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.

Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK).

Introduction: Vitamin K deficiency among patients on hemodialysis (HD) affects the function of matrix GLA protein (MGP), a potent vitamin K-dependent inhibitor of vascular calcification (VC). Methods: We conducted a single-center randomized controlled trial (RCT) on maintenance HD patients to examine if vitamin K2 supplementation can reduce progression of coronary artery calcification (CAC) over an 18-month study period. Patients were randomized to vitamin K2 group receiving menaquinone-7360 µg 3 times/wk or control group. The primary outcome was CAC scores at the end of the study period. The secondary outcomes were aortic valve calcification (AVC), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), dephosphorylated undercarboxylated MGP (dp-ucMGP) levels, major adverse cardiac events (MACE), and vascular access events. Results: Of the 178 patients randomized, follow-up was completed for 138 patients. The CAC scores between the 2 groups were not statistically different at the end of 18 months (relative mean difference [RMD] 0.85, 95% CI 0.55-1.31). The secondary outcomes did not differ significantly in AVC (RMD 0.82, 95% CI 0.34-1.98), cfPWV (absolute mean difference [AMD] 0.55, 95% CI -0.50 to 1.60), and AIx (AMD 0.13, 95% CI -3.55 to 3.80). Supplementation with vitamin K2 did reduce dp-ucMGP levels (AMD -86, 95% CI -854 to -117). The composite outcome of MACE and mortality was not statistically different between the 2 groups (Hazard ratio = 0.98, 95% CI 0.50-1.94). Conclusion: Our study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of VC in this population at the studied dose and duration.

The effect of calcium supplementation on calcium and bone metabolism during load carriage in women: protocol for a randomised controlled crossover trial.

BACKGROUND: Military field exercises are characterised by high volumes of exercise and prolonged periods of load carriage. Exercise can decrease circulating serum calcium and increase parathyroid hormone and bone resorption. These disturbances to calcium and bone metabolism can be attenuated with calcium supplementation immediately before exercise. This randomised crossover trial will investigate the effect of calcium supplementation on calcium and bone metabolism, and bone mineral balance, during load carriage exercise in women. METHODS: Thirty women (eumenorrheic or using the combined oral contraceptive pill, intrauterine system, or intrauterine device) will complete two experimental testing sessions either with, or without, a calcium supplement (1000 mg). Each experimental testing session will involve one 120 min session of load carriage exercise carrying 20 kg. Venous blood samples will be taken and analysed for biochemical markers of bone resorption and formation, calcium metabolism, and endocrine function. Urine will be collected pre- and post-load carriage to measure calcium isotopes for the calculation of bone calcium balance. DISCUSSION: The results from this study will help identify whether supplementing women with calcium during load carriage is protective of bone and calcium homeostasis. TRIAL REGISTRATION: NCT04823156 (clinicaltrials.gov).

Diagnosis and management of mineral and bone disorders in infants with CKD: clinical practice points from the ESPN CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce.

BACKGROUND: Infants with chronic kidney disease (CKD) form a vulnerable population who are highly prone to mineral and bone disorders (MBD) including biochemical abnormalities, growth retardation, bone deformities, and fractures. We present a position paper on the diagnosis and management of CKD-MBD in infants based on available evidence and the opinion of experts from the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce. METHODS: PICO (Patient, Intervention, Comparator, Outcomes) questions were generated, and relevant literature searches performed covering a population of infants below 2 years of age with CKD stages 2-5 or on dialysis. Clinical practice points (CPPs) were developed and leveled using the American Academy of Pediatrics grading matrix. A Delphi consensus approach was followed. RESULTS: We present 34 CPPs for diagnosis and management of CKD-MBD in infants, including dietary control of calcium and phosphate, and medications to prevent and treat CKD-MBD (native and active vitamin D, calcium supplementation, phosphate binders). CONCLUSION: As there are few high-quality studies in this field, the strength of most statements is weak to moderate, and may need to be adapted to individual patient needs by the treating physician. Research recommendations to study key outcome measures in this unique population are suggested. A higher resolution version of the Graphical abstract is available as Supplementary information.

