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Portuguese Journal of Nephrology & Hypertension

versão impressa ISSN 0872-0169

Port J Nephrol Hypert vol.29 no.1 Lisboa mar. 2015

 

ORIGINAL ARTICLE

 

Anti-phospholipase A2 receptor antibodies in the diagnosis of idiopathic membranous nephropathy

Anticorpo anti recetor da fosfolipase A2 no diagnóstico de nefropatia membranosa idiopática

 

Guida Meneses1, Helena Viana1,2, Maria C. Santos3, Carina Ferreira1, Joaquim Calado1, Fernanda Carvalho2, Francisco Remedio1, Fernando Nolasco1

1 Nephrology Department, Hospital Curry Cabral. Lisbon, Portugal

2 Renal Morphology Laboratory, Hospital Curry Cabral. Lisbon, Portugal

3 Immunology Laboratory, Hospital Curry Cabral. Lisbon, Portugal

 

Correspondence to:

 

ABSTRACT

Circulating anti-phospholipase A2 receptor antibodies (anti-PLA2R) have been described in 70% to 80% of the patients with idiopathic membranous nephropathy (iMN), but not in patients with secondary membranous nephropathy or other glomerular diseases. The goal of this study was to evaluate the sensitivity and specificity of the assay for anti-PLA2R in the diagnosis of iMN. Anti-PLA2R IgG, Elisa and immunofluorescence tests were used to detect circulating anti-PLA2R. These tests were applied in 53 patients who had a kidney biopsy. Of these, 38 had histological diagnosis of membranous nephropathy (MN) and the remaining had other glomerular diseases. The MN was classified as idiopathic in 33 patients after clinical exclusion of secondary causes. Anti-PLA2R were positive in 57.6% of the patients with iMN. All patients with secondary membranous nephropathy or other glomerular diseases did not show circulating anti-PLA2R. The sensitivity was 57.6% (CI 39.2-74.5) and specificity 100% (CI 47.8-100), AUC 0.788; p < 0.0001 for the detection of iMN. 71.4% of the iMN patients that tested negative for anti-PLA2R were in partial or complete remission. The detection of anti-PLA2R in the studied population had a specificity of 100% for the iMN diagnosis. Prior treatments seem to make the test negative and contribute to a lower sensitivity.

Key-Words: Anti-phospholipase A2 receptor; idiopathic membranous nephropathy; nephrotic syndrome; podocyte.

 

RESUMO

Anticorpos circulantes anti recetor da fosfolipase A2 (anti-RFLA2) têm sido descritos em 70% a 80% dos doentes com nefropatia membranosa idiopática (NMi) mas não em doentes com nefropatia membranosa secundária ou outras doenças glomerulares. O objetivo deste estudo foi avaliar a sensibilidade e especificidade do teste para anti-RFLA2 no diagnóstico de NMi. Foram utilizados os testes Elisa e imunofluorescência para deteção do Anti-RFLA2, IgG. Estes testes foram aplicados a 53 doentes com biópsia renal. Destes, 38 tiveram o diagnóstico histológico de nefropatia membranosa (NM), enquanto os restantes 15 doentes apresentaram outras doenças glomerulares. A NM foi classificada como idiopática em 33 doentes, após exclusão de causas secundárias. O Anti-RFLA2 foi positivo em 57,6% (n = 19) dos doentes com NMi. Todos os doentes com nefropatia membranosa secundária ou outras doenças glomerulares não apresentaram anti-RFLA2. A sensibilidade foi de 57,6% (IC 39,2-74,5) e a especificidade de 100% (IC 47,8-100), AUC 0,788; p < 0,0001 para a deteção de NMi. 71,4% (n = 10) dos 14 doentes com NMi que tiveram teste negativo para anti-RFLA2 estavam em remissão parcial ou completa. A deteção do anti-RFLA2 na população estudada apresentou uma especificidade de 100% para o diagnóstico de NMi. O sucesso do tratamento prévio terá contribuído para a baixa sensibilidade.

