Complement System and C4d expression in cases of Membranous nephropathy

Abstract Introduction: Membranous nephropathy (MN) is one of the major causes of nephrotic syndrome. The complement system plays a key role in the pathophysiology of MN. Objectives: To identify the complement pathway possibly activated in MN cases and correlate the presence of C4d with more severe clinical and histological markers. Methods: Sixty nine cases from renal biopsy with membranous nephropathy were investigated. The presence of C1q was analyzed by direct immunofluorescence; and expression of C4d by immunohistochemistry. Clinical and epidemiological data were obtained upon biopsy request. Results: The presence of focal segmental glomerulosclerosis, global glomerulosclerosis, vascular lesions and tubulointerstitial fibrosis were collected by anatomopathological report. C4d(+) was found in 58 (84%), and C1q(+) was found in 12 (17%) of the cases. Twelve patients had C4d(+)/C1q(+), 46 had C4d(+)/C1q(-), and 11 patients had C4d(-)/C1q(-), probably indicating the activation of the classical, lectin and alternative pathways, respectively. Conclusion: C4d was associated with increased interstitial fibrosis, but not with clinical markers of poor prognosis. Through the deposition of C4d and C1q we demonstrated that all complement pathways may be involved in MN, highlighting the lectin pathway. The presence of C4d has been associated with severe tubulointerstitial lesions, but not with clinical markers, or can be taken as a universal marker of all cases of MN.摘要：膜性肾病（membranous nephropathy, MN）是肾病综合征的主要致病原因之一，补体系统在膜性肾病的病理生理机制中发挥核心作用。 研究目的：明确膜性肾病患者中可能激活的补体通路，并分析C4d的表达与更严重的临床及组织学指标的相关性。 研究方法：纳入69例经肾活检确诊的膜性肾病患者进行研究。采用直接免疫荧光法（direct immunofluorescence）检测C1q的表达，免疫组化法（immunohistochemistry）检测C4d的表达；临床及流行病学数据来源于肾活检申请资料。 研究结果：通过病理解剖报告收集了局灶节段性肾小球硬化、球性硬化、血管病变及肾小管间质纤维化的相关数据。本研究中，58例（84%）患者检测为C4d阳性，12例（17%）为C1q阳性；其中12例患者为C4d(+)/C1q(+)，46例为C4d(+)/C1q(-)，11例为C4d(-)/C1q(-)，该结果分别提示经典补体通路、凝集素通路及替代补体通路的激活。 研究结论：C4d的表达与间质纤维化程度加重相关，但与不良预后的临床指标无显著关联。通过检测C4d与C1q的沉积情况，本研究证实所有补体通路均可能参与膜性肾病的发病过程，其中凝集素通路的作用尤为突出。C4d的表达与严重的肾小管间质病变相关，但与临床预后指标无关，或可作为所有膜性肾病病例的通用标志物。