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Pilot study of the effect of cholecalciferol supplementation on hepcidin in children with chronic kidney disease: Results of the D-fense Trial

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Abstract

Background

Hepcidin is a key mediator of the anemia of chronic kidney disease (CKD). There is emerging evidence that 25-hydroxyvitamin D (25D) regulates hepcidin production.

Methods

A randomized controlled trial of daily vitamin D supplementation for 12 weeks was performed with the aim to test the effects of 4000 versus 400 IU of cholecalciferol on serum hepcidin levels in children with non-dialysis CKD recruited at a tertiary care children’s hospital. Hepcidin was quantified using a validated competitive enzyme-linked immunosorbent assay. 25D levels were measured using the chemiluminescence Liaison 25(OH)D assay system. Co-variables included hemoglobin, C-reactive protein, ferritin, and serum calcium and phosphorus for safety monitoring.

Results

A total of 34 subjects were randomized to either the intervention or control group, of whom 26.5% were female and 23.5% were African American. The mean age of the study cohort was 10.9 [standard deviation (SD) 5.8] years, the mean baseline glomerular filtration rate was 60 (SD 17.6) ml/min/1.73 m2, and mean baseline 25D level was 29.7 (SD 11.5) ng/ml. At baseline, 50% of subjects were 25D deficient. There were no significant differences in baseline characteristics between the intervention and control groups. Treatment with 4000 IU cholecalciferol was not associated with significant change in hepcidin level at 4 or 12 weeks, and multivariable generalized estimating equation regression demonstrated no significant difference in change in hepcidin over the treatment period in either arm. The median C-reactive protein level decreased significantly at 12 weeks in the intervention group.

Conclusions

These results do not suggest that daily nutritional vitamin D supplementation modifies serum hepcidin levels in children with CKD. Further study will be required to determine whether supplementation may be effective in children with more advanced CKD or those on dialysis.

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References

  1. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R, Investigators TREAT (2009) A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361:2019–2032

    Article  PubMed  Google Scholar 

  2. Unger EF, Thompson AM, Blank MJ, Temple R (2010) Erythropoiesis-stimulating agents—time for a reevaluation. N Engl J Med 362:189–192

    Article  CAS  PubMed  Google Scholar 

  3. Atkinson MA, Martz K, Warady BA, Neu AM (2010) Risk for anemia in pediatric chronic kidney disease patients: a report of NAPRTCS. Pediatr Nephrol 25:1699–1706

    Article  PubMed  Google Scholar 

  4. Poli M, Asperti M, Ruzzenenti P, Regoni M, Arosio P (2014) Hepcidin antagonists for potential treatments of disorders with hepcidin excess. Front Pharmacol 586:1–13

    Google Scholar 

  5. Mercadel L, Metzger M, Haymann JP, Thervet E, Boffa JJ, Flamant M, Vrtovsnik F, Houillier P, Froissart M, Stengel B, the NephroTest Study Group (2014) The relation of hepcidin to iron disorders, inflammation and hemoglobin in chronic kidney disease. PLoS One 9:e99781

    Article  PubMed  PubMed Central  Google Scholar 

  6. Babitt JL, Lin HY (2010) Molecular mechanisms of hepcidin regulation: Implications for the anemia of CKD. Am J Kidney Dis 55:726–7441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Malyszko J, Mysliwiec M (2007) Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res 30:15–30

    Article  CAS  PubMed  Google Scholar 

  8. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. J Clin Invest 306:2090–2093

    CAS  Google Scholar 

  9. Roy CN, Andrews NC (2005) Anemia of inflammation: the hepcidin link. Curr Opin Hematol 12:107–111

    Article  CAS  PubMed  Google Scholar 

  10. Atkinson MA, White CT (2012) Hepcidin in anemia of chronic kidney disease: review for the pediatric nephrologist. Pediatr Nephrol 27:33–40

    Article  PubMed  Google Scholar 

  11. Preza GC, Pinon R, Ganz T, Nemeth E (2013) Cellular catabolism of the iron-regulatory protein hepcidin. PLoS One 8:e58934

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zaritsky J, Young B, Wang HJ, Westerman M, Olbina G, Nemeth E, Ganz T, Rivera S, Nissenson AR, Salusky IB (2009) Hepcidin—a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol 4:1051–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zaritsky J, Young B, Gales B, Wang HJ, Rastogi A, Westerman M, Nemeth E, Ganz T, Salusky IB (2010) Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. Clin J Am Soc Nephrol 5:1010–1014

    Article  PubMed  PubMed Central  Google Scholar 

  14. Atkinson MA, Kim JY, Roy CN, Warady BA, White CT, Furth SL (2015) Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort. Pediatr Nephrol 30:635–643

