HCV-negative mixed cryoglobulinemia and kidney involvement: in-depth review on physiopathological and histological bases

Type II mixed cryoglobulinemia without evidence of HCV infection but rather with renal involvement has been occasionally described. The pathogenesis of cryoglobulinemic kidney disease is most likely related to immune complex deposition including cryoglobulins, and cryoaggregation after cold exposure could play a pivotal role in clinical expression of cryoglobulinemia. In these cases, acute kidney injury and proteinuria remain the most frequent clinical expression of a cryoglobulinemic glomerulonephritis. Type II cryoglobulinemia with the laboratory finding of both monoclonal and polyclonal cryoglobulins is the most prevalent bio-humoral pattern among HCV-negative phenotypes with renal involvement, while type III cryoglobulinemia with polyclonal Ig is rare. Histological data in renal biopsies support the hypothesis that regardless of the HCV status cryoglobulinemia vasculitis share the same frequent pathological finding of membranoproliferative glomerulonephritides, but other histological patterns have also been observed in a minority of cases. In HCV-negative mixed cryoglobulinaemia, the paraneoplastic origin of the immune dysfunction should be ruled out and sporadic cases have been reported, while there is no cumulative evidence on the prevalence of these tumour-associated manifestations. Moving from the classification criteria and the etiopathogenesis of mixed cryoglobulinaemia, we provide a comprehensive review of the literature on the appearance of the disease with kidney injury in association with malignancies or autoimmune disorders without HCV coexistence.