Nephrotic Syndrome in a Child With NPHS2 Mutation.

Steroid resistant nephrotic syndrome (SRNS) accounts for 30% of all cases of nephrotic syndrome (NS) in children and frequently leads to end stage kidney disease (ESKD). About 30% of children with SRNS demonstrate causative mutations in podocyte- associated genes. Early identification of genetic forms of SRNS is critical to avoid potentially harmful immunosuppressive therapy. A 2-year-old male patient with NS and no family history of renal disease did not respond to 4-week steroid treatment. Kidney biopsy demonstrated mesangial proliferative glomerulopathy with basement membrane dysmorphism. Tacrolimus and Lisinopril were added to therapy pending results of genetic testing. Kidney Gene panel showed a NPHS2 c.413G>A (p.Arg138Gln) homozygous pathogenic variant. This missense variant is considered a common pathogenic founder mutation in European populations. A diagnosis of autosomal-recessive form of nonsyndromic SRNS due to NPHS2 causative variant was made. Immunosuppresive therapy was stopped, Lizinopril dose was increased and weekly infusions of Albumin/furosemide were initiated to manage edema. This case demonstrates that early genetic testing in children with SRNS avoids prolonged potentially harmful immunosuppressive therapy, allows for timely genetic family counseling, and allows earlier consideration for future living related donor kidney transplantation.

Analysis of the association of NPHS2 and ACTN4 genes polymorphism with nephrotic syndrome in Egyptian children.

BACKGROUND: One of the most common kidney illnesses in developing countries is pediatric nephrotic syndrome (PNS), which is frequently associated with dyslipidemia and edema. The rapid discovery of genes related to NS has aided in the understanding of the molecular mechanics of glomerular filtration. The goal of this study is to determine the relationship between NPHS2 and ACTN4 in PNS youngsters. METHODS: A study with 100 NS children and 100 healthy matched volunteers was conducted. Genomic DNA was extracted from peripheral blood. Single-nucleotide polymorphisms were genotyped using ARMS-PCR. RESULTS: A substantial decline in the level of albumin was found in NS cases (P < 0.001) Further on, a significantly difference in T.C and TG level between healthy and NS patient. Molecular study showed a highly significant difference of NS patients from controls regarding NPHS2 rs3829795 polymorphic genotypes as the GA heterozygous genotype shows highly significant difference from controls (P < 0.001) as well as GA + AA genotypes (P < 0.001) in comparison with GG genotype. Regarding rs2274625, The GA heterozygous genotype showed no statistically significant difference between genotypes and alleles with NS (P = 0.246). Association of AG haplotype NPHS2 rs3829795-rs2274625 haplotypes found a significant association with the risk of developing NS (P = 0.008). Concerning the ACTN4 rs121908415 SNP, there was no link between this mutation and NS children. CONCLUSION: The correlation of AG haplotype NPHS2 rs3829795-rs2274625 haplotypes identified a strong association with the likelihood of getting NS, according to our findings. There was no connection found between the ACTN4 rs121908415 SNP and NS children.

Analysis of the clinical characteristics of arthritis with renal disease caused by a NPHS2 gene mutation.

The co-existence of juvenile idiopathic arthritis (JIA)/rheumatoid arthritis (RA) and focal segmental glomerulosclerosis (FSGS) is rare, and the existence of co-pathogenesis remains unknown. In this study, we analyzed the clinical and gene mutation characteristics of a patient with JIA and FSGS caused by a NPHS2 gene mutation, and evaluated the potential connections between these two diseases. We summarized the clinical manifestations, related examination results, and gene mutation characteristics of the patient who presented at our center and six reported cases of arthritis with renal disease. Most of the cases were polyarticular arthritis with varying degrees of renal damage (hematuria, proteinuria, and renal dysfunction) and different prognoses. Among these patients, two developed end-stage renal disease (ESRD), with one dying as a result, while the other patients had a relatively good prognosis. Patients with a family history of renal disease had a poor prognosis. After excluding occasional factors and drug influences, our analysis indicated the existence of co-pathogenesis of arthritis with renal damage (especially FSGS). NPHS2 mutations might account for the family aggregation. Therefore, evaluation of more clinical cases is necessary to further clarify the underlying co-pathogenesis of these diseases.

