• Users Online: 236
  • Print this page
  • Email this page


 
 
Table of Contents
STUDY PROTOCOL
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 67-73

Determining the optimal dose of cholecalciferol supplementation in children with chronic kidney disease (C3 Trial): Design of an open-label multicenter randomized controlled trial


1 Department of Pediatric Nephrology, St John's Medical College Hospital, Bengaluru, Karnataka, India
2 Department of Pediatric Nephrology, Government Medical College, Trivandrum, Kerala, India
3 Department of Nephrology, KEM Hospital, Pune, Maharashtra, India
4 Department of Pediatrics, Mehta Children's Hospital, Chennai, Tamil Nadu, India, India
5 Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

Date of Web Publication27-Dec-2018

Correspondence Address:
Dr Arpana Aprameya Iyengar
Department of Pediatric Nephrology, St John's Medical College Hospital, Bengaluru . 560 034, Karnatak
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJPN.AJPN_34_18

Rights and Permissions
  Abstract 


Introduction: 25-hydroxyvitamin D (25OHD) deficiency is common in children with chronic kidney disease (CKD) and can affect bone mineralization and cardiovascular morbidity. It is important to treat 25OHD deficiency appropriately in a manner that ensures not only replenishing stores but also sustaining adequate 25OHD levels without causing toxicity. The present study was planned to determine the appropriate dosing regimen for oral cholecalciferol that achieves and maintains normal 25OHD levels in children with CKD stage 2–4 and to assess the effect of various dosing regimens on bone biomarkers, secondary hyperparathyroidism, and vitamin D toxicity. Methods: We present the design of an open-label, multicenter randomized controlled trial conducted across four pediatric nephrology centers in India. Children in CKD stages 2–4 with 25OHD levels <30 ng/ml will be randomized to one of three therapy regimens for oral cholecalciferol (3000 IU daily, 25,000 IU weekly, or 100,000 IU monthly) given for 3 months, allowing an equivalent cumulative cholecalciferol dose in all arms over this intensive replacement therapy phase. After 3 months, patients with 25OHD levels ≥30 ng/ml will continue on maintenance therapy, administered at 1000 IU cholecalciferol orally daily for 9 months. Outcomes include the median change in the level of 25OHD from baseline to the end of intensive phase; proportions of children in each limb that attain and maintain normal 25OHD levels after intensive replacement and maintenance treatment; the change in levels of bone biomarkers and the incidence of adverse effects with each therapy regimes. Conclusion: The study design of a multicenter randomized controlled trial in children with CKD is described. Trial Registration: Clinical Trials Registry of India; www.ctri.nic.in; CTRI/2015/11/010180.

Keywords: Pediatric, mineral bone disease, calcium, randomized controlled trial, vitamin D deficiency


How to cite this article:
Iyengar AA, Kamath N, Hamsa V, Uthup S, Sharma J, Singhal J, Ekambaram S, Shroff R. Determining the optimal dose of cholecalciferol supplementation in children with chronic kidney disease (C3 Trial): Design of an open-label multicenter randomized controlled trial. Asian J Pediatr Nephrol 2018;1:67-73

How to cite this URL:
Iyengar AA, Kamath N, Hamsa V, Uthup S, Sharma J, Singhal J, Ekambaram S, Shroff R. Determining the optimal dose of cholecalciferol supplementation in children with chronic kidney disease (C3 Trial): Design of an open-label multicenter randomized controlled trial. Asian J Pediatr Nephrol [serial online] 2018 [cited 2019 May 21];1:67-73. Available from: http://www.ajpn-online.org/text.asp?2018/1/2/67/248645




  Introduction Top


25-hydroxyvitamin D (25OHD) deficiency, observed in 28%–77% children with chronic kidney disease (CKD),[1],[2],[3],[4] is associated with bone demineralization, cardiovascular morbidity, reduced immunity, and progression of CKD.[5],[6] Racial differences have been observed, with a higher prevalence of deficiency in South Asian compared to Caucasian children with CKD.[7] The deficiency of 25OHD was four times more prevalent among south Indian children with CKD[8] compared to North American participants of the CKD in Children (CKiD) cohort.[1],[9] A 15-fold increase in the diagnosis of 25OHD deficiency was observed between 2008 and 2014 in the UK, with older age (≥10 years), nonwhite ethnicity, and social deprivation as independent risk factors for the diagnosis; there was, simultaneously, a 20-fold increase in prescription of vitamin D supplements.[10]

