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Background: Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. We performed this study to report histopathological findings, the correlation between clinical and histopathological features, and the response to steroids and other immunosuppressive drugs and outcomes in Syrian children with INS., Methods: A single-center retrospective observational cohort study was conducted at Children's University Hospital in Damascus, and included all patients aged 1-14 years, admitted from January 2013 to December 2022, with INS and who underwent kidney biopsy., Results: The study included 109 patients, with a male/female ratio of 1.13:1, and a median age of 5 years with interquartile range (2.8-10). The main indication of kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) (57.8%). The main histopathological patterns were minimal change disease (MCD) (45%) and focal segmental glomerulosclerosis (FSGS) (37.6%). FSGS was the most common histopathological pattern in SRNS (44.3%). In SRNS, we used calcineurin inhibitors to induce remission. Tacrolimus was used in 49 patients with response rate (complete remission of proteinuria) of 69.4% and cyclosporine in 20 patients with response rate of 50%. In steroid-dependent nephrotic syndrome (SDNS), we used mycophenolate mofetil (MMF) and cyclophosphamide to prevent relapses; MMF was used in 9 patients with response rate (maintaining sustained remission) of 89% and cyclophosphamide in 3 patients with response rate of 66.7%. Rituximab was used in four patients with FSGS, two SRNS patients and two SDNS patients, with sustained remission rate of 100%. Fifteen patients (13.7%) progressed to chronic kidney disease stage 5. Of them, 7 patients had FSGS and 8 patients had focal and global glomerulosclerosis;14 of them were steroid-resistant and one patient was steroid-dependent with persistent relapses. The most common outcome was sustained remission (47%) in MCD and frequent relapses (31.7%) in FSGS., Conclusions: FSGS was the most common histopathological pattern in idiopathic SRNS and had the worst prognosis. Calcineurin inhibitors could be an effective therapy to induce complete remission in SRNS. Rituximab may be an effective treatment to achieve sustained remission in SDNS and frequently relapsing NS and may have a potential role in SRNS with further studies required., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India., Methods: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life., Results: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%., Conclusions: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background/purpose: Congenital nephrotic syndrome (CNS) is one of the important causes of end-stage kidney disease in children. Studies on the genotype, phenotype, and clinical outcome in infants with CNS caused by genetic mutations are scarce., Methods: We analyzed the genetic background, clinical manifestations, treatment response, and prognosis of pediatric patients with CNS in Taiwan., Results: Fifteen infants with CNS were enrolled, and 11 patients of median age 21 (interquartile range 3∼44) days caused by genetic mutations from 10 unrelated families were included in the study. Of the eleven patients, 9 had extra-renal manifestations including microcephaly, facial dysmorphism, and skeletal anomalies. More than two-thirds of the patients had disease onset before 1 month of age. Diffuse meningeal sclerosis was the most common histological characteristic. Whole exome sequencing followed by direct Sanger sequence revealed mutations in OSGEP (R247Q), WT1 (R366H and R467Q), LAMB2 (Q1209∗ and c. 5432-5451 19 bp deletion), NUP93 (D302V), and LAGE3 (c.188+1G > A). Three of the variants were novel. Corticosteroids and/or immunosuppressants were administered in 2 patients, but both were refractory to treatment. During the mean 3.5 years of follow-up, all but two died of uremia and sepsis. The two survivors reached end-stage kidney disease and required peritoneal dialysis, and one of them underwent uneventful renal transplantation., Conclusion: The majority of patients with CNS in Taiwan were caused by OSGEP followed by WT1 mutation. R247Q is the hotspot mutation of OSGEP in Taiwan. CNS patients in Taiwan suffer from significant morbidity and mortality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

A two-and-a-half-month-old female infant presented with generalized edema for 10 days. At presentation, she had periorbital puffiness, moderate ascites, and pedal edema. Laboratory investigations revealed serum albumin 1.3 g/dL, spot urine protein to creatinine ratio (Up:Uc) 20.87 mg/mg, total cholesterol 380 mg/dL, and serum creatinine 0.31 mg/dL. Exome sequencing revealed compound heterozygous variants in LAMA5 gene (NM_005560.6). There was a heterozygous likely pathogenic missense variant in exon 2: LAMA5: c.385C > A (depth 195 ×) and another heterozygous pathogenic variant in exon 31: LAMA5: c.3932_3936dup; parental segregation by Sanger sequencing proved that the variants were in trans. Kidney biopsy showed diffuse mesangial sclerosis (DMS). Our case adds LAMA5 gene to the constellation of genes causing DMS, in addition to the classically described WT1, LAMB2, and PLCE1 genes and to the list of genes causing congenital nephrotic syndrome (CNS)., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: The variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype-phenotype relationships and elucidate the role of nucleoporins in SRNS., Methods: Four patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed., Results: All four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously., Conclusion: This report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals., (© 2024. The Author(s).)

Background: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of kidney failure in children and adults under the age of 20 years. Previously, we were able to detect by exome sequencing (ES) a known monogenic cause of SRNS in 25-30% of affected families. However, ES falls short of detecting copy number variants (CNV). Therefore, we hypothesized that causal CNVs could be detected in a large SRNS cohort., Methods: We performed genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on a cohort of 138 SRNS families, in whom we previously did not identify a genetic cause through ES. We evaluated ES and CNV data for variants in 60 known SRNS genes and in 13 genes in which variants are known to cause a phenocopy of SRNS. We applied previously published, predefined criteria for CNV evaluation., Results: We detected a novel CNV in two genes in 2 out of 138 families (1.5%). The 9,673 bp homozygous deletion in PLCE1 and the 6,790 bp homozygous deletion in NPHS2 were confirmed across the breakpoints by PCR and Sanger sequencing., Conclusions: We confirmed that CNV analysis can identify the genetic cause in SRNS families that remained unsolved after ES. Though the rate of detected CNVs is minor, CNV analysis can be used when there are no other genetic causes identified. Causative CNVs are less common in SRNS than in other monogenic kidney diseases, such as congenital anomalies of the kidneys and urinary tract, where the detection rate was 5.3%. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Congenital nephrotic syndrome (NS) is characterized by early-onset heavy proteinuria. Most cases of congenital NS are associated with genetic mutations in the podocyte proteins. The causal relationship of perinatal infections with congenital NS has not yet been proven. Inadequate response to the treatment of such infections should prompt us to conduct genetic testing for congenital NS. The heavy proteinuria associated with congenital NS is usually difficult to control with conventional treatment. It often results in progressive kidney disease with a high risk of mortality in early life. Here, we describe an infant who developed congenital NS and was found to have a coexisting Cytomegalovirus infection and an underlying NPSH1 mutation. Proteinuria did not respond to a standard dose of enalapril. A supramaximal dose of enalapril was tried and was effective and safe in controlling the proteinuria. It was associated with improved growth, complete resolution of edema, normal serum albumin, and normal renal function beyond 2 years of age., (Copyright © 2023 Copyright: © 2023 Saudi Journal of Kidney Diseases and Transplantation.)

