsy. Two patients with hypertension and chronic lymphocytic leukemia had a membranoproliferative glomerulonephritis pattern on kidney biopsy associated with monoclonal immunoglobulin G deposits. Both patients experienced partial remission of their disease and 1 patient was able to come off hemodialysis therapy after treatment with 7 and 11 biweekly doses of rituximab, 375 mg/m2, in addition to angiotensin-converting enzyme inhibitor and angiotensin receptor blocker. Both patients subsequently experienced relapse of their hematologic and renal diseases and eventually progressed to end-stage renal disease and death. A third patient had diffuse proliferative glomerulonephritis with immunoglobulin G deposits on renal biopsy. She was treated with an angiotensin receptor blocker and two 1,000-mg infusions of rituximab separated by 2 weeks, with sustained partial remission at 18 months’ follow-up. Rituximab therapy, in addition to corticosteroids and angiotensin blockade, may improve the clinical course of patients with renal diseases associated with dysproteinemias, delaying the onset of end-stage renal failure or other adverse outcomes. Additional clinical studies should be planned. Am J Kidney Dis 50:641-644. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Rituximab; paraproteinemias; plasma cell dyscrasia; glomerulonephritis.
D
ysproteinemias, characterized by the presence of an abnormal circulating monoclonal protein, are associated with a diverse spectrum of renal manifestations. Disease entities are diverse and include light chain (myeloma) cast nephropathy, amyloidosis, monoclonal immunoglobulin deposition disease (involving light or heavy chains of immunoglobulin), fibrillary and immunotactoid glomerulonephritis, and proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits. Clinical manifestations include nephrotic syndrome, non-nephrotic proteinuria, Fanconi syndrome, nephrogenic diabetes insipidus, and decreased glomerular filtration rate. Although these diseases are clinically and pathologically distinct, all are associated with hypersecretion of pathogenic immunoglobulin or immunoglobulin fragment by clonal proliferations of plasma cells. Clinical presentations and outcomes are variable, and there currently are no standardized treatment regimens.1-3 Rituximab is a chimeric monoclonal antibody against the CD20 antigen on the surface of B lymphocytes. It leads to profound depletion of B-cell subsets through complement-mediated lysis and antibody-dependent cell-mediated cytoxicity.4,5 Rituximab initially was developed as a
B-cell–depleting agent for treatment of patients with B-cell malignancies.5,6 It also was used to treat patients with such autoimmune diseases as rheumatoid arthritis,7 cold agglutinin disease,8 vasculitis,9,10 and systemic lupus erythematosus.11-14 It generally is well tolerated.15 Depletion of B cells by rituximab may limit damage from immune complex deposition in patients with glomerular diseases without the side effects of traditional immunosuppressive treatments, ie, corticosteroids and cytotoxic agents. Recently, rituximab was used in patients with idiopathic membranous nephropathy, with a decrease in proteinuria and stabilization of renal function during 1 year of follow-up.16 Because renal
From the Department of Medicine (Nephrology), Columbia University Medical Center, New York, NY. Received November 8, 2006. Accepted in revised form May 18, 2007. Originally published online as doi: 10.1053/j.ajkd.2007.05.027 on August 24, 2007. Address correspondence to Jai Radhakrishnan, MD, 622 W 168 St, PH4124, New York, NY 10032. E-mail: jr55@ columbia.edu © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/5004-0015$32.00/0 doi:10.1053/j.ajkd.2007.05.027
American Journal of Kidney Diseases, Vol 50, No 4 (October), 2007: pp 641-644
641
65/White/F/CLL
62/White/M/CLL
43/White/F
2
3
Note: GFR was estimated using the Modification of Diet in Renal Disease Study equation. To convert serum creatinine in mg/dL to mol/L, multiply by 88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, multiply by 0.01667. Abbreviations: M, male; F, female; CLL, chronic lymphocytic leukemia; MPGN, membranoproliferative glomerulonephritis; GN, glomerulonephritis; Uprot, urinary protein excretion (expressed as urinary protein-creatinine ratio); NA, not available; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate; ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker.
