Growth hormone binding protein and free growth hormone in chronic renal failure

Chronic renal failure in children is associated with growth failure. While the pathogenesis of uremic growth failure is multifactorial, an abnormal growth hormone/insulin-like growth factor (GH-IGF) axis is an important contributory element. Patients with uremia exhibit insensivivity to the action of GH, as exemplified by high plasma GH levels, low IGF-I activity, and poor somatic growth. This insensitivity can be overcome by supraphysiological doses of exogenous GH. Plasma GH binding protein (GHBP, the circulating ectodomain of the GH receptor) levels are decreased in patients with renal failure, as are hepatic GH receptor levels in animal models. Since GHBP levels are thought to reflect GH receptor levels in tissues, it is likely that the uremic GH insensitivity in humans is mediated by a decreased number of GH receptors. Another implication of the low plasma GHBP is a disproportionate elevation of free plasma GH (the biologically active moiety) relative to total GH, lending additional support to the concept of GH insensitivity in uremia. GH kinetics are altered in renal failure because of: (1) inability to excrete GH and (2) changes in the bound fraction of GH in the circulation.     

SH2B1 regulation of energy balance,body weight,and glucose metabolism

The Src homology 2B(SH2B)family members(SH2B1,SH2B2 and SH2B3)are adaptor signaling proteins containing characteristic SH2 and PH domains.SH2B1(also called SH2-B and PSM)and SH2B2(also called APS)are able to form homo-or hetero-dimers via their N-terminal dimerization domains.Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins,including Janus kinase 2(JAK2),TrkA,insulin receptors,insulin-like growth factor-1 receptors,insulin receptor substrate-1(IRS1),and IRS2.SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex.SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins.Accordingly,genetic deletion of SH2B1 results in severe leptin resistance,insulin resistance,hyperphagia,obesity,and type 2 diabetes in mice.Neuronspecific overexpression of SH2B1βtransgenes protects against diet-induced obesity and insulin resistance.SH2B1 in pancreaticβcells promotesβcell expansion and insulin secretion to counteract insulin resistance in obesity.Moreover,numerous SH2B1 mutations are genetically linked to leptin resistance,insulin resistance,obesity,and type 2 diabetes in humans.Unlike SH2B1,SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis.The metabolic function of the SH2B family is conserved from insects to humans.     

Influence of growth hormone and insulin-like growth factor-I on kidney function and kidney growth

Decreased glomerular filtration rate (GFR) in hypopituitarism and increased GFR in acromegaly suggest that growth hormone (GH) has a substantial effect on renal haemodynamics. Extractive and recombinant human (rh) GH in healthy volunteers increased effective renal plasma flow (ERPF) and GFR by 10% and 15% respectively. Renal response to GH was delayed and occurred at the same time as an increase in plasma insulin-like growth factor (IGF)-I values, whereas infusion of rhIGF-I promptly increased GFR and ERPF, indicating that the haemodynamic response of the kidney to GH is mediated by IGF-I. In chronic renal failure (CRF), the acute effect of GH on GFR is obliterated. This might protect the diseased kidney against the undesired consequences of hyperfiltration. Indeed, rhGH treatment for 1 year in children with CRF did not lead to an accelerated decline in GFR compared with the year before treatment. GH and IGF-I also effect renal growth. Exposure to excessive GH in transgenic mice causes renomegaly and progressive glomerular selerosis. In acromegalic humans, increased renal size and weight and increased glomerular diameter are well known, whereas renal failure is not a long-term hazard. At least in normal and hypophysectomized rats treated with doses comparable with the therapeutic regimens used in stunted children, rhGH increased renal weight but in proportion to the increase in body weight indicating an isometric effect of GH on renal growth. From these data, major renal longterm side effects of rhGH treatment in children with CRF appear unlikely.     

