The significance of serum phospholipase A2 receptor antibody in remission of idiopathic membranous nephropathy

Objective To identify the significance of serum phospholipase A2 receptor antibody (PLA2R-Ab) in idiopathic membranous nephropathy (IMN) patients. Methods A total of 108 patients diagnosed as IMN by medical history, physical examination, laboratory examination and renal biopsy in Tongji Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology between Dec 1, 2014 and Aug 31, 2017 were enrolled, and all related data were recorded. According to the results of serum PLA2R-Ab test, patients were divided to positive group and negative group, and the data were compared with the independent sample t test and the chi-square test. Kaplan-Meier survival analysis was performed to compare remission rates between groups, and the Log-rank method was used to evaluate the significance of differences. Univariate and multivariate Cox regression analysis were used to verify predicting factors for achieving remission. Results Overall, 67.6%(73/108) patients had detectable serum PLA2R-Ab. Compared with patients in negative group, patients in positive group exhibited higher proportion of male patients (P=0.002), lower level of serum albumin (P＜0.001), higher level of cholesterol (P＜0.001), lower level of immunoglobulin G (P＜0.001), higher level of proteinuria (P=0.003), a lower of chance of remission (P=0.049), longer time needed to achieve partial remission (P=0.001) and complete remission (P=0.002). The 1- and 2-year cumulative renal partial remission rates were 72.4%, 86.1%, and the cumulative renal complete remission rates were 43.8%, 54.0%, respectively. Patients in negative group had higher partial remission(χ2=9.84, P=0.002) and complete remission (χ2=15.50, P＜0.001) than those in positive group. Multivariate Cox regression model indicated that serum positive PLA2R-Ab was a significant independent risk factor. Conclusions IMN patients with serum PLA2R-Ab show more severe condition and lower remission rates than those without serum PLA2R-Ab. Serum positive PLA2R-Ab is an independent remission-related predictor for IMN patients.     

成人膜性肾病患者血清抗PLA2R抗体与病情的相关性

目的 分析成人膜性肾病患者血清抗M型磷脂酶A2受体(PLA2R)抗体与特发性膜性肾病( IMN)实验室指标的相关性,探讨抗PLA2R抗体在IMN发病中的作用.方法 选取经肾活检证实的46例肾小球疾病患者,包括20例IMN、7例IgA肾病、6例乙型肝炎病毒相关性膜性肾病( HBV-MN)、6例微小病变性肾病、4例局灶性节段性肾小球硬化、3例Ⅴ型狼疮肾炎.应用Western印迹法检测血清抗PLA2R抗体,并对其与IMN患者血清白蛋白、24 h尿蛋白量、血清总胆固醇和Scr作相关性分析.结果 20例IMN患者中15例血清抗PLA2R抗体阳性,阳性比例为75％;7例IgA肾病患者中1例抗PLA2R抗体阳性,阳性比例为14.29％;6例HBV-MN患者中1例阳性,阳性比例为16.67％;其余患者均为阴性.IMN患者血清抗PLA2R抗体阳性比例显著高于继发性膜性肾病和其他肾小球肾炎(均P＜0.01),且抗PLA2R抗体水平与IMN患者尿蛋白量呈正相关(r=0.803,P＜0.01);与血清白蛋白呈负相关(r=-0.816,P＜0.01).结论 IMN患者血清抗PLA2R抗体阳性比例高,提示抗PLA2R抗体可能是IMN的特异性抗体.该抗体与尿蛋白量呈正相关,提示抗PLA2R抗体可能是IMN的致病性抗体.     

