Utility of serum anti-phospholipase A2 receptor antibody as a biomarker in membranous nephropathy: An experience from a tertiary care center of Eastern India

Background: Membranous nephropathy (MN) is a pattern of glomerular injury. Exact categorization into primary membranous nephropathy (PMN) or secondary membranous nephropathy (SMN) is essential for treatment. An endogenous podocyte antigen, M-type phospholipase A2 receptor (PLA2R) has been discovered to be involved in the pathogenesis of PMN. Aims and Objectives: In this article, we aimed to analyze renal tissue PLA2R and serum anti-PLA2R antibodies in MN cases and determined the diagnostic utility. Materials and Methods: The study was of prospective type carried out from March 2019 to August 2020. Analysis of cases of MN was performed with PLA2R paraffin immunoflourescence and serum anti-PLA2R antibody ELISA. Results: Overall sensitivity, specificity, PPV, and NPV of serum anti-PLA2R ELISA for PMN was 91.3%, 80%, 75%, and 93.3%, respectively, and of tissue PLA2R staining for PMN was 91.67%, 81.08%, 75.86%, and 93.75%, respectively. There was strong concordance between two methods. In the patients that were followed up, we found baseline serum anti-PLA2R antibody was less in complete remission group than that in non-remission group and the reduction in serum anti-PLA2R antibody was more in complete remission group than that in non-remission group. Conclusion: Routine light and immunofluorescence examination are incapable of giving exact categorical opinion regarding PMN and SMN. Serum anti-PLA2R antibody detection and renal tissue PLA2R analysis are sensitive and specific in detecting PMN. Baseline serum anti-PLA2R antibody and anti-PLA2R antibody quantification trends are related to prognosis of PMN. So they can be incorporated as additional biomarker.

Pharmacogenetic testing improves treatment responses in patients with PLA2R-related membranous nephropathy / 南方医科大学学报

OBJECTIVE@#To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients.@*METHODS@#A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment.@*RESULTS@#Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (P < 0.05).@*CONCLUSION@#Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.

Primary Membranous Nephropathy With Extremely High Levels Of Ca-125 / Nefropatía Membranosa Primaria Con Niveles Extremadamente Altos De Ca-125

Abstract Membranous nephropathy is a glomerular disease that causes nephrotic syndrome. Absent phospholipase A2 receptor antibodies and absent staining with IgG4 may be linked to malignancy-associated MN. Here we present a case that defies that suggestion. A 42-year-old female presented with anasarca. Kidney biopsy revealed membranous nephropathy, stained positive for IgG but negative for IgG4. Absent phospholipase A2 receptor antibodies was negative. Abdominal tomography revealed a partial thrombosis of the left ovarian vein which raised suspicion for ovarian cancer. Even though her ovaries did not uptake FDG on PET scan, a carbohydrate antigen-125 was ordered. She had extremely high levels of carbohydrate antigen-125 which was unexpected in the course of benign events. Thorax CT, endoscopy, colonoscopy, mammography, and positron emission tomography were clear in terms of malignancy. Samples from both pleural effusion and ascites were consistent with transudate. Tuberculosis tests were negative. Cytology samples were negative for malign cells. Exploratory surgery was planned but rejected by the patient. She was treated as primary disease with cyclosporine and methylprednisolone. Rituximab was off-limits due to insurance rules. She had prompt and excellent response. Steroids were tapered and stopped at sixth month and cyclosporine at twelfth month. In her 36 months of drug-free follow up there has been no disease recurrence or a sign of cancer. Even when all odds are towards malignancy-associated membranous nephropathy, primary disease is still a possibility. We need better markers for malignancy-associated membranous nephropathy.A very high level of CA-125 does not necessarily mean cancer.

Resumen La nefropatía membranosa es una enfermedad glomerular que causa el síndrome nefrótico. La ausencia de anticuerpos contra el receptor de fosfolipasa A2 y de tinción para IgG4 puede deberse a una nefropatía membranosa asociada a cáncer. A continuación, se presenta un caso que desafía esta sugerencia. Una paciente de 42 años realizó una consulta por anasarca. A partir de la biopsia de riñón, se diagnosticó nefropatía membranosa con tinción positiva para IgG, pero negativa para IgG4. No se detectó la presencia de anticuerpos contra el receptor de fosfolipasa A2. La tomografía abdominal reveló una trombosis parcial en la vena ovárica izquierda, lo cual generó sospecha de cáncer de ovario. Si bien los ovarios no mostraron absorción de FDG en la tomografía por emisión de positrones, se solicitó una prueba de antígeno carbohidrato 125. Se le detectaron niveles elevados del antígeno carbohidrato 125, lo cual no es esperable en casos de eventos benignos. La tomografía computarizada de tórax, endoscopía, colonoscopía, mamografía y tomografía por emisión de positrones no mostraron tumores. Las muestras de derrame pleural y de ascitis fueron indicativas de trasudado. Las pruebas de tuberculosisarrojaron resultados negativos. El examen citológico fue negativo para células malignas. Se sugirió una cirugía exploradora, pero la paciente no aceptó. Se la trató con ciclosporina y metilprednisolona por enfermedad primaria. No se utilizó rituximab por reglas de su cobertura médica. La paciente tuvo una excelente respuesta al tratamiento de forma rápida. Los esteroides se disminuyeron de forma progresiva y se suspendieron a los seis meses, y la ciclosporina, a los doce meses. Durante los 36 meses de seguimiento sin medicación no ha habido recidiva ni signos de cáncer. Incluso cuando existen grandes probabilidades de que se trate de una nefropatía membranosa asociada a cáncer, aún es posible que se trate de una enfermedad primaria. Es necesario contar con mejores marcadores de nefropatía membranosa asociada a cáncer. Un nivel elevado de CA-125 no necesariamente es indicador de cáncer.