Background: Primary steroid resistant nephrotic syndrome (SRNS) is thought to have either genetic or immune-mediated aetiology. Knowing which children to screen for genetic causes can be difficult. Several studies have described the prevalence of genetic causes of primary SRNS to be between 30 and 40%, but these may reflect a selection bias for genetic testing in children with congenital, infantile, syndromic or familial NS and thus may overestimate the true prevalence in a routine clinical setting., Methods: Retrospective electronic patient record analysis was undertaken of all children with non-syndromic SRNS and presentation beyond the first year of life, followed at our centre between 2005 and 2020., Results: Of the 49 children who met the inclusion criteria, 5 (10%) had causative variants identified, predominantly in NPHS2. None responded to immunosuppression. Of the 44 (90%) who had no genetic cause identified, 33 (75%) had complete or partial remission after commencing second-line immunosuppression and 67% of these had eGFR > 90 ml/min/1.73 m 2 at last clinical follow-up. Of the children who did not respond to immunosuppression, 64% progressed to kidney failure., Conclusions: In our cohort of children with non-syndromic primary SRNS and presentation beyond the first year of life, we report a prevalence of detectable causative genetic variants of 10%. Those with identified genetic cause were significantly (p = 0.003) less likely to respond to immunosuppression and more likely (p = 0.026) to progress to chronic kidney disease. Understanding the genetics along with response to immunosuppression informs management in this cohort of patients and variant interpretation. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Rationale: Congenital nephrotic syndrome (CNS) is a heterogeneous disorder in which massive proteinuria, hypoproteinemia, and hyperlipidemia and marked edema are the main manifestations before 3 months-of-age. Here, we present a case involving the genetic diagnosis of a child with CNS., Patient Concerns: A 31-day-old male infant with diarrhea for 25 days and generalized edema for more than 10 days. There was no family history of kidney disease. On proband whole exome sequencing, a compound heterozygous mutation of the NPHS1 gene was identified, including a novel in-frame mutation in exon 14 (c.1864_1866dupACC p. T622dup) and a missense mutation in exon 8 (c.928G>A p. D310N)., Diagnoses: Based on the clinical and genetic findings, this patient was finally diagnosed with CNS., Interventions: The main treatment options for the patient were 2-fold: anti-infective treatment and symptomatic treatment., Outcomes: The patient died in follow-up 2 months later; the specific reason for death was unclear., Lessons: Whole exome sequencing and Sanger sequencing confirmed that the infant had CNS. Our study identified a novel mutation in an infant, thus expanding the gene-mutation spectrum of the NPHS1 gene, thus providing an efficient prenatal screening strategy and early genetic counseling., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Steroid remains the keystone therapy for Idiopathic Nephrotic Syndrome (NS). Besides genetic factors and histological changes, pharmacogenomic factors also affect the steroid response. The upregulation of P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP-1) modulate the pharmacokinetics of steroids and may contribute to steroid resistance. Flow-cytometric analysis of P-gp, MRP-1 expression and functional activity on peripheral blood mononuclear cells (PBMCs) was carried out in steroid-sensitive nephrotic syndrome (SSNS) (n = 171, male 103, mean age = 8.54 ± 4.3); and steroid-resistant nephrotic syndrome (SRNS) (n = 83, male 43, mean age = 7.43 ± 4.6) patients. The genotypings of MDR-1 gene were carried out using PCR-RFLP. We observed that the percentage expression of P-gp (10.01 ± 2.09 and 3.79 ± 1.13, p < 0.001); and MRP-1 (15.91 ± 3.99 and 7.40 ± 2.33, p < 0.001) on lymphocyte gated population were significantly higher in SRNS than that of SSNS. The functional activity of P-gp and MRP-1 was also significantly escalated in SRNS as compared to SSNS (68.10 ± 13.35 and 28.93 ± 7.57, p < 0.001); (72.13 ± 8.34 and 31.56 ± 8.65, p < 0.001) respectively. AUC-ROC curve analysis revealed that P-gp and MRP-1 expression with a cut-off value of 7.13% and 9.62% predicted SRNS with the sensitivity of 90% and 80.7%; and specificity 90% and 80%, respectively. Moreover, MDR-1 homozygous mutant TT+AA for G2677T/A (rs2032582) was significantly associated with SRNS (p = 0.025, OR = 2.86 CI = 1.14-7.14). The expression of P-gp (9.68 ± 4.99 v/s 5.88 ± 3.38, p = 0.002) was significantly higher in the patients of homozygous mutant alleles compared to wildtype GG. The increased expression and functionality of P-gp and MRP-1 contribute to steroid resistance, and MDR-1 homozygous mutant G2677T/A promotes steroid resistance by inducing P-gp expression in NS., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Kidney disease affects 10% of the world population and is associated with increased mortality. Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children, often failing standard immunosuppression. Here, we report the results of a prospective study to investigate the immunological impact and safety of a gluten-free and dairy-free (GF/DF) diet in children with SRNS. The study was organized as a four-week summer camp implementing a strict GF/DF diet with prospective collection of blood, urine and stool in addition to whole exome sequencing WES of DNA of participants. Using flow cytometry, proteomic assays and microbiome metagenomics, we show that GF/DF diet had a major anti-inflammatory effect in all participants both at the protein and cellular level with 4-fold increase in T regulatory/T helper 17 cells ratio and the promotion of a favorable regulatory gut microbiota. Overall, GF/DF can have a significant anti-inflammatory effect in children with SRNS and further trials are warranted to investigate this potential dietary intervention in children with SRNS., Competing Interests: FH is a cofounder of Goldfinch-Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pérez-Sáez, Uffing, Leon, Murakami, Watanabe, Borges, Sabbisetti, Cureton, Kenyon, Keating, Yee, Fernandes Satiro, Serena, Hildebrandt, Riella, Libermann, Wang, Pascual, Bonventre, Cravedil, Fasano and Riella.)

