Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein-4 (IGFBP-4) and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) have high serum levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), -2, and -6. The excess IGFBP-2 and -1 may play a role in the growth failure of CRF children by sequestering IGF peptides. In contrast, IGFBP-3 levels rise with GH treatment of CRF children, suggesting a role for IGFBP-3 in their accelerated growth. The present studies used sensitive and specific antisera to characterize levels and forms of IGFBP-4 and -5 in serum from CRF children. By RIA, the mean baseline serum level of IGFBP-4 was high in CRF children compared to that in normal children, but the IGFBP-4 level in CRF serum did not correlate with height SD score; by immunoblot, high CRF levels were associated with increases in both intact and fragmented IGFBP-4. Mean RIA levels of IGFBP-5 were comparable in sera from CRF and normal children. Treating CRF children with GH for 12 months increased serum IGFBP-4 levels by 26% and IGFBP-5 levels by 49%, as determined by RIA; levels of IGFBP-5, but not IGFBP-4, correlated significantly with serum levels of IGF-I, IGF-II, IGFBP-3, and acid-labile subunit and with growth rate in these GH-treated children. In summary, IGFBP-4 levels are high in serum of CRF children, and GH increases serum levels of IGFBP-4 and IGFBP-5 in these children. The data suggest a role for IGFBP-5 in the accelerated growth of GH-treated CRF children, perhaps as part of a ternary complex with acid-labile subunit and IGFs. Additional studies on the relationship between intact IGFBP-4 levels and growth are needed to determine what role IGFBP-4 plays in the linear growth process in vivo.

Metabolic consequences of 5-year growth hormone (GH) therapy in children treated with GH for idiopathic short stature. Genentech Collaborative Study Group.

In a multicenter study the metabolic effects of 5 yr of GH therapy in children with idiopathic short stature were evaluated. Patients received 0.3 mg/kg.week recombinant human GH. Of the 121 patients who entered the study, data for 62 were analyzed at the final 5 yr point. Routine laboratory determinations were available for all 62 subjects at the 5 yr point. Special laboratory determinations, such as postprandial glucose and insulin, were available for only a subset of patients. Mean insulin-like growth factor I levels rose to 283 +/- 101 micrograms/L, within the normal range using age-appropriate reference standards. T4, cholesterol, triglycerides, blood chemistries, and blood pressure showed no significant changes during the 5-yr period. Mean baseline and 2-h postprandial glucose levels remained unchanged. Both fasting and postprandial insulin levels rose substantively from low normal levels to the normal range (median, 4.9-43 mU/L). Mean hemoglobin A1c levels remained within the normal range throughout the study. In summary, careful monitoring has not revealed any currently discernible metabolic side-effects of clinical significance after GH therapy in this 5-yr study of children with idiopathic short stature.

Insulin-like growth factor-binding protein-6 levels are elevated in serum of children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.

Previous studies suggest that growth retardation in children with chronic renal failure (CRF) results in part from inhibition of insulin-like growth factor (IGF) action by excess serum IGF-binding proteins (IGFBPs). Excess IGFBPs in CRF serum include IGFBP-1, -2, and -3 and a diffuse approximately 24- to 28-kDa IGFBP band identified by [125I]IGF ligand blot. The present studies characterized this diffuse approximately 24- to 28-kDa band. Initial studies identified this band as IGFBP-6, because it was immunoprecipitated by antiserum raised against a synthetic peptide of human IGFBP-6 (hIGFBP-6). Additional [125I]IGF ligand blots found that the immunoprecipitated band was 1) recognized by [125I]IGF-II but not [125I]IGF-1, 2) more abundant in CRF than in normal serum, and 3) more abundant in serum from dialyzed than nondialyzed prepubertal CRF children. Using the hIGFBP-6 antiserum in a specific and sensitive RIA, we found that serum IGFBP-6 levels were 4.7 +/- 1.7 nmol/L in 10 normal prepubertal children, 21.4 +/- 6.1 nmol/L in 44 nondialyzed prepubertal CRF children, 73.5 +/- 14.4 nmol/L in 7 dialyzed prepubertal CRF children, and 94.6 +/- 26.2 nmol/L in 14 dialyzed pubertal CRF children. IGFBP-6 levels were also elevated in 71 nondialyzed European children with CRF. In nondialyzed CRF children, serum IGFBP-6 levels 1) correlated inversely with the glomerular filtration rate, 2) did not correlate with height SD score, and 3) were not altered by 12 months of daily recombinant hGH treatment. In summary, a specific antiserum and RIA were used to demonstrate elevated levels of intact IGF-II-binding IGFBP-6 in serum of CRF children. We postulate that the excess IGFBP-6 may modulate the action of IGF-II on target tissues.

Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group.

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 hormone treatment in the United States: demographic and diagnostic features of 2331 children.

