CRYOGLOBULINEMIC GLOMERULONEPHRITIS - A MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS INDUCED BY HEPATITIS-C VIRUS

Mixed cryoglobulins (MCs) are proteins that precipitate from cooled se rum, and are composed of a polyclonal immunoglobulin G (IgG) bound to another immunoglobulin that acts as an anti-IgG rheumatoid factor (RF) . In type II mixed cryoglobulinemia, the antiglobulin component, usual ly of the IgM class, is monoclonal; it is polyclonal in type III mixed cryoglobulinemia. The majority of MCs are found in patients with conn ective tissue diseases, infectious or lymphoproliferative disorders, h epatobiliary diseases, or immunologically mediated glomerular diseases (secondary MCs), The etiology is not clear for 30% of all MCs, and th is type of cryoglobulinemia is called ''essential.'' There is a common clinical syndrome in types II and III essential mixed cryoglobulinemi a (EMC) characterized by purpura, weakness, and arthralgia, In type II EMC only, in which an IgMk is the monoclonal RF, a membranoproliferat ive glomerulonephritis (MPGN) occurs with some peculiar morphologic an d clinical features; this is termed ''cryoglobulinemic GN.'' Glomerulo nephritis can be differentiated from idiopathic MPGN, especially in th e acute stage, which is characterized by an acute nephritic syndrome, by the following findings: (1) the presence of large deposits filling the capillary lumen that sometimes are shown to have a characteristic fibrillar or crystalloid structure by electron microscopy; (2) the ext ent of the exudative component consequent to the frequently massive in filtration of monocytes; (3) a more diffuse and evident thickening of the glomerular basement membrane, which has a double-contoured appeara nce that is mainly due to the peripheral interposition of monocytes, w ith less evident mesangial expansion; and (4) possibly some vasculitis in small and medium-sized renal arteries without concomitant features of segmental necrotizing GN or crescentic GN, The proposed pathogenet ic mechanisms for EMC and for the renal damage that occurs in type II EMC are analyzed in this review, with special emphasis on the role of hepatitis C virus (HCV) infection, Hepatitis C virus antibodies and HC V RNA (indicating active viral infection) are detected in the majority of cases with essential and secondary MCs, it has been suggested that by infecting the B cells the virus may trigger abnormal production of the polyclonal RF component of the cryoglobulins in type III MCs and, in association with some other unidentified factors, may induce abnor mal proliferation of a special clone that produces the monoclonal RF c omponent in type II MCs, Cryoglobulinemic MPGN occurs only when this m onoclonal RF (usually an IgMk) is produced as a consequence of the HCV infection. The presence in the serum of an IgMk RF with specific, as yet unknown characteristics seems to be essential for the development of the glomerular damage associated with HCV infection, although the p ossibility that HCV can induce an immune complex-mediated MPGN indepen dently of the induction of type II MCs (as hepatitis B virus does) can not be ruled out. Cryoglobulinemic GN might be initiated by a binding either in situ or in the circulation of IgG antibodies-HCV complexes t o IgMk RF, the nephrotoxicity being due to a particular affinity of th e IgMk RF for the glomerular matrix, The potential role of interferon- alpha in the treatment of mixed cryoglobulinemia associated with HCV a nd of cryoglobulinemic GN is emphasized. (C) 1995 by the National Kidn ey Foundation, Inc.