Disparities in dialysis treatment and outcomes for Dutch and Belgian children with immigrant parents

BACKGROUND: In Belgium and the Netherlands, up to 40% of the children on dialysis are children with immigrant parents of non-Western European origin (non-Western). Concerns exist regarding whether these non-Western patients receive the same quality of care as children with parents of Western European origin (Western). We compared initial dialysis, post-initial treatment, and outcomes between non-Western and Western patients on dialysis. METHODS: All children <19 years old on chronic dialysis in the Netherlands and Belgium between September 2007 and May 2011 were included in the study. Non-Western patients were defined as children of whom one or both parents were born in non-Western countries. RESULTS: Seventy-nine of the 179 included patients (44%) were non-Western children. Compared to Western patients, non-Western patients more often were treated with hemodialysis (HD) instead of peritoneal dialysis (PD) as first dialysis mode (52 vs. 37%, p = 0.046). Before renal transplantation, non-Western patients were on dialysis for a median (range) of 30 (5-99) months, vs. 15 (0-66) months in Western patients (p = 0.007). Renal osteodystrophy was diagnosed in 34% of non-Western vs. 18% of Western patients (p = 0.028). The incidence rate ratio [95% confidence interval] for acute peritonitis was 2.44 [1.43-4.17] (p = 0.032) for non-Western compared to Western patients. CONCLUSIONS: There are important disparities between children on chronic dialysis with parents from Western European origin and those from non-Western European origin in the choice of modality, duration, and outcomes of dialysis therapy

Peritonitis in children on peritoneal dialysis in Cape Town, South Africa: epidemiology and risks

Peritonitis is a frequent complication of peritoneal dialysis (PD) in children as well in adults. Data on PD and peritonitis in pediatric patients are very scarce in developing countries. A retrospective cohort study was performed between 2000 and 2008 with the aim to evaluate PD treatment and peritonitis epidemiology in pediatric patients in South Africa and identify risk factors for peritonitis. Baseline characteristics and potential risk factors of peritonitis were recorded, including housing, socio-economic circumstances, distance to PD center, type of PD, mode of catheter placement, race, presence of gastrostomy tube, weight, and height. Outcome indices for peritonitis were peritonitis rate, time to first peritonitis, and number of peritonitis-free patients. The patient cohort comprised 67 patients who were on PD for a total of 544 months. The total number of peritonitis episodes was 129. Median peritonitis rate was one episode every 4.3 patient months (2.8 episodes/patient-year, range 0–21.2). Median time to first infection was 2.03 months (range 0.1–21.5 months), and 28.4% of patients remained free from peritonitis. Patients with good housing and good socio-economic circumstances had a significantly lower peritonitis rate and a longer time to first peritonitis episode. Peritonitis rate was high in this cohort, compared to numbers reported for the developed world; the characteristics of causative organisms are comparable. The most important risk factors for the development of peritonitis were poor housing and poor socio-economic circumstances. More intensive counseling may be beneficial, but improvement of general socio-economic circumstances will have the greatest influence on PD success

Patient and caregiver perspectives on blood pressure in children with chronic kidney disease

Background: More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care. / Methods: Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology—Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8–21 years) and caregivers (of children ages 0–21 years) pertaining to blood pressure. / Results: Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects). / Conclusions: For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD

Nutrition aspects in children receiving maintenance hemodialysis: impact on outcome

Children with end-stage renal disease (ESRD) have rates of mortality estimated to be 30-times higher than expected for age compared with those of healthy children. Physical manifestations of under-nutrition, such as body mass index (BMI) and low height standard deviation score (SDS), have been associated with increased risk of mortality. Traditional measures, such as height, weight and serum albumin concentration, may not be accurate indicators to assess the nutritional status of children receiving maintenance hemodialysis. Normalized protein catabolic rate (nPCR) has emerged as a better marker of nutritional status of such children. Meeting the special nutritional needs of these children often requires nutritional supplementation, by either the enteral or the parenteral route. Recently, in children receiving maintenance hemodialysis who are malnourished, intradialytic parenteral nutrition (IDPN) has been utilized as a means to provide additional protein and calories. This article is a state-of-the-art review of malnutrition in children receiving maintenance hemodialysis, with special focus on outcome, nPCR and IDPN

Chronic kidney disease in children: the global perspective

In contrast to the increasing availability of information pertaining to the care of children with chronic kidney disease (CKD) from large-scale observational and interventional studies, epidemiological information on the incidence and prevalence of pediatric CKD is currently limited, imprecise, and flawed by methodological differences between the various data sources. There are distinct geographic differences in the reported causes of CKD in children, in part due to environmental, racial, genetic, and cultural (consanguinity) differences. However, a substantial percentage of children develop CKD early in life, with congenital renal disorders such as obstructive uropathy and aplasia/hypoplasia/dysplasia being responsible for almost one half of all cases. The most favored end-stage renal disease (ESRD) treatment modality in children is renal transplantation, but a lack of health care resources and high patient mortality in the developing world limits the global provision of renal replacement therapy (RRT) and influences patient prevalence. Additional efforts to define the epidemiology of pediatric CKD worldwide are necessary if a better understanding of the full extent of the problem, areas for study, and the potential impact of intervention is desired

