Advertisement
American Journal of Kidney Diseases

Hepatitis C Virus Infection, Mixed Cryoglobulinemia, and Kidney Disease

Published:October 29, 2012DOI:https://doi.org/10.1053/j.ajkd.2012.08.040
      Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Wintrobe M.
        • Buell M.
        Hyperproteinemia associated with multiple myeloma: with report of a case in which an extraordinary hyperproteinemia was associated with thrombosis of the retinal veins and symptoms suggesting Raynaud's disease.
        Bull Hopkins Hosp. 1933; 52: 156-164
        • Lerner A.
        • Watson C.
        Studies of cryoglobulins.
        Am J Med. 1947; 214: 410-418
        • Meltzer M.
        • Franklin E.
        • Elias K.
        • McCluskey R.
        • Cooper N.
        Cryoglobulinemia—a clinical and laboratory study.
        Am J Med. 1966; 40: 837-856
        • Brouet J.
        • Clauvel J.
        • Danon F.
        • Klein M.
        • Seligmann M.
        Biologic and clinical significance of cryoglobulins.
        Am J Med. 1974; 57: 775-788
        • Fabrizi F.
        • Colucci P.
        • Ponticelli C.
        • Locatelli F.
        Kidney and liver involvement in cryoglobulinemia.
        Semin Nephrol. 2002; 22: 309-318
        • Choo Q.
        • Kuo G.
        • Weiner A.
        • Overby L.
        • Bradley D.
        • Houghton M.
        Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.
        Science. 1989; 244: 359-362
        • Kuo G.
        • Choo Q.
        • Alter H.
        • et al.
        An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis.
        Science. 1989; 244: 362-364
        • Cacoub P.
        • Poynard T.
        • Ghillani P.
        • et al.
        • MULTIVIRC Group
        Multidepartment virus C: extra-hepatic manifestations of chronic hepatitis C.
        Arthritis Rheum. 1999; 42: 2204-2212
        • Trejo O.
        • Ramos-Casals M.
        • Garcia-Carrasco M.
        • et al.
        Cryoglobulinemia, study of etiological factors and clinical and immunological features in 443 patients from a single center.
        Medicine. 2001; 80: 252-262
        • Saadoun D.
        • Sellam J.
        • Ghillani-Dalbin P.
        • Crecel R.
        • Piette J.C.
        • Cacoub P.
        Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia.
        Arch Intern Med. 2006; 166: 2101-2108
        • Cruzado J.
        • Carrera M.
        • Torras J.
        • Grinyo J.
        Hepatitis C virus infection and de novo glomerular lesions in renal allografts.
        Am J Transplant. 2001; 1: 171-178
        • Morales J.
        • Pascual-Capdevila J.
        • Campistol J.M.
        • et al.
        Membranous glomerulonephritis associated with hepatitis C virus infection in renal transplant patients.
        Transplantation. 1997; 63: 1634-1639
        • Roth D.
        • Cirocco R.
        • Zucker K.
        • et al.
        De novo membranoproliferative glomerulonephritis in hepatitis C virus-infected renal allograft recipients.
        Transplantation. 1995; 59: 1676-1682
        • El-Serag H.
        • Hampel H.
        • Yeh C.
        • Rabaneck L.
        Extra-hepatic manifestations of hepatitis C among United States male veterans.
        Hepatology. 2002; 36: 1439-1445
        • Tsui J.
        • Vittinghoff E.
        • Shlipak M.
        • O'Hare A.
        Relationship between hepatitis C and chronic kidney disease: results from the Third National Health and Nutrition Examination Survey.
        J Am Soc Nephrol. 2006; 17: 1168-1174
        • Tsui J.
        • Vittinghoff E.
        • Shlipak M.
        • et al.
        Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease.
        Arch Intern Med. 2007; 167: 1271-1276
        • Dalrymple L.
        • Koepsell T.
        • Sampson J.
        • et al.
        Hepatitis C virus infection and the prevalence of renal insufficiency.
        Clin J Am Soc Nephrol. 2007; 2: 715-721
        • Moe S.
        • Pampalone A.
        • Ofner S.
        • Rosenman M.
        • Teal E.
        • Hui S.
        Association of hepatitis C virus infection with prevalence and development of kidney disease.
