Skip to main content

Advertisement

SpringerLink
Log in

Pubertal development in children with chronic kidney disease

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Impairment of pubertal growth and sexual maturation resulting in reduced adult height is an significant complication in children suffering from chronic kidney disease (CKD). Delayed puberty and reduced pubertal growth are most pronounced in children with pre-existing severe stunting before puberty, requiring long-term dialysis treatment, and in transplanted children with poor graft function and high glucocorticoid exposure. In pre-dialysis patients, therapeutic measures to improve pubertal growth are limited and mainly based on the preservation of renal function and the use of growth hormone treatment. In patients with end-stage CKD, early kidney transplantation with steroid withdrawal within 6 months of renal transplantation allows for normal pubertal development in the majority of patients. This review focuses on the underlying pathophysiology and strategies for improving height and development in these patients.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Franke D, Winkel S, Gellermann J, Querfeld U, Pape L, Ehrich JH, Haffner D, Pavičić L, Zivičnjak M (2013) Growth and maturation improvement in children on renal replacement therapy over the past 20 years. Pediatr Nephrol 28:2043–2051

    Article  PubMed  Google Scholar 

  2. Harambat J, Bonthuis M, van Stralen KJ, Ariceta G, Battelino N, Bjerre A, Jahnukainen T, Leroy V, Reusz G, Sandes AR, Sinha MD, Groothoff JW, Combe C, Jager KJ, Verrina E, Schaefer F (2014) Adult height in patients with advanced CKD requiring renal replacement therapy during childhood. Clin J Am Soc Nephrol 9:92–99

    Article  PubMed  Google Scholar 

  3. Fine RN, Martz K, Stablein D (2010) What have 20 years of data from the North American Pediatric Renal Transplant Cooperative Study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease? Pediatr Nephrol 25:739–746

    Article  PubMed  Google Scholar 

  4. Klare B, Montoya CR, Fischer DC, Stangl MJ, Haffner D (2012) Normal adult height after steroid-withdrawal within 6 months of pediatric kidney transplantation: a 20 years single center experience. Transpl Int 25:276–282

    Article  CAS  PubMed  Google Scholar 

  5. Furth SL, Stablein D, Fine RN, Powe NR, Fivush BA (2002) Adverse clinical outcomes associated with short stature at dialysis initiation: a report of the North American Pediatric Renal Transplant Cooperative Study . Pediatrics 109:909–913

    Article  PubMed  Google Scholar 

  6. Hartung EA, Furth SL (2013) Growth in children on renal replacement therapy: a shrinking problem? Pediatr Nephrol 28:1905–1908

    Article  PubMed  PubMed Central  Google Scholar 

  7. Haffner D, Fischer DC (2012) Growth and pubertal development in dialyzed children and adolescents. In: Warady BA, Schaefer F, Alexander SR (eds) Pediatric dialysis, 2nd edn. Springer, New York, pp 453–481

    Chapter  Google Scholar 

  8. Schaefer F, Seidel C, Binding A, Gasser T, Largo RH, Prader A, Schärer K (1990) Pubertal growth in chronic renal failure. Pediatr Res 28:5–10

    Article  CAS  PubMed  Google Scholar 

  9. Nissel R, Brázda I, Feneberg R, Wigger M, Greiner C, Querfeld U, Haffner D (2004) Effect of renal transplantation in childhood on longitudinal growth and adult height. Kidney Int 66:792–800

    Article  PubMed  Google Scholar 

  10. Rizzoni G, Broyer M, Brunner FP, Brynger H, Challah S, Kramer P, Oulès R, Selwood NH, Wing AJ, Balás EA (1985) Combined report on regular dialysis and transplantation of children in Europe, XIII, 1983. Proc Eur Dial Transplant Assoc Eur Ren Assoc 21:66–95

    CAS  PubMed  Google Scholar 

  11. Burke BA, Lindgren B, Wick M, Holley K, Manivel C (1989) Testicular germ cell loss in children with renal failure. Pediatr Pathol 9:433–444

    Article  CAS  PubMed  Google Scholar 

  12. Tainio J, Qvist E, Vehmas R, Jahnukainen K, Hölttä T, Valta H, Jahnukainen T, Jalanko H (2011) Pubertal development is normal in adolescents after renal transplantation in childhood. Transplantation 92:404–409

