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      Membranoproliferative Glomerulonephritis Type I, Mixed Cryoglobulinemia and Lymphoma in the Absence of Hepatitis C Infection

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          Chronic hepatitis C virus infection has been linked to cryoglobulinemia, membranoproliferative glomerulonephritis, and malignant B-cell lymphoproliferation, suggesting a possible pathogenetic link between these disorders. We report a patient with the latter clinical triad in the absence of hepatitis C infection. We postulate that the persistent and dysregulated immunologic activity associated with chronic antigen stimulation, inflammation and/or B-cell malignancy induces nephritogenic autoantibodies, including cryoglobulins, that produce a similar clinical syndrome in genetically susceptible individuals.

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          Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.

          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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            Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy.

            Several authors have reported on the effectiveness of alpha-interferon (IFN-alpha) in the treatment of patients with mixed cryoglobulinemia. This prompted the authors to investigate the long term effects of this drug on clinical, hematologic, and virologic parameters in a group of 20 patients (13 women and 7 men) affected by mixed cryoglobulinemia. In all patients, bone marrow biopsy, phenotyping of marrow cells, and polymerase chain reaction (PCR) immunoglobulin gene rearrangement in peripheral blood lymphocytes were performed before therapy and at the end of the follow-up. A liver biopsy was obtained in patients with biochemical signs of chronic liver disease. The presence of hepatitis C virus (HCV) RNA in serum was assessed by detection of anti-HCV antibodies, and by PCR amplification of the 5' untranslated region of HCV. The HCV genotype was also determined by PCR amplification of the core region of the virus with type-specific primers. The treatment schedule followed by all patients was 3 million units of recombinant IFN-alpha 2b 3 times weekly for 1 year. In 6 patients, the marrow histology before therapy showed a massive (more than 50%) monomorphous infiltration by plasmacytoid lymphocytes, indicating the presence of low grade non-Hodgkin's lymphoma. Anti-HCV antibodies were present in 19 (95%) subjects, and HCV-RNA was detectable in all patients. In addition, all patients affected by Type II mixed cryoglobulinemia showed a monoclonal B-cell expansion in peripheral blood mononuclear cells (PBMC). With therapy, 5 patients (25%) achieved a complete response and 11 patients (55%) a partial response, whereas minor responses were observed in the remaining 4 patients (20%). One of the complete responders and all patients showing partial responses relapsed a few months after therapy withdrawal. At the end of the follow-up, four patients had obtained a complete remission. Bone marrow examination showed that B-lymphocytic monoclonal infiltrate disappeared in three patients. Moreover, these three patients had become negative for B-cell expansion in PBMC. Lack of response, or relapse, was associated with the presence of Type II HCV. HCV may be the cause of mixed cryoglobulinemia. The disease is associated with a high prevalence of bone marrow B-cell lymphomas. IFN-alpha appears to be an effective agent for the treatment of mixed cryoglobulinemia. It also seems able to determine regression of the lymphoproliferative disorder. The HCV genotype appears to be the most important predictive factor for the response to antiviral therapy.
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              Renal pathologic findings associated with monoclonal gammopathies.

              The myeloma kidney is characterized by casts in the distal and collecting tubules. The glomeruli are hardly affected unless amyloidosis is present. When the glomeruli are involved, the proteinuria is nonselective and, in some cases, the whole paraprotein is excreted in the urine. Nephrocalcinosis may be present and focal myeloma cell infiltration in the interstitium is a characteristic, but inconstant, finding. The nephrotic syndrome is extremely rare; if it exists, amyloidosis should be suspected. In contrast to multiple myeloma, the glomeruli are frequently involved in macroglobulinemia of Waldenstrom. Hyaline intracapillary deposits consisting of pure IgM are a characteristic finding as is infiltration of the kidney with lymphoid cells. No characteristic lesion of the kidney has been described in the heavy-chain diseases. Mixed cryoglobulinemia associated with an IgM paraprotein can produce glomerulonephritis that is due to the deposition in the glomeruli of an immune complex consisting of IgG, IgM, and complement.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 1999
                26 November 1999
                : 19
                : 5
                : 599-604
                aPENN Kidney Center and Renal-Electrolyte and Hypertension Division, Department of Medicine, and bDepartment of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
                13527 Am J Nephrol 1999;19:599–604
                © 1999 S. Karger AG, Basel

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                Figures: 4, References: 36, Pages: 6
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