        Am J Kidney Dis. 2008; 51: 885-892
        • Asrani S.
        • Buchanan P.
        • Pinsky B.
        • Rey L.
        • Schnitzler M.
        • Kanwal F.
        Lack of association between hepatitis C infection and chronic kidney disease.
        Clin Gastroenterol Hepatol. 2010; 8: 79-84
        • Lee J.
        • Lin M.
        • Yang Y.
        • Lu S.
        • Chen H.
        • Hwang S.
        Association of hepatitis C and B virus infection with chronic kidney disease in an endemic area in Taiwan: a cross-sectional survey.
        Am J Kidney Dis. 2010; 56: 23-31
        • Butt A.
        • Wang X.
        • Fried L.
        HCV infection and the incidence of chronic kidney disease.
        Am J Kidney Dis. 2011; 57: 396-402
        • Wyatt C.
        • Malvestutto C.
        • Coca S.
        • Klotman P.
        • Parkh C.
        The impact of hepatitis C virus co-infection on HIV-related kidney disease: a systematic review and meta-analysis.
        AIDS. 2008; 22: 1799-1807
        • Izzedine H.
        • Sene D.
        • Cacoub P.
        • et al.
        Kidney diseases in HIV/HCV-co-infected patients.
        AIDS. 2009; 23: 1219-1226
        • Alric L.
        • Plaisier E.
        • Thébault S.
        • et al.
        Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN.
        Am J Kidney Dis. 2004; 43: 617-623
        • Liangpunsakul S.
        • Chalasani N.
        Relationship between hepatitis C and microalbuminuria: results from the NHANES III.
        Kidney Int. 2005; 67: 285-290
        • Huang J.
        • Chuang W.
        • Dai C.
        • et al.
        Viral hepatitis and proteinuria in an area endemic for hepatitis B and C infections: another chain of link?.
        J Intern Med. 2006; 260: 255-262
        • Davis C.
        • Gretch D.
        • Perkins J.
        • et al.
        Hepatitis C-associated glomerular disease in liver transplant recipients.
        Liver Transpl Surg. 1995; 1: 166-175
        • Sikaneta T.
        • Williams W.
        • Chung R.
        • Cosimi A.
        • Pascual A.
        Remission of hepatitis C virus-associated cryoglobulinemic glomerulonephritis with interferon alpha-2b and ribavirin combination therapy after liver transplantation.
        Transplantation. 2002; 74: 1767-1768
        • Montalbano M.
        • Pasulo L.
        • Sonzogni A.
        • Remuzzi G.
        • Colledan M.
        • Strazzabosco M.
        Treatment with pegylated interferon and ribavirin for hepatitis C virus-associated severe cryoglobulinemia in a liver/kidney transplant recipient.
        J Clin Gastroenterol. 2007; 41: 216-220
        • Cacoub P.
        • Maisonobe T.
        • Thibault V.
        • et al.
        Systemic vasculitis in patients with hepatitis C.
        J Rheumatol. 2001; 28: 109-118
        • Beddhu S.
        • Bastacky S.
        • Johnson J.P.
        The clinical and morphologic spectrum of renal cryoglobulinemia.
        Medicine (Baltimore). 2002; 81: 398-409
        • Takyar S.
        • Li D.
        • Wang Y.
        • Trowbridge R.
        • Gowans E.
        Specific detection of minus-strand hepatitis C virus RNA by reverse-transcription polymerase chain reaction on PolyA(+)-purified RNA.
        Hepatology. 2000; 32: 382-387
        • Sung V.M.
        • Shimodaira S.
        • Doughty A.
        • et al.
        Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptopic effects of virus infection.
        J Virol. 2003; 77: 2134-2146
        • De Vita S.
        • De Re V.
        • Sansonno D.
        • et al.
        Lack of HCV infection in malignant cells refutes the hypothesis of a direct transforming action of the virus in the pathogenesis of HCV-associated B-cell NHLs.
        Tumori. 2002; 88: 400-406
        • Marukian S.
        • Jones C.
        • Andrus L.
        • et al.
        Cell-culture produced hepatitis C virus does not infect peripheral blood mononuclear cells.
        Hepatology. 2008; 48: 1843-1850
        • Johnson R.
