Anti-nephrin autoantibodies: a biomarker for kidney disease?

STOCKHOLM — Patients with a difficult-to-diagnose kidney disease related to nephrotic syndrome have been shown to have particularly high levels of anti-nephrin autoantibodies, suggesting new biomarkers and breakthroughs in the diagnosis and management of the disease.

“The discovery of anti-nephrin autoantibodies has completely transformed our understanding of idiopathic nephrotic syndrome, minimal change disease (MCD), and primary nephrotic syndrome. Focal glomerulosclerosis (FSGS) is often classified as an anti-nephrin-associated podocytosis,” said co-author Nicola Martin-Thomas, MD, PhD, of the University Medical Center Hamburg-Eppendorf in Hamburg, Germany. Medscape Medical News.

“This study provides an explanation for anti-nephrin-positive patients to understand what they are suffering from and invalidates the 'idiopathic' nature of the disease,” he said.

The study was published May 25th. 61st Congress of the European Society of Nephrology (ERA) 2024 and Simultaneous release In New England Journal of Medicine.

Nephrotic syndrome is characterized by elevated levels of protein in the urine, which can lead to infections and blood clots. In adults, it is known as MCD or primary FSGS, and in idiopathic Childhood Nephrotic Syndrome.

Diagnosis of these diseases is challenging due to overlapping symptoms and histological features. The cause can usually be identified by renal biopsy, but few patients undergo this option, especially in younger patients, highlighting the need for biomarkers.

Previous studies have suggested that patients with MCD have autoantibodies that target nephrin, but the clinical significance was unclear, so the authors sought to investigate further in the current multicenter study.

The study enrolled 357 patients with MCD, FSGS, and other glomerular diseases from the United States and Europe. Membranous nephropathy, IgA nephropathyantineutrophil cytoplasmic antibody-associated glomerulonephritis, or Lupus nephritis.

In addition, 182 children with idiopathic nephrotic syndrome and 117 controls were enrolled.

Anti-nephrin autoantibodies were detected in 46 of 105 (44%) adults with MCD and in 7 of 74 (9%) adults with FSGS.

Importantly, anti-nephrin autoantibodies were rarely detected in other conditions.

Of 182 children with idiopathic nephrotic syndrome, 94 (52%) had autoantibodies.

In the subgroup ImmunosuppressionIn untreated patients with active MCD and idiopathic nephrotic syndrome, the prevalence of anti-nephrin autoantibodies was high at 69% and 90%, respectively.

“Immunosuppressant therapy can rapidly reduce the levels of anti-nephrin antibodies in the blood, so if immunosuppression has not yet been initiated, you will see a higher rate of anti-nephrin positivity,” Thomas explained.

Of note, levels of anti-nephrin autoantibodies correlated with disease activity at baseline and follow-up, highlighting their potential as biomarkers of disease progression.

To further explore the potential effects of nephrin immunization, the authors performed studies in a mouse model mimicking MCD and, importantly, demonstrated that single nephrin immunization Rapid illness Improved resolution even at low antibody concentrations.

New Hybrid Detection Technology

Previous studies had suggested the presence of anti-nephrin autoantibodies but “they have been difficult to detect,” explained co-author Tobias B. Huber, MD, PhD, of the University Medical Center Hamburg-Eppendorf, in a study statement.

“Even with the enhanced assay, we were unable to identify a strong anti-nephrin autoantibody signal,” he continued.

As a solution, they developed a novel hybrid detection technique that combines immunoprecipitation and nephrin ELISA, allowing quantitative measurement of anti-nephrin autoantibody levels.

“Quantification of such antibodies may transform the management of nephrotic syndrome by providing a non-invasive alternative for the diagnosis of patients with recurrent primary FSGS, enhancing treatment evaluation, and improving kidney transplant strategies,” the authors explain.

They argue that the specificity of autoantibodies in glomerular disease, as well as the strong correlation between disease activity and detection of anti-nephrin autoantibodies, “suggests that these antibodies are not simply a by-product of podocyte damage but play a causative role in the pathobiology of the disease.”

“Depending on further research, anti-nephrin autoantibodies may help predict patients' risk for different disease trajectories, guide treatment decisions, and ultimately lay the foundation for the development of specific antibody-targeted therapies to avoid the side effects of extensive immunosuppression that remains the current standard of care,” Thomas added.

To comment Medscape Medical NewsIvan Ryklik, a medical doctor at the Faculty of Medicine at Charles University in Prague, Czech Republic, said the study has important implications.

“[The study] “This study is of great interest to clinical nephrologists as it provides new insights into understanding the pathophysiology of nephrotic syndrome caused by immune-mediated podocytosis,” said Rychlik, who co-chaired the session.

“In addition to our finding of a significant correlation of anti-nephrin autoantibodies, it is instructive to note that we also observed a significant correlation with disease activity throughout the study period,” said Dr. Rychlik.

“The added value is that it will prove the correct diagnosis early on, which will certainly lead to better outcomes for both the patient and the treating physician,” he added.

“Moreover, this treatment offers new hope to patients suffering from these diseases.”

Huber has disclosed relationships with Alexion Pharmaceuticals, Amicus Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, the German Federal Ministry of Education and Research, Da Vita, the German Research Foundation, EuroImmune, Novartis, Pfizer, Renovate, Sanofi, Travele Therapeutics, and Vifor Fresenius Medical Care Renal Pharma. Thomas has disclosed relationships with AstraZeneca and the German Research Foundation. Riklik reports no relevant financial relationships.