Diagnostic value of serum PLA2R antibody detection for idiopathic membranous nephropathy: A meta-analysis / 临床检验杂志

Objective To evaluate the diagnostic value of serum M-type phospholipase A2 receptor(PLA2R) antibody detection for the diagnosis of idiopathic membranous nephropathy(IMN) by meta analysis.Methods By searching the databases of PubMed,Emabse,Wanfang and CNKI from inception to May,2017,all the literatures referred to serum PLA2R antibody for the diagnosis of IMN in both English and Chinese were reviewed and selected according to the inclusion and exclusion criteria.QUADAS was used to assess the quality of eligible studies.Meta-disc 1.4 was used to analyze heterogeneity and pooled effectsize and Stata 12.0 was used to analyze publication bias.Results A total of 20 studies with high quality were included.Heterogeneity test indicated there was no threshold effect.The pooled sensitivity was 0.69 (95 ％ CI:0.67 to 0.72),the pooled specificity was 0.97 (95 ％ CI:0.96 to 0.98) and the summary area under curve was 0.880.Sensitivity analysis indicated that the result was stable.Deek's funnel plot indicated there was no publication bias.Conclusion The sensitivity of detection of serum PLA2R antibody was acceptable for the diagnosis of IMN with high specificity,so more attention on PLA2R antibody should be paid in the clinical practice.

Diagnostic significance of PLA2R and IgG4 in elderly patients with idiopathic membranous nephropathy / 解放军医学杂志

Objective To evaluate the diagnostic significance of PLA2R and IgG4 in elderly patients with idiopathic membranous nephropathy (IMN).Methods The clinical data were retrospectively analyzed of patients with IMN (49 males and 49 females,aged 66.6 ± 5.4 years) or Non-IMN (57 males and 41 females,aged 67.1 ± 6.5 years) who were admitted in the authors served Department of Nephrology from Apr.2014 to Feb.2016 and accepted renal biopsy.SPSS13.0 was employed to evaluate the sensitivity,specificity and calculate the area under ROC curve (AUC) of serum anti-PLA2R antibody,glomerular PLA2R and IgG1-4 subclasses on diagnosing IMN.Results On diagnosing IMN,the sensitivity and specificity of serum anti-PLA2R antibody were 77.6％ and 89.8％ [AUC=0.869(0.816-0.923)],of glomerular PLA2R were 66.3％ and 94.9％ [AUC=0.805(0.741-0.87)],and of glomerular IgGl-IgG4 were 80.6％ and 78.6％,60.2％ and 83.7％,41.8％ and 84.7％,and 93.9％ and 89.8％,respectively [AUC=0.767(0.696-0.838),0.709(0.635-0.783),0.628(0.549-0.706) and 0.94(0.901-0.978),respectively].As to the combined use of glomerular PLA2R and IgG4 on diagnosing IMN,the sensitivity was 93.9％ when either one of glomerular PLA2R and IgG4 was positive,or the specificity was 96.9％ when both glomerular PLA2R and IgG4 were positive.Conclusion PLA2R and IgG4 can effectively serve the diagnosis of IMN,and the combined use of PLA2R and IgG4 may be better than single indicator alone.

Expression of Serum Anti PLA2 R Antibodies in Idiopathic Membranous Nephropathy / 现代检验医学杂志