Randomized controlled trials (RCTs) to guide evidence-based management of 25OHD deficiency are lacking. Despite widespread use of vitamin D, either as ergocalciferol or cholecalciferol, the dose and duration required to correct and maintain adequate 25OHD levels in adults or children with CKD is not clear. While supplementation with vitamin D in healthy children is based on age,[11] the Kidney Disease: Improving Global Outcomes recommendations[12] for children with CKD are guided by 25OHD levels. The European Society of Paediatric Nephrology[13] recommends using a treatment regimen guided by age and vitamin D concentration for the prevention and treatment of vitamin D deficiency in children with CKD stages 2–5D. However, the guidelines are based on low-quality evidence, and the optimal dosing regimen is not clear.

The aim of this study is to determine the dosing regimen of cholecalciferol that is most effective in achieving and maintaining normal 25OHD levels in children with CKD stage 2–4 and to examine the rates of vitamin D toxicity and secondary hyperparathyroidism associated with various dosing regimens.


  Methods Top


This open-label randomized controlled trial shall be conducted across four Pediatric Nephrology centers in India, namely St John's Medical College Hospital (SJMCH), Bangalore, Government Medical College, Trivandrum, KEM Hospital, Pune and Mehta Children's Hospital, Chennai. The study includes 2 years of recruitment (including the screening visit and the run-in period) and 12 months of follow-up.

Participants

Children will be screened for eligibility when attending the outpatient clinics or admitted to the four participating centers. Inclusion and exclusion criteria are listed in [Table 1]. Enrolment shall follow written informed consent from parents or guardians and assent from children, where appropriate. The trial is registered under the Clinical Trials Registry of India (CTRI-REF/2015/11/010180; www.ctri.nic.in) and has received approval from the Institutional Ethics Committees (2015/11/010180) across participating centers.
Table 1: Inclusion and exclusion criteria

Click here to view


Outcomes

The primary endpoint is to determine the median change in the level of 25OHD from baseline to the end of an intensive phase in three groups of children administered cholecalciferol using daily, weekly, and monthly supplementation regimens. The secondary endpoints are (i) safety of therapy, as assessed by serum calcium and urine calcium to creatinine ratio at 3 monthly visits; (ii) free 25OHD levels; (iii) levels of bone biomarkers; and (iv) proportion of children in each group who do not achieve adequate 25OHD levels.

Screening

Parents or guardians of children between 1 and 18 years of age who are diagnosed with CKD stages 2–4 will be approached to participate in the study. Written informed consent will be obtained. All medical details including the inclusion and exclusion criteria will be reviewed and blood samples for 25OHD levels collected. Samples from all sites will be couriered to a central laboratory in Bengaluru for measurement of 25OHD levels. The period from screening to randomization visits (up to 2 weeks) will serve as the run-in period to confirm the participant's eligibility by reviewing the 25OHD level and to counsel the family to adhere to regular follow-up. Additional blood and urine samples will be collected at the recruitment visit and at the end of follow-up to analyze markers of bone and mineral metabolism and the urine calcium to creatinine ratio [Figure 1].
Figure 1: Study flow. 25OHD: 25-hydroxyvitamin D; FGF: Fibroblast growth factor; PTH: Parathormone

Click here to view


A questionnaire will be completed by children and their parents to document outdoor activities, sun exposure and dietary intake of vitamin D. The weekly consumption of dairy products, fish oil and any other vitamin D containing nutritional supplements will be recorded. Children on multivitamin supplements, including over the counter unlicensed products, will be advised to stop these preparations for 3 months and then 25OHD levels will be rechecked. Outdoor physical activity scale will assess the duration of outdoor activity per week as 0 to <4 hr/week, 4 to10 hr/week, or >10 hr/week. Standard treatment medications will be continued as per their physician's advice. All data, including laboratory samples, will be fully anonymized at the point of collection, and only the local study investigators will have access to patient records.

