Patient data are increasingly available in (multi)national registries, especially for rare diseases. This study aims to provide an overview of current European registries of paediatric kidney ...transplantation (PKT) care, their coverage, and their focus. Based on these data, we assess whether the current status is optimal for achieving our common goal: the optimalisation of health care.
A list of all PKT centres within the European Union (EU) as well as active PKT registries was compiled using existing literature and the European Platform on Rare Disease Registration. Registry staff members were contacted to obtain information about the parameters collected and the registry design. These data were compared between registries.
In total, 109 PKT centres performing PKT surgery were identified in the 27 EU Member States. Currently, five European PKT registries are actively collecting data. In 39% of these centres, no data were registered within any of these five existing international registries. A large variety was observed in the number of patients, centres, and countries involved in the registries. Furthermore, variability existed regarding the inclusion criteria, definitions used, and parameters collected. Collection of perioperative urologic data are currently underrepresented in the registries.
Currently, multiple registries are collecting valuable information in the field of PKT, covering the majority of PKT centres in Europe. Due to a large variety in the parameters collected as well as different focuses, data collection is currently fragmented and suboptimal; therefore, the current existing data are incomplete. In addition, a considerable proportion of the transplantation centres do not enter data in any international registry. Combining available information and harmonising future data collection could empower the aim of these registries-namely increasing insights into the strengths and potential of current care and therefore improve healthcare.
Posterior urethral valves (PUV) is a congenital disorder causing an obstruction of the lower urinary tract that affects approximately 1 in 4,000 male live births. PUV is considered a multifactorial ...disorder, meaning that both genetic and environmental factors are involved in its development. We investigated maternal risk factors for PUV.
We included 407 PUV patients and 814 controls matched on year of birth from the AGORA data- and biobank and three participating hospitals. Information on potential risk factors (family history of congenital anomalies of the kidney and urinary tract (CAKUT), season of conception, gravidity, subfertility, and conception using assisted reproductive techniques (ART), plus maternal age, body mass index, diabetes, hypertension, smoking, and use of alcohol and folic acid) was derived from maternal questionnaires. After multiple imputation, adjusted odds ratios (aORs) were estimated using conditional logistic regression corrected for minimally sufficient sets of confounders determined using directed acyclic graphs.
A positive family history and low maternal age (<25 years) were associated with PUV development aORs: 3.3 and 1.7 with 95% confidence intervals (95% CI) 1.4-7.7 and 1.0-2.8, respectively, whereas higher maternal age (>35 years) was associated with a lower risk (aOR: 0.7 95% CI: 0.4-1.0). Maternal preexisting hypertension seemed to increase PUV risk (aOR: 2.1 95% CI: 0.9-5.1), while gestational hypertension seemed to decrease this risk (aOR: 0.6 95% CI: 0.3-1.0). Concerning use of ART, the aORs for the different techniques were all above one, but with very wide 95% CIs including one. None of the other factors studied were associated with PUV development.
Our study showed that family history of CAKUT, low maternal age, and potentially preexisting hypertension were associated with PUV development, whereas higher maternal age and gestational hypertension seemed to be associated with a lower risk. Maternal age and hypertension as well as the possible role of ART in the development of PUV require further research.
Context: Hypospadias is a common congenital malformation of the male external genitalia with a multifactorial etiology. Little is known about the genes involved in hypospadias. A few genetic ...associations have been reported but mainly in studies of small sample size. Most of these associations have not been replicated.
Objective: The aim of this study was to investigate whether previously reported associations for four single-nucleotide polymorphisms (SNPs) in genes involved in hormonal pathways could be replicated in a large Dutch hypospadias sample. The SNPs investigated are rs523349 in steroid-5α-reductase (SRD5A2), rs6932902 in estrogen receptor 1 (ESR1), rs2987983 in ESR2, and rs11119982 in activating transcription factor 3 (ATF3).
Design, Participants, and Methods: We genotyped 620 Caucasian hypospadias cases and 596 controls for these SNPs using TaqMan-based genotyping.
Results: We did not replicate the associations of the SNPs in SRD5A2 and ESR1 with hypospadias. The SNPs in ESR2 and ATF3 were borderline associated with hypospadias odds ratios 0.9 (95% confidence interval 0.7–1.0) and 1.2 (95% confidence interval 1.0–1.4), respectively but in the opposite direction compared with earlier publications. Stratification according to localization of the urethral opening produced comparable results in the subgroups.
Conclusions: The lack of consistency between our and previously performed studies might represent spurious results or chance findings in our or the earlier studies, differences in criteria used to select the study populations, or a real difference between populations, i.e. different genes contributing to disease risk. These results once again confirm the importance of replication in genetic association approaches.
Previously found associations between hypospadias and single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 could not be replicated in a large Caucasian cohort.
Anorectal malformations (ARM) are rare congenital malformations of the gastrointestinal tract. Approximately 60 % of the patients have additional congenital malformations, such as hypospadias. A ...recently published article showed that deletion of one single gene, dickkopf WNT signaling pathway inhibitor-1 (
Dkk1
), resulted in an imperforate anus with rectourinary fistula and preputial hypospadias in mice. To determine whether
DKK1
also plays a role in the etiology of ARM and hypospadias in humans, we sequenced the four exons of the
DKK1
gene in 17 patients affected with both ARM and hypospadias. No new potential disease-causing variant was identified. However, we detected a known non-synonymous variant in one patient, which was predicted in silico to be damaging, and the corresponding unaffected amino acid is highly conserved.
