• 1.

    Takeuchi K, et al. New anti-nephrin antibody mediated podocyte injury model using a C57BL/6 mouse strain. Nephron 2018; 138:7187. doi: 10.1159/000479935

  • 2.

    Watts AJB, et al. Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol 2022; 33:238252. doi: 10.1681/ASN.2021060794

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  • 3.

    Hengel FE, et al.; International Society of Glomerular Disease. Autoantibodies targeting nephrin in podocytopathies. N Engl J Med 2024; 391:422433. doi: 10.1056/NEJMoa2314471

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    • Export Citation
  • 4.

    Shirai Y, et al. A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis. Kidney Int 2024; 105:608617. doi: 10.1016/j.kint.2023.11.022

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  • 5.

    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1S276. doi: 10.1016/j.kint.2021.05.021

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Antinephrin Autoantibodies: Advances in Understanding Podocytopathies

Benjamin Wooden Benjamin Wooden, MD, is assistant professor of medicine at Columbia University Irving Medical Center, New York, NY. Gerald B. Appel, MD, FASN, is professor of medicine at Columbia University Irving Medical Center and codirector of the David Koch Jr. Glomerular Kidney Center at Columbia University.

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Gerald B. Appel Benjamin Wooden, MD, is assistant professor of medicine at Columbia University Irving Medical Center, New York, NY. Gerald B. Appel, MD, FASN, is professor of medicine at Columbia University Irving Medical Center and codirector of the David Koch Jr. Glomerular Kidney Center at Columbia University.

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In recent decades, there have been major advances in understanding the clinical course, histopathology, and treatment of the two major podocytopathies: minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS). Despite advancements in understanding the pathogenesis of other glomerulopathies, the mechanisms behind podocytopathies have remained elusive, largely due to unidentified pathogenic circulating immune factors. However, new studies offer hope to unravel these immune factors and revolutionize our approach to podocytopathies.

Autoantibodies targeting nephrin—a component of the podocyte slit diaphragm—have emerged as key in the pathogenesis in both MCD and primary FSGS. Antinephrin antibodies were known to produce the nephrotic syndrome in animal models (1). In 2022, Watts et al. (2) reported that 29% of patients with MCD in several cohorts had detectable circulating antinephrin autoantibodies, which correlated with punctate immunoglobulin G (IgG) in podocytes and colocalized with nephrin on biopsies (also known as “dusting” on immunofluorescence). More recently, a report by Hengel and colleagues (3), published in The New England Journal of Medicine, documents that an even larger subset of primary podocytopathies may be driven by autoantibodies against nephrin.

In a multicenter cohort of over 500 patients, Hengel et al. (3) found that these antibodies were present in 44% of 105 adults with MCD and in 52% of 182 children with idiopathic nephrotic syndrome (INS). In the adults with MCD, 69% of those with nephrotic range proteinuria and not receiving immunosuppression were positive, and in the children with INS, 90% of those with nephrotic range proteinuria and not receiving immunosuppression were positive. Only 9% of 74 adults with primary FSGS had antinephrin antibodies, and among controls with other diseases, almost no antinephrin autoantibodies were found. Antinephrin antibodies correlated with disease activity and became negative with clinical remission.

In addition, an experimental murine model showed that the development of antinephrin antibodies led to full nephrotic syndrome, with histologic findings of MCD, IgG localized to the podocyte slit diaphragm, nephrin phosphorylation, and podocyte slit diaphragm alterations. Another recent study found all of the 11 kidney transplant patients with recurrent FSGS to have antinephrin autoantibodies, whereas none of the patients with nonrecurrent FSGS or genetic forms of FSGS did (4).

Together, these findings have important implications for the diagnosis and management of primary podocytopathies. It is conceivable that the use of antinephrin antibody testing will become analogous to that of antiphospholipase A2 receptor antibodies in membranous nephropathy, providing noninvasive diagnostics and enabling detection of “immunologic remission,” even before clinical remission occurs (5). Accordingly, future studies need to determine the sensitivity and specificity of antinephrin antibodies and whether their depletion reliably predicts clinical remission.

Footnotes

The authors report no conflicts of interest.

References

  • 1.

    Takeuchi K, et al. New anti-nephrin antibody mediated podocyte injury model using a C57BL/6 mouse strain. Nephron 2018; 138:7187. doi: 10.1159/000479935

  • 2.

    Watts AJB, et al. Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel autoimmune etiology. J Am Soc Nephrol 2022; 33:238252. doi: 10.1681/ASN.2021060794

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Hengel FE, et al.; International Society of Glomerular Disease. Autoantibodies targeting nephrin in podocytopathies. N Engl J Med 2024; 391:422433. doi: 10.1056/NEJMoa2314471

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

    Shirai Y, et al. A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis. Kidney Int 2024; 105:608617. doi: 10.1016/j.kint.2023.11.022

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

    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1S276. doi: 10.1016/j.kint.2021.05.021

    • PubMed
    • Search Google Scholar
    • Export Citation
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