    Article  PubMed  Google Scholar 

  13. Förster J, Ahlenstiel-Grunow T, Zapf A, Mynarek M, Pape L (2016) Pubertal development in pediatric kidney transplant patients receiving mammalian target of rapamycin inhibitors or conventional immunosuppression. Transplantation. doi:10.1097/TP.0000000000001037

    PubMed  Google Scholar 

  14. Zivicnjak M, Franke D, Ehrich JH, Filler G (2000) Does growth hormone therapy harmonize distorted morphology and body composition in chronic renal failure? Pediatr Nephrol 15:229–235

    Article  CAS  PubMed  Google Scholar 

  15. Zivicnjak M, Franke D, Filler G, Haffner D, Froede K, Nissel R, Haase S, Offner G, Ehrich JH, Querfeld U (2007) Growth impairment shows an age-dependent pattern in boys with chronic kidney disease. Pediatr Nephrol 22:420–429

    Article  PubMed  Google Scholar 

  16. Franke D, Thomas L, Steffens R, Pavičić L, Gellermann J, Froede K, Querfeld U, Haffner D, Živičnjak M (2015) Patterns of growth after kidney transplantation among children with ESRD. Clin J Am Soc Nephrol 10:127–134

    Article  CAS  PubMed  Google Scholar 

  17. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O (2000) Effect of growth hormone treatment on the adult height of children with chronic renal failure. German study group for growth hormone treatment in chronic renal failure. N Engl J Med 343:923–930

    Article  CAS  PubMed  Google Scholar 

  18. Nissel R, Lindberg A, Mehls O, Haffner D, Pfizer International Growth Database (KIGS) International Board (2008) Factors predicting the near-final height in growth hormone-treated children and adolescents with chronic kidney disease. J Clin Endocrinol Metab 93:1359–1365

    Article  CAS  PubMed  Google Scholar 

  19. Nissel R, Latta K, Gagnadoux MF, Kelly D, Hulton S, Kemper MJ, Ruder H, Söderdahl G, Otte JB, Cochat P, Roquet O, Jamieson NV, Haffner D (2006) Body growth after combined liver-kidney transplantation in children with primary hyperoxaluria type 1. Transplantation 82:48–54

    Article  PubMed  Google Scholar 

  20. Rees L, Greene SA, Adlard P, Jones J, Haycock GB, Rigden SP, Preece M, Chantler C (1988) Growth and endocrine function in steroid sensitive nephrotic syndrome. Arch Dis Child 63:484–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Haffner D, Weinfurth A, Manz F, Schmidt H, Bremer HJ, Mehls O, Schärer K (1999) Long-term outcome of paediatric patients with hereditary tubular disorders. Nephron 83:250–260

    Article  CAS  PubMed  Google Scholar 

  22. Greco M, Brugnara M, Zaffanello M, Taranta A, Pastore A, Emma F (2010) Long-term outcome of nephropathic cystinosis: a 20-year single-center experience. Pediatr Nephrol 25:2459–2467

    Article  PubMed  Google Scholar 

  23. Seikaly MG, Salhab N, Gipson D, Yiu V, Stablein D (2006) Stature in children with chronic kidney disease: analysis of NAPRTCS database. Pediatr Nephrol 21:793–799

    Article  PubMed  Google Scholar 

  24. United States Renal Data System (USRDS) 2008 report. USRDS Coordinating Center, Minneapolis, pp 296–297. http://www.usrds.org/adr.aspx

  25. Mak RH, Cheung WW, Zhan JY, Shen Q, Foster BJ (2012) Cachexia and protein-energy wasting in children with chronic kidney disease. Pediatr Nephrol 27:173–181

    Article  PubMed  Google Scholar 

  26. Bonthuis M, van Stralen KJ, Verrina E, Groothoff JW, Alonso Melgar Á, Edefonti A, Fischbach M, Mendes P, Molchanova EA, Paripović D, Peco-Antic A, Printza N, Rees L, Rubik J, Stefanidis CJ, Sinha MD, Zagożdżon I, Jager KJ, Schaefer F (2013) Underweight, overweight and obesity in paediatric dialysis and renal transplant patients. Nephrol Dial Transplant 28 [Suppl 4]:v195–iv204

    Article  Google Scholar 

  27. Vester U, Schaefer A, Kranz B, Wingen AM, Nadalin S, Paul A, Malagò M, Broelsch CE, Hoyer PF (2005) Development of growth and body mass index after pediatric renal transplantation. Pediatr Transplant 9:445–449

