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Saudi Journal of Kidney Diseases and Transplantation
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SPECIAL ARTICLE Table of Contents   
Year : 1994  |  Volume : 5  |  Issue : 4  |  Page : 466-469
Pathogenesis of growth failure in renal diseases


1 Department of Pediatrics, Postgraduate Medical Institute, Lahore, Pakistan
2 Department of Pediatrics, Hunan Medical University, Hunan, People's Republic of China, China
3 Nephrology Division, Children's Medical Center, Richmond, Virginia, USA

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   Abstract 

This article reviews our current understanding of the mechanisms of growth failure in chronic renal disease. The neuro-endocrine control of growth hormone secretion and insulin-like growth factor gene expression subject to use of corticosteroids, uremia, and metabolic acidosis are presented. It has been shown in other non-growth hormone deficient conditions such as Turner's syndrome that the use of exogenous growth hormone increases linear growth but also accelerates closure of the growth plate with no significant difference in the final height of such children. An understanding of growth factors is especially important and timely because of the tendency these days to use growth hormone to overcome the growth impairment of children with chronic renal failure.

Keywords: Growth failure, Growth hormone, Insulin-like growth factor, IGF-binding protien, Growth hormone receptor mRNA, CRF.

How to cite this article:
Ahmed TM, Yi ZW, Chan JC. Pathogenesis of growth failure in renal diseases. Saudi J Kidney Dis Transpl 1994;5:466-9

How to cite this URL:
Ahmed TM, Yi ZW, Chan JC. Pathogenesis of growth failure in renal diseases. Saudi J Kidney Dis Transpl [serial online] 1994 [cited 2020 Mar 29];5:466-9. Available from: http://www.sjkdt.org/text.asp?1994/5/4/466/41141

   Introduction Top


The growth failure of children with chronic renal diseases is due to a combination of factors prominent amongst which are the use of corticosteroids, metabolic acidosis, the effects of uremia, and other complications of chronic uremia. The recent availability of recombinant human growth hormone [1],[2],[3],[4],[5],[6] has provided hope that accelerated growth can be optimized even in the presence of uremia.­However, concern persists as to the risk of glomerulosclerosis [7] and hypercalciuria [8] , especially when the growth hormone is used in conjunction with 1,25-dihydroxy vitamin D, which is commonly needed for treatment of renal osteodystrophy. This article reviews some of these considerations and provides an understanding of the neuro-endocrine control of growth hormone secretion and gene expression of insulin-like growth factor-1 (IGF-1) at the target sites. It also reviews the effects of corticosteroids, metabolic acidosis as well as nephrotic syndrome on the growth hormone/ insulin-like growth factor-1 tissue expression.


   Effects of glucocorticoids on growth hormone secretion Top


Corticosteroid therapy is commonly employed in various types of renal diseases, such as nephrotic syndrome and after renal transplantation [4] . Growth hormone secretion from somatotropes has been shown to be increased after glucocorticoid administration [9],[10] . This increased secretion, in the face of the well known observation of growth retardation secondary to the use of corticosteroids, has been paradoxical and inexplicable until recent data showed that there was a reduction in the total number of somato­tropes secondary to the chronic use of glucocorticoid [11] . Although the individual somatotrope secretes a larger amount of growth hormone in response to growth hormone releasing factors [11],[12] , the reduced number of somatotropes results in a lower total concentration of growth hormone secretion and thus constitutes a proximal cause for the growth failure associated with the chronic use of corticosteroids.


   Growth hormone secretion in uremia Top


The reduced secretion of growth hormone in the presence of uremia appears to be determined by a large number of factors; prominent among which are the impaired nutritional intake [12] , the degree of uremia [13] and metabolic acidosis. Recent research has demonstrated that the anorexia associated with uremia gives rise to a reduction in the secretion of growth hormone in response to growth hormone releasing hormone challenge [14] . Furthermore, in severe uremia, the food efficiency ratio appears to be compromised [13] . Growth hormone transgenic mice with markedly increased secretion gave rise to hypercholesterolemia and severe glomerulosclerosis [7] ; thus additional studies on the mechanism of hypercholesterolemia in renal diseases are needed to provide a better understanding of the relationship of growth hormone, hypercholesterolemia and possible kidney function deterioration [15],[16],[17] .


