Pediatric Nephrology

, Volume 25, Issue 4, pp 659–667 | Cite as

The IGF/IGFBP system in relation to macroscopic bone architecture in pediatric renal transplant patients

  • Daniela Kiepe
  • Eva-Maria Rüth
  • Werner F. Blum
  • Subburaman Mohan
  • Lutz T. Weber
  • Burkhard Tönshoff
Original Article

Abstract

The post-transplant bone disease of the peripheral skeleton in pediatric renal transplant recipients is characterized by an inadequately thin bone cortex in relation to muscular force. A major hormonal modulator of periosteal growth is the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system. We therefore hypothesized that the reduced cortical thickness in these patients may be due to functional IGF deficiency. To test this hypothesis, we investigated 55 patients (mean estimated glomerular filtration rate 86.3 ± 30.0 ml/min/1.73 m2) in a cross-sectional study. Parameters of macroscopic bone architecture and forearm muscle size were analyzed by peripheral quantitative computed tomography (pQCT), and serum IGF/IGFBP system components were measured by specific radioimmunoassays. The mean (± standard deviation) standardized serum IGF-I (0.20 ± 1.16 score) level was normal, while the mean IGF-II (1.16 ± 0.11 score) level was significantly elevated. Serum IGFBP-1 and IGFBP-2 levels were not altered, whereas the IGFBP-3 (1.34 ± 0.15 score) level was significantly increased. The serum IGFBP-4 level was slightly elevated (by 11%), the IGFBP-6 level was markedly (2.3-fold) elevated, while the IGFBP-5 level was comparable to that of the control. The respective age-adjusted cortical thickness at both the proximal (r = 0.407, P < 0.005) and distal (r = 0.383, P < 0.01) forearm was positively correlated with the standardized serum IGF-I level. In conclusion, the serum IGF/IGFBP system in pediatric renal transplant recipients is characterized by an increase in the levels of the inhibitory IGFBPs, IGFBP-3, -4 and -6, resulting in a functional IGF deficiency. The positive correlation of IGF-I with cortical thickness underlines the importance of this hormonal system in the modeling of bone, particularly periosteal growth.

Keywords

IGF/IGFBP system Pediatric renal transplant recipients Peripheral quantitative computed tomography Post-transplant bone disease 