        • Gretch D.
        • Couser W.
        • et al.
        Hepatitis C virus-associated glomerulonephritis.
        Kidney Int. 1994; 46: 1700-1704
        • Ferri C.
        • Greco F.
        • Longombardo G.
        • et al.
        Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia.
        Arthritis Rheum. 1991; 34: 1606-1610
        • Fabrizi F.
        • Pozzi C.
        • Farina M.
        • et al.
        Hepatitis C virus infection and acute or chronic glomerulonephritis: an epidemiological and clinical appraisal.
        Nephrol Dial Transplant. 1998; 13: 1991-1997
        • Agnello V.
        • Chung R.
        • Kaplan L.
        A role for hepatitis C virus infection in type II cryoglobulinemia.
        N Engl J Med. 1992; 327: 1490-1495
        • Cacoub P.
        • Fabiani F.L.
        • Musset L.
        • et al.
        Mixed cryoglobulinemia and hepatitis C virus.
        Am J Med. 1994; 96: 124-132
        • Sansonno D.
        • Gesualdo L.
        • Manno C.
        • Schena F.
        • Dammacco F.
        Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinaemic membranoproliferative glomerulonephritis.
        Hepatology. 1997; 25: 1237-1244
        • Charles E.
        • Dustin L.
        Hepatitis C virus-induced cryoglobulinemia.
        Kidney Int. 2009; 76: 818-824
        • Rigolet A.
        • Cacoub P.
        • Schnuriger A.
        • et al.
        Genetic heterogeneity of the hypervariable region I of hepatitis C virus and lymphoproliferative disorders.
        Leukemia. 2005; 19: 1070-1076
        • Rosa D.
        • Saletti G.
        • De Gregorio E.
        • et al.
        Activation of naive B lymphocytes via CD81, pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders.
        Proc Natl Acad Sci U S A. 2005; 102: 18544-18549
        • Vallat L.
        • Benhamou Y.
        • Gutierrez M.
        • et al.
        Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection.
        Arthritis Rheum. 2004; 50: 3668-3678
        • Charles E.
        • Green R.
        • Marukian S.
        • et al.
        Clonal expansion of immunoglobulin M+CD27+ B-cells in HCV-associated mixed cryoglobulinemia.
        Blood. 2008; 111: 1344-1356
        • Landau D.A.
        • Rosenzwajg M.
        • Saadoun D.
        • Klatzmann D.
        • Cacoub P.
        The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders.
        Ann Rheum Dis. 2009; 68: 337-344
        • Fabris M.
        • Quartuccio L.
        • Sacco S.
        • et al.
        B-Lymphocyte stimulator (BLys) up-regulation in mixed cryoglobulinemia syndrome and hepatitis C virus infection.
        Rheumatology (Oxford). 2007; 46: 37-43
        • Sene D.
        • Ghillani-Dalbin P.
        • Thibault V.
        • et al.
        Long-term course of mixed cryoglobulinemia in patients infected with hepatitis C virus.
        J Rheumatol. 2004; 31: 2199-2206
        • Landau D.A.
        • Saadoun D.
        • Calabrese L.H.
        • Cacoub P.
        The pathophysiology of HCV induced B-cell clonal disorders.
        Autoimmun Rev. 2007; 6: 581-587
        • Trendelenburg M.
        • Fossati-Jimack L.
        • Cortes-Hernandez J.
        • et al.
        The role of complement in cryoglobulin-induced immune complex glomerulonephritis.
        J Immunol. 2005; 175: 6909-6914
        • Roccatello D.
        • Isidoro C.
        • Mazzucco G.
        • et al.
        Role of monocytes in cryoglobulinemia-associated nephritis.
        Kidney Int. 1993; 43: 1150-1155
        • Reininger L.
        • Berney T.
        • Shibata T.
        • Spertini F.
        • Merino R.
        • Izui S.
        Cryoglobulinemia induced by a murine IgG3 rheumatoid factor: skin vasculitis and glomerulonephritis arise from distinct pathogenic mechanisms.
        Proc Natl Acad Sci U S A. 1990; 87: 1038-1042
        • Floyd M.
        • Tesar J.
        The role of IgM rheumatoid factor in experimental immune vasculitis.
