Skip to main content

Advertisement

SpringerLink
Log in

Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Elevated fibroblast growth factor 23 (FGF-23) concentrations associate with left ventricular hypertrophy (LVH) and adverse outcomes in adult patients with chronic kidney disease. We hypothesized that similar associations are present in pediatric patients on maintenance hemodialysis.

Methods

In this retrospective study of 26 young patients on chronic hemodialysis, aged 6–21 years, cardiac structure and geometry were measured by echocardiography, and circulating levels of FGF-23 and calciotropic hormones were obtained.

Results

FGF-23 levels were uniformly elevated in all patients from three- to 835-fold above the upper limit of normal. The average LV mass index (LVMI) was 43 ± 13 g/m2.7 and reflected LVH in 55 % of patients. Log-transformed FGF-23 concentrations correlated with LVMI (p = 0.03) and were independently associated with the interventricular septal thickness Z-score (p < 0.001). Concentric LVH was associated with the highest FGF-23 concentrations and the highest LVMI measurements (p < 0.001). Each 1 standard deviation increase in log-transformed FGF-23 levels was associated with a 17 % increase in LVMI.

Conclusions

FGF-23 levels are strongly associated with increased LVMI and with prevalent LVH in pediatric hemodialysis patients. Our cross-sectional findings provide observational evidence supporting the hypothesis linking FGF-23 to cardiac hypertrophy in patients with chronic kidney disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Foley RN, Parfrey PS, Sarnak MJ (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32[Suppl]:S112–119

    Article  PubMed  CAS  Google Scholar 

  2. United States Renal Data System (1998) USRDS: causes of death. Am J Kidney Dis 32[Suppl]:S81–88

    Google Scholar 

  3. Mitsnefes MM, Barletta GM, Dresner IG, Chand DH, Geary D, Lin JJ, Patel H (2006) Severe cardiac hypertrophy and long-term dialysis: the Midwest pediatric nephrology consortium study. Pediatr Nephrol 21:1167–1170

    Article  PubMed  Google Scholar 

  4. Gruppen MP, Groothoff JW, Prins M, van-der-Wouw P, Offringa M, Bos WJ, Davin JC, Heymans HS (2003) Cardiac disease in young adult patients with end-stage renal disease since childhood: a Dutch cohort study. Kidney Int 63:1058–1065

    Article  PubMed  Google Scholar 

  5. Kopple JD (2005) The phenomenon of altered risk factor patterns or reverse epidemiology in persons with advanced chronic kidney failure. Am J Clin Nutr 81:1257–1266

    PubMed  CAS  Google Scholar 

  6. Pilz S, Tomaschitz A, Drechsler C, de Boer RA (2011) Vitamin D and heart disease. Kidney Int 1[Suppl]:S111–115

    Google Scholar 

  7. Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T, Yamashita T, Fukumoto S, Shimada T (2011) Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int 78:975–980

    Article  Google Scholar 

  8. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359:584–592

    Article  PubMed  CAS  Google Scholar 

  9. Wesseling-Perry K, Pereira RC, Wang H, Elashoff RM, Sahney S, Gales B, Juppner H, Salusky IB (2009) Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis. J Clin Endocrinol Metab 94:511–517

    Article  PubMed  CAS  Google Scholar 

  10. Hsu HJ, Wu MS (2009) Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci 337:116–122

    Article  PubMed  Google Scholar 

  11. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christenson R, Wang TJ, de Filippi C, Wolf M (2009) Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119:2545–2552

    Article  PubMed  CAS  Google Scholar 

  12. Foundation NK (2006) K/DOQI clinical practice guidelines for hemodialysis adequacy, update 2006. Am J Kidney Dis 48[Suppl]:S13–77

    Google Scholar 

  13. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group (2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl:S1-130

  14. Center of Disease Control and Prevention (2011) CDC Growth Chart. Available at: http://wwwcdcgov/growthcharts/clinical_chartshtm. Accessed 15 Dec 2011

  15. Barlow SE (2007) Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 120(Suppl):S164–192

    Article  PubMed  Google Scholar 

  16. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576

    Article  Google Scholar 

  17. Foundation NK (2008) K/DOQI clinical practice guidelines for nutrition in children with CKD: update 2008. Am J Kidney Dis 53(Suppl):S61–69

    Google Scholar 

  18. Seeherunvong W, Abitbol CL, Chandar J, Zilleruelo G, Freundlich M (2009) Vitamin D insufficiency and deficiency in children with early chronic kidney disease. J Pediatr 154:906–911

