title: Serum glomerular permeability activity in patients with podocin mutations (NPHS2) and steroid-resistant nephrotic syndrome.
abstract: A plasma factor displaying permeability activity in vitro and possibly determining proteinuria has been hypothesized in idiopathic focal segmental glomerulosclerosis (FSGS). In vitro permeability activity (P(alb)) was determined in sera of five patients with autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), an inherited condition indistinguishable from idiopathic FSGS on clinical grounds, but in which proteinuria is determined by homozygous mutations of podocin, a key component of the glomerular podocyte. All patients had presented intractable proteinuria with nephrotic syndrome; four developed renal failure and received a renal allograft. For comparison, sera from 31 children with nephrotic syndrome were tested. Pretransplant P(alb) was high in all cases (mean 0.81 +/- 0.06), equivalent to levels observed in idiopathic FSGS. Overall, P(alb) did not correlate with proteinuria. The posttransplant outcome was complicated in two patients by recurrence of proteinuria after 10 and 300 d, respectively, that responded to plasmapheresis plus cyclophosphamide. P(alb) levels were high at the time of the recurrence episodes and steadily decreased after plasmapheresis, to reach normal levels in the absence of proteinuria after the seventh cycle. In an attempt to explain high P(alb) in these patients, putative inhibitors of the permeability activity were studied. Coincubation of serum with homologous nephrotic urine reduced P(alb) to 0, whereas normal urine did not determine any change, which suggests loss of inhibitory substances in nephrotic urine. The urinary levels of the serum P(alb) inhibitors apo J and apo E were negligible in all cases, thus suggesting that other urinary inhibitors were responsible for the neutralizing effect. These data indicate that P(alb) is high in NPHS2, probably resulting from loss of inhibitors in urine. Lack of correlation of P(alb) with proteinuria suggests a selective loss of inhibitors. As in idiopathic FSGS, proteinuria may also recur after renal transplantation in NPHS2 patients, and post-transplant proteinuria is associated with high P(alb). The relationship between elevated P(alb) and proteinuria in NPHS2 remains to be determined.
authors.affiliation: Laboratorio di Fisiopatologia dell'Uremia, Istituto G. Gaslini, Largo G. Gaslini 5, 16148 Genoa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Carraro
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bruschi
authors.forename: Mary
authors.initials: M
authors.lastname: Artero
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Zennaro
authors.forename: Luca
authors.initials: L
authors.lastname: Musante
authors.forename: Giovanni
authors.initials: G
authors.lastname: Candiano
authors.forename: Francesco
authors.initials: F
authors.lastname: Perfumo
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001790:Blood Physiological Phenomena; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D010539:Permeability; D012709:Serum Albumin / Q000378:metabolism; D013256:Steroids / Q000627:therapeutic use*; D016896:Treatment Outcome; D014556:Urine / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012709:Serum Albumin; D013256:Steroids