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.     

Growth hormone and renal function

Summary: Recombinant human growth hormone (rhGH) has been recognized to be beneficial for improving growth retardation in uraemic children. the potential effect of growth hormone (GH) on renal haemodynamics results in an increase in glomerular filtration rate and renal plasma flow. However, in GH transgenic mice and uraemic rats treated with GH, GH has been reported to aggravate glomerular sclerosis and induce deterioration in renal function. Therefore, the potential of adverse effect of GH on deterioration in renal function has been of concern in uraemic children receiving rhGH. Growth hormone enhances protein anabolism and promotes a positive nitrogen balance. It is more likely that the anabolic effect of GH used at the conventional dose may reduce renal solute load and slow the progression of end-stage renal failure (ESRF) in rhGH-treated uraemic children. A low protein diet with adequate calories slows the deterioration of renal function in uraemic patients. the effects of GH on growth promotion, renal haemodynamics and protein anabolism are mainly mediated by insulin-like growth factor-I (IGF-I). Insulinlike growth factor-I enhances glomerular filtration rate and promotes glomerular hypertrophy, but IGF-I administration is unlikely to give rise to glomerular sclerosis. the efficacy and the safety of concomitant therapy of recombinant GH or IGF-I and low protein diet should therefore be considered in uraemic children.     

The acute effect of growth hormone on GFR is obliterated in chronic renal failure

Recombinant human growth hormone (rhGH) has become available for treatment of growth failure in uremic children. Since GH raises the glomerular filtration rate (GFR) in healthy individuals, there has been concern that treatment with rhGH, by its action on glomerular hemodynamics, may adversely affect the progression of renal failure. To further address this issue, inulin clearance (enzymatic steady-state infusion technique) was measured in 7 healthy normotensive adult volunteers and 7 patients with chronic renal failure from glomerular or non-glomerular causes. Subjects were given 4.5 U bid of rhGH by s.c. injection for 3 days. In volunteers, a significant increase in Cin was noted 72 h after start of rhGH administration from 120 ml/min/1.73 m2 (range 91-158) to 133 (108-167) (p less than 0.02). In contrast, no significant increase in Cin was noted in patients with chronic renal failure (baseline Cin 21 ml/min/1.73 m2, 15-32; after rhGH 22 ml/min/1.73 m2, 15-32) despite pronounced effects of GH on S-cholesterol and urea excretion rate. The results show that stimulation of GFR by short-term administration of rhGH is obliterated in chronic renal failure.     

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     

Growth hormone receptor abundance in tibial growth plates of uremic rats: GH/IGF-I treatment

BACKGROUND: Children with chronic renal failure (CRF) exhibit growth retardation and a disturbed growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. Treatment of children with CRF with GH or GH/IGF-I can partially restore linear growth. The molecular basis for decreased longitudinal growth is not known but may involve an impaired action of GH. METHODS: We used the growth-retarded uremic rat model to determine the abundance and distribution of GH receptors (GHRs) in the tibial epiphyseal growth plate and the influence of GH, IGF-I, or combined GH/IGF-I treatment. Pair-fed rats were used as the control. RESULTS: While all treatment regimes increased body length and weight in both rat groups, only GH/IGF-I treatment increased the total growth plate width. This involved an increase in cell number in the hypertrophic zone, which could also be induced by IGF-I alone. Immunohistochemical analysis showed that uremic rats had decreased abundance of GHRs in the proliferative zone, and only GH/IGF-I therapy could overcome this decrease. These data thus suggest that growth retardation in uremic rats is, at least in part, due to a decrease in GHR abundance in chondrocytes of the proliferative zone of the tibial growth plate. This decreased GHR abundance can be overcome by combined GH/IGF-I therapy, thus enhancing generation and proliferation of hypertrophic zone chondrocytes and increasing growth-plate width. CONCLUSION: These studies point to a mechanism for the growth retardation seen in children with CRF, and suggest that combined GH/IGF-I treatment may provide more effective therapy for these patients than GH alone.     

