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      Daclatasvir/asunaprevir based direct-acting antiviral therapy ameliorate hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis: a case report

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          Abstract

          Background

          Direct-acting antivirals (DAAs) dramatically improve the treatment of hepatitis C virus (HCV) infections. However, the effects of DAAs on extra-hepatic manifestations such as HCV-associated glomerulonephritis, especially in cases with renal dysfunction, are not well elucidated.

          Case presentation

          A 69-year-old Japanese woman was diagnosed as having chronic hepatitis C, genotype 1b at the age of 55. She presented with hypertension, microscopic hematuria, proteinuria, renal dysfunction, purpura, and arthralgia at the age of 61. She also had hypocomplementemia and cryoglobulinemia. Renal biopsy revealed membranoproliferative glomerulonephritis (MPGN), and she was diagnosed as having HCV-associated cryoglobulinemic MPGN. She declined interferon therapy at the time and was treated with antihypertensive medications as well as oral corticosteroid that were effective in reducing proteinuria. However, when the corticosteroid dose was reduced, proteinuria worsened. She began antiviral treatment with daclatasvir/asunaprevir (DCV/ASV). Clearance of HCV-RNA was obtained by 2 weeks and sustained, and liver function was normalized. In addition, microhematuria turned negative, proteinuria decreased, hypocomplementemia and estimated glomerular filtration rate were improved, whereas cryoglobulinemia persisted. She completed 24 weeks of therapy without significant adverse effects.

          Conclusion

          In a case of HCV-associated cryoglobulinemic MPGN with renal dysfunction, DCV/ASV -based DAAs ameliorated microhematuria, proteinuria and renal function without significant side effects.

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          Most cited references11

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          Daclatasvir Plus Asunaprevir for Chronic HCV Genotype 1b Infection

          Hiromitsu Kumada, Yoshiyuki Suzuki, Kenji Ikeda … (2014)
          All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24). This study is registered with http://ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia. Conclusion: Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083–2091)
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            Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.

            David Gretch, H Yamabe, L Corey … (1993)
            Hepatitis C virus (HCV) infection causes both acute and chronic liver disease and is also associated with mixed cryoglobulinemia. Whether HCV is also associated with renal disease, as is the hepatitis B virus, is not known. We describe the clinical, pathologic, virologic, and immunologic features of eight patients with HCV infection who were referred to nephrologists for glomerulonephritis. Four patients were treated with interferon alfa. All eight patients had proteinuria, and seven had decreased renal function. Renal biopsy in all patients revealed membranoproliferative glomerulonephritis, characterized by the deposition of IgG, IgM, and C3 in glomeruli. Electron microscopy of the biopsy specimens showed cryoglobulin-like structures in three of four patients. All eight patients had HCV RNA detected in their serum, elevated serum aminotransferase concentrations, and hypocomplementemia, and the majority had cryoglobulins and circulating immune complexes in their serum. Cryoprecipitates from the three patients who were tested contained HCV RNA and IgG anti-HCV antibodies to the nucleocapsid core antigen (HCVc or c22-3). IgM rheumatoid factors, present in all patients, bound anti-HCV IgG in all six patients tested. Four patients received interferon alfa for 2 to 12 months; all had evidence of decreased HCV replication and improvement of their renal and liver disease. Chronic HCV infection is associated with cryoglobulinemia and membranoproliferative glomerulonephritis. The pathogenesis is unknown, but may relate to deposition within glomeruli of immune complexes containing HCV, anti-HCV IgG, and IgM rheumatoid factors.
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              Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents.

              Meghan E. Sise, Allyson Bloom, Jessica Wisocky … (2016)
              Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events.
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                Author and article information

                Contributors
                Michiko Shimada:
                ORCID: http://orcid.org/0000-0003-2278-6078
                81-172-39-5056 , mshimada@hirosaki-u.ac.jp
                Norio Nakamura: nnakamur@r2.dion.ne.jp
                Tetsu Endo: endo16@hirosaki-u.ac.jp
                Hideaki Yamabe: h-yamabe@lapis.plala.or.jp
                Masayuki Nakamura: msyknkmr@hirosaki-u.ac.jp
                Reiichi Murakami: murakami.01@live.jp
                Ikuyo Narita: iku621@yahoo.co.jp
                Hirofumi Tomita: tomitah@hirosaki-u.ac.jp
                Journal
                Journal ID (nlm-ta): BMC Nephrol
                Journal ID (iso-abbrev): BMC Nephrol
                Title: BMC Nephrology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2369
                Publication date (Electronic): 29 March 2017
                Publication date PMC-release: 29 March 2017
                Publication date Collection: 2017
                Volume: 18
                Electronic Location Identifier: 109
                Affiliations
                [1 ]ISNI 0000 0001 0673 6172, GRID grid.257016.7, Department of Cardiology and Nephrology, , Hirosaki University Graduate School of Medicine, ; 5 Zaifu-cho, Hirosaki, Japan 036-8562
                [2 ]ISNI 0000 0001 0673 6172, GRID grid.257016.7, Community Medicine, , Hirosaki University Graduate School of Medicine, ; Hirosaki, Japan
                [3 ]ISNI 0000 0001 0673 6172, GRID grid.257016.7, Department of Gastroenterology and Hematology, , Hirosaki University Graduate School of Medicine, ; Hirosaki, Japan
                Author information
                http://orcid.org/0000-0003-2278-6078
                Article
                Publisher ID: 534
                DOI: 10.1186/s12882-017-0534-5
                PMC ID: 5372252
                SO-VID: 07fd9c2d-3080-4065-99bf-1bfcbe990bf4
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 17 April 2016
                Date accepted : 24 March 2017
                Categories
                Subject: Case Report
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Nephrology
                Keywords: membranoproliferative glomerulonephritis,cryoglobulinemia,hcv-associated glomerulonephritis,direct-acting antivirals
                Data availability:
                ScienceOpen disciplines: Nephrology
                Keywords: membranoproliferative glomerulonephritis, cryoglobulinemia, hcv-associated glomerulonephritis, direct-acting antivirals

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