References

  1. 1.
    Heaf JG (2003) Bone disease after renal transplantation. Transplantation 75:315–325CrossRefPubMedGoogle Scholar
  2. 2.
    Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD (1991) Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 325:544–550PubMedGoogle Scholar
  3. 3.
    Horber FF, Casez JP, Steiger U, Czerniak A, Montandon A, Jaeger P (1994) Changes in bone mass early after kidney transplantation. J Bone Miner Res 9:1–9CrossRefPubMedGoogle Scholar
  4. 4.
    Pichette V, Bonnardeaux A, Prudhomme L, Gagné M, Cardinal J, Ouimet D (1996) Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am J Kidney Dis 28:105–114CrossRefPubMedGoogle Scholar
  5. 5.
    Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH (2000) High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 11:1093–1099PubMedGoogle Scholar
  6. 6.
    Feber J, Filler G, Cochat P (2003) Is decreased bone mineral density in pediatric transplant recipients really a problem? Pediatr Transplant 7:342–344CrossRefPubMedGoogle Scholar
  7. 7.
    Helenius I, Remes V, Salminen S, Valta H, Mäkitie O, Holmberg C, Palmu P, Tervahartiala P, Sarna S, Helenius M, Peltonen J, Jalanko H (2006) Incidence and predictors of fractures in children after solid organ transplantation: a 5-year prospective, population-based study. J Bone Miner Res 21:380–387CrossRefPubMedGoogle Scholar
  8. 8.
    Rüth EM, Weber LT, Schoenau E, Wunsch R, Seibel MJ, Feneberg R, Mehls O, Tönshoff B (2004) Analysis of the functional muscle-bone unit of the forearm in pediatric renal transplant recipients. Kidney Int 66:1694–1706CrossRefPubMedGoogle Scholar
  9. 9.
    Negri AL, Lombas C, Cuevas C, Schiavelli R, Bogado CE, Zanchetta JR (2005) Evaluation of cortical bone by peripheral quantitative computed tomography in renal transplant recipients. Transplant Proc 37:1020–1022CrossRefPubMedGoogle Scholar
  10. 10.
    Libanati C, Baylink DJ, Lois-Wenzel E, Srinvasan N, Mohan S (1999) Studies on the potential mediators of skeletal changes occurring during puberty in girls. J Clin Endocrinol Metab 84:2807–2814CrossRefPubMedGoogle Scholar
  11. 11.
    Woods KA, Camacho-Hübner C, Savage MO, Clark AJ (1996) Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335:1363–1367CrossRefPubMedGoogle Scholar
  12. 12.
    Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D (2002) Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110:771–781PubMedGoogle Scholar
  13. 13.
    Hoeflich A, Götz W, Lichanska AM, Bielohuby M, Tönshoff B, Kiepe D (2007) Effects of insulin-like growth factor binding proteins in bone – a matter of cell and site. Arch Physiol Biochem 113:142–153CrossRefPubMedGoogle Scholar
  14. 14.
    Tanner JM (1962) Growth at adolescence, 2nd edn. Blackwell, OxfordGoogle Scholar
  15. 15.
    Rauch F, Neu CM, Manz F, Schoenau E (2001) The development of metaphyseal cortex: implications for distal radius fractures during growth. J Bone Miner Res 1:1547–1555CrossRefGoogle Scholar
  16. 16.
    Neu C, Manz F, Rauch F, Schoenau E (2001) Modeling of cross-sectional bone size and geometry at the proximal radius—a study of normal bone development using peripheral quantitative computed tomography. Osteoporos Int 12:538–547CrossRefPubMedGoogle Scholar
  17. 17.
    Blum WF, Albertsson-Wikland K, Rosberg S, Ranke MB (1993) Serum levels of insulin-like growth factor I (IGF-I) and IGF binding protein 3 reflect spontaneous growth hormone secretion. J Clin Endocrinol Metab 76:1610–1606CrossRefPubMedGoogle Scholar
  18. 18.
    Blum WF, Ranke MB, Bierich JR (1988) A specific radioimmunoassay for insulin-like growth factor II: the interference of IGF binding proteins can be blocked by excess IGF-I. Acta Endocrinol (Copenh) 118:374–380Google Scholar
  19. 19.