Longitudinal analysis of T-helper cell phenotypes in renal-transplant recipients undergoing growth hormone therapy

BACKGROUND: Treatment with recombinant human growth hormone (rhGH) in growth-retarded children after renal transplantation is effective, but there have been concerns regarding the safety of rhGH because of its possible immunomodulatory actions. We therefore evaluated the immune phenotypes of pediatric renal-transplant recipients and controls in response to rhGH with regard to a possible shift toward a T-helper (TH)1-type response. METHODS: Intracellular cytokines, activation markers, costimulatory, and adhesion molecules were studied in 13 children after renal transplantation (Tx+GH). Children with chronic renal failure (CRF+GH, n=11) before and under rhGH therapy and pediatric renal-transplant recipients without rhGH therapy (Tx, n=33) served as controls. Measurements were performed by four-color flow cytometry before and 4, 12, 18 and 24 weeks after initiation of rhGH therapy. RESULTS: Under baseline conditions, Tx+GH patients did not differ from Tx patients. During rhGH therapy in children with transplants, interleukin (IL)-2 production increased threefold at 4 weeks, and IL-4 and IL-13 increased by 70% at 12 weeks. All three cytokines returned to baseline after 18 weeks. No patient experienced rejection. In CRF+GH patients, baseline values for all investigated cytokines were higher than in patients with transplants but did not change in response to rhGH therapy. CONCLUSION: Our data indicates that rhGH therapy in stable, pediatric renal-transplant recipients has a mild and transient immunostimulatory effect in vivo. Immunosuppression and graft function in patients with transplants undergoing rhGH treatment should therefore carefully be monitored.     

The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure

Renal failure is associated with dramatic changes in the growth hormone/insulin-like growth factor (GH/IGF) axis. In children, this results in growth retardation, which is treated with injections of recombinant human GH (rhGH). Given the many recent advances in the knowledge of the components of the GH/IGF axis, it is timely to review the role of GH in renal failure and to discuss likely new treatments for growth failure. Renal failure is not a state of GH deficiency but a state of GH and IGF resistance, making other approaches to manipulating the GH axis more logical than treatment with rhGH alone. Although in children rhGH is safe, in critically ill adults it can be lethal. As the mechanisms of these lethal actions of rhGH are unknown, caution is advised when using rhGH outside approved indications. In renal failure, an optimal balance between safety and efficacy for growth may be achieved with the use of the combination of rhGH and rhIGF-I, as animal studies have shown synergistic growth responses. However, inhibition of the GH axis, with the use of GH antagonists, is likely to be tested clinically given the beneficial effects of GH antagonists on renal function in animal models of renal disease. Manipulating IGF-I by either administering rhIGF-1 or its binding proteins or increasing IGF-I bioavailability with the use of IGF displacers could prove to be a safer and more effective alternative to the use of rhGH in renal failure. In the future, both rhGH and rhIGF-1 likely will be included in growth-promoting hormone cocktails tailored to correct specific growth disorders.     

Longitudinal growth in children following kidney transplantation: from conservative to pharmacological strategies

Impairment of longitudinal growth in children with chronic renal failure (CRF) is multifactorial. It is mainly due to disturbances in the growth hormone (GH)/insulin-like growth factor (IGF)/IGF-binding protein axis. Growth failure can be managed by optimizing nutrition and fluid/electrolyte homeostasis, and overcoming the growth-inhibiting effects of uremia by high-dose recombinant human (rh) GH treatment. A sufficient catch-up growth is one of the determining issues for the overall success of pediatric kidney transplantation (Tx). However, despite satisfactory renal function, spontaneous catch-up growth is often insufficient as glucocorticoid treatment is the main inhibiting factor for longitudinal growth after Tx. In addition, longitudinal growth may be jeopardized by low glomerular filtration rate (GFR) and African American or Hispanic background. Supraphysiological doses of GH and/or IGF-I in vitro and in vivo can partially overcome the growth-inhibiting effects of glucocorticoid treatment. GH-associated increase of leukocyte proliferation and cytotoxicity with stimulated interferon synthesis have been demonstrated. However, it is not clear whether such stimulatory effects on leukocyte function are a transitory or a constant risk factor after organ Tx. Clinical trials of GH in children after renal Tx have suggested a rather moderate or transient effect of rhGH on the immune system, and corticosteroids induce a hyporesponsiveness to the action of GH. As long as corticosteroids are believed to be essential after renal Tx, rhGH should be considered to optimize longitudinal growth in children.     

