NDT Advance Access originally published online on August 8, 2007
Nephrology Dialysis Transplantation 2007 22(12):3674-3676; doi:10.1093/ndt/gfm514
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Rituximab induces complete remission in a case of membranous nephropathy associated with hepatitis C virus- related infection
Email: c.manno{at}nephro.uniba.it
Sir,
Idiopathic membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Corticosteroids, cytotoxic agents and cyclosporine have been largely used in idiopathic MN, but their use may be ineffective or contraindicated in some patients [1]. The pathogenetic potential of B cells in this disease has been employed to explore the therapeutic use of new drugs, such as rituximab, a monoclonal antibody to B-cell antigen CD20. CD20 expression is limited to B cells, begins in humans at the early pre-B-cell stage, and persists until the B cells undergo terminal plasma cell differentiation. The binding of rituximab to the surface receptor of B cells inhibits their activation, proliferation, differentiation and production of immunoglobulins [2].
In the last few years, rituximab has been used in the treatment of type II mixed cryoglobulinaemia (MC), a systemic vasculitis associated in most cases with hepatitis C virus (HCV) infection, and sustained by proliferation of oligoclonal cells. In some categories of patients, anti-viral treatment of active HCV infection may be ineffective or not tolerated, whereas current immunosuppressive treatments may lead to relevant complications and enhance the viral load [3].
Case report
A 69-year-old man was admitted to our unit in July 2000 for nephrotic syndrome. In 1998, HCV-related infection and urinary abnormalities had been diagnosed in another hospital. On admission, the physical examination showed peripheral oedema. Blood pressure was 120/80 mmHg, and no clinical chest or abdominal abnormalities were found. Laboratory investigation revealed the following: serum creatinine (sCr) 0.9 mg/dl, proteinuria (Upr) 9.1 g/24 h, serum total proteins 5.1 g/dl, serum albumin 2.4 g/dl, aspartate aminotransferase (AST) 17 IU/l, alanino aminotransferase (ALT) 13 IU/l, gammaglutamiltransferase (GGT) 6 IU/l, alkaline phosphatase (ALP) 91 IU/l. No macroscopic and/or microscopic haematuria were present. Urinary sediment showed granular and epithelial casts. Complement factors, such as C3, C4, circulating immune complexes, serum immunoglobulins and reumathoid factor were in the normal range.
Anti-dsDNA antibodies, anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies and cryoglobulins were absent. The amount of HCV RNA was 620 000 IU/ml, using an in-house real-time polymerase chain reaction assay (lower detection cut-off 600 IU/ml); HCV genotype was 2a/2c. The patient underwent ultrasound-guided renal biopsy which revealed, at light microscopy, a diffuse thickening of glomerular basement membrane with granular subepithelial and intramembranous deposits. Parietal IgG and C3 deposits were present at immunofluorescence. These features were consistent with MN (stage III). A liver biopsy was also performed and showed a mild infiltration of inflammatory cells in portal spaces (stage II).
Prednisone (15–10 mg/day) plus 
-interferon (three millions units three times per week) were administered for 6 months (Fig. 1). Subsequently, a 3 month course of -peg-interferon (50 mcg/week) was administered. At the end of this treatment regimen, Upr decreased to 0.08 g/24 h; renal and liver functions were found to be normal (sCr 1.0 mg/dl, AST 30 IU/l, ALT 38 IU/l, GGT 16 IU/l, ALP 81 IU/l), while HCV RNA level was not modified (576 000 IU/ml). Then, the patient was treated with enalapril (20 mg), which has been continued up to the present. In July 2004, the patient was thus admitted to our unit for a relapse of nephrotic syndrome. There were no thoracic, cardiac or abdominal pathological signs, in the presence of kidney oedema and arterial hypertension (140/90 mmHg). Laboratory investigation revealed sCr 0.8 mg/dl, proteinuria 10.4 g/24 h, levels of serum total proteins 5.4 g/dl, albumin 2.0 g/dl, cholesterol 322 mg/dl, AST 25 IU/l, ALT 30 IU/l, GGT 18 IU/l, ALP 80 IU/l; cryoglobulins were in the normal range. HCV RNA was 278 000 IU/ml. Rituximab was started at a dosage of 375 mg/m2/week i.v. for 4 weeks and administration of enalapril was continued regularly. No fever, pain or allergic reaction occurred after every infusion of rituximab. After this short course of therapy, Upr decreased to 1.8 g/24 h and reached levels of complete remission after 6 months; CD20 B lymphocytes decreased from 9.8% to 0.1%; a decrease in HCV RNA levels was also observed (193 574 UI/ml). Kidney oedema disappeared and blood pressure was normal (115/80 mmHg). After 24 months, the patient was in complete remission, with Upr of 0.24 g/24 h and sCr 0.9 mg/dl, AST 36 IU/l, ALT 50 IU/l, GGT 17 IU/l, ALP 63 IU/l; HCV RNA levels further decreased to 8420 UI/ml.
