膜性肾病诊断和治疗的初步研究

发布时间：2018-05-21 01:27

本文选题：膜性肾病 + 抗PLA2R抗体　；参考：《北京协和医学院》2014年博士论文

【摘要】：研究目的 1、了解我院特发性膜性肾病(IMN)和继发性膜性肾病(SMN)患者血清抗磷脂酶A2受体(PLA2R)抗体的阳性率,并比较免疫荧光法(IFA)和酶联免疫吸附法(ELISA)检测结果的一致性； 2、了解IMN和膜型狼疮肾炎(MLN)患者血清抗PLA2R抗体与肾小球IgG4亚型的关系,评价血清抗PLA2R抗体和肾小球IgG亚型在膜性肾病诊断中的价值,探索其在SMN和不典型膜性肾病(AMN)诊断中的应用。 3、评估初始治疗时血浆白蛋白(SAlb)处于不同水平的IMN患者,接受免疫抑制治疗后的缓解率、达到缓解所需反应时间、药物暴露时间或累积量和不良反应发生情况。研究方法本研究对2011年10月到2014年4月于北京协和医院行肾活检并诊断为IMN、SMN(主要是MLN)和AMN的部分患者进行IFA血清抗PLA2R抗体检测,计算其在不同疾病中的阳性率,同时对上述患者肾小球IgG亚型免疫荧光结果进行回顾性整理,分析4种IgG亚型在不同疾病中的分布特点；根据上述结果,进一步制作诊断评价四格表,计算血清抗PLA2R抗体和肾小球IgG4亚型单独或联合使用时,在IMN和MLN鉴别诊断中的灵敏度、特异度、阳性预测值、阴性预测值和符合率,并应用这些指标对其他SMN患者和病因不明的AMN患者进行分析。对部分血清样本同时行ELISA检测,与IFA的检测结果进行比较。本研究对2010年1月至2012年12月于我院行肾穿明确诊断后接受规范治疗、于门诊规律随诊1年及以上、且临床资料保存完整的IMN患者进行回顾性分析,根据初始治疗时SAlb浓度分为H-ALB组(SAlb25g/L)和L-ALB组(SAlb≤25g/L),记录随诊过程中主要临床指标包括动脉血压、SAlb.血肌酐(Scr)、24小时尿蛋白(24hUPro)、药物种类和剂量、不良反应发生情况,分别计算两组到达终点时,处于疾病活动期(AD)、达到部分缓解(PR)和完全缓解(CR)的患者比例,对达到PR和CR的患者,计算其从治疗开始到缓解所经历的反应时间和药物暴露时间或累积量,比较两组患者免疫抑制剂的使用种类、缓解率、反应时间、药物暴露时间或累积量和不良反应发生率有无统计学差异。研究结果 IMN组共纳入59例,其中血清抗PLA2R抗体阳性者41例,阳性率69.5%,MLN组共纳入21例,其中血清抗PLA2R抗体阳性者1例,阳性率4.8%。IMN组肾小球IgG亚型以IgG4为主,阳性率为88.1%,显著高于MLN组(P0.001),MLN组以IgG3和IgGl为主,IgG3阳性率为81.0%,高于IMN组但无显著性差异(P=0.097),IgG1阳性率为66.7%,显著高于IMN组(P=0.006)。IMN组35人血清抗PLA2R抗体和肾小球IgG4同为阳性,6人血清抗PLA2R抗体阳性而肾小球IgG4阴性,17人血清抗PLA2R抗体阴性而肾小球IgG4阳性,1人血清抗PLA2R抗体和肾小球IgG4同为阴性。单独使用血清抗PLA2R抗体对IMN和MLN进行鉴别时,灵敏度为69.5%,特异度为95.2%,符合率为76.2%；单独使用肾小球IgG4亚型进行鉴别时(临界值为++),灵敏度为78.0%,特异度为71.4%,符合率为76.2%；联合血清抗PLA2R抗体和肾小球IgG4进行鉴别(一者为阳性)时,灵敏度为91.5%,特异度为66.7%,符合率为85.0%。AMN组共纳入26例,其中乙型肝炎病毒(HBV)相关性膜性肾病患者血清抗PLA2R抗体阳性率为66.7%(4/6),干燥综合征(pSS)相关性膜性肾病患者血清抗PLA2R抗体阳性率为33.3%(1/3)。ELISA和IFA测定的24例血清样本抗PLA2R抗体结果均为17例阳性,7例阴性,ELISA所得浓度与IFA所得荧光强度具有线性相关性(R2=0.506)。H-ALB组共纳入60人,其中53人接受免疫抑制治疗,平均随访25.1±8.0月,L-ALB组共纳入52人,全部接受免疫抑制治疗,平均随访24.7±9.3月。H-ALB组肾病综合征患者比例为35%,L-ALB组为98%,后者显著高于前者(P0.001);H-ALB组使用1种免疫抑制剂的比例为54.7%,L-ALB组为48.1%,两者无统计学差异(P=0.435);H-ALB组使用激素的比例为90.6%,L-ALB组为96.2%,两者无统计学差异(P=0.449)。H-ALB组PR和CR的比例为86.8%(46/53),L-ALB组为88.5%(46/52),两者无统计学差异(P=0.795);H-ALB组达到PR的时间为3.6±2.9月,达到CR的时间为9.8±3.7月,L-ALB组达到PR的时间为6.0±5.2月,达到CR的时间为11.8±5.0月,H-ALB组达到PR和CR的时间均短于L-ALB组,且前者具有统计学差异(P=0.006)；达到PR时H-ALB组激素平均使用3.5±2.8月,L-ALB组为5.8±5.0月,具有统计学差异(P=0.013)；两组环孢素A(CsA)平均使用时间分别为3.1±3.4月和5.8±5.0月,环磷酰胺(CTX)平均累积使用量分别为6.7±3.4g和11.0±2.5g,均无统计学差异(P分别为0.086和0.069)；达到CR时,两组在激素、CsA暴露时间和CTX累积量上亦无统计学差异(P分别为0.072,0.112和0.380);H-ALB组不良反应发生率为45.3%,L-ALB组为59.6%,两组无统计学差异(P=0.141)。结论 1、1、血清抗PLA2R抗体是IMN的特异性抗体,阳性率达69.5%,但也可在个别SMN患者体内检测到。2、肾小球IgG亚型在IMN和MLN中的分布呈不同特点,IMN以IgG4为主,MLN则以IgG3和IgGl为主。3、血清抗PLA2R抗体和肾小球IgG4鉴别IMN和MLN时,与病理诊断的符合率相同,两者联用可提高灵敏度和符合率,对判断SMN患者是否为两种疾病合并发生,以及AMN患者继发性病因的诊断有所帮助。4、ELISA法和IFA法检测血清抗PLA2R抗体的结果相一致。5、初始治疗时SAlb水平对激素和免疫抑制剂的选择无显著影响。6、初始治疗时SAlb水平较高的患者2年内的缓解率与SAlb水平较低的患者相近；初始治疗时SAlb水平较高的患者达到PR的时间短于SAlb水平较低的患者,达到PR时激素暴露时间短于SAlb水平较低的患者,CsA和CTX的使用时间和累积量有少于SAlb水平较低患者的趋势；初始治疗时SAlb水平较高的患者达到CR的时间有短于SAlb水平较低患者的趋势,达到CR时药物暴露时间和累积剂量有少于SAlb水平较低患者的趋势；7、初始治疗时SA1b水平对不良反应发生率有低于SAlb水平较低患者的趋势。
[Abstract]:research objective