Expression and significance of M-type phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A in adult idiopathic membranous nephropathy

Objective To detect the M-type phospholipase A2 receptor (PLA2R), and thrombospondin type-1 domain-containing 7A (THSD7A) expression in renal tissue and the levels of their antibodies in adult idiopathic membranous nephropathy (IMN). Also to determine the value of the two markers in the diagnosis of IMN. Methods One hundred and sixteen patients with biopsy-proven MN at the Second Hospital of Hebei Medical University from December 2014 to August 2015 were enrolled, including 86 patients with IMN, 10 patients with HBV-MN and 10 patients with stage V lupus nephritis (LN-V). Twenty patients with minimal change disease (MCD) were regarded as control group. We conducted immunohistochemical analysis of the presence of THSD7A and PLA2R the Paraffin section and enzyme linked immunosorbent assay (ELISA) detecting serum PLA2R-AB and THSD7A-AB concentration to investigate whether there was a correlation between them and clinical indicators. Results Compared with the SMN and MCD groups, the positive rates of PLA2R and PLA2R-AB were significantly higher in IMN groups. Expression PLA2R was detected in 88.4%, 47.4%, 10% and 0% and PLA2R-AB in 82.6%, 15%, 10%, 0%, respectively, of the patients with IMN, HBV-MN, LN-V and MCD. Expression THSD7A was detected in 2.3% of the patients with IMN while not detected in SMN and MCD. THSD7A-AB antibody was negative in all patients. Compared with serum PLA2R-Ab negative individuals, patients with serum PLA2R-Ab positive had lower serum albumin (P＜0.001), higher urine protein excretion (P=0.01). The sensitivity of PLA2R-AB, PLA2R,THSD7A and PLA2R+THSD7A in the diagnosis of IMN were 82.6%, 88.4%, 2.3%, 88.6%, and the specificity was 92%, 66.7%, 100%, 66.7%, respectively. Conclusions PLA2R in renal tissue and serum PLA2R-AB are specific markers for the diagnosis of IMN, which are closely related with the severity of IMN. Expression of THSD7A is only positive in some of IMN patients with negative PLA2R, which can be used as a supplementary examination of IMN patients with negative PLA2R.     

Prevalence of idiopathic membranous nephropathy and clinicopathologic correlation with serum anti-PLA2R antibody in a single center

Objective To conduct a single-center retrospective analysis on the distribution characteristics and prevalence of idiopathic membranous nephropathy (IMN) patients diagnosed with pathology for the past 16 years, to investigate diagnostic and differential diagnostic value of serum anti-phospholipase A2 receptor antibodies (PLA2R-Ab), and to evaluate the correlation between PLA2R-Ab and clinical disease activity. Methods (1) 6996 biopsy-proven primary glomerular nephropathy (PGN) patients, including 1567 IMN cases, admitted to the First Affiliated Hospital of Xi'an Jiaotong University from January 2000 to December 2015 were involved. Demographics and pathological type were gathered from all patients. (2) 433 cases receiving renal biopsy and testing PLA2R-Ab from June 2015 to December 2015 were involved, with their clinical and laboratorial data being collected. During the period patients' follow-up time, therapeutic schedule and laboratory results were recorded. Results (1) IMN accounted for 22.4% of primary glomerular disease, and patients above 40 years old accounted for more than 60% of the IMN. (2) The sensitivity and specificity of serological PLA2R-Ab were 58.1%(95%CI 47.0%-68.5%) and 98.6%(95%CI 95.6%-99.6%) respectively. PLA2R-Ab positive rate was affected by immunosuppression therapy. (3) The PLA2R-Ab titers wasn't correlated with 24-hour urinary protein (r=-0.017, P=0.887), serum albumin (r=-0.072, P=0.549) and urinary red blood cell count (r=-0.030, P=0.802). There was no difference between PLA2R-Ab positive positive and PLA2R-Ab negative on proportion of IMN pathological stage I-II (P＞0.05). Thirteen cases of patients with PLA2R-Ab positive were all prescribed glucocorticoid combined with immunosuppressant. After (2.21±1.09) months, the decrease of PLA2R-Ab titers was in accordance with 24-hour urinary protein quantity descending and serum albumin ascending (P＜0.05). Conclusions The incidence of IMN increase year by year, especially in the mid-aged and the elderly. Serum PLA2R-Ab correlates not with IMN pathological stage, but with the development of IMN. Monitoring PLA2R-Ab titers individually may access the efficiency of treatment.     

