Cryoglobulinemic Glomerulonephritis Franco Ferrario San Carlo Borromeo Hospital Milan, Italy

Case History: A 58 years old man reported since 1991 recurrent episodes of leg's purpura. April 1992 : paresis a "frigore" of facial nerve. October 1994: for the presence of fever, unresponsive to antibiotic therapy, diffuse edema and leg purpura he was admitted to our Nephrology Department. Exames : acute renal failure (S. Creatinine 1,2 → 3,5 mg/dl), hypoalbuminemia, nephrotic range proteinuria (5,5 gr/24 h) with microhematuria. Sonography: normal kidneys. First Renal Biopsy: Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Light Microscopy: the renal sample presented 7 glomeruli. No glomeruli showed global sclerosis . All glomeruli showed mild expansion of mesangial matrix, very intense hypercellularity due to mesangial cell proliferation and massive intracapillary infiltration of inflammatory cells (exudative lesion). Diffuse thickening of the glomerular basement membrane with diffuse and conspicuous double-contour appearance. Presence of intraluminal thrombi variable for size and diffusion, entirely filling the capillary lumen. They appeared amorphous, eosinophilic, PAS positive and Congo red negative. Monoclonal antibodies against leukocyte population demonstrated a prevalent and massive intracapillary infiltration of monocyte-macrophages (CD68 pos cells). Interstitium and vessels were normal. Immunofluorescence Microscopy: By Immunofluorescence an intense staining of intraluminal thrombi for IgG and IgM was present; only faint segmental staining of peripheral loops was present. Electron Microscopy: Electron Microscopy confirmed the presence of massive infiltration of monocyte-macrophages in close contact with subendothelial and intraluminal deposits. Moreover these deposits have a randomly arranged microtubular structure. Further exams: Reduced C3 and markedly reduced C4, RA test and Waaler Rose positive, rise of Hepatic indexes, ANA and Anti-DNA negative, ANCA negative. Antibody anti HCV and HCV-RNA positive; IgG-IgM/K Cryoglobulins with serum and urinary monoclonal component of IgM/K; Cryocrit 80%. Hepatic biopsy: active chronic hepatitis. Therapy: Interpheron α 3.000.000 UI (9 per week) Metilprednisolone pulses (1 gr x 3 days) + oral corticosteroid 0,5 mg/kg/d Oral Cyclophosphamide 2 mg/kg per 8 weeks Plasma exchange (classic treatment) After 3 months normal renal function (S. Creatinine 0,95 mg/dl), proteinuria 0,5 gr/24 h. After 6 months normal renal function, proteinuria 0,3 gr/24 h. Second Renal Biopsy: Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Light Microscopy: The renal sample presented 33 glomeruli. No glomeruli showed global sclerotic lesions. All glomeruli appeared a little enlarged without evident mesangial matrix expansion or mesangial cell proliferation. No intracapillary inflammatory cells were seen. Only few and segmental thickening of glomerular basement membrane without double-contour appearance. No intraluminal thrombi were present. Immunofluorescence Microscopy: By Immunofluorescence faint segmental parietal deposits of IgG and IgM were detected. Differential Hitological Diagnosis Waldenstrom's macroglobulinemia : characterized by intracapillary deposits frequently very huge strongly positive, by Immunofluorescence, for IgM. Usually there is not evident hypercellularity and the glomerular basement membranes are normal. Idiopathic Membranoproliferative glomerulonephritis: characterized by marked mesangial matrix expansion, mesangial cells proliferation and diffuse tickening of glomerular basement membrane with double-countour appearance. Intracapillary inflammatory cells infiltration, when present, is usually mild. By Immunofluorescence parietal deposits of C3 are prevalent on Electronic Microscopy never show structured deposits. Diffuse Lupus Nephritis : in few cases some intracapillary "thrombi" can be present such as intracapillary inflammatory cells. Wire loop aspect of capillary walls and "full house" pattern at Immunofluorescence are characteristic of this disease. By Electron Microscopy in rare cases is possible to find a structured deposits with a peculiar characteristic called "finger prints" (not randomly arranged). Henoch-Schonlein purpura: in some cases a morphological pattern of membranoproliferative lesion is present without evidence of tuft necrosis. The prevalent mesangio-parietal deposits of IgA is diagnostic of this disease. Thrombotic Microangiopathy (Thrombotic Thrombocytogenic purpura): characterized by the presence of thrombi predominantly in small-size arteries, arterioles and also glomerular capillaries. Mesangial cells proliferation is usually absent or very mild, endothelial edema and degeneration is very common and "double contour" appearance of basement membrane is usual. This newly formed sub-endothelial space is not occupied by Immunodeposits but is filled with fluffy materials. In severe cases collapse of the tuft with wrinkling of the capillary walls is common. Immunofluorescence is negative except for Fibrinogen positivity in vessels thrombosis. Cryoglobulinemic glomerulonephritis : typically characterized by membranoproliferative-exudative pattern, with massive intracapillary moncyte-macrophages accumulation, diffuse basement membrane tickening with "double contour" appearance and in many cases diffuse intracapillary "thrombi" strongly positive for IgG and IgM (Cryoglobulin precipitation). By electron microscopy frequent presence of structured deposit characterized by randonly arranged microtubular structures. Diagnosis: Morphological lesions of the biopsy case is highly suggestive of Cryoglobulinemic glomerulonephritis. Further exams: ANA, Anti-DNA, ANCA negative Hypo C3 and marked Ipo C4, Ra Test and Waaler-Rose positive; antibody anti HCV and HCV-RNA positive; IgG-IgM/K; Cryocrit 80%. These data confirmed a diagnosis of Cryoglobulinemic Glomerulonephritis. Therapy with Interpheron α, Metilprednisolone pulses, Cyclophosphamide and plasma exchange. The patient, after 6 months, was in complete clinical remission (S. Creatinine 0,95 mg/dl – Proteinuria 0,3 gr/24h). The second renal biopsy showed a quite complete resolution of histological and Immunohistological lesions. These data further confirme a diagnosi of Cryoglobulinemic Glomerulonephritis that usually present a very good renal follow-up with rare progression to End Stage Kidney. References: Ferrario F, Rastaldi MP. Henoch-Schonlein nephritis. J Nephrol. 2005 Nov-Dec;18(6):637-41. Ferrario F, Rastaldi MP. Histopathological atlas of renal diseases. Membranoproliferative glomerulonephritis. J Nephrol. 2004 Jul-Aug;17(4):483-6. 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