Kidney Week

Abstract: TH-PO604

Overview of the Characteristics of a Phospholipase A2 Receptor (PLA2R)-Negative Membranous Nephropathy Cohort

Session Information

• Membranous Nephropathy, FSGS, and Minimal Change Disease
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Inácio, António da Silva, Centro Hospitalar de Setubal EPE, Setubal, Portugal

António da Silva Inácio, MD

• Domingues, Patrícia Andreia da Costa, Centro Hospitalar de Setubal EPE, Setubal, Portugal

Patrícia Andreia da Costa Domingues, MD

• Piedade, Ana D., Centro Hospitalar de Setubal EPE, Setubal, Portugal

Ana D. Piedade, MD

• Mendes, Beatriz Branco, Centro Hospitalar de Setubal EPE, Setubal, Portugal

Beatriz Branco Mendes

• da Fonseca, Francisca Gaudêncio, Centro Hospitalar de Setubal EPE, Setubal, Portugal

Francisca Gaudêncio da Fonseca, MD

• Vrana, Julie A., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Julie A. Vrana, PhD

• Theis, Jason David, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Jason David Theis

• Fervenza, Fernando C., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Fernando C. Fervenza, MD, PhD, FASN

• Soto, Karina, Centro Hospitalar de Setubal EPE, Setubal, Portugal

Karina Soto, MD, PhD

• Sethi, Sanjeev, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Sanjeev Sethi, MD, PhD

Background

Recent insights into target antigens involved in Membranous Nephropathy’s (MN) pathophysiology have propelled towards its antigen-based classification. While most are PLA2R-positive, a subset involves a variety of proteins. Antigen identification provides valuable clues regarding underlying disease or exposure, influencing clinical investigation and management. We aimed to characterize a single-center cohort of PLA2R-negative MN through antigen identification.

Methods

Retrospective analysis of all MN cases diagnosed at our Center with negative serum PLA2R titer between 2013-2023. Glomerular laser capture microdissection (LMD) was performed on paraffin-embedded kidney biopsy samples, followed by tandem mass spectrometry (MS) for antigen identification. Clinical data was included for comprehensive analysis.

Results

Of 26 biopsy-proven MN, 14 had negative serum PLA2R. Of those, 11 cases had available tissue sample for LMD/MS. LMD/MS identified a MN antigen in 8 (72.7%) cases. These included: 3 PLA2R (one case with paraproteinemia, other with syphilis and other with no underlying disease); 2 NELL-1 (one with paraproteinemia and other with lung cancer); 1 EXT1/2 (with mixed connective tissue disease and multiple myeloma); 1 HTRA1 (with multiple myeloma and uncharacterized autoimmune disease); 1 NDNF (with thyroid cancer); and 1 THSD7A (had no underlying diagnosis). In 3 (27.3%) cases no antigen was identified by MS. The diagnosis of NELL1, EXT1/EXT2 and THSD7A was confirmed by immunohistochemistry.
Time from MN diagnosis to underlying disease diagnosis ranged from >2 years before up to >5 years after.
Clinical course and outcomes were widely variable from spontaneous remission to ESKD progression.

Conclusion

More than half of MN cases had negative serum anti-PLA2R antibodies. Our analysis revealed diverse target-antigens involved, reflecting various underlying diseases, and exhibiting different clinical courses. The antigens detected on LMD/MS correlated with the clinical and pathologic findings. We also highlight the sensitivity of LMD/MS in identifying PLA2R, particularly in cases with negative serum measurements. We observed that negative PLA2R IHC staining can be misleading, underlining the need for caution in its interpretation.