    Article  PubMed  Google Scholar 

  15. Adams JS, Hewison M (2008) Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 4:80–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Baeke F, Gysemans C, Korf H, Mathieu C (2010) Vitamin D insufficiency: implications for the immune system. Pediatr Nephrol 25:1597–1606

    Article  PubMed  Google Scholar 

  17. Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K, Nayak A, Wesseling-Perry K, Westerman M, Hollis BW, Salusky IB, Hewison M (2014) Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol 25:564–572

    Article  CAS  PubMed  Google Scholar 

  18. Institute of Medicine, National Academies of Science, Engineering, and Medicine (2010) EAR, “Dietary reference intakes for calcium and vitamin D”. http://iom.nationalacademies.org/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/calciumvitd_lg.jpg. Accessed September 2016

  19. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M (2008) Immunoassay for human serum hepcidin. Blood 112:4292–4297

    Article  CAS  PubMed  Google Scholar 

  21. Havers FP, Detrick B, Cardoso SW, Berendes S, Lama JR, Sugandhavesa P, Mwelase NH, Campbell TB, Gupta A (2014) ACTG A5175 PEARLS and NWCS319 Study Teams. Change in vitamin d levels occurs early after antiretroviral therapy initiation and depends on treatment regimen in resource-limited settings. PLoS One 9:e95164

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lai S, Fishman EK, Lai H, Pannu H, Detrick B (2009) Serum IL-6 levels are associated with significant coronary stenosis in cardiovascularly asymptomatic inner-city black adults in the US. Inflamm Res 58:15–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. KDOQI Work Group (2009) KDOQI clinical practice guideline for nutrition in children with CKD: 2008 update. Am J Kidney Dis 53:S11–104

    Google Scholar 

  24. White H (1980) A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometrica 48:817–838

    Article  Google Scholar 

  25. Zughaier SM, Alvarez JA, Sloan JH, Konrad RJ, Tangpricha V (2014) The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes. J Clin Transl Endocrinol 1:19–25

    Article  PubMed  PubMed Central  Google Scholar 

  26. Alvarez J, Wasse H, Tangpricha V (2012) Vitamin D supplementation in pre-dialysis chronic kidney disease: A systematic review. Dermatoendocrinol 4:118–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lehmann U, Hirche F, Stangl GI, Westphal S, Dierkas J (2015) Bioavailability of vitamin D(2) and D(3) in healthy volunteers, a randomized placebo-controlled trial. J Clin Endocrinol Metab 98:4339–4345

    Article  Google Scholar 

  28. Marckmann P, Agerskov H, Thineshkumar S, Bladbjerg EM, Sidelmann JJ, Jespersen J, Nybo M, Rasmussen LM, Hansen D, Scholze A (2012) Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D. Nephrol Dial Transplant 27:3523–3531

    Article  CAS  PubMed  Google Scholar 

  29. Bikle D (2009) Nonclassic actions of vitamin D. J Clin Endocrinol Metab 94:26–34

    Article  CAS  PubMed  Google Scholar 

  30. Means RT (2009) Hepcidin and cytokines in anaemia. Hematology 9:357–362

    Article  Google Scholar 

  31. Nemeth E (2010) Targeting the hepcidin–ferroportin axis in the diagnosis and treatment of anemias. Adv Hematol 2010:750643

    PubMed  Google Scholar 

  32. Smith EM, Alvarez JA, Kearns MD, Hao L, Sloan JH, Konrad RJ, Ziegler TR, Zughaier TV (2016) High-dose vitamin D3 reduces circulating hepcidin concentrations; A pilot, randomized, double-blind, placebo-controlled trial in healthy adults. Clin Nutr. doi:10.1016/j.clnu.2016.06.015

    Google Scholar 

  33. Atkinson MA, Melamed ML, Kumar J, Roy CN, Miller ER 3rd, Furth SL, Fadrowski JJ (2014) Vitamin D, race, and risk for anemia in children. J Pediatr 164:153–158

    Article  CAS  PubMed  Google Scholar 

  34. Kendrick J, Targher G, Smits G, Chonchol M (2009) 25-Hydroxyvitamin D deficiency and inflammation and their association with hemoglobin levels in chronic kidney disease. Am J Nephrol 30:64–72

    Article  CAS  PubMed  Google Scholar 

  35. Smith EM, Tangpricha V (2015) Vitamin D and anemia; insights into an emerging association. Curr Opin Endocrinol Diabetes Obes 22:1–7

    Article  Google Scholar 

  36. Saab G, Young DO, Gincherman Y, Giles K, Norwood K, Coyne DW (2007) Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract 105:c132–138