100/100/100/100 0.6/0.6/0.7/0.6 3.0/3.0/1.0/0.8 18 ARB
10/10/38/ESRD 6.1/6.1/1.9/ESRD 4.8/9.0/2.0/NA 48
4.1/4.1/4.1/ESRD 11.6/10.5/2.3/NA 35
ACE inhibitor and ARB Corticosteroids
Follow-Up (mo) Concomitant Therapy
1
MPGN with infiltrative B-cell lymphoma, IgG deposits Immunotactoid GN, IgG1 deposits Proliferative GN with MPGN and segmental membranous with IgG deposits
Serum Creatinine at Time of Biopsy/Start of Rituximab Treatment/End of Rituximab Treatment/ Final Follow-Up (mg/dL) Uprot at Time of Biopsy/Start of Rituximab Treatment/ Final Follow-Up (g/d/ 1.73 m2) Pathological Characteristics
A 65-year-old white woman with hypertension and a 4-year history of untreated chronic lymphocytic leukemia (CLL) had nephrotic proteinuria (protein, 11.6 g/d/1.73 m2), serum creatinine level of 0.9 mg/dL (79.6 mol/L), and blood pressure of 170/75 mm Hg. Monoclonal IgG1 and were detected by means of serum protein electrophoresis. Renal biopsy showed membranoproliferative glomerulonephritis associated with glomerular IgG deposits (negative for IgM, IgA, and ) by means of immunofluorescence. Treatment with prednisone (0.5 to 1.0 mg/kg), angiotensinconverting enzyme inhibitor, and angiotensin receptor blocker was maintained for 29 months, during which time she had continued heavy proteinuria and creatinine level increasing to 4.1 mg/dL (362.4 mol/L). A second kidney biopsy showed renal infiltration by CD20⫹ cells and a membranoproliferative glomerulonephritis pattern with monoclonal IgG deposits. Rituximab therapy was started, 11 total infusions of 375 mg/m2 administered at 2-weekly intervals, without concomitant immunosuppression. Angiotensinconverting enzyme inhibitor and angiotensin receptor blocker
Age (y)/Race/Sex/ Comorbidity
Patient 1
Patient No.
CASE REPORTS
Table 1. Baseline and Follow-Up Patient Characteristics
diseases associated with dysproteinemias are pathogenically related to clonal proliferation of B cells, rituximab may improve the clinical course in these diseases. There are recent reports of successful use of rituximab in the treatment of patients with type II mixed cryoglobulinemia associated with hepatitis C virus infection.17,18 To investigate the effect of B-cell depletion on renal dysproteinemias not associated with hepatitis C virus infection, we retrospectively examined our experience with rituximab in 3 patients with renal disease associated with monoclonal immunoglobulin deposits. All patients had monoclonal IgG deposits demonstrated by renal biopsy performed with immunofluorescence staining for IgG subclasses2 and were hepatitis C virus negative. Two patients were treated with rituximab 375-mg/m2 intravenous infusion biweekly for a total of 7 and 11 treatments based on dosing in clinical trials in patients with nonHodgkin lymphoma.6 An alternative regimen, 1,000 mg administered twice at a 2-week interval, was used with success in patients with rheumatoid arthritis7 and was used for a third patient. Urinary protein excretion (grams per day per 1.73 m2), serum creatinine level (milligrams per deciliter), and glomerular filtration rate, estimated using the Modification of Diet in Renal Disease Study equation (milliliters per minute per 1.73 m2),19 at the time of biopsy and follow-up intervals are listed in Table 1.
12/12/12/ESRD
Bhat et al eGFR at Time of Biopsy/ Start of Rituximab Treatment/End of Rituximab Treatment/Final Follow-Up (mL/min/1.73 m2)
642
Rituximab Treatment for Renal Dysproteinemias therapy were continued. After 30 months, proteinuria decreased (protein, 2.3 g/d/1.73 m2) and creatinine level stabilized (4.1 mg/dL [362.4 mol/L]). However, CLL subsequently progressed, with leukocytosis, lymphadenopathy, and renal failure progressing to end-stage renal disease treated with peritoneal dialysis. Thirty-five months after rituximab treatment, the patient died of polymicrobial sepsis related to peritonitis. No further treatment for CLL or renal disease was offered because of overwhelming infection.