        Clin Exp Immunol. 1979; 36: 165-174
        • Saadoun D.
        • Bieche I.
        • Maisonobe T.
        • et al.
        Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy.
        Arthritis Rheum. 2005; 52: 2917-2925
        • Boyer O.
        • Saadoun D.
        • Abriol J.
        • et al.
        CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis.
        Blood. 2004; 103: 3428-3430
        • Landau D.A.
        • Rosenzwajg M.
        • Saadoun D.
        • Trébeden-Negre H.
        • Klatzmann D.
        • Cacoub P.
        Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis.
        Arthritis Rheum. 2008; 58: 2897-2907
        • Charles E.
        • Brunette C.
        • Marukian S.
        • et al.
        Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21 low B-cell subset.
        Blood. 2011; 117: 5425-5437
        • Terrier B.
        • Joly F.
        • Vazquez T.
        • et al.
        Expansion of functionally anergic CD21-/low marginal zone-like B cell clones in hepatitis C virus infection-related autoimmunity.
        J Immunol. 2011; 187: 6550-6553
        • Fornasieri A.
        • Armelloni S.
        • Bernasconi P.
        • et al.
        High binding of immunoglobulin M kappa rheumatoid factor from type II cryoglobulins to cellular fibronectin: a mechanism for induction of in situ immune complex glomerulonephritis?.
        Am J Kidney Dis. 1996; 27: 476-483
        • Fornasieri A.
        • Li M.
        • Armelloni S.
        • et al.
        Glomerulonephritis induced by human IgMκ-IgG cryoglobulins in mice.
        Lab Invest. 1993; 69: 531-540
        • Barsoum R.
        Hepatitis C virus: from entry to renal injury—facts and potentials.
        Nephrol Dial Transplant. 2007; 22: 1840-1848
        • D'Amico G.
        Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis.
        Kidney Int. 1998; 54: 650-671
        • Cacoub P.
        • Ghillani P.
        • Revelen R.
        • et al.
        Anti-endothelial cell auto-antibodies in hepatitis C virus mixed cryoglobulinemia.
        J Hepatol. 1999; 31: 598-603
        • Kaplanski G.
        • Maisonobe T.
        • Marin V.
        • et al.
        Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in the pathogenesis of severe forms of vasculitis due to hepatitis C-associated mixed cryoglobulinemia.
        J Hepatol. 2005; 42: 334-340
        • Sansonno D.
        • Lauletta G.
        • Montrone M.
        • Grandaliano G.
        • Schena F.
        • Dammacco F.
        Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated with laser capture microdissection.
        Clin Exp Immunol. 2005; 140: 498-506
        • Wornle M.
        • Schmid H.
        • Banas B.
        • et al.
        Novel role of Toll-like receptor 3 in hepatitis C-associated glomerulonephritis.
        Am J Pathol. 2006; 168: 370-385
        • Costa J.
        • Resende C.
        • de Carvalho M.
        Motor-axonal polyneuropathy associated with hepatitis C virus.
        Eur J Neurol. 2003; 10: 183-185
        • Authier F.
        • Pawlotsky J.
        • Viard J.
        • Guillevin L.
        • Degos J.
        • Gherardi R.
        High incidence of hepatitis C virus infection in patients with cryoglobulinemic neuropathy.
        Ann Neurol. 1993; 34: 749-750
        • Saadoun D.
        • Terrier B.
        • Semoun O.
        • et al.
        Hepatitis C virus-associated polyarteritis nodosa.
        Arthritis Care Res (Hoboken). 2011; 63: 427-435
        • Valli G.
        • De Vecchi A.
        • Gaddi L.
        • Nobile-Orazio E.
        • Tarantino A.
        • Barbieri S.
        Peripheral nervous system involvement in essential cryoglobulinemia and nephropathy.
        Clin Exp Rheum. 1989; 7: 479-483
        • Casato M.
        • Saadoun D.
        • Marchetti A.
        • et al.
        Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests.
        J Rheumatol. 2005; 32: 484-488
        • Terrier B.
        • Saadoun D.
        • Sène D.
        • Scerra S.
        • Musset L.
        • Cacoub P.
        Presentation and outcome of gastrointestinal involvement in hepatitis C virus-related systemic vasculitis: a case-control study from a single-centre cohort of 163 patients.
