title: Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin.
abstract: BACKGROUND
  Congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) is caused by mutations in the NPHS1 gene. NPHS1 codes for nephrin, a cell adhesion protein located at the glomerular slit diaphragm. Renal transplantation is the only treatment option for most patients with NPHS1. We have previously described recurrence of severe proteinuria in grafts transplanted to children with NPHS1. Here we studied the pathophysiology of this proteinuria.
  
  
  METHODS
  Clinical data, light and electron microscopic findings as well as the expression of nephrin in the proteinuric grafts were studied. The patients' sera were screened for antibodies against kidney glomerulus and nephrin molecule using indirect immunofluorescence and ELISA.
  
  
  RESULTS
  Fifteen episodes of recurrent nephrotic syndrome occurred in 13 (25%) of 51 grafts transplanted to 45 Finnish children with NPHS1. All nine patients with recurrence had a Fin-major/Fin-major genotype, which leads to absence of nephrin in the native kidney. Rescue therapy (cyclophosphamide) was successful in seven episodes, but six kidneys were lost due to this process. Antibodies reacting against glomerulus were found in eight, and high anti-nephrin antibody levels were detected in four of the nine patients. In electron microscopy, the fusion of the foot process and decreases in the detectable slit diaphragms in the podocyte pores were observed. The expression of nephrin mRNA was markedly reduced in two, and granular staining for nephrin was seen in three of five grafts.
  
  
  CONCLUSIONS
  Circulating anti-nephrin antibodies seem to have a pathogenic role in the development of heavy proteinuria in kidney grafts of NPHS1 patients with Fin-major/Fin-major genotype.
authors.affiliation: Hospital for Children and Adolescents, Biomedicum Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Patrakka
authors.forename: Vesa
authors.initials: V
authors.lastname: Ruotsalainen
authors.forename: Paula
authors.initials: P
authors.lastname: Reponen
authors.forename: Erik
authors.initials: E
authors.lastname: Qvist
authors.forename: Jarmo
authors.initials: J
authors.lastname: Laine
authors.forename: Christer
authors.initials: C
authors.lastname: Holmberg
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Hannu
authors.initials: H
authors.lastname: Jalanko
mesh_terms: D001323:Autoantibodies / Q000097:blood; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D007678:Kidney Glomerulus / Q000276:immunology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008565:Membrane Proteins; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000209:etiology; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000032:analysis; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; C113267:nephrin