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     

Effects of growth hormone on kidney function in pediatric transplant recipients

Recent evidence suggests that treatment with recombinant human growth hormone (rhGH) after a successful kidney transplant improves the growth rate of children with short stature. We prospectively investigated eight children (6 boys, 2 girls), focusing on acute rejection episodes and changes in serum creatinine levels during rhGH treatment. The children (mean age 11.6±3.4 years) received rhGH daily (0.04–0.05 mg/kg subcutaneously). Seven patients completed at least 12 months (20±8 months) of rhGH treatment. Their mean serum creatinine level was 1.3±0.7 mg/dl 12 months before, and increased to 3.4±4.2 mg/dl after 12 months of rhGH treatment, but did not achieve statistical significance (P=0.06). Their mean calculated glomerular filtration rate was 58±20 ml/min per 1.73 m² 12 months before, and decreased to 38±21 ml/min per 1.73 m² 12 months before, and decreased to 38±21 ml/min per 1.73 m² after 12 months of rhGH treatment, but did not achieve statistical significance (P=0.08). Of the seven patients, two developed acute rejection after 5 and 6 rejection-free years; three lost their grafts and returned to dialysis. These preliminary observations describe untoward renal events in children receiving rhGH treatment after a kidney transplant.     

Effects of grwoth hormone therapy and malnutrition on the growth of rats with renal failure

We examined the effects of methionylhuman growth hormone (met-hGH) and malnutrition on the growth of 5/6 nephrectomized rats and sham-operated controls. One group of shamoperated rats (PFS) was pair-fed with a group of nephrectomized rats in renal failure (RF); another group of sham-operated rats was fed ad libitum (ALS), and a final group of rats with renal failure (RF-GH) was treated with 4 IU/day met-hGH. After 4 weeks, RF-GH rats gained 12.3±1.7 cm in length; this was more than the 10.2±1.2 cm gain of RF rats (P<0.05). Ingested food was converted into weight gain more efficiently by RF-GH rats than RF rats (267±26 vs 235±38 mg weight gain/g food intake,P<0.05). RF-GH rats also gained more weight (122±25 g) than RF rats (98±27 g), but this difference was not significant (0.05<P<0.1). Insulin-like growth factor (IGF)-I, glucose and insulin levels were not different between RF and RF-GH rats. Food intake of RF and PFS rats was 64% of ALS intake and was associated with poor gains in weight and length by the PFS and RF groups (relative weight and length gains were ALS>PFS>RF,P<0.05 for all comparisons); this suggests that the poor growth of RF rats when compared with PFS rats was due to factors other, than food intake. Serum IGF-I levels of 771±249 ng/ml in PFS rats were lower than levels of 1109±253 ng/ml found in the ALS group (P<0.05); this is consistent with the malnourished state of PFS rats. Serum IGF-I levels in RF rats (950±236 ng/ml) were not different from ALS or PFS levels despite the fact that RF rats gained less weight and length than either the ALS or PFS rats. We conclude that RF rats increase in length, use ingested calories more efficiently, and fail to develop marked insulin resistance when treated with met-hGH. We find that, in addition to poor food intake, other factors contribute to growth failure in this model of renal failure. Finally, we find that RF rats have normal levels of IGF-I, suggesting that low IGF-I levels are not a major cause of growth failure in rats with renal failure.     

Carbonic adsorbent AST-120 retards progression of renal failure by additive effect with ACEI and protein restriction diet