   The growth hormone gene expression Top


Growth hormone usually expresses its peripheral action mediated by IGF-1 [7] . The liver is the principal organ for the production of IGF-1 in response to growth hormone stimulation. In the presence of uremia, the gene expression of IGF-1 is suppressed [18] . In addition, hepatic growth hormone receptor gene expression is also decreased [18] . It is thus possible, that despite the increased circulating level of growth hormone resulting from diminishing excretory ability of the failing kidney, growth failure results due to growth hormone resistance, both at the IGF-1 as well as growth hormone receptor sites. Finally, the expression of IGF-1 in chondrocytes of the growth plate also shows unusual findings in the presence of uremia [19] . IGF staining was demonstrated at both hypertrophic and proliferative zones of the growth plate in uremic rats. Widening of the growth plate was seen at the proliferative zone [19] and not at the hypertrophy zone, a reversal of the normal situation and provides further documentation of resistance to IGF-1 at the bone site.


   Growth hormone secretion in metabolic acidosis Top


It has been shown that children with renal tubular acidosis have blunted growth hormone secretory response to stimuli from arginine infusion. A recent study using the multi-parametric deconvolution data analysis, have demonstrated impaired secretion of growth hormone in the presence of metabolic acidosis [20] . The data has further demonstrated that the inhibition is specific because of the lack of change in the growth hormone half-life; whereas pair-fed control animals compared with the acidotic animals demonstrated a reduction in growth hormone half-life [20] . In addition, the hepatic gene expression of IGF and circulating concentrations of IGF-1 were also observed to be decreased in the presence of metabolic acidosis [21] .


   Growth hormone gene expression in the nephrotic syndrome Top


Experimental studies [22] with puromycin induced nephrosis have demonstrated a suppressed growth hormone receptor gene expression as well as reduced IGF-1 mRNA in the nephrotic animals as compared with pair­fed and control animals. Thus, the growth failure of nephrotic syndrome results not only from protein malnutrition, and/or the effects of corticosteroid on IGF/growth hormone axis, but also from the impaired gene expression of both growth hormone and IGF-1 and is the proximal cause of this growth retardation [22] .


   Conclusion Top


On-going basic research offers the exciting prospect of opening the window to understand the molecular basis of growth failure in children with chronic renal insufficiency. Elevated circulating serum concentrations of growth hormone, the decrease in circulating IGF-1 and the increase in circulating serum IGF-binding proteins have been evoked as causes of the growth failure in children with chronic renal diseases. However, the serum concentrations of these variables are dependent on the variable reduction in renal excretory rates. The recent demonstration of reduced hepatic IGF-1 expression and depressed abundance of growth hormone receptors in experimental uremia clearly provide evidence of tissue resistance to growth hormone and a rationale for the use of recombinant human growth hormone in uremia.


   Acknowledgements Top


The authors thank Betty Timozek for secretarial assistance, Linda L. Benson, B.Sc. and Ellen Chan for editorial assistance.

