Serum Glomerular Permeability Activity in Patients with Podocin Mutations (NPHS2) and Steroid-ResistantNephrotic Syndrome

Abstract

ABSTRACT. A plasma factor displaying permeability activityin vitroand possibly determining proteinuria has been hypothesized in idiopathic focal segmental glomerulosclerosis (FSGS).In vitropermeability activity (Palb) was determined inseraof 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 Palbwas high in all cases (mean 0.81 ± 0.06), equivalent to levels observed in idiopathic FSGS. Overall, Palbdid 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. Palblevels 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 Palbin these patients, putative inhibitors of the permeability activity were studied. Coincubation of serum with homologous nephrotic urine reduced Palbto 0, whereas normal urine did not determine any change, which suggests loss of inhibitory substances in nephrotic urine. The urinary levels of the serum Palbinhibitors 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 Palbis high in NPHS2, probably resulting from loss of inhibitors in urine. Lack of correlation of Palbwith 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 Palb. The relationship between elevated Palband proteinuria in NPHS2 remains to be determined.