nach oben

Erschienen in:

01.08.2018 | Original Article

Routine immunohistochemical staining in membranous nephropathy: in situ detection of phospholipase A2 receptor and thrombospondin type 1 containing 7A domain

verfasst von: Vincenzo L’Imperio, Federico Pieruzzi, Renato Alberto Sinico, Manuela Nebuloni, Antonio Granata, Andrew Smith, Antonella Radice, Fabio Pagni

Erschienen in: Journal of Nephrology | Ausgabe 4/2018

Einloggen, um Zugang zu erhalten

Abstract

Background

Membranous nephropathy (MN) can be idiopathic (iMN) or manifest as a result of systemic underlying conditions as a secondary epiphenomenon. For the prognostic and predictive consequences of this discrimination, the routine use of reliable markers is crucial. This large MN series aimed to evaluate the routine and standardized immunohistochemical (IHC) employment of a panel of 3 biomarkers—phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), and immunoglobulin (Ig)G4—in the differential diagnosis of MN forms, contributing to the validation of the technique and the correct interpretation of reproducible patterns of reactivity.

Methods

We classified 95 patients with a biopsy proven diagnosis of MN as primary (n = 72) or secondary (n = 23) cases based on clinical data. After performing an IHC assay directed against PLA2R, THSD7A and IgG4 antigens, samples were interpreted by three different nephropathologists to assess the positivity/negativity of the staining according to new interpretation criteria.

Results

Useful interpretation criteria were introduced to exclude false positive patterns of reactivity and to identify only true granular membranous or mesangial deposits in MN. The IHC directed against PLA2R resulted positive in 51 iMN cases and negative in 21, while 4/23 secondary forms were considered positive. Based on these data the technique showed a sensitivity of 71% and specificity of 83%. On the other hand, the IHC analysis for IgG4 resulted positive in 44 cases of iMN and negative in 28 cases, while only 4/23 secondary forms were positive (same cases positive to PLA2R). Finally, THSD7A was found to be positive only in 1 case, which was negative to PLA2R and IgG4. The combination of the results allowed a classification of the series into two major groups: “double-positive” (PLA2R+/IgG4+/THSD7A−) and “triple-negative” (PLA2R−/IgG4−/THSD7A−) cases.

Conclusions

Based on these data, the diagnostic performance of the three biomarkers used in a “tandem fashion” can reach 79% sensitivity and 83% specificity, significantly reducing the risk of a false-positive or false-negative result and improving the routine characterization of this frequent glomerulonephritis.

Hsu HC, Lin GH, Chang MH, Chen CH (1983) Association of hepatitis B surface (HBs) antigenemia and membranous nephropathy in children in Taiwan. Clin Nephrol 20:121–129PubMed

Slusarczyk J, Michalak T, Nazarewicz-de Mezer T et al (1980) Membranous glomerulopathy associated with hepatitis B core antigen immune complexes in children. Am J Pathol 98:29–43PubMedPubMedCentral

Takekoshi Y, Tanaka M, Shida N et al (1978) Strong association between membranous nephropathy and hepatitis-B surface antigenaemia in Japanese children. Lancet 2:1065–1068CrossRefPubMed

Kleinknecht C, Levy M, Gagnadoux MF, Habib R (1979) Membranous glomerulonephritis with extra-renal disorders in children. Medicine (Baltimore) 58:219–228CrossRef

Ronco P, Debiec H (2014) Anti-phospholipase A2 receptor antibodies and the pathogenesis of membranous nephropathy. Nephron Clin Pract 128:232–237. https://doi.org/10.1159/000368588 CrossRefPubMed

Ponticelli C, Zucchelli P, Passerini P et al (1995) A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 48:1600–1604CrossRefPubMed

Branten AJ, Reichert LJ, Koene RA, Wetzels JF (1998) Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency. QJM Mon J Assoc Physicians 91:359–366CrossRef

Hofstra JM, Fervenza FC, Wetzels JFM (2013) Treatment of idiopathic membranous nephropathy. Nat Rev Nephrol 9:443–458. https://doi.org/10.1038/nrneph.2013.125 CrossRefPubMed

Barbari A (2017) Continuing the paradigm shift in the treatment of idiopathic membranous nephropathy. Nat Rev Nephrol 13:720–720. https://doi.org/10.1038/nrneph.2017.134 CrossRefPubMed

10.