    CAS  PubMed  Google Scholar 

  37. Kumar VA, Kujubu DA, Sim JJ, Rasgon SA, Yang PS (2011) Vitamin D supplementation and recombinant human erythropoietin utilization in vitamin D-deficient hemodialysis patients. J Nephrol 24:98–105

    Article  PubMed  Google Scholar 

  38. Kiss Z, Ambrus C, Almasi C, Berta K, Deak G, Horonyi P, Kiss I, Lakatos P, Marton S, Molner MZ, Nemeth Z, Szabo A, Mucsi I (2011) Serum 25(OH)-cholecalciferol concentration is associated with hemoglobin level and erythropoietin resistance in patients on maintenance hemodialysis. Nephron Clin Pract 117:c373–378

    Article  CAS  PubMed  Google Scholar 

  39. Rianthavorn P, Boonyapapong P (2013) Ergocalciferol decreases erythropoietin resistance in children with chronic kidney disease stage 5. Pediatr Nephrol 28:1261–1266

    Article  PubMed  Google Scholar 

  40. Miskulin D, Majchrzak K, Tighiouart H, Muther RS, Kapoian T, Johnson DS, Weiner DE (2016) Ergocalciferol supplementation in hemodialysis patients with vitamin D deficiency: A randomized clinical trial. J Am Soc Nephrol 27:1801–1810

    Article  PubMed  Google Scholar 

  41. Macdougall IC, Malyszko J, Hider RC, Bansal SS (2010) Current status of the measurement of blood hepcidin levels in chronic kidney disease. Clin J Am Soc Nephrol 5:1681–1689

    Article  CAS  PubMed  Google Scholar 

  42. Cangemi G, Pistorio A, Miano M, Gattorno M, Acquila M, Bicocchi MP, Gastaldi R, Riccardi F, Gatti C, Fioredda F, Calvillo M, Melioli G, Martini A, Dufour C (2013) Diagnostic potential of hepcidin testing in pediatrics. Eur J Haematol 90:323–330

    Article  CAS  PubMed  Google Scholar 

  43. Ford BA, Eby CS, Scott MG, Coyne DW (2010) Intra-individual variability in serum hepcidin precludes its use as a marker of iron status in hemodialysis patients. Kidney Int 78:769–773

    Article  CAS  PubMed  Google Scholar 

  44. Troutt JS, Rudling M, Persson L, Stahle L, Angelin B, Butterfield AM, Schade AE, Cao G, Konrad RJ (2012) Circulating human hepcidin-25 concentrations display a diurnal rhythm, increase with prolonged fasting, and Are reduced by growth hormone administration. Clin Chem 58:1225–1232

    Article  CAS  PubMed  Google Scholar 

  45. Schaap CCM, Hendriks JCM, Kortman GAM, Klaver SM, Kroot JJC, Laarakkers CMM, Wiegerinck ET, Tjalsma H, Janssen MCH, Swinkels DW (2013) Diurnal rhythm rather than dietary iron mediates daily hepcidin variations. Clin Chem 59:527–535

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Meredith Atkinson and the D-Fense Trial were supported by the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K23-DK-084116). At the Johns Hopkins University School of Medicine, Dr. Atkinson was also supported by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of NIDDK, NCRR or NIH.

Study data were collected and managed using REDCap electronic data capture tools hosted at Johns Hopkins [Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform 42:377–381]. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trains for tracking data manipulation and export procedures; (3) automated export procedures for seamless downloads to common statistical packages; and (4) procedures for importing data from external sources.

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Authors and Affiliations

  1. Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, 200 N. Wolfe St., Baltimore, MD, 21287, USA

    Meredith A. Atkinson & Michael S. Bertenthal

  2. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Stephen P. Juraschek & Edgar R. Miller III

  3. The Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Stephen P. Juraschek & Edgar R. Miller III

  4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Barbara Detrick

  5. The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Susan L. Furth

Authors
  1. Meredith A. Atkinson
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  3. Michael S. Bertenthal
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Corresponding author

Correspondence to Meredith A. Atkinson.

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Ethics

This study was approved by the Johns Hopkins Institutional Review Boards. All participants 18 years and older provided written informed consent in adherence with the Declaration of Helsinki. For participants aged <18 years, written informed consent was provided by a parent/legal guardian.

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Atkinson, M.A., Juraschek, S.P., Bertenthal, M.S. et al. Pilot study of the effect of cholecalciferol supplementation on hepcidin in children with chronic kidney disease: Results of the D-fense Trial. Pediatr Nephrol 32, 859–868 (2017). https://doi.org/10.1007/s00467-016-3563-6

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  • DOI: https://doi.org/10.1007/s00467-016-3563-6

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