Enrolment

25OHD levels will be analyzed in the central laboratory within 3 days, and the local chief investigator informed by e-mail with the results. If the 25OHD level is found to be <30 ng/ml and all other inclusion and exclusion criteria are fulfilled, the child will be called in for randomization. Samples will be stored for C-terminal Parathormone (PTH), 1,25 dihydroxy vitamin D, bone-specific alkaline phosphatase (BSALP), fibroblast growth factor-23 (FGF23), and Klotho at recruitment and end of the follow-up.

Randomization

Eligible patients will be randomly allocated in a 1:1:1 ratio to one of the three treatment groups, as described below. Block randomization using blocks of 6 will be performed with a secure, web-based randomization service (www.randomizer.org). Blinding is not possible as it would be inconvenient to blind to receive daily, weekly, or monthly oral cholecalciferol supplementation. Randomization shall be conducted centrally on receipt of screening form confirming eligibility of patient screened at any center, and the allocation shall be conveyed to the site investigator.

Intervention and allocation concealment

Cholecalciferol sachets, procured from the pharmacy of SJMCH, will be divided and weighed to prepare smaller sachets of 3000 IU, 25,000 IU, and 100,000 IU. The accuracy of the weight of divided portions will be confirmed by the pharmacy by randomly testing five sachets in every batch. The three different cholecalciferol dosage sachets will be wrapped in paper envelopes with the name of the supplement, dose per sachet, and expiry date written on the envelope. The sachets will be couriered to the study centers, and at the point of dispensing the sachets, the patient's name and study ID will be written on the envelope. The treatment will consist of an intensive replacement phase and a maintenance phase. The treatment schedule and sampling strategies are depicted in [Figure 1].

Intensive replacement phase

Children will be randomized to receive one of the three cholecalciferol treatment doses: 3000 IU daily, 25,000 IU weekly, or 100,000 IU monthly orally for the first 3 months, to ensure an equivalent cumulative dose of cholecalciferol in all three groups during the intensive phase. A list of “Do's and Don'ts” will be provided with the sachets [Supplementary Table 1[Additional file 1]].

Maintenance phase

After 3 months, 25OHD levels will be checked, and those with levels ≥30 ng/ml will receive maintenance therapy at 1000 units of cholecalciferol (prepared by central pharmacy) orally daily for 9 months [Figure 1]. Children with 25OHD levels <30 ng/dl will be given a second course of intensive treatment, following the same dosage schedule as per their allocation at randomization. Those who fail to achieve 25OHD levels >30 ng/ml will receive one more course (third course) of intensive replacement therapy. Children who fail to achieve 25OHD levels >30 ng/dl with a maximum of three courses of intensive replacement therapy will be considered as treatment failure.

Concomitant therapies

Children with serum calcium levels less than expected by age (defined by KDOQI)[15] will receive calcium supplements (not containing vitamin D) at 75–100 mg/kg/day. Children with serum phosphate levels greater than age expected values will be advised dietary phosphate restriction; if hyperphosphatemia persists at 4 weeks, calcium-based or noncalcium-based phosphate binders will be prescribed in doses as indicated.

Process evaluation of the intervention

To optimize adherence with the study medication, parents will be asked to fill out drug diaries, and the study coordinators at each center will make weekly phone calls to parents to assess and encourage compliance, and identify any problems with medications. In case of missed doses, a prespecified protocol will be followed: For patients on daily therapy, a missed dose once a week is permitted; on the weekly regimen, the missed dose could be taken within 3–4 days of the scheduled dose; and for patients on the monthly regimen, the missed dose could be taken within 2 weeks of the scheduled dose. A compliance sheet will be collected from patients at each clinic visit and these data recorded.

Biochemical measures

25OHD levels (total of 25OHD2 and 25OHD3 levels) will be estimated by liquid chromatography-tandem mass spectrometry in the central laboratory. Serum creatinine will be measured by modified Jaffe's method corrected to isotope dilution mass spectrometry, serum phosphate by phosphomolybdate method and intact PTH by chemiluminescent immune assay.

Statistical methods

An intention to treat analysis will be undertaken, and the study reported as per the CONSORT statement. Continuous variables will be represented as mean and standard deviation or median with interquartile range based on their distribution, and categorical variables as percentages. Data will be analyzed using Statistical package for social sciences (SPSS) version 16. The primary outcome, change in vitamin D levels between treatment groups will be studied using the repeated measures ANOVA model, with baseline and end of study measurements as response variables, and intervention, visit, and their interaction as covariates. To evaluate the treatment effect differences between CKD stages, two-way ANOVA models, will be used with the percentage of change of serum calcium, phosphate and intact PTH as response variables, and treatment, CKD stage, and their interaction as the factors. All P values will be described as two-tailed, and P < 0.05 will be considered statistically significant.