    Article  PubMed  Google Scholar 

  28. Brungger M, Hulter HN, Krapf R (1997) Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: new cause of growth hormone insensitivity in humans. Kidney Int 51:216–221

    Article  CAS  PubMed  Google Scholar 

  29. Parekh RS, Flynn JT, Smoyer WE, Milne JL, Kershaw DB, Bunchman TE, Sedman AB (2001) Improved growth in young children with severe chronic renal insufficiency who use specified nutritional therapy. J Am Soc Nephrol 12:2418–2426

    CAS  PubMed  Google Scholar 

  30. Haffner D, Fischer DC (2010) Bone cell biology and pediatric renal osteodystrophy. Minerva Pediatr 62:273–284

    CAS  PubMed  Google Scholar 

  31. Chesney RW, Moorthy AV, Eisman JA, Jax DK, Mazess RB, DeLuca HF (1978) Increased growth after long-term oral 1,25-vitamin D3 in childhood renal osteodystrophy. N Engl J Med 298:238–242

    Article  CAS  PubMed  Google Scholar 

  32. Chan JC, Kodroff MB, Landwehr DM (1981) Effects of 1,25-dihydroxyvitamin-D3 on renal function, mineral balance, and growth in children with severe chronic renal failure. Pediatrics 68:559–571

    CAS  PubMed  Google Scholar 

  33. Jabs K (1996) The effects of recombinant human erythropoietin on growth and nutritional status. Pediatr Nephrol 10:324–327

    Article  CAS  PubMed  Google Scholar 

  34. Schaefer F, Seidel C, Mitchell R, Scharer K, Robertson WR (1991) Pulsatile immunoreactive and bioactive luteinizing hormone secretion in adolescents with chronic renal failure. the cooperative study group on pubertal development in chronic renal failure (CSPCRF). Pediatr Nephrol 5:566–571

    Article  CAS  PubMed  Google Scholar 

  35. Schaefer F, Veldhuis JD, Robertson WR, Dunger D, Scharer K (1994) Immunoreactive and bioactive luteinizing hormone in pubertal patients with chronic renal failure. cooperative study group on pubertal development in chronic renal failure. Kidney Int 45:1465–1476

    Article  CAS  PubMed  Google Scholar 

  36. Schaefer F, Daschner M, Veldhuis JD, Oh J, Qadri F, Scharer K (1994) In vivo alterations in the gonadotropin-releasing hormone pulse generator and the secretion and clearance of luteinizing hormone in the uremic castrate rat. Neuroendocrinology 59:285–296

    Article  CAS  PubMed  Google Scholar 

  37. Daschner M, Philippin B, Nguyen T, Wiesner RJ, Walz C, Oh J, Sandow J, Mehls O, Schaefer F (2002) Circulating inhibitor of gonadotropin releasing hormone secretion by hypothalamic neurons in uremia. Kidney Int 62:1582–1590

    Article  CAS  PubMed  Google Scholar 

  38. Schaefer F, Vogel M, Kerkhoff G, Woitzik J, Daschner M, Mehls O (2001) Experimental uremia affects hypothalamic amino acid neurotransmitter milieu. J Am Soc Nephrol 12:1218–1227

    CAS  PubMed  Google Scholar 

  39. Mitchell R, Bauerfeld C, Schaefer F, Scharer K, Robertson WR (1994) Less acidic forms of luteinizing hormone are associated with lower testosterone secretion in men on haemodialysis treatment. Clin Endocrinol 41:65–73

    Article  CAS  Google Scholar 

  40. Blum WF, Ranke MB, Kietzmann K, Tonshoff B, Mehls O (1991) Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia. Pediatr Nephrol 5:539–544

    Article  CAS  PubMed  Google Scholar 

  41. Haffner D, Schaefer F, Girard J, Ritz E, Mehls O (1994) Metabolic clearance of recombinant human growth hormone in health and chronic renal failure. J Clin Invest 93:1163–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tonshoff B, Veldhuis JD, Heinrich U, Mehls O (1995) Deconvolution analysis of spontaneous nocturnal growth hormone secretion in prepubertal children with preterminal chronic renal failure and with end-stage renal disease. Pediatr Res 37:86–93

    Article  CAS  PubMed  Google Scholar 

  43. Schaefer F, Veldhuis JD, Stanhope R, Jones J, Scharer K (1994) Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative study group of pubertal development in chronic renal failure. J Clin Endocrinol Metab 78:1298–1306

