Semaphorin 3B–associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients: Kidney International

S. Sethi, H. Debiec, B. Madden, M. Vivarelli, M.C. Charlesworth, A. Ravindran, L. Gross, T. Ulinski, D. Buob, C.L. Tran, F. Emma, F. Diomedi-Camassei, F.C. Fervenza, P. Ronco

Research output: Contribution to journalArticlepeer-review


Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients. © 2020 International Society of Nephrology
Original languageEnglish
Pages (from-to)1253-1264
Number of pages12
JournalKidney Int.
Issue number5
Publication statusPublished - 2020


  • kidney biopsy
  • mass spectrometry
  • membranous nephropathy
  • Semaphorin 3B
  • complement component C1q
  • complement component C3
  • creatinine
  • cyclosporine
  • dipeptidyl carboxypeptidase inhibitor
  • immunoglobulin A
  • immunoglobulin G
  • immunoglobulin G1
  • immunoglobulin G3
  • immunoglobulin M
  • mycophenolate mofetil
  • rituximab
  • semaphorin
  • semaphorin 3B
  • steroid
  • tacrolimus
  • unclassified drug
  • adult
  • Article
  • child
  • clinical article
  • cohort analysis
  • confocal microscopy
  • controlled study
  • creatinine blood level
  • female
  • glomerulus basement membrane
  • human
  • human tissue
  • immunohistochemistry
  • infant
  • male
  • membranous glomerulonephritis
  • nephrotic syndrome
  • onset age
  • pediatric patient
  • priority journal
  • protein analysis
  • protein function
  • protein localization
  • remission
  • staining
  • treatment duration
  • treatment withdrawal
  • validation study
  • Western blotting


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