Sample size calculation

The sample size was estimated based on the randomized controlled trial on the use of ergocalciferol versus placebo in children with CKD.[16] The median 25OHD level at baseline was 50.2 ± 19.5 nmol/ml, and after intensive phase treatment was 96.5 ± 16.2 nmol/ml. As there are no previous randomized controlled trials comparing various regimens of vitamin D therapy, we assumed a 5% difference between treatment groups in achieving 25OHD levels after intensive phase treatment. At 80% power, with 5% level of significance, 20 patients per group would be required. Expecting a 20% drop out rate, the number required in each group will be 24. Multicenter recruitment strategy will address the target sample size.

Data and safety monitoring

The lead investigator at each site will be expected to report any serious adverse events (SAE) to the study coordinators in the lead center within 24 hr. The conduct of the trial will be assessed 3-monthly at the lead center by an independent data monitoring committee from St. John's Research Institute. In the event of an SAE related to vitamin D supplementation, the Institutional Ethics Committee will be notified. Specific aspects that will be reviewed include recruitment rate and loss to follow-up, data quality, compliance with the protocol by participants and investigators, protocol modifications, and continuing appropriate collection of participant information.

Interim analysis will be done after all subjects recruited in the study complete the intensive phase of treatment. Auditing will be done annually by the Institutional Ethics Committee, and a report will be provided to the principal investigator. The data of subjects recruited in the trial will be kept confidential, and the data will be maintained for 2 years after completion of the trial. Protocol modifications, if any, will be conveyed to the study centers and Ethics committee. The posttrial care of all the subjects recruited in the study will be according to the standard management of CKD. Confidentiality regarding the personal information of the patients will be maintained by the study investigators.

Current status

The trial was initiated in January 2016. Currently, enrollment into the study has been completed, and the last follow-up is expected to be completed by January 2019.


  Discussion Top


The C3 trial aims at determining fundamental aspects of vitamin D dosing that have not been previously studied. It is not known whether regimens differing in the frequency of supplementation of vitamin D (namely daily, weekly, or monthly) deliver the same equivalent dose over a 3-month period, achieve comparable 25OHD levels and/or are safe.

The burden of vitamin D deficiency in children with CKD varies widely across regions.[1],[17],[18],[19] Using a 25OHD level of <20 ng/ml as a threshold, a study from a tropical region revealed vitamin D deficiency in 28% of children with CKD,[20] similar to the burden reported by the North American CKiD study.[1] CKD was predominantly comprised of nonglomerular disease, and there was male predominance, similar to observations in previous studies[3],[18] However, another study had excluded children with nephrotic syndrome.[18] Both these studies reported seasonal variation in 25OHD levels, which is relatively unlikely in the present study as it is being conducted in a region that enjoys year-long sunshine. Studies that enrolled patients predominantly with CKD stages 2–4,[1],[3],[4] have shown no significant difference in 25OHD levels between CKD stages. However, an inverse association between 25OHD levels and severity of CKD[2],[20] has been reported in cohorts including children on dialysis.

There is no consensus on the optimal dose of vitamin D supplementation and duration of treatment that is required to maintain normal levels on the long-term.[21] Besides, with the increasing use of vitamin D supplementation, it becomes imperative to be aware of the rare possibility of vitamin D toxicity, usually seen with large doses of vitamin D. Vitamin D administered at 240,000–4,500,000 U is known to cause hypercalcemia and high 25OHD levels.[22] The European guidelines[13] recommend that vitamin D supplementation is discontinued at serum 25OHD concentrations of 120 nmol/L (48 ng/mL). Symptomatic toxicity from vitamin D is noted at serum 25OHD above 250 nmol/L, in the form of hypercalcemia, hypercalciuria, and suppressed PTH. Megadoses of vitamin D are not recommended in children with CKD due to the risk of hypercalcemia.[13],[22] The comparison of three regimens of vitamin D supplementation in 482 healthy adolescents with a high prevalence of vitamin D deficiency[23] showed that dosing of 60,000 IU/week for 8 weeks was most effective in achieving 25OHD levels >30 ng/ml compared to 4 and 6 weeks regimens. In healthy children, Stoss therapy, that uses a single megadose of vitamin D (300,000 IU and 600,000 IU), while not shown to affect the rate of improvement of rickets, can cause hypercalcemia.[24] In adults with osteoporosis, a single dose of 300,000 IU caused 50% increase in FGF23 levels from baseline.[25] Since hypercalcemia can cause a significant acute decline in renal function, particularly in patients with CKD, and leads to high FGF23 level that is linked to adverse cardiac effects, we do not recommend megadose vitamin D treatment regimens in children with CKD and are not testing this regimen.