Demographic, diagnostic, and baseline clinical data were collected for a large cohort (N = 2331) of children who started treatment with biosynthetic human growth hormone (GH) between October 1985 and October 1987. Eighty-one percent met classic criteria for GH deficiency and were classified as having idiopathic GH deficiency (59%), organic GH deficiency (18%), or septo-optic dysplasia (4%). The remaining 19.8% had short stature of varied causes. Height standard deviation score at diagnosis, maximum GH response to stimulation, and heights of parents were examined according to gender, race, age at diagnosis, and previous treatment history. The predominance of boys in all subgroups except septooptic dysplasia, and the observation that girls with idiopathic GH deficiency were comparatively shorter than boys at diagnosis, suggest ascertainment bias. Black children with idiopathic GH deficiency were shorter than white children at diagnosis, and their low overall representation (6.0%) compared with their percentage in the at-risk population (12.9%) also suggest ascertainment bias among races. These data provide a profile of GH deficiency as it is currently defined and expose possible inherent biases in the diagnostic process. Now that GH supply is no longer limited, criteria for its use should be formulated to avoid apparent underascertainment or late diagnosis of GH deficiency in girls and black children.

Equivalent potency and pharmacokinetics of recombinant human growth hormones with or without an N-terminal methionine.

Two forms of human GH (hGH) have been produced by recombinant DNA technology. One form has an amino acid sequence identical to that of the natural pituitary hormone (rhGH) and the other form has an additional N-terminal methionine (Met-hGH). The biological potencies of these 2 polypeptides have been compared in hypophysectomized rats in a multidose study measuring body weights and several long bone growth parameters. The pharmacokinetic profiles after iv and sc injection were determined in cynomolgus monkeys in a 4-period cross-over study. All of the measured parameters in all the studies indicated that there was no difference in the two forms of hGH. Measurements taken after 27 daily injections of rhGH or Met-hGH (30-500 micrograms/kg.day) indicated that femur length and width of the proliferative zone in the tibial epiphysis showed dose-related effects for both forms of hGH but no difference between them. The relative potency, based on body weight gain, was calculated using a parallel line bioassay. Weight gain after 8 daily injections in the 5-dose long bone growth study indicated a rhGH potency of 0.80 (95% confidence interval, 0.5-1.23) relative to Met-hGH. It was concluded that the presence of an N-terminal methionine on hGH has no effect on potency in this model. The pharmacokinetic parameters after iv administration were estimated by fitting serum concentration-time data to a 2-compartment model. Parameters after sc injection were computed by compartment-independent methods. Met-hGH and rhGH had very similar pharmacokinetic profiles after both routes of administration. Comparison of the pharmacokinetic parameters indicated that the clearance after iv administration (rhGH, 15 ml/min; Met-hGH, 13 ml/min) and the sc bioavailability (rhGH, 0.72 +/- 0.21; Met-hGH, 0.59 +/- 0.21) were not significantly different for the 2 forms of hGH. It was concluded that rhGH and Met-hGH have equivalent bioavailability and pharmacokinetics in cynomolgus monkeys.

Carbohydrate and lipid metabolism in Turner syndrome: effect of therapy with growth hormone, oxandrolone, and a combination of both.

To evaluate the effects of growth-promoting therapy on carbohydrate metabolism in girls with Turner syndrome, we determined glucose and insulin concentrations during oral glucose tolerance tests (OGTTs) at baseline and after 5 days, 2 months, and 12 months of treatment with growth hormone (GH), oxandrolone, or a combination of GH and oxandrolone, or after the same intervals with no therapy. Before therapy, subjects had a significantly greater glucose response during OGTT than published normal control values. There were no significant changes in mean fasting glucose, cholesterol, or triglyceride concentrations in any of the treatment groups. The integrated glucose concentrations rose significantly over baseline values in the oxandrolone group at 2 and 12 months and in the combination group at 5 days. There were significant increases in the mean integrated insulin concentrations at 2 and 12 months for the group receiving oxandrolone alone and at all three times for the group receiving combination therapy. Thus oxandrolone, alone or in combination with GH, had significant effects on carbohydrate metabolism in subjects with Turner syndrome, whereas GH alone did not.

Effects of bacteria-produced human alpha, beta, and gamma interferons on in vitro immune functions.

The effects of bacteria-produced human interferons (HuIFN) alpha, beta, and gamma on in vitro immune functions of human peripheral blood mononuclear cells (PBMC) were studied. Proliferative response to phytohemagglutinin was significantly inhibited by the addition of HuIFN-alpha 2 or HuIFN-beta at 10, 100, or 1000 U/ml. In contrast, HuIFN-gamma showed suppressive activities only when added at 1000 U/ml. HuIFN-alpha 2 or HuIFN-beta caused significant inhibition of human mixed-lymphocyte reaction (MLR) as measured by [3H]thymidine incorporation. Similar inhibition was caused by HuIFN-gamma when it was added only at very low concentrations (1 U/ml); 10, 100, or 1000 U/ml resulted in no or only a modest increase in MLR. All three interferons exhibited dose-related effects on PWM-induced immunoglobulin synthesis in cultures of PBMC. These data demonstrate that purified interferons produced by recombinant DNA technology can significantly alter in vitro immune functions and that HuIFN-gamma has properties which are different from those of HuIFN-alpha 2 or HuIFN-beta.