    Breier BH, Milsom SR, Blum WF, Schwander J, Gallaher BW, Gluckman PD (1993) Insulin-like growth factors and their binding proteins in plasma and milk after growth hormone-stimulated galactopoiesis in normally lactating women. Acta Endocrinol (Copenh) 129:427–435Google Scholar
  20. 20.
    Blum WF, Horn N, Kratzsch J, Jørgensen JO, Juul A, Teale D, Mohnike K, Ranke MB (1993) Clinical studies of IGFBP-2 by radioimmunoassay. Growth Regul 3:100–104PubMedGoogle Scholar
  21. 21.
    Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR (1990) A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70:1292–1298CrossRefPubMedGoogle Scholar
  22. 22.
    Honda Y, Landale EC, Strong DD, Baylink DJ, Mohan S (1996) Recombinant synthesis of insulin-like growth factor-binding protein-4 (IGFBP-4): Development, validation, and application of a radioimmunoassay for IGFBP-4 in human serum and other biological fluids. J Clin Endocrinol Metab 81:1389–1396CrossRefPubMedGoogle Scholar
  23. 23.
    Mohan S, Libanati C, Dony C, Lang K, Srinivasan N, Baylink DJ (1995) Development, validation, and application of a radioimmunoassay for insulin-like growth factor binding protein-5 in human serum and other biological fluids. J Clin Endocrinol Metab 80:2638–2645CrossRefPubMedGoogle Scholar
  24. 24.
    Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 34:571–590PubMedGoogle Scholar
  25. 25.
    Prader A, Largo RH, Molinari L, Issler C (1989) Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development. Helv Paediatr Acta Suppl 52:1–125PubMedGoogle Scholar
  26. 26.
    Schoenau E, Neu CM, Rauch F, Manz F (2001) The development of bone strength at the proxi-mal radius during childhood and adolescence. J Clin Endocrinol Metab 86:613–618CrossRefPubMedGoogle Scholar
  27. 27.
    Schoenau E, Neu CM, Mokov E, Wassmer G, Manz F (2000) Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab 85:1095–1098CrossRefPubMedGoogle Scholar
  28. 28.
    Neu C, Manz F, Rauch F, Schoenau E (2001) Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography. Bone 28:227–232CrossRefPubMedGoogle Scholar
  29. 29.
    Blum WF (1992) Insulin-like growth factors and their binding proteins. In: Ranke MG (ed) Funtional endocrinologic diagnostics in children and adolescence. J & J Verlag, Mannheim, pp 102–117Google Scholar
  30. 30.
    Hokken-Koelega AC, Stijnen T, de Jong RC, Donckerwolcke RA, Groothoff JW, Wolff ED, Blum WF, de Muinck Keizer-Schrama SM, Drop SL (1996) A placebo-controlled, double-blind trial of growth hormone treatment in prepubertal children after renal transplant. Kidney Int Suppl 53:S128–134PubMedGoogle Scholar
  31. 31.
    Hokken-Koelega AC, Stijnen T, de Muinck Keizer-Schrama SM, Blum WF, Drop SL (1993) Levels of growth hormone, insulin-like growth factor-I (IGF-I) and -II, IGF-binding protein-1 and -3, and cortisol in prednisone-treated children with growth retardation after renal transplantation. J Clin Endocrinol Metab 77:932–938CrossRefPubMedGoogle Scholar
  32. 32.
    Tönshoff B, Haffner D, Mehls O, Dietz M, Ruder H, Blum WF, Heinrich U, Stöver B (1993) Efficacy and safety of growth hormone treatment in short children with renal allografts: three year experience. Kidney Int 44:199–207CrossRefPubMedGoogle Scholar
  33. 33.
    Tönshoff B, Kiepe D, Ciarmatori S (2005) Growth hormone/insulin-like growth factor system in children with chronic renal failure. Pediatr Nephrol 20:279–289CrossRefPubMedGoogle Scholar
  34. 34.
    Wabitsch M, Blum WF, Muche R, Heinze E, Haug C, Mayer H, Teller W (1996) Insulin-like growth factors and their binding proteins before and after weight loss and their associations with hormonal and metabolic parameters in obese adolescent girls. Int J Obes Relat Metab Disord 20:1073–1080PubMedGoogle Scholar
  35. 35.
    Bang P, Degerblad M, Thorén M, Schwander J, Blum W, Hall K (1993) Insulin-like growth factor (IGF) I and II and IGF binding protein (IGFBP) 1, 2 and 3 in serum from patients with Cushing’s syndrome. Acta Endocrinol (Copenh) 128:397–404Google Scholar