Background. In order to slow the progression of chronic renal failure (CRF), a multimodal approach should be applied if the efficacy is proved. Although compelling evidence of a beneficial effect exists for the use of angiotensin-converting enzyme inhibitors (ACEIs) and low-protein diets, there is little evidence on whether carbon adsorbent has an effect on retardation of the progression of CRF.Methods. In experiment 1, we examined whether the oral carbon adsorbent, AST-120, conferred an additive effect with captopril and an 80% restriction diet on the survival rate of 3/4 nephrectomized rats (3/4 NX). The 3/4 NX rats were divided into three groups (C, control, n = 7; AD, captopril (an ACEI) +80% restriction diet (RD), n = 8; and ADK, ACEI + RD + AST-120, n = 8) and survival was observed for 72 weeks. In experiment 2, 3/4 NX rats were divided into four groups (C, control, n = 4; D, 80% restriction diet, n = 4; AD, temocapril + RD, n = 9; and ADK, temocapril + RD + AST-120, n = 9) for the examination of renal function, blood pressure, hematocrit (Ht), serum albumin, and proteinuria every month. We analyzed morphological changes in the kidney at 48 weeks.Results. In experiment 1, ADK did not improve the survival rate compared with AD, although ADK prolonged the survival significantly compared with C (C vs AD, P = 0.24; C vs ADK, P = 0.0007; AD vs ADK, P = 0.073). In experiment 2, renal function and proteinuria were significantly ameliorated in the ADK group compared with AD at 48 weeks. Concomitantly with the preservation of renal function, pathological indices, including the glomerular sclerosis index and the interstitial fibrosis index, were significantly improved in ADK compared with AD. In the ADK group, Ht and serum albumin did not change over the 48 weeks.Conclusions. Administration of AST-120 in addition to an ACEI and a restriction diet preserves renal function independently of blood pressure control, angiotensin II inhibition, and protein restriction in 3/4 NX rats at 48 weeks, but does not improve the survival significantly.     

Daily but not pulse calcitriol therapy improves growth in experimental uremia

Calcitriol (C) pulse therapy is widely used to suppress secondary renal hyperparathyroidism. However, high C serum concentrations may have an antiproliferative effect on growth cartilage cells and may suppress growth rate. The study was designed to evaluate whether daily C and pulse C therapy have differential effects on growth in uremic rats. Female Sprague-Dawley rats (150 g, n=5–10 per group) underwent two-stage subtotal nephrectomy (U). The duration of uremia was 14–18 days. The animals were fed a standard diet or a diet with a low-calcium content. Rats on a low-calcium diet were randomized for recombinant human growth hormone (rhGH) treatment (2.5 IU/kg per day) or solvent. C was injected subcutaneous twice daily (15 pmol/day) or intraperitoneal (105 pmol) twice per week. Weight gain and length gain was determined weekly. After sacrifice, total body calcium was determined by total body neutron activation analysis. Bone micromorphometric analysis of third lumbar vertebra and double staining with tetracycline for determination of mineralization rate were performed. Whereas daily C significantly increased total body length gain within 2 weeks, pulse C did not (U solvent 4.0±0.3 cm, UC bolus 4.3±0.4 cm, UC daily 5.3±0.3 cm, P<0.05). A low-calcium diet reduced and rhGH increased basal length gain and weight gain; regardless of these preconditions, daily but not bolus C increased length gain significantly. C both daily and in bolus form reduced bone osteoid content, but daily C improved mineral apposition rate more than C bolus. Total body calcium corrected for body weight decreased with a low-calcium diet, was lowest with concomitant rhGH treatment, and was not improved by C. In conclusion, daily but not bolus C treatment improves growth in uremic rats. Received: 5 October 1999 / Revised: 1 February 2000 / Accepted: 10 February 2000     

The immune status of uraemic children/adolescents with chronic renal failure and renal replacement therapy

In adults with chronic renal failure (CRF) and/or renal replacement therapy (RRT) various immunological abnormalities have been described, but few data are available for the paediatric age group. We performed basic in vitro immunological studies in 26 patients 10 months–19 years of age with advanced renal failure, 11 with CRF (creatinine clearance 16.8±5.2 ml/min per 1.73 m²), 15 on RRT with haemodialysis (HD;n=9) and continuous ambulatory peritoneal dialysis (CAPD;n=6) as well as in 16 healthy controls. None had clinical evidence of deranged immune function. No significant differences were found in the percentages of B- and T-cells, T-cell subsets CD3, CD4, CD8 and mitogenic responses to phytohaemagglutinin and concanavalin A (Con A) between RRT patients (HD=CAPD) and control children. Most parameters in CRF patients were also normal, although they had a low percentage of B-cells (12.1±4.1; RRT: 19.7±6.5; controls: 18.5±7.1;P<0.01), relatively low levels of serum immunoglobulin G (948.4±209.4 mg/dl; HD: 1374.7±235.2 mg/dl;P<0.01; CAPD: 966.3±430.2 mg/dl, NS) and a high normal response to Con A (34.3±13.6 cpm ×10^–3; RRT: 34.5±11.3 cpm ×10^–3; controls: 23.4±9.9 cpm ×10^–3,P<0.01). All these values were, however, well within the normal accepted range. These data indicate that children/adolescents with CRF and/or RRT have no significant basic in vitro immunological defects. This study did not test the functional immune status of the young uraemic patients.     

