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    Representative biopsy of 77-year-old man with primary membranous nephropathy (MN)

  • 1.

    Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: An update. Semin Immunopathol 2014; 36:381397. doi: 10.1007/s00281-014-0423-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Fogo AB, et al.. AJKD Atlas of Renal Pathology: Membranous nephropathy. Am J Kidney Dis 2015; 66:e15−e17. doi: 10.1053/j.ajkd.2015.07.006

  • 3.

    Beck LH Jr, et al.. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Tomas NM, et al.. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Sethi S. New ‘antigens’ in membranous nephropathy. J Am Soc Nephrol 2021; 32:268278. doi: 10.1681/ASN.2020071082

  • 6.

    Sethi S, et al.. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int 2020; 97:163174. doi: 10.1016/j.kint.2019.09.014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Sethi S, et al.. Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients. Kidney Int 2020; 98:12531264. doi: 10.1016/j.kint.2020.05.030

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Sethi S, et al.. Protocadherin-7 associated membranous nephropathy. ASN Kidney Week 2020 Reimagined. 2020; FR-OR36. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3445270

    • Search Google Scholar
    • Export Citation
  • 9.

    Sethi S, et al.. Exostosin 1/exostosin 2-associated membranous nephropathy. J Am Soc Nephrol 2019; 30:11231136. doi: 10.1681/ASN.2018080852

  • 10.

    Caza T, et al.. Neural cell adhesion molecule 1 is a novel autoantigen in membranous lupus nephritis. Kidney Int [ published online ahead of print October 9, 2020]. doi: 10.1016/j.kint.2020.09.016; https://www.kidney-international.org/article/S0085-2538(20)31180-7/fulltext

    • Search Google Scholar
    • Export Citation
  • 11.

    Al-Rabadi L, et al.. High temperature recombinant protein A1 (HTRA1): A novel antigen in membranous nephropathy. ASN Kidney Week 2020 Reimagined. 2020; FR-OR35. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3447205

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Newer Antigens and Membranous Nephropathy

  • 1 Randy L. Luciano, MD, PhD, is Associate Professor of Medicine and Associate Program Director, Nephrology Fellowship, at Yale University School of Medicine in New Haven, CT.
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Membranous nephropathy

Membranous nephropathy (MN) is a common cause of nephrotic syndrome, attributed to approximately 25% of adult patients with nephrotic-range proteinuria or nephrotic syndrome (1). This number is significantly less in children with nephrotic syndrome. The clinical course of MN is insidious, with variable degrees of proteinuria, hypoalbuminemia, and hyperlipidemia that can lead to significant edema and in extreme cases, a rapid loss of kidney function, anasarca, acute kidney injury, and thromboembolic events. The clinical presentation is the resulting immune complex formation on the epithelia side of the glomerular basement membrane (GBM).

MN is classified as primary, based on the presence of autoantigens; secondary, based on the association with systemic autoimmune disease, malignancy, medications, or infections; or alloimmune, based on humoral responses between host and donor antigens. Historically, diagnosis of MN was largely clinical, with support from a kidney biopsy showing non-proliferative glomeruli with thickened capillary loops, immunoglobulin G (IgG) and variable C3 positivity on immunofluorescence, and electron microscopy with subepithelial immune complexes in the GBM (Figure 1) (2). Within the last 12 years, there has been the discovery of numerous antigens that not only aid in the diagnosis of MN but that can also be used to gauge prognosis and guide therapy.

Figure 1.
Figure 1.

Representative biopsy of 77-year-old man with primary membranous nephropathy (MN)

Citation: Kidney News 13, 4

(Top left) Hematoxylin and eosin (H&E)-stained section showing a glomerulus with thickened capillary loops. (Top right) Immunofl uorescence with IgG showing glomerular basement membrane staining. (Bottom left) Immunofl uorescence with C3 showing glomerular basement membrane staining. (Bottom right) Electron microscopy showing glomerular basement membrane with subepithelial deposits.

The first antigen: PLA2R

Although the idea that an autoantigen was responsible for the pathophysiology of MN was first demonstrated in 1959, it was not until 2009 that the first antigen, the M-type phospholipase A2 receptor-1 (PLA2R), was identified (3). PLA2R, a 180-kDa transmembrane glycoprotein, is implicated in approximately 80% of all primary membranous cases and 55% of all MN. Since the discovery of PLA2R, there is now a commercially available antibody that has aided in the diagnosis of MN through both tissue-specific antigen staining and through a serum assay. Additionally, serum PLA2R levels have provided a means to identify aggressive disease, monitor treatment, and predict relapse.

The second antigen: THSD7A

Thrombospondin type 1 domain-containing 7A (THSD7A) is a 250-kDa protein that is expressed on the podocyte. The antigenicity of THSD7A was brought to light in 2014 (4). Antibodies against THSD7A are prevalent in up to 10% of all patients with primary MN. In patients with THSD7A-positive MN, there was an upwards of 20% incidence of malignancy within 3 months of diagnosis, suggesting an antigen association to a diagnosis that was formerly thought to be a secondary cause of MN.

