Growth Hormone

1.1.1

Introduction

GH is a key mediator of growth and anabolic activities in humans and primarily exerts its somatotropic and metabolic effects by stimulating production of insulin-like growth factor-1 (IGF-1). Most of the circulating IGF-1 is derived from that released into the bloodstream from the liver and IGF-1 functions as a classic endocrine hormone. IGF-1 also is produced locally by many cells where it exerts paracrine/autocrine effects in specific tissues. The production and interactions of GH and IGF-1 are complex and are significantly transformed in individuals with renal insufficiency, related to level of renal impairment, nutritional status, altered systemic hormones, and sex steroids (estrogen, testosterone).

Renal insufficiency in children and adults is marked by significant metabolic and hormonal derangements, including alterations in the GH/IGF-1 axis; GH/IGF-1 abnormalities may develop at any stage of renal insufficiency and are more pronounced with longer duration of renal dysfunction. In individuals with renal insufficiency, other factors than renal function also impact the GH/IGF-1 axis since the extent of the abnormalities is not linearly related to the level of renal insufficiency. The GH/IGF-1 axis is most importantly a regulator of growth and metabolism, but abnormalities in this axis may lead to a variety of other systemic effects. In children with renal disease, altered GH and IGF-1 may contribute to impaired linear growth. Other potential consequences, such as decreased muscle mass, decreased bone mass, impaired neurocognitive development, and disordered plasma lipids, may also develop and lead to significant morbidity. In adults with renal insufficiency, GH and IGF-1 abnormalities have also been identified and have been correlated with decreased muscle mass, decreased bone mass, altered plasma lipids, and altered metabolism. Altered GH/IGF-1 effects are now recognized as a complication of CKD, and may also be important in acute renal insufficiency. Moreover, proper recognition of the clinical consequences and appropriate management of GH/IGF-1 abnormalities can lead to decreased morbidity in children and adults with CKD. This represents an important framework in the care of individuals with CKD and has opened up possibilities for improvement in care of children and adults with acute renal failure (ARF).

1.1.2

Normal GH/IGF-1 Axis

The complexities of the GH/IGF-1 axis and the effects of these peptides have been well delineated. The GH/IGF-1 axis involves:

• 1.

  the autocrine and paracrine effector peptides GH (191 amino acids, 22,000 D MW), IGF-1 (70 amino acids, 7649 D MW) and IGF-2 and

• 2.

  a regulatory feedback process and modulation by important regulators, such as the hypothalamic hormones GH-releasing hormone (GHRH) and somatostatin (SRIF) and systemic peptides, such as ghrelin.

As shown in Fig. 15.1 and Table 15.1 , normal pulsatile GH production and release by the anterior pituitary is stimulated by GHRH and inhibited by SRIF. Circulating GH and IGF-1 levels provide negative feedback to the hypothalamus. Release of GH is also stimulated by ghrelin, a 28-amino acid peptide with GH-releasing properties which is secreted by the stomach and hypothalamus and imparts nutritional regulation of the GH/IGF-1 axis. Circulating GH stimulates the production and release of IGF-1, primarily from the liver. GH receptors are present in many tissues of epithelial and mesenchymal origin; additional IGF-1 production by these tissues contributes little to circulating levels of IGF-1 but may have important local paracrine/autocrine effects in specific tissues, such as bone.

The importance of local paracrine/autocrine effects of IGF-1 is highlighted by studies in IGF-1 knockout mice that demonstrated that surviving IGF-1-deficient mice are profoundly growth retarded, while liver-specific IGF-1 knockout mice have low levels of circulating IGF-1 but normal growth. GH supplementation of IGF-1-deficient knockout mice does not improve growth. These findings indicate that while the ability to generate IGF-1 is essential for normal postnatal growth, liver generated circulating IGF-1 is not required for normal growth, underscoring the importance of local GH effects and/or locally produced IGF-1 on bone growth.

More than 97% of circulating IGF-1 is bound to six IGF-binding proteins (IGFBP-1 to IGFBP-6) with the greatest amount complexed to IGFBP-3 and acid-labile subunit (ALS). Less than 1% of circulating IGF-1 occurs in the free or bioactive form. The 150 kD ternary complex of IGF-1, IGFBP-3, and ALS represents a storage form of IGF-1 in the circulation with a half-life of several hours. IGF-1 binding to IGFBPs limits the bioactivity of IGF-1 since only free IGF-1 is able to activate the IGF-1 receptor. Free IGF-1 mediates many of the biologic effects of GH, including stimulation of longitudinal bone growth and regulation of renal hemodynamics.