The identification of monogenic causes in patients with proteinuria has revealed that the encoded proteins functionally participate in distinct cellular tasks and signaling pathways in the slit diaphragms of the glomerular basement membrane. FAT1 is a member of a small family of vertebrate-cadherin-like genes, which is a crucial component in slit diaphragms and has a vital role in tubular regeneration. Only 5 cases with glomerulonephritis having FAT1 gene biallelic variants have been reported. However, only one had the biallelic truncating variant, and others had missense variants. Therefore, we need further evidence of this gene being responsible for steroid-resistant nephrotic syndrome (SRNS) or glomerulonephritis. Here we describe a 5-year-old boy in who proteinuria was detected at the age of 3 years without any extrarenal symptom. The pathological findings were examined, and targeted exome sequencing was performed. We also conducted reviews for all previously-reported cases of glomerulonephritis possessing FAT1 biallelic gene variants. We found two novel truncating variants in FAT1 (NM&#95;005245.3), c.12867dup in exon 10, and, c.5480&#95;5483del in exon 25. Our case showed mild proteinuria compared to previously-reported cases who showed SRNS and extrarenal symptoms that might have been because the latter variant in our patient was located on out of cadherin domains; however, our follow up period is short and we further need careful follow up. Our findings corroborate the evidence that individuals with FAT1-truncating variants can show isolated mild proteinuria. Further studies are needed to investigate the genotype-phenotype correlation in this disease. Therefore, our case will provide vital information regarding this rare condition.

Background: Little data are available for infants who started renal replacement therapy before 6 months of age. Because of extra-renal comorbidities and uncertain outcomes, whether renal replacement therapy in neonates is justified remains debatable., Methods: We performed a retrospective analysis of all patients who began chronic peritoneal dialysis below 6 months between 2007 and 2017 in two tertiary centres. Results are presented as median (min;max)., Results: Seventeen patients (10 boys) were included (8 prenatal diagnoses, 6 premies), with the following diagnoses: congenital anomalies of kidney and urinary tract (n=9), oxalosis (n=5), congenital nephrotic syndrome (n=2) and renal vein thrombosis (n=1). Five patients had associated comorbidities. At peritoneal dialysis initiation, age was 2.6 (0.1;5.9) months, height-standard deviation score (SDS) -1.3 (-5.7;1.6) and weight-SDS -1.4 (-3.6;0.6). Peritoneal dialysis duration was 12 (2;32) months, and at peritoneal dialysis discontinuation height-SDS was -1.0 (-4.3;0.7) weight-SDS -0.7 (-3.2;0.2), parathyroid hormone 123 (44;1540) ng/L, and hemoglobin 110 (73;174) g/L. During the first 6 months of peritoneal dialysis, the median time of hospitalisation stay was 69 (15;182) days. Ten patients presented a total of 27 peritonitis episodes. Reasons for peritoneal dialysis discontinuation were switch to hemodialysis (n=6), transplantation (n=6), recovery of renal function (n=2) and death (n=1). After a follow-up of 4.3 (1.7;10.3) years, 12 patients were transplanted, 2 patients were still on peritoneal dialysis, 2 patients were dialysis free with severe chronic kidney disease and 1 patient had died. Seven patients displayed neurodevelopmental delay, of whom five needed special schooling., Conclusion: We confirm that most infants starting peritoneal dialysis before 6 months of age will be successfully transplanted and will have a favourable growth outcome. Their quality of life will be impacted by recurrent hospitalisations and neurodevelopmental delay is frequent., (Copyright © 2020 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Genetic screening paradigms for the nephrotic syndrome (NS) in the developed world are well established; however, screening in developing countries has received only minor attention. We retrospectively analyzed a cohort of all children who underwent genetic testing for challenging NS from our registry in the 10-year interval from 2000 to 2010 and based on 58 patients aged 0-12 years with at least one of the following clinical diagnosis: Nonsyndromic steroid-resistant nephrotic syndrome (SRNS), familial NS, and congenital NS. Of these, 23 patients (~40%) had a history of familial disease occurrence. All cases were screened for NPHS2 and WT1 mutations by direct sequencing of all exons of the genes. In addition, all patients who were diagnosed during the first three months of life were screened for NPHS1 mutations too. A genetic disease cause was identified in 12 patients (20.7%); of these, five novel mutations, all in NPHS2 accounting for 42% of all mutations and 9% of the cohort. Nine patients were found to have NPHS2 mutations. Only one case with SRNS had a mutation in WT1. Of the five congenital NS, two cases were found to have NPHS1 mutations and one case with NPHS2 mutation. Therefore, mutations in NPHS2 were the most commonly identified and explained in 15.5% of the screened patients and WT1 mutation in 1.7% of cases, whereas NPHS1 mutations were found in 40% of congenital NS cases. A genetic disease cause was identified in 20.7% of the screened patients. Among 12 identified mutations, abnormalities in NPHS2 (n = 9) were most commonly identified.

Background: Herein, a 3-year-old boy presented with hidden-onset isolated proteinuria was reported. The disease was induced by COQ8B (previously termed ADCK4) compound heterozygous variants, including c.[271C > T] and c.[737G > A], which were inherited from his father and mother, respectively., Case Presentation: The patient visited our clinic due to non-nephrotic range proteinuria for 3 months, but no obvious abnormality was detected in the vital signs or laboratory test results. Renal histopathology revealed mitochondrial nephropathy, which manifested as mild glomerular abnormalities under light microscope, together with mitochondrial proliferation and hypertrophy and crowded arrangement under electron microscope. As suggested by whole exome sequencing, the patient inherited the COQ8B compound heterozygous variants from both of his parents who showed normal phenotype. After literature review, it was confirmed that one of the variant site (c.[271C > T]) had not been reported among the East Asian populations so far., Conclusions: Steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis are the most common phenotypes and renal histopathological manifestations of COQ8B variant. Nonetheless, our case shows that such variant may have hidden and mild clinical manifestations at the early onset. Therefore, early diagnosis will help to identify children at the early disease stage who have opportunity to benefit from oral coenzyme Q10 supplementation.

Background: Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding the characteristics of CNS and INS. This study aimed to clarify the characteristics of CNS and INS in Japan., Methods: This cross-sectional nationwide survey obtained data from 44 institutions in Japan managing 92 patients with CNS or INS, by means of two survey questionnaires sent by postal mail. Patients aged < 16 years by 1 April 2015, with a diagnosis of CNS or INS, were included in this study. The primary outcome was end-stage kidney disease., Results: A total of 83 patients with CNS or INS were analyzed. The most frequent disease type was non-Finnish (60.2%); 33 patients (39.8%) had Finnish type. Among those with non-Finnish-type disease, 26 had no syndrome and 24 had a syndrome, of which the most frequent was Denys-Drash syndrome (70.8%). Patients with non-Finnish-type disease with syndrome showed the earliest progression to end-stage kidney disease compared with the other two groups, whereas patients with non-Finnish-type disease without syndrome progressed more slowly compared with the other two groups. In the Finnish-type group, the disease was diagnosed the earliest; a large placenta was reported more frequently; genetic testing was more frequently performed (93.8%); mental retardation was the most frequent extra-renal symptom (21.2%); and thrombosis and infection were more frequent compared with the other groups. Patients with non-Finnish-type disease with syndrome had a higher frequency of positive extra-renal symptoms (79.2%), the most common being urogenital symptoms (54.2%). Treatment with steroids and immunosuppressants was more frequent among patients with non-Finnish-type disease without syndrome. Two patients with non-Finnish-type disease without syndrome achieved complete remission. In all groups, unilateral nephrectomy was performed more often than bilateral nephrectomy and peritoneal dialysis was the most common renal replacement therapy., Conclusions: The present epidemiological survey sheds light on the characteristics of children with CNS and INS in Japan. A high proportion of patients underwent genetic examination, and patient management was in accord with current treatment recommendations and practices., Trial Registration: Not applicable.

