Villa Annalisa, Gigante Antonietta, Pellicano Chiara, Radovic Klara, Giannakakis Konstantinos, Casato Milvia, Visentini Marcella
Department of Transitional and Precision Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
J Clin Med. 2025 Jun 19;14(12):4369. doi: 10.3390/jcm14124369.
Cryoglobulinemia is a rare disorder characterized by the presence of abnormal proteins (cryoglobulins) in the blood that precipitate at low temperatures. It presents with a wide clinical spectrum, from mild symptoms to severe, life-threatening disease. In mixed cryoglobulinemia (MC), vascular damage results from immune complexes-typically monoclonal IgM with rheumatoid factor activity and polyclonal IgG (Type II), or polyclonal/oligoclonal IgM and IgG (Type III). These complexes can obstruct small blood vessels, leading to ischemia and leukocytoclastic vasculitis. Renal involvement occurs in about 30% of MC patients and it is a manifestation with poor prognosis. Nowadays, types II and III MC are the most common forms, often linked to autoimmune diseases like Sjögren's syndrome and systemic lupus erythematosus, or to viral infections such as hepatitis B or persisting despite hepatitis C eradication. This review explores renal involvement in MC, offering a comprehensive perspective on current knowledge, including recent advances in pathophysiological understanding, evolving diagnostic strategies, and novel therapeutic approaches. In this context, "perspectives" refers to the growing recognition of the shifting epidemiology of MC-particularly the changing etiological landscape following hepatitis C virus eradication-as well as the integration of emerging clinical and pathological entities such as cryofibrinogenemia and monoclonal gammopathy of renal significance into diagnostic and management frameworks. Furthermore, the review highlights current therapeutic strategies recognized as most effective, emphasizing the importance of a multidisciplinary and multimodal approach that combines etiological treatment, B-cell-targeted therapy (notably rituximab), plasma exchange in selected cases, and comprehensive supportive care for renal and systemic complications. Moreover, the landscape of management could be enriched in future years, since clinical trials are ongoing to explore novel therapies for refractory or relapsing cases of MC with renal involvement.
冷球蛋白血症是一种罕见的疾病，其特征是血液中存在在低温下会沉淀的异常蛋白质（冷球蛋白）。它具有广泛的临床谱，从轻微症状到严重的、危及生命的疾病。在混合性冷球蛋白血症（MC）中，血管损伤是由免疫复合物引起的——典型情况是具有类风湿因子活性的单克隆IgM和多克隆IgG（II型），或多克隆/寡克隆IgM和IgG（III型）。这些复合物会阻塞小血管，导致局部缺血和白细胞破碎性血管炎。约30%的MC患者会出现肾脏受累，这是一种预后不良的表现。如今，II型和III型MC是最常见的形式，通常与自身免疫性疾病如干燥综合征和系统性红斑狼疮有关，或与病毒感染如乙型肝炎有关，或在丙型肝炎根除后仍持续存在。本综述探讨了MC中的肾脏受累情况，对当前知识提供了全面的视角，包括病理生理理解的最新进展、不断发展的诊断策略和新的治疗方法。在这种背景下，“视角”指的是对MC流行病学变化的日益认识——特别是丙型肝炎病毒根除后病因格局的变化——以及将新兴的临床和病理实体如冷纤维蛋白原血症和具有肾脏意义的单克隆丙种球蛋白病纳入诊断和管理框架。此外，该综述强调了目前被认为最有效的治疗策略，强调了多学科和多模式方法的重要性，这种方法结合了病因治疗、B细胞靶向治疗（特别是利妥昔单抗）、在特定病例中进行血浆置换以及对肾脏和全身并发症的全面支持治疗。此外，由于正在进行临床试验以探索针对伴有肾脏受累的难治性或复发性MC病例的新疗法，未来几年管理格局可能会更加丰富。