Changes in bone biomarkers in response to different dosing regimens of cholecalciferol supplementation in children with chronic kidney disease.

BACKGROUND: The effect of different dosing regimens of cholecalciferol supplementation on bone biomarkers has not been studied in children with chronic kidney disease (CKD). METHODS: This is a post hoc analysis of a multi-center randomized controlled trial which included children with CKD stages 2-4 with vitamin D deficiency (25-hydroxy vitamin D (25OHD) < 30 ng/ml) randomized 1:1:1 to receive an equivalent dose of oral cholecalciferol as daily, weekly or monthly treatment. Markers of bone formation (bone alkaline phosphatase (BAP), procollagen I N terminal peptide (PINP)), bone resorption (tartarate-resistant acid phosphatase 5b (TRAP), C terminal telopeptide (CTX)), and osteocyte markers (intact fibroblast growth factor 23 (iFGF23), sclerostin) and soluble klotho were measured at baseline and after 3 months of intensive replacement therapy. The change in biomarkers and ratio of markers of bone formation to resorption were compared between treatment arms. BAP and TRAP were expressed as age- and sex-specific z-scores. RESULTS: 25OHD levels increased with cholecalciferol supplementation, with 85% achieving normal levels. There was a significant increase in the BAP/TRAP ratio (p = 0.04), iFGF23 (p = 0.004), and klotho (p = 0.002) with cholecalciferol therapy, but this was comparable across all three therapy arms. The BAPz was significantly higher in the weekly arm (p = 0.01). The change in 25OHD (Δ25OHD) inversely correlated with ΔPTH (r = - 0.4, p < 0.001). CONCLUSIONS: Although cholecalciferol supplementation was associated with a significant increase in bone formation, the three dosing regimens of cholecalciferol supplementation have a comparable effect on the bone biomarker profile, suggesting that they can be used interchangeably to suit the patient's needs and optimize adherence to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

Determining the optimal cholecalciferol dosing regimen in children with CKD: a randomized controlled trial.

BACKGROUND: The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2-4. METHODS: An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment. RESULTS: Ninety children were randomized to daily (n = 30), weekly (n = 29) or monthly (n = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity. CONCLUSION: Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease.

Quality and use of unlicensed vitamin D preparations in primary care in England: Retrospective review of national prescription data and laboratory analysis.

AIM: To evaluate the type (licensed vs unlicensed) and cost of preparations used to fulfil vitamin D prescriptions in England over time, and to compare measured vitamin D content of selected vitamin D preparations against labelled claim. METHODS: Retrospective analysis of vitamin D prescription data in primary care in England (2008-2018). Laboratory analysis of 13 selected vitamin D preparations. RESULTS: Alongside a rise in the number of oral licensed colecalciferol preparations from 0 to 27 between 2012 and 2018, the proportion of vitamin D prescriptions in which licensed vitamin D preparations were supplied increased from 11.8 to 54.2%. However, the use of unlicensed food supplements (dose strength 400-50 000 IU) remained high, accounting for 39.7% of vitamin D prescriptions in 2018. The two licensed preparations showed mean (±SD) vitamin D content of 90.9 ± 0.7% and 90.5 ± 3.9% of the labelled claimed amount, meeting the British Pharmacopeia specification for licensed medicines (90-125% of labelled claim). The 11 food supplements showed vitamin D content ranging from 41.2 ± 10.6% to 165.3 ± 17.8% of the labelled claim, with eight of the preparations failing to comply with the food supplement specification (80-150% of labelled claim). CONCLUSIONS: Despite the increasing availability of quality assured licensed preparations, food supplements continued to be used interchangeably with licensed preparations to fulfil vitamin D prescriptions. Food supplements, manufactured under less stringent quality standards, showed wide variations between measured and declared vitamin D content, which could lead to the risk of under- and over-dosing.

Dietary calcium intake does not meet the nutritional requirements of children with chronic kidney disease and on dialysis.

