Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls, and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy.

Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is < 37°C, precipitate in a reversible manner in the serum, and re-dissolve after re-warming. The presence of either of polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type Ill) indentifies the mixed cryoglobulinemia (MC). The identification of the HCV infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. Nevertheless, the kidney represents the most common organ presentation and the presence of glomerulonephritis is a key element when considering prognosis. In this review, we discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.