Palavras-Chave: Anti recetor da fosfolipase A2; nefropatia membranosa idiopática; podócito; síndrome nefrótico.

 

INTRODUCTION

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with up to one-third of patients progressing to end-stage renal disease1,2.

This is an auto-immune disease that affects the kidney glomerulus, resulting from the formation of immune deposits on the outer regions of the glomerular basement membrane. This disease is classified as idiopathic when any identified aetiology is excluded, or secondary if caused by other clinical conditions.Recently the identification of several antigens has helped understanding the molecular bases of MN3,4.

The M-type phospholipase A2 receptor (PLA2R) was identified as autoantigen in the idiopathic membranous nephropathy (iMN). This is located in the glomerular capillary wall at the podocyte cell membrane5.

The phospholipase A2 receptor (PLA2R) is a type I transmembrane glycoprotein related to the C-type animal lectin family that includes the mannose receptor. PLA2R regulates a variety of biological responses elicited by specific types of secretory phospholipase A2 (sPLA2s). Group IB sPLA2 (sPLA2-IB) acts as an endogenous PLA2R ligand that induce responses like cell proliferation, cell migration, and lipid mediator production6.

Circulating anti-phospholipase A2 receptor antibodies (anti-PLA2R) has been described in 70% to 80% of the patients with iMN, but not in patients with other glomerular diseases and rarely in secondary membranous nephropathy7. The use of anti-PLA2R has been evaluated, however, doubts remain about whether it is a sensitive and specific marker for iMN.

The goal of this study was to evaluate the sensitivity and specificity of the assay for anti-PLA2R in the diagnosis of iMN.

SUBJECTS AND METHODS

The population was chosen among patients (n = 53) followed in Nephrology Clinic, with nephrothic syndrome/nephrotic proteinuria and histological diagnosis by kidney biopsy.

Anti-PLA2R IgG, Elisa and immunofluorescence tests were used to detect serum circulating anti-PLA2R. The tests were applied prospectively for 18 months (November 2011 to May 2013).

Secondary causes of MN were excluded after clinical workup including detailed medical history, clinical examination, analysis like lupus antibodies, hepatitis B, C and HIV, and at least chest X-ray and abdominal ultrasound.

The Fisher exact test was used to compare variables.

A ROC curve was used to determine the sensitivity and specificity of the assay, and p < 0.05 was considered as statistically significant. Medcalc 12.4.0 was used as statistical software.

RESULTS

The results of biopsies of the 53 patients evaluated are listed in Table I. Of these, 38 had histological diagnosis of membranous nephropathy and the remaining 15 patients had other glomerular diseases.

 

 

We did not find histological differences between idiopathic and secondary MN. The MN was idiopathic after clinical exclusion of secondary causes in 33 patients. The characteristics of iMN patients are listed in Table II.

 

 

Anti-PLA2R was positive in 57.6% (n = 19) of the 33 patients with iMN. All patients with secondary membranous nephropathy or other glomerular diseases did not show circulating anti-PLA2R (Table III).

 

 

The sensitivity was 57.6% (CI 39.2-74.5) and specificity 100% (CI 47.8-100), AUC 0.788; p < 0.0001 for the detection of iMN (Fig. 1).

 

 

Ten (71.4%) of the 14 iMN patients with negative test for anti-PLA2R were already in treatment when the test was done and were in partial or complete remission of the disease (Table IV). In three patients the test was repeated and we observed that Anti-PLA2R became negative in two patients with iMN after treatment with cyclosporine and Anti-PLA2R became positive in one patient with relapse.

 

 

DISCUSSION

Anti-PLA2R in the studied population was only detected in the serum of patients with idiopathic MN and was negative in all patients with secondary MN or with other glomerular diseases. The high specificity of this test can help to make a diagnosis in patients with nephrotic syndrome/nephrotic proteinuria when a kidney biopsy is not performable. A positive test in these patients is highly suggestive of an idiopathic MN as the cause of the disease2,3.