Childhood nephrotic syndrome in tropical Africa: then and now.

This descriptive and comparative review examines the changing epidemiology, treatment, renal and patient outcome of childhood nephrotic syndrome (NS) in tropical Africa (TpAfr). In the 1960s to 1980s, corticosteroid-resistant non-minimal change disease (nMCD) including quartan malaria nephropathy (QMN) was the dominant renal histopathology type. The overall incidence of NS was 0.35-1.34% of hospital admissions. Median age at onset of NS ranged between 4.0 and 12.0 years while the mean (SD) age range was 5.8 (3.8) to 10.3 (4.8) years across studies. The male: female ratio was 1.6:1.0. The overall mean (SD) incidence of idiopathic minimal change disease (MCD) [21.6 (18.6%)] compared with idiopathic nMCD [59.1 (25.7%)] demonstrates significant dominance of the latter (p = 0.0001). Post-1989, the following mean (SD) incidences of histopathological types were: MCD 20.4 (17.7%), focal segmental glomerulosclerosis 39.0 (26.3%), membranoproliferative glomerulonephritis 25.4 (16.8%), proliferative glomerulonephritis 16.7 (27.0%) and membranous nephropathy 7.4 (4.5%). While the mean (SD) proportion of steroid resistance (SR) [73.5 (19.2%)] was significantly greater than the mean complete remission (CR) [26.5 (19.2%)] during 1960-1989 (p=0.005), mean (SD) SR [27.4 (25.3%)] was significantly lower than mean (SD) CR [66.1 (28.0%)] post-1989 (p < 0.001). Unlike QMN, hepatitis B virus, HIV infection, sickle cell disease and systemic lupus erythematosus are now increasingly being associated with NS in TpAfr. Mean (SD) renal survival post-1989 was 58.3 (37.0%) while all-cause mortality was 9.8%. Children with NS now survive better than before, reflecting improved access to healthcare and transition to a clinical pattern favouring idiopathic NS and increased sensitivity to corticosteroids.

Characterization of NPHS2 gene polymorphisms associated to steroid resistance nephrotic syndrome in Indian children.

Nephrotic syndrome (NS) is the common glomerular disease in children. These children are treated with steroids, depending upon their behavior. They are either steroid sensitive (SSNS) or steroid resistant (SRNS). NPHS2 gene mutants are linked to the risk of autosomal recessive SRNS and in some cases to SSNS. The present study has been performed to screen single nucleotide polymorphisms (SNPs) of the NPHS2 gene in a group of 90 Indian children suffering with NS (30 SSNS, 30 SRNS and 30 Controls) by PCR method followed by direct exon sequencing. Effect of SNPs on fold expression changes at transcript level of podocin was checked using quantitative real time PCR (qRT-PCR). SNPs identified through sequencing helps to carry out in-silico analysis. Overall 17 SNPs were identified in NPHS2 gene where 6 were found novel. Three missense SNPs p.R299Q, p.P20L and p.G35D were also identified in this population where SNP, p.G35D was found novel. In addition to sequencing analysis, results of in silico analysis shows that a mutant with these three missense SNPs has least ligand binding efficiency compared to native model. Moreover the significant observation of this study included two intronic SNPs c.451+23C>T and c.451+58A>T present in SRNS group of patients. These SNPs has shown high level of clinical significance within genomic and allelic frequency along with haplotypes and linkage disequilibrium count. The qRT-PCR analysis shows, down expression of podocin protein at transcript level in SRNS patients compared to SSNS patients. All these results support the fact that SNPs present in this population could affect the protein structural stability. Thus it is concluded that the polymorphisms predicted in this study might be disease causing in the NPHS2 gene and may have influence on the therapeutic response of NS patients.

