BackgroundThe physiological and pathophysiological characteristics regarding plasma renin activity (PRA) in the context of the renin-angiotensin-aldosterone-system (RAAS) are well investigated in adults, whereas less is known in paediatric population suffering from heart failure. Challenges in the conduct of paediatric investigations limit the enrolled children often to specific age groups allowing only a partial revaluation of the maturating RAAS. To constitute the comprehensive picture of the paediatric RAAS from 0–18 years, a compilation of available PRA data was conducted via literature search.MethodsA systematic literature search was accomplished in the context of the ‘Labeling of Enalapril from Neonates up to Adolescence’ (LENA) project in the MEDLINE database via PubMed in January 2019. Key words: plasma renin activity and congenital heart disease/dilative cardiomyopathy/heart failure/congenital heart defect and child/neonate/infant/toddler/paediatric. Eligible records included PRA values in children of 0–18 years of age. Exclusion criteria comprised foetuses, preterm, cord blood, urine, adults, < 2500 g birthweight, ex vivo studies and deviant diseases.ResultsLiterature search resulted in 167 findings of which 58 full-text articles were assessed for eligibility. Finally, 33 publications were classified as relevant. Of these, 21 and 12 records were assigned for healthy and cardiac diseased population respectively, leading to PRA data sets of 2000 healthy and 254 diseased children. Visual check of data revealed an age dependent decrease of PRA, in particular in the early childhood, and a substantial elevation of PRA in heart failure patients.ConclusionThe conducted literature search allowed a systematic description of PRA values in healthy and cardiac diseased paediatrics, which facilitates a classification of reference ranges of the maturing RAAS for LENA and future paediatric trials.Disclosure(s)Fabian K. Suessenbach, Tanja Gangnus, Ilja Burdman, Nina Makowski, Stephanie Laeer and Bjoern B Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
BackgroundN-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable biomarker for diagnosis and prognosis of heart failure in adults, included into the European Society Guidelines for heart failure (2016).1 It is also considered as a diagnostic and follow-up marker in paediatric heart failure. The aetiology of paediatric heart failure is heterogeneous and maturation of the cardiac and neurohumoral system influences NT-proBNP levels. Since substantial information is mandatory to enable a long-term follow-up of children with heart failure, the aim was to collect published paediatric NT-proBNP data.MethodsIn January 2019, a literature search using PubMed was performed comprising the following keywords: NT-proBNP, heart failure/dilated cardiomyopathy/congenital heart defect/congenital heart disease/healthy and child/neonate/toddler/infant/paediatric. Eligible publications had to determine levels of NT-proBNP in plasma or serum in paediatric heart failure or healthy children (0–18 years) with the Roche NT-proBNP-immunoassay.ResultsThe search resulted in 343 records, of which 95 measured NT-proBNP in paediatric controls or heart failure. Of them, 48 studies were excluded due to the use of other immunoassays. Following, 47 studies were included into the analysis of which 27 reported NT-proBNP levels in 3435 healthy children and 38 NT-proBNP concentrations in 1885 children with heart failure. The age range of reported levels comprised the day of birth up to 18 years in both groups. The data set revealed that younger children have higher NT-proBNP values than older children and that heart failure patients had increased NT-proBNP levels compared to healthy controls which are also dependent on the severity of disease.ConclusionThe literature search and analysis confirmed that NT-proBNP is an important marker for the detection of heart failure and classification of disease severity in children. Thus, the compiled data set forms a solid data basis for long-term follow-up of a paediatric patient population with heart failure.ReferencesPonikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (ESC)developed with the special contribution of the heart failure association (HFA) of the esc. Eur Heart J 2016;37(27):2129–200.Disclosure(s)Tanja Gangnus, Fabian K. Suessenbach, Nina Makowski, Ilja Burdman, Stephanie Laeer, Björn B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework programme (FP/2007–2013) under grant agreement n°602295 (LENA).