Newer antigens

The technique of laser microdissection of glomeruli from patients with antigen-negative primary MN, followed by mass spectroscopy, has led to the identification of newer antigens (5).

Neural epidermal growth factor-like 1 (NELL-1) is a potential podocyte-associated protein that has been implicated as an antigen for MN (6). This 90-kDa secreted protein was identified in approximately 16% of all unidentified MN cases, representing 2.5% of all MN cases. In addition, there has been an association with malignancy in upwards of 33% of patients with MN with detectable antibodies to NELL-1.

Semaphorin-3B (Sema3B) is an 83-kDa secreted protein that has been detected in podocytes (7). Autoantibodies to this antigen were found on immunoblots under reducing conditions, suggesting a difficult-to-identify antigen epitope. Autoantibodies to Sema3B were found in a greater proportion of infants, children, and young adults, some of whom had a known family history. MN from Sema3B autoantibodies accounts for <3% of all MN, but in the pediatric population, this increases to 15% of MN patients.

Protocadherin 7 (PCDH7) is a 116-kDa transmembrane protein, most likely functioning in cell signaling. Autoantibodies to PCDH7 are seen in older patients (mean age of 61) with no apparent disease or malignancy association (8). Biopsy samples of patients with PCDH7 autoantibodies demonstrated trace to no complement activation, a finding that is much different than patients with the other forms of antigen-mediated MN. Interestingly, in patients with PCDH7-associated MN, there was a high percentage of patients who developed spontaneous remission. The presence of PCDH7 may be a marker for disease severity and progression and can have potential use to guide the use or non-use of therapeutic agents in the future; however, more studies are necessary to elucidate this role.

Exostosin 1/Exostosin 2 (EXT1/EXT2) protein complexes have been identified in patients with MN secondary to autoimmune disease, such as systemic lupus erythematosus (SLE) and mixed connective tissue disease (9). EXT1/EXT2-associated MN is more commonly seen in younger patients, with a higher percentage of female patients. However, circulating antibodies to EXT1/EXT2 have not been identified, making the antigenicity of this protein complex unclear at this time.

Potential antigens

Recently, two additional proteins have been identified as potential antigens for MN. Neural cell adhesion molecule 1 (NCAM1) was found to be an antigen in MN, colocalizing to immune complexes in tissue from patients with MN and also present as an autoantibody in serum (10). The prevalence was 6.6% in patients with SLE class V and 2% in patients with primary MN.

Another potential antigen that was recently identified in three patients with primary MN is high-temperature recombinant protein A1 (HTRA1) (11). Anti-HTRA1 antibodies colocalize to the capillary loops with IgG4. Additional studies in large cohorts will be necessary to establish a prevalence of this potential antigen.

Redefining membranous nephropathy

In little over a decade, MN has evolved from a disease that was divided into primary versus secondary disease associations into a syndrome that can be defined through specific antigens (Table 1). Although the identification of antigens apart from PLA2R is not part of routine clinical practice yet, one can envision in the next decade the clinical availability of a panel of MN antigen-specific antibodies. These antibodies can be used in conjunction with or separately from a kidney biopsy to diagnose MN, understand prognosis, guide treatment strategies, and predict relapse in MN.

t1

The author reports no conflict of interest.

References

  • 1.

    Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: An update. Semin Immunopathol 2014; 36:381397. doi: 10.1007/s00281-014-0423-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Fogo AB, et al.. AJKD Atlas of Renal Pathology: Membranous nephropathy. Am J Kidney Dis 2015; 66:e15−e17. doi: 10.1053/j.ajkd.2015.07.006

  • 3.

    Beck LH Jr, et al.. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Tomas NM, et al.. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Sethi S. New ‘antigens’ in membranous nephropathy. J Am Soc Nephrol 2021; 32:268278. doi: 10.1681/ASN.2020071082

  • 6.

    Sethi S, et al.. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int 2020; 97:163174. doi: 10.1016/j.kint.2019.09.014

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Sethi S, et al.. Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients. Kidney Int 2020; 98:12531264. doi: 10.1016/j.kint.2020.05.030

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Sethi S, et al.. Protocadherin-7 associated membranous nephropathy. ASN Kidney Week 2020 Reimagined. 2020; FR-OR36. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3445270

    • Search Google Scholar
    • Export Citation
  • 9.

    Sethi S, et al.. Exostosin 1/exostosin 2-associated membranous nephropathy. J Am Soc Nephrol 2019; 30:11231136. doi: 10.1681/ASN.2018080852

  • 10.

    Caza T, et al.. Neural cell adhesion molecule 1 is a novel autoantigen in membranous lupus nephritis. Kidney Int [ published online ahead of print October 9, 2020]. doi: 10.1016/j.kint.2020.09.016; https://www.kidney-international.org/article/S0085-2538(20)31180-7/fulltext

    • Search Google Scholar
    • Export Citation
  • 11.

    Al-Rabadi L, et al.. High temperature recombinant protein A1 (HTRA1): A novel antigen in membranous nephropathy. ASN Kidney Week 2020 Reimagined. 2020; FR-OR35. https://www.asn-online.org/education/kidneyweek/2020/program-abstract.aspx?controlId=3447205

    • Search Google Scholar
    • Export Citation
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