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ABSTRACT: Many children with chronic renal insufficiency (CRI) show growth retardation and severely delayed pubertal development. Successful renal transplantation (RTx) also rarely results in full growth rehabilitation. Pubertal height gain in CRI patients is only 58% and 48% of that observed in late-maturing boys and girls, respectively. Growth retardation in both CRI and RTx patients is not the result of abnormal GH secretion or decreased levels of IGF-I, but rather of elevated levels of IGFBPs inhibiting the bioavailability of the IGFs. In RTx patients prednisone may also inhibit growth directly via inhibition of bone matrix formation. Several studies have convincingly shown that GH therapy at a dose of 4 IU/m2/day results in a sustained improvement of growth in prepubertal and pubertal children with CRI and in growth-retarded prepubertal and pubertal post-transplant patients. The following consensus was reached concerning optimal therapy of puberty in children with chronic renal disease. GH therapy does not lead to an earlier start of puberty. It is safe to give GH to RTx patients if transplant function is stable. GH therapy will not accelerate bone maturation and can improve the final height of children with CRI and after RTx. Increasing the GH dose above 4 IU/m2/day in pubertal RTx patients does not increase height gain or final height and is not advised as it may increase insulin resistance. GH should best be started before the start of the pubertal growth spurt but will still be effective in RTx patients with advanced bone age. GH testing should not be a prerequisite for starting GH therapy. It is important to optimise other therapies during puberty. During GH therapy of RTx patients use minimum daily, not alternate-day, steroid dosing. Further research is still required on the possible long-term effects of GH therapy in children with chronic diseases. Two studies demonstrated improved long-term growth and final height within the target height range, without significant side effects. Renal graft function did not deteriorate more than in matched controls. A GH dose of 4 IU/m2/day proved adequate.
Journal of pediatric endocrinology & metabolism: JPEM 08/2001; 14 Suppl 2:945-52. · 0.88 Impact Factor
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I M van der Sluis,
A M Boot,
J Nauta,
W C Hop,
M C de Jong,
M R Lilien,
J W Groothoff,
A E van Wijk,
H A Pols, A C Hokken-Koelega,
S M de Muinck Keizer-Schrama
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ABSTRACT: Metabolic bone disease and growth retardation are common complications of chronic renal failure (CRF). We evaluated bone mineral density (BMD), bone metabolism, body composition and growth in children with CRF, and the effect of growth hormone treatment (GHRx) on these variables. Thirty-three prepubertal patients with CRF were enrolled including 18 children with growth retardation, who were treated with growth hormone for 2 years. Every 6 months, BMD of lumbar spine and total body, and body composition were measured by dual-energy X-ray absorptiometry. Biochemical parameters of bone turnover were assessed. Mean BMD of children with CRF did not differ from normal. During GHRx, BMD and bone mineral apparent density of lumbar spine and height SDS increased, whereas BMD of total body did not change. Lean body mass increased in the GH group. Alkaline phosphatase increased significantly in the GH group only. The other biochemical parameters of bone turnover increased in both groups, none of them correlated with the changes in BMD. No serious adverse effects of GHRx were reported. In conclusion, BMD of children with CRF did not differ from healthy children. Adequate treatment with alpha-calcidiol or the short duration of renal failure may have attributed to the absence of osteopenia in our patients. BMD of the axial skeleton and growth improved with GHRx.