Recombinant insulin-like growth factor-1 as a therapy for IGF-1 deficiency in renal failure

Renal disease in children disrupts the growth hormone (GH) and insulin-like growth factor (IGF) axis and causes growth failure. Although GH therapy stimulates growth in these children, their short stature is likely due to a form of IGF-1 deficiency (IGFD) rather than GH deficiency. Recent experimental data have caused us to reconsider the importance of IGF-1 and IGFD to human growth. Pharmacology studies in rodents, as well as studies in patients with no functional GH receptors and primary IGFD, have shown that IGF-1 is an effective growth-promoting therapy. Gene knockout studies in mice have shown that IGF-1, rather than GH, is the major hormone controlling growth. In addition, both pharmacological and genetic studies have shown that there are effects of GH and IGF-1 that require their combined presence. In children with primary IGFD, where there is no GH signaling, recombinant human (rh)IGF-1 produces a large growth response, while in children who are GH and IGF-1 deficient, treatment with rhGH is the most-appropriate therapy. Children with short stature due to renal failure are GH sufficient and have some GH receptor signaling capacity, so that rhIGF-1, or rhIGF-1 plus rhGH, are logical therapeutic options and merit clinical testing.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Growth hormone/insulin-like growth factor system in children with chronic renal failure

Disturbances of the somatotropic hormone axis play an important pathogenic role in growth retardation and catabolism in children with chronic renal failure (CRF). The apparent discrepancy between normal or elevated growth hormone (GH) levels and diminished longitudinal growth in CRF has led to the concept of GH insensitivity, which is caused by multiple alterations in the distal components of the somatotropic hormone axis. Serum levels of IGF-I and IGF-II are normal in preterminal CRF, while in end-stage renal disease (ESRD) IGF-I levels are slightly decreased and IGF-II levels slightly increased. In view of the prevailing elevated GH levels in ESRD, these serum IGF-I levels appear inadequately low. Indeed, there is both clinical and experimental evidence for decreased hepatic production of IGF-I in CRF. This hepatic insensitivity to the action of GH may be partly the consequence of reduced GH receptor expression in liver tissue and partly a consequence of disturbed GH receptor signaling. The actions and metabolism of IGFs are modulated by specific high-affinity IGFBPs. CRF serum has an IGF-binding capacity that is increased by seven- to tenfold, leading to decreased IGF bioactivity of CRF serum despite normal total IGF levels. Serum levels of intact IGFBP-1, -2, -4, -6 and low molecular weight fragments of IGFBP-3 are elevated in CRF serum in relation to the degree of renal dysfunction, whereas serum levels of intact IGFBP-3 are normal. Levels of immunoreactive IGFBP-5 are not altered in CRF serum, but the majority of IGFBP-5 is fragmented. Decreased renal filtration and increased hepatic production of IGFBP-1 and -2 both contribute to high levels of serum IGFBP. Experimental and clinical evidence suggests that these excessive high-affinity IGFBPs in CRF serum inhibit IGF action in growth plate chondrocytes by competition with the type 1 IGF receptor for IGF binding. These data indicate that growth failure in CRF is mainly due to functional IGF deficiency. Combined therapy with rhGH and rhIGF-I is therefore a logical approach.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Plasma growth hormone-binding activity is low in uraemic children

Plasma growth hormone-binding protein (GH-BP) activity was evaluated in two groups of prepubertal children with chronic renal failure (CRF) who had been treated with recombinant human GH (rhGH). Group 1 consisted of eight children (mean chronological age 10.8 years) with advanced renal failure; group 2 consisted of nine children (mean chronological age 6 years) presenting with end-stage renal disease, who were on dialysis. Before treatment the specific binding of (¹²⁵I)hGH to highaffinity GH-BP was low in the two groups (group 1, 17.3±1.6% of radioactivity; group 2, 14.2±1.4%) compared with the mean value obtained in normal prepubertal children (24.8±1.7%). No significant changes in GH-BP activity were found during the 1st year of GH therapy, although growth velocity and plasma levels of insulin-like growth factor-I increased significantly in both groups. The low GH-binding activity found in children with CRF supports the state of GH resistance. The reason for the absence of a GH-BP response to GH therapy has to be clarified.     

Distrubance of growth hormone-insulin-like growth factor axis in uraemia

The growth hormone/insulin-like growth factor (IGF) axis is disturbed in uraemia. Elevated plasma growth hormone (GH) levels despite diminished growth suggest GH resistance, which may be due in part to a decreased expression of the growth hormone receptor at the cell membrane. The hepatic production of IGFs under the control of GH is impaired. Furthermore, there is an excess of IGF-binding protein over total IGF as a consequence of reduced renal clearance of low-molecular-weight subunits of the IGF-binding protein (IGF-BP). This results in an absolute (diminished production) and a relative (low bioavailability) deficiency of IGF. Recombinant human growth hormone (rhGH) in doses of 4 IU/m² per day is able to induce catch-up growth in children with preterminal and terminal renal failure. The growth stimulation of exogenous GH is attributed to its potency to increase the ratio of IGF-I to IGF-BP, followed by a normalization of IGF bioactivity. In renal transplanted children growth is not only disturbed by decreased renal function but also by steroid treatment. Corticosteroids, are responsible for catabolism, for suppression of pituitary GH secretion and for inhibition of local production of IGFs. Exogenous rhGH is able to counteract these growth-inhibiting effects. However, it remains to be seen whether long-term GH treatment definitely improves final adult height.     

