Cryofibrinogen-associated glomerulonephritis with paraproteinemia

Xuanli Tang¹Mengya Jiang¹Huaqin Zhang¹Peng Bi¹Jun Wang¹Tian Ye¹Jie Zheng¹Mengli Tong¹Xingyu Zhu¹Xiaotao Hou²Shuhua Bao¹Yi Lin¹Xue Jiang¹Hongyu Chen¹Feng Wan^1*Haichun Yang³

• ¹Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, China
• ²King Medical Diagnostics Center, Guangzhou, China
• ³Vanderbilt University Medical Center, Nashville, Tennessee, United States

Introduction: Cryofibrinogen-associated glomerulonephritis (CF-GN) is a rare disease that lacks comprehensive research and requires further investigation to improve our understanding of its pathophysiology.Methods: Based on the morphological findings from a kidney biopsy and blood tests, an elderly patient was diagnosed with CF-GN. Biological materials obtained from peripheral blood were utilized to treat cultured mesangial cells and mice.The patient presented with nephrotic syndrome and chronic kidney failure. The biopsy revealed a membranoproliferative glomerulonephritis pattern with distinct substructures and positive fibrinogen staining. Cryofibrinogen was detectable under cold conditions, and monoclonal immunoglobulin (MIg) was exclusively identified within cryoprecipitates. Genetic analysis uncovered an intronic mutation. The patient partially responded to immunosuppressive therapy, but later relapsed with paraproteinemia, and the MIg was detected to have cryoactivity. To investigate the pathophysiology of CF-GN further, its cryoactivity was detected when mixing the serum (with or without MIg) with healthy control plasma. When exposed to the patient's cryoprecipitates, cultured mesangial cells showed significant proliferation, phagocytosis of fibrinogen, and lysosomal degeneration. Injection of these cryoprecipitates into mice induced proliferative glomerulonephritis and other organ damage.This study provides valuable insights into the diagnosis, treatment, and pathophysiology of CF-GN with paraproteinemia. The identification of the complex of cryofibrinogen and MIg as a potential mechanism of glomerular damage shed light on the pathogenesis of this rare disease.