Growth hormone and the kidney: the use of recombinant human growth hormone (rhGH) in growth-retarded children with chronic renal insufficiency.

Hypothalamic production of growth hormone releasing hormone stimulates the anterior pituitary gland to release growth hormone (GH). The clinical manifestations of GH on tissues are either direct or are mediated by insulin-like growth factors (IGF). Both the somatic effects of GH and the renal manifestations of an increase in glomerular filtration rate and renal plasma flow are mediated by IGF. The increase in glomerular filtration rate/renal plasma flow that occurs with either exogenous or endogenous GH is not apparent in patients with chronic renal failure (CRF); therefore, it is unlikely that recombinant human growth hormone (rhGH) treatment of patients with CRF will result in glomerular hyperfiltration. Longitudinal studies are required to determine if the glomerulosclerosis and renal functional impairment occurring in GH and growth hormone releasing hormone transgenic mice occurs after rhGH treatment of growth-retarded uremic rats with GH resulted in an improvement in growth velocity. This led to preliminary studies in growth-retarded children with CRF by using rhGH. The acceleration of growth velocity was dramatic despite the fact that GH levels are elevated in uremia. The elevated IGF carrier proteins in uremic children may contribute to the growth retardation. Treatment with rhGH may be efficacious by stimulating a net increase in the free (unbound) IGF levels. Hyposecretion of GH may contribute to the failure to achieve optimal growth after successful renal transplantation. Treatment with rhGH may be efficacious in improving the growth velocity of renal allograft recipients.     

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.     

Recombinant human growth hormone in infants and young children with chronic renal insufficiency

Children with chronic renal insufficiency (CRI) secondary to congenital structural abnormalities frequently have significant growth retardation by 2 years of age. In a multicenter placebo-controlled study of the use of recombinant human growth hormone (rhGH), 30 of 125 (24%) participants were<2.5 years of age at enrollment. Since the treatment arms of the study were balanced for age at randomization, data for these patients were examined for efficacy and safety. During the first 2 years of the study, approximately two-thirds of the patients (n=19) received rhGH 0.05 mg/kg per day subcutaneously and one-third (n=11) received placebo injections. At entry into the study, the mean (± SD) calculated creatinine clearance was 29.2±14.3 (range 12.0–63.7) ml/min per 1.73 m² in the rhGH-treated group and 23.3±15.1 (range 8.0–59.4) ml/min per 1.73 m² in the placebo-treated group. The 1st year growth rate was 14.1±2.6 cm/year for the rhGH-treated group and 9.3±1.5 cm/year in the placebo-treated group (P<0.00005). During the 2nd year of the study, the growth rate was 8.6±1.2 cm/year in the rhGH-treated group compared with 6.9±1.0 in the placebo groupP=0.025). The height standard deviation score was +2.0±0.7 for the rhGH-treated group compared with –0.2±1.1 in the placebo-treated group (P<0.00005) during the 2 years of the study. Minor adverse events occurred with similar frequency in both groups. These data suggest that rhGH is efficacious and safe in children with CRI under age 2.5 years. rhGH therapy may correct significant loss of growth at this age when used in conjunction with optimal medical management.     

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

Body composition is altered in children with chronic renal failure (CRF) and contributes to the significant growth failure seen in these children. Recombinant human growth hormone (rhGH) has been used in the past several years to improve the somatic growth of children with CRF. To determine if the growth achieved in these children occurs concomitantly with body compositional changes, seven prepubertal (n=6) and pubertal (n=1) children with chronic renal insufficiency (n=4) and end-stage renal disease (n=3) underwent measurements of total body fat (FM), fat free mass (FFM), bone mineral density (BMD), total bone mineral mass (TBBM), total body water (TBW), and total body potassium (TBK) before and 6 months after initiation of subcutaneous recombinant human growth hormone (rhGH) at 0.35 mg/kg per week. The techniques used included dual- energy X-ray absorptiometry (for measurement of FM, BMD, and TBBM), total body potassium counting (for measurement of TBK), and deuterated water for assessment of TBW. Significant increases in both height and weight were seen following 6 months of rhGH therapy. These increases were accompanied by significant re- ductions in FM (4.4±1.4 kg vs. 3.6±1.2 kg, P=0.002) and percentage fat (18.6±3.9% vs. 14.5±3.4%, P=0.04), while FFM (17.9±3.0 kg vs. 20.7±3.6 kg, P=0.04) increased significantly as did TBBM (776±171 g vs. 844±177 g, P=0.001). Increases in TBK, a measure of body cell mass, were also seen. No difference in total BMD was observed. Thus, growth in CRF is occurring with repletion of the FFM and TBBM compartments. Despite these improvements, no change was observed in the body mass index (BMI). Measurement of BMI alone does not define the compartmental catabolic losses in FFM. Received: 20 September 1999 / Revised: 31 January 2000 / Accepted: 8 February 2000     