Background: Mutations in COQ8B (*615567) as a defect of coenzyme Q10 (CoQ10) cause steroid resistant nephrotic syndrome (SRNS)., Methods: To define the clinical course and prognosis of COQ8B nephropathy, we retrospectively assessed the genotype and phenotype in patients with COQ8B mutations from Chinese Children Genetic Kidney Disease Database. We performed the comparing study of renal outcome following CoQ10 treatment and renal transplantation between early genetic detection and delayed genetic detection group., Results: We identified 20 (5.8%) patients with biallelic mutations of COQ8B screening for patients with SRNS, non-nephrotic proteinuria, or chronic kidney disease (CKD) of unknown origin. Patients with COQ8B mutations showed a largely renal-limited phenotype presenting with proteinuria and/or advanced CKD at the time of diagnosis. Renal biopsy uniformly showed focal segmental glomerulosclerosis. Proteinuria was decreased, whereas the renal function was preserved in five patients following CoQ10 administration combined with angiotensin-converting enzyme (ACE) inhibitor. The renal survival analysis disclosed a significantly better outcome in early genetic detection group than in delayed genetic detection group (Kaplan-Meier plot and log rank test, p = .037). Seven patients underwent deceased donor renal transplantation without recurrence of proteinuria or graft failure. Blood pressure showed decreased significantly during 6 to 12 months post transplantation., Conclusions: COQ8B mutations are one of the most common causes of adolescent-onset proteinuria and/or CKD of unknown etiology in the Chinese children. Early detection of COQ8B nephropathy following CoQ10 supplementation combined with ACE inhibitor could slow the progression of renal dysfunction. Renal transplantation in patients with COQ8B nephropathy showed no recurrence of proteinuria., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Atypical haemolytic uraemic syndrome and steroid-resistant nephrotic syndrome are highly rare kidney diseases that can occur in childhood. In some cases, genetic variants may trigger these conditions, although in atypical haemolytic uraemic syndrome they mostly confer only a predisposition to the disease. Most variants causing atypical haemolytic uraemic syndrome were identified in genes encoding proteins regulating the complement pathway; on the other hand, there are approximately 58 genes encoding distinct proteins primarily causing steroid-resistant nephrotic syndrome. We present a child with steroid-resistant nephrotic syndrome and a confirmed homozygous c.966G > A, p.Trp322Ter pathogenic variant in DGKE. This variant was also found in compound with a novel DGKE heterozygous deletion c.171delG, p.Ser58Alafs*111 in a patient from our paediatric cohort with atypical haemolytic uraemic syndrome. Both cases presented with hypertension, nephrotic proteinuria and severe acute kidney injury followed by renal recovery; however, their renal histology was different. In this paper, we deal with the clinical course of children with disrupted DGKE, including the steroid-resistant nephrotic syndrome and atypical haemolytic uraemic syndrome overlap., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Rationale: Infection is a major trigger or pathogenic origin in a substantial proportion of glomerulonephritis (GN) patients, typically manifesting infection-related GN (IRGN). Various microorganisms, infection sites, and clinical and histopathological features are involved in IRGN. Once an infectious origin is identified and successfully eradicated, nephrotic syndrome or kidney dysfunction is spontaneously resolved. However, if patients are asymptomatic and the origin is undetermined, the diagnosis and treatment of GN is challenging. This case presentation reported on an IRGN case manifesting steroid-resistant nephrotic syndrome associated with asymptomatic sinusitis as a pathogenic origin., Patient Concerns: A 68-year-old male presented with severe kidney dysfunction and edema in both extremities., Diagnosis: The patient was clinically diagnosed with hypocomplementemic nephrotic syndrome and kidney dysfunction and histopathologically with diffuse proliferative GN and a focal pattern of membranoproliferative GN. The findings suggested that idiopathic membranoproliferative glomerulonephritis type I was more likely than IRGN, given a critical lack of apparent infection., Interventions: Combined intravenous methylprednisolone, oral prednisolone, and cyclosporin did not improve the patient's condition. Thus, IRGN associated with inapparent infectious origin was suspected. Repeated thorough and careful examinations including CT scan showed sinusitis in his left maxillary sinus. Moreover, reanalysis of kidney specimen revealed positive nephritis-associated plasmin receptor in glomeruli, a typical finding for IRGN, supporting a pathogenic significance of his sinusitis. Medical treatment was initiated with 200 mg oral clarithromycin daily., Outcomes: Oral clarithromycin gradually improved proteinuria and hypocomplementemia and resulted in nephrotic syndrome remission in parallel with opacification resolution of sinuses shown on CT., Lessons: This case presentation showed that asymptomatic sinusitis is potentially a pathogenic IRGN origin. A gold standard therapy for idiopathic GN, corticosteroid could be damaging in uncontrolled or underdiagnosed infection. In asymptomatic patients, a thorough screening of infectious diseases, including sinusitis, together with a renal histological evaluation of glomerular nephritis-associated plasmin receptor deposition is also essential in treating a wide spectrum of GN.

Background and Objectives: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients., Design, Setting, Participants, & Measurements: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics., Results: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies., Conclusions: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome., (Copyright © 2020 by the American Society of Nephrology.)

Background: There is a paucity of information on epidemiology, diagnosis, and treatment outcomes of congenital nephrotic syndrome (CNS) in developing countries., Methods: Retrospective (2012-2017) review of case records undertaken across 12 Indian pediatric nephrology centers., Results: Sixty-five children (58% male, median birth weight 2.4 kg [interquartile range (IQR) 2.1-2.86]) were identified with CNS. Nearly half (45%) were preterm with previous history of fetal loss/sibling death in 22% and history of consanguinity in a third. No infective etiology was confirmed. Genetic reports available for 15 (23%) children identified causal mutations in 10 (8 in NPHS1 [1 novel variant], 1 in WT 1 [novel variant], and 1 in PLCE-1 gene). In addition, 1 child was clinically diagnosed as Galloway Mowat syndrome. Next-generation sequencing showed 80% yield and Sanger sequencing 20%. Albumin infusion and angiotensin-converting enzyme inhibitors were used initially in around two-third of cohort, while only 12% of children received indomethacin. Totally, 22 (34%) children were lost to follow-up after initial visit, and among the rest median follow-up was 69 days (IQR 20-180) with 18 (42%) deaths. Eight children showed partial response (including 2 with NPHS1 compound mutation), 1 complete response, and all of them were alive at last follow-up in contrast to 53% mortality among nonresponders, p = 0.004., Conclusion: This largest reported series on CNS from India revealed suboptimal management with poor outcome as well as low number of CNS being subjected to genetic evaluation., (© 2019 S. Karger AG, Basel.)