Recombinant human growth hormone therapy in autosomal recessive polycystic kidney disease

Patients with autosomal recessive polycystic kidney disease (ARPKD) may have growth retardation that is disproportionate to the degree of renal dysfunction. We treated growth-retarded ARPKD patients with recombinant growth hormone (rhGH) and document the response to therapy and effect of rhGH on the rate of progression of renal failure. The diagnosis of ARPKD and congenital hepatic fibrosis was made on the basis of clinical findings and by abdominal ultrasound examinations. Seventeen patients (6 girls/11 boys) aged 0.3-18.3 years were studied. Diagnosis was made prenatally in 6, after birth in 3, and in 8 between 0.33 and 10 years. Follow-up was 2 months to 14.3 years (median 6.9 years). Growth, growth velocity, weight, and bone age were measured before and after treatment with rhGH. Insulin-like growth factor-1 and IGF binding protein 3 were measured prior to rhGH therapy. Five children (1 girl/4 boys) with height Z-scores < or =1.2 (5/17) aged 4.5-11.9 years received rhGH therapy. Duration of rhGH therapy was 0.3-5.4 years. All responded to rhGH (Z-score before -2.8 vs. -1.26 after treatment, P=0.03). An increase in height Z-score was noted 0.5-1.5 years after starting rhGH therapy. There were no side effects from rhGH therapy. The initial Z-score in the untreated group was -0.35 and the final score was -0.64. Initial glomerular filtration rate (GFR) in the treated group was 77 versus 104 ml/min per 1.73 m(2) in the non-treated group. GFR in 3 of 6 growth-retarded patients (<5th percentile) was 38, 65, and 30 ml/min per 1.73 m(2). GFR in 2 of 11 non-growth-retarded patients was 30 and 26 ml/min per 1.73 m(2). The change from initial GFR and final GFR in treated patients was 77 versus 76 ml/min per 1.73 m(2), and non-treated patients 104 versus 89 ml/min per 1.73 m(2) ( P>0.05). Growth failure in ARPKD may be attributable to factors other than chronic renal insufficiency alone. Use of rhGH therapy in ARPKD is safe, effective, and has the potential to improve the physical and psychological well-being of these children.     

Renal effects of growth hormone. I. Renal function and kidney growth

Growth hormone (GH) affects renal function and kidney growth. Pituitary-derived or recombinant human GH (rhGH), acting via insulin-like growth factor-1 (IGF-1), increases glomerular filtration rate (GFR) and renal plasma flow (RPF) in GH-deficient as well as in normal adults. Furthermore, GFR and RPF are low in hypopituitarism and elevated in acromegaly. These effects of GH on GFR and RPF have not been demonstrated in moderate renal insufficiency. IGF-1 is implicated in compensatory renal hypertrophy. Markedly elevated levels of serum GH accelerate glomerular sclerosis in rodents, although the significance of these findings for GH treatment in humans is uncertain. rhGH therapy offers great promise to children with short stature from various aetiologies. Preliminary report on the use of rhGH in children with renal disease and after renal transplantation have not shown any consistent change in kidney function, although follow-up times are short. The long-term impact of rhGH therapy on kidney function in short children needs further evaluation.Part II of this review will be published in Pediatr Nephrol (1992) Volume 6, Number 5     

Plasma levels of soluble CD30 are increased in children with chronic renal failure and with primary growth deficiency and decrease during treatment with recombination human growth hormone.

BACKGROUND: Previous studies have suggested that in vivo Th2 lymphocyte activation is related to increased soluble CD30 (sCD30) plasma levels. As various hormones (dehydroepiandrosterone, glucocorticoids, progesterone) can regulate the Th1/Th2 balance, and because growth hormone (GH) enhances lymphocyte function, we measured sCD30 plasma levels, before and after treatment with recombinant human GH (rhGH), in children with growth failure due to chronic renal failure (CRF) or to isolated GH deficiency in order to evaluate the potential effects of rhGH treatment on Th1/Th2 balance. METHODS: sCD30 plasma levels were determined by ELISA assay in 30 children with CRF (mean age 10.7+/-3.7 years), in five children with isolated GH deficiency (mean age 11.4+/-2.6 years), and in 10 normal controls (mean age 10.1+/-3.5 years). RESULTS: sCD30 levels were higher in the 30 children with CRF than in the 10 controls (179.8+/-79.4 vs 11.3+/-10.9 U/ml, P<0.001) exhibiting an inverse correlation with glomerular filtration rate (GFR) (r=-0.7860, P<0.001). In 11 children with CRF, after 19.9+/-16.7 months of rhGH treatment, a decrease of sCD30 plasma level (170+/-50 vs 134+/-49 U/ml, P<0.01) was observed. The five children with primary GH deficiency had higher sCD30 plasma level than controls (mean 147+/-105 vs 11+/-10 U/ml, P<0.004) and sCD30 plasma levels decreased to 95.2+/-109.6 U/ml after rhGH treatment. CONCLUSIONS: The finding that rhGH treatment decreased sCD30 plasma levels in children with CRF, and that children with primary GH deficiency had higher sCD30 plasma levels than controls, suggest that GH may regulate CD30 expression and possibly the balance of Th1/Th2. Whether the uraemia-induced increase in sCD30 is due to decreased renal excretion, to overproduction or both, remains to be determined.     

