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Abstract: TH-PO454

NSAID-Associated Membranous Nephropathy (MN) Is Associated With PCSK6

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Sethi, Sanjeev, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Casal Moura, Marta Isabel Rodrigues, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Madden, Benjamin J., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
  • Fervenza, Fernando C., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
Background

Drugs are an important secondary cause of MN. The most common drugs associated with MN are non-steroidal anti-inflammatory drugs (NSAIDs). The target antigen in NSAID-associated MN is not known.

Methods

We performed laser microdissection of glomeruli followed by mass spectrometry (MS) in 250 cases of PLA2R-negative MN to identify novel antigenic targets of MN. This was followed by immunohistochemistry to localize the target antigen along the glomerular basement membrane (GBM) and western blot analyses of serum/eluate of frozen biopsy tissue to detect binding of IgG to the novel antigenic target.

Results

MS studies revealed high total spectral counts (average 44.8) of a novel protein Proprotein Convertase Subtilisin/Kexin Type 6 (PCSK 6) in 4 (1.6%) of the 250 cases (Fig 1). The mean age was 55 (± 4.5) years, serum creatinine 0.88 (±0.2) mg/dL, proteinuria 8.0 (± 4.2) gms/day, and serum albumin 1.7 gms/dL (± 0.8) at presentation. No underlying disease association was found in all cases except for heavy NSAID use of >2 years in 3 of the 4 cases that included ibuprofen, naproxen, and meloxicam. In 1 patient, clinical charts were not available. All cases were negative for known antigens including PLA2R, THSD7A, EXT1/EXT2, NELL1, SEMA3B, PCDH7, FAT1, CNTN1 and NCAM1. All cases showed IgG (3+) and C3 (2+) along GBM, tubular atrophy and interstitial fibrosis was less than 10%, and EM showed stage I-II in all cases. Importantly, western blot analyses (Fig 2) using eluate from frozen tissue showed IgG binding to PCSK6 in the NSAID-associated MN (lane 2) but not in PLA2R-positive MN (lane 3).

Conclusion

PCSK6 is a likely novel antigenic target in NSAID-associated MN.

MS studies.

Western blot studies.