本文選題：膜性腎病 + 抗PLA2R抗體　； 參考：《北京協(xié)和醫(yī)學院》2014年博士論文

【摘要】：研究目的 1、了解我院特發(fā)性膜性腎病(IMN)和繼發(fā)性膜性腎病(SMN)患者血清抗磷脂酶A2受體(PLA2R)抗體的陽性率,并比較免疫熒光法(IFA)和酶聯(lián)免疫吸附法(ELISA)檢測結(jié)果的一致性； 2、了解IMN和膜型狼瘡腎炎(MLN)患者血清抗PLA2R抗體與腎小球IgG4亞型的關系,評價血清抗PLA2R抗體和腎小球IgG亞型在膜性腎病診斷中的價值,探索其在SMN和不典型膜性腎病(AMN)診斷中的應用。 3、評估初始治療時血漿白蛋白(SAlb)處于不同水平的IMN患者,接受免疫抑制治療后的緩解率、達到緩解所需反應時間、藥物暴露時間或累積量和不良反應發(fā)生情況。 研究方法 本研究對2011年10月到2014年4月于北京協(xié)和醫(yī)院行腎活檢并診斷為IMN、SMN(主要是MLN)和AMN的部分患者進行IFA血清抗PLA2R抗體檢測,計算其在不同疾病中的陽性率,同時對上述患者腎小球IgG亞型免疫熒光結(jié)果進行回顧性整理,分析4種IgG亞型在不同疾病中的分布特點；根據(jù)上述結(jié)果,進一步制作診斷評價四格表,計算血清抗PLA2R抗體和腎小球IgG4亞型單獨或聯(lián)合使用時,在IMN和MLN鑒別診斷中的靈敏度、特異度、陽性預測值、陰性預測值和符合率,并應用這些指標對其他SMN患者和病因不明的AMN患者進行分析。對部分血清樣本同時行ELISA檢測,與IFA的檢測結(jié)果進行比較。本研究對2010年1月至2012年12月于我院行腎穿明確診斷后接受規(guī)范治療、于門診規(guī)律隨診1年及以上、且臨床資料保存完整的IMN患者進行回顧性分析,根據(jù)初始治療時SAlb濃度分為H-ALB組(SAlb25g/L)和L-ALB組(SAlb≤25g/L),記錄隨診過程中主要臨床指標包括動脈血壓、SAlb.血肌酐(Scr)、24小時尿蛋白(24hUPro)、藥物種類和劑量、不良反應發(fā)生情況,分別計算兩組到達終點時,處于疾病活動期(AD)、達到部分緩解(PR)和完全緩解(CR)的患者比例,對達到PR和CR的患者,計算其從治療開始到緩解所經(jīng)歷的反應時間和藥物暴露時間或累積量,比較兩組患者免疫抑制劑的使用種類、緩解率、反應時間、藥物暴露時間或累積量和不良反應發(fā)生率有無統(tǒng)計學差異。 研究結(jié)果 IMN組共納入59例,其中血清抗PLA2R抗體陽性者41例,陽性率69.5%,MLN組共納入21例,其中血清抗PLA2R抗體陽性者1例,陽性率4.8%。IMN組腎小球IgG亞型以IgG4為主,陽性率為88.1%,顯著高于MLN組(P0.001),MLN組以IgG3和IgGl為主,IgG3陽性率為81.0%,高于IMN組但無顯著性差異(P=0.097),IgG1陽性率為66.7%,顯著高于IMN組(P=0.006)。IMN組35人血清抗PLA2R抗體和腎小球IgG4同為陽性,6人血清抗PLA2R抗體陽性而腎小球IgG4陰性,17人血清抗PLA2R抗體陰性而腎小球IgG4陽性,1人血清抗PLA2R抗體和腎小球IgG4同為陰性。單獨使用血清抗PLA2R抗體對IMN和MLN進行鑒別時,靈敏度為69.5%,特異度為95.2%,符合率為76.2%；單獨使用腎小球IgG4亞型進行鑒別時(臨界值為++),靈敏度為78.0%,特異度為71.4%,符合率為76.2%；聯(lián)合血清抗PLA2R抗體和腎小球IgG4進行鑒別(一者為陽性)時,靈敏度為91.5%,特異度為66.7%,符合率為85.0%。