Objectives: To review voiding dysfunction caused by 3 different etiologies; dysfunction voiding syndrome (DVS), neurogenic bladder secondary to spinal dysraphisim (NB), and valve bladder syndrome ...(VBS). Methods: A single-center retrospective study on children with voiding dysfunction followed up at King Abdulaziz University Hospital, Jeddah, Saudi Arabia from 2005 to 2017. Results: One hundred and ninety-nine children (67.3% boys) were included: Group 1 (n=75, DVS), Group 2 (n=64, NB), and Group 3 (n=60, VBS). Further classification according to the age at presentation; infants (46%), toddlers (27%) and school aged (28%). Management categories: 31% children needed observation only, 25% needed clean intermittent catheterization (CIC), 13% needed only surgery and 31% needed both surgery and CIC. Associated comorbidities: hydronephrosis (81%), vesicoureteral reflux (47%), pyelonephritis (37%) and renal scar (60%), all have negative impact on estimated glomerular filtration rate (eGFR). Urodynamic studies revealed poor bladder compliance in 57.6% and atonic bladder in 1.1%, progression to chronic kidney disease (22%), commenced on renal replacement therapy 11.5% and 4% died with ESKD. Overall improvement in the last eGFR is observed (p<0.001), but VBS group was the least to improve (p=0.021). There was a negative correlation between the last eGFR and age at presentation (p=0.002). Conclusion: Early diagnosis and management of childhood voiding dysfunction was associated with better prognosis. Children managed conservatively have better preservation of kidney function than those who needed surgery. Keywords: dysfunction voiding syndrome, Hinman's syndrome, neurogenic bladder, post valve bladder phrase omitted
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing
COL4A1
...(13q33–34) has been implicated in vesicoureteral reflux (VUR), but mutations in
COL4A1
have not been reported in CAKUT. We hypothesized that
COL4A1
mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (
n
= 257) and with nephrotic syndrome (NS) due to monogenic causes (
n
= 100). We identified a not previously reported heterozygous missense variant in
COL4A1
in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in
COL4A1
in 11 individuals from 11 unrelated families with CAKUT, while no
COL4A1
mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the
COL4A1
-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas
COL4A1
-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous
COL4A1
mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established
COL4A1
-related disorders and predominantly caused by non-glycine substitutions.
Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as ...risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association.
Case-control study.
African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium.
Genetic variants in HLA-DQA1 (C34Y rs1129740; F41S rs1071630) and APOL1 high-risk alleles.
SSNS and SRNS.
Direct sequencing for the HLA-DQA1 and APOL1 variants in 115 African American children (65 with SSNS and 50 with SRNS). Imputation of classic HLA alleles and amino acids was done in 363 South Asian children.
The 2 HLA-DQA1 variants were significantly associated with SSNS in African American children (C34Y: P=5.7 × 10-11; OR, 3.53; 95% CI, 2.33-5.42; F41S: P=1.2 × 10-13; OR, 4.08; 95% CI, 2.70-6.28), but not with SRNS (C34Y: P=0.6; F41S: P=0.2). APOL1 high-risk variants were not associated with SSNS (P=0.5) but showed significant associations with SRNS (P=1.04 × 10-7; OR, 4.17; 95% CI, 2.23-7.64). HLA-DQA1*0201, HLA-DQB1*0201, and HLA-DRB1*0701 were the classic HLA alleles with the most significant associations with SSNS risk. The most significantly associated amino acid positions were HLA-DQα1 56 and 76 (both P=2.8 × 10-7). Conditional analysis revealed that these variants most likely account for the observed association.
Modest sample size and limited statistical power to detect small to moderate effect sizes. Children studied may not be representative of all African American children in the United States.
HLA-DQA1 is a risk locus for SSNS, but not SRNS, in African American children, consistent with its role in SSNS risk in children of European, Asian, and African ancestries. There is little evidence of a significant role for the APOL1 high-risk alleles in childhood SSNS in African American children. Refinement of the HLA-DQA1 association identified the critical classic HLA antigen types and amino acids of the HLA-DQ α1 molecule.
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%.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be ...caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human nonsyndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.
Bladder dysfunction in children is common, the most frequent underlying causes are neurologic bladder (NB), dysfunctional voiding syndrome (DVS), and the valve bladder syndrome (VBS). The aim of this ...study was to determine the 10-y survival rate and the associated morbidities in children with bladder dysfunction. One hundred ninety-nine children were included in the study; 60 with VBS, 75 DVS, and 64 NB. The mean age was 44 mo (CI: 37–50.9) and mean GFR 50.1 (CI 44.6–55.6) mL/min/1.73m
2
. The 10-y survival rate was 89%. Compared with patients with VBS, the mortality was 11 times higher among patients with NB (
p
= 0.02) but not significantly higher than patients with DVS (
p
= 0.2). GFR < 15 mL/min/1.73 m
2
increases mortality rate by 6 times compared with normal GFR (
p
= 0.007). Late age at presentation (> 5 y) increases mortality risk and/or the need for renal replacement therapy (RRT) by almost 5 times (
p
= 0.013). It was concluded that the etiology of bladder dysfunction, baseline GFR, and the age at presentation significantly influence the survival rate and morbidities.
Background
Approximately 50% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing ...drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications.
Methods
A prospective open-label non-randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia, or active infection. The recruited children were allocated either to the oral cyclophosphamide (3 mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m
2
/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months.
Results
Forty-six subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR 0.36; 95% CI 0.09–1.45;
p
= 0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (
N
= 10) and 6.3 months in the rituximab group (
N
= 3). Both treatments were associated with a significant (
p
< 0.001) reduction in prescribed dose of oral alternate-day steroid from 1.02 to 0.36 mg/kg (cyclophosphamide) and 0.86 to 0.08 mg/kg (rituximab). Importantly, a significantly (
p
= 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity besides severe leucopenia and neutropenia in the 7th week of treatment with complete recovery with the withdrawal of cyclophosphamide and maintenance of remission. A minor infusion-related reaction in the form of a generalized macular skin rash was observed in one patient (5%) in the rituximab group.
Conclusions
Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide.
Graphical abstract
Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are ...known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES.
We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping.
In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype–phenotype correlation.
We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.
Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity ...mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.
Advanced chronic kidney disease with mineral and bone disorder have a significant obstacles to control serum bone profile serum intact parathyroid hormone (iPTH), calcium and phosphorus which ...subsequently have major effect on optimal bone strength, final adult height, and cardiovascular health. A retrospective, observational study, including a total of 36 children with end-stage kidney disease (ESKD). Fourteen children who were prescribed cinacalcet had been compared with the remaining 22 children who were managed with standard care. We report the efficacy and safety of cinacalcet for treatment of refractory secondary hyperparathyroidism (SHPT) in children with ESKD. After 6 months of cinacalcet treatment, the mean level of iPTH serum level decreased by 56% from 202 pmol/L 95% confidence interval (CI): 150-253 to 88 pmol/L (95% CI: 41-136), compared to the change observed in the control group (P <0.001). None of our patients reported serious adverse effects or developed hypocalcemia. Cinacalcet could be an effective and safe alternative to treat severe SHPT in children with ESKD. Further long-term and large-scale studies are necessary to confirm its safety and efficacy.
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