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Abstract: FR-OR50

Cubilin Is a Novel Target Antigen in Anti-Brush Border Disease

Session Information

Category: Pathology and Lab Medicine

  • 1600 Pathology and Lab Medicine

Authors

  • Morelle, Johann, Cliniques universitaires Saint-Luc, Brussels, Belgium
  • Caza, Tiffany, Arkana Laboratories, Little Rock, Arkansas, United States
  • Debiec, Hanna, INSERM, Paris, Île-de-France, France
  • Devuyst, Olivier, Universitat Zurich, Zurich, Switzerland
  • Ronco, Pierre M., Hopital Tenon, Paris, Île-de-France, France
  • Larsen, Christopher Patrick, Arkana Laboratories, Little Rock, Arkansas, United States
Background

Anti-brush border antibody disease (ABBA) is an autoimmune kidney disease that frequently progresses to kidney failure. It is characterized by proximal tubule damage, IgG-positive immune deposits along the tubular basement membrane (TBM), and circulating autoantibodies directed against the brush border. To date, the multiligand receptor megalin (also known as LDL receptor-related protein 2, LRP2) is the only target antigen associated with ABBA.

Methods

Here, we investigated a patient with LRP2-negative ABBA and applied mass spectrometry and confocal microscopy to identify a novel target antigen.

Results

A 75-year-old European female patient with past history of hypertension, type 2 diabetes and stage G3/A1 CKD was referred for rapid decline in kidney function (decrease in CKD-EPI estimated glomerular filtration rate from 37 to 16 ml/min per 1.73 m2 over a few months). This was associated with new onset proximal tubule dysfunction, as attested by low molecular weight proteinuria and aminoaciduria. There was no evidence of monoclonal gammopathy, systemic autoimmune disease or exposure to environmental toxins, and serum cobalamin level was normal.
The kidney biopsy revealed a protracted pattern of tubular injury, granular IgG deposits along the TBM, with a predominance of IgG1 subclass, and electron-dense deposits in the TBM on ultrastructural analysis. There was no light chain restriction. Although indirect immunofluorescence showed reactivity of the patient’s serum against normal kidney brush border, consistent with the diagnosis of ABBA, immunofluorescence failed to detect LRP2 within TBM deposits.
Protein G immunoprecipitation followed by mass spectrometry revealed cubilin (CUBN), another multiligand, endocytic-membrane glycoprotein of the proximal tubule, to be uniquely present within immune complexes eluted from frozen biopsy tissue. Confocal microscopy confirmed CUBN specifically colocalized with IgG in the TBM. Such colocalization was specific to the disease and not observed in other immune complex-mediated tubulointerstitial diseases, including LRP2 nephropathy, IgG4-related kidney disease, idiopathic hypocomplementemic interstitial nephritis, lupus nephritis, or polyomavirus nephritis.

Conclusion

CUBN is a novel target antigen in ABBA.