Patient 2 A 62-year-old white man with hypertension and a 3-year history of untreated CLL (white blood cell count ⬎ 30 ⫻ 103/L [⬎30 ⫻ 109/L]) had proteinuria (protein, 9 g/d/ 1.73 m2), microscopic hematuria with red blood cell casts, blood pressure of 160/85 mm Hg, and acute renal failure requiring hemodialysis. Serum protein electrophoresis was negative. Renal biopsy showed a membranoproliferative glomerulonephritis pattern, tubular atrophy, and T-cell– predominant interstitial infiltrates. Immunofluorescence was positive for IgG1 with restriction. Electron microscopy showed a microtubular substructure consistent with immunotactoid glomerulopathy. Before renal biopsy, the patient was treated with prednisone, 1 mg/kg/d. After renal biopsy, he was treated with 7 doses of rituximab (375 mg/m2 every 2 weeks), corticosteroids, and angiotensin-converting enzyme inhibitor. After 1 year, proteinuria decreased from protein of 4.8 to 2.0 g/d/1.73 m2, creatinine level decreased from 6.1 to 1.9 mg/dL (539.2 to 168.0 mol/L), and hemodialysis therapy was discontinued. He remained off immunosuppression and hemodialysis therapy at 36 months’ followup. However, at 42 months’ follow-up, there was progression of CLL and subsequent development of end-stage renal disease. He died at 48 months’ follow-up of cardiovascular complications of end-stage renal disease without further treatment for CLL or renal disease.
Patient 3 A 44-year-old white woman with no previous medical history with 3⫹ proteinuria and microhematuria on urine dipstick had urinary protein excretion of 3.0 g/d/1.73 m2 and serum creatinine level of 0.7 mg/dL (61.9 mol/L). Blood pressure and serum protein electrophoresis results were normal. Renal biopsy showed diffuse proliferative glomerulonephritis with immunofluorescence dominance for IgG3 and , suggesting proliferative glomerulonephritis associated with monoclonal IgG deposits.3 Creatinine level was 0.6 mg/dL (53.0 mol/L) at the time of biopsy. Treatment consisted of an angiotensin receptor blocker and two 1,000-mg infusions of rituximab separated by 2 weeks with no concomitant immunosuppression. Eighteen months after treatment with rituximab, urinary protein excretion decreased to 1.0 g/d/1.73 m2 and serum creatinine level remained stable.
DISCUSSION
Traditional treatment regimens for immunemediated glomerular disease included immunosuppressive agents combined with measures to
643
decrease proteinuria. These strategies improved patient outcomes, but treatment failures were frequent and corticosteroids and cytotoxic agents had unfavorable side-effect profiles. The search for more “targeted” immunosuppression is intense, and this topic recently was reviewed.20 Selective B-cell depletion by means of rituximab was used successfully in small series of patients with refractory lupus,11,12 membranous nephropathy,16,21 and vasculitis.9,10,22 We report our experience with rituximab in 3 patients with renal disease related to dysproteinemias. There was short-term stabilization of renal function and proteinuria in all 3 patients. One patient experienced sustained long-term improvement in proteinuria and renal function. Follow-up ranged from 18 to 48 months. There were no serious adverse events related to rituximab. Because this spectrum of diseases is associated with clonal proliferation of B cells or plasma cells, we speculate that rituximab is a targeted therapy against further proliferation and deposition of immunoglobulin and immunoglobulin components in the renal parenchyma. What lessons can be learned from this report? It appears that rituximab can be effective monotherapy in patients with monoclonal immune complex diseases of the kidney. The renal response to rituximab is variable in the short term. Of note, substantial short-term improvement was seen in renal function and proteinuria in 2 patients with B-cell–associated malignancies. It is important to note that the 2 patients with B-cell– associated malignancies in association with glomerular diseases were treated with higher total doses of rituximab as part of oncological protocols. There are several limitations in this series: small number of patients, heterogeneity of the population in disease type and severity, short duration of follow-up, and lack of standardized immunosuppressive regimens and dosing protocols for rituximab. Furthermore, the natural history of these diseases is not well known, and it is possible that some patients may have improved even without B-cell–depleting therapy. However, we see that some patients appear to benefit from this therapy in the short term without serious adverse effects. The response to rituximab for other renal diseases associated with dysproteinemias is of interest. Specifically, no patients
644
Bhat et al
with light chain and/or heavy chain deposition diseases were included in this series. Of course, rituximab is not indicated for patients with renal disease associated with multiple myeloma or amyloidosis, for whom there are other accepted therapies. Furthermore, fludarabine or cyclophosphamide should be considered first in patients with high-grade lymphoma or B symptoms associated with CLL.23 Emphasizing the need for caution in the application of novel therapies to new indications, we highlight a recent Food and Drug Administration advisory warning of 2 cases of progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus nephritis treated with rituximab.24 In conclusion, rituximab generally was well tolerated in patients with glomerular disease related to dysproteinemias and may delay progression of these diseases. Prospective trials are needed to better evaluate the role of rituximab in the treatment of patients with glomerular diseases. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: G.B. Appel is a consultant for, on the speakers’ bureau of, or has research grants with Genentech, Aspreva, LaJolla Pharm, Merck, Pfizer, Astra Zeneca, and BM Squibb. J. Radhakrishnan is a consultant for Genentech.
