Abstract. Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroidresistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.Nephrotic syndrome (NS) is defined as the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. It constitutes one of the most common diagnoses in pediatric nephrology. Approximately 80% of all children with sporadic NS respond to steroid treatment. For decades, NS has been separated into two broad categories on the basis of the response to standard steroid therapy, i.e., steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) (1,2). In SRNS, approximately 75% of patients exhibit renal histologic features of FSGS and 20% demonstrate minimal-change NS (MCNS). Conversely, in SSNS, renal histologic features indicate MCNS in 80% of cases and FSGS in 20% (3). The pathogenesis of NS has been elusive, despite decades of research on its renal histologic and protein biochemical features. Protein biochemistry approaches have been applied to the study of the pathogenesis of FSGS, with some indicating a circulating "FSGS factor" (4 -6). The most prominent hypothesis regarding the pathogenesis of SSNS was an immunopathogenetic concept. ...

According to the data acquired in this study, patients presenting with a female phenotype and SRNS and male patients presenting with genital abnormalities should especially be screened to take advantage of the important genetic information on potential Wilms' tumor risk and differential therapy. This will also help to provide more data on the phenotype/genotype correlation in this patient population.

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. In 26% of cases it is caused by recessive mutations in NPHS2 (podocin). Congenital nephrotic syndrome (CNS) is caused by mutations in NPHS1 (nephrin) or NPHS2. In three families mutations in NPHS1 and NPHS2 had been reported to occur together, and these tri-allelic mutations were implicated in genotype/phenotype correlations. To further test the hypothesis of tri-allelism, we examined a group of 62 unrelated patients for NPHS1 mutations, who were previously shown to have NPHS2 mutations; 15 of 62 patients had CNS. In addition, 12 CNS patients without NPHS2 mutation were examined for NPHS1 mutations. Mutational analysis yielded three different groups. (1) In 48 patients with two recessive NPHS2 mutations (11 with CNS), no NPHS1 mutation was detected, except for 1 patient, who had one NPHS1 mutation only. This patient was indistinguishable clinically and did not have CNS. (2) In 14 patients with one NPHS2 mutation only (4 with CNS), we detected two additional recessive NPHS1 mutations in the 4 patients with CNS. They all carried the R229Q variant of NPHS2. The CNS phenotype may be sufficiently explained by the presence of two NPHS1 mutations. (3) In 12 patients without NPHS2 mutation (all with CNS), we detected two recessive NPHS1 mutations in 11 patients, explaining their CNS phenotype. We report ten novel mutations in the nephrin gene. Our data do not suggest any genotype/phenotype correlation in the 5 patients with mutations in both the NPHS1 and the NPHS2 genes.

Mutations in the NPHS2 gene encoding podocin are associated with steroid-resistant nephrotic syndrome (SRNS) in childhood. Patients usually present with focal segmental glomerulosclerosis (FSGS). It is unclear to what extent SRNS due to NPHS2 mutations predisposes to recurrence of proteinuria/FSGS after renal transplantation (RTx). A 4-year-old girl with infantile SRNS was started on peritoneal dialysis because of end-stage renal disease due to FSGS. Mutational screening of the patient and her parents revealed a novel single nucleotide deletion in exon 8 of the NHPS2 gene (948delT), for which the patient was homozygous and her parents confirmed heterozygous asymptomatic carriers. At the age of 4.5 years the patient received a renal graft from her mother. On day 7 after RTx, the patient developed progressive proteinuria (urine protein/creatinine ratio 2.4 g/g), which responded within 1 week to prednisone pulse therapy, an increased cyclosporin A dosage, and ramipril therapy. The patient has maintained stable graft function and no further recurrence of proteinuria has been observed. In conclusion, patients with SRNS due to NPHS2 mutations are not protected from recurrence of proteinuria after RTx. The quick response to increased immunosuppression in our patient suggests an immune-mediated pathomechanism for recurrence of proteinuria.

Abstract. Steroid-resistant nephrotic syndrome (SRNS) leads to end-stage renal disease (ESRD) in childhood or young adulthood. Positional cloning for genes causing SRNS has opened the first insights into the understanding of its pathogenesis. This study reports a genome-wide search for linkage in a consanguineous Palestinian kindred with SRNS and deafness and detection of a region of homozygosity on chromosome 14q24.2. Multipoint analysis of 12 markers used for further fine mapping resulted in a LOD score Z max of 4.12 ( ϭ 0) for marker D14S1025 and a two-point LOD score of Z max ϭ 3.46 ( ϭ 0) for marker D14S77.