Studies in children with CKD report a wide range of doses and treatment regimens for native vitamin D supplementation. An RCT testing the treatment recommended by KDOQI[26] showed that daily ergocalciferol supplementation for an intensive phase of 3 months followed by 12 months' maintenance therapy was associated with delayed onset of secondary hyperparathyroidism but inconsistent normal 25OHD levels in children with higher stages of CKD.[16] Two single-center prospective observational studies examined a single dose of vitamin D3 (300,000 IU intramuscularly)[27] and oral vitamin D3 given orally at 2,000 IU/day for 26 weeks.[28] While single megadose was associated with increase in 25OHD level and decline in serum PTH from baseline, 25OHD levels at 12 weeks were lower than that seen at 4 weeks. Oral daily regimen showed normalization of 25OHD in only 11% patients at 6 months and no change in serum PTH. In another study,[19] 42 patients with CKD stages 2–4, vitamin D deficiency and hyperparathyroidism, were administered 600,000 IU of cholecalciferol over 3 days (four sachets of 60000 IU on day one followed by three sachets each on days 2 and 3). At 6 weeks, 25OHD level was significantly increased, and median PTH levels decreased from baseline, while serum calcium, phosphate, and alkaline phosphatase levels were unchanged.

A systematic review[29] on vitamin D supplementation in adults included 3 studies[30],[31],[32] in patients with CKD stage 3–4, administered oral cholecalciferol in differing schedules (50,000 IU of cholecalciferol or placebo once weekly for one and 3 months; cholecalciferol 5000 IU versus 20,000 IU once a week for 12 months). All regimens were associated with a significant increase in 25OHD and decline in PTH levels without significant intergroup differences. Studies including 74 adults with CKD stages 3–4[33],[34] revealed 93% prevalence of vitamin D deficiency. Levels of 25OHD correlated inversely with BSALP and were significantly lower in patients with PTH >300 pg/ml. Adequate 25OHD levels were achieved in 64% cases with therapy with ergocalciferol at >600,000 IU; the total dose used being more relevant than the dosing frequency. Another study[35] revealed that 50,000 IU of ergocalciferol given weekly for 8 weeks effectively corrects vitamin D deficiency, and continued treatment with 50,000 IU of ergocalciferol every other week for up to 6 years prevents its recurrence in most patients.


  Conclusion Top


The C3 trial, a multicenter RCT in children with CKD stages 2–4, is being undertaken to determine the optimal dose and duration of oral cholecalciferol that is required to treat vitamin D deficiency appropriately, in a manner that would ensure not only replenishing stores but also sustaining adequate and safe levels of 25OHD. This study is expected to provide high-level evidence to develop guidelines for the optimal vitamin D dosing schedule.

Financial support and sponsorship

Navajbai Ratan Tata Trust, Bombay House, 24 Homi Mody Street, Mumbai - 400 001, Maharashtra, India (Reference Number: Health-CKCC-20141118). This being an “Investigator initiated trial” will receive only partial support from the Trust towards supporting expenses of clinical tests vitamin D supplements.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kumar J, McDermott K, Abraham AG, Friedman LA, Johnson VL, Kaskel FJ, et al. Prevalence and correlates of 25-hydroxyvitamin D deficiency in the chronic kidney disease in children (CKiD) cohort. Pediatr Nephrol 2016;31:121-9.  Back to cited text no. 1
    
2.
Kalkwarf HJ, Denburg MR, Strife CF, Zemel BS, Foerster DL, Wetzsteon RJ, et al. Vitamin D deficiency is common in children and adolescents with chronic kidney disease. Kidney Int 2012;81:690-7.  Back to cited text no. 2
    