Objective: To explore the genetic basis for a fetus suspected for congenital nephrotic syndrome of Finland (CNF)., Methods: Genomic DNA was extracted from peripheral and umbilical cord blood samples derived from both parents and the fetus. Potential variants were detected by using next-generation sequencing. Suspected variants were confirmed by Sanger sequencing., Results: The fetus was found to carry compound heterozygous variants c.1440+1G>A and c.925G>T of the NPHS1 gene, which were respectively inherited from its mother and father., Conclusion: Identification of the compound heterozygous NPHS1 variants has enabled diagnosis of CNF in the fetus and genetic counseling for the affected family.

Introduction: Idiopathic nephrotic syndrome (INS) is the most common glomerulopathy that results in childhood chronic kidney disease in China, but the relationships between different clinical phenotypes and immunological genetic variants observed in patients with INS are ambiguous and have not been well studied. A cohort study combined with whole exome sequencing might further identify the effects of immunological genetic variants on clinical phenotypes and treatment outcomes., Methods and Analysis: We describe a 3 year prospective observational single-centre cohort study to be conducted in the Children's Hospital of Chongqing Medical University in China. This study will recruit and investigate 336 patients with childhood-onset INS presenting with different clinical phenotypes. Whole exome sequencing will be conducted when patients progress to a confirmed clinical phenotype during follow-up. Relevant clinical and epidemiological data, as well as conventional specimens, will be collected at study entry and 1 month, 3 months, 6 months, 1 year, 2 years and 3 years after disease onset. After this cohort is generated, the immunological genetic variants of steroid-sensitive nephrotic syndrome without frequent relapse, steroid-resistant nephrotic syndrome and steroid-dependent/frequent relapse nephrotic syndrome will be evaluated., Ethics and Dissemination: The study protocol is approved by Ethics Committee of Children's Hospital of Chongqing Medical University (reference number 2018-140). The results will be disseminated through peer-reviewed journals and conference presentations., Trial Registration Number: ChiCTR1800019795., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nephrotic syndrome (NS) is one of the most common kidney diseases seen in children. It is a disorder characterized by severe proteinuria, hypoproteinemia, hyperlipidemia, and generalized edema resulting from alterations of permeability at the glomerular capillary wall. Endothelin-1 (ET1) has a central role in the pathogenesis of proteinuria and glomerulosclerosis and has a role in assessment of the clinical course of NS in children. This study aims to investigate the relationship between ET1 serum level and the response to steroid therapy in children with primary NS. Serum ET1 levels were evaluated in 55 children with NS. They were classified into two groups: 30 patients with steroid-sensitive NS (SSNS) and 25 patients with steroid-resistant NS (SRNS). The SSNS group was further divided into infrequent-relapsing NS (IFRNS) and steroid-dependent NS (SDNS), while the SRNS group was subdivided into two groups according to renal pathology. ET1 levels were significantly higher in the SRNS group (52.5 ± 45.8 pg/dL) compared to the SSNS group (18.3 ± 17 pg/dL) (P <0.001). Furthermore, ET1 levels were significantly higher in SDNS (54.3 ± 18.6) compared to IFRNS (11.9 ± 7.8, P = 0.001). There was no statistically significant difference in ET1 levels between minimal change disease group and focal segmental glomerulosclerosis group, (P = 0.28). Serum ET1 can be considered as a predictor for response to steroid therapy.

Introduction: Nephrotic syndrome is a heterogeneous disease in children, with nearly 10% categorized as steroid-resistant. In this study we evaluated disease related mutations within NPHS1, NPHS2 and new potential variants in other genes., Methods: In the first phase of study, 25 patients with SRNS were analyzed by Sanger sequencing for NPHS1 (exon 2, 26) and all exons of NPHS2 genes. In the next step, whole exome sequencing was performed on 10 patients with no mutation in NPHS1 and NPHS2., Results: WES analysis revealed a novel mutation in FAT1 (c.10570C > A; Q3524K). We identified 4 pathogenic mutations, located in exon 4 and 5 of NPHS2 gene in 20% of patients (V180M, P118L, R168C and Leu156Phe). Also our study has contributed to the description of previously known pathogenic mutations across WT1 (R205C) and SMARCAL1 (R764Q) and a novel polymorphism in CRB2., Conclusion: It seems that NPHS2, especially exons 4 and 5, should be considered as the first step in genetic evaluation of Iranian patients. We suggest conducting WES after NPHS2 screening to identify the potential genes associated with SRNS, Further studies are required to examine more common genes in the first step and then designing native laboratory panels.

Aim: Nephrotic syndrome is a urinary disease, causing high morbidity and mortality. However, the mutation prevalence of major susceptible genes in childhood-onset steroid-resistant nephrotic syndrome (SRNS) in China is limited. In this study, we performed a systematic analysis of the mutations in 18 major SRNS-susceptible genes in Chinese SRNS children., Methods: Mutation analysis was performed to sequence 18 major SRNS-susceptible genes ( NPHS1, NPHS2, CD2AP, PLCE1, ACTN4, TRPC6, INF2, WT1, LMX1B, LAMB2, LAMB3, GLA, ITGB4, SCARB2, COQ2, PDSS2, MTTL1 , and SMARCAL1 ) using a PCR-based MassArray technology in 38 childhood-onset SRNS patients in China. This cohort included 10 sporadic cases and 28 familial cases from 7 SRNS families with disease onset between the ages of 1-13 years., Results: Our analysis detected a heterozygous missense mutation (p.E447K, pathogenic) in NPHS1 in 3/28 familial patients (10.7%) and 1/10 (10.0%) patient without a family history. In addition, two NPHS2 mutations (p.R138X and p.R291W, pathogenic) were identified in 2 patients from another family (7.1% familial cases, 0% sporadic cases, 5.2% overall). Pathogenic mutations of remaining 16 SRNS-susceptible genes were not detected., Conclusion: Our results have verified the significant prevalence of pathogenic NPHS1 and NPHS2 mutations in childhood-onset SRNS in China, while the other 16 SRNS-susceptible genes seem to have lesser contribution to child-onset SRNS. Therefore, our study indicates that it is very necessary to make more efforts to target NPHS1 and NPHS2 for childhood-onset SRNS treatment, especially in China., (© 2019 by the Association of Clinical Scientists, Inc.)

