Disclosures: Watts reports filing a patent “Methods for identifying and treating patients with antibody-mediated acquired primary or recurrent idiopathic nephrotic syndrome” and receiving funding from the NIH T32 training fellowships T32HL007627 and T32DK007527.

January 12, 2022
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Discovery of autoantibodies attacking nephrin in minimal change disease supports research

Disclosures: Watts reports filing a patent “Methods for identifying and treating patients with antibody-mediated acquired primary or recurrent idiopathic nephrotic syndrome” and receiving funding from the NIH T32 training fellowships T32HL007627 and T32DK007527.

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Findings of minimal change disease in adults and children with autoantibodies targeting nephrin supports prior research demonstrated in animal models.

“Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease (MCD). The etiology remains unknown,” Andrew J. B. Watts, MB, ChB, a research fellow in the department of pathology at Brigham and Women’s Hospital and of Harvard Medical School in Boston, and colleagues wrote. “The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease.”

Researchers collaborated with four institutions to evaluate renal biopsies and assessed sera from patients with biopsy-proven MCD from the Nephrotic Syndrome Study Network (NEPTUNE) cohort consisting of 41 (66%) children and 21 (34%) adults.

According to the study, researchers looked for circulating nephrin autoantibodies by indirect enzyme-linked immunosorbent assay and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. Similarly, biopsies were examined for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence.

Among the patients in the NEPTUNE study, 29% (with an equal number of adults and children) tested positive for autoantibodies against nephrin. Circulating nephrin autoantibodies were also identified in the other patient cohort but were “significantly reduced” in patients with MCD. Analyses revealed a correlation between autoantibodies and podocyte-associated punctuate IgG in renal biopsies.

Additionally, researchers discovered a patient with steroid-dependent childhood MCD that became end-stage kidney disease. Researchers wrote, “she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies.”

“This study describes the novel discovery in both adults and children with minimal change disease of autoantibodies targeting nephrin, a critical component of the podocyte slit diaphragm that ensures integrity of the glomerular filtration barrier. This observation aligns with the established proteinuric effect of anti-nephrin antibodies demonstrated in animal models,” Watts and colleagues wrote. “These findings identify an important autoimmune mechanism in a subset of patients with MCD and provide a framework for the application and development of precision medicine strategies in this condition.”