Therapeutic efficacy and safety of ACE inhibitors in the hypertensive paediatric population: a review

Purpose: Since 1997, strong incentives have been introduced worldwide to improve access to safe and effective medicines addressing the therapeutic needs of children. ACE inhibitors, the most prescribed antihypertensive drugs in the paediatric population, are one of the prototype drugs targeted by the legislation initiatives. Our purpose in assembling this review is to evaluate and describe the current evidence for the efficacy and safety profile of ACE inhibitors in the paediatric population. Methods: The authors made a descriptive review of the literature from 1980 to 2015 using the following search terms: hypertension, child, paediatric, ACE (inhibitors), renin angiotensin aldosterone system, captopril, lisinopril, enalapril, ramipril and fosinopril. Results: A total of 16 studies evaluating efficacy and safety of ACE inhibitors were included in this review. The included studies demonstrate that ACE inhibitors have the potency to decrease the systolic and/or diastolic blood pressure with an overall favourable safety profile in a short-term period. More importantly, the incentives resulted in an improvement of the overall availability of paediatric labelling, dosing and safety information for ACE inhibitors. However, they failed to fulfil several of paediatric needs: absence of long-term safety data on growth and maturation, absence of commercially available child-friendly formulations and incomplete evaluation of the entire paediatric hypertension population. Conclusion: Additional efforts are needed to close the gap between the availability of drugs that are labelled and indicated for paediatric use and the actual drug usage in children, especially in young children, neonates and children with severe hypertension, renal transplantation or severe renal impairment

Conceptualisation and validation of a paradigm based on uraemic toxins for management of chronic kidney disaese in paediatric patients

C

10-year follow-up of the teratogenic effects and neurocognitive development after prenatal ACE-inhibitor exposure: a case report

Background/Aims: Angiotensin-converting enzyme inhibitors (ACE-inhibitors) are among the most frequently prescribed antihypertensive drugs. Ingestion during pregnancy has a known increased risk of fetopathy, with well-described congenital malformations. Until now, little is known about the long-term outcome and the impact on a child’s life. The objective of this case report is to analyze long term outcome following prenatal exposure to ACE-inhibitors and describe the subsequent impact. Case report: A 10-year-old child has been in follow-up for almost a decade. During his fetal period, his mother suffered malignant hypertension and had to continue her prescribed ACE-inhibitors despite known teratogenic effects.. The mother gave birth to a 33 weeks old infant through a semi-urgent caesarean section. During the neonatal phase, a severe kidney impairment due to bilateral hypodysplasia was observed. After initial need for dialysis, renal function recovered partially, but caused the need for dialysis and kidney transplantation at the age of 4-years. Aside from renal impairment, the child was born with hypocalvaria (i.e. incompletely formed skull bones) as well as severe abnormalities of the central nervous system, resulting in motor impairment (including a right-sided paresis) as well as cognitive retardation Conclusion: renal hypoplasia is well known in newborns prenatally exposed to ACE-inhibition, but there is a gap in knowledge on other organs and long-term prognosis. This case documents that other organs are equally involved, and that long-term neurocognitive development is compromised