Pediatric Nephrology 01/2001; 15(3-4):221-8. · 2.52 Impact Factor
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ABSTRACT: The aim of this study was to assess body proportions in children with short stature born small for gestational age (SGA) before and during 6 years of growth hormone (GH) treatment. A prospective randomised double-blind dose-response study comparing the effects of 3 vs. 6 IU GH/m2/day. Seventy-nine children with short stature (height SD-score < -1.88) born small for gestational age (birth length SD-score < -1.88). Before and during GH treatment, height, sitting height (SH), hand (Hand) and foot length (Foot), biacromial (Biac) and biiliacal diameter (Biil) were measured. All results were adjusted for age and sex, and expressed as SD-scores (SDS) using reference values for healthy Dutch children. To describe the size of SH, Hand, Foot, Biac, and Biil in relation to height, these values were adjusted for the SDS of height. At baseline, these short children had small hands and feet and narrow shoulders and pelvis compared to healthy peers. Height and SH, were, however, even more affected. Consequently, on average, these children had relatively large hands and feet, and relatively broad shoulders and pelvis compared to their height, but a normal sitting height in proportion to height. In most of the individuals, the values for body proportions were, however, within the normal range. During 6 years of GH treatment the SD-scores of all measurements increased significantly towards values more close to zero. The mean size of Hand, Foot, and Biil decreased in proportion to height. The mean SH increased relatively more than height, however, to values well within the normal range. The mean Biac in relation to height had not changed after 6 years of GH treatment. No differences in the 6-year changes in body proportions were found between the two GH dosage groups. Untreated short children born small for gestational age have, on average, relatively large hands and feet, and broad shoulders and pelvis, but a normal sitting height compared to height. The increase in height during 6 years of GH treatment is accompanied by an improvement of the proportions of the size of hands, feet, and biiliacal diameter, in relation to height. The increase in height appeared to be the result of the increase in sitting height as well as leg length, but the sitting height SD-score increased slightly more than that of leg length. The changes in body proportion during GH treatment were dose-independent. Thus, 6-year continuous GH treatment with either 3 or 6 IU/m2/day in children with short stature born small for gestational age does not negatively influence body proportions.
Clinical Endocrinology 12/2000; 53(6):675-81. · 3.17 Impact Factor
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ABSTRACT: Some very preterm neonates admitted to the neonatal intensive care unit show circulatory and respiratory problems that improve after administration of steroids. It is unclear whether these symptoms could be caused by adrenal insufficiency. The objective of our study was to investigate the cortisol levels and the cortisol release from the adrenals after ACTH in very preterm infants with and without severe illness and to find whether a relation exists between adrenal function and outcome. An ACTH test (0.5 microg) was performed on d 4 in 21 very preterm infants (gestational age, 25.6-29.6 wk; birth weight, 485-1265 g). Baseline cortisol and 17-hydroxyprogesterone (17OHP) levels and the cortisol levels 30, 60, and 120 min after ACTH administration were measured. The Score for Neonatal Acute Physiology was used to measure illness severity. All infants showed an increase in cortisol levels after ACTH, but the cortisol levels were significantly lower in the ventilated more severely ill infants. After adjusting for birth weight and gestational age, the mean baseline cortisol levels and cortisol/17OHP ratios were significantly lower and the 17OHP levels significantly higher in the ventilated infants compared with the nonventilated infants. Patients with an adverse outcome had significantly lower baseline cortisol/17OHP ratios and 60-min cortisol levels during ACTH testing (p = 0.002 and p = 0.03, respectively). These data suggest an insufficient adrenal response to stress in sick ventilated very preterm infants with gestational ages younger than 30 wk compared with nonventilated less sick preterm infants. Further studies are required to investigate whether supplementation with physiologic doses of hydrocortisone may benefit the outcome.
Pediatric Research 12/2000; 48(5):629-33. · 2.70 Impact Factor
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ABSTRACT: To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission. On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18). Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs. 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs. 231 ng/L). Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs. 17), TSH (0.97 vs. 0.29 mE/L), T3 (0.53 vs. 0.38 nmol/L), reverse T3 (rT3) (0.75 vs. 1.44 nmol/L), C-reactive protein (34 vs. 78 mg/L), nonesterified fatty acids (0.32 vs. 0.95 mmol/L), and lactate (7.3 vs. 3.2 mmol/L). In those who survived, the most important changes within 48 h were seen in a normalization of cortisol and ACTH levels, but without a circadian rhythm; a decrease of rT3 and an increase in the T3/rT3 ratio; and a decrease in the levels of the nonesterified free fatty acids and an unaltered high urinary nitrogen excretion. At this moment, it is yet unknown whether the hormonal abnormalities are determining factors in the outcome of acute meningococcal sepsis or merely represent secondary effects. Understanding the metabolic and endocrine alterations is required to design possible therapeutic approaches. The striking difference between nonsurvivors and survivors calls for reconsideration of corticosteroid treatment in children with meningococcal sepsis.