        Gut. 2010; 59: 1709-1715
        • Viegi G.
        • Fornari E.
        • Ferri C.
        • et al.
        Lung function in essential mixed cryoglobulinemia: a short-term follow-up.
        Clin Rheum. 1989; 8: 331-338
        • Gorevic P.
        • Kassab H.
        • Levo Y.
        • et al.
        Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients.
        Am J Med. 1980; 69: 287-308
        • Tarantino A.
        • De Vecchi A.
        • Montagnino G.
        • et al.
        Renal disease in essential mixed cryoglobulinemia.
        Q J Med. 1981; 50: 1-30
        • Tarantino A.
        • Campise R.
        • Banfi G.
        • et al.
        Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis.
        Kidney Int. 1995; 47: 618-623
        • Ferri C.
        Mixed cryoglobulinemia.
        Orphanet J Rare Dis. 2008; 3: 25
        • Roccatello D.
        • Fornasieri A.
        • Giachino O.
        • et al.
        Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis.
        Am J Kidney Dis. 2007; 49: 69-82
        • Terrier B.
        • Semoun O.
        • Saadoun D.
        • Sène D.
        • Resche-Rigon M.
        • Cacoub P.
        Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis.
        Arthritis Rheum. 2011; 63: 1748-1757
        • Fabrizi F.
        • Lunghi G.
        • Messa P.G.
        • Martin P.
        Therapy of hepatitis C virus-associated glomerulonephritis: current approaches.
        J Nephrol. 2008; 21: 813-825
        • Perico N.
        • Cattaneo D.
        • Bibkov B.
        • Remuzzi G.
        Hepatitis C infection and chronic renal diseases.
        Clin J Am Soc Nephrol. 2009; 4: 207-220
      1. Kidney Disease: Improving Global Outcomes.
        Kidney Int Suppl. 2008; 109: S1-S99
        • Mazzaro C.
        • Panarello G.
        • Carniello S.
        • et al.
        Interferon versus steroids in patients with hepatitis C virus-associated cryoglobulinaemic glomerulonephritis.
        Dig Liver Dis. 2000; 32: 708-715
        • Bruchfeld A.
        • Lindahl K.
        • Stahle L.
        • Soderberg M.
        • Schvarcz R.
        Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency.
        Nephrol Dial Transplant. 2003; 18: 1573-1580
        • Garini G.
        • Allegri L.
        • Iannuzzella F.
        • Vaglio A.
        • Buzio C.
        HCV-related cryoglobulinemic glomerulonephritis: implications of antiviral and immunosuppressive therapies.
        Acta Biomed. 2007; 78: 51-59
        • Abbas G.
        • Hussain S.
        • Shafi T.
        Effect of antiviral therapy on hepatitis C virus related glomerulopathy.
        Saudi J Kidney Dis Transplant. 2008; 19: 775-780
        • Rossi P.
        • Bertani T.
        • Baio P.
        • et al.
        Hepatitis C virus-related cryoglobulinemic glomerulonephritis: long-term remission after antiviral therapy.
        Kidney Int. 2003; 63: 2236-2241
        • Saadoun D.
        • Resche-Rigon M.
        • Thibault V.
        • Piette J.C.
        • Cacoub P.
        Antiviral therapy for hepatitis C virus-associated mixed cryoglobulinemia vasculitis: a long-term follow-up study.
        Arthritis Rheum. 2006; 54: 3696-3706
        • Saadoun D.
        • Resche Rigon M.
        • Sene D.
        • et al.
        Rituximab plus peg-interferon-alpha/ribavirin compared with peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia.
        Blood. 2010; 116: 326-334
        • McHutchison J.G.
        • Everson G.T.
        • Gordon S.C.
        • et al.
        • PROVE1 Study Team
        Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.
        N Engl J Med. 2009; 360: 1827-1838
        • Hezode C.
        • Forestier N.
        • Dusheiko G.
        • et al.
        • PROVE2 Study Team
        Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.
        N Engl J Med. 2009; 360: 1839-1850
        • Ghany G.
        • Nelson D.
        • Strader D.
        • Thomas D.
        • Seeff L.
        An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guidelines by the American Association for the Study of Liver Diseases.
