Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

Abstract

SummaryBackground and objectives To date, very few cases with adult-onset focal segmental glomerulosclerosis (FSGS) carrying NPHS2 variants have been described, all of them being compound heterozygous for the p.R229Q variant and one pathogenic mutation.Design, setting, participants, & measurements Mutation analysis was performed in 148 unrelated Spanish patients, of whom 50 presented with FSGS after 18 years of age. Pathogenicity of amino acid substitutions was evaluated through an in silico scoring system. Haplotype analysis was carried out using NPHS2 single nucleotide polymorphism and microsatellite markers.Results Compound heterozygous or homozygous NPHS2 pathogenic mutations were identified in seven childhood-onset steroid-resistant nephrotic syndrome (SRNS) cases. Six additional cases with late childhood-and adult-onset SRNS were compound heterozygotes for p.R229Q and one pathogenic mutation, mostly p.A284V. p.R229Q was more frequent among SRNS cases relative to controls (odds ratio ϭ 2.65; P ϭ 0.02). Significantly higher age at onset of the disease and slower progression to ESRD were found in patients with one pathogenic mutation plus the p.R229Q variant in respect to patients with two NPHS2 pathogenic mutations.Conclusions NPHS2 analysis has a clinical value in both childhood-and adult-onset SRNS patients. For adult-onset patients, the first step should be screening for p.R229Q and, if positive, for p.A284V. These alleles are present in conserved haplotypes, suggesting a common origin for these substitutions. Patients carrying this specific NPHS2 allele combination did not respond to corticoids or immunosuppressors and showed FSGS, average 8-year progression to ESRD, and low risk for recurrence of FSGS after kidney transplant.

Is the red cell distribution width strong predictor for treatment response in primary glomerulonephritides?

“…3 In another study, 4 the serum IgG level and IgG: IgM ratio were found to be significantly lower in children who had corticosteroid-resistant NS. Nowicka et al stated in their study that plasma levels of Suppressors of Cytokine Signaling (SOCS) 3 and SOCS 5 might predict initial resistance to steroids in NS patients.…”

“…Unfortunately, no reliable predictor of treatment response for all patients with NS due to PGN has been defined yet. [2][3][4] Red cell distribution width (RDW) is an inexpensive emerging cardiovascular risk predictor, and several recent studies have documented that inflammatory activity was closely associated with RDW values. [5][6][7] No clinical trial evaluating the relationship between RDW levels and response to therapy in patients with NS has been carried out yet.…”

The amino acid mutations of the podocin in proteinuria: a meta-analysis

“…Perhaps it is because these mutations play as modifiers other than oligoallelic causative factors. For example, A242V and A284V were considered causal in trans-association to R229Q, [26][27][28] and NPHS1 polymorphism may enhance pathogenicity of P118L in podocin. 29 Furthermore, the sample size is usually small in control Note: NS, Nephrotic syndrome; FSGS, focal segmental glomerulosclerosis; SRNS, steroid-resistant nephrotic syndrome; Excluded, the samples were excluded as compound station; WT, wild type; Het, heterozygous; Hom, homozygous; N/A, not applicable as non-human population was mentioned.…”

“…The number of participants are usually too little to estimate the causative effect as the low allele frequencies (4-7% in Europeans and 0-1.5% in African and Asian populations), especially for the more rare oligoallelic or homozygous events. 34,35 . Of the included 21 studies, only three derived positive results.…”

Mechanisms of Glucocorticoid Resistance in Idiopathic Nephrotic Syndrome

“…Although it may have only a weak biological effect, it is now known that compound heterozygosity for R229Q and p.A284V maybe characteristic of late childhood- or adult-onset SRNS [50,51,52]. Santin et al [53] also found that the phenotypes of late childhood- and adult-onset SRNS are more similar to each other than to early childhood-onset SRNS. Researchers have speculated that specific podocin mutations might determine the age of onset of SRNS and that R229Q might be an ancient mutation that has expanded by population migration.…”