Abstract
Endothelial dysfunction, an early step in atherogenesis, is prevalent in children with renal insufficiency. Endothelial dysfunction in growth hormone deficiency is reversed by growth hormone (rhGH) therapy. Renal failure induces growth hormone resistance at the receptor and post-receptor level, which can be overcome by rhGH therapy. This study investigates the influence of rhGH therapy in children with renal failure on flow-mediated dilation (FMD) of the brachial artery, a marker of endothelial function. We studied 8 patients, who were on rhGH for at least 6 months, and 8 healthy children for comparison. FMD of the brachial artery was measured non-invasively as the percentage increase in diameter during post-ischemic hyperemia. Patients were studied at baseline, after 4 weeks interruption of rhGH therapy, and 4 weeks after resumption of therapy. FMD was significantly lower in patients (4.7%) than healthy controls (13.8%) (P=0.01). During the administration of rhGH, FMD was significantly higher (3.9%) than during interruption of the treatment (1.4%) (P=0.04). Our data support the theory that a disturbance in the GH-IGF axis contributes to the endothelial dysfunction of renal failure. Treatment with rhGH not only improves growth but may also favorably influence the risk for atherogenesis.
Similar content being viewed by others
References
Groothoff JW, Gruppen MP, Offringa M, Hutten J, Lilien MR, Van De Kar NJ, Wolff ED, Davin JC, Heymans HS (2002) Mortality and causes of death of end-stage renal disease in children: a Dutch cohort study. Kidney Int 61:621–629
Kari JA, Donald AE, Vallance DT, Bruckdorfer KR, Leone A, Mullen MJ, Bunce T, Dorado B, Deanfield JE, Rees L (1997) Physiology and biochemistry of endothelial function in children with chronic renal failure. Kidney Int 52:468–472
Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner K, Maurer G, Weidinger F (2000) Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol 86:207–210
Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, Karas RH (2001) Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 38:1843–1849
Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A (2000) Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101:948–954
Alonso R, Mata P, De Andres R, Villacastin BP, Martinez-Gonzalez J, Badimon L (2001) Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin. Atherosclerosis 157:423–429
Tönshoff B, Schaefer F, Mehls O (1990) Disturbance of growth hormone--insulin-like growth factor axis in uraemia. Implications for recombinant human growth hormone treatment. Pediatr Nephrol 4:654–662
Laron Z, Wang XL, Klinger B, Silbergeld A, Davidovits M, Eisenstein B, Wilcken DE (1996) Growth hormone treatment increases circulating lipoprotein(a) in children with chronic renal failure. J Pediatr Endocrinol Metab 9:533–537
Querfeld U, Haffner D, Wuhl E, Wingen AM, Wolter K, Friedrich B, Michalk DV, Mehls O (1996) Treatment with growth hormone increases lipoprotein(a) serum levels in children with chronic renal insufficiency. Eur J Pediatr 155:913
Querfeld U (1996) Is the impact of recombinant human growth hormone (rhGH) on the plasma lipid profile beneficial or harmful? Br J Clin Pract [Suppl] 85:54–55
Evans LM, Davies JS, Goodfellow J, Rees JA, Scanlon MF (1999) Endothelial dysfunction in hypopituitary adults with growth hormone deficiency. Clin Endocrinol (Oxf) 50:457–464
Christ ER, Chowienczyk PJ, Sonksen PH, Russel-Jones DL (1999) Growth hormone replacement therapy in adults with growth hormone deficiency improves vascular reactivity. Clin Endocrinol (Oxf) 51:21–25
Lilien MR, Stroes ES, Op’t Roodt J, Jongh S de, Schroder CH, Koomans HA (2003) Vascular function in children after renal transplantation. Am J Kidney Dis 41:684–691
Tönshoff B, Eden S, Weiser E, Carlsson B, Robinson IC, Blum WF, Mehls O (1994) Reduced hepatic growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia. Kidney Int 45:1085–1092
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
Bluyssen HAR, Xanthakis D, Dijk A, Koomans HA, Braam B (2003) Oxidative stress modulates endothelial dysfunction via JAK-STAT activation and differential regulation of SOCS proteins. J Am Soc Nephrol 14:642A
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
Tsukahara H, Gordienko DV, Tönshoff B, Gelato MC, Goligorsky MS (1994) Direct demonstration of insulin-like growth factor-I-induced nitric oxide production by endothelial cells. Kidney Int 45:598–604
Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, Montellano PR de, Kemp BE, Pearson RB (1999) The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol 9:845–848
Wickman A, Jonsdottir IH, Bergstrom G, Hedin L (2002) GH and IGF-I regulate the expression of endothelial nitric oxide synthase (eNOS) in cardiovascular tissues of hypophysectomized female rats. Eur J Endocrinol 147:523–533
Beld AW van den, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE (2003) Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol 157:25–31
Christ ER, Chowienczyk PJ, Sonksen PH, Russel-Jones DL (1999) Growth hormone replacement therapy in adults with growth hormone deficiency improves vascular reactivity. Clin Endocrinol (Oxf) 51:21–25
Böger RH, Skamira C, Bode-Boger SM, Brabant G, Muhlen A zur, Frolich JC (1996) Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study. J Clin Invest 98:2706–2713
Lopes LA, Theintz GE, Torresani T, Sizonenko PC (1992) Comparison between short- and long-term insulin-like growth factor response to recombinant human growth hormone. Horm Res 38:245–249
Raitakari OT, Adams MR, Celermajer DS (1999) Effect of Lp(a) on the early functional and structural changes of atherosclerosis. Arterioscler Thromb Vasc Biol 19:990–995
Schlaich MP, John S, Langenfeld MR, Lackner KJ, Schmitz G, Schmieder RE (1998) Does lipoprotein(a) impair endothelial function? J Am Coll Cardiol 31:359–365
Acknowledgements
Part of this study was published in abstract form at the World Congress of Nephrology, Berlin, June 2003.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lilien, M.R., Schröder, C.H., Levtchenko, E.N. et al. Growth hormone therapy influences endothelial function in children with renal failure. Pediatr Nephrol 19, 785–789 (2004). https://doi.org/10.1007/s00467-004-1495-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-004-1495-z