Journal of Clinical Endocrinology & Metabolism 11/2000; 85(10):3746-53. · 6.50 Impact Factor
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ABSTRACT: Insulin-like growth factor binding protein-6 (IGFBP-6) is a relatively unknown member of a family of six specific structurally related IGF binding proteins which are involved in the modulation of the biological effects of the IGFs. A distinctive property of IGFBP-6 is its preferential affinity for IGF-II relative to IGF-I. In order to obtain more insight into the clinical significance and regulation of circulating levels of IGFBP-6 we developed a specific radioimmunoassay (RIA) for this protein.
Selected human biological fluids and plasma from 847 normal subjects were analysed. In addition, plasma samples from patients with different disorders (i.e. GH-deficiency, acromegaly, cancer, corticosteroid-treated children suffering from different kinds of severe illness and chronic renal failure) were investigated.
The IGFBP-6 assay is competitive, utilizing a rabbit polyclonal antibody raised against a synthetic peptide comprising amino acids 90-118 of the hIGFBP-6 sequence and an additional tyrosine residue. It is calibrated against recombinant human (rh)IGFBP-6. The 125I tracer is prepared by iodination of the synthetic peptide. There is no significant cross-reactivity with other IGFBPs and no interference with the IGFs.
Extensive normative range values for IGFBP-6 were determined using 847 plasma samples from normal males and females, ranging from 0 to 75 years of age. IGFBP-6 levels increased gradually (about two-fold) with age. In childhood the plasma levels of IGFBP-6 in females tended to be slightly higher than those for males. For the adult population the reverse was observed. Overall, the mean +/- SD value for males was higher than that for females (149 +/- 57 vs. 139 +/- 45 micrograms/l, P < 0.004). GH status did not appear to influence IGFBP-6 level since normal levels were found for both untreated acromegalic patients and GH-deficient subjects. GH treatment of the latter group of patients did not alter IGFBP-6 in plasma. Pharmacological doses of glucocorticosteroids affected circulating IGFBP-6 levels only slightly. IGFBP-6 levels in plasma samples derived both from children with acute lymphoblastic leukaemia and from patients with various types of solid neoplasms were generally within the normal range. In contrast, plasma samples from four of six patients with non-islet cell tumour induced hypoglycaemia (NICTH) showed elevated concentrations of IGFBP-6 (SDS > 2.9). An excess of IGFBP-6 was also found in plasma of both dialysed and non-dialysed prepubertal growth retarded children with chronic renal failure (CRF) (mean SDS: 23.0 and 9.3, respectively). IGFBP-6 levels were inversely correlated with glomerular filtration rate. In a group of CRF patients who underwent renal transplantation circulating IGFBP-6 levels were markedly lower (mean SDS: 4.6). The presence of IGFBP-6 could also be demonstrated in several other human biological fluids. Low amounts were detected in saliva (3-12 micrograms/l) and breast milk (6-45 micrograms/l) while the levels in amniotic fluid and follicular fluid were comparable with those determined in normal plasma. The IGFBP-6 content of cerebrospinal fluid (CSF) ranged between 25 and 87 micrograms/l, which is rather high in relation to the relatively low concentration of total protein in this body fluid.
Measurements of IGFBP-6 have been shown so far to be of relatively minor clinical relevance. The exceptions are chronic renal failure patients and subjects with large tumours and non-islet cell tumour induced hypoglycaemia who may exhibit elevated circulating levels of this IGFBP. The physiological significance of this observation remains to be elucidated. The possibility of quantifying IGFBP-6 by specific RIA will facilitate further in vitro and in vivo studies of its regulation and function in man.
