Kidney Week

Abstract: FR-OR36

Protocadherin 7-Associated Membranous Nephropathy

Session Information

• Glomerular Diseases: Charting New Territory
  October 23, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

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

Sanjeev Sethi, MD, PhD



Dr. Sanjeev Sethi graduated from Assam Medical College, India. He pursued graduate studies thereafter at Albany Medical College, NY, and received his Ph.D. in Experimental Pathology. Subsequently, Dr. Sethi completed his Pathology residency at Yale University and his fellowship in Renal Pathology at Brigham and Women’s Hospital, Harvard University. He is currently a Professor at Mayo Clinic, Rochester. He has over 215 peer-reviewed publications.

• Madden, Benjamin J., Mayo Clinic, Rochester, Minnesota, United States

Benjamin J. Madden,

• Gross, Louann, Mayo Clinic, Rochester, Minnesota, United States

Louann Gross,

• Negron, Vivian C., Mayo Clinic, Rochester, Minnesota, United States

Vivian C. Negron,

• Charlesworth, Cristine, Mayo Clinic, Rochester, Minnesota, United States

Cristine Charlesworth,

• Debiec, Hanna, Sorbonne Universite, Paris, Île-de-France, France

Hanna Debiec,

• Ronco, Pierre M., Sorbonne Universite, Paris, France

Pierre M. Ronco,

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

Fernando C. Fervenza,

Background

Membranous nephropathy (MN) results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane (GBM). Although PLA2R, THSD7A, and NELL-1 account for a majority (approximately 80%) of the target antigens, the target antigen in the remaining MN is not known.

Methods

We performed laser microdissection and mass spectrometry (MS) of glomeruli in kidney biopsies of 85 cases of PLA2R-negative MN. We detected high spectral counts of a unique protein Protocadherin 7 (PCDH7) in 8 cases. Immunohistochemistry (IHC) for PCDH7 was then performed to confirm MS results.

Results

MS identified a unique protein, PCDH7 in 8 cases (9.4%) of PLA2R-negative MN. MS failed to detect PCDH7 in remaining 77 PLA2R-negative MN, 23 PLA2R-positive MN, and 88 controls that included IgA nephropathy, diabetes, FSGS and minimal change disease. Among the 77 PLA2R-negative MN, MS detected NELL1 (14 cases), EXT1/EXT2 (6 cases), PLA2R (4 cases labeled PLA2R-negative on IF), Sema3B (3 cases), THSD7A (2 cases), and DNAJB9 (4 cases of fibrillary GN, misdiagnosed as MN as EM was not done). PCDH7 localized as granular deposits along the GBM by IHC (Figure 1). Kidney biopsy showed a grade II MN in 6 cases, grade I in 1 and grade III in 1 case. Immunofluorescence microscopy showed GBM staining for IgG and C3 in all cases. IgG subtyping done in 2 cases showed IgG4 in both. The mean age was 64 years (+/- 11) and 7 of the 8 patients were males. The average serum creatinine and proteinuria was 1.28 mg/dL (+/- 0.3) and 4.9 gm/L (+/- 3.0), respectively. Interestingly, 3 of 8 cases had associated malignancies. Further studies including evaluation for circulating antibodies are ongoing.

Conclusion

Protocadherin 7-associated MN may represent distinct type of MN.

Figure 1 shows bright granular capillary wall staining for PCDH7 in 3 cases (A, B, C) of PCDH7-associated MN, and negative staining in a case (D) of PLA2R-negative MN.