1, to understand the positive rate of serum anti phospholipase A2 receptor (PLA2R) antibody in patients with idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy (SMN), and to compare the consistency between the results of immunofluorescence (IFA) and enzyme linked immunosorbent assay (ELISA).
2, to understand the relationship between serum anti PLA2R antibody and glomerular IgG4 subtype in patients with IMN and membranous lupus nephritis (MLN), to evaluate the value of serum anti PLA2R antibody and glomerular IgG subtype in the diagnosis of membranous nephropathy, and to explore its application in the diagnosis of SMN and atypical membranous nephropathy (AMN).
3, IMN patients at different levels of plasma albumin (SAlb) were assessed at the initial treatment. The remission rate after immunosuppressive therapy was accepted, and the time of remission, the time of drug exposure, the cumulative amount of drug exposure and the occurrence of adverse reactions were achieved.
research method
In this study, the serum anti PLA2R antibody of IFA, IMN, SMN (mainly MLN) and AMN, was detected in the Peking Union Medical College Hospital from October 2011 to April 2014. The positive rates of IFA in different diseases were calculated. The results of the immunofluorescence of IgG subtype in the glomeruli were reviewed and 4 IgG subtypes were analyzed. Distribution characteristics in different diseases; based on the above results, the four grid of diagnostic evaluation was further made to calculate the sensitivity, specificity, positive predictive value, negative predictive value and coincidence rate in the differential diagnosis of IMN and MLN when serum anti PLA2R antibody and glomerular IgG4 subtype were used alone or combined, and these indexes were applied to other SMN patients. AMN patients with unknown etiology were analyzed. Some serum samples were measured by ELISA and compared with the results of IFA. This study received standardized treatment after a clear diagnosis of renal puncture in our hospital from January 2010 to December 2012, and a retrospective analysis was made for 1 years and more of IMN patients with complete preservation of the bed data. According to the initial treatment, the concentration of SAlb was divided into group H-ALB (SAlb25g/L) and group L-ALB (SAlb < < 25g/L). The main clinical indicators included arterial blood pressure, SAlb. serum creatinine (Scr), 24 hour urinary protein (24hUPro), drug type and dose, adverse reaction, and two groups of arrival points at the disease activity period (AD) respectively. The proportion of patients with partial remission (PR) and complete remission (CR), for patients with PR and CR, were calculated from the time of reaction and time of exposure or accumulation of drug exposure from the beginning of the treatment to remission, and the use of the two groups of immunosuppressive agents, the remission rate, the counter time, the time of drug exposure or the cumulative amount of adverse reactions and the occurrence of adverse reactions. There is no statistical difference in rate.
