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 trial of two maintenance doses of vitamin D in children with chronic kidney disease.

BACKGROUND: Correction of nutritional vitamin deficiency is recommended in children with chronic kidney disease (CKD). The optimal daily dose of vitamin D to achieve or maintain vitamin D sufficiency is unknown. METHODS: We conducted a phase III, double-blind, randomized trial of two doses of vitamin D3 in children ≥ 9 years of age with CKD stages 3-5 or kidney transplant recipients. Patients were randomized to 1000 IU or 4000 IU of daily vitamin D3 orally. We measured 25-hydroxvitamin D (25(OH)D) levels at baseline, 3 months and 6 months. The primary efficacy outcome was the percentage of patients who were vitamin D replete (25(OH)D ≥ 30 ng/mL) at 6 months. RESULTS: Ninety-eight patients were enrolled: 49 randomized into each group. Eighty (81.6%) patients completed the study and were analyzed. Baseline plasma 25(OH)D levels were ≥ 30 ng/mL in 12 (35.3%) and 12 (27.3%) patients in the 1000 IU and 4000 IU treatment groups, respectively. At 6 months, plasma 25(OH)D levels were ≥ 30 ng/mL in 33.3% (95% CI: 18.0-51.8%) and 74.4% (95% CI: 58.8-86.5%) in the 1000 IU and 4000 IU treatment groups, respectively (p = 0.0008). None of the patients developed vitamin D toxicity or hypercalcemia. CONCLUSIONS: In children with CKD, 1000 IU of daily vitamin D3 is unlikely to achieve or maintain a plasma 25(OH)D ≥ 30 ng/mL. In children with CKD stages 3-5, a dose of vitamin D3 4000 IU daily was effective in achieving or maintaining vitamin D sufficiency. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01909115.

Safety and efficacy of sucroferric oxyhydroxide in pediatric patients with chronic kidney disease.

BACKGROUND: Pediatric patients with advanced chronic kidney disease (CKD) are often prescribed oral phosphate binders (PBs) for the management of hyperphosphatemia. However, available PBs have limitations, including unfavorable tolerability and safety. METHODS: This phase 3, multicenter, randomized, open-label study investigated safety and efficacy of sucroferric oxyhydroxide (SFOH) in pediatric and adolescent subjects with CKD and hyperphosphatemia. Subjects were randomized to SFOH or calcium acetate (CaAc) for a 10-week dose titration (stage 1), followed by a 24-week safety extension (stage 2). Primary efficacy endpoint was change in serum phosphorus from baseline to the end of stage 1 in the SFOH group. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: Eighty-five subjects (2-18 years) were randomized and treated (SFOH, n = 66; CaAc, n = 19). Serum phosphorus reduction from baseline to the end of stage 1 in the overall SFOH group (least squares [LS] mean ± standard error [SE]) was - 0.488 ± 0.186 mg/dL; p = 0.011 (post hoc analysis). Significant reductions in serum phosphorus were observed in subjects aged ≥ 12 to ≤ 18 years (LS mean ± SE - 0.460 ± 0.195 mg/dL; p = 0.024) and subjects with serum phosphorus above age-related normal ranges at baseline (LS mean ± SE - 0.942 ± 0.246 mg/dL; p = 0.005). Similar proportions of subjects reported ≥ 1 TEAE in the SFOH (75.8%) and CaAc (73.7%) groups. Withdrawal due to TEAEs was more common with CaAc (31.6%) than with SFOH (18.2%). CONCLUSIONS: SFOH effectively managed serum phosphorus in pediatric patients with a low pill burden and a safety profile consistent with that reported in adult patients.

Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome.