GH also appears to have a direct effect on several tissues, including bone. Local production of IGF-1 may mediate some or all of these important effects, particularly in growth cartilage. According to the dual effector theory, GH and IGF-1 act on different bone cell types to stimulate longitudinal growth. GH induces differentiation of epiphyseal growth plate precursor cells toward chondrocytes. These GH-stimulated chondrocytes then become responsive to IGF-1 and concomitantly express IGF-1 mRNA. IGF-1 stimulates the clonal expansion of differentiated chondrocytes, thus leading to longitudinal bone growth.

The GH/IGF-1 axis is present in the kidney and is important in kidney structure and function. GH receptors are present in the proximal tubule and thick ascending limb. IGF-1 receptors are primarily present in the glomerulus (glomerular mesangial, endothelial, and mesangial cells) and proximal and distal tubules. Both circulating GH and IGF-1 increase renal plasma flow and glomerular filtration rate (GFR). The GFR response to GH appears to be primarily related to the IGF-1 level achieved. In IGF-1 knockout mice, renal development is normal, suggesting that IGF-1 is not essential to normal renal development. The effects of supraphysiologic levels of GH and IGF-1 on the kidney can be quite different. For example, mice transgenic for IGF-1 develop glomerular hypertrophy while mice that are transgenic for GH develop glomerular sclerosis.

1.1.3

Pathophysiology of the Disordered GH/IGF-1 Axis in Renal Insufficiency

In renal insufficiency the GH/IGF-1 axis is markedly deranged ( Fig. 15.1 and see Table 15.1 ). Circulating levels of GH are typically increased as a result of the combination of increased pulsatile release by the pituitary and reduced renal GH clearance. Total IGF1- levels are normal, not elevated as might be expected in relation to circulating GH levels, and the biologic effectiveness of endogenous GH and IGF-1 is reduced. Free, bioactive IGF-1 levels are reduced as a result of increased levels of most circulating IGFBPs, especially the high-affinity forms IGFBP-1, -2, and -6, in relation to the decline in renal function. The increased levels of IGFBP-1 and -2 appear to be most responsible for sequestering IGF from IGF-1 receptors. Increased proteolysis of IGFBP-3 leads to less IGF-1 in association with the IGFBP-3 and ALS ternary complex. The end result is less cellular IGF-1 receptor activation.

Despite normal to elevated levels of circulating total GH and IGF-1, CKD is also marked by GH and IGF-1 resistance. Undoubtedly, this resistance plays an important role in the reduction of linear bone growth observed in CKD and, therefore, is a significant factor in the growth impairment seen in children with CKD. The mechanisms responsible for IGF-1 resistance in CKD are not completely understood but appear to involve a defect in the postreceptor GH-activated Janus kinase 2 (JAK2) signal transducer and activator of the transcription (STAT) pathway ( Fig. 15.3 ). This signaling pathway is integral to the process of stimulated IGF-1 gene expression which is the key cellular response to GH receptor activation. A decrease in cellular GH receptors may also contribute to the blunted IGF-1 response to GH seen in CKD.

1.1.4

Growth Hormone and Growth Hormone Resistance in CKD

The GH abnormalities in CKD are complex and include:

• 1.

  abnormal GH secretion

• 2.

  decreased serum growth hormone binding protein (GHBP) and

• 3.

  decreased renal clearance of GH.

In uremic individuals the sum of these disturbances can be quite variable but the most common pattern is a slight elevation in serum GH with blunted cellular responses to GH. The interplay of uremia and a number of additional factors modulate the extent and final outcome of these abnormalities.

In prepubertal children with CKD, there is increased pituitary pulsatile release of GH. In pubertal children with CKD, the typical increase in GH secretion is impaired. Schaefer analyzed GH secretion and elimination in 43 peripubertal boys with CKD. The estimated plasma GH half-life was significantly increased in children with CKD compared to control children. In the pre- and early pubertal CKD boys, the calculated GH secretion rate was low normal or reduced when expressed in absolute numbers or normalized per unit distribution volume or body surface. In late puberty, while body surface-corrected GH secretion was double the prepubertal value seen in normal boys, it did not differ significantly from the prepubertal rate of GH secretion seen in CKD boys. In adolescents with CKD, the lower than expected GH secretion resulted from a decrease in the amount of GH released within each burst, with burst frequency unchanged.

