补体C3与原发性膜性肾病患者尿蛋白水平及蛋白尿缓解情况的相关性

Association of complement C3 with urine protein level and proteinuria remission status in patients with primary membranous nephropathy

目的:探究补体C3与原发性膜性肾病患者尿蛋白水平及蛋白尿缓解情况的相关性,以期更好地指导临床个体化治疗。方法:该研究为单中心回顾性研究。收集2017年1月至2022年6月南京医科大学第一附属医院行肾活检的原发性膜性肾病患者的临床资料。对24 h尿蛋白量≥3.5 g且接受标准治疗患者出院后随访,以最后1次门诊或住院复查作为随访终点。收集24 h尿蛋白量,评估蛋白尿缓解情况。Kaplan-Meier法分析血清及肾组织补体与蛋白质缓解的相关性。Cox回归分析法分析血清C3水平及肾组织C3沉积情况与蛋白尿缓解的相关性。结果:该研究纳入507例原发性膜性肾病患者,年龄54(43,64)岁,男性312例(61.54%)。与24 h尿蛋白量<3.5 g组相比,24 h尿蛋白量≥3.5 g组男性比例(χ^(2)=22.479,P<0.001)、年龄(Z=-2.521,P=0.012)、收缩压(Z=-4.148,P<0.001)、舒张压(Z=-4.084,P<0.001)、血清磷脂酶A2受体抗体滴度(Z=-7.019,P<0.001)、总胆固醇(Z=-8.796,P<0.001)、三酰甘油(Z=-6.158,P<0.001)、低密度脂蛋白胆固醇(Z=-8.716,P<0.001)、血清肌酐(Z=-7.368,P<0.001)、血清C3(Z=-3.663,P<0.001)、血清C4(Z=-6.560,P<0.001)、使用糖皮质激素比例(χ^(2)=116.417,P<0.001)和使用免疫抑制剂比例(χ^(2)=53.839,P<0.001)均较高,而血清白蛋白(Z=12.518,P<0.001)、eGFR(Z=6.345,P<0.001)和血IgG(Z=7.321,P<0.001)均较低。在268例随访队列中,基线24 h尿蛋白量为7.15(5.14,10.24)g,血清磷脂酶A2受体抗体滴度为61.44(14.35,193.24)RU;ml,血清C3为1.005(0.864,1.150)g;L,血清C4为0.260(0.214,0.317)g;L。Kaplan-Meier生存曲线结果显示,血清C3>1.005 g;L组蛋白尿未完全缓解率低于血清C3≤1.005 g;L组(Log-rankχ^(2)=4.757,P=0.029),而血清C4≤0.260 g;L组和血清C4>0.260 g;L组蛋白尿未完全缓解率的差异无统计学意义(Log-rankχ^(2)=3.543,P=0.060)。肾组织C1q(Log-rankχ^(2)=0.167,P=0.683)、C4(Log-rankχ^(2)=1.927,P=0.165)沉积对膜性肾病患者蛋白尿缓解情况无明显影响,而肾组织有C3沉积患者蛋白尿未完全缓解率高于无C3沉积患者(Log-rankχ^(2)=7.018,P=0.008)。单因素Cox回归分析结果显示,血清C3水平及肾组织C3沉积是蛋白尿未完全缓解的影响因素(均P<0.05),而在校正性别、年龄、平均动脉压、血清磷脂酶A2受体抗体、血清白蛋白、24 h尿蛋白量等因素后,血清C3≤1.005 g;L(HR=1.374,95%CI 1.021~1.849,P=0.036)、肾组织C3沉积(HR=1.949,95%CI 1.098~3.460,P=0.023)、血清C3≤1.005 g;L且伴肾组织C3沉积是蛋白尿未完全缓解的独立影响因素(HR=1.472,95%CI 1.093~1.983,P=0.011)。结论:血清C3水平及肾组织C3沉积与原发性膜性肾病患者尿蛋白水平及蛋白尿缓解情况密切相关。尿蛋白水平较高患者血清C3水平较高;而对于大量蛋白尿者,血清C3≤1.005 g;L、肾组织C3沉积及血清C3≤1.005 g;L且伴肾组织C3沉积是蛋白尿未完全缓解的独立危险因素。