Bone density and body composition in chronic renal failure: effects of growth hormone treatment

Metabolic bone disease and growth retardation are common complications of chronic renal failure (CRF). We evaluated bone mineral density (BMD), bone metabolism, body composition and growth in children with CRF, and the effect of growth hormone treatment (GHRx) on these variables. Thirty-three prepubertal patients with CRF were enrolled including 18 children with growth retardation, who were treated with growth hormone for 2 years. Every 6 months, BMD of lumbar spine and total body, and body composition were measured by dual-energy X-ray absorptiometry. Biochemical parameters of bone turnover were assessed. Mean BMD of children with CRF did not differ from normal. During GHRx, BMD and bone mineral apparent density of lumbar spine and height SDS increased, whereas BMD of total body did not change. Lean body mass increased in the GH group. Alkaline phosphatase increased significantly in the GH group only. The other biochemical parameters of bone turnover increased in both groups, none of them correlated with the changes in BMD. No serious adverse effects of GHRx were reported. In conclusion, BMD of children with CRF did not differ from healthy children. Adequate treatment with α-calcidiol or the short duration of renal failure may have attributed to the absence of osteopenia in our patients. BMD of the axial skeleton and growth improved with GHRx. Received: 18 April 2000 / Revised: 26 June 2000 / Accepted: 29 June 2000     

The application of knemometry in renal disease: preliminary observations

Short-term lower leg length was measured longitudinally using a high-precision device called a knemometer in 11 children with chronic renal failure and 12 normal children. The method has a high accuracy (mean standard error 0.13 mm) and may prove useful for prediction of long-term total body growth. Its application in renal patients undergoing corticosteroid, growth hormone (GH) and erythropoietin (EPO) therapy is documented. GH was shown to improve lower leg growth in an adolescent who already had passed the maximum of his pubertal spurt. EPO treatment produced no consistent increase of short-term growth.     

Modulation of growth hormone signal transduction in kidneys of streptozotocin-induced diabetic animals: effect of a growth hormone receptor antagonist

Growth hormone (GH) and IGFs have a long distinguished history in diabetes, with possible participation in the development of renal complications. The implicated effect of GH in diabetic end-stage organ damage may be mediated by growth hormone receptor (GHR) or postreceptor events in GH signal transduction. The present study investigates the effects of diabetes induced by streptozotocin (STZ) on renal GH signaling. Our results demonstrate that JAK2, insulin receptor substrate (IRS)-1, Shc, ERKs, and Akt are widely distributed in the kidney, and after GH treatment, there is a significant increase in phosphorylation of these proteins in STZ-induced diabetic rats compared with controls. Moreover, the GH-induced association of IRS-1/phosphatidylinositol 3-kinase, IRS-1/growth factor receptor bound 2 (Grb2), and Shc/Grb2 are increased in diabetic rats as well. Immunohistochemical studies show that GH-induced p-Akt and p-ERK activation is apparently more pronounced in the kidneys of diabetic rats. Administration of G120K-PEG, a GH antagonist, in diabetic mice shows inhibitory effects on diabetic renal enlargement and reverses the alterations in GH signal transduction observed in diabetic animals. The present study demonstrates a role for GH signaling in the pathogenesis of early diabetic renal changes and suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.     