Correlation of M-type phospholipase A2 receptor genetic polymorphism with idiopathic membranous nephropathy

Objective To investigate the correlation of M-type phospholipase A2 receptor (PLA2R) genetic polymorphism in two single nucleotide polymorphisms (SNPs) with idiopathic membranous nephropathy (IMN) of Chinese Han population in Northeast China. Methods A total of 327 individuals were enrolled in the study including 95 adult patients with biopsy-proved IMN (IMN group) followed up for (25.4±11.6) months and 232 healthy people identified by healthy examination in China-Japan Union Hospital of Jilin University (HC group). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequency of rs35771982 and rs3828323 site in PLA2R gene. The χ2 test was performed to compare the distribution difference of allelic frequency and genotype frequency of the two sites in PLA2R gene between two groups. Unconditional Logistic regression analysis was used to determine the risk factor of IMN. Results IMN and HC group were matched in male predominance and body mass index (BMI). Patients with IMN were older than the healthy controls and had higher Scr, serum total cholesterol (TC), 24-hour urine protein level and lower serum albumin (Alb) level, lower estimated glomerular filtration rate (eGFR) than the healthy controls (all P＜0.01). The CC genotype frequency and the C allele frequency at SNP rs35771982 site of PLA2R gene in IMN group were significantly higher than those in HC group ( χ2＝13.658, P＝0.001; χ2＝15.315, P＝9.10×10-5), whereas there was no distribution difference of genotype and allele frequency at rs3828323 site between two groups (χ2＝2.844, P＝0.241;χ2＝2.959, P＝0.085). The CC genotype at rs35771982 site in patients with IMN was not related to age, gender, BMI, blood pressure and several laboratory indexes such as Alb, TC, Scr, eGFR and 24-hour urine protein level (all P＞0.05). Unconditional Logistic regression analysis revealed that the genotype at rs35771982, age, TC, Scr and eGFR were correlated with IMN occurrence. The CC genotype at rs35771982 was the risk factor of IMN (OR＝4.408, 95%CI 1.488-13.058). Conclusions The CC genotype and C allele at rs35771982 site in PLA2R may be associated with the susceptibility to IMN, whereas the correlation between gene polymorphism at rs3828323 site and IMN is not demonstrated. The CC genotype at rs35771982 is the independent risk factor of IMN in Chinese Han population in Northeast China.     

The clinical outcome and risk factors of phospholipase A2 receptor-associated idiopathic membranous nephropathy in adults

Objective To report the spontaneous remission and induced remission of phospholipase A2 receptor (PLA2R)-associated idiopathic membranous nephropathy (IMN) in adults, as well as to explore the potential prognostic factors. Methods A total of 120 patients with IMN in Huashan Hospital during 2012 and 2017 were enrolled and their clinical data were collected. Results PLA2R-associated IMN patients accounted for 89.2% of the IMN patients. Spontaneous remission occurred in 35.5% of PLA2R-associated IMN patients. The patients with higher serum albumin and lower level of PLA2R antibody were more likely to achieve spontaneous remission (both P＜0.05). Multivariate logistic regression analysis showed that male was an independent risk factor for spontaneous remission in PLA2R-associated IMN patients (OR=0.060, 95%CI 0.007-0.493, P=0.009), while higher serum albumin at baseline (OR=1.480, 95%CI 1.144-1.932, P=0.004) and the improvement of serum albumin after 3 months' non-immunosuppressive treatment (OR=2.040, 95%CI 1.322-3.151, P=0.001) were independent protective factors for spontaneous remission. About 42.1% PLA2R-associated IMN patients had received immunosuppressive therapy, with induced remission rate being 70.7%. High serum albumin before treatment was an independent protective factor for induced remission (OR=1.268, 95%CI 1.014-1.585, P=0.038). Conclusions PLA2R-associated IMN accounts for most of the IMN patients, with a spontaneous remission rate of 35.5%, during the follow-up period, which is even higher in patients with higher baseline serum albumin and lower PLA2R antibody titer. Induced remission rate is 70.7% in patients in need of immunosuppresants. The serum albumin level may be helpful in predicting spontaneous remission and response to immunosuppressive therapy.     