Objective To investigate the correlation between complement C3 and urine protein level and proteinuria remission status in patients with primary membranous nephropathy(PMN),and better guide individualized clinical treatment.Methods It was a single-center retrospective study.The clinical data of PMN patients who underwent renal biopsy in the First Affiliated Hospital of Nanjing Medical University from January 2017 to June 2022 were collected.Patients with 24 h urinary protein≥3.5 g were followed up after receiving standard treatment,and the last outpatient or inpatient review was used as the end point of follow-up.24 h urine protein was collected to evaluate the remission status of proteinuria.Kaplan-Meier method was used to analyze the correlation between serum and renal complements and proteinuria remission.Cox regression analysis method was used to analyze the correlation between serum C3 level and renal tissue C3 deposition and proteinuria remission.Results This study included 507 PMN patients with 312(61.54%)males,aged 54(43,64)years old.Compared with 24 h urinary protein<3.5 g group,proportion of males(χ^(2)=22.479,P<0.001),age(Z=-2.521,P=0.012),systolic blood pressure(Z=-4.148,P<0.001),diastolic blood pressure(Z=-4.084,P<0.001),serum anti-phospholipase A2 receptor(PLA2R)antibody titer(Z=-7.019,P<0.001),total cholesterol(Z=-8.796,P<0.001),triglyceride(Z=-6.158,P<0.001),low density lipoprotein cholesterol(Z=-8.716,P<0.001),serum creatinine(Z=-7.368,P<0.001),serum C3(Z=-3.663,P<0.001),serum C4(Z=-6.560,P<0.001),proportion of glucocorticoid use(χ^(2)=116.417,P<0.001)and proportion of immunosuppressant use(χ^(2)=53.839,P<0.001)were all higher,while serum albumin(Z=12.518,P<0.001),estimated glomerular filtration rate(Z=6.345,P<0.001)and serum IgG(Z=7.321,P<0.001)were all lower in 24 h urinary protein≥3.5 g group.There were 268 patients included in the follow-up cohort with baseline 24 h urinary protein of 7.15(5.14,10.24)g,serum anti-PLA2R antibody titer of 61.44(14.35,193.24)RU;ml,serum C3 of 1.005(0.864,1.150)g;L,and serum C4 of 0.260(0.214,0.317)g;L.Kaplan-Meier survival curve showed that the incomplete remission rate of proteinuria in serum C3>1.005 g;L group was lower than that in serum C3≤1.005 g;L group(log-rankχ^(2)=4.757,P=0.029).There was no significant difference in the incomplete remission rate of proteinuria between serum C4≤0.260 g;L group and serum C4>0.260 g;L group(log-rankχ^(2)=3.543,P=0.060).Renal C1q(log-rankχ^(2)=0.167,P=0.683)and C4(log-rankχ^(2)=1.927,P=0.165)deposition had no significant effects on proteinuria remission in PMN patients.The incomplete remission rate of proteinuria in patients with renal C3 deposition was higher than that in patients without renal C3 deposition(log-rankχ^(2)=7.018,P=0.008).Univariate Cox regression analysis showed that serum C3 level and C3 deposition in renal tissues were influencing factors of incomplete remission of proteinuria(both P<0.05),while adjusting for gender,age,mean arterial pressure,serum anti-PLA2R antibody,serum albumin and 24 h urinary protein,serum C3≤1.005 g;L(HR=1.374,95%CI 1.021-1.849,P=0.036),C3 deposition in renal tissues(HR=1.949,95%CI 1.098-3.460,P=0.023),and serum C3≤1.005 g;L combined with C3 deposition in renal tissues(HR=1.472,95%CI 1.093-1.983,P=0.011)were independent influencing factors of incomplete remission of proteinuria.Conclusions The serum C3 level and C3 deposition in renal tissues are closely related to urinary protein level and proteinuria remission status in PMN patients.The patients with higher urinary protein have higher serum C3.For patients with massive proteinuria,serum C3≤1.005 g;L,C3 deposition in renal tissues,serum C3≤1.005 g;L combined with C3 deposition in renal tissues are independent risk factors of incomplete remission of proteinuria.