3.
Stein DR, Feldman HA, Gordon CM. Vitamin D status in children with chronic kidney disease. Pediatr Nephrol 2012;27:1341-50.  Back to cited text no. 3
    
4.
Menon S, Valentini RP, Hidalgo G, Peschansky L, Mattoo TK. Vitamin D insufficiency and hyperparathyroidism in children with chronic kidney disease. Pediatr Nephrol 2008;23:1831-6.  Back to cited text no. 4
    
5.
Coyne DW, Andress DL, Amdahl MJ, Ritz E, de Zeeuw D. Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: Results of the VITAL study. Nephrol Dial Transplant 2013;28:2260-8.  Back to cited text no. 5
    
6.
Shroff R, Aitkenhead H, Costa N, Trivelli A, Litwin M, Picca S, et al. Normal 25-hydroxyvitamin D levels are associated with less proteinuria and attenuate renal failure progression in children with CKD. J Am Soc Nephrol 2016;27:314-22.  Back to cited text no. 6
    
7.
Belostotsky V, Mughal MZ, Berry JL, Webb NJ. Vitamin D deficiency in children with renal disease. Arch Dis Child 2008;93:959-62.  Back to cited text no. 7
    
8.
Kamath N, Iyengar AA. Chronic kidney disease (CKD): An observational study of etiology, severity and burden of comorbidities. Indian J Pediatr 2017;84:822-5.  Back to cited text no. 8
    
9.
Wong CJ, Moxey-Mims M, Jerry-Fluker J, Warady BA, Furth SL. CKiD (CKD in children) prospective cohort study: A review of current findings. Am J Kidney Dis 2012;60:1002-11.  Back to cited text no. 9
    
10.
Basatemur E, Horsfall L, Marston L, Rait G, Sutcliffe A. Trends in the diagnosis of Vitamin D deficiency. Pediatrics 2017;139. pii: e20162748.  Back to cited text no. 10
    
11.
Royal College for Paediatric and Child Health. Guidance for vitamin D in childhood; 2013. Available from: http://www.rcpch.ac.uk/vitamin-d. [Last accessed on 2017 Mar 26].  Back to cited text no. 11
    
12.
Ketteler M, Block GA, Evenepoel P, Fukagawa M, Herzog CA, McCann L, et al. Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: What's changed and why it matters. Kidney Int 2017;92:26-36.  Back to cited text no. 12
    
13.
Shroff R, Wan M, Nagler EV, Bakkaloglu S, Fischer DC, Bishop N, et al. Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease stages 2-5 and on dialysis. Nephrol Dial Transplant 2017;32:1098-113.  Back to cited text no. 13
    
14.
Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 2009;4:1832-43.  Back to cited text no. 14
    
15.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int 2009;76(suppl 113):S1-130.  Back to cited text no. 15
    
16.
Shroff R, Wan M, Gullett A, Ledermann S, Shute R, Knott C, et al. Ergocalciferol supplementation in children with CKD delays the onset of secondary hyperparathyroidism: A randomized trial. Clin J Am Soc Nephrol 2012;7:216-23.  Back to cited text no. 16
    
17.
Coccia P, Blazquez J, Contreras M, Ferrais V, Raddavero C, Ghezzi L, et al. High prevalence of vitamin D deficiency among children with chronic kidney disease and kidney transplant. Arch Argent Pediatr 2017;115:220-6.  Back to cited text no. 17
    
18.
Ali FN, Arguelles LM, Langman CB, Price HE. Vitamin D deficiency in children with chronic kidney disease: Uncovering an epidemic. Pediatrics 2009;123:791-6.  Back to cited text no. 18
    
19.
Hari P, Gupta N, Hari S, Gulati A, Mahajan P, Bagga A, et al. Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease. Pediatr Nephrol 2010;25:2483-8.  Back to cited text no. 19
    
20.
Seeherunvong W, Abitbol CL, Chandar J, Zilleruelo G, Freundlich M. Vitamin D insufficiency and deficiency in children with early chronic kidney disease. J Pediatr 2009;154:906-110.  Back to cited text no. 20
    
21.
Shroff R, Knott C, Rees L. The virtues of vitamin D – But how much is too much? Pediatr Nephrol 2010;25:1607-20.  Back to cited text no. 21
    