BACKGROUND: Bartter syndrome (BS) is a salt-wasting tubulopathy with induced expression of cyclooxygenase-2 in the macula densa, leading to increased prostaglandin production and hyperreninemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in BS; however, there is limited information on the impact of NSAIDs at treatment initiation or the potential utility of plasma renin level to guide therapy in patients with BS. METHODS: We included 19 patients with BS treated with NSAIDs between 1994 and 2016. We assessed serum levels of renin, aldosterone, electrolytes, calcium, phosphorus, vitamin D, and intact parathyroid hormone (iPTH) before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and changes in urine calcium. RESULTS: Median age at diagnosis was 0.9 months [IQR 0-6.9]. Seven patients had BS types 1 or 2, 12 had BS type 3 and two had no mutation identified. There was a trend towards a decrease in sodium chloride supplementation after initiation of NSAIDs. When defining response to treatment based on the normalization of plasma renin level, responders had a greater reduction in their electrolytes supplementation. NSAIDs treatment was associated with a reduction in urine calcium. Before treatment, half of the patients had elevated iPTH, but iPTH normalized following initiation of NSAIDs in all but one patient. CONCLUSIONS: This study confirms that NSAIDs reduce urine wasting of sodium and calcium in patients with BS. Monitoring serum renin levels may be useful to identify the lowest effective dose of NSAIDs that optimizes reduction of urine electrolyte losses.

Efficacy and safety of paricalcitol in children with stages 3 to 5 chronic kidney disease.

BACKGROUND: Elevated intact parathyroid hormone (iPTH) levels can contribute to morbidity and mortality in children with chronic kidney disease (CKD). We evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in reducing iPTH levels in children with stages 3-5 CKD. METHODS: Children aged 10-16 years with stages 3-5 CKD were enrolled in two phase 3 studies. The stage 3/4 CKD study characterized paricalcitol pharmacokinetics and compared the efficacy and safety of paricalcitol with placebo followed by an open-label period. The stage 5 CKD study evaluated the efficacy and safety of paricalcitol (no comparator) in children with stage 5 CKD undergoing dialysis. RESULTS: In the stage 3/4 CKD study, mean peak plasma concentration and area under the time curve from zero to infinity were 0.13 ng/mL and 2.87 ng•h/((or ng×h/))mL, respectively, for 12 children who received 3 µg paricalcitol. Thirty-six children were randomized to paricalcitol or placebo; 27.8% of the paricalcitol group achieved two consecutive iPTH reductions of ≥30% from baseline versus none of the placebo group (P = 0.045). Adverse events were higher in children who received placebo than in those administered paricalcitol during the double-blind treatment (88.9 vs. 38.9%; P = 0.005). In the stage 5 CKD study, eight children (61.5%) had two consecutive iPTH reductions of ≥30% from baseline, and five (38.5%) had two consecutive iPTH values of between 150 and 300 pg/mL. Clinically meaningful hypercalcemia occurred in 21% of children. CONCLUSIONS: Oral paricalcitol in children aged 10-16 years with stages 3-5 CKD reduced iPTH levels and the treatment was well tolerated. Results support an initiating dose of 1 µg paricalcitol 3 times weekly in children aged 10-16 years.

Assessment of dietary intake of children with chronic kidney disease.

OBJECTIVE: Our aim was to characterize the nutrient intake of children with chronic kidney disease (CKD) relative to recommended intake levels. METHODS: We conducted a cross-sectional study of dietary intake assessed by Food Frequency Questionnaire (FFQ) in The North American Chronic Kidney Disease in Children (CKiD) prospective cohort study. Nutrient intake was analyzed to estimate the daily consumption levels of various nutrients and compared with national guidelines for intake. RESULTS: There were 658 FFQs available for analysis; 69.9 % of respondents were boys, with a median age [Interquartile range (IQR)] of 11 years (8-15). Median daily sodium, potassium, and phosphorus intake was 3089 mg (2294-4243), 2384 mg (1804-3076), and 1206 mg (894-1612) respectively. Sodium and phosphorus consumptions were higher than recommended in all age groups. Caloric intake decreased with dropping glomerular filtration rate (GFR) (p = 0.003). The median daily caloric intakes were 1307 kcal in male children 2-3 years old, 1875 kcal in children 4-8 years old, 1923 kcal in those 9-13 years old, and 2427 kcal in those 14-18 years old. Respective levels for girls were 1467 kcal, 1736 kcal, 1803 kcal, and 2281 kcal. Median protein intake exceeded recommended levels in all age groups, particularly among younger participants. Younger children were more likely than older children to exceed the recommended intakes for phosphorus (p < 0.001) and the age-specific recommended caloric intake (p < 0.001). Macronutrient distribution (carbohydrate:fat:protein) was consistent with recommendation. CONCLUSIONS: Children in the CKiD cohort consumed more sodium, phosphorus, protein, and calories than recommended. The gap between actual consumption and recommendations indicates a need for improved nutritional counseling and monitoring.