Conclusion
: In this human study, a potential interesting non-synonymous variant was found in the
DKK1
gene. Whether this variant plays a contributory role in the genesis of ARM or hypospadias would require a much larger study.
Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific ...genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model.
We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing.
When we applied a MAF of ≥1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing.
Our results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.
Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live ...births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (
P
< 1 × 10
−5
). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.
Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development.
To identify genetic variants associated with ...kidney injury in patients with obstructive uropathy.
We included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase.
Signs of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues.
Despite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10–7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization.
This study identified CDH12 as a candidate gene for kidney injury in PUV.
We found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.
We found that variants of CDH12 increase the risk of kidney injury in patients with posterior urethral valves. This is the first time that this gene has been reported on in this context. Our study provides interesting new information about pathways involved in obstructive uropathies and important leads for further research.
To develop a prediction model for postoperative complications after primary one-stage hypospadias correction to improve preoperative parental counseling.
In this retrospective cohort study, data were ...collected from 356 patients with anterior or middle hypospadias who had a one-stage hypospadias correction from 2003 onwards. Potential treatment- and patient-related factors were selected and used to develop a prediction model for postoperative complications within one year (wound-related complications, urinary tract infections, fistulas, stenosis, and prepuce-related complications). Multivariable logistic regression analysis with stepwise backward selection and a p-value of 0.20 was used to select the final model, which was internally validated using the bootstrap procedure.
Complications within one year postoperatively occurred in 66 patients (19%), of which 13% and 37% were seen in anterior and middle type of hypospadias, respectively. Hypospadias phenotype, surgical technique, chordectomy, and surgeon's experience were included in the final prediction model, whereas none of the patient-related factors were. The final model had a good discriminative ability (bias corrected C statistic 0.70) and calibration.
Using easily obtainable information, this model showed good accuracy in predicting complications within one year after hypospadias surgery. It is a first step towards individualized risk prediction of postoperative complications for anterior and middle hypospadias and can assist in preoperative parental counseling.
Prognostic study.
Level II.
Hypospadias is a common male genital malformation and is regarded as a complex disease affected by multiple genetic as well as environmental factors. In a previous genome-wide scan for familial ...hypospadias, we reported suggestive linkage in nine chromosomal regions. We have extended this analysis by including new families and additional markers using non-parametric linkage. The fine mapping analysis displayed an increased LOD score on chromosome 8q24.1 and 10p15 in altogether 82 families. On chromosome 10p15, with the highest LOD score, we further studied AKR1C2, AKR1C3 and AKR1C4 involved in steroid metabolism, as well as KLF6 expressed in preputial tissue from hypospadias patients. Mutation analysis of the AKR1C3 gene showed a new mutation, c.643G>A (p.(Ala215Thr)), in a boy with penile hypospadias. This mutation is predicted to have an impact on protein function and structure and was not found in controls. Altogether, we homed in on four chromosomal regions likely to harbor genes for hypospadias. Future studies will aim for studying regulatory sequence variants in these regions.
Compensatory hypertrophy is present in most children with unilateral ureteropelvic junction obstruction after sufficient follow-up time. Contralateral kidney length provided no clear prognostic value ...for developing kidney injury. Studies with more patients and additional biomarkers of kidney injury are needed to personalise care further.
Compensatory hypertrophy is common in children with solitary functioning kidney, but it is unknown whether it also develops in children with unilateral partial reduction of kidney function.
The aim of this study was to assess whether children with a unilateral ureteropelvic junction obstruction (UPJO) show compensatory growth of the unaffected kidney. Furthermore, we investigated whether the length of the unaffected kidney was related to the degree of split kidney function lost and other possible risk factors. Lastly, we studied a possible relationship with signs of kidney injury.
We retrospectively analysed clinical information from 194 children with a unilateral UPJO who participated in the Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children (AGORA) data- and biobank. Data on kidney length, split kidney function, and other factors possibly associated with kidney length were extracted from electronic patient records.
Pearson’s correlation coefficients between the split kidney function and unaffected kidney length were calculated. Multivariable logistic regression analyses were performed to identify factors associated with kidney length and signs of kidney injury.
Most children with a UPJO had an unaffected kidney length above the reference for age at the end of follow-up (median age 6.5 yr). A correlation with split kidney function was present only in children with a split kidney function of ≥60% in the unaffected kidney (r = 0.41). Aside from split kidney function, UPJO side was the only determinant of kidney length, while no associations between kidney length and kidney injury were identified.
Compensatory growth was visible in most children with a UPJO after sufficient follow-up time and was correlated with split kidney function in children with a severe UPJO. Contralateral kidney length provided no clear prognostic value for developing kidney injury. Studies with more patients and additional biomarkers of kidney injury are needed to further personalise care.
Children with obstruction of urine outflow in one kidney often had a larger contralateral kidney. However, the size of this kidney could not be used to predict which children would develop kidney injury.
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