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

Abstract

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 Ϯ 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.

Circulating suPAR in Two Cohorts of Primary FSGS

“…22,23 Carraro et al analyzed five patients with autosomal recessive steroid-resistant nephrotic syndrome (SRNS) (NPHS2) for serum glomerular permeability activity (Palb), and found high pretransplant Palb in all cases, equivalent to values observed in idiopathic FSGS. 24 In the PodoNet cohort, circulating suPAR levels were higher in familial FSGS and FSGS with documented NPHS2 mutations, and the difference remained significant after adjustment for other covariates. Our results justify larger cohort studies, with more comprehensive assessment of FSGS-associated mutations including TRPC6.…”

Inherited Podocytopathies

“…A recent report described assays of glomerular permeability in five patients with recessive NPHS2-associated NS (46). Plasma permeability activity was high in all cases.…”

Focal Segmental Glomerulosclerosis (FSGS) Recurrence in Kidney Allograft Recipients

“…These inhibitory serum factors may be normal serum components such as apolipoproteins E and J (20). Further studies found that urine of patients with FSGS neutralize the PF activity of the serum, suggesting loss of an inhibitor in the urine (21), that may play a central role in the process after kidney transplantation and possibly also in the original disease (17). These findings suggest the deficiency of an inhibitor to the normally occurring PF as a primary cause for proteinuria.…”

“…Rarely PF may be present in patients with podocin (NPHS2) mutations. High pretransplant P alb was found in 5 children with autosomal recessive podocin mutations, in which FSGS recurred after transplantation in four out of five (17). Since the PF is mildly anionic, it is unlikely that the effect of this factor is to neutralize the anionic sites on the GBM.…”

“…Some of the homozygous carriers of podocin mutations present early recurrence of proteinuria after renal transplantation in association with high values of P alb , which suggest a role of PF also in this inherited condition (30). Carraro et al revealed the high pre-transplant P alb activity in 5 children with inherited FSGS due to autosomal recessive podocin mutations (17). The post-transplant outcome was complicated in two (with 413G>A mutation) by recurrence of proteinuria after 10 and 300 days with high P alb levels at onset that decreased to reach normal levels in the absence of proteinuria after the 7 th cycle of PP.…”