BACKGROUND: Adequate calcium (Ca) intake is required for bone mineralization in children. We assessed Ca intake from diet and medications in children with CKD stages 4-5 and on dialysis (CKD4-5D) and age-matched controls, comparing with the UK Reference Nutrient Intake (RNI) and international recommendations. METHODS: Three-day prospective diet diaries were recorded in 23 children with CKD4-5, 23 with CKD5D, and 27 controls. Doses of phosphate (P) binders and Ca supplements were recorded. RESULTS: Median dietary Ca intake in CKD4-5D was 480 (interquartile range (IQR) 300-621) vs 724 (IQR 575-852) mg/day in controls (p = 0.00002), providing 81% vs 108% RNI (p = 0.002). Seventy-six percent of patients received < 100% RNI. In CKD4-5D, 40% dietary Ca was provided from dairy foods vs 56% in controls. Eighty percent of CKD4-5D children were prescribed Ca-based P-binders, 15% Ca supplements, and 9% both medications, increasing median daily Ca intake to 1145 (IQR 665-1649) mg/day; 177% RNI. Considering the total daily Ca intake from diet and medications, 15% received < 100% RNI, 44% 100-200% RNI, and 41% > 200% RNI. Three children (6%) exceeded the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) upper limit of 2500 mg/day. None with a total Ca intake < RNI was hypocalcemic, and only one having > 2 × RNI was hypercalcemic. CONCLUSIONS: Seventy-six percent of children with CKD4-5D had a dietary Ca intake < 100% RNI. Restriction of dairy foods as part of a P-controlled diet limits Ca intake. Additional Ca from medications is required to meet the KDOQI guideline of 100-200% normal recommended Ca intake. Graphical abstract.

Energy and protein requirements for children with CKD stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

Dietary management in pediatric chronic kidney disease (CKD) is an area fraught with uncertainties and wide variations in practice. Even in tertiary pediatric nephrology centers, expert dietetic input is often lacking. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, was established to develop clinical practice recommendations (CPRs) to address these challenges and to serve as a resource for nutritional care. We present CPRs for energy and protein requirements for children with CKD stages 2-5 and those on dialysis (CKD2-5D). We address energy requirements in the context of poor growth, obesity, and different levels of physical activity, together with the additional protein needs to compensate for dialysate losses. We describe how to achieve the dietary prescription for energy and protein using breastmilk, formulas, food, and dietary supplements, which can be incorporated into everyday practice. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgment. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.

Cinacalcet use in paediatric dialysis: a position statement from the European Society for Paediatric Nephrology and the Chronic Kidney Disease-Mineral and Bone Disorders Working Group of the ERA-EDTA.

Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD) in children, which is often difficult to treat with conventional therapy. The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor. It has proven to be effective and safe in adults to suppress parathyroid hormone (PTH), but data on its use in children are limited. To date, studies in children only consist of two randomized controlled trials, nine uncontrolled interventional or observational studies, and case reports that report the efficacy of cinacalcet as a PTH-lowering compound. In 2017, the European Medical Agency approved the use of cinacalcet for the treatment of SHPT in children on dialysis in whom SHPT is not adequately controlled with standard therapy. Since evidence-based guidelines are so far lacking, we present a position statement on the use of cinacalcet in paediatric dialysis patients based on the available evidence and opinion of experts from the European Society for Paediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA. Given the limited available evidence the strength of these statements are weak to moderate, and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. Audit and research recommendations to study key outcome measures in paediatric dialysis patients receiving cinacalcet are suggested.

Vitamin D prescribing in children in UK primary care practices: a population-based cohort study.

