Etiological differentiation optimizes diagnosis

Distinguishing primary from secondary membranous nephropathy

One of the main causes of nephrotic syndrome in adults, membranous nephropathy (MN), is most often autoimmune in nature due to autoantibodies against the phospholipase A2 receptor (PLA2R). These cases are referred to as primary MN. The remainder of cases are referred to as secondary MN and are associated with other autoantibodies related to other diseases or exposures. The natural course of MN varies and cannot be predicted, resulting in ongoing challenges for disease management.

A distinct classification

Membranous nephropathy occurs as a result of the accumulation of immune complexes, or antigen-antibody complexes, along the subepithelial region of the glomerular basement membrane. Until recently, researchers and clinicians described primary MN as idiopathic; however, the discovery of two target antigens for immune complexes, PLA2R in 2009, and THSD7A in 2014, established MN as a kidney-specific autoimmune disease.

Advancing discovery

The presence of PLA2R and THSD7A accounts for approximately 70% of primary MN cases. In 2019, Mayo Clinic researchers identified another antigen-antibody complex, identified as neural epidermal growth factor-like 1 (NELL-1), as the second most common antigen associated with primary MN. Classification of MN disease subtypes is critical to ensure accurate diagnosis and intervention.

By the numbers


of patients with primary MN are positive for PLA2R


of patients with primary MN are positive for NELL-1


of patients with primary MN are positive for THSD7A

Your partner for accuracy

Extensive clinical, laboratory, and pathologic evaluation to accurately identify the underlying etiology is required to distinguish primary MN from secondary MN.1  Mayo Clinic Laboratories offers comprehensive renal testing services, concise results, and access to more than 150 years of advanced medical knowledge to deliver the answers your practice needs to increase accuracy, improve outcomes, and keep care local.

A Test in Focus

John Lieske, M.D., gives an overview of the phospholipase A2 receptor antibodies testing available through Mayo Clinic Laboratories. He discusses when this testing should be ordered, how this testing improves upon previous testing approaches, and what clinical action can be taken due to the results of this testing.

Identify the antigen

PLA2R | Phospholipase A2 Receptor Antibodies, Serum

Anti-phospholipase A2 receptor (PLA2R) antibodies are highly specific for the diagnosis of primary MN. A titer increase, decrease, or disappearance generally precedes a change in clinical status.

Clinical utility

  • Distinguishes primary from secondary MN
  • Determines PLA2R antibody levels to predict remission or disease relapse (PLA2R test only)
  • Guides treatment plan by determining if an immunological remission is achievable
  • Determines the likelihood of associated diseases or exposures
  • Determines relapse recurrence in chronic kidney disease patients awaiting transplant
  • Provides an alternative diagnostic option for patients who cannot undergo kidney biopsies

Confirm the causation

Comprehensive, clinically validated testing elevates primary MN diagnosis. Mayo Clinic Laboratories offers a full menu of assays to assess renal pathologies.

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.

NELL1 | Neural Epidermal Growth Factor-Like 1 Protein Immunostain, Technical Component Only (Temporarily unavailable)

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.


  1. Couser WG. Primary Membranous Nephropathy [published correction appears in Clin J Am Soc Nephrol. 2017 Sep 7;12 (9):1528]. Clin J Am Soc Nephrol. 2017;12(6):983–997.
  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;3(2):498–501.
  3. Floege J,Barbour SJ, Cattran DC, et al. Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kid Int. 2019;95(2):268–280.
  4. Anis S. Role of immunology laboratory in diagnosing renal diseases. Clin Nephrol Res. 2018;2(1):26-31.
  5. Sanjeev, S. New ‘Antigens’ in Membranous Nephropathy. Journal of American Society of Nephrology. 2021;32(2);268-278.