Physiologically based modeling of lisofylline pharmacokinetics following intravenous administration in mice

Lisofylline (LSF), is the R-(−) enantiomer of the metabolite M1 of pentoxifylline, and is currently under development for the treatment of type 1 diabetes. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model of LSF in mice and to perform simulations in order to predict LSF concentrations in human serum and tissues following intravenous and oral administration. The concentrations of LSF in serum, brain, liver, kidneys, lungs, muscle, and gut were determined at different time points over 60 min by a chiral HPLC method with UV detection following a single intravenous dose of LSF to male CD-1 mice. A PBPK model was developed to describe serum pharmacokinetics and tissue distribution of LSF using ADAPT II software. All pharmacokinetic profiles were fitted simultaneously to obtain model parameters. The developed model characterized well LSF disposition in mice. The estimated intrinsic hepatic clearance was 5.427 ml/min and hepatic clearance calculated using the well-stirred model was 1.22 ml/min. The renal clearance of LSF was equal to zero. On scaling the model to humans, a good agreement was found between the predicted by the model and presented in literature serum LSF concentration–time profiles following an intravenous dose of 3 mg/kg. The predicted LSF concentrations in human tissues following oral administration were considerably lower despite the twofold higher dose used and may not be sufficient to exert a pharmacological effect. In conclusion, the mouse is a good model to study LSF pharmacokinetics following intravenous administration. The developed PBPK model may be useful to design future preclinical and clinical studies of this compound

Growth hormone axis in chronic kidney disease

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD

Graded Smad2/3 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells

The Transforming Growth Factor (TGF) β signalling family includes morphogens, such as Nodal and Activin, with important functions in vertebrate development. The concentration of the morphogen is critical for fate decisions in the responding cells. Smad2 and Smad3 are effectors of the Nodal/Activin branch of TGFβ signalling: they are activated by receptors, enter the nucleus and directly transcribe target genes. However, there have been no studies correlating levels of Smad2/3 activation with expression patterns of endogenous target genes in a developmental context over time. We used mouse Embryonic Stem (ES) cells to create a system whereby levels of activated Smad2/3 can be manipulated by an inducible constitutively active receptor (Alk4*) and an inhibitor (SB-431542) that blocks specifically Smad2/3 activation. The transcriptional responses were analysed by microarrays at different time points during activation and repression. We identified several genes that follow faithfully and reproducibly the Smad2/3 activation profile. Twenty-seven of these were novel and expressed in the early embryo downstream of Smad2/3 signalling. As they responded to Smad2/3 activation in the absence of protein synthesis, they were considered direct. These immediate responsive genes included negative intracellular feedback factors, like SnoN and I-Smad7, which inhibit the transcriptional activity of Smad2/3. However, their activation did not lead to subsequent repression of target genes over time, suggesting that this type of feedback is inefficient in ES cells or it is counteracted by mechanisms such as ubiquitin-mediated degradation by Arkadia. Here we present an ES cell system along with a database containing the expression profile of thousands of genes downstream of Smad2/3 activation patterns, in the presence or absence of protein synthesis. Furthermore, we identify primary target genes that follow proportionately and with high sensitivity changes in Smad2/3 levels over 15–30 hours. The above system and resource provide tools to study morphogen function in development

Range and Heterogeneity of Outcomes in Randomized Trials of Pediatric Chronic Kidney Disease

OBJECTIVE: To determine the range and heterogeneity of outcomes reported in randomized controlled trials of interventions for children with chronic kidney disease (CKD). STUDY DESIGN: The Cochrane Kidney and Transplant Specialized Register was searched to March 2016. Randomized trials involving children across all stages of CKD were selected. All outcome domains and measurements were extracted from included trials. The frequency and characteristics of the outcome domains and measures were evaluated. RESULTS: From 205 trials included, 6158 different measurements of 100 different outcome domains were reported, with a median of 22 domains per trial (IQR 13-41). Overall, 52 domains (52%) were surrogate, 38 (38%) were clinical, and 10 (10%) were patient-reported. The 5 most commonly reported domains were blood pressure (76 [37%] trials), relapse/remission (70 [34%]), kidney function (66 [32%]), infection (61 [30%]), and height/pubertal development (51 [25%]). Mortality (14%), cardiovascular disease (4%), and quality of life (1%) were reported infrequently. The 2 most frequently reported outcomes, blood pressure and relapse/remission, had 56 and 81 different outcome measures, respectively. CONCLUSIONS: The outcomes reported in clinical trials involving children with CKD are extremely heterogeneous and are most often surrogate outcomes, rather than clinical and patient-centered outcomes such as cardiovascular disease and quality of life. Efforts to ensure consistent reporting of outcomes that are important to patients and clinicians will improve the value of trials to guide clinical decision-making. In our study, non-English articles were excluded