The clinical features of hereditary nephrotic syndrome caused by NPHS 2 mutation in two pediatric patients / 临床儿科杂志

Objective To explore the clinical features of steroid resistant nephrotic syndrome caused by NPHS2 gene mutation. Methods The clinical data of two pediatric patients with steroid resistant nephrotic syndrome were retrospectively analyzed. The pertinent literatures were reviewed. Results Both patients were male with onset age at 2 and 3 years old. The clinical features were heavy proteinuria, hypoalbuminemia, and hypercholesterolemia, which met the diagnostic criteria of nephrotic syndrome. Renal pathology found one patient with focal segmental glomerulosclerosis, and other with minimal-change. Both of them suffered from recurrent inguinal hernioplasty and one was accompanied with hypoplasia of left testis. Gene detection verified a NPHS2 gene mutation. Both of them were hormone resistant at the beginning of onset and later hormone combined with different kinds of immunosuppressive therapy was still ineffective. Both of them entered the end-stage of renal disease 3 years after onset. Conclusions For male pediatric patients with steroid resistant nephrotic syndrome, combined with non-renal manifestations such as multiple hernia or testicular abnormalities, the possibility of the hereditary nephrotic syndrome caused by NPHS2 mutations should be considered.

NPHS2 R229Q polymorphism in steroid resistant nephrotic syndrome: is it responsive to immunosuppressive therapy?

Steroid-resistant nephrotic syndrome (SRNS) patients with NPHS2 gene mutations have been reported as non-responsive to immunosuppressive therapy. Inter-ethnic differences can have influence over the frequency of mutations. The present study was undertaken to find out the incidence and treatment response. Mutational analysis of NPHS2 gene was performed in 20 sporadic idiopathic SRNS, 90 steroid-sensitive nephrotic syndrome (SSNS) and 50 normal controls. NPHS2 gene analysis showed R229Q polymorphism in six SRNS (30%), four SSNS (4.4%) and 13 controls (26%). The polymorphism (G→A) showed Hardy-Weinberg distribution and risk allele (G) had strong association with the disease (odds ratio 3.14, 95% CI 1.33-7.43) than controls. Five cases of SRNS having polymorphism showed partial remission to cyclosporine and prednisolone. Overall, partial remission was achieved in 14(70%), complete remission in four (20%), one(5%) patient had no response and one(5%) died. Thus, NPHS2 gene showed R229Q polymorphism and patients achieved partial remission to therapy.

Familial steroid-sensitive idiopathic nephrotic syndrome: seven cases from three families in China

OBJECTIVES: Familial steroid-sensitive idiopathic nephrotic syndrome is rare, and only approximately 3% of patients have affected siblings. METHODS: Herein, we report seven cases of patients with steroid-sensitive idiopathic nephrotic syndrome from three Chinese families. Mutational screening of the Nphs2 gene was performed in all the patients. RESULTS: All seven of the familial steroid-sensitive idiopathic nephrotic syndrome cases in our sample exhibited minimal change disease, and one case also presented with mesangial proliferative glomerulonephritis, according to the renal pathology. No significant was associations were found between Nphs2 gene mutations and the onset of proteinuria and nephrotic syndrome in these familial cases. CONCLUSIONS: The presence of minimal change disease is important, but it is not an unusual finding in patients with familial steroid-sensitive idiopathic nephrotic syndrome, which appears to be clinically benign and genetically distinct from other types of nephrosis. .

NPHS2 and CD2AP gene mutation in children with primary steroid-resistant nephrotic syndrome in Guangdong province / 中华实用儿科临床杂志

