Assessment and management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation: clinical practice points from the Pediatric Renal Nutrition Taskforce.

Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation.The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested.

Estimating Total Energy Expenditure to Determine Energy Requirements in Free-Living Children With Stage 3 Chronic Kidney Disease: Can a Structured Approach Help Improve Clinical Care?

OBJECTIVE: Malnutrition and obesity are complex burdensome challenges in pediatric chronic kidney disease (CKD) management that can adversely affect growth, disease progression, wellbeing, and response to treatment. Total energy expenditure (TEE) and energy requirements in children are essential for growth outcomes but are poorly defined, leaving clinical practice varied and insecure. The aims of this study were to explore a practical approach to guide prescribed nutritional interventions, using measurements of TEE, physical activity energy expenditure (PAEE), and their relationship to kidney function. DESIGN AND METHODS: In a cross-sectional prospective age-matched and sex-matched controlled study, 18 children with CKD (6-17 years, mean stage 3) and 20 healthy, age-matched, and gender-matched controls were studied. TEE and PAEE were measured using basal metabolic rate (BMR), activity diaries and doubly labeled water (healthy subjects). Results were related to estimated glomerular filtration rate (eGFR). The main outcome measure was TEE measured by different methods (factorial, doubly labeled water, and a novel device). RESULTS: Total energy expenditure and PAEE with or without adjustments for age, gender, weight, and height did not differ between the groups and was not related to eGFR. TEE ranged from 1927 ± 91 to 2330 ± 73 kcal/d; 95 ± 5 to 109 ± 5% estimated average requirement (EAR), physical activity level (PAL) 1.52 ± 0.01 to 1.71 ± 0.17, and PAEE 24 to 34% EAR. Comparisons between DLW and alternative methods in healthy children did not differ significantly, except for 2 (factorial methods and a fixed PAL; and the novel device). CONCLUSION: In clinical practice, structured approaches using supportive evidence (weight, height, BMI sds), predictive BMR or TEE values and simple questions on activity, are sufficient for most children with CKD as a starting energy prescription.

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation.

Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever. One key defense during bacterial infection is nutritional immunity: host cells attempt to restrict bacterial replication by denying bacteria access to key nutrients or supplying toxic metabolites. Here, a cellular genome-wide association study of intracellular replication by S. Typhi in nearly a thousand cell lines from around the world-and extensive follow-up using intracellular S. Typhi transcriptomics and manipulation of magnesium availability-demonstrates that the divalent cation channel mucolipin-2 (MCOLN2 or TRPML2) restricts S. Typhi intracellular replication through magnesium deprivation. Mg2+ currents, conducted through MCOLN2 and out of endolysosomes, were measured directly using patch-clamping of the endolysosomal membrane. Our results reveal Mg2+ limitation as a key component of nutritional immunity against S. Typhi and as a source of variable host resistance.

Integration of the Salmonella Typhimurium Methylome and Transcriptome Reveals That DNA Methylation and Transcriptional Regulation Are Largely Decoupled under Virulence-Related Conditions.

Despite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged single-molecule, real-time sequencing (SMRT-seq) to examine the m6A DNA methylome of two Salmonella enterica serovar Typhimurium strains: 14028s and a ΔmetJ mutant with derepressed methionine metabolism, grown in Luria broth or medium that simulates the intracellular environment. We found that the methylome is remarkably static: >95% of adenosine bases retain their methylation status across conditions. Integration of methylation with transcriptomic data revealed limited correlation between changes in methylation and gene expression. Further, examination of the transcriptome in ΔyhdJ bacteria lacking the m6A methylase with the most dynamic methylation pattern in our data set revealed little evidence of YhdJ-mediated gene regulation. Curiously, despite G(m6A)TC motifs being particularly resistant to change across conditions, incorporating dam mutants into our analyses revealed two examples where changes in methylation and transcription may be linked across conditions. This includes the novel finding that the ΔmetJ motility defect may be partially driven by hypermethylation of the chemotaxis gene tsr. Together, these data redefine the S. Typhimurium epigenome as a highly stable system that has rare but important roles in transcriptional regulation. Incorporating these lessons into future studies will be critical as we progress through the epigenomic era. IMPORTANCE While recent breakthroughs have enabled intense study of bacterial DNA modifications, limitations in current work have potentiated a surprisingly untested narrative that DNA methylation is a common mechanism of the bacterial response to environmental conditions. Essentially, whether epigenetic regulation of bacterial transcription is a common, generalizable phenomenon is a critical unanswered question that we address here. We found that most DNA methylation is static in Salmonella enterica serovar Typhimurium, even when the bacteria are grown under dramatically different conditions that cause broad changes in the transcriptome. Further, even when the methylation of individual bases change, these changes generally do not correlate with changes in gene expression. Finally, we demonstrate methods by which data can be stratified in order to identify coupled changes in methylation and gene expression.

Basal metabolic rate in children with chronic kidney disease and healthy control children.

BACKGROUND: Meeting energy requirements of children with chronic kidney disease (CKD) is paramount to optimising growth and clinical outcome, but little information on this subject has been published. In this study, we examined basal metabolic rate (BMR; a component of energy expenditure) with the aim to determine whether it is related to kidney function independently of weight, height and lean body mass (LBM). METHODS: Twenty children with CKD and 20 healthy age- and gender-matched control children were studied on one occasion. BMR was measured by indirect open circuit calorimetry and predicted by the Schofield equation. Estimated glomerular filtration rate (eGFR) was related to BMR and adjusted for weight, height, age and LBM measured by skinfold thickness. RESULTS: The adjusted BMR of children with CKD did not differ significantly from that of healthy subjects (1296 ± 318 vs.1325 ± 178 kcal/day; p = 0.720). Percentage of predicted BMR also did not differ between the two groups (102 ± 12% vs. 99 ± 14%; p = 0.570). Within the CKD group, eGFR (mean 33.7 ± 20.5 mL/min/m(2)) was significantly related to BMR (ß 0.3, r = 0.517, p = 0.019) independently of nutritional status and LBM. CONCLUSIONS: It seems reasonable to use estimated average requirement as the basis of energy prescriptions for children with CKD (mean CKD stage 3 disease). However, those who were sicker had significantly lower metabolic rates.