Autoantibodies Targeting Nephrin in Podocytopathies
A large multicentre study found antibodies against nephrin — a key protein holding the kidney's filter together — in about half of adults with minimal change disease and in children with idiopathic nephrotic syndrome, and showed in mice that these antibodies can themselves cause the disease.
Background
Minimal change disease and primary focal segmental glomerulosclerosis in adults, and idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies whose target antigen had not been established. Antibodies to nephrin, a slit-diaphragm protein, had been reported in minimal change disease, but their clinical and pathophysiological role was unclear.
Study design
A multicentre study analysed antinephrin autoantibodies in 539 patients (357 adults and 182 children) with glomerular disease — minimal change disease, primary FSGS, membranous nephropathy, IgA nephropathy, ANCA-associated glomerulonephritis and lupus nephritis — alongside 117 controls, complemented by an experimental mouse model using active immunisation with recombinant murine nephrin.
Key findings
Antinephrin autoantibodies were detected in 46 of 105 adults (44%) with minimal change disease and 7 of 74 (9%) with primary FSGS, but only rarely in the other conditions. Among the 182 children with idiopathic nephrotic syndrome, 94 (52%) were positive. In untreated patients with active disease the prevalence rose to 69% (minimal change disease) and 90% (childhood idiopathic nephrotic syndrome), and antibody levels tracked disease activity at inclusion and during follow-up.
Clinical implications
Experimental immunisation induced nephrotic syndrome with a minimal change-like phenotype, IgG localisation to the slit diaphragm, nephrin phosphorylation and cytoskeletal change — evidence of pathogenicity rather than epiphenomenon. This supports antibody measurement as a marker of disease activity and provides a rationale for B-cell-directed therapy in antibody-positive patients.
Category
News
Source
The New England Journal of Medicine
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