Accelerated growth in short children with chronic renal failure treated with both strict dietary therapy and recombinant growth hormone

In a 12-month study, nine boys, aged 4.8–15.6 years, with bone ages 4.6–13 years, with moderate to severe chronic renal failure and resultant growth failure were treated with daily recombinant human growth hormone (rhGH), in conjunction with a strict low-protein/low-phosphate diet supplemented with keto and amino forms of the essential amino acids, histidine and additional energy. Improved growth had previously been observed with this dietary management over that obtained with conventional treatment for chronic renal failure. Each child had been on this diet for at least 2 years before rhGH was commenced. Mean height velocity increased from 4.6±1.3 to 9.0±1.3 cm/year (P<0.001) in the pre-pubertal group, and in the pubertal group from 5.4±1.4 to 10.4±1.8 cm/year (P<0.01). The mean height velocity standard deviation scores (SDSs) increased from –1.2±0.6 to +2.3±0.9 (P<0.001) in the pre-pubertal group and from –0.4±0.6 to +1.9±1.1 (P<0.01) in the pubertal group. Mean height SDS for chronological age increased from –2.2±0.7 to –1.5±0.5 (P<0.01) in the pre-pubertal group and from –1.9±0.7 to –1.3±0.9 in the pubertal group (P<0.02). There was no significant deterioration in renal function or renal bone disease, and bone age did not advance more than chronological age over the 12-month period.     

Growth hormone for children with chronic renal failure and on dialysis

We studied all children with CRF who received recombinant human growth hormone (rhGH) for more than a year (mean±SD duration of therapy 3.7±2.5 years) over an 11-year period. There were 32 children. Twenty-one children were conservatively managed, with a mean glomerular filtration rate (GFR) of 24±12 mL min^–1/1.73 m² at the start of rhGH. Their height standard deviation score improved from –2.5±1.4 to –2.1±0.7 at 1 year (P=0.3), –2.0±0.7 at 2 years (P=0.01), and –1.6±0.6 at 3 years (P=0.001). After that there was no improvement. Eleven children were on dialysis, six on haemodialysis (HD) and five on peritoneal (PD). Ht SDS improved from –2.7±0.5 to –2.3±0.5 at 1 year (P=0.02). Thereafter there was no further improvement. RhGH was stopped because of transplantation in 29 patients at a mean±SD age of 12.1±4.0 years. Mean Ht SDS was –1.8±0.8 at transplant and there was no change over the following 5 years. In conclusion, treatment with rhGH resulted in improvement in Ht SDS in conservatively managed CRF for up to 3.0 years and for 1 year in children on dialysis. Discontinuation of rhGH after transplantation resulted in little change in Ht SDS.     

Short dialyzed children respond less to growth hormone than patients prior to dialysis