REFERENCES 1. Lin J, Markowitz GS, Valeri AM, et al: Renal monoclonal immunoglobulin deposition disease: The disease spectrum. J Am Soc Nephrol 12:1482-1492, 2001 2. Markowitz GS: Dysproteinemia and the kidney. Adv Anat Pathol 11:49-63, 2004 3. Nasr SH, Markowitz GS, Stokes MB, et al: Proliferative glomerulonephritis with monoclonal IgG deposits: A distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 65:85-96, 2004 4. Browning JL: B Cells move to centre stage: Novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5:564-576, 2006 5. Davis TA, Grillo-Lopez AJ, White CA, et al: Rituximab anti-CD20 monoclonal antibody therapy in nonHodgkin’s lymphoma: Safety and efficacy of re-treatment. J Clin Oncol 18:3135-3143, 2000 6. Huhn D, von Schilling C, Wilhelm M, et al: Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood 98:1326-1331, 2001 7. Edwards JC, Szczepanski L, Szechinski J, et al: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572-2581, 2004
8. Zaja F, Russo D, Fuga G, et al: Rituximab in a case of cold agglutinin disease. Br J Haematol 115:232-233, 2001 9. Keogh KA, Wylam ME, Stone JH, et al: Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52:262-268, 2005 10. Keogh KA, Ytterberg SR, Fervenza FC, et al: Rituximab for refractory Wegener’s granulomatosis: Report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 173:180-187, 2006 11. Leandro MJ, Cambridge G, Edwards JC, et al: B-Cell depletion in the treatment of patients with systemic lupus erythematosus: A longitudinal analysis of 24 patients. Rheumatology (Oxford) 44:1542-1545, 2005 12. Leandro MJ, Edwards JC, Cambridge G, et al: An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum 46:2673-2677, 2002 13. Looney RJ, Anolik JH, Campbell D, et al: B Cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose-escalation trial of rituximab. Arthritis Rheum 50:2580-2589, 2004 14. Sfikakis PP, Boletis JN, Tsokos GC: Rituximab antiB-cell therapy in systemic lupus erythematosus: pointing to the future. Curr Opin Rheumatol 17:550-557, 2005 15. Kimby E: Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 31:456-473, 2005 16. Ruggenenti P, Chiurchiu C, Brusegan V, et al: Rituximab in idiopathic membranous nephropathy: A one-year prospective study. J Am Soc Nephrol 14:1851-1857, 2003 17. Roccatello D, Baldovino S, Rossi D, et al: Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant 19:3054-3061, 2004 18. Zaja F, De Vita S, Mazzaro C, et al: Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827-3834, 2003 19. Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461470, 1999 20. Javaid B, Quigg RJ: Treatment of glomerulonephritis: Will we ever have options other than steroids and cytotoxics? Kidney Int 67:1692-1703, 2005 21. Remuzzi G, Chiurchiu C, Abbate M, et al: Rituximab for idiopathic membranous nephropathy. Lancet 360:923924, 2002 22. Specks U, Fervenza FC, McDonald TJ, et al: Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum 44:28362840, 2001 23. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996 24. FDA: Information for Healthcare Professionals: Rituximab (marketed as Rituxan). Available at:http://www.fda.gov/ cder/drug/infopage/rituximab/default.htm. Accessed December 20, 2006
D
ysproteinemias, characterized by the presence of an abnormal circulating monoclonal protein, are associated with a diverse spectrum of renal manifestations. Disease entities are diverse and include light chain (myeloma) cast nephropathy, amyloidosis, monoclonal immunoglobulin deposition disease (involving light or heavy chains of immunoglobulin), fibrillary and immunotactoid glomerulonephritis, and proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits. Clinical manifestations include nephrotic syndrome, non-nephrotic proteinuria, Fanconi syndrome, nephrogenic diabetes insipidus, and decreased glomerular filtration rate. Although these diseases are clinically and pathologically distinct, all are associated with hypersecretion of pathogenic immunoglobulin or immunoglobulin fragment by clonal proliferations of plasma cells. Clinical presentations and outcomes are variable, and there currently are no standardized treatment regimens.1-3 Rituximab is a chimeric monoclonal antibody against the CD20 antigen on the surface of B lymphocytes. It leads to profound depletion of B-cell subsets through complement-mediated lysis and antibody-dependent cell-mediated cytoxicity.4,5 Rituximab initially was developed as a