The major metabolic pathway for GH clearance is renal excretion, so in renal insufficiency there is a tendency toward high serum GH levels. Balancing this is the decrease in serum GHBP seen in CKD, which allows more renal excretion of free GH for the level of renal function. The overall result is typically normal or mildly increased levels of serum GH (see Fig. 15.1 ). In CKD, nutritional status may also contribute to GH levels since gastrointestinal hormones such as ghrelin are elevated in patients with CKD.

One indication of the presence of GH resistance in CKD is suggested from the absence of elevated circulating levels of IGF-1 despite slightly elevated GH. The cellular basis for GH resistance in CKD has been explained, in part, by a decrease in cellular GH receptor number. In humans with CKD, a decrease in GH receptor number is surmised from the observation of decreased levels of serum GHBP, a product of proteolytic cleavage of the GH receptor that is quantitatively related to cellular GH receptor number. In fact, in individuals with CKD, decreased levels of circulating GHBP are directly related to the level of renal function. In contrast, Greenstein and colleagues demonstrated that monocytes from individuals with CKD have normal levels of GH receptors. Thus, not all tissues in individuals with CKD may participate in this mechanism for GH resistance.

GH resistance in CKD may also be mediated through inhibition of transduction signaling. Activation of the GH receptor phosphorylates JAK2 which then activates cytoplasmic STAT. Following translocation to the nucleus, STATs form homodimers to activate nuclear receptors, stimulating transcription of a number of proteins, including IGF-1. GH resistance in uremia may be caused by increased levels of suppressors of cytokine signaling (SOCS) which can inhibit the JAK2/STAT pathway. In experimental uremia, increased SOCS expression has been demonstrated. This mechanism may occur via upregulation of SOCS2 and SOCS3 expression and/or from increased protein tyrosine phosphatase activity with enhanced dephosphorylation and deactivation of the signaling proteins (see Fig. 15.2 ). Whether increased SOCS expression is secondary to the CKD per se or to the often accompanying chronic inflammation is uncertain.

1.1.5

Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-1 Abnormalities in CKD

The presence of IGF-1 resistance in CKD is at least partially due to increased levels of circulating IGFBP-1, -2, -4, and -6, which lead to a reduction in the concentration of bioavailable IGF-1 (see Fig. 15.1 ). IGFBP-1 and -2 appear to be most responsible for reducing IGF-1 bioavailability. In addition, increased proteolysis of IGFBP-3 leads to a decrease in IGF-1 available for the formation of IGF-1–ALS–IGFBP-3 complexes. Taken together, these events impair both direct and indirect effects of GH by affecting IGF-1 bioactivity.

The mechanism for increased serum IGFBP-1 and IGFBP-2 (low molecular weight IGF binding proteins) is not clear but may be related to either decreased renal excretion and/or increased hepatic production. Elevated IGFBPs invariably lead to lower serum free IGF-1 concentration (see Fig. 15.1 ). In the circulation, IGF-1 is mainly bound to the IGFBP-3 isoform, its free serum concentration representing under 0.5% of serum total IGF-1. In children with CKD, height correlates positively with serum IGF-1 levels but inversely with serum IGFBP-2, which may be regarded as a marker for bioavailable IGF-1. The bioavailability of IGF-1 is also affected by activity of IGFBP proteases, while malnutrition, a feature of CKD, influences serum IGF-1 independent of the IGFBP mechanism.

As with GH resistance, IGF-1 resistance may also involve the inhibition of transduction signaling pathways. Chronic inflammation, mediated by inflammatory cytokines such as IL-1 and tumor necrosis factor α (TNFα), is an important feature of CKD. TNFα inhibits the phosphorylation of the IGF receptor docking molecules, the insulin receptor substrates IRS-1 and IRS-2, an early step in the IGF-1 transduction pathway. IGF-1 transduction signaling may also be inhibited downstream by metabolic acidosis in CKD, which can independently decrease phosphatidylinositol-3-kinase (PI3 kinase) activity and subsequent gene expression.