BackgroundThe European multicentre paediatric trials for the drug development programme of LENA (FP7 Grant agreement No. 602295); ‘Labeling of Enalapril from Neonates up to Adolescents’ require the determination of laboratory safety parameters. It was anticipated that the laboratory normal reference values and age range classifications vary depending on the clinical site. Thus, the objective was a seamless and clear depiction of the laboratory parameters to allow an adequate subsequent analysis of data.MethodsFourteen haematological and biochemical safety parameters plus the biomarker N-terminal pro-brain natriuretic peptide were considered. The laboratory normal reference values received from eight clinical sites were screened on data gaps, uncertainties, misclassifications and overlap of age range classifications. These aspects were revised. If further data were necessary for clarification the responsible person of the respective laboratory was contacted by email or telephone.ResultsData gaps and uncertainties of the laboratory normal reference values such as missing data for one sex, missing data for an age range classification, missing data for a parameter or overlap of age range classification were identified. All issues were solved by communication with the sites. Each laboratory parameter was categorized in between 1 and 23 age range classifications between an age from birth to 4744 days depending on the classification of the clinical site. Furthermore, up to 4 various units were recorded per laboratory parameter and subsequently harmonised into one unit.ConclusionThe developed seamless depiction of the laboratory parameters will allow the assessment and classification of the paediatric trial data and are essential for the adequate subsequent analysis.Disclosure(s)Samieh Farahani, Elisabeth Feles, Bjoern B. Burckhardt, Stephanie Laeer declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grand agreement n°602295 (LENA)
BackgroundIn cell line experiments, the selective NK-1-receptor antagonist Aprepitant was able to inhibit the cardiotoxic adverse effects of Doxorubicin,1 a common cytostatic used in paediatric cancer therapies. Cytostatic therapy is one of the principal reasons for toxic cardiomyopathy in children, resulting in dilated cardiomyopathy and consequently leading to heart failure. However, Aprepitant is currently licenced for adults and children and is indicated amongst others in the antiemetic supportive therapy of Doxorubicin regimes. To address the hypothesis of any indication of Aprepitant in preventing cardiotoxic adverse effects of Doxorubicin, systematic literature research is needed.MethodsSystematic literature research was examined using PubMed in January 2019. Selected inclusion criteria were: ‘Substance P’ or ‘Aprepitant’ and ‘Doxorubicin’/’cardiac inflammation’/’cardiomyopathy’ or ‘Aprepitant’ and ‘paediatrics’/’neonates’/’children’. The use of Aprepitant in adults and children as an antiemetic agent and the involvement of Substance P in (neurogenic) inflammation, cardiac infarction or diabetes led to the exclusion of publications.ResultsThe PubMed search resulted in 220 identified publications whereby 33 were relevant concerning the potential use of Aprepitant in the prevention of cardiotoxic adverse effects of Doxorubicin. It emphasises the potential use of Aprepitant in the prevention of toxic cardiomyopathy by antagonizing the inflammatory effects of the endogenous NK-1-agonist Substance P regarding cell and animal models.1 2 Based on these models, Substance P is associated with adverse cardiac remodelling and cardiac inflammation. However, in children, Aprepitant was only used as an antiemetic agent and no off-label indication was described.ConclusionSince toxic cardiomyopathy is a severe adverse effect in the Doxorubicin therapy in children, the evaluation of the role of Substance P is a promising and worthy approach to condense the knowledge about a potential use of Aprepitant in preventing paediatric toxic cardiomyopathy.ReferencesRobinson P, Kasembeli M, Bharadwaj U, et al. Substance P receptor signaling mediates doxorubicin-induced cardiomyocyte apoptosis and triple-negative breast cancer chemoresistance. Biomed Res Int2016; 2016. doi:10.1155/2016/1959270Levick SP, Soto-Pantoja DR, Bi J, et al. Doxorubicin-induced myocardial fibrosis involves the neurokinin-1 receptor and direct effects on cardiac fibroblasts. Heart Lung Circ. Published Online First: September 2018. doi:10.1016/j.hlc.2018.08.003Disclosure(s)Martin Feickert and Bjoern B. Burckhardt declare that there is no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