    CAS  PubMed  Google Scholar 

  44. Challa A, Chan W, Krieg RJ Jr, Thabet MA, Liu F, Hintz RL, Chan JC (1993) Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor. Kidney Int 44:1224–1227

    Article  CAS  PubMed  Google Scholar 

  45. Rabkin R, Sun DF, Chen Y, Tan J, Schaefer F (2005) Growth hormone resistance in uremia, a role for impaired JAK/STAT signaling. Pediatr Nephrol 20:313–318

    Article  PubMed  Google Scholar 

  46. Farquharson C, Ahmed SF (2013) Inflammation and linear bone growth: the inhibitory role of SOCS2 on GH/IGF-1 signaling. Pediatr Nephrol 28:547–556

    Article  PubMed  Google Scholar 

  47. Tonshoff B, Kiepe D, Ciarmatori S (2005) Growth hormone/insulin-like growth factor system in children with chronic renal failure. Pediatr Nephrol 20:279–289

    Article  PubMed  Google Scholar 

  48. Schaefer F, Hamill G, Stanhope R, Preece MA, Scharer K (1991) Pulsatile growth hormone secretion in peripubertal patients with chronic renal failure. Cooperative study group on pubertal development in chronic renal failure. J Pediatr 119:568–577

    Article  CAS  PubMed  Google Scholar 

  49. Olney RC (2009) Mechanisms of impaired growth: effect of steroids on bone and cartilage. Horm Res 72 [Suppl 1]:30–35

    Article  CAS  PubMed  Google Scholar 

  50. Neu AM, Bedinger M, Fivush BA, Warady BA, Watkins SL, Friedman AL, Brem AS, Goldstein SL, Frankenfield DL (2005) Growth in adolescent hemodialysis patients: data from the Centers for Medicare & Medicaid Services ESRD Clinical Performance Measures Project. Pediatr Nephrol 20:1156–1160

    Article  PubMed  Google Scholar 

  51. Katz A, Bock GH, Mauer M (2000) Improved growth velocity with intensive dialysis. Consequence or coincidence? Pediatr Nephrol 14:710–712

    Article  CAS  PubMed  Google Scholar 

  52. Fischbach M, Terzic J, Menouer S, Dheu C, Seuge L, Zalosczic A (2010) Daily on line haemodiafiltration promotes catch-up growth in children on chronic dialysis. Nephrol Dial Transplant 25:867–873

    Article  CAS  PubMed  Google Scholar 

  53. Hoppe A, von Puttkamer C, Linke U, Kahler C, Booss M, Braunauer-Kolberg R, Hofmann K, Joachimsky P, Hirte I, Schley S, Utsch B, Thumfart J, Briese S, Gellermann J, Zimmering M, Querfeld U, Müller D (2011) A hospital-based intermittent nocturnal hemodialysis program for children and adolescents. J Pediatr 158:95–99

    Article  PubMed  Google Scholar 

  54. Pape L, Ehrich JH, Zivicnjak M, Offner G (2005) Growth in children after kidney transplantation with living related donor graft or cadaveric graft. Lancet 366:151–153

    Article  CAS  PubMed  Google Scholar 

  55. Höcker B, Weber LT, Feneberg R, Drube J, John U, Fehrenbach H, Pohl M, Zimmering M, Fründ S, Klaus G, Wühl E, Tönshoff B (2010) Improved growth and cardiovascular risk after late steroid withdrawal: 2-year results of a prospective, randomised trial in paediatric renal transplantation. Nephrol Dial Transplant 25:617–624

    Article  PubMed  Google Scholar 

  56. Webb NJ, Douglas SE, Rajai A, Roberts SA, Grenda R, Marks SD, Watson AR, Fitzpatrick M, Vondrak K, Maxwell H, Jaray J, Van Damme-Lombaerts R, Milford DV, Godefroid N, Cochat P, Ognjanovic M, Murer L, McCulloch M, Tönshoff B (2015) Corticosteroid-free kidney transplantation improves growth: 2-year follow-up of the TWIST randomized controlled trial. Transplantation 99:1178–1185