Research results
Group IMN included 59 cases, of which 41 cases of serum anti PLA2R antibody positive, positive rate 69.5%, group MLN were included in 21 cases, of which 1 cases of serum anti PLA2R antibody positive, positive rate of 4.8%.IMN group IgG subtype IgG4, positive rate was 88.1%, significantly higher than MLN group (P0.001), MLN group was IgG3 and IgGl, the positive rate was 81%, but higher than that of the group of 81%, but higher than that of the group but higher than that of the group but higher than that of the group of 81%. There was no significant difference (P=0.097), the positive rate of IgG1 was 66.7%, which was significantly higher than that in group IMN (P=0.006) in group.IMN (P=0.006). The serum anti PLA2R antibody and glomerular IgG4 were positive, 6 serum anti PLA2R antibody positive and glomerular IgG4 negative, 17 serum anti PLA2R antibody negative and glomerular IgG4 positive, 1 serum anti PLA2R antibodies and glomerular glomeruli were negative. The sensitivity was 69.5%, the specificity was 95.2%, the coincidence rate was 76.2% when the serum anti PLA2R antibody was used alone. The sensitivity was 78%, the specificity was 71.4% and the coincidence rate was 76.2% when the glomerular IgG4 subtype was identified alone. The combination of serum anti PLA2R antibody and glomerular IgG4 was identified. The sensitivity was 91.5% and the specificity was 66.7%, and the coincidence rate was 66.7% in group 85.0%.AMN. The positive rate of serum anti PLA2R antibody in patients with hepatitis B virus (HBV) related membranous nephropathy was 66.7% (4/6), and the positive rate of anti PLA2R antibody in serum of patients with dryness syndrome (pSS) related membranous nephropathy was 33.3% (1/3).ELISA and 24. The results of anti PLA2R antibody in serum samples were all 17 positive and 7 negative. The concentration of ELISA was linearly correlated with the fluorescence intensity of IFA (R2=0.506) and 60 people were included in.H-ALB group, of which 53 were treated with immunosuppressive therapy, the average follow-up was 25.1 + 8 months. The group of L-ALB was included in 52 people, all received immunosuppressive therapy, the average follow-up was 24.7 + 9.3 months. In group.H-ALB, the proportion of patients with nephrotic syndrome was 35%, group L-ALB was 98%, the latter was significantly higher than that of the former (P0.001); the proportion of 1 immunosuppressants in group H-ALB was 54.7% and group L-ALB was 48.1% (P=0.435); the proportion of hormone in H-ALB group was 90.6% and L-ALB group was 96.2%. There was no statistical difference between the two groups (P=0.449).H-ALB group PR and CR. The proportion of the group was 86.8% (46/53) and 88.5% (46/52) in group L-ALB (P=0.795). The time of reaching PR in H-ALB group was 3.6 + 2.9 months, the time reached CR was 9.8 + 3.7 months, the time of L-ALB group reached PR 6 + 5.2 months, and the time of reaching CR was 11.8 + 5 months. The average use of hormone in group H-ALB was 3.5 + 2.8 months at PR and 5.8 + 5 months in group L-ALB (P=0.013). The average use time of cyclosporin A (CsA) in the two group was 3.1 + 3.4 months and 5.8 + 5 months respectively, and the average accumulation of cyclophosphamide (CTX) was 6.7 + 3.4g and 11 + 2.5G respectively (P, respectively). For 0.086 and 0.069), there was no significant difference between the two groups on the hormone, the CsA exposure time and the CTX accumulation (P was 0.072,0.112 and 0.380) in the two groups (0.072,0.112 and 0.380), and the adverse reaction rate was 45.3% in the H-ALB group and 59.6% in the L-ALB group, and there was no statistical difference between the two groups (P=0.141).
conclusion
1,1, serum anti PLA2R antibody is a specific antibody of IMN, the positive rate is 69.5%, but it can also be detected in a few SMN patients. The distribution of IgG subtype in the glomerulus is different in IMN and MLN, and IMN is mainly IgG4. Similarly, the combination of the two can improve the sensitivity and the coincidence rate. It is helpful to determine whether the SMN patients are combined with two diseases, and the diagnosis of secondary causes of AMN patients is helpful to.4. The results of the ELISA and IFA detection of serum anti PLA2R antibodies are consistent.5. In the initial treatment, the SAlb level has no significant effect on the selection of the hormone and immunosuppressant. In patients with higher SAlb levels in the initial treatment, the remission rate in 2 years was similar to those with lower SAlb levels; at the time of initial treatment, the patients with higher SAlb levels reached PR shorter than those with lower SAlb levels, and the time and accumulation of CsA and CTX were less than those of lower SAlb levels when PR was reached, and the time and accumulation of CsA and CTX were less than SAlb water. The trend of lower patients was lower; patients with higher SAlb level in initial treatment were shorter than those with lower SAlb levels, and the time and cumulative dose of drugs were less than those of lower SAlb levels when reaching CR; and 7, the incidence of SA1b at SA1b levels in the initial treatment was lower than that of the lower SAlb level. Trend.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R692

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