Clinical Endocrinology 05/1999; 50(5):601-9. · 3.17 Impact Factor
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T C Sas,
S M de Muinck Keizer-Schrama,
T Stijnen,
A van Teunenbroek, A C Hokken-Koelega,
J J Waelkens,
G G Massa,
T Vulsma,
W J Gerver,
H M Reeser,
H E Delemarre-van de Waal,
M Jansen,
S L Drop
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ABSTRACT: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol.
Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years).
Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years).
To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS).
The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment.
Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.
Archives of Disease in Childhood 01/1999; 80(1):36-41. · 2.88 Impact Factor
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ABSTRACT: Osteopenia has been reported in adult patients with chronic renal failure (CRF). Only a few studies have been performed in children. The objective of this study was to evaluate bone mineral density (BMD), bone turnover, body composition in children with CRF and to study the effect of GH on these variables.
Two groups were identified: patients with growth retardation who received GH (GH-group) and patients most of whom were not growth retarded who did not receive GH (no-GH-group). After an observation period of 6 months, the patients in the GH-group started GH treatment. Patients were studied every 6 months during 18 months.
Thirty-six prepubertal patients (27 boys and 9 girls), mean age 7.9 years, with CRF participated in the study. The GH-group consisted of 17 patients of whom 14 completed one year treatment. The no-GH-group consisted of 19 patients, of whom 16 were followed for 6 months, 14 for 12 months and 13 for 18 months.
Lumbar spine BMD, total body BMD and body composition were assessed by dual energy X-ray absorptiometry, compared to age-and sex-matched reference values of the same population and expressed as standard deviation scores (SDS). BMD of appendicular bone was measured by quantitative microdensitometry (QMD). Blood samples were obtained to assess bone metabolism and growth factors.
Baseline mean lumbar spine and total body BMD SDS of all patients were not significantly different from normal. Mean lumbar spine and total body BMD SDS did not change significantly in the GH-group during GH treatment. The change of QMD at the midshaft during the first 6 months of GH treatment was significantly smaller than during the observation period (P < 0.01). Height SDS and biochemical markers of both bone formation and bone resorption increased significantly during GH treatment; 1,25-dihydroxyvitamin D remained stable. Lean tissue mass increased (P < 0.001) and percentage body fat decreased (P < 0.01) during GH treatment. BMD, the biochemical markers of bone turnover which are independent of renal function, and body composition remained stable in the no-GH-group.
Mean lumbar spine and total body BMD of children with chronic renal failure did not differ from healthy controls. The lack of a GH-induced increase in 1,25-dihydroxyvitamin D levels, probably due to treatment with alpha-calcidol, might be linked to the absence of a response in BMD during GH treatment in children with chronic renal failure.
Clinical Endocrinology 12/1998; 49(5):665-72. · 3.17 Impact Factor
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A C Hokken-Koelega
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ABSTRACT: Recombinant human growth hormone (rhGH) therapy in a dose of 28-30 i.u./m2/week results in a significant and sustained improvement of height in most pubertal patients with growth retardation secondary to chronic renal insufficiency (CRI), dialysis or after renal transplantation (RTx). Long-term data indicate that rhGH therapy leads to a significant improvement in the final height of growth-retarded pubertal patients after renal transplantation.
British journal of clinical practice. Supplement 09/1996; 85:12-3.
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ABSTRACT: In the intermediate term, recombinant human growth hormone (rhGH) therapy in a dose of 28-30 i.u./m2/week accelerates growth significantly in most pubertal patients with growth retardation secondary to chronic renal insufficiency (CRI), dialysis and after renal transplantation (RTx), without evidence of adverse effects or acceleration of bone maturation. Therefore, rhGH therapy may well improve the final height of these patients.
British journal of clinical practice. Supplement 09/1996; 85:5-6.