OBJECTIVE: To examine temporal changes in the incidence and patterns of vitamin D supplementation prescribing by general practitioners (GPs) between 2008 and 2016. DESIGN: Population-based cohort study. SETTING: UK general practice health records from The Health Improvement Network. PARTICIPANTS: Children aged 0 to 17 years who were registered with their general practices for at least 3 months. OUTCOME MEASURES: Annual incidence rates of vitamin D prescriptions were calculated, and rate ratios were estimated using multivariable Poisson regression to explore differences by sociodemographic factors. Data on the type of supplementation, dose, dosing schedule, linked 25-hydroxyvitamin D (25(OH)D) laboratory test results and clinical symptoms suggestive of vitamin D deficiency were analysed. RESULTS: Among 2 million children, the crude annual incidence of vitamin D prescribing increased by 26-fold between 2008 and 2016 rising from 10.8 (95% CI: 8.9 to 13.1) to 276.8 (95% CI: 264.3 to 289.9) per 100 000 person-years. Older children, non-white ethnicity and general practices in England (compared with Wales/Scotland/Northern Ireland) were independently associated with higher rates of prescribing. Analyses of incident prescriptions showed inconsistent supplementation regimens with an absence of pre-supplementation 25(OH)D concentrations in 28.7% to 56.4% of prescriptions annually. There was an increasing trend in prescribing at pharmacological doses irrespective of 25(OH)D concentrations, deviating in part from UK recommendations. Prescribing at pharmacological doses for children with deficient status increased from 3.8% to 79.4%, but the rise was also observed in children for whom guidelines recommended prevention doses (0% to 53%). Vitamin D supplementation at pharmacological doses was also prescribed in at least 40% of children with no pre-supplementation 25(OH)D concentrations annually. CONCLUSIONS: There has been a marked and sustained increase in vitamin D supplementation prescribing in children in UK primary care. Our data suggests that national guidelines on vitamin D supplementation for children are not consistently followed by GPs.

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update.

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis. Methods: Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations. Recommendations: The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters.

The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease.

Cardiovascular Phenotypes in Children with CKD: The 4C Study.

BACKGROUND AND OBJECTIVES: Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m2. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. RESULTS: A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. CONCLUSIONS: The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.

Genetic, Environmental, and Disease-Associated Correlates of Vitamin D Status in Children with CKD.

BACKGROUND AND OBJECTIVES: Vitamin D deficiency is endemic in children with CKD. We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Serum 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5. All patients were participants of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study, had CKD stage 3-5, and were age 6-18 years old. Patients were genotyped for single-nucleotide polymorphisms in the genes encoding 25-hydroxylase, vitamin D binding protein, 7-dehydrocholesterol reductase, and 24-hydroxylase. Associations of genetic status, season, local solar radiation, oral vitamin D supplementation, and disease-associated factors with vitamin D status were assessed. RESULTS: Two thirds of patients were vitamin D deficient (25-hydroxy-vitamin D <16 ng/ml). 25-Hydroxy-vitamin D concentrations varied with season and were twofold higher in vitamin D-supplemented patients (21.6 [14.1] versus 10.4 [10.1] ng/ml; P<0.001). Glomerulopathy, albuminuria, and girls were associated with lower 25-hydroxy-vitamin D levels. 24,25-dihydroxy-vitamin D levels were closely correlated with 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D (r=0.87 and r=0.55; both P<0.001). 24,25-dihydroxy-vitamin D concentrations were higher with higher c-terminal fibroblast growth factor 23 and inversely correlated with intact parathyroid hormone. Whereas 25-hydroxy-vitamin D levels were independent of renal function, 24,25-dihydroxy-vitamin D levels were lower with lower eGFR. Vitamin D deficiency was more prevalent in Turkey than in other European regions independent of supplementation status and disease-related factors. Single-nucleotide polymorphisms in the vitamin D binding protein gene were independently associated with lower 25-hydroxy-vitamin D and higher 24,25-dihydroxy-vitamin D. CONCLUSIONS: Disease-related factors and vitamin D supplementation are the main correlates of vitamin D status in children with CKD. Variants in the vitamin D binding protein showed weak associations with the vitamin D status.

Revisiting KDIGO clinical practice guideline on chronic kidney disease-mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference.

A new definition and classification of chronic kidney disease-mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.

Mineral metabolism in European children living with a renal transplant: a European society for paediatric nephrology/european renal association-European dialysis and transplant association registry study.