BackgroundPhysiological and pathophysiological circumstances of the paediatric renin-angiotensin-aldosterone-system (RAAS) are still inadequately understood. Due to the limited paediatric data available, the LENA (Labeling of Enalapril from Neonates up to Adolescents) project aimed to comprehensively investigate the drug enalapril and its effect on humoral parameters of the RAAS. Examination of four humoral parameters, including plasma renin activity (PRA), was conducted regarding cardiac diseased paediatric population receiving enalapril, of which 60% were below 1 year of age. To fully address the agreed Paediatric Investigation Plan (EMEA-001706-PIP) of the LENA project, reliable small-volume assays for pharmacodynamics determination were mandatory to ensure the reliable data sets.Materials and methodsA commercial PRA enzyme linked immunosorbent assay (ELISA) was tailored for paediatric application and validated according to European Medicine Agency (EMA) and U.S. Food and Drug Administration (FDA) bioanalytical guidelines.1 2 In this context, accuracy, precision, total error, linearity, parallelism, matrix effects and stability were investigated.ResultsThe adopted bioanalytical PRA-assay was successfully validated. Between-run precision (CV) and accuracy (relative error) ranged from 1.6% to 19.6% and -13.0% to +11.2% respectively. Samples of five different human sources showed no substantial matrix effect and facilitated the assay’s application to heterogeneous populations. The obtained precision of parallelism of five dilution steps ranged from 7.7% to 8.3% allowing to dilute high samples within the calibration range. Stability measurements proved four freeze and thaw cycles plus short-term and long-term (37 weeks) stability. Overall, all results were complied with guideline requirements.ConclusionThe FDA/EMA-compliant PRA assay is able to accurately and precisely quantify PRA values in 50 µL plasma and is applicable for GCLP-compliant clinical studies enabling sophisticated investigations in children within the LENA project.ReferencesCommittee for Medicinal Products for Human Use (CHMP): EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2** Guideline on bioanalytical method validation, June, 2015U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM): Bioanalytical Method Validation Guidance for Industry, May 2018Disclosure(s)Fabian K. Suessenbach, Martin Feickert, Jutta Tins and Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
BackgroundA validation is crucial to ensure the quality of an analytical method and its results. However, the validation is only a first step, further quality assessment has to be utilised to ensure high quality research. Specifications for the validation process, but also for the assessment of data, acquired in a study setting, are given by the EMA and FDA to ensure highest quality of the data.1 2 MethodsA multi-level analytical quality system was established. Data of the calibration standards (CSs), quality control samples (QCs), and incurred sample reanalysis (ISR) were evaluated according to the specifications given by the EMA and FDA guidelines.[1,2] For a run to be considered valid ≥6 levels or 75% of the CSs and 67% of the QCs (≥50% per level) had to vary ≤±20% (LLOQ ≤±25%) from their nominal concentration.[1,2] For the ISR analysis at least 67% of the ISR samples have to lay in ±30% to the nominal concentration of the mean of the original and reanalysed value.[1]ResultsSeventy analytical runs were conducted, applying the quality measures, 79% runs were classified as valid and were used to determine unknown samples in a paediatric study. The high quality of the acquired data is reflected in the high conformity of the CSs and QCs to the EMA and FDA guidelines, 99% of the CSs and 95% of the QCs were accepted. Further underlining the high quality of the acquired data, 85% of the IRS have also been accepted. The assay was successfully used over a time period of 29 months.ConclusionThe results of the quality assessment confirmed the robustness of the aldosterone assay throughout the whole study duration. Thus, the samples measured by this assay are reliable and facilitate the high quality research in the paediatric population.ReferencesGuideline on bioanalytical method validation. European Medicines Agency, London, UK (2011).Guidance for Industry: Bioanalytical Method Validation. US Department of Health and Human Services, US FDA Rockville, MD, USA (2018).Disclosure(s)Nina Makowski, Ilja Burdman, Mohsin Ali, Bartel A, Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).
