Evelien Snauwaert

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.

Concentrations of representative uraemic toxins in a healthy versus non-dialysis chronic kidney disease paediatric population

Background Chronic kidney disease (CKD) in childhood is poorly explained by routine markers (e.g. urea and creatinine) and is better depicted in adults by other uraemic toxins. This study describes concentrations of representative uraemic toxins in non-dialysis CKD versus healthy children. Methods In 50 healthy children and 57 children with CKD Stages 1-5 [median estimated glomerular filtration rate 48 (25th-75th percentile 24-71) mL/min/1.73 m2; none on dialysis], serum concentrations of small solutes [symmetric and asymmetric dimethyl-arginine (SDMA and ADMA, respectively)], middle molecules [β2-microglobuline (β2M), complement factor D (CfD)] and protein-bound solutes [p-cresylglucuronide (pCG), hippuric acid (HA), indole-acetic acid (IAA), indoxyl sulphate (IxS), p-cresyl sulphate (pCS) and 3-carboxy-4-methyl-5-propyl-furanpropionic acid (CMPF)] were measured. Concentrations in the CKD group were expressed as z-score relative to controls and matched for age and gender. Results SDMA, CfD, β2M, IxS, pCS, IAA, CMPF and HA concentrations were higher in the overall CKD group compared with controls, ranging from 1.7 standard deviations (SD) for IAA and HA to 11.1 SD for SDMA. SDMA, CfD, β2M, IxS and CMPF in CKD Stages 1-2 with concentrations 4.8, 2.8, 4.5, 1.9 and 1.6 SD higher, respectively. In contrast, pCS, pCG and IAA concentrations were only higher than controls from CKD Stages 3-4 onwards, but only in CKD Stage 5 for ADMA and HA (z-score 2.6 and 20.2, respectively). Conclusions This is the first study to establish reference values for a wide range of uraemic toxins in non-dialysis CKD and healthy children. We observed an accumulation of multiple uraemic toxins, each with a particular retention profile according to the different CKD stages.

A plea for more uremic toxin research in children with chronic kidney disease

Progressive loss of kidney function in childhood is paralleled by the development of a complex clinical picture, also referred to as the pediatric uremic syndrome. This syndrome, caused by chronic kidney disease or acute renal injury, is affecting nearly all organ systems (Table 1), and consequently, results in a significantly decreased quality of life and increased mortality during, and also beyond, childhood [1–3]. The complexity of the uremic syndrome is also related to its multifactorial character: due to (1) the deterioration of the renal endocrine function (e.g., erythropoietin and calcitriol deficiency), (2) the dysregulation of fluid and electrolyte homeostasis, (3) the development of specific symptoms related to kidney disease (hypertension, fluid overload) and its causes (e.g., diabetes, autoimmune disorders) or (4) treatment (e.g., reactions to bioincompatible dialysis materials), and (5) the accumulation of toxic organic metabolites (i.e., Buremic toxins^) due to decreased renal excretion and/or accompanied by increased toxin generation (Fig. 1) [4, 5]. Without neglecting the multifactorial character of the uremic syndrome, this editorial commentary will focus mainly on the accumulation of uremic toxins and its impact within the pediatric uremic syndrome. In recent decades, rapid progress in both identification of uremic retention solutes and evaluation of their toxicity has been accomplished. Currently, more than 140 uremic toxins are identified [6]. As proposed by the European Uremic Toxin Workgroup (EUTox), uremic toxins can be subdivided into three major classes based on their physicochemical properties that affect their removal during dialysis: (1) small water-soluble compounds (< 500 Da; e.g., urea) that are easily removed by diffusion, (2) middle molecules (≥ 500 Da; e.g., β2-microglobulin) that are most efficiently removed using large pore dialyzer membranes and by adding convect ive transpor t (hemodiafiltration), and (3) protein-bound compounds (e.g., indoxyl sulfate) that most often have a low molecular weight but are poorly removed by dialysis due to their protein binding [5, 7]. In experimental and clinical studies, many of these uremic toxins exert some degree of toxicity on one or more functional systems that contributes to the uremic syndrome and its complications [8]. In general, the cardiovascular, inflammatory, and fibrogenic system were most frequently affected by uremic toxins in experimental and clinical studies [8]. Nearly all these clinical studies on uremic solute retention were performed in adult chronic kidney disease (CKD) patients, and to the best of our knowledge, studies investigating the impact of uremic toxins on the growing child are virtually non-existent. Nevertheless, children, and the uremic syndrome they are suffering from, have particular characteristics that hamper the full translation of adult experience and knowledge in uremic toxicity into childhood (Fig. 2). First, children have physiological peculiarities that might affect the accumulation pattern of uremic toxins. For instance, children have proportionally larger body water volumes and lower circulating proteins than adults. Therefore, it is unlikely that the distribution, the inter-compartmental clearance, the removal pattern during dialysis, and the retention profile of uremic toxins would be identical to those in adults [9]. Also, the diet of children differs on several aspects from adults, e.g., relatively higher protein and caloric needs per kilogram bodyweight. As diet is one of the major determinants of intestinal microbiota, it is thus likely that the accumulation pattern of uremic toxins originating from microbial metabolism might be impacted, irrespectively of kidney function [10, 11]. * Evelien Snauwaert Evelien.Snauwaert@UZGent.Be

Building on evidence to improve patient care

Evidence-based medicine (EBM) is gaining importance in the current paediatric healthcare landscape. Improvement of paediatric health status is its major aim. However, for EBM to be successful, all stakeholders involved should understand what EBM really is, why and how EBM should or should not be practiced, and have the necessary skills to distinguish methodologically sound papers from biased opinion papers, and understand how and why guidelines are different from systematic reviews. Improving patient outcome requires attention to high-quality evidence and understanding of the processes of medical decision-making. Rigorous methodology is the cornerstone of guideline production, but in cases where quality evidence cannot be produced, as is often the case in paediatric nephrology because of low patient numbers, consensus-based guidance may be suitable to assist the practitioner at the bedside, as long as the underlying process is transparent. Most importantly, EBM should support patient involvement in a shared decision-making process. The more consistent and accurately predictable the effect of certain interventions is, clinically relevant to patients rather than affecting surrogate outcomes, and a priority for patients and other stakeholders, the more likely it is that adherence to the guidance provided will improve the outcome of patients.