Type II mixed cryoglobulinaemia, hepatitis C virus infection, and glomerulonephritis

Mixed cryoglobulins (MC) are immunoglobulins which precipitate reversibly in the cold. Type II mixed cryoglobulins are composed of a monoclonal component (usually IgMk) with rheumatoid factor (RF) activity against polyclonal IgG. In type III MC, all the components are polyclonal. The majority of MC are secondary to connective tissue diseases, infectious or lymphoproliferative disorders, hepatobiliary diseases, or immunologically mediated glomerular diseases. The aetiology of MC is not clear and cryoglobulinaemia was considered 'essential' until an association between hepatitis C virus (HCV) infection and MC was recognized. The renal pattern includes typical glomerular lesions characterized by a particular glomerular monocyte infiltration, double-contoured appearance of the glomerular basement membrane (GBM) and by the presence of intraluminal 'hyaline thrombi' due to deposition of circulating cryoglobulins. The progression of renal disease is variable: in one-third of patients remission of renal symptoms occurs, 20% of patients experienced nephritic or nephrotic flare-ups during the course of the disease. Uraemia is observed in only 10% of patients 10 years after renal disease onset, but 50% of patients had already died from cardiovascular disease, infectious liver failure, or neoplasia during those 10 years. This review analyses the pathogenic mechanisms of MC and associated GN, with particular attention to the role of HCV infection. HCV RNA is detected in most patients with MC. HCV, by infecting B cells, could trigger abnormal production of polyclonal RF in type III MC and, together with other factors, a clone selection of B cells to produce monoclonal IgMk RF in type II MC. The presence of IgMk in serum appears essential for glomerular damage to occur. Cryoglobulinaemic GN might be initiated by IgG antibody-HCV complexes binding to IgMk RF, either in situ or in circulation, nephrotoxicity being due to a particular affinity of the IgMk RF for cellular fibronectin present in the mesangial matrix. Glomerular damage can be perpetuated by the reduced effectiveness of monocytes to remove cryoglobulins.