B-cell–depleting agent for treatment of patients with B-cell malignancies.5,6 It also was used to treat patients with such autoimmune diseases as rheumatoid arthritis,7 cold agglutinin disease,8 vasculitis,9,10 and systemic lupus erythematosus.11-14 It generally is well tolerated.15 Depletion of B cells by rituximab may limit damage from immune complex deposition in patients with glomerular diseases without the side effects of traditional immunosuppressive treatments, ie, corticosteroids and cytotoxic agents. Recently, rituximab was used in patients with idiopathic membranous nephropathy, with a decrease in proteinuria and stabilization of renal function during 1 year of follow-up.16 Because renal
From the Department of Medicine (Nephrology), Columbia University Medical Center, New York, NY. Received November 8, 2006. Accepted in revised form May 18, 2007. Originally published online as doi: 10.1053/j.ajkd.2007.05.027 on August 24, 2007. Address correspondence to Jai Radhakrishnan, MD, 622 W 168 St, PH4124, New York, NY 10032. E-mail: jr55@ columbia.edu © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/5004-0015$32.00/0 doi:10.1053/j.ajkd.2007.05.027
American Journal of Kidney Diseases, Vol 50, No 4 (October), 2007: pp 641-644
641
65/White/F/CLL
62/White/M/CLL
43/White/F
2
3
Note: GFR was estimated using the Modification of Diet in Renal Disease Study equation. To convert serum creatinine in mg/dL to mol/L, multiply by 88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, multiply by 0.01667. Abbreviations: M, male; F, female; CLL, chronic lymphocytic leukemia; MPGN, membranoproliferative glomerulonephritis; GN, glomerulonephritis; Uprot, urinary protein excretion (expressed as urinary protein-creatinine ratio); NA, not available; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate; ACE, angiotensinconverting enzyme; ARB, angiotensin receptor blocker.
100/100/100/100 0.6/0.6/0.7/0.6 3.0/3.0/1.0/0.8 18 ARB
10/10/38/ESRD 6.1/6.1/1.9/ESRD 4.8/9.0/2.0/NA 48
4.1/4.1/4.1/ESRD 11.6/10.5/2.3/NA 35
ACE inhibitor and ARB Corticosteroids
Follow-Up (mo) Concomitant Therapy
1
MPGN with infiltrative B-cell lymphoma, IgG deposits Immunotactoid GN, IgG1 deposits Proliferative GN with MPGN and segmental membranous with IgG deposits
Serum Creatinine at Time of Biopsy/Start of Rituximab Treatment/End of Rituximab Treatment/ Final Follow-Up (mg/dL) Uprot at Time of Biopsy/Start of Rituximab Treatment/ Final Follow-Up (g/d/ 1.73 m2) Pathological Characteristics
A 65-year-old white woman with hypertension and a 4-year history of untreated chronic lymphocytic leukemia (CLL) had nephrotic proteinuria (protein, 11.6 g/d/1.73 m2), serum creatinine level of 0.9 mg/dL (79.6 mol/L), and blood pressure of 170/75 mm Hg. Monoclonal IgG1 and were detected by means of serum protein electrophoresis. Renal biopsy showed membranoproliferative glomerulonephritis associated with glomerular IgG deposits (negative for IgM, IgA, and ) by means of immunofluorescence. Treatment with prednisone (0.5 to 1.0 mg/kg), angiotensinconverting enzyme inhibitor, and angiotensin receptor blocker was maintained for 29 months, during which time she had continued heavy proteinuria and creatinine level increasing to 4.1 mg/dL (362.4 mol/L). A second kidney biopsy showed renal infiltration by CD20⫹ cells and a membranoproliferative glomerulonephritis pattern with monoclonal IgG deposits. Rituximab therapy was started, 11 total infusions of 375 mg/m2 administered at 2-weekly intervals, without concomitant immunosuppression. Angiotensinconverting enzyme inhibitor and angiotensin receptor blocker
Age (y)/Race/Sex/ Comorbidity
Patient 1
Patient No.