BACKGROUND AND OBJECTIVES: Data on mineral metabolism in pediatric renal transplant recipients largely arise from small single-center studies. In adult patients, abnormal mineral levels are related to a higher risk of graft failure. This study used data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry to study the prevalence and potential determinants of mineral abnormalities, as well as the predictive value of a disturbed mineral level on graft survival in a large cohort of European pediatric renal transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included 1237 children (0-17 years) from 10 European countries, who had serum calcium, phosphorus, and parathyroid hormone measurements from 2000 onward. Abnormalities of mineral metabolism were defined according to European guidelines on prevention and treatment of renal osteodystrophy in children on chronic renal failure. RESULTS: Abnormal serum phosphorus levels were observed in 25% (14% hypophosphatemia and 11% hyperphosphatemia), altered serum calcium in 30% (19% hypocalcemia, 11% hypercalcemia), and hyperparathyroidism in 41% of the patients. A longer time since transplantation was associated with a lower risk of having mineral levels above target range. Serum phosphorus levels were inversely associated with eGFR, and levels above the recommended targets were associated with a higher risk of graft failure independently of eGFR. CONCLUSIONS: Abnormalities in mineral metabolism are common after pediatric renal transplantation in Europe and are associated with graft dysfunction.

Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia.

BACKGROUND: Vitamin A accumulates in renal failure, but the prevalence of hypervitaminosis A in children with predialysis chronic kidney disease (CKD) is not known. Hypervitaminosis A has been associated with hypercalcemia. In this study we compared dietary vitamin A intake with serum retinoid levels and their associations with hypercalcemia. METHODS: We studied the relationship between vitamin A intake, serum retinoid levels, and serum calcium in 105 children with CKD stages 2-5 on dialysis and posttransplant. Serum retinoid measures included retinol (ROH), its active retinoic acid (RA) metabolites [all-trans RA (at-RA) and 13-cis RA] and carrier proteins [retinol-binding protein-4 (RBP4) and transthyretin (TTR)]. Dietary vitamin A intake was assessed using a food diary. RESULTS: Twenty-five children were in CKD 2-3, 35 in CKD 4-5, 23 on dialysis and 22 posttransplant; 53 % had vitamin A intake above the Reference Nutrient Intake (RNI) value. Children receiving supplemental feeds compared with diet alone had higher vitamin A intake (p = 0.02) and higher serum ROH (p < 0.001). Notably, increased ROH was seen as early as CKD stage 2. For every 10 ml/min/1.73 m(2) fall in estimated glomerular filtration rate (eGFR), there was a 13 % increase in ROH. RBP4 levels were increased in CKD 3-5 and dialysis patients. The lowest ratios of ROH:RBP4 were seen in dialysis compared with CKD 2-3 (p = 0.03), suggesting a relative increase in circulating RBP4. Serum ROH, RBP4 and at-RA were associated with serum calcium. On multivariable analysis RBP4 levels and alfacalcidol dose were significant predictors of serum calcium (model R (2) 32 %) in dialysis patients. CONCLUSIONS: Hypervitaminosis A is seen in early CKD, with highest levels in children on supplemental feeds compared with diet alone. Serum retinoid levels significantly predict hypercalcemia.

Management of hyperphosphataemia in chronic kidney disease: summary of National Institute for Health and Clinical Excellence (NICE) guideline.

Bone disease and ectopic calcification are the two main consequences of hyperphosphataemia of chronic kidney disease (CKD). Observational studies have demonstrated that hyperphosphataemia in CKD is associated with increased mortality. Furthermore, the use of phosphate binders in dialysis patients is associated with significantly lower mortality. The UK Renal Registry data show significant underachievement of phosphate targets in dialysis patients. It is believed to be due to wide variation in how management interventions are used. The National Institute for Health and Clinical Excellence (NICE) has developed a guideline on the management of hyperphosphataemia in CKD. This is based on the evidence currently available using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. This review outlines the recommendations including research recommendations and discusses methodology, rationale and challenges faced in developing this guideline and the health economic model used to assess the cost-effectiveness of different phosphate binders.