Our study demonstrated a low sensitivity for idiopathic MN diagnosis (57.5%). We think that this result was the consequence of some patients being already in treatment when the test was done. Some authors showed reduction of the antibody levels with treatment8,11. It seems that the treatment and the disease remission are associated to a negative test in patients with idiopathic MN proven by biopsy and a negative clinical evaluation.

This test seems to be a useful predictor of iMN with a high diagnostic value for iMN at the active stage. Other studies also showed high specificity in predicting IMN (between 91% and 100%) and a lower sensitivity for both active and remission stages (between 47% and 69%)9-11,13. Three patients had successive determinations of Anti-PLA2R. This test became negative in two patients with iMN after treatment with cyclosporine. Anti-PLA2R became positive in one patient with relapse. The usefulness of this assay as a treatment response marker should be evaluated.

All patients with sMN tested negative. The test proved consistently negative in patients with lupus nephritis12.

These findings strongly suggest that lupus MN is not related to PLA2R. All in all, large-cohort prospective studies are required, integrating the degree of proteinuria, immunosuppressive treatment, time of observation, repetitive measurements of anti-PLA2R levels and glomerular immune deposits of anti-PLA2R13,14.

 

References

1. McGrogan A, Franssen CF, De Vries CS. The incidence of primary glomerulonephritis worlwide: A systematic review of the literature. Nephrol Dial Transplant 2011; 26(2):414-430.         [ Links ]

2. Segal PE, Choi MJ Recent advances and prognosis in idiopathic membranous nephropathy. Adv Chronic Kidney Dis 2012;19(2):114-119.         [ Links ]

3. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361(1):11-21.

4. Glassock RJ, The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey. Am J Kidney Dis 2010;56(1):157-167.         [ Links ]

5. Ronco P, Debiec H. Antigen identification in membranous nephropathy moves toward targeted monitoring and new therapy. J Am Soc Nephrol 2010; 21(4):564-569.         [ Links ]

6. Hanasaki K, Arita H. Phospholipase A2 receptor: a regulator of biological functions of secretor phospholipase A2. Prostaglandins Other Lipid Mediat 2002;68-69: 71-82.         [ Links ]

7. Debiec H, Ronco P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy. N Engl J Med 2011; 364(7):689-690.         [ Links ]        [ Links ]

9. Behnert A, Fritzler MJ, Teng B, et al. An anti-phospholipase A2 receptor quantitative immunoassay and epitope analysis in membranous nephropathy reveals different antigenic domains of the receptor. PLoS One 2013;8(4):e61669.         [ Links ]

10. Kanigicherla D, Gummadova J, McKenzie EA et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy. Kidney Int 2013;83(5):940-948,         [ Links ]

11. Oh YJ, Yang SH, Kim DK, Kang SW, Kim YS Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy. PLoS One 2013;8(4):e62151.         [ Links ]

12. Gunnarsson I, Schlumberger W, Rönnelid J. Antibodies to M-type phospholipase A2 receptor (PLA2R) and membranous lupus nephritis. Am J Kidney Dis 2012;59(4):585-586.         [ Links ]

13. Hu SL, Wang D, Gou WJ, Lei QF, Ma TA, Cheng JZ. Diagnostic value of phopholipase A2 receptor in idiopathic membranous nephropathy: a systematic review and metaanalysis. J Nephrol 2014;27(2):111-116.         [ Links ]

14. Hofstra JM, Wetzels JF. Anti-PLA2R antibodies in membranous nephropathy: ready for routine clinical practice? Neth J Med 2012;70(3):109-113.         [ Links ]

 

Correspondence to:

Drª Guida Menezes

Nephrology Department, Hospital de Curry Cabral. Centro Hospitalar de Lisboa Central

Rua Beneficência 8, 1069-166 Lisbon, Portugal.

E-mail: guidameneses@gmail.com

 

Conflict of interest statement: None declared

 

Received for publication: 20/08/2014

Accepted in revised form: 03/11/2014

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