  36. 36.
    Jehle PM, Ostertag A, Schulten K, Schulz W, Jehle DR, Stracke S, Fiedler R, Deuber HJ, Keller F, Boehm BO, Baylink DJ, Mohan S (2000) Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy. Kidney Int 57:423–436CrossRefPubMedGoogle Scholar
  37. 37.
    Tönshoff B, Blum WF, Wingen AM, Mehls O (1995) Serum insulin-like growth factors (IGFs) and IGF binding proteins 1, 2, and 3 in children with chronic renal failure: relationship to height and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. J Clin Endocrinol Metab 80:2684–2691CrossRefPubMedGoogle Scholar
  38. 38.
    Van Doorn J, Cornelissen AJ, Van Buul-Offers SC (2001) Plasma levels of insulin-like growth factor binding protein-4 (IGFBP-4) under normal and pathological conditions. Clin Endocrinol (Oxf) 54:655–664CrossRefGoogle Scholar
  39. 39.
    Van Doorn J, Ringeling AM, Shmueli SS, Kuijpers MC, Hokken-Koelega AC, van Buul-Offers SC, Jansen M (1999) Circulating levels of human insulin-like growth factor binding protein-6 (IGFBP-6) in health and disease as determined by radioimmunoassay. Clin Endocrinol (Oxf) 50:601–609CrossRefGoogle Scholar
  40. 40.
    Ulinski T, Mohan S, Kiepe D, Blum WF, Wingen AM, Mehls O, Tönshoff B (2000) Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. Pediatr Nephrol 14:589–597CrossRefPubMedGoogle Scholar
  41. 41.
    Fukuda I, Hizuka N, Okubo Y, Takano K, Asakawa-Yasumoto K, Shizume K, Demura H, Kimata N, Ishikawa N, Toma H (1998) Changes in serum insulin-like growth factor binding protein-2, -3, and -6 levels in patients with chronic renal failure following renal transplantation. Growth Horm IGF Res 8:481–486CrossRefPubMedGoogle Scholar
  42. 42.
    Mohan S, Baylink DJ (2005) Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences. J Endocrinol 185:415–420CrossRefPubMedGoogle Scholar
  43. 43.
    Amaar YG, Thompson GR, Linkhart TA, Chen ST, Baylink DJ, Mohan S (2002) Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J Biol Chem 277:12053–12060CrossRefPubMedGoogle Scholar
  44. 44.
    Mohan S, Farley JR, Baylink DJ (1995) Age-related changes in IGFBP-4 and IGFBP-5 levels in human serum and bone: implications for bone loss with aging. Prog Growth Factor Res 6:465–473CrossRefPubMedGoogle Scholar
  45. 45.
    Nicolas V, Mohan S, Honda Y, Prewett A, Finkelman RD, Baylink DJ, Farley JR (1995) An age-related decrease in the concentration of insulin-like growth factor binding protein-5 in human cortical bone. Calcif Tissue Int 57:206–212CrossRefPubMedGoogle Scholar
  46. 46.
    Miyakoshi N, Richman C, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S (2001) Evidence that IGF-binding protein-5 functions as a growth factor. J Clin Invest 107:73–81CrossRefPubMedGoogle Scholar
  47. 47.
    Kiepe D, Andress DL, Mohan S, Ständker L, Ulinski T, Himmele R, Mehls O, Tönshoff B (2001) Intact IGF-binding protein-4 and -5 and their respective fragments isolated from chronic renal failure serum differentially modulate IGF-I actions in cultured growth plate chondrocytes. J Am Soc Nephrol 12:2400–2410PubMedGoogle Scholar

Copyright information

© IPNA 2009

Authors and Affiliations

  • Daniela Kiepe
    • 1
  • Eva-Maria Rüth
    • 1
    • 2
  • Werner F. Blum
    • 3
  • Subburaman Mohan
    • 4
  • Lutz T. Weber
    • 1
    • 5
  • Burkhard Tönshoff
    • 1
  1. 1.University Children’s HospitalHeidelbergGermany
  2. 2.Department of Pediatric NephrologyUniversity Hospital ErlangenErlangenGermany
  3. 3.Lilly Research LaboratoriesEli Lilly & Co.Bad HomburgGermany
  4. 4.Musculoskeletal Disease CenterJerry L Pettis Memorial Veterans Affairs Medical CenterLoma LindaUSA
  5. 5.Pediatric Nephrology, Dr. von Haunersches Kinderspital, University Children’s Hospital Ludwig-Maximilian’s UniversityMunichGermany

Personalised recommendations