Objective To study NPHS2 and CD2AP gene mutation with primary steroid-resistant nephroticsyndrome (SRNS) children in Guangdong province,and to investigate the relationship between NPHS2,CD2AP genemutation and SRNS,so as to provide a theoretical basis for the diagnosis and treatment of SRNS in children.Methods Twenty-six SRNS children and 20 cases of the healthy children as controls were chosen randomly in Guangdong province.Genomic DNA was isolated from peripheral blood leucocytes of these patients and the healthy children.Mutational analysis was performed in 8 exons of NPHS2 gene and 18 exons of CD2AP gene after sequencing directly.The results were compared with United States National Center for Biotechnology Information (NCBI) gene database,the detected gene mutation.Results The variation analysis revealed 3 polymorphisms (288C ＞ T,954T ＞ C,1038A ＞ G) in 14 cases out of 26 patients and 4 cases of the healthy children studied,which had been reported before,but there was no significant difference in the genotypic and allelic frequencies of these polymorphisms between the patients and the controls (all P ＞ 0.05).One CD2AP heterozygous mutation (1917 + 20 C ＞ G) was detected in intron in 2 cases of SRNS children.Conclusions NPHS2 gene variation may not be the main mechanism of SRNS in Guangdong province.CD2APgene mutation may increase the possibility of SRNS and focal segmental glomerulosclerosis in children.CD2AP mutation in intron may involve in the pathogenesis of SRNS.

The correlation between NPHS2 polymorphism and IgA nephropathy in northern Chinese patients / 中华内科杂志

Objective To examine the polymorphism in NPHS2 gene of IgA nephropathy in northern Chinese patients and to investigate the possible association of the NPHS2 polymorphism with the development of IgA nephropathy, as well as its clinical and histologic manifestations.Methods The polymorphism of NPHS2 was analyzed by direct DNA sequencing in 32 northern Chinese patients with IgA nephropathy (16 with heavy proteinuria and 16 with isolated hematuria).According to preliminary results, a total of 537 IgA nephropathy patients were genotyped for the NPHS2 C357T polymorphism by PCR combined with restriction fragment length polymorphism (PCR-RFLP). We collected clinical and histologic manifestations for gene analysis in patients with IgA nephropathy, such as age, sex, urine protein excretion and so on.ResultsEight NPHS2 polymorphisms (-931A＞T, -601C ＞T, 19G＞T, 171A＞G, 357C ＞ T, IVS3-21C ＞ T, 1023C ＞ T and 1107A ＞ G) were identified.The preliminary results of gene sequencing showed that the frequency of 357T allele in nephrotic syndrome group was obviously lower than isolated hematuria group (0.038 vs 0.125, P ＜0.05).In 537 IgA nephropathy patients with clinical and histologic data, the average urinary protein excretion in the patients with the 357CT/TT genotype was less (P =0.023).The incidence of urinary protein of more than 3.5 g/d was significantly lower in patients with T allele and TT/CT genotype, respectively (P =0.017 and 0.011).The logistic regression analysis indicated that, even after adjusting for the effect of hypertension and age of patients, the CT/II genotype of NPHS2 C357T was an independent protective factor for the urinary protein excretion more than 3.5 g/d(P =0.012,OR = 0.485, 95％ CI 0.275-0.84).ConclusionsEight NPHS2 polymorphisms were identified in northern Chinese IgA nephropathy patients. The frequencies of NPHS2 T allele and TT/CT genotype were the protective factors for urinary protein, especially with that of more than 3.5 g/d.

A familial steroid-responsive nephrotic syndrome report / 中华肾脏病杂志

Objective To report a familial steroid responsive idiopathic nephrotic syndrome,describe the clinic and pathologic features of the family and screen the potential mutations of NPHS2 in the kindred. Methods Clinopathological data of the family members were collected(including patients) . The reports on familial steroid responsive idiopathic nephrotic syndrome were reviewed. The characteristics were compared between them. NPHS2 mutation was screened through DHPLC for the patients. Resutts There were two brothers with steroid responsive nephrotic syndrome in this family,and the renal pathology was minimal change disease. One of them had massive proteinuria and hypertension,whose renal biopsy showed mild mesangial proliferative nephritis. In this family,any mutation in NPHS2 gene was not found as it was reported in other populations. Conclusions The present study is the first report of familial steroid responsive idiopathic nephrotic syndrome in Chinese population. No relationship between the disease and NPHS2 gene mutation in this family is found.