不典型膜性肾病的治疗反应和肾脏预后分析

Analysis of treatment responses and kidney prognosis of atypical membranous nephropathy

目的分析不典型膜性肾病(membranous nephropathy,MN)患者的临床病理表现特征、治疗效果及肾脏预后,为该类患者的临床诊治提供依据。方法回顾性收集和分析2008年1月至2020年6月在北京大学第一医院确诊、治疗和随访的不典型MN和同期原发性MN患者的临床资料,比较两组患者临床病理、实验室指标、治疗反应及肾脏预后的差异。免疫荧光法检测两组患者肾组织磷脂酶A2受体(PLA2R)抗原的表达,酶联免疫吸附法检测患者血清抗PLA2R抗体水平。比较PLA2R相关MN组与非PLA2R相关MN组患者临床病理指标的差异。Kaplan-Meier生存曲线(Log-rank检验)和多因素Cox回归法分析不典型MN患者肾脏不良预后的影响因素。主要随访终点事件为肾功能不全,定义为终末期肾病或估算肾小球滤过率(eGFR)较基线值下降>30%且<60 ml·min^(-1)·(1.73 m2)-1。结果65例不典型MN患者入选本研究。与原发性MN组(n=324)相比,不典型MN组患者年龄较小(Z=-4.229,P<0.001),合并血尿比例(χ^(2)=5.555,P=0.018)、24 h尿蛋白量(Z=2.228,P=0.026)较高,eGFR较低(t=-5.108,P<0.001);肾组织IgG4沉积阳性比例较低(χ^(2)=8.081,P=0.004),IgA(χ^(2)=16.969,P<0.001)、IgM(χ^(2)=9.281,P=0.002)沉积阳性比例较高。两组患者在性别组成、血白蛋白、抗PLA2R抗体阳性比例、抗PLA2R抗体水平、肾脏C3/C1q沉积阳性比例等项目上的差异无统计学意义(均P>0.05)。不典型MN组患者接受肾素-血管紧张素-醛固酮系统抑制剂(49.3%比57.1%)、钙调磷酸酶抑制剂(27.7%比19.1%)、环磷酰胺(21.5%比23.8%)治疗的比例与原发性MN组的差异无统计学意义(均P>0.05)。两组在临床缓解率(80.0%比77.2%)、部分缓解率(44.6%比44.1%)、完全缓解率(35.4%比33.1%)、自发缓解率(36.9%比42.6%)、环磷酰胺治疗缓解率(85.7%比81.8%)、钙调磷酸酶抑制剂治疗缓解率(88.9%比79.0%)、复发率(30.8%比26.8%)等项目上的差异亦无统计学意义(均P>0.05)。中位随访时间30.0(21.5,61.5)个月,不典型MN组有15例(23.1%)患者eGFR下降>30%,其中7例(10.8%)eGFR下降>50%,3例(4.6%)进入终末期肾病,两组在肾脏不良预后比例上的差异无统计学意义(均P>0.05)。Kaplan-Meier生存曲线分析结果显示,年龄>39岁(χ^(2)=10.092,P=0.001)、eGFR≤100 ml·min^(-1)·(1.73 m2)-1(χ^(2)=5.491,P=0.019)、合并肾小管间质损害(χ^(2)=6.999,P=0.008)、肾病未缓解(χ^(2)=22.952,P<0.001)的患者中发生肾脏不良预后的时间更早。多因素Cox回归分析结果显示,肾病未缓解(HR=12.604,95%CI 2.691~59.037,P=0.001)是不典型MN患者发生肾脏不良预后的独立影响因素。结论不典型MN与原发性MN在治疗反应及肾脏预后等方面无明显差异,可以参考原发性MN的治疗指南和经验进行临床诊治。

Objective To analyze the clinicopathological characteristics,treatment responses and kidney outcomes of patients with atypical membranous nephropathy(MN),and to provide information for the clinical practice.Methods The clinical data of patients with atypical MN and synchronous primary MN who were diagnosed,treated and followed up in Peking University First Hospital from January 2008 to June 2020 were retrospectively collected and analyzed.Clinicopathological features,treatment responses and kidney prognosis were compared between the two groups.The expression of phospholipase A2 receptor(PLA2R)in kidney tissues was detected by immunofluorescence.Serum anti-PLA2R antibody was detected by enzyme-linked immunosorbent assay.Clinicopathological indexes were compared between PLA2R-related MN group and non-PLA2R-related MN group.Kaplan-Meier(Log-rank test)survival curve and multivariate Cox regression analysis methods were used to analyze the influencing factors of kidney prognosis in patients with atypical MN.The primary endpoint of renal adverse outcome was renal insufficiency,defined as end-stage renal disease or estimated glomerular filtration rate(eGFR)decline>30%baseline and<60 ml·min^(-1)·(1.73 m2)-1.Results A total of 65 atypical MN patients were enrolled in this study.Compared with primary MN(n=324),patients with atypical MN had younger age(Z=-4.229,P<0.001),higher proportion of hematuria(χ^(2)=5.555,P=0.018),higher level of urinary protein(Z=2.228,P=0.026)and lower level of eGFR(t=-5.108,P<0.001);the proportion of IgG4 deposition in kidneys was lower(χ^(2)=8.081,P=0.004),and the proportions of IgA(χ^(2)=16.969,P<0.001)and IgM(χ^(2)=9.281,P=0.002)deposition were higher.There was no significant difference on gender,serum albumin,positive proportion of anti-PLA2R antibody,anti-PLA2R antibody level and kidney C3/C1q deposition between the two groups(all P>0.05).The proportions of atypical MN patients receiving renin-angiotensin aldosterone system inhibitors(49.3%vs 57.1%),calcineurin inhibitors(27.7%vs 19.1%)and cyclophosphamide(21.5%vs 23.8%)were comparable to those of primary MN patients(all P>0.05).The rates of clinical remission(80.0%vs 77.2%),partial remission(44.6%vs 44.1%),complete remission(35.4%vs 33.1%),spontaneous remission(36.9%vs 42.6%),response to cyclophosphamide(85.7%vs 81.8%),response to calcineurin inhibitor(88.9%vs 79.0%),and relapse(30.8%vs 26.8%)in atypical MN patients were comparable to those in primary MN patients(all P>0.05).During the follow-up 30.0(21.5,61.5)months,15 atypical MN patients(23.1%)had eGFR reduction>30%,among whom 7 patients(10.8%)had eGFR reduction>50%and 3 patients(4.6%)had end-stage kidney disease.There was no significant difference on poor kidney prognosis between the two groups(all P>0.05).Kaplan-Meier survival curve showed that patients with age>39 years old(χ^(2)=10.092,P=0.001),eGFR≤100 ml·min^(-1)·(1.73 m2)-1(χ^(2)=5.491,P=0.019),tubular interstitial lesion(χ^(2)=6.999,P=0.008)and no nephropathy remission(χ^(2)=22.952,P<0.001)had earlier poor renal prognosis.Multivariate Cox regression analysis showed that no nephropathy remission(HR=12.604,95%CI 2.691-59.037,P=0.001)was an independent influencing factor for poor renal prognosis in atypical MN patients.Conclusion No significant difference is found between atypical MN and primary MN on treatment responses and kidney prognosis,which implies that clinical practice of atypical MN can be performed by referring to the guidelines and experience of primary MN.