Skip to main content
Log in

Neuroendocrine adaptations in renal disease

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

Abstract

Chronic renal failure (CRF) disrupts the time-dependent secretion of multiple hormones. The present review focuses on altered pulsatile release of peptide hormones. CRF is marked by impaired tissue actions, disorderly release patterns, and relative [growth hormone (GH)] or absolute [luteinizing hormone (LH)] deficiency of secretion. At the hypothalamo-pituitary level, experimental evidence suggests that CRF reduces the synthesis and/or release of the cognate hypothalamic releasing factors, GHRH and LHRH, and enforces excessive inhibition by somatostatin. Parathyroid hormone (PTH) and insulin are secreted in both basal and pulsatile modes, wherein the latter is putatively coordinated by autonomic innervation. Amplitude and frequency-dependent adaptations of PTH and insulin outflow fail in CRF, as assessed under steady-state conditions and during metabolic drive (i.e., calcium for PTH and glucose for insulin). A common feature in CRF is a diminished mass of hormone released per burst, due in principle to attenuation of feedforward signals and/or accentuation of (unknown) feedback signals. Damping of neuronal control and/or prolonged network response times may contribute to aberrant pulse frequency, disproportionate basal (nonpulsatile) hormone release, and consistent erosion of secretory process regularity in the uremic state. The homeostatic consequences of distorted secretory dynamics, tissue resistance, impaired hormone clearance, and altered mean agonist concentrations are evident in certain therapeutic interventions, such as GH supplementation in CRF.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2A, B.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  1. Schaefer F, Mehls O (1998) Endocrine disorders. In: Barrett TM, Avner ED, Harmon W (eds) Pediatric nephrology. Lippincott, Williams and Wilkins

  2. Veldhuis JD, Carlson ML, Johnson ML (1987) The pituitary secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc Natl Acad Sci U S A 84:7686–7690

    CAS  PubMed  Google Scholar 

  3. Pincus SM, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD (1996) Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc Natl Acad Sci U S A 93:14100–14105

    Article  CAS  PubMed  Google Scholar 

  4. Veldhuis JD, Pincus SM (1998) Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses. Eur J Endocrinol 138:358–362

    CAS  PubMed  Google Scholar 

  5. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe CA, Barkan A, Johnson ML, Pincus SM (2001) Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol 280:R721–R729

    CAS  Google Scholar 

  6. 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

    CAS  PubMed  Google Scholar 

  7. Schaefer F, Baumann G, Haffner D, Faunt LM, Johnson ML, Mercado M, Ritz E, Mehls O, Veldhuis JD (1996) Multifactorial control of the elimination kinetics of unbound (free) growth hormone (GH) in the human: regulation by age, adiposity, renal function, and steady state concentrations of GH in plasma. J Clin Endocrinol Metab 81:22–31

    CAS  PubMed  Google Scholar 

  8. Schaefer F, Veldhuis JD, Stanhope R, Jones J, Schärer K (1994) Alterations in growth hormone secretion and clearance in peripubertal boys with chronic renal failure and after renal transplantation. Cooperative Study Group for Pubertal Development in Chronic Renal Failure. J Clin Endocrinol Metab 78:1298–1306

    CAS  PubMed  Google Scholar 

  9. Tönshoff 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

    CAS  PubMed  Google Scholar 

  10. Veldhuis JD, Iranmanesh A, Wilkowski MJ, Samojlik E (1994) Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men. Eur J Endocrinol 131:489–498

    CAS  PubMed  Google Scholar 

  11. 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 80:2684–2691

    PubMed  Google Scholar 

  12. Tönshoff B, Powell DR, Zhao D, Durham SK, Coleman ME, Domene HM, Blum WF, Baxter RC, Moore LC, Kaskel FJ (1997) Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein-1 and -2 gene expression in experimental uremia. Endocrinology 138:938–946

    PubMed  Google Scholar 

  13. Schaefer F, Chen Y, Tsao T, Nouri P, Rabkin R (2001) Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia. J Clin Invest 108:467–475