AMN組共納入26例,其中乙型肝炎病毒(HBV)相關性膜性腎病患者血清抗PLA2R抗體陽性率為66.7%(4/6),干燥綜合征(pSS)相關性膜性腎病患者血清抗PLA2R抗體陽性率為33.3%(1/3)。ELISA和IFA測定的24例血清樣本抗PLA2R抗體結(jié)果均為17例陽性,7例陰性,ELISA所得濃度與IFA所得熒光強度具有線性相關性(R2=0.506)。H-ALB組共納入60人,其中53人接受免疫抑制治療,平均隨訪25.1±8.0月,L-ALB組共納入52人,全部接受免疫抑制治療,平均隨訪24.7±9.3月。H-ALB組腎病綜合征患者比例為35%,L-ALB組為98%,后者顯著高于前者(P0.001);H-ALB組使用1種免疫抑制劑的比例為54.7%,L-ALB組為48.1%,兩者無統(tǒng)計學差異(P=0.435);H-ALB組使用激素的比例為90.6%,L-ALB組為96.2%,兩者無統(tǒng)計學差異(P=0.449)。H-ALB組PR和CR的比例為86.8%(46/53),L-ALB組為88.5%(46/52),兩者無統(tǒng)計學差異(P=0.795);H-ALB組達到PR的時間為3.6±2.9月,達到CR的時間為9.8±3.7月,L-ALB組達到PR的時間為6.0±5.2月,達到CR的時間為11.8±5.0月,H-ALB組達到PR和CR的時間均短于L-ALB組,且前者具有統(tǒng)計學差異(P=0.006)；達到PR時H-ALB組激素平均使用3.5±2.8月,L-ALB組為5.8±5.0月,具有統(tǒng)計學差異(P=0.013)；兩組環(huán)孢素A(CsA)平均使用時間分別為3.1±3.4月和5.8±5.0月,環(huán)磷酰胺(CTX)平均累積使用量分別為6.7±3.4g和11.0±2.5g,均無統(tǒng)計學差異(P分別為0.086和0.069)；達到CR時,兩組在激素、CsA暴露時間和CTX累積量上亦無統(tǒng)計學差異(P分別為0.072,0.112和0.380);H-ALB組不良反應發(fā)生率為45.3%,L-ALB組為59.6%,兩組無統(tǒng)計學差異(P=0.141)。 結(jié)論 1、1、血清抗PLA2R抗體是IMN的特異性抗體,陽性率達69.5%,但也可在個別SMN患者體內(nèi)檢測到。2、腎小球IgG亞型在IMN和MLN中的分布呈不同特點,IMN以IgG4為主,MLN則以IgG3和IgGl為主。3、血清抗PLA2R抗體和腎小球IgG4鑒別IMN和MLN時,與病理診斷的符合率相同,兩者聯(lián)用可提高靈敏度和符合率,對判斷SMN患者是否為兩種疾病合并發(fā)生,以及AMN患者繼發(fā)性病因的診斷有所幫助。4、ELISA法和IFA法檢測血清抗PLA2R抗體的結(jié)果相一致。5、初始治療時SAlb水平對激素和免疫抑制劑的選擇無顯著影響。6、初始治療時SAlb水平較高的患者2年內(nèi)的緩解率與SAlb水平較低的患者相近；初始治療時SAlb水平較高的患者達到PR的時間短于SAlb水平較低的患者,達到PR時激素暴露時間短于SAlb水平較低的患者,CsA和CTX的使用時間和累積量有少于SAlb水平較低患者的趨勢；初始治療時SAlb水平較高的患者達到CR的時間有短于SAlb水平較低患者的趨勢,達到CR時藥物暴露時間和累積劑量有少于SAlb水平較低患者的趨勢；7、初始治療時SA1b水平對不良反應發(fā)生率有低于SAlb水平較低患者的趨勢。
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R692

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