    Article  PubMed  CAS  Google Scholar 

  19. Chien KR, Knowlton KU, Zhu H, Chien S (1991) Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J 5:3037–3046

    PubMed  CAS  Google Scholar 

  20. Shimada T, Urakawa I, Isakova T, Yamazaki Y, Epstein M, Wesseling-Perry K, Wolf M, Salusky IB, Juppner H (2010) Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. J Clin Endocrinol Metab 95:578–585

    Article  PubMed  CAS  Google Scholar 

  21. Colan SD, Parness IA, Spevak PJ, Sanders SP (1992) Developmental modulation of myocardial mechanics: age- and growth-related alterations in afterload and contractility. J Am Coll Cardiol 19:619–629

    Article  PubMed  CAS  Google Scholar 

  22. Sluysmans T, Colan SD (2005) Theoretical and empirical derivation of cardiovascular allometric relationships in children. J Appl Physiol 99:445–457

    Article  PubMed  Google Scholar 

  23. Daniels SR, Kimball TR, Morrison JA, Khoury P, Meyer RA (1995) Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease. Am J Cardiol 76:699–701

    Article  PubMed  CAS  Google Scholar 

  24. Khoury PR, Mitsnefes M, Daniels SR, Kimball TR (2009) Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr 22:709–714

    Article  PubMed  Google Scholar 

  25. Bakkaloglu SA, Borzych D, Soo Ha I, Serdaroglu E, Buscher R, Salas P, Patel H, Drozdz D, Vondrak K, Watanabe A, Villagra J, Yavascan O, Valenzuela M, Gipson D, Ng KH, Warady BA, Schaefer F (2011) Cardiac geometry in children receiving chronic peritoneal dialysis: findings from the International Pediatric Peritoneal Dialysis Network (IPPN) registry. Clin J Am Soc Nephrol 6:1926–1933

    Article  PubMed  Google Scholar 

  26. de Simone G, Daniels SR, Kimball TR, Roman MJ, Romano C, Chinali M, Galderisi M, Devereux RB (2005) Evaluation of concentric left ventricular geometry in humans: evidence for age-related systematic underestimation. Hypertension 45:64–68

    PubMed  Google Scholar 

  27. Mitsnefes MM, Kimball TR, Kartal J, Witt SA, Glascock BJ, Khoury PR, Daniels SR (2006) Progression of left ventricular hypertrophy in children with early chronic kidney disease: 2-year follow-up study. J Pediatr 149:671–675

    Article  PubMed  Google Scholar 

  28. London GM (2003) Cardiovascular disease in chronic renal failure: pathophysiologic aspects. Semin Dial 16:85–94

    Article  PubMed  Google Scholar 

  29. Parekh RS, Carroll CE, Wolfe RA, Port FK (2002) Cardiovascular mortality in children and young adults with end-stage kidney disease. J Pediatr 141:191–197

    Article  PubMed  CAS  Google Scholar 

  30. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 322:1561–1566

    Article  PubMed  CAS  Google Scholar 

  31. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, Barre PE (1995) Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 47:186–192

    Article  PubMed  CAS  Google Scholar 

  32. Mitsnefes MM, Daniels SR, Schwartz SM, Meyer RA, Khoury P, Strife CF (2000) Severe left ventricular hypertrophy in pediatric dialysis: prevalence and predictors. Pediatr Nephrol 14:898–902

    Article  PubMed  CAS  Google Scholar 

  33. Borzych D, Bakkaloglu SA, Zaritsky J, Suarez A, Wong W, Ranchin B, Qi C, Szabo AJ, Coccia PA, Harambat J, Mitu F, Warady BA, Schaefer F (2011) Defining left ventricular hypertrophy in children on peritoneal dialysis. Clin J Am Soc Nephrol 6:1934–1943

    Article  PubMed  Google Scholar 

  34. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutierrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M (2011) Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305:2432–2439

    Article  PubMed  CAS  Google Scholar 

  35. Kirkpantur A, Balci M, Gurbuz OA, Afsar B, Canbakan B, Akdemir R, Ayli MD (2011) Serum fibroblast growth factor-23 (FGF-23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrol Dial Transplant 26:1346–1354

    Article  PubMed  CAS  Google Scholar 

  36. Hughes SE (1997) Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. J Histochem Cytochem 45:1005–1019

    Article  PubMed  CAS  Google Scholar 

  37. Liu L, Pasumarthi KB, Padua RR, Massaeli H, Fandrich RR, Pierce GN, Cattini PA, Kardami E (1995) Adult cardiomyocytes express functional high-affinity receptors for basic fibroblast growth factor. Am J Physiol 268:H1927–1938