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A C Hokken-Koelega
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ABSTRACT: Various studies have convincingly shown that recombinant human growth hormone (rhGH) therapy accelerates growth significantly in children with growth retardation secondary to chronic renal insufficiency (CRI) and after renal transplantation (RTx). rhGH therapy appeared remarkably safe intermediate-term, but paediatricians are concerned about the potential adverse effects on glucose homeostasis and insulin action. Particularly in children with CRI and after RTx, pre-existing insulin resistance may be aggravated by exogenous rhGH therapy. Patients after RTx had significantly higher pretreatment insulin levels than controls (p < 0.001). Various studies in both patient groups showed that one year of rhGH therapy at 4 i.u./m2/day did not impair glucose tolerance but significantly increased plasma insulin levels (p < 0.001). No patients developed impaired glucose tolerance or permanent diabetes mellitus (DM), but from these studies, it was concluded that euglycemia was maintained at the expense of increased insulin levels. The long-term consequences of the compensatory hyperinsulinaemia are not yet known. Although permanent DM has not been reported in any of the rhGH trials in renal patients, it cannot be excluded that some patients with CRI or after RTx may develop impaired glucose tolerance and/or permanent DM during long-term rhGH therapy, particularly those with risk factors such as familial type II DM and obesity. Long-term studies, including careful monitoring of carbohydrate metabolism, are required.
British journal of clinical practice. Supplement 09/1996; 85:56-8.
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A C Hokken-Koelega
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ABSTRACT: Growth failure is a major problem for many children with chronic renal disease. For approximately 75% of pediatric renal allograft recipients final height falls below the third percentile. In the intermediate term, recombinant human growth hormone (GH) therapy at a dose of 28-30/m2/week accelerates growth significantly in patients with growth retardation secondary to chronic renal failure and after renal transplantation, without evidence of adverse effects or acceleration of bone maturation. Therefore, GH therapy may well improve final height of these patients.
Journal of pediatric endocrinology & metabolism: JPEM 07/1996; 9 Suppl 3:359-64. · 0.88 Impact Factor
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ABSTRACT: Sustained growth retardation in spite of a successful renal transplantation (RTx) is a serious problem for many pediatric allograft recipients. Biosynthetic growth hormone (GH) was given to 11 prepubertal children with severe growth retardation after RTx in a placebo-controlled double-blind study, assessing its effect on height velocity (HV), bone maturation, renal function, plasma IGF-I and IGF-II, serum IGF-binding proteins (IGFBP), and lipid and carbohydrate metabolism. Six months of GH (4 IU/m2/day s.c.) was either preceded or followed by six months of placebo. The patients underwent a full examination every three months. All children completed the study. Mean HV improved significantly with GH therapy (P < 0.0001), but there was also some improvement with placebo (P = 0.06). The GH-induced HV increment exceeded that of placebo by 2.9 cm/six months. Bone maturation was not accelerated. Acute renal graft rejection did not occur in any of the patients. 125I-thalamate and 131I-hippuran tests showed that mean glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) did not change significantly during GH therapy. GH caused a significant increase in IGF-I (P < 0.0001), which was far greater than the insignificant increase in serum IGFBP-3 levels (P = 0.16). Mean serum levels of total cholesterol, low density lipoprotein, apolipoprotein-A1 and -B, which are elevated at the start of the study compared with that of controls, did not change significantly during GH therapy. GH induced a significant increase in mean integrated plasma insulin levels during oral glucose tolerance test, without changing plasma glucose levels. Serum fructosamine and parathyroid hormone levels remained constant. Impressive HV increment can be achieved with GH therapy in children with growth retardation after RTx, without significant changes in renal function. Bone maturation appears unaffected, suggesting an improve final height.
Kidney international. Supplement 01/1996; 53:S128-34.