Mysterious diagnosis in a child with failure to thrive

Mysterious diagnosis in a child with failure to thrive Matthys A1, Gheuens L1, Karamaria S2,3, Prytula A2,3, Snauwaert E2,3,Dossche L2,3, Vande Walle J2,3, Dehoorne J2,3, Raes A2,3 1Department of Pediatrics, UZ Gent, 2Ghent, Ghent University, 3Department of Pediatric Nephrology, UZ Gent, Ghent Introduction Mutations of several genes encoding the transporters involved in salt reabsorption in the thick ascending limb cause different types of Bartter syndrome (BS), with variable phenotypic expression and severity. Type I and II are the most severe presenting with polyhydramnios, prematurity and characteristically hypokalemia, metabolic alkalosis, polyuria and hypercalciuria. Case We report the case of a 9 month old girl referred because of fever, vomiting, dehydration and electrolyte abnormalities despite fluid administration. Medical history revealed unexplained maternal polyhydramnios, prematurity (34weeks) and dysmaturity (birth weight 1,75kg). She was admitted in a neonatal unit and after a smooth course, was discharged after 36 days (weight 2,2kg). At 4months she presented with feeding difficulties and failure to thrive with no biochemical abnormalities or polyuria were . At admission, laboratory examination revealed plasma potassium (K) level <3.0 mmol/L, combined with inappropriately high excretion (44%), metabolic alkalosis and hypernatremia (154 mmol/l). Despite IV fluids the biochemical abnormalities persisted but polyuria became prominent Blood pressure (BP) was 115/64mmHg with normal vital parameters. She had pronounced frontal bossing, small hands and a wide nose bridge. Neurological examination was normal. Additional findings of hyperreninemia hyperaldosteronism, hypercalciuria and nephrocalcinosis were suggestive of a tubulopathy, namely BS. However hypernatremia and high BP are no typical features of BS. The introduction of indomethacin treatment, in addition to K supplementation, compensation of fluid losses and hypercaloric nutrition lead to a stable condition with gradual weight gain. Mutational screening revealed a homozygous variant of unknown clinical significance of SLC12A1, a gene involved in BS type I. Interestingly there is also a heterozygous gain of function mutation of SCNN1 gene, usually associated with Liddle syndrome (LS). Further genetic testing, including of the parents, is pending. Conclusion This is the first report of a girl with a phenotypic overlap between BS and LS. Although genetic analysis revealed homozygosity for a SLC12A1 variant of unknown significance, clinical picture of BS indicates that this is associated with the girl’s disease. The heterozygosity for SCNN1B, with subsequently enhanced renal sodium reabsorption, leads us to hypothesize that this variant may balance the renal salt wasting caused by BS

Comparative genomics of Pandoraea, a genus enriched in xenobiotic biodegradation and metabolism

Comparative analysis of partial gyrB, recA, and gltB gene sequences of 84 Pandoraea reference strains and field isolates revealed several clusters that included no taxonomic reference strains. The gyrB, recA, and gltB phylogenetic trees were used to select 27 strains for whole-genome sequence analysis and for a comparative genomics study that also included 41 publicly available Pandoraea genome sequences. The phylogenomic analyses included a Genome BLAST Distance Phylogeny approach to calculate pairwise digital DNA-DNA hybridization values and their confidence intervals, average nucleotide identity analyses using the OrthoANIu algorithm, and a whole-genome phylogeny reconstruction based on 107 single-copy core genes using bcgTree. These analyses, along with subsequent chemotaxonomic and traditional phenotypic analyses, revealed the presence of 17 novel Pandoraea species among the strains analyzed, and allowed the identification of several unclassified Pandoraea strains reported in the literature. The genus Pandoraea has an open pan genome that includes many orthogroups in the 'Xenobiotics biodegradation and metabolism' KEGG pathway, which likely explains the enrichment of these species in polluted soils and participation in the biodegradation of complex organic substances. We propose to formally classify the 17 novel Pandoraea species as P. anapnoica sp. nov. (type strain LMG 31117(T) = CCUG 73385(T)), P. anhela sp. nov. (type strain LMG 31108(T) = CCUG 73386(T)), P. aquatica sp. nov. (type strain LMG 31011(T) = CCUG 73384(T)), P. bronchicola sp. nov. (type strain LMG 20603(T) = ATCC BAA-110(T)), P. capi sp. nov. (type strain LMG 20602(T) = ATCC BAA-109(T)), P. captiosa sp. nov. (type strain LMG 31118(T) = CCUG 73387(T)), P. cepalis sp. nov. (type strain LMG 31106(T) = CCUG 39680(T)), P. commovens sp. nov. (type strain LMG 31010(T) = CCUG 73378(T)), P. communis sp. nov. (type strain LMG 31110(T) = CCUG 73383(T)), P. eparura sp. nov. (type strain LMG 31012(T) = CCUG 73380(T)), P. horticolens sp. nov. (type strain LMG 31112(T) = CCUG 73379(T)), P. iniqua sp. nov. (type strain LMG 31009(T) = CCUG 73377(T)), P. morbifera sp. nov. (type strain LMG 31116(T) = CCUG 73389(T)), P. nosoerga sp. nov. (type strain LMG 31109(T) = CCUG 73390(T)), P. pneumonica sp. nov. (type strain LMG 31114(T) = CCUG 73388(T)), P. soli sp. nov. (type strain LMG 31014(T) = CCUG 73382(T)), and P. terrigena sp. nov. (type strain LMG 31013(T) = CCUG 73381(T))