BackgroundSince sample volume is limited in children, innovative bioanalytical methods and enrichment procedures are highly required. The analysis of endogenous substances by liquid chromatography coupled to mass spectrometry is a highly specific method because of its selectivity and accuracy. However reliable detection of endogenous substances can only be achieved by a hybrid assay approach combining immunocapture and mass spectrometry. Key element of the immunocapture procedure is the selection of the appropriate antibody for capturing the desired antigen. This study is meant to identify the most suitable antibody that facilitates the development of an hybrid assay approach concerning reliable detection of endogenous prorenin in paediatric samples.MethodsDynabeads magnetic beads were coupled to three different antibodies from three different vendors (GeneTex, Molecular Innovations, R&D systems). 500 µL human plasma which was spiked with 20 ng recombinant human prorenin (Cayman chemicals). The immunocapture step was followed by protease digestion and a custom-made µelution solid-phase extraction protocol. The digest was analyzed by Shimadzu Nexera LC-system coupled with Sciex TripleTOF 6600 mass spectrometer.ResultsThe analysis of the captured prorenin was performed by the surrogate peptide approach. In this case the surrogate peptide was identified as unique. The comparison of the three available antibodies showed that one antibody did not ensure reliable binding properties in human matrix. Among the two remaining antibodies only one showed sufficient binding capacities to be applied in small sample volumes commonly available in paediatric samples. Using this hybrid approach enabled the enrichment of the required volume by factor of 20.ConclusionThis study identified the most suitable antibody for the immunocapture procedure of the prorenin hybrid approach. This is now followed by further mass spectrometric method development and validation prior to its application in paediatric samples.Disclosure(s)Declaration of interest: none Ilja Burdman and Bjoern B. Burckhardt declare that there is no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
BackgroundAs the initiator of the Renin-Angiotensin-Aldosterone-system, renin plays an essential role in the vicious circle of heart failure. Therefore, renin was determined in the investigators driven ‘Labelling of Enalapril from neonates up to adolescents’ (LENA) study to evaluate its role in paediatric heart failure. Due to the often long-lasting periods of recruitment of paediatric subjects, the assay performance has to be guaranteed over the whole recruiting time. Therefore, to ensure the high quality of the determined renin study samples after successful assay validation,1 a multi-step quality approach was used to get reliable results over a period of 30 months.MethodsBased on a multi-step quality approach consisting of calibration standards (CSs), quality controls (QCs) and incurred sample reanalysis (ISR), study samples of unknown renin concentrations were determined. Results within predefined limits of CSs (6 levels) and QCs according to European Medicine Agency (EMA) guidelines were required for evaluating the study samples.2 ISR was performed for randomly selected paediatric samples to evaluate the long-term accuracy of the validated assay.Results133 analytical runs were conducted for renin from February 2016 to August 2018. In 119 (88.8%) valid runs, a total number of 1414 of CCs and 952 of QCs were determined. Thereof 99.9% of CCs and 98.3% of QCs were in the predefined limits according to EMA. 143 incurred sample pairs were reanalysed resulting in 95.8% of samples within EMA guidelines. Using this multi-step quality approach, the reliable determination of 965 LENA paediatric study samples was guaranteed.ConclusionIn addition to the assay validation, the multi-step quality approach ensured the reliability of the determined renin concentrations in the continuous bioanalysis of the paediatric study samples and guaranteed the high quality of the collected data in the LENA study.ReferencesSchaefer J, Burckhardt BB, Tins J, et al. Validated low-volume immunoassay for the reliable determination of direct renin especially valuable for pediatric investigations. J Immunoass Immunochem 2017;38:579–94. doi:10.1080/15321819.2017.1350707Guideline on bioanalytical method validation. European Medicines Agency, London, UK (2011).Disclosure(s)Martin Feickert, Ilja Burdman, Nina Makowski, Moshin Ali, Anke Bartel, and Bjoern B. Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.