Relationship between renal phospholipase A2 receptor expression and clinical characteristics,prognosis in idiopathic membranous nephropathy patients

Objective To explore the relationship of phospholipase A2 receptor (PLA2R) expression in renal tissue with clinical characteristics, prognosis of idiopathic membranous nephropathy(IMN) patients. Methods 134 patients diagnosed as nephropathy proven by biopsy was selected as subjects of this research, including 98 patients with IMN patients, 10 patients with secondary membranous nephropathy and 26 patients with other renal glomerular diseases. The expression of PLA2R antigen in renal tissue was detected by immuno-fluorescence chemistry staining. Results The positive rate of renal PLA2R expression in IMN patients was higher than that in SMN patients (91.84% vs 40.00%, P＜0.01), whereas there is no expression in other glomerular diseases. The PLA2R negative group were mainly stage I membranous nephropathy, and positive group was mainly in stage II. The distribution of pathological stage between the two groups was statistically significant (P＜0.01). Compared with the positive group, the negative group was manifested with higher eGFR[(115.91±23.32) ml?min-1?(1.73 m2)-1 vs (94.06±27.38) ml?min-1?(1.73 m2)-1, P=0.031], associated with the higher 12-month complete remission rate (87.50% vs 44.07%, P=0.021). Conclusions The expression of PLA2R antigen in renal tissue plays an important role in the diagnosis, disease evaluation and prognosis of IMN. The negative PLA2R in kidney tissue of IMN may indicate a good clinical prognosis.     

Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies

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Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice

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血清磷脂酶A2受体抗体预测利妥昔单抗治疗特发性膜性肾病疗效价值的初探

目的 探索血清磷脂酶A2受体抗体预测利妥昔单抗治疗特发性膜性肾病疗效的预测价值.方法 纳入2017年8月1日至2020年5月31日新疆维吾尔自治区人民医院首次确诊或长期随访使用利妥昔单抗治疗的特发性膜性肾病的患者120例,依据血清磷脂酶A2受体抗体情况将患者分为阳性组和阴性组,进行组间资料比较,用Kaplan-Meie...     

Analysis of clinical manifestations and outcomes of idiopathic membranous nephropathy compared with diabetic nephropathy in patients with type 2 diabetes

Objective To evaluate the predictive factors and renal outcomes of idiopathic membranous nephropathy (IMN) in patients with type 2 diabetes (T2DM). Methods In this retrospective study, clinical data of 101 IMN patients with T2DM and 96 patients with diabetic nephropathy (DN) were consecutively collected. Logistic regression was used to assess potential clinical factors indicating IMN and COX regression was employed to analyze risks of IMN in developing to end-stage renal disease (ESRD), as compared with that of DN, in patients with T2DM. Results In a multivariate model, age≥55 years old, presence of nephrotic syndrome, estimated glomerular filtration rate (eGFR)＞60 ml?min-1?(1.73 m2)-1, duration of diabetes≤5 years and absence of diabetic retinopathy, were associated with IMN, as compared with DN, in patients with T2DM. In T2DM patients presented with nephrotic syndrome, age≥55 years old, eGFR＞60 ml?min-1?(1.73 m2)-1, duration of diabetes≤5 years and absence of diabetic retinopathy, were also associated with IMN, as compared with DN. Receiver operating characteristic curve (ROC) showed eGFR 65.5 ml?min-1?(1.73 m2)-1 was an optimal cutoff in differentiating DN and IMN. DN was associated with 16.8 times as high risk of incident ESRD as compared with IMN in T2DM patients. Conclusions In patients with T2DM, age≥55 years, presence of nephrotic syndrome, early stage of CKD, duration of diabetes≤5 years and absence of retinopathy, may indicate IMN rather than DN. T2DM patients with IMN have much better renal prognosis as compared with DN.     