    Article  CAS  PubMed  Google Scholar 

  14. Poletti LF, Krieg RJ Jr, Santos F, Niimi K, Hanna JD, Chan JC (1992) Growth hormone secretory capacity of individual somatotropes in rats with chronic renal insufficiency. Pediatr Res 31:528–531

    CAS  PubMed  Google Scholar 

  15. Metzger DL, Kerrigan JR, Krieg RJ, Chan JC, Rogol AD (1993) Alterations in the neuroendocrine control of growth hormone secretion in the uremic rat. Kidney Int 43:1042–1048

    Google Scholar 

  16. Garcia E, Santos F, Rodriguez J, Martinez V, Rey C, Veldhuis JD, Krieg RJ Jr (1997) Impaired secretion of growth hormone (GH) in experimental uremia: relevance of caloric deficiency. Kidney Int 52:648–653

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Challa A, Krieg RJ Jr, Thabet MA, Veldhuis JD, Chan JC (1993) Metabolic acidosis inhibits growth hormone secretion in rats: mechanism of growth retardation. Am J Physiol 265:E547–E553

    CAS  PubMed  Google Scholar 

  19. Giustina A, Veldhuis JD (1998) Pathophysiology of the neuroregulation of GH secretion in experimental animals and the human. Endocr Rev 9:717–797

    Google Scholar 

  20. Urban RJ, Evans WS, Rogol AD, Kaiser DL, Johnson ML, Veldhuis JD (1988) Contemporary aspects of discrete peak detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men. Endocr Rev 9:3–37

    CAS  PubMed  Google Scholar 

  21. Schaefer F, Veldhuis JD, Robertson WR, Dunger D, Schärer 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

    CAS  PubMed  Google Scholar 

  22. Schaefer F, Daschner M, Veldhuis JD, Oh J, Quadri F, Schärer 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

    CAS  PubMed  Google Scholar 

  23. 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 

  24. 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 

  25. Schmitt CP, Schaefer F, Bruch A, Veldhuis JD, Schmidt-Gayk H, Stein G, Ritz E, Mehls O (1996) Control of pulsatile and tonic parathyroid hormone secretion by ionized calcium. J Clin Endocrinol Metab 81:4236–4243

    CAS  PubMed  Google Scholar 

  26. Stern JE, Cardinali DP (1994) Influence of the autonomic nervous system on calcium homeostasis in the rat. Biol Signals 3:15–25

    CAS  PubMed  Google Scholar 

  27. Schmitt CP, Löcken S, Mehls O, Veldhuis JD, Lehnert T, Ritz E, Schaefer F (2003) PTH pulsatility but not calcium sensitivity is restored after total parathyroidectomy with heterotopic autotransplantation. J Am Soc Nephrol 14:407–414

    CAS  PubMed  Google Scholar 

  28. Schmitt CP, Huber D, Mehls O, Maiwald J, Stein G, Veldhuis JD, Ritz E, Schaefer F (1998) Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism. J Am Soc Nephrol 9:1832–1844

    CAS  PubMed  Google Scholar 

  29. Song SH, Kjerns L, McIntyre SM, Johnson ML, Veldhuis JD, Butler PC (2002) Pulsatile insulin secretion by human pancreatic islets. J Clin Endocrinol Metab 87:213–221

    CAS  PubMed  Google Scholar 

  30. Feneberg R, Sparber M, Veldhuis JD, Mehls O, Ritz E, Schaefer F (2002) Altered temporal organization of plasma insulin oscillations in chronic renal failure. J Clin Endocrinol Metab 87:1965–1973

    CAS  PubMed  Google Scholar 

  31. Porksen N, Hollingdal M, Juhl C, Butler P, Veldhuis JD, Schmitz O (2002) Pulsatile insulin secretion: detection, regulation, and role in diabetes. Diabetes 51 [Suppl 1]:S245–S254

  32. Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR (1999) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329–339

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Franz Schaefer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Feneberg, R., Schaefer, F. & Veldhuis, J.D. Neuroendocrine adaptations in renal disease. Pediatr Nephrol 18, 492–497 (2003). https://doi.org/10.1007/s00467-003-1160-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-003-1160-y

Keywords

Navigation