Fiorentino M, Tondolo F, Bruno F et al (2016) Treatment with rituximab in idiopathic membranous nephropathy. Clin Kidney J 9:788–793. https://doi.org/10.1093/ckj/sfw091 CrossRefPubMedPubMedCentral

11.

Moroni G, Depetri F, Del Vecchio L et al (2016) Low-dose rituximab is poorly effective in patients with primary membranous nephropathy. Nephrol Dial Transplant 32:gfw251. https://doi.org/10.1093/ndt/gfw251 CrossRef

12.

Matsui S, Tsuji H, Takimoto Y, Ono S (2011) Clinical improvement of membranous nephropathy after endoscopic resection of double early gastrointestinal cancers. Clin Exp Nephrol 15:285–288. https://doi.org/10.1007/s10157-010-0389-6 CrossRefPubMed

13.

Zheng X-Y, Wei R-B, Tang L et al (2012) Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis. World J Gastroenterol 18:821–832. https://doi.org/10.3748/wjg.v18.i8.821 CrossRefPubMedPubMedCentral

14.

Beck LH, Bonegio RGB, Lambeau G et al (2009) M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361:11–21. https://doi.org/10.1056/NEJMoa0810457 CrossRefPubMedPubMedCentral

15.

Radice A, Pieruzzi F, Trezzi B et al (2017) Diagnostic specificity of autoantibodies to M-type phospholipase A2 receptor (PLA2R) in differentiating idiopathic membranous nephropathy (IMN) from secondary forms and other glomerular diseases. J Nephrol. https://doi.org/10.1007/s40620-017-0451-5 PubMedCrossRef

16.

Debiec H, Ronco P (2014) Immunopathogenesis of membranous nephropathy: an update. Semin Immunopathol 36:381–397. https://doi.org/10.1007/s00281-014-0423-y CrossRefPubMed

17.

Tomas NM, Beck LH, Meyer-Schwesinger C et al (2014) Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 371:2277–2287. https://doi.org/10.1056/NEJMoa1409354 CrossRefPubMedPubMedCentral

18.

Hoxha E, Wiech T, Stahl PR et al (2016) A mechanism for cancer-associated membranous nephropathy. N Engl J Med 374:1995–1996. https://doi.org/10.1056/NEJMc1511702 CrossRefPubMed

19.

Stahl PR, Hoxha E, Wiech T et al (2017) THSD7A expression in human cancer. Genes Chromosom Cancer 56:314–327. https://doi.org/10.1002/gcc.22440 CrossRefPubMed

20.

Larsen CP, Messias NC, Silva FG et al (2013) Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol 26:709–715. https://doi.org/10.1038/modpathol.2012.207 CrossRefPubMed

21.

Svobodova B, Honsova E, Ronco P et al (2013) Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy. Nephrol Dial Transplant 28:1839–1844. https://doi.org/10.1093/ndt/gfs439 CrossRefPubMed

22.

Hoxha E, Kneißler U, Stege G et al (2012) Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int 82:797–804. https://doi.org/10.1038/ki.2012.209 CrossRefPubMed

23.

Lefaucheur C, Stengel B, Nochy D et al (2006) Membranous nephropathy and cancer: epidemiologic evidence and determinants of high-risk cancer association. Kidney Int 70:1510–1517. https://doi.org/10.1038/sj.ki.5001790 CrossRefPubMed

24.

Petri M, Orbai A-M, Alarcón GS et al (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–2686. https://doi.org/10.1002/art.34473 CrossRefPubMedPubMedCentral

25.

Aletaha D, Neogi T, Silman AJ et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581. https://doi.org/10.1002/art.27584 CrossRefPubMed

26.

Dai H, Zhang H, He Y (2015) Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis. Sci Rep 5:8803. https://doi.org/10.1038/srep08803 CrossRefPubMedPubMedCentral

27.

Hara S, Goto S, Kamiura N et al (2015) Reappraisal of PLA2R1 in membranous nephropathy: immunostaining method influence and association with IgG4-dominant phenotype. Virchows Arch An Int J Pathol. https://doi.org/10.1007/s00428-015-1754-3 CrossRef

28.

Qin W, Beck LH, Zeng C et al (2011) Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol 22:1137–1143. https://doi.org/10.1681/ASN.2010090967 CrossRefPubMedPubMedCentral

29.