Background: Approximately 10-20% of children with idiopathic nephrotic syndrome (NS) fail to respond to steroid therapy. NS is divided into steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). Over 45 recessive and dominant genes have been found to be associated with SRNS and/or focal segmental glomerulosclerosis (FSGS)., Methods: Targeted sequencing of 339 candidate genes, expressed in glomerular filtration barrier or located in the signaling pathway of podocyte function, were sequenced by NGS in a cohort of total 89 Chinese Han children (29 sporadic SRNS, 33 sporadic SSNS, and 27 healthy)., Results: Two variants (WT1 p.R441X and NPHS2 p.G149V) were screened out as pathogenic mutations and 14 variants were likely pathogenic. Mutations of KIRREL2 (SRNS vs SSNS: 24.1% vs 3.0%, adjusted OR = 10.11, 95% CI: 1.56-198.66, P = 0.039) were significantly associated with the risk of pediatric sporadic SRNS. Besides, three pathogenic or likely pathogenic variants were identified in HP gene., Conclusion: Two pathogenic mutations and 14 likely pathogenic mutations were discovered through targeted sequencing of 339 candidate genes. Two genes, HP and KIRREL2, as candidate genes, were first proposed to be associated with the risk of pediatric sporadic SRNS.

Background: Children with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children., Methods: We conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS., Results: Eighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6 months, 30 (68%) by 1 year, and 40 (91%) by 2 years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n = 5) or peritonitis (n = 4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6 months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months., Conclusions: Infants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data.

Background: Congenital nephrotic syndrome (CNS) is characterised by increased proteinuria, hypoproteinemia, and edema beginning in the first 3 months of life. Recently, molecular genetic studies have identified several genes involved in the pathogenesis of CNS. A systematic investigation of the genes for CNS in China has never been performed; therefore, we conducted a mutational analysis in 12 children with CNS,with the children coming from 10 provinces and autonomous regions in China., Methods: Twelve children with CNS were enrolled from 2009 to 2016. A mutational analysis was performed in six children by Sanger sequencing in eight genes (NPHS1, NPHS2, PLCE1, WT1, LAMB2, LMXIB, COQ6 and COQ2) before 2014, and whole-exome sequencing was used from 2014 to 2016 in another six children. Significant variants that were detected by next generation sequencing were confirmed by conventional Sanger sequencing in the patients' families., Results: Of the 12 children, eight patients had a compound heterozygous NPHS1 mutation, one patient had a de novo mutation in the WT1 gene, and another patient with extrarenal symptoms had a homozygous mutation in the COQ6 gene. No mutations were detected in genes NPHS2, PLCE1, LAMB2, LMXIB, and COQ2 in the 12 patients., Conclusions: This study demonstrates that the majority of CNS cases (67%, 8/12 patients) are caused by genetic defects, and the NPHS1 mutation is the most common cause of CNS in Chinese patients. A mutational analysis of NPHS1 should be recommended in Chinese patients with CNS in all exons of NPHS1 and in the intron-exon boundaries.

Background: Steroid resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disease with significant phenotypic variability. More than 53 podocyte-expressed genes are implicated in SRNS which complicates the routine use of genetic screening in the clinic. Next generation sequencing technology (NGS) allows rapid screening of multiple genes in large number of patients in a cost-effective manner., Methods: We developed a targeted panel of 17 genes to determine relative frequency of mutations in south Indian ethnicity and feasibility of using the assay in a clinical setting. Twenty-five children with SRNS and 3 healthy individuals were screened., Results: In this study, novel variants including 1 pathogenic variant (2 patients) and 3 likely pathogenic variants (3 patients) were identified. In addition, 2 novel variants of unknown significance (VUS) in 2 patients (8% of total patients) were also identified., Conclusions: The results show that genetic screening in SRNS using NGS is feasible in a clinical setting. However the panel needs to be screened in a larger cohort of children with SRNS in order to assess the utility of the customised targeted panel in Indian children with SRNS. Determining the prevalence of variants in Indian population and improvising the bioinformatics-based filtering strategy for a more accurate differentiation of pathogenic variants from those that are benign among the VUS will help in improving medical and genetic counselling in SRNS.

Mutations in the transmembrane protein nephrin (encoded by NPHS1) underlie nearly half of all cases of congenital nephrotic syndrome (CNS), which is caused by aberrations in the blood filtering function of glomerular podocytes. Nephrin directly contributes to the structure of the filtration barrier, and it also serves as a signaling scaffold in podocytes, undergoing tyrosine phosphorylation on its cytoplasmic tail to recruit intracellular effector proteins. Nephrin phosphorylation is lost in several human and experimental models of glomerular disease, and genetic studies have confirmed its importance in maintenance of the filtration barrier. To date, however, the effect of CNS-associated NPHS1 variants on nephrin phosphorylation remains to be determined, which hampers genotype-phenotype correlations. Here, we have characterized a novel nephrin sequence variant, A419T, which is expressed along with C623F in a patient presenting with CNS. Nephrin localization is altered in kidney biopsies, and we further demonstrate reduced surface expression and ER retention of A419T and C623F in cultured cells. Moreover, we show that both mutations impair nephrin tyrosine phosphorylation, and they exert dominant negative effects on wildtype nephrin signaling. Our findings thus reveal that missense mutations in the nephrin extracellular region can impact nephrin signaling, and they uncover a potential pathomechanism to explain the spectrum of clinical severity seen with mild NPHS1 mutations., Competing Interests: The authors have declared that no competing interests exist.

Background: Congenital nephrotic syndrome (CNS) is primarily a monogenetic disease, with the majority of cases due to changes in five different genes: the nephrin (NPHS1), podocin (NPHS2), Wilms tumor 1 (WT1), laminin ß2 (LAMB2), and phospholipase C epsilon 1 (PLCE1, NPHS3) gene. Usually CNS is not responsive to immunosuppressive therapy, but treatment with ACE inhibitors, AT1 receptor blockade and/or indomethacin can reduce proteinuria. If the disease progresses to end-stage renal disease, kidney transplantation is the therapy of choice., Case-Diagnosis: Here, we present the case of a 4-month-old girl with congenital nephrotic syndrome. Upon admission, the patient presented with life-threatening anasarca, hypoalbuminemia, proteinuria, and impaired growth. There was no evidence of an infectious or immunological etiology. The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS. In addition to daily parenteral albumin infusions plus furosemide, a pharmacological antiproteinuric therapy was started to reduce protein excretion. Based on the genetic results, immunosuppressive therapy with prednisolone was initiated, but without response. However, following cyclosporine A treatment, the patient achieved complete remission and now has good renal function, growth, and development., Conclusions: A profound search for the cause of CNS is necessary but has its limitations. The therapeutic strategy should be adapted when the etiology remains unclear.