22.
Vogiatzi MG, Jacobson-Dickman E, DeBoer MD; Drugs, and Therapeutics Committee of The Pediatric Endocrine Society. Vitamin D supplementation and risk of toxicity in pediatrics: A review of current literature. J Clin Endocrinol Metab 2014;99:1132-41.  Back to cited text no. 22
    
23.
Garg MK, Marwaha RK, Khadgawat R, Ramot R, Obroi AK, Mehan N, et al. Efficacy of vitamin D loading doses on serum 25-hydroxy Vitamin D levels in school going adolescents: An open label non-randomized prospective trial. J Pediatr Endocrinol Metab 2013;26:515-23.  Back to cited text no. 23
    
24.
Mittal H, Rai S, Shah D, Madhu SV, Mehrotra G, Malhotra RK, et al. 300,000 IU or 600,000 IU of oral Vitamin D3 for treatment of nutritional rickets: A randomized controlled trial. Indian Pediatr 2014;51:265-72.  Back to cited text no. 24
    
25.
Turner C, Dalton N, Inaoui R, Fogelman I, Fraser WD, Hampson G, et al. Effect of a 300 000-IU loading dose of ergocalciferol (Vitamin D2) on circulating 1,25(OH) 2-Vitamin D and fibroblast growth factor-23 (FGF-23) in vitamin D insufficiency. J Clin Endocrinol Metab 2013;98:550-6.  Back to cited text no. 25
    
26.
KDOQI Work Group. KDOQI clinical practice guideline for nutrition in children with CKD: 2008 update. Executive summary. Am J Kidney Dis 2009;53:S11-104.  Back to cited text no. 26
    
27.
Kari JA, Baghdadi OT, El-Desoky S. Is high-dose cholecalciferol justified in children with chronic kidney disease who failed low-dose maintenance therapy? Pediatr Nephrol 2013;28:933-7.  Back to cited text no. 27
    
28.
Kari JA, El Desoky SM, El-Morshedy SM, Habib HS. Vitamin D insufficiency and deficiency in children with chronic kidney disease. Ann Saudi Med 2012;32:473-8.  Back to cited text no. 28
    
29.
Kandula P, Dobre M, Schold JD, Schreiber MJ Jr., Mehrotra R, Navaneethan SD, et al. Vitamin D supplementation in chronic kidney disease: A systematic review and meta-analysis of observational studies and randomized controlled trials. Clin J Am Soc Nephrol 2011;6:50-62.  Back to cited text no. 29
    
30.
Chandra P, Binongo JN, Ziegler TR, Schlanger LE, Wang W, Someren JT, et al. Cholecalciferol (Vitamin D3) therapy and Vitamin D insufficiency in patients with chronic kidney disease: A randomized controlled pilot study. Endocr Pract 2008;14:10-7.  Back to cited text no. 30
    
31.
Dogan E, Erkoc R, Sayarlioglu H, Soyoral Y, Dulger H. Effect of depot oral cholecalciferol treatment on secondary hyperparathyroidism in stage 3 and stage 4 chronic kidney diseases patients. Ren Fail 2008;30:407-10.  Back to cited text no. 31
    
32.
Oksa A, Spustová V, Krivosíková Z, Gazdíková K, Fedelesová V, Lajdová I, et al. Effects of long-term cholecalciferol supplementation on mineral metabolism and calciotropic hormones in chronic kidney disease. Kidney Blood Press Res 2008;31:322-9.  Back to cited text no. 32
    
33.
Jabbar Z, Aggarwal PK, Chandel N, Khandelwal N, Kohli HS, Sakhuja V, et al. Noninvasive assessment of bone health in Indian patients with chronic kidney disease. Indian J Nephrol 2013;23:161-7.  Back to cited text no. 33
[PUBMED]  [Full text]  
34.
Pepper KJ, Judd SE, Nanes MS, Tangpricha V. Evaluation of Vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract 2009;15:95-103.  Back to cited text no. 34
    
35.
Pietras SM, Obayan BK, Cai MH, Holick MF. Vitamin D2 treatment for vitamin D deficiency and insufficiency for up to 6 years. Arch Intern Med 2009;169:1806-8.  Back to cited text no. 35
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Methods
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed475    
    Printed86    
    Emailed0    
    PDF Downloaded120    
    Comments [Add]    

Recommend this journal