 
   References Top

1.Nakano M, Kainer G, Foreman JW, Ko DJ, Chan JC. The effects of exogenous rat growth hormone therapy on growth of uremic rats fed an 8% protein diet. Pediatr Res 1989;26:204-7.  Back to cited text no. 1    
2.Tonshoff B, Mehis O, Heinrich U, Blum WF, Ranke MB, Schauer A. Growth-stimulating effects of recombinant human growth hormone in children with end-stage renal disease. J Pediatr 1990;116:561-6.  Back to cited text no. 2    
3.Fine RN, Yadin O, Nelson PA. Recombinant human growth hormone treatment of children following renal transplantation. Pediatr Nephrol 1991;5:147-51.  Back to cited text no. 3    
4.Blum WF, Ranke MB, Kietzmann K, Tonshoff B, Mehls O. Growth hormone resistance and inhibition of somatomedin activity by excess of insulinlike growth factor binding protein in uraemia.Pediatr Nephrol 1991;5:539-44.  Back to cited text no. 4    
5.Hokken-Koelega AC, Stijnen T, de-Muinck­Keizer-Schrama SM, et al. Placebo­controlled, doubleblind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet 1991;338:585-90.  Back to cited text no. 5    
6.Broyer M, Guest G, Gagnadoux MF. Growth rate in children receiving alternate­day corticosteroid treatment after kidney transplantation. J Pediatr 1992;120:721-5.  Back to cited text no. 6    
7.Thabet MA, Krieg RJ Jr, Chan JC. Growth hormone in uremia. Kidney 1992;l:248-50.  Back to cited text no. 7    
8.Kainer G, Nakano M, Massie FS Jr, Foreman JW, Chan JC. Hypercalciuria due to combined growth hormone and calcitriol therapy in uremia. Effects of growth hormone on mineral homeostasis in 75% nephrectomized weanling rats. Pediatr Res 1991;30:528-33.  Back to cited text no. 8    
9.Krieg RJ Jr, Niimi K, Chan JC, et al. Cortisone effects on growth, food efficiency and in vitro growth hormone release. Kidney Int 1991;39:1135-9.  Back to cited text no. 9    
10.Poletti F, Krieg RJ Jr, Santos F, Niimi K, Hanna JD, Chan JC. Growth hormone secretory capacity of individual somatotropes in rats with chronic renal insufficiency. Pedriatr Res 1992;31:528-31.  Back to cited text no. 10    
11.Niimi K, Krieg RJ Jr, Hanna JD, Santos F, Chan JC. Glucocorticoid-induced changes in the quantity and secretory capacity of individual rat somatotropes. J Am Soc Nephrol 1993;3:1428-33.  Back to cited text no. 11    
12.Santos F, Chan JC, Krieg RJ, et al. Growth hormone secretion from pituitary cells in chronic renal insufficiency. Kidney Int 1992;41:356-60.  Back to cited text no. 12    
13.Santos F, Chan JC, Hanna JD, Niimi K, Krieg RJ Jr, Wellons MD. The effect of growth hormone on the growth failure of chronic renal failure. Pediatr Nephrol 1992;6:262-6.  Back to cited text no. 13    
14.Metzger DL, Kerrigan JR, Krieg RJ Jr, Chan JC, Rogol AD. Alterations in the neuroendocrine control of growth hormone secretion in the uremic rat. Kidney Int 1993;43:1042-8.  Back to cited text no. 14    
15.Thabet MA, Salcedo JR, Chan JC. Hyperlipidemia in childhood nephrotic syndrome, Pediatr Nephrol 1993;7:559-66.  Back to cited text no. 15    
16.Thabet MA, Challa A, Chan JC, Pandak WM, Heuman DM, Vlahcevic ZR. Studies of alteration of hepatic cholesterol metabolism in puromycininduced nephrotic syndrome in rats. Kidney Int 1993;44:789-94.  Back to cited text no. 16    
17.Pandak WM, Vlahcevic ZR, Heuman DM, Krieg RJ, Hanna JD, Chan JC. Post­transcriptional regulation of 3-hydroxy-3­methylglutaryl coenzyme A reductase and cholesterol 7 oc-hydroxylase in rats with subtotal nephrectomy. Kid Int 1994;46:358-64.  Back to cited text no. 17    
18.Chan W, Valerie KC, Chan JC. Expression of insulin-like growth factor-1 in uremic rats: growth hormone resistance and nutritional intake. Kidney Int 1993;43:790-95.  Back to cited text no. 18    
19.Hanna JD, Santos F, Wellons MD, Chan JC. Insulin-like growth factor-1 immunoreactivity and morphometrics in the uremic growth plate following the recombinant human growth hormone treatment. 25th Annual Meeting. American Society of Nephrology, Baltimore, MD, November 15-18, 1992.  Back to cited text no. 19    
20.Challa A, Krieg RJ Jr, Thabet MA, Veldhuis JD, Chan JC. Metabolic acidosis inhibits growth hormone secretion in rats: mechanism of growth retardation. Am J Physiol 1993;265:E547-53.  Back to cited text no. 20    
21.Challa A, Chan W, Krieg RJ Jr., et al. Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor. Kidney Int 1993;44:1224-7.  Back to cited text no. 21    
22.Thabet MA, Challa A, Chan W, Liu F, Hintz RL, Chan JC. Insulin-like growth factor and growth hormone receptor in nephrotic rats. Am J Physiol 1994;266:E102-6.  Back to cited text no. 22    

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James CM Chan
MCV Station, Box 498, Richmond, VA 23298-0498
USA
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    Abstract
    Introduction
    Effects of gluco...
    Growth hormone s...
    The growth hormo...
    Growth hormone s...
    Growth hormone g...
    Conclusion
    Acknowledgements
    References
 

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