Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial. Placebo-controlled, double-blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Double blind trial comparing the effects of two doses of growth hormone in prepubertal patients with chronic renal insufficiency. Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized double-blind placebo-controlled study. Genentech Cooperative Study Group. Recombinant human growth hormone post-renal transplantation in children: a randomized controlled study of the NAPRTCS. Recombinant human growth hormone treatment, using two dose regimens in children with chronic renal failure--a report on linear growth and adverse effects. Randomised controlled trial of recombinant human growth hormone in prepubertal and pubertal renal transplant recipients. British Association for Pediatric Nephrology. Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group. Growth hormone treatment in growth-retarded adolescents after renal transplant. Growth hormone and the skeleton in pediatric renal allograft recipients.
Our aim was to evaluate the growth-promoting effect of growth hormone (GH) treatment in infants with chronic renal failure (CRF) and persistent growth retardation despite adequate nutritional and metabolic management.
                The study design included randomized, parallel groups in an open, multicenter trial comparing GH (0.33 mg/kg per wk) with nontreatment with GH during 12 months. Sixteen infants who had growth retardation, were aged 12+/-3 months, had CRF (GFR<or=60 ml/min per 1.73 m2), and had adequate nutritional intake and good metabolic control were recruited from eight pediatric nephrology departments from Spain and Portugal. Main outcome measures were body length, body weight, bone age, biochemical and hormonal analyses, renal function, bone mass, and adverse effects.
                Length gain in infants who were treated with GH was statistically greater (P<0.05) than that of nontreated children (14.5 versus 9.5 cm/yr; SD score 1.43 versus -0.11). The GH-induced stimulation of growth was associated with no undesirable effects on bone maturation, renal failure progression, or metabolic control. In addition, GH treatment improved forearm bone mass and increased serum concentrations of total and free IGF-I and IGF-binding protein 3 (IGFBP-3), whereas IGF-II, IGFBP-1, IGFBP-2, GH-binding protein, ghrelin, and leptin were not modified.
                Infants with CRF and growth retardation despite good metabolic and nutritional control benefit from GH treatment without adverse effects during 12 months of therapy. Stunted growth is a serious problem for children with chronic renal failure (CRF) despite normal endogenous growth hormone secretion and normal or elevated plasma concentrations of insulin-like growth factors (IGF) I and II. Biosynthetic growth hormone (GH) was given to 20 prepubertal children (eleven boys, nine girls; mean age 9.5 years, range 4-16) with CRF and severe growth retardation in a placebo-controlled, double-blind, cross-over trial. 6 months of subcutaneous injection of GH (4 IU/m2 per day) was either preceded or followed by 6 months of placebo injection. The patients had a full examination every 3 months. Sixteen children completed the study. Height velocity improved significantly with GH therapy (p less than 0.0001) and placebo (p less than 0.04), but the GH-induced height-velocity increase exceeded that of placebo by 2.9 cm per 6 months. There was a positive relationship between prestudy height velocity and height-velocity increase. Bone maturation was not affected. GH caused a significant increase in IGF-I and a moderate increase in IGF-II plasma concentrations. The pretreatment elevation of IGF-binding protein-1 decreased by almost 50% during GH therapy, while IGF-binding protein-3 increased significantly in concentration, although this increase was significantly smaller than the GH-induced increase in IGF-I. Fructosamine, lipid, and parathyroid concentrations remained constant. Renal function deterioration did not accelerate. Impressive height-velocity increase can be achieved with GH therapy in children with CRF and growth retardation without changes in renal function. Bone maturation appears unaffected suggesting improved final height. Treatment is best started before growth retardation becomes considerable. Growth retardation is a major problem for children with chronic renal insufficiency (CRI). Recent studies have convincingly shown that recombinant human GH accelerates growth significantly, but the optimal GH dose with regard to long term growth response and safety has not yet been established. GH therapy was given to 23 prepubertal children (18 boys and 5 girls; mean +/- SD age, 7.1 +/- 3.6 yr; range, 1.6-14.1) with CRI and severe growth retardation in a double blind, dose-response trial. Patients were randomly assigned to either 2 or 4 IU GH/m2.day for 2.5 yr. During the first 6 months, there were comparable and significant increases in height velocity SD score for chronological age with both doses (P < 0.001). However, during the ensuing 2 yr, the higher GH dose induced a significantly greater improvement in height velocity SD score for chronological age than 2 IU GH. Catch-up growth was only sustained for 2.5 yr with 4 IU. In contrast, catch-up growth ceased after 6 months with 2 IU. Neither 2 nor 4 IU GH resulted in accelerated bone maturation during 2.5 yr of therapy. There was a significant increase in plasma insulin-like growth factor-I (IGF-I) levels with either dose, but significantly more so with 4 IU. Plasma IGF-II levels only increased significantly with 4 IU. The pretreatment elevation of IGF-binding protein-1 (IGFBP-1) levels decreased by 50% during the first study year with the higher GH dose, whereas there was no decrease with 2 IU. The elevated pretreatment IGFBP-3 levels increased comparably and significantly with either GH dose. Interestingly, only 4 IU resulted in a significantly greater increase in IGF-I than in IGFBP-3 levels. Regardless of GH dose, there was an insignificant decrease in fructosamine levels, whereas lipid and parathyroid concentrations remained constant. Renal function deterioration did not accelerate. GH therapy with 4 IU/m2.day induced and maintained catch-up growth during 2.5 yr in children with CRI without evidence of adverse effects. Bone maturation did not accelerate. This suggests that this higher GH dose may be beneficial for children with severe growth retardation secondary to CRI. To determine whether treatment with recombinant human growth hormone (rhGH) enhances growth rate in growth-retarded children with chronic renal failure.