CASE REPORTS
Table 1. Baseline and Follow-Up Patient Characteristics
diseases associated with dysproteinemias are pathogenically related to clonal proliferation of B cells, rituximab may improve the clinical course in these diseases. There are recent reports of successful use of rituximab in the treatment of patients with type II mixed cryoglobulinemia associated with hepatitis C virus infection.17,18 To investigate the effect of B-cell depletion on renal dysproteinemias not associated with hepatitis C virus infection, we retrospectively examined our experience with rituximab in 3 patients with renal disease associated with monoclonal immunoglobulin deposits. All patients had monoclonal IgG deposits demonstrated by renal biopsy performed with immunofluorescence staining for IgG subclasses2 and were hepatitis C virus negative. Two patients were treated with rituximab 375-mg/m2 intravenous infusion biweekly for a total of 7 and 11 treatments based on dosing in clinical trials in patients with nonHodgkin lymphoma.6 An alternative regimen, 1,000 mg administered twice at a 2-week interval, was used with success in patients with rheumatoid arthritis7 and was used for a third patient. Urinary protein excretion (grams per day per 1.73 m2), serum creatinine level (milligrams per deciliter), and glomerular filtration rate, estimated using the Modification of Diet in Renal Disease Study equation (milliliters per minute per 1.73 m2),19 at the time of biopsy and follow-up intervals are listed in Table 1.
12/12/12/ESRD
Bhat et al eGFR at Time of Biopsy/ Start of Rituximab Treatment/End of Rituximab Treatment/Final Follow-Up (mL/min/1.73 m2)
642
Rituximab Treatment for Renal Dysproteinemias therapy were continued. After 30 months, proteinuria decreased (protein, 2.3 g/d/1.73 m2) and creatinine level stabilized (4.1 mg/dL [362.4 mol/L]). However, CLL subsequently progressed, with leukocytosis, lymphadenopathy, and renal failure progressing to end-stage renal disease treated with peritoneal dialysis. Thirty-five months after rituximab treatment, the patient died of polymicrobial sepsis related to peritonitis. No further treatment for CLL or renal disease was offered because of overwhelming infection.
Patient 2 A 62-year-old white man with hypertension and a 3-year history of untreated CLL (white blood cell count ⬎ 30 ⫻ 103/L [⬎30 ⫻ 109/L]) had proteinuria (protein, 9 g/d/ 1.73 m2), microscopic hematuria with red blood cell casts, blood pressure of 160/85 mm Hg, and acute renal failure requiring hemodialysis. Serum protein electrophoresis was negative. Renal biopsy showed a membranoproliferative glomerulonephritis pattern, tubular atrophy, and T-cell– predominant interstitial infiltrates. Immunofluorescence was positive for IgG1 with restriction. Electron microscopy showed a microtubular substructure consistent with immunotactoid glomerulopathy. Before renal biopsy, the patient was treated with prednisone, 1 mg/kg/d. After renal biopsy, he was treated with 7 doses of rituximab (375 mg/m2 every 2 weeks), corticosteroids, and angiotensin-converting enzyme inhibitor. After 1 year, proteinuria decreased from protein of 4.8 to 2.0 g/d/1.73 m2, creatinine level decreased from 6.1 to 1.9 mg/dL (539.2 to 168.0 mol/L), and hemodialysis therapy was discontinued. He remained off immunosuppression and hemodialysis therapy at 36 months’ followup. However, at 42 months’ follow-up, there was progression of CLL and subsequent development of end-stage renal disease. He died at 48 months’ follow-up of cardiovascular complications of end-stage renal disease without further treatment for CLL or renal disease.
Patient 3 A 44-year-old white woman with no previous medical history with 3⫹ proteinuria and microhematuria on urine dipstick had urinary protein excretion of 3.0 g/d/1.73 m2 and serum creatinine level of 0.7 mg/dL (61.9 mol/L). Blood pressure and serum protein electrophoresis results were normal. Renal biopsy showed diffuse proliferative glomerulonephritis with immunofluorescence dominance for IgG3 and , suggesting proliferative glomerulonephritis associated with monoclonal IgG deposits.3 Creatinine level was 0.6 mg/dL (53.0 mol/L) at the time of biopsy. Treatment consisted of an angiotensin receptor blocker and two 1,000-mg infusions of rituximab separated by 2 weeks with no concomitant immunosuppression. Eighteen months after treatment with rituximab, urinary protein excretion decreased to 1.0 g/d/1.73 m2 and serum creatinine level remained stable.