血、尿中PLA2R抗体以及THSD7A抗体在特发性膜性肾病中的临床意义

目的通过检测膜性肾病(MN)患者中血清、尿中M型磷脂酶A2受体(PLA2R)抗体以及1型血小板反应蛋白7A域(THSD7A)抗体浓度,探讨其在特发性膜性肾病(IMN)中的临床意义。 方法选取2015年7月至2017年12月在山西医科大学第二医院肾内科经过肾活检确诊为MN的患者,通过酶联免疫吸附方法(ELISA)测定血清、尿中PLA2R抗体以及THSD7A抗体浓度水平。采用SPSS 21.0软件对数据进行统计分析。 结果经临床、病理确诊为MN的患者189例,其中IMN组165例(87.3%)。(1)IMN患者血清、尿PLA2R抗体的阳性率分别64.8%、60.0%,血清、尿THSD7A抗体的阳性率分别为8.4%、5.4%;(2)IMN患者血清、尿PLA2R抗体浓度与24 h尿蛋白定量呈正相关(P<0.05),与血清白蛋白呈负相关(P<0.05);(3)IMN患者中血清、尿THSD7A抗体浓度与24 h尿蛋白定量呈正相关(P<0.05),与血清白蛋白无相关性(P>0.05);(4)IMN患者中血清PLA2R、抗体浓度与尿PLA2R抗体浓度呈正相关(P<0.05),血清THSD7A抗体浓度与尿THSD7A抗体浓度呈正相(P<0.05)。 结论血清、尿中PLA2R抗体以及THSD7A抗体均可作为IMN诊断的特异性指标,相对于THSD7A抗体而言,PLA2R抗体检出率更高,且这两种抗体在血清、尿中浓度水平与临床指标存在一定的相关性。     

血清抗核抗体阳性的不典型膜性肾病与狼疮膜性肾病及特发性膜性肾病的临床病理比较

目的 探讨血清抗核抗体（ANA）阳性的不典型膜性肾病（AMN）与狼疮膜性肾病（LMN）、特发性膜性肾病（IMN）的关系，寻找对诊断LMN具有较高预测价值的临床和病理学指标。 方法 2003年1月至2006年12月期间在北京协和医院住院并行肾活检，临床、病理资料保存完整的患者为对象。分组：AMN组（n = 28）：血清ANA滴度≥1∶80，少于4条美国风湿病学会（ARA）修订的系统性红斑狼疮分类标准，病理呈肾小球基底膜病变伴系膜增生和（或）免疫荧光C1q阳性；IMN组（n = 100）；LMN组（n = 45）。回顾性分析各组病例的临床表现、病理学特点。应用免疫组化法，对各组部分病例肾活检组织行IgG亚型染色，半定量分析染色强度。对各组部分病例肾活检组织行免疫荧光双染色（IgG-TRITC，C3-FITC），用激光扫描共聚焦显微镜观察肾小球沉积的IgG和C3的空间分布。 结果 (1)AMN组起病年龄（38±17）岁，女∶男比为2.5∶1，介于LMN和IMN之间。3组起病年龄差异有统计学意义（P < 0.01），AMN组女∶男比高于IMN组（P = 0.017）。AMN组血液系统异常、血抗SSA抗体阳性百分比较高（21.4%、40.7%）。(2)AMN组系膜增生、系膜区及内皮下电子致密物出现的百分比高于IMN组（P < 0.01）。(3)AMN和LMN组肾小球IgG3沉积占优势的百分比分别为78.9%、73.9%；IMN组IgG4沉积占优势的百分比为61.1%，差异均有统计学意义（IMN组与AMN、LMN组比较, P < 0.01）。(4)IMN组常出现IgG和C3在上皮下的共沉积现象，而在AMN和LMN组中少见。(5)在鉴别LMN和IMN的指标中，敏感性较高的有肾小球IgG4不占优势（91.3%）；特异性较高的有内皮下电子致密物（100.0%）、血抗SSA抗体（95.5%）、肾小球IgG3占优势（94.4%）。 结论 AMN的临床表现与IMN类似，而各项病理学特点，尤其是肾小球IgG亚型沉积特点与LMN更为接近。它有可能是狼疮肾炎中较为隐匿的一个亚型。     