    Article  CAS  PubMed  Google Scholar 

  57. Sarwal MM, Ettenger RB, Dharnidharka V, Benfield M, Mathias R, Portale A, McDonald R, Harmon W, Kershaw D, Vehaskari VM, Kamil E, Baluarte HJ, Warady B, Tang L, Liu J, Li L, Naesens M, Sigdel T, Waskerwitz J, Salvatierra O (2012) Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up. Am J Transplant 12:2719–2729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Billing H, Burmeister G, Plotnicki L, Ahlenstiel T, Fichtner A, Sander A, Höcker B, Tönshoff B, Pape L (2013) Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients. Transpl Int 26:903–909

    Article  CAS  PubMed  Google Scholar 

  59. Kassmann K, Rappaport R, Broyer M (1992) The short-term effect of testosterone on growth in boys with hemodialysis. Clin Nephrol 37:148–154

    CAS  PubMed  Google Scholar 

  60. Van Steenbergen MW, Wit JM, Donckerwolcke RAMG (1991) Testosterone esters advance skeletal maturation more than growth in short boys with chronic renal failure and delayed puberty. Eur J Pediatr 150:676–780

  61. Haffner D, Schaefer F (2013) Searching the optimal PTH target range in children undergoing peritoneal dialysis: new insights from international cohort studies. Pediatr Nephrol 28:537–545

    Article  PubMed  Google Scholar 

  62. Muscheites J, Wigger M, Drueckler E, Fischer DC, Kundt G, Haffner D (2008) Cinacalcet for secondary hyperparathyroidism in children with end-stage renal disease. Pediatr Nephrol 23:1823–1829

    Article  PubMed  Google Scholar 

  63. Nakagawa K, Pérez EC, Oh J, Santos F, Geldyyev A, Gross ML, Schaefer F, Schmitt CP (2008) Cinacalcet does not affect longitudinal growth but increases body weight gain in experimental uraemia. Nephrol Dial Transplant 23:2761–2767

    Article  CAS  PubMed  Google Scholar 

  64. Mehls O, Ritz E, Hunziker EB, Eggli P, Heinrich U, Zapf J (1988) Improvement of growth and food utilization by human recombinant growth hormone in uremia. Kidney Int 33:45–52

    Article  CAS  PubMed  Google Scholar 

  65. Powell DR, Durham SK, Liu F, Baker BK, Lee PD, Watkins SL, Campbell PG, Brewer ED, Hintz RL, Hogg RJ (1998) The insulin-like growth factor axis and growth in children with chronic renal failure: a report of the southwest pediatric nephrology study group. J Clin Endocrinol Metab 83:1654–1661

    CAS  PubMed  Google Scholar 

  66. Rees L (2015) Growth hormone therapy in children with CKD after more than two decades of practice. Pediatr Nephrol. doi:10.1007/s00467-015-3179-2

    Google Scholar 

  67. Hokken-Koelega A, Mulder P, De Jong R, Lilien M, Donckerwolcke R, Groothof J (2000) Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency. Pediatr Nephrol 14:701–706

    Article  CAS  PubMed  Google Scholar 

  68. Haffner D, Wühl E, Schaefer F, Nissel R, Tonshoff B, Mehls O (1998) Factors predictive of the short- and long-term efficacy of growth hormone treatment in prepubertal children with chronic renal failure. The German Study Group for Growth Hormone Treatment in Chronic Renal Failure. J Am Soc Nephrol 9:1899–1907

    CAS  PubMed  Google Scholar 

  69. Kovács GT, Oh J, Kovács J, Tönshoff B, Hunziker EB, Zapf J, Mehls O (1996) Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia. Kidney Int 49:1413–1421

    Article  PubMed  Google Scholar 

  70. Mauras N, Gonzalez de Pijem L, Hsiang HY, Desrosiers P, Rapaport R, Schwartz ID, Klein KO, Singh RJ, Miyamoto A, Bishop K (2008) Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 93:823–831

    Article  CAS  PubMed  Google Scholar 

  71. Mendly SR, Spyropoulos F, Counts DR (2015) Short stature in chronic kidney disease treated with growth hormone and an aromatase inhibitor. Case Rep Pediatr 2015:738571

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Dieter Haffner & Miroslav Zivicnjak

Authors
  1. Dieter Haffner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miroslav Zivicnjak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dieter Haffner.

Ethics declarations

Conflicts of interest

None declared.

Additional information

Answers

1. d

2. c

3. d

4. b

5. b

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haffner, D., Zivicnjak, M. Pubertal development in children with chronic kidney disease. Pediatr Nephrol 32, 949–964 (2017). https://doi.org/10.1007/s00467-016-3432-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-016-3432-3

Keywords

Search

Navigation