Matignon Marie, Cacoub Patrice, Colombat Magali, Saadoun David, Brocheriou Isabelle, Mougenot Béatrice, Roudot-Thoraval Françoise, Vanhille Philippe, Moranne Olivier, Hachulla Eric, Hatron Pierre-Yves, Fermand Jean-Paul, Fakhouri Fadi, Ronco Pierre, Plaisier Emmanuelle, Grimbert Philippe
From Nephrology and Transplantation Department (MM, PG), Henri Mondor Hospital, AP-HP, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), and Paris XII University, Créteil; Internal Medicine Department (PC, DS), Pitié Salpêtrière Hospital, AP-HP, Paris, and CNRS UMR 7087, Université Pierre et Marie Curie, Paris VI; Pathology Department (MC, BM), Tenon Hospital, AP-HP, Paris; Pathology Department (IB), Pitié Salpêtrière Hospital, AP-HP, Paris; Public Health and Biostatistics Department (FRT), Henri Mondor Hospital, AP-HP and Paris XII University, Créteil; Nephrology Department (PV), Valenciennes Hospital, Valenciennes; Nephrology Unit (OM), Nice University Hospital, Nice; Internal Medicine Department (EH, PYH), CHRU, Lille; Hematology Department (JPF), Saint-Louis Hospital, AP-HP, Paris; Nephrology and Dialysis Department (FF), Necker Hospital, AP-HP, Paris; and Nephrology and Dialysis Department (PR, EP), Tenon Hospital, AP-HP, Paris, France.
Medicine (Baltimore). 2009 Nov;88(6):341-348. doi: 10.1097/MD.0b013e3181c1750f.
Hepatitis C virus (HCV) infection represents, by far, the major cause of mixed cryoglobulinemia (MC). The renal disease associated with this pathological condition is now well described. By contrast, renal involvement in patients with MC not associated with HCV has been only poorly described, and few cases have been reported. We analyzed the demographic, clinical, and laboratory features and outcome in patients presenting with renal disease associated with MC not related to HCV infection. Records of 20 patients with MC and renal disease, with no evidence of HCV by serology and polymerase chain reaction analysis, were retrospectively analyzed. Renal biopsies and extensive searches for lymphoproliferative disorder were performed in all patients at presentation. MC was related to primary Sjögren Syndrome (pSS) in 9 patients, and to non-Hodgkin lymphoma in 1 patient, while MC was classified as essential in the remaining 10 cases. Renal involvement was characterized by microscopic hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% of patients (mean glomerular filtration rate, 46 mL/min per 1.73 m). Membranoproliferative glomerulonephritis with subendothelial deposits was observed in all kidney specimens. Skin vasculitis was the main extrarenal manifestation. In all patients, cryoglobulinemia was classified as type II MC, characterized by monoclonal IgMkappa and polyclonal IgG. Most patients (17/20) were treated with steroids or immunosuppressive agents, or both. Initial renal remission was observed in 94% of patients. However, renal relapse occurred in most patients, with 10% reaching end-stage renal disease. Three patients with essential MC developed B-cell lymphoma 36-48 months after the diagnosis of MC. Unexpectedly, B-cell lymphoma induced by Epstein-Barr virus infection occurred in only 1 of the 9 pSS patients. Forty percent of patients died as a result of extrarenal causes.Renal disease associated with MC unrelated to HCV is characterized by the high prevalence of pSS (45%), the finding of CD20+ B-lymphocyte nodular infiltrates in the kidney interstitium, and a high incidence of overt B-cell lymphoma during follow-up. These findings emphasize the need for repetitive clinical evaluation in those patients.
迄今为止，丙型肝炎病毒（HCV）感染是混合性冷球蛋白血症（MC）的主要病因。与这种病理状况相关的肾脏疾病现已得到充分描述。相比之下，与HCV无关的MC患者的肾脏受累情况描述甚少，仅有少数病例报道。我们分析了与非HCV感染相关的MC伴发肾脏疾病患者的人口统计学、临床和实验室特征及预后。对20例MC伴肾脏疾病且血清学和聚合酶链反应分析均无HCV证据的患者记录进行了回顾性分析。所有患者就诊时均进行了肾活检并广泛排查淋巴增殖性疾病。9例患者的MC与原发性干燥综合征（pSS）相关，1例与非霍奇金淋巴瘤相关，其余10例MC被归类为特发性。肾脏受累的特征为所有患者均有镜下血尿，75%的患者有肾病范围蛋白尿，80%的患者有高血压，85%的患者有肾衰竭（平均肾小球滤过率为46 mL/min/1.73 m²）。所有肾脏标本均观察到伴有内皮下沉积物的膜增生性肾小球肾炎。皮肤血管炎是主要的肾外表现。所有患者的冷球蛋白血症均被归类为II型MC，其特征为单克隆IgMκ和多克隆IgG。大多数患者（17/20）接受了类固醇或免疫抑制剂治疗，或两者兼用。94%的患者出现初始肾脏缓解。然而，大多数患者出现肾脏复发，10%的患者发展至终末期肾病。3例特发性MC患者在MC诊断后36 - 48个月发生B细胞淋巴瘤。出乎意料的是，9例pSS患者中只有1例发生了由爱泼斯坦 - 巴尔病毒感染诱导的B细胞淋巴瘤。40%的患者死于肾外原因。与非HCV相关的MC伴发的肾脏疾病的特征为pSS患病率高（45%），在肾间质中发现CD20 + B淋巴细胞结节状浸润，以及随访期间明显的B细胞淋巴瘤发病率高。这些发现强调了对这些患者进行重复临床评估的必要性。