        Hepatology. 2011; 54: 1433-1434
        • Casato M.
        • Agnello V.
        • Pucillo L.P.
        • et al.
        Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection.
        Blood. 1997; 90: 3865-3873
        • Misiani R.
        • Bellavita P.
        • Fenili D.
        • et al.
        Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus.
        N Engl J Med. 1994; 330: 751-756
        • Dammacco F.
        • Sansonno D.
        • Han J.H.
        • et al.
        Natural interferon-alpha versus its combination with 6-methyl-prednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study.
        Blood. 1994; 84: 3336-3343
        • Naarendorp M.
        • Kallemuchikkal U.
        • Nuovo G.J.
        • Gorevic P.D.
        Long-term efficacy of interferon-alpha for extrahepatic disease associated with hepatitis C virus infection.
        J Rheumatol. 2001; 28: 2466-2473
        • Zuckerman E.
        • Keren D.
        • Slobodin G.
        • et al.
        Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferon-alpha.
        J Rheumatol. 2000; 27: 2172-2178
        • Cacoub P.
        • Lidove O.
        • Maisonobe T.
        • et al.
        Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis.
        Arthritis Rheum. 2002; 46: 3317-3326
        • Fabrizi F.
        • Bruchfeld A.
        • Mangano S.
        • Dixit V.
        • Messa P.
        • Martin P.
        Interferon therapy for HCV-associated glomerulonephritis: meta-analysis of controlled trials.
        Int J Artif Organs. 2007; 30: 212-219
        • Ohta S.
        • Yokoyama H.
        • Wada T.
        • et al.
        Exacerbation of glomerulonephritis in subjects with chronic hepatitis C virus infection after interferon therapy.
        Am J Kidney Dis. 1999; 33: 1040-1048
        • Strader D.
        • Wright T.
        • Thomas D.
        • Seeff L.
        • American Association for the Study of Liver Diseases
        Diagnosis, management, and treatment of hepatitis C.
        Hepatology. 2004; 39: 1147-1171
        • Roccatello D.
        • Baldovino S.
        • Rossi D.
        • et al.
        Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis.
        Nephrol Dial Transplant. 2004; 19: 3054-3061
        • Quartuccio L.
        • Soardo G.
        • Romano G.
        • et al.
        Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids.
        Rheumatology. 2006; 45: 842-846
        • Sansonno D.
        • De Re V.
        • Lauletta G.
        • Tucci F.A.
        • Boiocchi M.
        • Dammacco F.
        Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20.
        Blood. 2003; 101: 3818-3826
        • Roccatello D.
        • Baldovino S.
        • Rossi D.
        • et al.
        Rituximab as a therapeutic tool in severe mixed cryoglobulinemia.
        Clin Rev Allergy Immunol. 2008; 34: 111-117
        • Zaja F.
        • De Vita S.
        • Mazzaro C.
        • et al.
        Efficacy and safety of rituximab in type II mixed cryoglobulinemia.
        Blood. 2003; 101: 3827-3834
        • Cacoub P.
        • Delluc A.
        • Saadoun D.
        • Landau D.A.
        • Sene D.
        Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand?.
        Ann Rheum Dis. 2008; 67: 283-287
        • Ghijsels E.
        • Lerut E.
        • Vanterghem Y.
        • Kuypers D.
        Anti-DC20 monoclonal antibody (rituximab) treatment for hepatitis C-negative therapy-resistant essential mixed cryoglobulinemia with renal and cardiac failure.
        Am J Kidney Dis. 2004; 43: e34-e38
        • Koukoulaki M.
        • Abeygunasekara S.
        • Smith K.
        • Jayne D.
        Remission of refractory hepatitis C-negative cryoglobulinaemic vasculitis after rituximab and infliximab.
        Nephrol Dial Transplant. 2005; 20: 213-216
        • Basse G.
        • Ribes D.
        • Kamar N.
        • et al.
        Rituximab therapy for mixed cryoglobulinemia in seven renal transplant patients.
        Transplant Proc. 2006; 38: 2308-2310
        • Braun A.
        • Neumann T.
        • Oelzner P.
        • et al.
        Cryoglobulinaemia type III with severe neuropathy and immune complex glomerulonephritis: remission after plasmapheresis and rituximab.
