Hepatitis C Virus, Cryoglobulinemia, and Kidney: Novel Evidence

Hindawi Publishing Corporation Scienti�ca Volume 2012, Article ID 128382, 11 pages http://dx.doi.org/10.6064/2012/128382 Review Article Hepatitis C Virus, Cryoglobulinemia, and Kidney: Novel Evidence Fabrizio Fabrizi Division of Nephrology and Dialysis, Maggiore Hospital and IRCCS Foundation, Pad. Croff, Via Commenda 15, 20122 Milano, Italy Correspondence should be addressed to Fabrizio Fabrizi; Received 11 June 2012; Accepted 26 June 2012 Academic Editors: I. Shoji and W. Vogel Copyright © 2012 Fabrizio Fabrizi. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hepatitis C virus infection can lead to chronic active hepatitis, cirrhosis, and liver failure; however, it is also associated with a wide range of extra-hepatic complications. HCV is associated with a large spectrum of histopathological lesions in both native and transplanted kidneys, and it is increasingly recognized as an instigator of B cell lympho-proliferative disorders including mixed cryoglobulinemia. Mixed cyoglobulinemia is a systemic vasculitis primarily mediated by immune complexes; it is characterized by variable organ involvement including skin lesions, chronic hepatitis, glomerulonephritis, peripheral neuropathy, and arthralgias. e most frequent HCV-associated nephropathy is type I membranoproliferative glomerulonephritis, usually in the context of type II mixed cryoglobulinemia. Various approaches have been tried for the treatment of HCV-related glomerulonephritis, including immunosuppressive therapy (corticosteroids and cytotoxic agents), plasma exchange and antiviral agents. Data on the antiviral treatment of HCV-associated glomerulonephritis are not abundant but encouraging results have been provided. Immunosuppressive therapy is particularly recommended for cryoglobulinemic kidney disease. Recent evidence has been accumulated on rituximab therapy for HCV-related cryoglobulinemic glomerulonephritis exists but several questions related to its use remain unclear. Distinct approaches should be considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis according to the level of proteinuria and kidney failure. 1. Introduction Cryoglobulinemia is a pathologic condition in which the blood contains immunoglobulins that have the property of reversible precipitation from human serum cooled to 4∘ C. e discovery in the human serum of proteins which reversibly precipitate in the cold was made in 1933 [1]. In 1947, Lerner and Watson found that these proteins were 𝛾𝛾-globulins and introduced the term cryoglobulins (cold precipitable serum globulins) [2]. A detailed nosographic placement to the cryoglobulinemic disease within the vast family of systemic vasculitis was made by Meltzer et al. who �rst described the clinical syndrome of essential mixed cryoglobulinemia (EMC), characterized by purpura, weakness, arthralgias, and, in some patients, organ involvement [3]. On the grounds of immunochemical studies, Brouet et al. identi�ed 3 types of cryoglobulins [4]. In type I, the cryoprecipitable immunoglobulin is a single monoclonal Ig. Types II and III cryoglobulinemias are both mixed types (MC), composed of at least two immunoglobulins. In both of them, a polyclonal immunoglobulin G (IgG) is bound to another Ig which is an antiglobulin and acts as a rheumatoid factor (RF). e main difference between two types of MCs is that in type II, the RF usually of the IgM class is monoclonal, whereas in type III, it is polyclonal. Both components of MCs, IgG, and IgM RF are necessary for precipitation in the cold, whereas the individual components do not have this property. Patients are considered to have a signi�cant cryoglobulin level when it is >0.05 g/L on two determinations. Some laboratories characterize cryoglobulinemia using immuno�xation or immunoelectrophoresis, and quantify the cryoglobulin level by determining the cryocrit, as the percentage of the total volume. e use of immunoblotting for immunochemical characterization is a sensitive and speci�c method allowing a full identi�cation in 98% [5]. When a cryoglobulin is suspected, serum should be kept warm, and tests should be carried out at 37∘ C. Serum cryoglobulins may also interfere with spurious quantitation of plasma proteins and erythrocyte sedimentation rate, pseudoleucocytosis, pseudothrombocytosis, or pseudomacrocytosis. Mixed cryoglobulinemia represent 60% to 75% of all cryoglobulinemias and are found in connective tissue diseases, infectious, or lymphoproliferative disorders, that is, secondary MC. Since the identi�cation of hepatitis C virus 2 Scienti�ca T 1: Extrahepatic manifestations of HCV infection. Source Kidney Skin Lung Joints yroid Bone marrow Nerves Muscles Glands Membranoproliferative GN, membranous nephropathy, focal segmental sclerosis, �brillary GN, immunotactoid nephropathy, IgA nephropathy, tubulointerstitial nephritis, thrombotic microangiopathy Purpura, ulcers; lichen planus; porphyria cutanea tarda Alveolitis; pulmonary �brosis Arthralgias; nonerosive arthritis Autoimmune thyroiditis; hypothyroidism; thyroid cancer Monoclonal gammopathies; B-cell lymphoma Peripheral neuropathy; mononeuritis Polymyositis Xerostomia; xeroalmia [6, 7], many authors have recognized it as the cause of 80% to 90% of MC [8, 9]. HCV is primarily associated with type II MC (which typically has an IgMk RF with antiidiotypic activity), and to a lesser extent, with type III MC [10–12]. In the absence of identi�ed etiologic factor (<5% of all MC), cryoglobulinemic vasculitis is de�ned as essential or idiopathic. is paper aims to describe, main characteristics of HCV-related cryoglobulinemia with a special focus on kidney involvement. 1.1. Epidemiology. Beside chronic liver disease, relevant extrahepatic manifestations of HCV include cryoglobulinemia, lymphoproliferative disorders, and renal diseases (Table 1). Several investigators have given evidence of the association between HCV and glomerular disease in both native [5] and transplanted kidneys [13–15]. A variety of kidney diseases have been associated with HCV. e kidney manifestations of HCV are uncommon, and the available information on their frequency is mostly based on small studies. El-Serag et al. [16] identi�ed 34,204 hospitalized male veterans with HCV (cases) in the US and 136,816 randomly selected patients without HCV (controls) between 1992 and 1999. A signi�cantly greater proportion of HCVinfected patients had porphyria cutanea tarda (0.77% versus 0.06%, P < 0.0001), vitiligo (0.17% versus 0.10%, P = 0.0002), lichen planus (0.30% versus 0.13%, P < 0.0001), and cryoglobulinemia (0.57% versus 0.05%, P < 0.0001). ere was a greater proportion of membranoproliferative glomeulonerphritis among patients with HCV (0.36% versus 0.05%, P < 0.0001), but not membranous glomerulopathy (0.33% versus 0. (...truncated)