Objective To analyze the expression of serum anti M phospholipase A2 receptor (PLA2R)antibody in idiopathic membranous nephropathy (IMN),and to investigate its value in the diagnosis and evaluation of idiopathic membranous ne-phropathy.Methods One hundred and eighteen patients with biopsy-proved glomerular diseases were involved in this study, including 97 cases with IMN,21 cases with IgA nephropathy (IgAN)and 19 healthy people.ELISA was used to detect ser-um anti-PLA2R antibodies.Correlations of anti-PLA2R antibody level with laboratory parameters,including serum albumin, 24-hour urine protein of IMN patients were evaluated.Results The median of anti PLA2R antibody in IMN group,IgAN group and healthy group was 45.2(3.6~705.9)RU/ml,5.9(2.3~10.6)RU/ml and 1.2(0.6~9.3)RU/ml.The levels of serum anti PLA2R antibody in IMN group were higher than those in IgA nephropathy group and healthy control group.The difference was statistically significant (t=-5.027,-3.077;P=0.05).Among 97 cases with IMN,76 cases showed posi-tive anti-PLA2R antibodies (positive rate 78.35%).There was none patient showed positive anti-PLA2R antibody respec-tively in IgAN and healthy people.Furthermore,anti-PLA2R antibody level was negatively correlated with serum albumin (r=-0.453,P=0.000)and positively correlated with CREA,TC,ESR,24 hour urine protein (r=0.233,0.234,0.363, 0.586;P=0.004,0.217,0.021,0.000)in IMN patients.Conclusion Serum anti PLA2R antibody may be used as a IMN specific marker for the diagnosis of IMN,and it has important reference value for evaluating the severity of IMN.

Serum anti-phospolipase A2 receptor antibodies and glomerular IgG4 in the diagnosis of membranous nephropathy / 中华肾脏病杂志

Objective To discuss the relationship between serum anti-Phosphalipase A2 receptor (PLA2R) antibodies and glomerular IgG4 subclass in patients with membranous nephropathy and evaluate the diagnostic value of the two markers.Methods Patients diagnosed as membranous nephropathy from October 2011 to April 2014 in Peking Union Medical College Hospital were included and divided into IMN and SMN groups accoding to their clinical diagnosis.Serum anti-PLA2R antibodies and glomerular IgG subclasses were both detected by indirect immunofluorescence assay.Receiver operator characteristic curves were used to evaluate the diagnostic efficiency of anti-PLA2R antibodies and glomerular IgG4.Results Prevalence of serum anti-PLA2R antibodies of IMN patients was 69.5％ (41/59); prevalence of MLN patients was 4.8％ (1/21).Within the IMN group,thirty-five patients showed positive results of both serum anti-PLA2R antibodies and glomerular IgG4; Six patients were positive for serum anti-PLA2R antibodies but negative for glomerular IgG4; Seventeen patients were positive for glomerular IgG4 but negative for serum anti-PLA2R antibodies; one patient was negative for both tests.The sensitivity of serum anti-PLA2R antibody was 69.5％ and the specificity was 95.2％; the sensitivity of glomerular IgG4 was 89.8％ and the specificity was 52.3％.The sensitivity of the combined marker consisting of serum anti-PLA2R antibody and glomerular IgG4 was 59.3％ and the specificity was 100％.Four out of the six patients secondary to HBV infection,one out of the three patients secondary to Sj(o)gren syndrome,one out of the three patients secondary to malignant tumor showed positive results of serum anti-PLA2R antibodies.Conclusions Serum antiPLA2R antibodies were of high prevalence among IMN patients; the prevalence among SMN patients varied with etiologies.Results of serum anti-PLA2R antibodies and glomerular IgG4 were helpful to rule out secondary etiologies in the diagnosis of membrnous nephropathy.

Diagnostic value of serum anti-PLA2 R in idiopathic membranous nephropathy:a meta-analysis / 中国免疫学杂志

Objective:To investigate the value of serum anti-PLA2 R as a diagnostic marker of idiopathic membranous nephropathy( IMN).Methods:All available articles about serum anti-PLA2 R as a marker of IMN which were published at home and abroad from 2009.1 to 2013.12 were pooled from the databases of PubMed,Elsevier,Springer,CNKI,VIP and Wanfang database et al. The quality of the papers were evaluated by the quality assessment for studies of diagnostic accuracy studies( QUADAS).And then a meta-analysis was conducted by the statistical softwares of Meta-Disc and Stata.The diagnostic value of serum anti-PLA2 R in IMN was evaluated by the statistical indicators of pooled sensitivity, pooled specificity, pooled likelihood ratio and summary receiver operating characteristic curve( ROC curve).Sensitivity analysis was performed by reducing a paper in order,and publication bias was tested by Egger funnel plot.Results: Seven articles were selected to the meta-analysis according to the inclusion criteria and 967 cases were included in the study ( 454 IMN patients and 513 controls ).Heterogeneity test showed no heterogeneity threshold effect ( Spearman correlation coefficient was 0.107,P=0.819),but there was heterogeneity caused by non threshold effects(Cochrane-Q was 16.89,P=0.009 7).So random model was used to pool the effect size.The overall combined effect sizes:sensitivity was 69%,95%CI:0.65-0.73;specificity:98%,95%CI:0.96-0.99;pooled positive likelihood ratio 16.37,95%CI:4.06-65.95;pooled negative likelihood ratio 0.32,95%CI:0.24-0.43;AUC of SROC:0.854 0,Q*=0.785 0.Sensitivity analysis showed that this research was stable and reliable and Egger funnel plot showed little publication bias.Conclusion: Serum anti-PLA2 R is an useful biomarker to the diagnosis of IMN.