Recent advances in high-throughput sequencing for clinical genetic testing have revealed novel disease-causing genes, such as Crumbs homolog 2 (CRB2) for early-onset steroid-resistant nephrotic syndrome (SRNS). We report the long-term clinicopathologic observation of a Japanese female patient with SRNS caused by a newly identified compound heterozygous mutation of CRB2 (p.Arg628Cys and p.Gly839Trp located in the 10th and 11th epidermal growth factor-like domains, respectively). She was initially examined during a mass urinary screening for 3.5-year-old children in Japan. Although she developed long-standing SRNS without any extrarenal clinical signs thereafter, her renal function was well-preserved over the next 17 years. In total, six sequential renal biopsy specimens revealed histologic alterations ranging from minor glomerular abnormalities to advanced focal segmental glomerulosclerosis (FSGS). A genetic analysis for SRNS performed at 19 years of age revealed a newly identified compound heterozygous mutation in CRB2. Glomerular CRB2 immunoreactivity in biopsy specimens from the patient was scanty, whereas intense expression was observed in those from patients with idiopathic FSGS or in controls. To our knowledge, this is the first report regarding a long-term outcome in a case of SRNS due to an identified CRB2 mutation. Although the phenotype of CRB2 mutation-related syndrome is now expanding, we believe that this case might provide a novel clinicopathologic aspect of this syndrome., (© 2018 Asian Pacific Society of Nephrology.)

A broad range of genetic and non-genetic factors can lead to kidney injury that manifests as focal segmental glomerulosclerosis (FSGS), which can be classified into primary (idiopathic) and secondary forms. Previous genetic approaches to familial or sporadic cases of FSGS or steroid-resistant nephrotic syndrome identified causal mutations in a subset of genes. Recently, next-generation sequencing (NGS) approaches are becoming a part of a standard assessment in medical genetics. Current knowledge of the comprehensive genomic information is changing the way we think about FSGS and draws attention not only to identification of novel causal genes, but also to potential roles for combinations of mutations in multiple genes, mutations with complex inheritance, and susceptibility genes with variable penetrance carrying relatively minor but significant effects. This review provides an update on recent advances in the genetic analysis of FSGS and highlights the potential as well as the new challenges of NGS for diagnosis and mechanism-based treatment of FSGS.

Background: The purpose of this study was to conduct a meta-analysis examining the efficacy of cyclophosphamide, cyclosporin, and tacrolimus in treating steroid resistant nephrotic syndrome., Methods: Medline, Cochrane, EMBASE, and Google Scholar were searched until May 02, 2017 using the keywords: immunosuppressive therapy, steroid-resistant nephrotic syndrome, cyclophosphamide, cyclosporine A, and tacrolimus. Inclusion criteria were randomized controlled trials (RCTs) including patients with SRNS treated with an immunosuppressive therapy or placebo., Results: Seven RCTs were included, and the number of patients ranged from 30 to 131. Conventional pair-wise meta-analysis indicated a higher odds of complete or partial remission with tacrolimus as compared to cyclophosphamide [odds ratio (OR) 4.908, 95% confidence interval (CI) 2.278-10.576, P < 0.001], and cyclophosphamide (OR 0.143, 95% CI 0.028-0.721, P = 0.019) and placebo (OR 0.043, 95% CI 0.012-0.157, P < 0.001) were associated with a lower likelihood of complete or partial remission than cyclosporine. Bayesian analysis indicated that tacrolimus and cyclosporine were the best and the second-best agents for inducing a complete or partial remission (rank probability = 0.53 for tacrolimus and 0.46 for cyclosporine)., Conclusion: As compared to cyclophosphamide and cyclosporin, tacrolimus is more effective at inducing remission in patients with SRNS.

Nephrotic syndrome (NS) is the most common primary glomerular disease among children. It runs a relapsing course involving prolonged periods of treatment with corticosteroids and other immunosuppressive medications. Soluble urokinase plasminogen activator receptor (suPAR) has been regarded as an inflammatory as well as a permeability factor. The aim of our study was to evaluate serum suPAR levels in children with NS and its relation to steroid responsiveness. Our study was carried out on 75 children who were already diagnosed as having NS; they were classified into three groups (steroid sensitive, steroid dependent, and steroid resistant). Furthermore, 40 apparently healthy children, age and sex matched with the NS patients, were enrolled as controls. All children had undergone assessment of serum suPAR, renal function tests (urea and creatinine), serum albumin, C-reactive protein, and 24-h protein in urine. The study found that suPAR level was significantly different between the studied groups (P <0.05), being highest in steroid-resistant NS (66.52 ± 9.7 ng/mL), followed by steroid dependent (56.82 ± 11.09 ng/mL), and steroid-sensitive patients (26.22 ± 3.86 ng/mL), and lowest in the control group (20.29 ± 0.69 ng/mL). When receiver operating characteristics curves were plotted, suPAR had high sensitivities and specificities in predicting steroid responsiveness, [area under the curve (AUC) = 0.99, 95% confidence interval (CI) = 0.911-1.000, P <0.001], steroid dependence (AUC = 1.00, 95% CI = 0.929-1.000, P <0.001), and predicting steroid resistance. Our study indicates that suPAR is significantly higher in children with primary NS and varies according to their response to steroid therapy. It may act as a marker for steroid responsiveness in these children., Competing Interests: None declared

Background: Uteroglobin (UG) is a multifunctional protein with anti-inflammatory properties. The aim of this study was to first evaluate the role of UG gene G38A polymorphism in childhood idiopathic nephrotic syndrome (INS), and determine whether this variation may be related to the occurrence of INS or a steroid response., Methods: One hundred and thirty-six children diagnosed with INS in Gaziantep University, Department of Pediatric Nephrology, and 70 healthy volunteers were included. Children with INS were divided into two groups: steroid-sensitive (n = 84), and steroid-resistant (n = 52). Samples were examined using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) enzyme method., Results: The distributions of AA, GG, and AG genotypes of UG gene G38A (G/A) were 16.9%, 44.9%, and 38.2% in the all-INS group, whereas they were 14.3%, 48.8%, and 36.9% in the steroid-sensitive INS (SSINS) group compared with 21.1%, 38.5%, and 40.4% in steroid-resistant INS (SRINS), and 5.7%, 41.4%, and 52.9% in controls. The risk of INS was increased almost 4-fold in children with the AA genotype (p = 0.016). The risk of having SSINS was increased 3.5-fold (p = 0.042) whereas the risk of SRINS was increased 4.8-fold in the same genotype (p = 0.014)., Conclusions: The uteroglobin gene may play an important role in the development of INS, and the AA genotype of UG gene G38A polymorphism was found more frequently in those children. Further studies evaluating all polymorphisms in larger patient groups are needed to exactly determine the effect of UG gene on the development of INS and steroid response in children.