Somatic and renal effects of growth hormone in rats with chronic renal failure

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P <0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct. Received June 7, 1996; received in revised form and accepted November 19, 1996     

Recombinant human growth hormone treatment of children following renal transplantation

Nine growth-retarded renal allograft recipients received either thrice weekly or daily subcutaneous recombinant human growth hormone (rhGH) for 6–30 months. The annualized growth velocity for the initial year of rhGH treatment was significantly greater than that of the preceding year (2.5±2.1 vs 5.7±2.7;P<0.0001). There was no advancement in bone age greater than the increase in chronological age, no significant increase in the mean fasting serum glucose or insulin levels, nor significant decrease in the calculated creatinine clearance following rhGH treatment. However, two patients experienced rejection episodes following rhGH treatment indicating the potiental adverse consequences of the treatment on allograft function. This will require further delineation in prospective controlled studies. The serum insulin-like growth factor-1 levels significantly increased at 6 months (P<0.009) and 12 months (P<0.002) following rhGH treatment compared with baseline values. These preliminary data indicate that rhGH treatment may be effective in improving the growth velocity of growth-retarded renal allograft recipients.     

Effect of chronic renal failure and prednisolone on the growth hormone-insulin-like growth factor axis

Abnormalities of the growth hormone (GH)/ insulin-like growth factor (IGF) axis have been reported in children with chronic renal failure (CRF) and post-transplant, and are thought to contribute to poor growth. This study examined the effect of CRF and steroid therapy (given post-transplant and to children with normal renal function) on the GH-IGF axis in children with normal and abnormal growth. Thirty-one children with CRF, ten on dialysis, 26 with renal transplants and ten taking steroid therapy but with normal renal function, were studied. IGF-I, measured by radioimmunoassay, was normal but IGF bioactivity was low in groups with a decreased glomerular filtration rate (P<0.05). Transplanted children growing at a subnormal growth rate had lower IGF bioactivity than those growing at a normal rate (P=0.03), but there was no such difference in bioactivity in children with CRF. There was no correlation between IGF bioactivity and prednisolone treatment. There was no correlation between IGF binding proteins 1, 2 or 3 and growth. Received: 1 August 2000 / Revised: 11 July 2001 / Accepted: 12 July 2001     

Is severe renal osteodystrophy a contraindication for recombinant human growth hormone treatment?

Recent extension of the use of recombinant growth hormone (rhGH) to non-growth hormone-deficient patients necessitates close attention to possible complications in these patients, including effects on bone. Recent studies on the use of rhGH in children with chronic renal failure (CRF) provide some early data. No significant differences in radiographic osteodystrophy scores, serum calcium, phosphorus, or parathyroid hormone (PTH) levels were found between treated and untreated groups. Alkaline phosphatase increased transiently. The effect of renal osteodystrophy on growth response has not yet been reported. Animal models demonstrate that GH stimulates chondrocyte proliferation. Experimental data further suggest that GH can weaken the epiphyseal plate. Slipped capital femoral epiphysis has been reported in GH-deficient patients, before, during, and after GH therapy. In CRF patients treated with GH, slipped capital femoral epiphysis has also been reported. As renal osteodystrophy and hypocalcemia are risk factors for this condition, the relationship to GH therapy is unclear in these patients. Avascular necrosis, known to be associated with slipped capital femoral epiphysis and CRF, has also been reported in patients receiving GH, although the relationship to the therapy is unknown. Children with CRF treated with rhGH should be serially monitored for renal osteodystrophy, slipped capital femoral epiphysis, and avascular necrosis with serial radiographs and serum calcium, phosphorus, alkaline phosphatase, and PTH levels.     