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Comments
Corticosteroids and cytotoxic agents have been largely used in the treatment of MN. In patients with contraindication to cytotoxic agents or non-responders, new approaches are represented by others agents such as cyclosporine, adrenocorticotropic hormone, tacrolimus and mycophenolate mofetil. No recommendations are provided for the treatment of MN associated with HCV infection.
The rationale for using rituximab in the treatment of glomerulonephritis associated with HCV infection is its action on B lymphocytes. Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody, which binds to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The Fc domain of rituximab recruits immune effector functions to mediate B cell lysis. Possible mechanisms of cytotoxicity include complement-dependent cytotoxicity resulting from C1q binding, and antibody-dependent cellular cytotoxicity, mediated by one or more of the Fcgamma receptors on the surface of granulocytes, macrophages and NK cells and apoptosis [4]. The relation between mixed cryoglobulinemia and HCV infection shows new links between viral infection, autoimmune phenomena and lymphoproliferative disorders. A monoclonal population may emerge by B-cell polyclonal proliferation stimulated chronically by HCV. In patients with HCV-related MC, the therapeutic strategy should include antiviral therapy. In determining the regression of B-cell lymphoproliferative disorder, rituximab could exert selective B-cell control, modulating and interfering with HCV proliferation.
In preliminary studies, Ruggenenti et al. [2] evaluated the outcome of eight idiopathic MN patients with persistent urinary protein excretion, given four weekly infusions of rituximab (375 mg/m2) in association with a full dose of ACE-inhibitors. At 3 and 12 months, proteinuria decreased by 51% and 66%, respectively; however, proteinuria remained in the nephrotic range in 4/8 patients. On the contrary, our case demonstrates that rituximab induced a complete remission in MN associated with HCV infection and no relapse occurred in the mid term after a short course.
In conclusion, rituximab infusion offers a new alternative approach, with a narrow disease-specific mechanism for the treatment of idiopathic MN, associated with the current therapeutic options including non-specific immunosuppression, conservative treatment with ACE inhibition, blood pressure reduction and lipid control. In MN associated with HCV infection, the rationale is enforced by the selective action of rituximab on B lymphocytes. However, large randomized clinical trials with longer follow-up are needed, to verify the efficacy and the long-term tolerability of rituximab therapy, in both idiopathic and secondary MN.
Department of Emergency and
Organ Transplantation,
Renal, Dialysis and
Transplant Unit,
University of Bari,
Bari,
Italy
Acknowledgements
We thank Mariella Mastrolonardo for her editorial assistance and for the English revision of the article.
Conflict of interest statements. None declared.
Notes
See http://www.oxfordjournals.org/our_journals/ndtplus/
*These authors contributed equally to this work. 
References
- Hogan S, Muller KE, Jennette JC, Falk RG. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis (1995) 25:862–875.[Web of Science][Medline]
- Ruggenenti P, Chiurchiu C, Brusegan V, et al. Rituximab in idiopathic membranous nephropathy: a one-year prospective study. J Am Soc Nephrol (2003) 14:1851–1857.
[Abstract/Free Full Text] - Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood (2003) 10:3827–3834.
- Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin's lymphoma. Eur J Haematol Suppl (2007) 67:5–14.[Medline]
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