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.

Population pharmacokinetics and dose optimisation of colecalciferol in paediatric patients with chronic kidney disease.

AIMS: The prevalence of vitamin D deficiency is high in children with chronic kidney disease (CKD). However, current dosing recommendations are based on limited pharmacokinetic (PK) data. This study aimed to develop a population PK model of colecalciferol that can be used to optimise colecalciferol dosing in this population. METHODS: Data from 83 children with CKD were used to develop a population PK model using a nonlinear mixed effects modelling approach. Serum creatinine and type of kidney disease (glomerular vs. nonglomerular disease) were investigated as covariates, and optimal dosing was determined based on achieving and maintaining 25-hydroxyvitamin D (25(OH)D) concentration of 30-48 ng/mL. RESULTS: The time course of 25(OH)D concentrations was best described by a 1-compartment model with the addition of a basal concentration parameter to reflect endogenous 25(OH)D production from diet and sun exposure. Colecalciferol showed wide between-subject variability in its PK, with total body weight scaled allometrically the only covariate included in the model. Model-based simulations showed that current dosing recommendations for colecalciferol can be optimised using a weight-based dosing strategy. CONCLUSION: This is the first study to describe the population PK of colecalciferol in children with CKD. PK model informed dosing is expected to improve the attainment of target 25(OH)D concentrations, while minimising the risk of overdosing.

A single centre experience of percutaneous nephrolithotomy in infants and its long-term outcomes.

BACKGROUND: Renal stones in infants requiring Percutaneous nephrolithotomy (PCNL) is rare. There is insufficient literature on the long-term implications of PCNL in growing kidneys of these children. OBJECTIVES: To review our experience of PCNL amongst infants i.e., < 1year of age and to analyse the safety and efficacy of this procedure and assess its long-term renal outcomes. STUDY DESIGN: This was a retrospective analysis of a prospectively maintained data base between 2005 and 2020. All infants with unilateral renal stones >12 mm underwent PCNL. Changes in the serum creatinine, estimated glomerular filtration rate and renal size prior to the PCNL and at the last follow up were monitored. The demographics, clinical profile, operative details, post-operative complications and follow up data were collated and analyzed. RESULTS: 86 children were diagnosed with renal stones of whom, 24 infants met our inclusion criteria and were included in the review. The average age was 9.75 months with fever being the commonest presenting symptom. Five infants were diagnosed with metabolic abnormalities, hypercalciuria being the commonest. Majority of the infants (22) had single stones and the lower calyx was the commonest site (50%). The mean stone burden was 19.5 mm. The stone free rate was 91% during the primary PCNL, which increased to 100% after re-do PCNL. The overall complication rate was 16% which was graded by the modified Clavien Dindo scale for surgical complications. The median follow up period was 144 months and average age at the last follow up was 10.5 years. At the last follow up, a mean serum creatinine of 0.4 mg/dl, mean estimated glomerular filtration rate of 98 ml/min/1.72 m2 and a mean renal size of 8.3 cm was recorded, which was comparable to that of a normal child, thus signifying no deterioration of renal functions and renal growth. Three children showed the presence of cortical scars on an isotope scan at follow up. However, all the 24 operated renal units demonstrated preserved renal functions. DISCUSSION & CONCLUSION: PCNL performed during infancy does not hinder the growth potential of the kidney. Each of the 24 children achieved the target renal size and estimated glomerular filtration rate corresponding to the duration and body size at the end of the follow-up. Thus, PCNL in infants <1 year of age is safe and effective with no adverse effects at long term follow-up.

Juvenile psammomatoid ossifying fibroma of maxillary sinus: case report with review of literature.

Juvenile psammomatoid ossifying fibroma is a rare benign fibro-osseous tumor of the gnathic and extragnathic craniofacial bones, particularly the periorbital, frontal and ethmoid bones. It is slowly progressive with aggressive local growth, invasion and destruction of the surrounding tissue, bone erosion and recurrence after surgical excision. It is distinguished from the other fibro-osseous lesions by its age of onset, clinical presentation and aggressive behavior.