Xie Q, Li Y, Xue J et al (2015) Renal phospholipase A₂ receptor in hepatitis B virus-associated membranous nephropathy. Am J Nephrol 41:345–353. https://doi.org/10.1159/000431331 CrossRefPubMed

30.

Murtas C, Ghiggeri GM (2016) Membranous glomerulonephritis: histological and serological features to differentiate cancer-related and non-related forms. J Nephrol 29:469–478. https://doi.org/10.1007/s40620-016-0268-7 CrossRefPubMed

31.

De Vriese AS, Glassock RJ, Nath KA et al (2017) A proposal for a serology-based approach to membranous nephropathy. J Am Soc Nephrol 28:421–430. https://doi.org/10.1681/ASN.2016070776 CrossRefPubMed

32.

Behnert A, Fritzler MJ, Teng B et al (2013) An anti-phospholipase A2 receptor quantitative immunoassay and epitope analysis in membranous nephropathy reveals different antigenic domains of the receptor. PLoS One 8:e61669. https://doi.org/10.1371/journal.pone.0061669 CrossRefPubMedPubMedCentral

33.

Fresquet M, Jowitt TA, Gummadova J et al (2015) Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy. J Am Soc Nephrol 26:302–313. https://doi.org/10.1681/ASN.2014050502 CrossRefPubMed

34.

Kao L, Lam V, Waldman M et al (2015) Identification of the immunodominant epitope region in phospholipase A2 receptor-mediating autoantibody binding in idiopathic membranous nephropathy. J Am Soc Nephrol 26:291–301. https://doi.org/10.1681/ASN.2013121315 CrossRefPubMed

35.

Huang CC, Lehman A, Albawardi A et al (2013) IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression. Mod Pathol 26:799–805. https://doi.org/10.1038/modpathol.2012.237 CrossRefPubMed

36.

Larsen CP, Cossey LN, Beck LH (2016) THSD7A staining of membranous glomerulopathy in clinical practice reveals cases with dual autoantibody positivity. Mod Pathol 29:421–426. https://doi.org/10.1038/modpathol.2016.32 CrossRefPubMedPubMedCentral

37.

Polak JM, Varndell IM (1984) Immunolabeling for electron microscopy. Elsevier, Amsterdam

38.

Kim YG, Choi Y-W, Kim S-Y et al (2015) Anti-phospholipase A2 receptor antibody as prognostic indicator in idiopathic membranous nephropathy. Am J Nephrol 42:250–257. https://doi.org/10.1159/000440983 CrossRefPubMed

39.

Timmermans SAMEG., Abdul Hamid MA, Cohen Tervaert JW et al (2015) Anti-PLA2R antibodies as a prognostic factor in PLA2R-related membranous nephropathy. Am J Nephrol 42:70–77. https://doi.org/10.1159/000437236 CrossRefPubMed

40.

Ramachandran R, Hn H, Kumar V et al (2015) Tacrolimus combined with corticosteroids versus modified ponticelli regimen in treatment of idiopathic membranous nephropathy: randomized control trial. Nephrology (Carlton). https://doi.org/10.1111/nep.12569 CrossRef

41.

Ruggenenti P, Debiec H, Ruggiero B et al (2015) Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol 26:2545–2558. https://doi.org/10.1681/ASN.2014070640 CrossRefPubMedPubMedCentral

42.

Glassock RJ (1992) Secondary membranous glomerulonephritis. Nephrol Dial Transplant 7(Suppl 1):64–71PubMed

Titel: Routine immunohistochemical staining in membranous nephropathy: in situ detection of phospholipase A2 receptor and thrombospondin type 1 containing 7A domain
verfasst von: Vincenzo L’Imperio
Federico Pieruzzi
Renato Alberto Sinico
Manuela Nebuloni
Antonio Granata
Andrew Smith
Antonella Radice
Fabio Pagni
Publikationsdatum: 01.08.2018
Verlag: Springer International Publishing
Erschienen in: Journal of Nephrology / Ausgabe 4/2018
Print ISSN: 1121-8428
Elektronische ISSN: 1724-6059
DOI: https://doi.org/10.1007/s40620-018-0489-z

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Background

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2018

Acute and chronic effects of metabolic acidosis on renal function and structure

Role of antiplatelet therapy in the durability of hemodialysis access

Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis

Assessment of physical performance and body composition in male renal transplant patients

Vocational activity and health insurance type among patients with end-stage renal disease: association with outcomes