肾小球IgG4沉积与原发性膜性肾病临床及病理的关系

目的分析原发性膜性肾病肾小球免疫荧光IgG4亚型分布特点,探讨IgG4阳性强度与肾脏病理、临床表现及预后的关系。方法回顾分析2015年9月至2017年4月本院行原位肾活检、免疫荧光显示毛细血管袢上有IgG沉积且至少一个IgG亚型阳性强度1+及以上的原发性膜性肾病病例,分析肾小球IgG4亚型分布特点,探讨IgG4阳性强度与临床表现、病理指标及临床缓解的关系。结果共纳入250例患者,其中男性157例(62.8%),女性93例(37.2%),年龄(54.4±14.6)岁;IgG4阴性组40例,IgG4阳性组210例;IgG4阳性组根据IgG4阳性程度又分为弱阳性组(1+,114例)、中度阳性组(2+,62例)、强阳性组(3+、4+,34例)。IgG4阳性组24 h尿蛋白量、肾组织磷脂酶A2受体染色强阳性比例均高于IgG4阴性组(均P<0.05);IgG4强阳性组血白蛋白水平低于IgG4弱阳性组(P<0.05),且随着IgG4的阳性程度增高,IgG1的阳性强度也增高,IgG4强阳性组IgG1强阳性比例明显高于IgG4弱阳性组(P<0.05);各组肾小球硬化比例、肾小管萎缩程度、IgG2、IgG3及其余免疫荧光指标组间比较差异均无统计学意义。中位随访180(122,209)d,32例患者失访,余218例患者中,45例(20.6%)完全缓解,104例(47.7%)部分缓解,69例(31.7%)未缓解。以未缓解定义为结局事件,多因素Cox回归分析显示,肾组织IgG4高阳性强度(HR=1.371,95%CI 1.068~1.759,P=0.013)、男性(HR=1.818,95%CI 1.028~3.214,P=0.040)、初始24 h尿蛋白量大(HR=1.108,95%CI 1.003~1.225,P=0.043)是疾病缓解的独立危险因素。结论肾小球IgG4阳性与否及阳性程度与原发性膜性肾病的疾病严重程度相关,肾小球IgG4阳性程度可能成为原发性膜性肾病治疗反应的指标之一。     

Antibodies to m‐type phospholipase A2 receptor in children with idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN), the commonest cause of adult nephrotic syndrome (NS), accounts for only a minority of paediatric NS. Antibodies to m‐type phospholipase A2 receptor (PLA2R) are seen in two‐thirds of adult IMN cases. PLA2R staining in glomerular deposits is observed in 74% and 45% of adult and paediatric IMN cases, respectively. However, there are no reports of anti‐PLA2R in paediatric IMN. We evaluated anti‐PLA2R levels and PLA2R in gloemrular deposits in paediatric IMN seen at our center. Five cases were enrolled, all the cases stained for PLA2R in glomeruli and three (60%) had antibodies to PLA2R antigen. There was a parellel reduction in proteinuria and anti‐PLA2R titer. The present report suggests that PLA2R has a contributory role in the pathogenesis of paediatric IMN.     

Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy

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