Intestinal microbiota in pediatric patients with end stage renal disease: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: End-stage renal disease (ESRD) is associated with uremia and increased systemic inflammation. Alteration of the intestinal microbiota may facilitate translocation of endotoxins into the systemic circulation leading to inflammation. We hypothesized that children with ESRD have an altered intestinal microbiota and increased serum levels of bacterially derived uremic toxins. METHODS: Four groups of subjects were recruited: peritoneal dialysis (PD), hemodialysis (HD), post-kidney transplant and healthy controls. Stool bacterial composition was assessed by pyrosequencing analysis of 16S rRNA genes. Serum levels of C-reactive protein (CRP), D-lactate, p-cresyl sulfate and indoxyl sulfate were measured. RESULTS: Compared to controls, the relative abundance of Firmicutes (P = 0.0228) and Actinobacteria (P = 0.0040) was decreased in PD patients. The relative abundance of Bacteroidetes was increased in HD patients (P = 0.0462). Compared to HD patients the relative abundance of Proteobacteria (P = 0.0233) was increased in PD patients. At the family level, Enterobacteriaceae was significantly increased in PD patients (P = 0.0020) compared to controls; whereas, Bifidobacteria showed a significant decrease in PD and transplant patients (P = 0.0020) compared to control. Alpha diversity was decreased in PD patients and kidney transplant using both phylogenetic and non-phylogenetic diversity measures (P = 0.0031 and 0.0003, respectively), while beta diversity showed significant separation (R statistic = 0.2656, P = 0.010) between PD patients and controls. ESRD patients had increased serum levels of p-cresyl sulfate and indoxyl sulfate (P < 0.0001 and P < 0.0001, respectively). The data suggests that no significant correlation exists between the alpha diversity of the intestinal microbiota and CRP, D-lactate, or uremic toxins. Oral iron supplementation results in expansion of the phylum Proteobacteria. CONCLUSIONS: Children with ESRD have altered intestinal microbiota and increased bacterially derived serum uremic toxins.

Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20-100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. METHODS: Multicenter longitudinal study of children (2-18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. RESULTS: Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty-seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p < 0.01) in children supplemented with vitamin D. CONCLUSIONS: In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2-4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS.

A new 'tac' for childhood nephrotic syndrome.

Calcineurin inhibitors (CNIs) are frequent first-line agents in children with steroid-resistant nephrotic syndrome (SRNS). However, limited randomized controlled trial (RCT) data are available comparing CNIs with alternative therapies. Gulati and colleagues report their experience with tacrolimus versus cyclophosphamide in childhood SRNS. Their results establish clear superiority of tacrolimus over cyclophosphamide and give further proof that RCTs in childhood SRNS are both feasible and vital for improving the standard of care.

Effect of intensified diet education on serum phosphorus and knowledge of pediatric peritoneal dialysis patients.

OBJECTIVE: To investigate the effect of intensive diet education on the knowledge and serum phosphorus levels of pediatric peritoneal dialysis (PD) patients and their parents. DESIGN: Interventional study using a pre-post design and convenience sample. SETTING: The study was performed in a pediatric PD clinic. PATIENTS: Sixteen patients ranging in age from 9 to 21 years and their parents. INTERVENTION: Patients routinely receive a review of laboratory results and a review of foods to limit. For the study, two additional education sessions were conducted. The additional phosphorus education to participants included a computer-based jeopardy game, handouts, education magnets and a hands-on learning activity. A 20 question before-and-after knowledge test was administered to the patients and parents separately. MAIN OUTCOME MEASURES: Change in serum phosphorus levels and the difference in pre and post knowledge test scores for both patients and parents. RESULTS: There was a significant increase in parent (p=0.003) and patient knowledge (p<0.001). There was a decrease in serum phosphorus from 2.3+/-0.68mmol/L to 2.16+/-0.58mmol/L (7.13+/-2.1mg/dL to 6.68+/-1.8mg/dL), but this change was not statistically significant (p=0.256). CONCLUSION: Intensive education regarding phosphorus led to improved patient and family knowledge in pediatric PD patients. Although increased knowledge did not result in a significant decrease in serum phosphorus, there was a slight decrease indicating some clinical relevance. Therefore, pediatric PD patients may benefit from intensive on-going diet education sessions.

