Diagnostic accuracy of anti-phospholipase A2 receptor (PLA2R) antibodies in idiopathic
      membranous nephropathy: an Italian experience

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Abstract

Background

Autoantibodies against-phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (iMN). Enzyme-linked immunosorbent assay (ELISA) is becoming the preferred method in many laboratories for the determination of anti-PLA2R antibodies, because it provides quantitative results, and is not prone to subjective interpretation, as is the case with indirect immunofluorescence assay.

Methods

The purpose of our study was to determine the diagnostic performance of serum PLA2R antibodies detected by commercially available ELISA in a large Italian multicenter cohort of patients with biopsy-proven iMN and in patients with other renal diseases, with special focus on evaluating the optimal cut-off value to discriminate positive and negative results. A total of 495 consecutive patients were recruited. Renal biopsies were performed in all patients, and blood samples were taken before the initiation of immunosuppressive treatment.

Results

According to the clinical diagnosis and to kidney biopsy, 126 patients were diagnosed with iMN and 369 had other non-membranous nephropathies. Anti-PLA2R autoantibodies were detected using a commercial anti-PLA2R ELISA. At a cut-off value of 20 relative units (RU)/ml indicated by the manufacturer for positive classification, sensitivity was 61.1% and specificity 99.7%. At a cut-off value of 14 RU/ml indicated by the manufacturer for borderline results, sensitivity was 63.5% and specificity remained the same (99.7%). At a cut-off of 2.7 RU/ml, selected as the optimal cut-off on the basis of ROC curve analysis, sensitivity was 83.3% and specificity 95.1%. The best overall efficiency of the test was observed at 2.7 RU/ml; however, the highest positive likelihood ratio and diagnostic odds ratio were achieved at 14 RU/ml. A cut-off threshold higher than 14 RU/ml or lower than 2.7 RU/ml entailed worse test performance.

Conclusion

Depending on the clinical use (early diagnosis or as a support to confirm clinical diagnosis), nephrologists may take advantage of this evidence by choosing the most convenient cut-off. However, renal biopsy remains mandatory for the definitive diagnosis of iMN and for the assessment of disease severity.

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Most cited references 30

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A new equation to estimate glomerular filtration rate.

Andrew Levey, Lesley Stevens, Christopher H Schmid … (2009)

Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.

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M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.

Gérard Lambeau, Ramon G. Bonegio, Judith Beck … (2009)

Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown. We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody. Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA(2)R. A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease. 2009 Massachusetts Medical Society

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Primary Membranous Nephropathy.

William G. Couser (2017)

Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.

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Author and article information

Contributors

Brunetta Porcelli:

ORCID: http://orcid.org/0000-0002-7447-9136

brunetta.porcelli@unisi.it

Journal

Journal ID (nlm-ta): J Nephrol

Journal ID (iso-abbrev): J Nephrol

Title: Journal of Nephrology

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1121-8428

ISSN (Electronic): 1724-6059

Publication date (Electronic): 29 October 2020

Publication date PMC-release: 29 October 2020

Publication date (Print): 2021

Volume: 34

Issue: 2

Pages: 573-579

Affiliations

[1 ]GRID grid.9024.f, ISNI 0000 0004 1757 4641, Dipartimento Biotecnologie Mediche, Sezione Biochimica, , Università degli Studi di Siena, Polo Scientifico Universitario San Miniato, ; Via Alcide De Gasperi 2, 53100 Siena, Italy

[2 ]UOC Laboratorio Patologia Clinica, Policlinico S. Maria Alle Scotte, AOU Senese, Siena, Italy

[3 ]UOC Nefrologia, Dialisi e Trapianti, Policlinico S. Maria alle Scotte, AOU Senese, Siena, Italy

[4 ]GRID grid.9024.f, ISNI 0000 0004 1757 4641, Dipartimento Scienze Mediche, Chirurgiche e Neuroscienze, , Università degli Studi di Siena, ; Siena, Italy

[5 ]UOC Patologia Clinica Universitaria, Dipartimento Scienze Biomediche e Oncologia Umana, Azienda Ospedaliero-Universitaria, Policlinico di Bari, Bari, Italy

[6 ]UOC Nefrologia Universitaria, Dipartimento dell’Emergenza e dei Trapianti d’Organo, Azienda Ospedaliero-Universitaria, Policlinico di Bari, Bari, Italy

[7 ]GRID grid.416290.8, ISNI 0000 0004 1759 7093, Laboratorio Unico Metropolitano, Ospedale Maggiore, ; Bologna, Italy

[8 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Dipartimento Scienze Mediche e Chirurgiche, , Università degli Studi di Bologna, ; Bologna, Italy

[9 ]GRID grid.6292.f, ISNI 0000 0004 1757 1758, Dipartimento Medicina Specialistica, Diagnostica e Sperimentale, , Università degli Studi di Bologna, ; Bologna, Italy

[10 ]UO Nefrologia, Dialisi e Trapianto, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy

[11 ]U.O. Nefrologia, Dialisi e Ipertensione, Azienda Ospedaliera-Universitaria Sant’Orsola, Bologna, Italy

[12 ]Laboratorio Immunologia e Allergologia, Dipartimento di Medicina di Laboratorio, Ospedale San Giovanni di Dio, AUSL Toscana Centro, Firenze, Italy

[13 ]SOC Nefrologia e Dialisi, Ospedale San Giovanni di Dio, AUSL Toscana Centro, Firenze, Italy

[14 ]GRID grid.415194.c, ISNI 0000 0004 1759 6488, SOC Nefrologia e Dialisi, Ospedale Santa Maria Annunziata, AUSL Toscana Centro, ; Firenze, Italy

[15 ]GRID grid.411492.b, Laboratorio di Patologia Clinica, Ospedale San Antonio, , Azienda Sanitaria Universitaria Integrata di Udine, ; Tolmezzo, Italy

Author information

Brunetta Porcelli http://orcid.org/0000-0002-7447-9136

Article

Publisher ID: 888

DOI: 10.1007/s40620-020-00888-w

PMC ID: 8036194

PubMed ID: 33123964

SO-VID: b5b7f2a5-eac2-4278-95de-62bf3f66524e

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 April 2020

Date accepted : 10 October 2020

Funding

Funded by: Università degli Studi di Siena

Open Access :

Open access funding provided by Università degli Studi di Siena within the CRUI-CARE Agreement.

Custom metadata

Keywords: anti-phospholipase a2 receptor (pla2r) autoantibodies,membranous nephropathy,cut-off value,enzyme-linked immunosorbent assay (elisa)

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Keywords: anti-phospholipase a2 receptor (pla2r) autoantibodies, membranous nephropathy, cut-off value, enzyme-linked immunosorbent assay (elisa)

Diagnostic accuracy of anti-phospholipase A2 receptor (PLA2R) antibodies in idiopathic membranous nephropathy: an Italian experience

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Abstract

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Results

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Italian Studies

Most cited references 30

A new equation to estimate glomerular filtration rate.

M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.

Primary Membranous Nephropathy.

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Contributors

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