Recombinant human growth hormone treatment of children with chronic renal failure: long-term (1- to 3-year) outcome

Treatment of nine boys, aged 2.8–16.3 years, with growth retardation consequent to chronic renal failure (CRF), with recombinant human growth hormone (rhGH) for 12–36 months demonstrated a significant improvement in growth velocity at each 12-month interval compared with that achieved the year prior to treatment. Despite the acceleration in growth velocity the bone age did not increase more than the increase in chronological age during the period of treatment. The mean calculated creatinine clearance did not decrease significantly during the 36 months of treatment; however, two patients required institution of dialysis at 18 and 30 months following the initiation of rhGH treatment. There was no exacerbation of the glucose intolerance of uremia following rhGH treatment. Currently, six of seven patients who have been treated for more than 24 months have achieved sufficient acceleration of growth velocity to attain a standard deviation score that was more positive than –2.00, and are above the 5th per centile for chronological age on the growth curve. These data indicate that rhGH treatment of growthretarded children with CRF results in accelerated growth velocity during the 2nd and 3rd years of treatment, and demonstrate the potential for such children to achieve normal stature for chronological age despite the continued presence of renal failure.     

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.     

Growth hormone, insulin-like growth factors and their binding proteins in adult hemodialysis patients treated with recombinant human growth hormone.

BACKGROUND: Growth deficiency and malnutrition in uremic children are often caused by malfunction of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis and can be corrected by treatment with GH. The purpose of this study was to evaluate the levels of GH, IGF-I and II and their binding proteins compared to changes in body composition in adult, enfeebled, uremic patients in chronic hemodialysis (HD), treated for 6 months with recombinant human growth hormone (rhGH). METHODS: 31 patients were included in a controlled, randomized, double-blinded study using either 4 IU/m2/day of rhGH or placebo injected subcutaneously every evening for 6 months. RESULTS: Fasting levels of GH were normal at start and increased significantly from 2.2 to 13.5 microg/l (p = 0.01) within the first 4 months of rhGH treatment. Before treatment IGF-I was at the upper limit of normal range (130 to 220 microg/l) in both groups, and it increased significantly from 213 to 348 microg/l (p = 0.01) during rhGH treatment. IGF-II was above the normal range in both groups, and remained unchanged throughout. IGFBP-1 decreased in the rhGH-treated group from 53.1 to 24.7 microg/l (p = 0.004), while IGFBP-3 increased from 5620 to 7100 microg/l (p = 0.004). The molar ratio of IGF-I/IGFBP-3 increased significantly from 14 to 25% (p = 0.01), while the ratio decreased in the placebo group (p = 0.01). During the treatment with rhGH the patients increased their lean body mass (= muscle mass) by a median of 3.18 kg (range 0.82 to 5.12 kg) (p = 0.0001) while their fat mass decreased by a median of 3.33 kg (range 0.18 to 5.82 kg) (p = 0.004). Total body mass (= weight) remained stable. No significant changes were observed in the placebo group. CONCLUSION: The baseline GH and IGF-I concentrations were normal in malnourished HD patients. When treated with rhGH in a dosage as used in growth-retarded uremic children, IGF-I increased to the levels seen in acromegalic persons. IGF-I increased more than IGFBP-3 whereby its biological activity obviously improved. This was reflected in an increased muscle mass and a decreased fat mass. The rhGH treatment was well tolerated.     

Growth hormone prevents steroid-induced growth depression in health and uremia.

Treatment with supraphysiological doses of corticosteroids results in protein wasting and impairment of growth, whereas exogenous growth hormone (GH) causes anabolism and improvement of growth. We wanted to know whether the growth depressing effects of methylprednisolone (MP) are more expressed in an organism which is chronically diseased and whether these effects can be counterbalanced by concomitant treatment with recombinant human growth hormone (rhGH). MP in doses from 1 to 9 mg/kg/day caused a dose dependent reduction of length gain, weight gain and weight gain/food intake ratio in 140 g healthy female Sprague-Dawley rats. Food intake was not affected by MP. This points to a change in food metabolism as a mechanism for growth impairment. In addition, treatment with MP inhibited endogenous GH secretion, documented by serum GH concentration profiles over seven hours, decreased IGF-1 serum concentration and disturbed growth cartilage plate architecture. Concomitant treatment with 2.5 to 20 IU/rhGH/kg/day prevented the negative effects of MP on growth in a dose dependent manner and normalized growth plate architecture. In uremic rats in which food efficiency and growth was already reduced, 6 mg MP/kg/day further decreased length gain and prevented weight gain completely by bringing the weight gain/food conversion ratio to the nadir. All effects of MP including reduction of muscle mass could be prevented by concomitant treatment with 10 IU rhGH/kg/day. The effects of MP and rhGH on food efficiency and growth in uremic animals were numerically nearly identical to those in pair fed ad libitum fed controls, but this may be more relevant in the diseased organism in which basal growth is already suppressed.