Intravenous paricalcitol for treatment of secondary hyperparathyroidism in children on hemodialysis.

BACKGROUND: Secondary hyperparathyroidism is a common complication in children receiving hemodialysis. Active vitamin D is an effective therapy, but its use is often limited by hypercalcemia and increased calcium x phosphorus (Ca x P) product. Paricalcitol, a selective vitamin D receptor activator, causes less sustained hypercalcemia and increase in Ca x P product than calcitriol and has been used effectively in adult hemodialysis patients. STUDY DESIGN: Double blind, placebo-controlled. SETTING & PARTICIPANTS: Hemodialysis units and pediatric subjects receiving hemodialysis. INTERVENTION: After a washout period of 2 to 6 weeks, 29 subjects aged 5 to 19 years received either paricalcitol or placebo for up to 12 weeks (0.04 mug/kg if initial intact parathyroid hormone [iPTH] level < 500 pg/mL [ng/L]; 0.08 mug/kg if initial iPTH level > 500 pg/mL [ng/L]). The dose was increased by 0.04 mug/kg every 2 weeks until there was a 30% decrease in iPTH level from baseline or calcium level greater than 11 mg/dL (>2.74 mmol/L) or Ca x P product greater than 75 mg(2)/dL(2) (>6.04 mmol(2)/L(2)). OUTCOMES & MEASUREMENTS: Two consecutive 30% decreases from baseline in iPTH levels and safety of paricalcitol, including hypercalcemia and increase in Ca x P product. RESULTS: 60% of the paricalcitol group had 2 consecutive 30% decreases from baseline iPTH levels compared with 21% in the placebo group (P = 0.06). The paricalcitol group had a mean decrease in iPTH level of 164 pg/mL (ng/L), whereas the placebo group had a mean increase of 238 pg/mL (ng/L; P = 0.03). There was no difference from baseline to final visit in calcium, phosphorus, or Ca x P product values in either group. LIMITATIONS: Low power to detect differences in safety between groups and a short-term study. CONCLUSION: Paricalcitol decreased iPTH levels in children receiving hemodialysis with no significant changes in serum calcium, phosphorus, or Ca x P product values during the course of the study.

Rickets in the Dairy State.

BACKGROUND: Nutritional vitamin D deficiency rickets occurs when children do not receive adequate vitamin D, which can be obtained from diet or manufactured in the skin when there is adequate sun exposure. A number of reports have described cases of vitamin D deficiency rickets in breastfed infants, but the public health significance of this problem in Wisconsin is unknown. OBJECTIVES: Our objectives were to identify cases of vitamin D deficiency rickets in Wisconsin infants and to determine the percentage of these infants participating in the Wisconsin Women, Infant and Children (WIC) program. METHODS: All cases of rickets due to nutritional vitamin D deficiency seen at Children's Hospital of Wisconsin or its associated outpatient clinics were identified by retrospective chart review. Data collected included date of birth, age at presentation, race, clinical presentation, diet history, history of vitamin supplementation, x-ray findings, and biochemical studies. The children with nutritional vitamin D deficiency rickets were cross-referenced with the Wisconsin WIC database. RESULTS: Fifty-one definite cases of nutritional vitamin D deficiency rickets were identified. Skeletal deformities, failure to thrive, fractures, seizures, incidental lab finding, tetany, and refusal to walk were the most common reasons for identifying rickets. All of the children were breastfed and did not receive vitamin supplementation. The infants had a mean age of 13.6 months and 46 (90%) were African American. Thirty-seven out of 51 children (73%) were enrolled in the Wisconsin WIC program. CONCLUSION: Vitamin D deficiency nutritional rickets is an important public health problem in Wisconsin. The Wisconsin WIC program may be an important site for intervention strategies.