Classify subtype, guide therapy, and monitor responses

The leading cause of nephrotic syndrome

Membranous nephropathy (MN) is one of the leading causes of nephrotic syndrome in adults. It is traditionally classified into primary and secondary membranous nephropathy. Cases without associated disorders are termed primary membranous nephropathy (PMN) while cases associated with other conditions, such as different autoimmune diseases, infectious or parasitic disease, tumor, or adverse reactions to certain medications, are referred to as secondary membranous nephropathy (SMN).

As more antigens that autoantibodies recognize are being identified, the distinction between PMN and SMN is becoming blurred. While certain target antigens are more strongly associated with specific secondary causes,1 other autoantibodies associated with the same antigen can be associated with both types. The variable and unpredictable natural course of MN and other associated diseases results in ongoing challenges for disease management.2

By the numbers

70%

of patients with primary MN are positive for PLA2R

2-5%

of patients with primary MN are positive for NELL-1

1%

of patients with primary MN are positive for THSD7A




A distinct classification

Historically, autoantibodies against the podocyte protein M-type phospholipase A2 receptor (PLA2R) in the kidney have been determined as the major target antigen for patients with PMN.3 A 2014 study identified antithrombospondin type-1 domain-containing 7A (THSD7A) as another target antigen in ~1% of patients with PMN.4 More recently, Mayo Clinic researchers identified several additional antigens associated with MN, including neural epidermal growth factor-like 1 (NELL-1),5  exostosin1/2,6 semaphorin 3B (Sema3B),7 protocadherin 7 (PCDH7),8 and protocadherin FAT1 (FAT1).9

Testing improves patient outcomes

Extensive clinical, laboratory, and pathologic evaluation is required to accurately identify the underlying etiology of the different types of MN. Mayo Clinic Laboratories offers comprehensive renal testing services, concise results, and access to more than 150 years of advanced medical knowledge to deliver answers your practice needs to increase accuracy, improve outcomes, and keep care local.

Identify the antigen

Mayo Clinic Laboratories offers a comprehensive menu of clinically validated assays to assist with the diagnosis of PMN, monitor disease progression, and guide clinical outcomes.

PMND1 | Primary Membranous Nephropathy Diagnostic Cascade, Serum

  • Detects low levels of anti-PLA2R antibodies in patients with borderline or negative PLA2R ELISA results.
  • Distinguishes PLA2R-associated MN from THSD7-associated MN in patients with biopsy-proven MN.
  • Determines levels of anti-PLA2R antibodies to predict remission or disease relapse status.
  • Determines relapse or presence of untreated disease in chronic kidney disease patients awaiting a transplant.
  • Provides an alternative diagnostic option for some patients who cannot undergo a kidney biopsy due to contraindications.
    • New KDIGO guidelines suggest a PMN diagnosis can be confirmed for PLA2R via ELISA or IFA if the eGFR is >60 and SMN causes are nonexistent.

PLA2M | Phospholipase A2 Receptor, Enzyme-Linked Immunosorbent Assay, Serum

  • Monitoring disease progression in patients with confirmed PLA2R-associated PMN.
  • Guiding immunosuppressive therapy in patients with confirmed PLA2R-associated PMN.

PLA2I | Phospholipase A2 Receptor, Immunofluorescence, Serum

  • Confirming remission of PLA2R-associated PMN after immunosuppressive therapy has been initiated and PLA2R ELISA titres are borderline or low.
  • Rule out false positive PLA2R ELISA result.

THSD7 | Thrombospondin Type-1 Domain-Containing 7A Antibodies, Serum

  • Confirm disease subtype in a patient with biopsy-proven MN who is PLA2R-negative.
  • Monitoring disease progression in patients with confirmed THSD7-associated PMN.
  • Guiding immunosuppressive therapy in patients with confirmed THSD7-associated PMN.

A Test in Focus

John Lieske, M.D., describes Mayo Clinic Laboratories' new test for primary membranous nephropathy. PMND1 is a diagnostic cascade that provides a cost-effective approach to detecting antigens known to cause membranous nephropathy — a condition that can lead to kidney failure.

Confirm the causation

Mayo Clinic Laboratories offers a comprehensive menu of ancillary renal pathology tests to assist with the diagnosis of membranous nephropathy.

RPCWT | Renal Pathology Consultation, Wet Tissue

*Note: RPCWT automatically performs IF staining for PLA2R if MN is present (based on LM and IF). If PLA2R IF is negative, IF staining for THSD7A and IHC staining for NELL-1 will be performed.


A Test in Focus

Sanjeev Sethi, M.D., Ph.D., discusses how Mayo Clinic Laboratories’ new immunohistochemistry test for the detection of NELL-1 antigen, a biomarker for membranous nephropathy found in 10% to 15% of all MN patients, provides diagnostic certainty and insight on disease expression.

Learn more about how to order this evaluation at your institution.


References

  1. Sethi S. New ‘antigens’ in membranous nephropathy. J Am Soc Nephrol. 2021 Feb;32(2):268-278. doi:10.1681/ASN.2020071082. Epub 2020 Dec 30. PMID: 33380523; PMCID: PMC8054892.
  2. Dahan K, Gillion V, Johanet C, Debiec H, Ronco P. The role of PLA2R antibody in treatment of membranous nephropathy. Kidney Int Rep. 2017 Nov 3;3(2):498-501. doi:10.1016/j.ekir.2017.10.013. PMID: 29725656; PMCID: PMC5932125.
  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 Jul 2;361(1):11-21. doi:10.1056/NEJMoa0810457. PMID: 19571279; PMCID: PMC2762083.
  4. Tomas NM, Beck LH Jr, Meyer-Schwesinger C, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014 Dec 11;371(24):2277-2287. doi:10.1056/NEJMoa1409354. Epub 2014 Nov 13. PMID: 25394321; PMCID: PMC4278759.
  5. Sethi S, Debiec H, Madden B, et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int. 2020 Jan;97(1):163-174. doi:10.1016/j.kint.2019.09.014. Epub 2019 Oct 7. PMID: 31901340.
  6. Sethi S, Madden BJ, Debiec H, et al. Exostosin 1/exostosin 2-associated membranous nephropathy. J Am Soc Nephrol. 2019 Jun;30(6):1123-1136. doi:10.1681/ASN.2018080852. Epub 2019 May 6. PMID: 31061139; PMCID: PMC6551791.
  7. Sethi S, Debiec H, Madden B, et al. Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients. Kidney Int. 2020 Nov;98(5):1253-1264. doi:10.1016/j.kint.2020.05.030. Epub 2020 Jun 11. PMID: 32534052.
  8. Sethi S, Madden B, Debiec H, et al. Protocadherin 7-associated membranous nephropathy. J Am Soc Nephrol. 2021 May 3;32(5):1249-1261. doi:10.1681/ASN.2020081165. Epub 2021 Apr 8. PMID: 33833079; PMCID: PMC8259689.
  9. Sethi S, Madden B, Casal Moura M, et al. Hematopoietic stem cell transplant-membranous nephropathy is associated with protocadherin FAT1. J Am Soc Nephrol. 2022 Mar 23:ASN.2021111488. doi:10.1681/ASN.2021111488. Epub ahead of print. PMID: 35321939.
  10. Bobart S, Tehranian S, Sethi S, et al. A target antigene-based approach to the classification of membranous nephropathy. Mayo Clin Proc. 2021;96(3):577-591, ISSN 0025-6196, https://doi.org/10.1016/j.mayocp.2020.11.028