Background: Glucocorticosteroid (GC) is one of the most effective drugs available for the treatment of primary nephrotic syndrome (PNS) in children. However, some patients show little or no response to GC. The purpose of our research was to observe and describe the different levels of histone deacetylase-2 (HDAC2) expression in peripheral blood lymphocytes in children with PNS compared with various responses to the GC treatment, with the primary aim to assess the correlation between HDAC2 and GC resistance in PNS children., Methods: Forty-eight patients with PNS suffering from their first attack prior to GC treatment were chosen as subjects. They were divided into two groups, those who had steroid-sensitive nephrotic syndrome (SSNS; n = 25) and those with steroid-resistant NS (SRNS; n = 23), according to their response to a 6-week course of oral prednisone. Twenty healthy children from the Physical Examination Center in the hospital served as the control group; Peripheral blood was collected at different time points prior to GC treatment and after regular therapy. RT-PCR, western blot, and enzyme-linked immunosorbent assay (ELISA) techniques were adopted to analyze HDAC2 mRNA, protein expression, and activity, respectively, in peripheral blood lymphocytes. The level of interleukin-8 (IL-8) in serum was measured by an ELISA., Results: Prior to GC treatment, HDAC2 expression level and activity were lower in the SRNS group than in the SSNS and control group. A statistically significant difference in HDAC2 expression and activity were observed after GC treatment between these groups, with HDAC2 expression and activity lower in the SRNS group than in the SSNS and control groups. In the SSNS group, the expression and activity of HDAC2 were higher following GC treatment than prior to GC treatment. There was a clear difference in HDAC2 expression and activity of SRNS at the different time points. No statistically significant difference was found between the two groups. The pre-treatment and post-treatment serum IL-8 levels in the SRNS group were significantly higher than those in the SSNS group. HDAC2 from children with PNS before GC treatment and after regular therapy for 6 weeks was negatively correlated with serum IL-8 level., Conclusion: The GC effect was influenced by the HDAC2 expression and activity, leading to decreased serum IL-8 levels in children with PNS. HDAC2 seems to be one of the markers of GC resistance in children with PNS.

Background: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of end-stage renal disease (ESRD) among patients manifesting at under 25 years of age. We performed mutation analysis using a high-throughput PCR-based microfluidic technology in 24 single-gene causes of SRNS in a cohort of 72 families, who presented with SRNS before the age of 25 years., Methods: Within an 18-month interval, we obtained DNA samples, pedigree information, and clinical information from 77 consecutive children with SRNS from 72 different families seen at Boston Children's Hospital (BCH). Mutation analysis was completed by combining high-throughput multiplex PCR with next-generation sequencing. We analyzed the sequences of 18 recessive and 6 dominant genes of SRNS in all 72 families for disease-causing variants., Results: We identified the disease-causing mutation in 8 out of 72 (11.1%) families. Mutations were detected in the six genes: NPHS1 (2 out of 72), WT1 (2 out of 72), NPHS2, MYO1E, TRPC6, and INF2. Median age at onset was 4.1 years in patients without a mutation (range 0.5-18.8), and 3.2 years in those in whom the causative mutation was detected (range 0.1-14.3). Mutations in dominant genes presented with a median onset of 4.5 years (range 3.2-14.3). Mutations in recessive genes presented with a median onset of 0.5 years (range 0.1-3.2)., Conclusion: Our molecular genetic diagnostic study identified underlying monogenic causes of steroid-resistant nephrotic syndrome in ~11% of patients with SRNS using a cost-effective technique. We delineated some of the therapeutic, diagnostic, and prognostic implications. Our study confirms that genetic testing is indicated in pediatric patients with SRNS.

Background and Objectives: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families., Design, Setting, Participants, & Measurements: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes., Results: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1 , PLCE1 , NPHS2 , and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome., Conclusions: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome., (Copyright © 2018 by the American Society of Nephrology.)

Background/purpose: Nephrotic syndrome is the commonest etiology of proteinuria in children. Steroid-resistant nephrotic syndrome (SRNS) is defined by resistance to standard steroid therapy, and it continues to be one of the most intractable etiologies of renal failure. Molecular studies discovered specialized molecules in podocytes that play a role in proteinuria. Mutations in NPHS2 that encodes for podocin constitute a frequent cause of SRNS worldwide. This study aimed to screen for podocin mutations in SRNS Egyptian children and their parents., Methods: Our study included patients from 10 unrelated Egyptian families diagnosed with SRNS. Mutational analysis of the NPHS2 gene was performed by polymerase chain reaction amplification of the whole coding region of the gene and direct sequencing., Results: Positive consanguinity was detected in five cases, and four of them had a positive family history of SRNS in a family member. Mutational analysis of NPHS2 revealed pathogenic mutations in four cases (40%) including a novel missense in one patient (c.1A>T; p.M1L)., Conclusion: Our study concludes that mutations of NPHS2 gene are common among Egyptian children with SRNS. We support a model where ethnicity plays an important role in specific NPHS2 mutations, since a novel mutation was found in one patient in this study. Future study on a large number of Egyptian patients with SRNS is warranted to identify the actual genetic contribution of this gene in the development of SRNS in our population, which might help in patients' prognosis and management., (Copyright © 2017. Published by Elsevier B.V.)

Introduction: There is evidence of the effectiveness of rituximab in treatment of nephrotic syndrome in children. The present study aimed to assess safety and the therapeutic effectiveness of rituximab in steroid- and cyclosporine-resistant pediatric nephrotic syndrome., Materials and Methods: Forty-three children with steroid- and cyclosporine-resistant or steroid- and cyclosporine-dependent noncongenital nephrotic syndrome were included in the study to receive intravenous rituximab, 375 mg/m2/wk, for 4 weeks. The children were followed up for 2 years. Effectiveness was defined as remission of proteinuria in response to rituximab. Side effects of rituximab were monitored., Results: Overall, 23 (57.1%) of the children had steroid- and cyclosporine-resistant nephrotic syndrome, of whom 8 (34.8%) revealed complete response and 3 (13%) revealed partial response. Seven children (16.7%) had late-resistant nephrotic syndrome, of whom 6 (85.7%) revealed complete response and none revealed partial response. Ten children (26.2%) had steroid- and cyclosporine-dependence all of whom revealed complete response to rituximab. Complete response rate was significantly higher in those with drug-dependent pattern than the other groups (P = .002). There was no association between response to rituximab and pathological basis of disease. Side effects were found in 4 patients as leukopenia in 2, alopecia in 1, and eosinophilia in 1., Conclusions: Rituximab is effective for children with nephrotic syndrome with high efficacy and well tolerability, especially in those with steroid- and cyclosporine-dependent nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.