Insulin-like growth factor binding proteins as growth inhibitors in children with chronic renal failure

Children with chronic renal failure (CRF) often fail to attain an adult height consistent with their genetic potential. The growth hormone (GH)/insulin-like growth factor (IGF)/growth plate chondrocyte axis has been intensively studied in these children to determine the basis for this growth failure. Evidence suggests that hepatic GH resistance results in deficient expression of IGF-I. However, serum IGF-I levels are usually normal and it is IGF-I action on target tissues which is inhibited, possibly by the presence of excess high-affinity IGF binding proteins (IGFBPs) in CRF serum. In this paper we evaluate the roles of IGFBP-1, -2, and -3 as growth inhibitors in CRF children. The data support a role for each of these IGFBPs as growth inhibitors. Currently, IGFBP-1 meets most criteria expected of a growth inhibitor, but IGFBP-2 and -3 will likely also meet these criteria and may well be important contributors to the growth failure of CRF. Ultimately, many or all of the six IGFBPs may be found to contribute to the excess high-affinity IGF binding sites which are a hallmark of CRF serum and are possible contributors to the growth failure of CRF children.     

Molecular mechanisms of erythropoietin signaling

Erythropoietin is an obligatory growth factor for red blood cell production. The receptor for erythropoietin contains a single membrane-spanning domain with no intrinsic tyrosine kinase motifs. On binding to erythropoietin, the receptor dimerizes and activates multiple intracellular signaling molecules, including but not limited to JAK2, STAT5, PI 3-kinase, IRS-2, RAS, and Ca2+ channels. This review focuses on cytoplasmic signaling cascades involved in erythropoietin action.     

How safe is the treatment of uraemic children with recombinant human growth hormone?

Exogenous growth hormone (GH) treatment for growth failure in uraemic children is effective over a period of up to 3 years. The safety of this new treatment modality is remarkably high, at least for this short period of time. Despite a reduced renal metabolic clearance rate of GH in uraemia, exogenous GH does not accumulate in the serum. In a dose range of 28 units/m² per week, GH does not impair glucose tolerance but increases serum insulin levels, indicating that euglycaemia is maintained at the expense of increased insulin secretion. No alterations of lipid metabolism, mineral metabolism, pituitary-thyroid axis and blood pressure were observed. The GH-induced glomerular hyperfiltration in healthy subjects seems to be obliterated in chronic renal failure. Accordingly, no accelerated progression of renal disease was observed under GH treatment. However, potential side effects during long-term treatment, especially regarding carbohydrate metabolism and malignancy in children under immunosuppression, are not yet excluded.     

Changes in body composition of children with chronic renal failure during growth hormone treatment

Growth hormone (GH) has different known metabolic effects, among which are lipolysis and anabolic action. We have studied the changes in body composition of children with chronic renal failure (CRF) after 1 year of daily treatment with GH. Body fat percentage and fat body mass (FBM) were derived from four site skinfold measurements; lean body mass (LBM) from total body potassium (TBK) and mid-arm muscle circumference (MAMC); bone mineral density (BMD) was measured by dual photon absorptiometry. GH treatment had a positive effect on weight, heigt and MAMC, but no effect on LBM (as reflected by TBK), FBM and BMD. Z-scores were derived in order to compare subjects with a normal population. While no significant change in z-score was noticed for weight, height, MAMC, FBM and BMD, TBK decreased during treatment. We conclude that GH therapy does not ultimately increase LBM in CRF patients compared with other GH-treated groups.     

Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement

Growth failure is a clinically important issue in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality. Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH)–insulin-like growth factor-I (IGF-I) axis, malnutrition, acidosis, and renal bone disease. The management of growth failure in children with CKD is complicated by the presence of other disease-related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, some practitioners and families have been reluctant to institute GH therapy, citing an unwillingness to comply with daily injections, reimbursement difficulties, or impending renal transplantation. Suboptimal attention to growth failure management may be further compounded by a lack of clinical guidelines for the appropriate assessment and treatment of growth failure in these children. This review of growth failure in children with CKD concludes with an algorithm developed by members of the consensus committee, outlining their recommendations for appropriate steps to improve growth and overall health outcomes in children with CKD.Members of the Consensus Committee that participated in this survey: Paul Fielder, PhD; Debbie S. Gipson, MD; Larry Greenbaum, MD, PhD; Marisa D. Juarez-Congelosi, BS, RD, LD; Frederick J. Kaskel, MD, PhD; Craig B. Langman, MD; Lynn D. Long, RN, MS; Dina Macdonald, RN, BSN, CNN; Deborah H. Miller, RN, MSN, CNN; Mark M. Mitsnefes, MD, MS; Valerie M. Panzarino, MD; Ron G. Rosenfeld, MD; Mouin G. Seikaly, MD; Brian Stabler, PhD; Sandra L. Watkins, MD.