    PubMed  CAS  Google Scholar 

  38. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro OM, Kusek JW, Keane MG, Wolf M (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393–4408

    Article  PubMed  CAS  Google Scholar 

  39. London GM (2002) Left ventricular alterations and end-stage renal disease. Nephrol Dial Transplant 17[Suppl]:29–36

    Article  PubMed  Google Scholar 

  40. Booth J, Pinney J, Davenport A (2011) N-terminal proBNP–marker of cardiac dysfunction, fluid overload, or malnutrition in hemodialysis patients? Clin J Am Soc Nephrol 5:1036–1040

    Article  Google Scholar 

  41. Shroff R, Weaver DJ Jr, Mitsnefes MM (2011) Cardiovascular complications in children with chronic kidney disease. Nat Rev Nephrol 7:642–649

    Article  PubMed  CAS  Google Scholar 

  42. Mitsnefes MM, Kimball TR, Kartal J, Witt SA, Glascock BJ, Khoury PR, Daniels SR (2005) Cardiac and vascular adaptation in pediatric patients with chronic kidney disease: role of calcium-phosphorus metabolism. J Am Soc Nephrol 16:2796–2803

    Article  PubMed  CAS  Google Scholar 

  43. Achinger SG, Ayus JC (2006) Left ventricular hypertrophy: is hyperphosphatemia among dialysis patients a risk factor? J Am Soc Nephrol 17:S255–261

    Article  PubMed  CAS  Google Scholar 

  44. Razzaque MS (2009) The FGF23-klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 5:611–619

    Article  PubMed  CAS  Google Scholar 

  45. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Juppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16:2205–2215

    Article  PubMed  CAS  Google Scholar 

  46. Srivaths PR, Goldstein SL, Silverstein DM, Krishnamurthy R, Brewer ED (2011) Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients. Pediatr Nephrol 26:945–951

    Article  PubMed  Google Scholar 

  47. van Husen M, Fischer AK, Lehnhardt A, Klaassen I, Moller K, Muller-Wiefel DE, Kemper MJ (2011) Fibroblast growth factor 23 and bone metabolism in children with chronic kidney disease. Kidney Int 78:200–206

    Article  Google Scholar 

  48. Mizobuchi M, Nakamura H, Tokumoto M, Finch J, Morrissey J, Liapis H, Slatopolsky E (2011) Myocardial effects of VDR activators in renal failure. J Steroid Biochem Mol Biol 121:188–192

    Article  Google Scholar 

  49. Freundlich M, Quiroz Y, Zhang Z, Zhang Y, Bravo Y, Weisinger JR, Li YC, Rodriguez-Iturbe B (2008) Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int 74:1394–1402

    Article  PubMed  CAS  Google Scholar 

  50. Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, Rigor DL, Stillman I, Tamez H, Kroeger PE, Wu-Wong RR, Karumanchi SA, Thadhani R, Kang PM (2007) Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci USA 104:16810–16815

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a grant from the Children’s Medical Services of the State of Florida. We thank Dr. Myles Wolf (University of Miami) for constructive discussions and valuable suggestions for the statistical analysis. The expertise and patient care shown by the nursing staff of the Pediatric Dialysis Unit at Holtz Children’s Hospital are greatly appreciated.

Author information

Authors and Affiliations

  1. Division of Pediatric Nephrology, University of Miami Miller School of Medicine and Holtz Children’s Hospital/Jackson Memorial Medical Center, PO Box 016960 (M-714), Miami, FL, 33101, USA

    Wacharee Seeherunvong, Carolyn L. Abitbol, Jayanthi Chandar & Gaston E. Zilleruelo

  2. Division of Pediatric Cardiology, University of Miami Miller School of Medicine and Holtz Children’s Hospital/Jackson Memorial Medical Center, Miami, FL, USA

    Paolo Rusconi

  3. Division of Pediatric Nephrology, University of Miami Miller School of Medicine, PO Box 016960 (M-714), Miami, FL, 33101, USA

    Michael Freundlich

Authors
  1. Wacharee Seeherunvong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carolyn L. Abitbol
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jayanthi Chandar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Rusconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gaston E. Zilleruelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Freundlich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Freundlich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seeherunvong, W., Abitbol, C.L., Chandar, J. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. Pediatr Nephrol 27, 2129–2136 (2012). https://doi.org/10.1007/s00467-012-2224-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-012-2224-7

Keywords

Search

Navigation