Recombinant human growth hormone (rhGH) is a new treatment modality for short children with chronic renal failure (CRF) prior to and during dialysis. It is difficult to analyze whether dialysis patients respond less to rhGH than children with CRF on conservative treatment because they are older and often in a pubertal age range. One hundred and eight patients were treated with 28–30 IU rhGH/kg per week for at least 1 year. We analyzed the growth response to rhGH in 56 prepubertal patients aged less than 10 years at the start of rhGH treatment; 38 children with a mean age of 6.5±2.4 years were on conservative treatment (CT) and 18 patients with a mean age of 6.5±2 years on dialysis treatment (D). Mean height velocity was 4.9±2.3 cm/year in children on CT and 4.6±1.8 cm/year in children on D. During the 1 st treatment year, height velocity was 9.5±3.8 cm/year in CT patients and 7.3±1.3 cm/year in D patients (P<0.05). The change in height was +1.1±0.8 standard deviation (SD) in CT patients and +0.5±0.4 SD in D patients (P<0.005). During the 2nd treatment year, the change in height was again greater in CT patients (0.5±0.4 SD vs. 0.2±0.4 SD;P<0.05). The difference in height velocity and change in height standard deviation score was also significant when a subgroup of patients was matched for sex, age, height. Height velocity and the change in height velocity during rhGH treatment were not correlated with residual renal function, the degree of anemia, or metabolic acidosis. We conclude that short children on D respond less to rhGH than short children on CT, indicating a greater insensitivity to rhGH during D treatment.Study group members: K. Bittner (Ansbach), J. H. H. Ehrich, G. Filler, J. Gellermann (Berlin), H. Hampel (Berlin), H. Bachmann (Bremen), H. Ruder (Erlangen), K. E. Bonzel, B. Scheller (Essen), J. Dippel (Frankfurt), L. B. Zimmerhackl (Freiburg), J. Kreuder, W. Rascher (Gießen), D. Müller-Wiefel (Hamburg), D. Haffner, O. Mehls, R. Nissel, E. Wühl (Heidelberg (coordinators)), J. Misselwitz, B. Rönnefarth (Jena), U. Querfeld (Köln), H. Eichstädt, C. Greiner, E. Keller (Leipzig), H. P. Weber (Lüdenscheid), H. R. Heise, D. Wiemann (Magdeburg), R. Beetz (Mainz), D. Sasse, M. Soergel (Marburg), K. Pistor, A. Zlotkowski (Moers), B. Klare (München), R. Eife (München), E. Kuwertz-Bröking (Münster), M. Wigger, M. Mix (Rostock), O. Eichler (Suhl)     

The effect of recombinant human growth hormone treatment on bone and mineral metabolism in haemodialysis patients

Background: Uraemia and chronical haemodialysis are associated with an abnormal growth hormone (GH)-insulin-like growth factor (IGF) axis which may contribute to malnutrition and renal bone disease. Short-term studies have shown a beneficial effect of treatment with recombinant human growth hormone (rhGH) on nutritional status in patients on haemodialysis. In the present study, we evaluated the effect of rhGH on bone and mineral metabolism. Methods: Twenty chronic malnourished patients on haemodialysis took part in a double-blind, placebo controlled trial with subcutaneous injections of rhGH (4 IU/m²/day) or placebo for 6 months. Results: During rhGH treatment, serum IGF-1 increased 264±52% (mean±SEM) (P<0.008). There were no significant changes in biochemical markers of mineral metabolism (serum ionized calcium, phosphate and parathyroid hormone). Among markers of bone metabolism, there was a significant increase in serum procollagen type I C-terminal propeptide (maximum 155±8%, P<0.001) and no significant changes in serum alkaline phosphatase. Bone densitometry showed a significant decrease in whole body bone mineral content (95.7±1.2%) after 6 months treatment. Conclusion: The effects of 6 months treatment with rhGH seen in this study are best explained by a GH- or IGF-1-induced increased bone turnover. Long-term treatment in larger cohorts followed by bone densitometry and, preferentially, bone histomorphometry are needed to evaluate whether this is a beneficial effect in haemodialysis patients.     

Ibandronate affects bone growth and mineralization in rats with normal and reduced renal function

Bisphosphonates have been shown to attenuate ectopic calcification in experimental uremia. While they are known to reduce bone turnover, the effects on endochondral bone formation have not yet been addressed. To address this issue, we administered male Sprague-Dawley rats weekly subcutaneous injections of either vehicle or ibandronate (1.25 μg/kg body weight) for a total of 10 weeks. The rats were randomly allocated into one of four groups: (1) vehicle-treated, sham-operated rats; (2) ibandronate-treated, sham-operated rats; (3) vehicle-treated, 5/6 nephrectomized rats; (4) ibandronate-treated, 5/6 nephrectomized rats. Bones were double labeled with tetracycline and demeclocycline in vivo, and tibiae were removed for analysis. Weight gain was similar in all groups. Ibandronate reduced body length gain and tibial growth rate in the sham-operated animals but not in the rats showing chronic renal failure (CRF). The height of the proliferative zone of the epiphyseal growth plate was reduced in the ibandronate-treated controls and tended to be reduced in CRF rats. A significant correlation between tibial growth rate and height of the proliferative zone was observed. Mineral apposition rates were significantly reduced in ibandronate-treated, sham-operated rats and tended to be reduced in CRF rats. In conclusion, ibandronate interferes with tibial growth and bone mineralization in young rats with normal and reduced renal function.     