                One hundred twenty-five prepubertal growth-retarded children with chronic renal failure were randomly assigned to receive either rhGH (n = 82) or placebo (n = 43) for 2 years.
                The study was undertaken at 17 pediatric nephrology centers in the United States.
                Growth rate, standardized height, bone age, fasting and 2-hour postprandial glucose and insulin levels, biochemical values, and insulin-like growth factor I and anti-growth hormone antibody levels were evaluated serially during the 2-year study period.
                Standardized height increased from -2.94 to -1.55 in the rhGH group after 24 months of treatment, and decreased from -2.82 to -2.91 in the placebo group (p < 0.00005). Patients in the rhGH group who completed 24 months of study (n = 55) had a greater growth rate during the first year (10.7 +/- 3.1 cm/yr) than during the second year (7.8 +/- 2.1 cm/yr) of treatment. These growth rates were significantly greater than those in the placebo group (n = 27) in the first (6.5 +/- 2.6 cm/yr) and second (5.5 +/- 1.9 cm/yr) years (p < 0.00005 for both years). The mean delta height age minus the delta bone age was positive in the rhGH group, suggesting improved final height potential. There was no significant difference in the change in calculated creatinine clearance over baseline values in the rhGH group from that in the placebo group after 24 months of study (p = 0.63). Mean fasting and postprandial insulin values were elevated at 12 months but not at 24 months in the rhGH-treated patients. Mean fasting and 2-hour postprandial glucose values at 24 months were not significantly elevated over baseline values in either group.
                Growth rate and standardized height were significantly increased in growth-retarded prepubertal children with chronic renal failure when rhGH was used. The acceleration in growth was not associated with undue advancement of bone age. No clinically significant side effects were associated with rhGH treatment. The use of rhGH in growth-retarded children with chronic renal failure may facilitate the achievement of the inherent growth potential of such children. Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken.
                Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment.
                After one year, the delta SDS (standardized height) was +0.49 +/- 0.10 in the treatment group (N = 30) compared to -0.10 +/- 0.08 in the control group (N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups.
                In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events. The aim of this study was to study the efficiency and the adverse effects of 2 or 4 IU/m2/day of growth hormone (GH) in the first year and 4 IU/m2/day in the second. Of 29 growth-retarded children with chronic renal failure (CRF) (aged 3.4-15.1 years), 23 completed the first year of therapy, and 16 completed the second year. Height velocity SDS (HVSDS) increased in the first year in the low-dose group with 3.0, and 3.8 in the high-dose group. In the second year, HVSDS increased by 1.3 in the low-dose group and by 2.1 in high-dose group (p < 0.05). The IGF-I/IGFBP-3 ratio rose identically during the first year (p < 0.01). The retarded bone age did not advance inappropriately. The integrated insulin levels (AUC) increased significantly after 1 year of therapy in both groups. HbA1c, levels did not change. The number of adverse events was highest in the low-dose group, in which one patient developed overt insulin dependent diabetes mellitus. In conclusion, glucose metabolism should be monitored in children with CRF during rhGH-treatment. GH therapy in our patients resulted in a significant increase in height velocity with no inappropriate bone age progression and few serious adverse effects, all without relation to the dose of rhGH. The low start dose (2 IU/m2/ day) was of no advantage compared to the high dose. To evaluate the efficacy (height velocity (HV), change in height standard deviation score (delta HSDS)), and safety (glomerular filtration rate (GFR), incidence of rejection, and calcium and glucose metabolism) of recombinant human growth hormone (rhGH) treatment after renal transplantation.
                A two year randomised controlled trial.
                Fifteen prepubertal and seven pubertal children: mean (SD) age, 13.0 (2.6) and 15.2 (2.4) years, respectively; mean (SD) GFR, 51 (30) and 48 (17) ml/min/1.73 m2, respectively. Six prepubertal and three pubertal children were controls during the first year; all received rhGH in the second year.
                In the first year, mean (SE) HV and delta HSDS in the prepubertal treated group increased compared with controls: 8.1 (0.9) v 3.7 (0.6) cm/year and 0.6 (0.1) v -0.3 (0.2), respectively. In the pubertal treated group, mean (SE) HV and delta HSDS were also greater: 10.1 (0.6) v 3.9 (1.3) cm/year and 0.6 (0.1) v -0.1 (0.2), respectively. Comparing all treated and control children, there was no significant change in GFR: treated group, mean (SE) 9.9 (5.4) ml/min/1.73 m2 v control group, -1.6 (7.6) ml/min/1.73 m2. There were also no differences in the incidence of rejection in the first year: eight episodes in 13 patients v five episodes in nine patients, respectively. Phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and fasting insulin concentrations rose during the first year of treatment, but not thereafter. In the second year of treatment, HV remained above baseline.