        Rheumatol Int. 2008; 28: 503-506
        • Visentini M.
        • Granata M.
        • Veneziano M.
        • et al.
        Efficacy of low-dose rituximab for mixed cryoglobulinemia.
        Clin Immunol. 2007; 125: 30-33
        • De Vita S.
        • Quartuccio L.
        • Fabris M.
        Rituximab in mixed cryoglobulinemia: increased experience and perspectives.
        Dig Liver Dis. 2007; 39: S122-S128
        • Petrarca A.
        • Rigacci L.
        • Monti M.
        • et al.
        Improvement in liver cirrhosis after treatment of HCV-related mixed cryoglobulinemia with rituximab.
        Dig Liver Dis. 2007; 39: S76-S82
        • Korte M.
        • van Heerde M.
        • de Man R.
        • Betjes M.
        Rituximab for the treatment of glomerulonephritis in hepatitis C associated cryoglobulinemia.
        Neth J Med. 2008; 66: 27-30
        • Saadoun D.
        • Resche-Rigon M.
        • Sene D.
        • Perard L.
        • Karras A.
        • Cacoub P.
        Rituximab combined with peg-interferon-ribavirin in refractory hepatitis C virus-associated cryoglobulinaemia vasculitis.
        Ann Rheum Dis. 2008; 67: 1431-1436
        • Ruch J.
        • McMahon B.
        • Ramsey G.
        • Kwaan H.
        Catastrophic multiple organ ischemia due to an anti-Pr cold agglutinin developing in a patient with mixed cryoglobulinemia after treatment with rituximab.
        Am J Hematol. 2009; 84: 120-122
        • Petrarca A.
        • Rigacci L.
        • Caini P.
        • et al.
        Safety and efficacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinemia and severe liver disease.
        Blood. 2010; 116: 335-342
        • Wink F.
        • Houtman P.
        • Jansen T.L.
        Rituximab in cryoglobulinaemic vasculitis, evidence for its effectivity: a case report and review of the literature.
        Clin Rheumatol. 2011; 30: 293-300
        • Dammacco F.
        • Tucci F.A.
        • Lauletta G.
        • et al.
        Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinaemia: a long-term study.
        Blood. 2010; 116: 343-353
        • Visentini M.
        • Ludovisi S.
        • Petrarca A.
        • et al.
        A phase II, single-arm multicenter study of low-dose rituximab for refractory mixed cryoglobulinemia secondary to hepatitis C virus infection.
        Autoimmun Rev. 2011; 10: 714-719
        • Ferri C.
        • Cacoub P.
        • Mazzaro C.
        • et al.
        Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature.
        Autoimmune Rev. 2011; 11: 48-55
        • De Vita S.
        • Quartuccio L.
        • Isola M.
        • et al.
        A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis.
        Arthritis Rheum. 2012; 64: 843-853
        • Sneller M.
        • Hu Z.
        • Langford C.
        A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis.
        Arthritis Rheum. 2012; 64: 835-842
        • Terrier B.
        • Saadoun D.
        • Sene D.
        • et al.
        Efficacy and tolerability of rituximab with or without pegylated interferon alfa-2b plus ribavirin in severe hepatitis C virus-related vasculitis: a long-term follow-up study of thirty-two patients.
        Arthritis Rheum. 2009; 60: 2531-2540
        • Sene D.
        • Ghillani-Dalbin P.
        • Amoura Z.
        • Musset L.
        • Cacoub P.
        Rituximab may form a complex with IgM-kappa mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus-induced vasculitis.
        Arthritis Rheum. 2009; 60: 3848-3855
        • Hausfater P.
        • Cacoub P.
        • Assogba U.
        • Lebon P.
        • Piette J.C.
        Plasma exchange and interferon-alpha pharmacokinetics in patients with hepatitis C virus-associated systemic vasculitis.
        Nephron. 2002; 91: 627-630
        • Fabrizi F.
        • Martin P.
        • Elli A.
        • et al.
        Hepatitis C virus infection and rituximab therapy after renal transplantation.
        Int J Artif Organs. 2007; 30: 445-449
        • Saadoun D.
        • Rosenzwajg M.
        • Joly F.
        • et al.
        Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis.
        N Engl J Med. 2011; 365: 2067-2077