Endothelin-1 in children with chronic renal failure

Endothelin-1 (ET-1) was meansured after extraction from plasma of normal adults (5.9±1.9 pg/ml,n=22), normal children (7.1±1.86 pg/ml,n=29), nonhaemodialysed children with chronic renal failure (CRF) (11.1±1.8 pg/ml),n=10), renal graft recipients (9.5±3.4 pg/ml,n=37), haemodialysed children 24 h after a haemodialysis session (20.02±10.9 pg/ml,n=26) and haemodialysed children before and after a haemodialysis session (15.31±10.6 and 13.8±8.5 respectively,n=14). A sensitive and specific radioimmunoassay was used. ET-1 was significantly higher in non-haemodialysed CRF children and in renal graft recipients than in normal children (P<0.001 andP<0.01, respectively) and significantly higher in haemodialysed children when compared with normal children, non-haemodialysed CRF children and renal graft recipients (P<0.001). ET-1 concentrations were similar in normal children and normal adults. ET-1 was inversely correlated with glomerular filtration rate in non-haemodialysed CRF children (r=–0.39,P<0.01) and positively correlated with extracellular volume in haemodialysed children (r=0.435,P<0.03). After haemodialysis, ET-1 increased in 6 and decreased in 8 of the 14 children studied before and after a haemodialysis session.     

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.     

Growth hormone treatment started in the first year of life in infants with chronic renal failure

Infants with chronic renal failure (CRF) are at high risk of experiencing severe growth retardation. We report a study of 12 infants with CRF who have been treated with recombinant human growth hormone (rhGH) since the age of 0.5 ± 0.3 years. A control group comprised 15 infants with less severe CRF who were being treated during the same period, but who did not receive rhGH. Despite the infants in the rhGH group had more severe renal failure, they grew at least as well as those in the control group and experienced catch-up growth that started earlier and was more sustained; they also gained more weight. Between the age of 0.5 and 2.5 years, the height standard deviation score (HtSDS) improved from −2.0 ± 1.2 to −0.9 ± 0.9 in the rhGH group (p < 0.005) and from −1.6 ± 1.6 to −1.0 ± 1.9 in the control group (p=non significant, n.s.). The average gain in HtSDS was +1.1 ± 0.8 in the treated group and +0.6 ± 1.4 in the control group (p = n.s.). During the same period, the weight SDS improved from −2.2 ± 0.9 to −0.6 ± 1.2 (p < 0.005) and from −1.9 ± 1.2 to −1.3 ± 1.2 (p=n.s.) in the treatment and control groups, respectively. Nutritional intake was similar in both groups, while parathyroid hormone levels tended to increase, although not significantly, after rhGH treatment (p=n.s.). The results of this pilot study suggest that very early treatment with rhGH in patients with early-onset CRF may improve growth.     

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.     

Differential effects of recombinant human growth hormone on glomerular filtration rate and renal plasma flow in chronic renal failure

In normal subjects recombinant human growth hormone (rhGH) increases glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) through the action of insulin-like growth factor-I (IGF-I). We have measured clearance of inulin and para-aminohippuric acid in 18 children with chronic renal failure (CRF) during their 1st year of rhGH treatment to look at the immediate (first 3 h), short-term (1 week) and long-term (1 year) effects of treatment. On day 1 mean (range) age was 9.1 (4.9–13.9) years, GFR 19 (9–58) and ERPF 77 (34–271) ml/min per 1.73 m². During treatment height velocity increased from 4.5 (1.7–6.5) to 9.5 (4.8–12.7) cm/year (P<0.0001). Two children required dialysis after 0.75 years and 1 child was electively transplanted after 0.5 years. There were no other serious adverse events. GFR and ERPF were unchanged in the 3 h following rhGH. GFR remained constant on day 8, 22 (6–56) and after 1 year, 20 (9–59) ml/min per 1.73 m². ERPF increased to 96 (33–276) ml/min per 1.73 m² on day 8P=0.005), and remained elevated, but not significantly so, at 99 (24–428) ml/min per 1.73 m² at 1 year. Fasting IGF-I increased from 147 (46–315) ng/ml to 291 (61–673) by day 8P<0.003), and to 341 (101–786) ng/ml at 1 year. There was no correlation between the change in IGF-I and renal function. Blood pressure, albumin excretion and dietary protein intake were unchanged by treatment. The significance of increased ERPF after 1 week of rhGH in CRF is unclear, but long-term follow-up of renal function is indicated.