                Treatment with rhGH improves growth in prepubertal and pubertal children with renal transplants, with no significant change in GFR or the incidence of rejection. Phosphate, ALP, PTH, and insulin increased during the first year of treatment. Anthropometric measurements and circulating growth factors were studied serially in 44 prepubertal children with growth failure and chronic renal failure (GFR = 10 to 40 ml/min/1.73 m2) who were randomized to receive either recombinant human growth hormone (rhGH; N = 30) or no treatment (N = 14). RhGH was given as Nutropin, 0.05 mg/kg/day, and the studies were carried out at baseline and after 3 and 12 months. At baseline, serum insulin-like growth factor binding protein (IGFBP)-1 and -2 levels were, while IGFBP-3 levels were not, higher than those of children with normal renal function. In addition, height SDS at baseline correlated inversely with serum IGFBP-2 levels (r = -0.461, P = 0.0016), but did not correlate significantly with any other factor. After 12 months of study, the 30 children receiving rhGH showed: (i) greater increase in height (9.1 +/- 2.8 vs. 5.5 +/- 1.9 cm, P < 0.0001); (ii) increases in serum levels of IGF-I, IGF-II, free IGF-I, IGFBP-3 and acid labile subunit (ALS); (iii) a greater decrease in serum IGFBP-1 levels; and (iv) no significant difference in serum IGFBP-2 levels, when compared to the 14 control patients. The change in height SDS after 12 months of rhGH (+0.8) in the 30 treated children correlated significantly and positively with serum ALS, IGFBP-3, total IGF, IGF-I, IGF-II and free IGF-I levels measured during treatment. These observations suggest that, in children with growth failure associated with chronic renal failure: (i) IGFBP-2, and not IGFBP-3, is likely to be a growth inhibitor; (ii) rhGH stimulates catch-up growth in part by increasing serum levels of IGF peptides; and (iii) linear growth is influenced by the balance between growth stimulating IGFs and growth inhibitory IGFBPs. Growth failure is a psychosocial problem for many patients who have undergone renal transplantation. 18 adolescents (mean age 15.6, range 11.3-19.5) with severe growth retardation after renal transplantation were treated with biosynthetic growth hormone (GH) for 2 years. All received prednisone, administered daily or on alternate days, with azathioprine and/or cyclosporin A. 16 were blindly assigned to one of two GH doses (4 vs 8 IU per m2 per day). Growth, bone maturation, renal graft function, plasma insulin-like growth factors, serum binding proteins, and other biochemical parameters were checked regularly. Glomerular filtration rate and effective renal plasma flow were tested with 125I-Thalamate and 131I-Hippuran. Data on growth and glomerular filtration rate during GH treatment were also compared with those of matched non-GH-treated controls. Mean (standard deviation) increment in height after 2 years of GH was 15.7 (5.1) cm, significantly greater (p < 0.0001) than in matched controls, 5.8 (3.4) cm. Results were similar for the two GH dosage groups. Bone maturation was not accelerated. Glomerular filtration rate and effective renal plasma flow did not change significantly. The incidence of a > 25% reduction in glomerular filtration rate over 2 years was not significantly higher in GH-treated patients than in non-GH-treated controls (39% vs 32%, p = 0.97). Although a few patients had deterioration of graft function, we could not find a relation with GH treatment. Our results show that sustained improvement of height can be achieved with GH in severely growth-retarded adolescents after renal transplantation. Recombinant human growth hormone has been utilized to augment linear growth in pediatric renal allograft recipients. The skeletal changes that accompany growth hormone therapy have not been described in children. Thus, 23 stable prepubertal pediatric kidney recipients, aged 10 +/- 3 years, with a mean transplant time of 3.4 +/- 2.5 years and histological findings of normal bone formation and adynamic bone on bone biopsies were prospectively randomized into two groups. These comprised a treated group that received 12 months of growth hormone and a control group that did not receive any treatment. Anthropometric measurements and blood for serum calcium, phosphorus, parathyroid hormone (PTH), osteocalcin, and insulin-like growth factor-I (IGF-I) were obtained every 3 months. Measurements of bone mass by dual-energy X-ray absorptiometry were performed at the beginning and end of the study period. All patients underwent an initial and final bone biopsy procedure after double tetracycline labeling. Annual growth velocity increased and standard deviation scores for height improved in the treated group. Serum IGF-I levels increased in the treated group and the increase was evident in patients with normal bone formation who received growth hormone but not in patients with adynamic bone. Serum calcium, phosphorus, osteocalcin, and PTH levels did not differ between the treated and control groups. Bone mass did not change in the treated group, but declined after 12 months in the control group. Bone formation rates did not increase with growth hormone treatment. Thus, growth hormone therapy improves linear growth and maintains bone mass, but does not favorably affect bone formation rates in stable pediatric renal allograft recipients.