DISCUSSION
Traditional treatment regimens for immunemediated glomerular disease included immunosuppressive agents combined with measures to
643
decrease proteinuria. These strategies improved patient outcomes, but treatment failures were frequent and corticosteroids and cytotoxic agents had unfavorable side-effect profiles. The search for more “targeted” immunosuppression is intense, and this topic recently was reviewed.20 Selective B-cell depletion by means of rituximab was used successfully in small series of patients with refractory lupus,11,12 membranous nephropathy,16,21 and vasculitis.9,10,22 We report our experience with rituximab in 3 patients with renal disease related to dysproteinemias. There was short-term stabilization of renal function and proteinuria in all 3 patients. One patient experienced sustained long-term improvement in proteinuria and renal function. Follow-up ranged from 18 to 48 months. There were no serious adverse events related to rituximab. Because this spectrum of diseases is associated with clonal proliferation of B cells or plasma cells, we speculate that rituximab is a targeted therapy against further proliferation and deposition of immunoglobulin and immunoglobulin components in the renal parenchyma. What lessons can be learned from this report? It appears that rituximab can be effective monotherapy in patients with monoclonal immune complex diseases of the kidney. The renal response to rituximab is variable in the short term. Of note, substantial short-term improvement was seen in renal function and proteinuria in 2 patients with B-cell–associated malignancies. It is important to note that the 2 patients with B-cell– associated malignancies in association with glomerular diseases were treated with higher total doses of rituximab as part of oncological protocols. There are several limitations in this series: small number of patients, heterogeneity of the population in disease type and severity, short duration of follow-up, and lack of standardized immunosuppressive regimens and dosing protocols for rituximab. Furthermore, the natural history of these diseases is not well known, and it is possible that some patients may have improved even without B-cell–depleting therapy. However, we see that some patients appear to benefit from this therapy in the short term without serious adverse effects. The response to rituximab for other renal diseases associated with dysproteinemias is of interest. Specifically, no patients
644
Bhat et al
with light chain and/or heavy chain deposition diseases were included in this series. Of course, rituximab is not indicated for patients with renal disease associated with multiple myeloma or amyloidosis, for whom there are other accepted therapies. Furthermore, fludarabine or cyclophosphamide should be considered first in patients with high-grade lymphoma or B symptoms associated with CLL.23 Emphasizing the need for caution in the application of novel therapies to new indications, we highlight a recent Food and Drug Administration advisory warning of 2 cases of progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus nephritis treated with rituximab.24 In conclusion, rituximab generally was well tolerated in patients with glomerular disease related to dysproteinemias and may delay progression of these diseases. Prospective trials are needed to better evaluate the role of rituximab in the treatment of patients with glomerular diseases. ACKNOWLEDGEMENTS Support: None. Financial Disclosure: G.B. Appel is a consultant for, on the speakers’ bureau of, or has research grants with Genentech, Aspreva, LaJolla Pharm, Merck, Pfizer, Astra Zeneca, and BM Squibb. J. Radhakrishnan is a consultant for Genentech.
REFERENCES 1. Lin J, Markowitz GS, Valeri AM, et al: Renal monoclonal immunoglobulin deposition disease: The disease spectrum. J Am Soc Nephrol 12:1482-1492, 2001 2. Markowitz GS: Dysproteinemia and the kidney. Adv Anat Pathol 11:49-63, 2004 3. Nasr SH, Markowitz GS, Stokes MB, et al: Proliferative glomerulonephritis with monoclonal IgG deposits: A distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 65:85-96, 2004 4. Browning JL: B Cells move to centre stage: Novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5:564-576, 2006 5. Davis TA, Grillo-Lopez AJ, White CA, et al: Rituximab anti-CD20 monoclonal antibody therapy in nonHodgkin’s lymphoma: Safety and efficacy of re-treatment. J Clin Oncol 18:3135-3143, 2000 6. Huhn D, von Schilling C, Wilhelm M, et al: Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood 98:1326-1331, 2001 7. Edwards JC, Szczepanski L, Szechinski J, et al: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572-2581, 2004
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