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ABSTRACT: Postnatal growth of 724 (423 premature, 301 full-term) small for gestational age infants (SGA, birth length less than the third length percentile (P3) for gestational age) was studied for the first 2 y of life. The study group consisted of all SGA infants who had been admitted over a period of 8 y at the Departments of Neonatology of three University Hospitals in The Netherlands with exclusion of infants with well defined causes for growth retardation, such as chromosomal disorders, syndromes, severe malformations, or complications during the neonatal period or later on. The aim of the study was to describe postnatal growth of SGA infants and to find predictive factors for catch-up growth > or = P3 during the first 2 y of life. The majority (around 85%) of the healthy SGA infants showed catch-up growth to a height > or = P3 during the first 2 y of life. The percentage of premature SGA infants with catch-up growth > or = P3 at 2 y of age (82.5%) was not significantly different from that of full-term SGA infants (87.5%). Birth length SDS was more sensitive than birth weight SDS in predicting catch-up > or = P3 in premature SGA infants. In contrast, birth weight SDS was the best predictor for catch-up > or = P3 in full-term SGA infants. Gestational age, multiple birth, and sex were not significantly associated with catch-up in height > or = P3.(ABSTRACT TRUNCATED AT 250 WORDS)
Pediatric Research 08/1995; 38(2):267-71. · 2.70 Impact Factor
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ABSTRACT: Early and late effects of treatment for acute lymphoblastic leukemia (ALL) on weight was retrospectively investigated in 113 children in continuous first remission. Weight was examined at diagnosis up to 10 y after cessation of treatment. There was an increased prevalence of overweight after treatment for ALL which persisted over time. All treatment regimens included corticosteroid therapy, and 52 patients received additional cranial irradiation. Patients treated with and without cranial irradiation did not differ in weight gain, indicating that not cranial irradiation but corticosteroid therapy might explain weight gain in children treated for ALL. Dexamethasone was associated with a significant increase of weight at cessation of treatment. Patients treated with a combination of prednisone and dexamethasone had as a late effect the highest prevalence of obesity (44%). Gender or age at diagnosis were not related to weight gain.
Pediatric Research 08/1995; 38(1):86-90. · 2.70 Impact Factor
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ABSTRACT: A cross sectional study assessed the bone mineral density (BMD) of 20 young adult patients who received a renal transplantation in childhood. The BMD of the lumbar spine, mainly trabecular bone, and of the total body, mainly cortical bone, were measured and expressed as an SD score. Fourteen patients (70%) had a BMD SD score of the lumbar spine below -1, of whom six patients were below -2. Fifteen patients (75%) had a BMD SD score of the total body below -1, of whom seven patients were below -2, Both trabecular and cortical bone appeared to be involved in the osteopenic process. The cumulative dose of prednisone was inversely correlated to both lumbar spine and total body BMD SD score. In a multiple regression analysis the cumulative dose of prednisone appeared to be the only factor with a significant effect on BMD SD score. Most young adult patients who had received a renal transplantation in childhood had moderate to severe osteopenia. Corticosteroid treatment played a major part in the development of osteopenia in these patients.
Archives of Disease in Childhood 07/1995; 72(6):502-6. · 2.88 Impact Factor
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ABSTRACT: The pathophysiological mechanisms underlying the failure of catch up-growth in children with short stature after intrauterine growth retardation (IUGR) remain obscure. Since GH secretion disturbances might play a role in the growth retardation of these children we have investigated various aspects of the GH/IGF axis.
Cross-sectional study in one group of patients.
Forty prepubertal children (15 girls/25 boys; mean age (range) 7.5 years (3.4-10.8)) with short stature (height below the third centile) after IUGR, defined as a birth length below the third centile for gestational age, were studied.
GH secretion was determined by a 24-hour plasma GH profile (sampling every 20 minutes) and, on a separate occasion, by a standard arginine provocation test (ATT). Plasma IGF-I and IGF-II levels were measured at the start of the GH profile. Urine was collected to measure urinary GH levels. Plasma and urinary GH were determined by double antibody RIA. IGF-I and IGF-II were determined by specific RIA after acid chromatography. The 24-hour GH profiles were analysed using Pulsar.
Endogenous GH secretion was similar for boys and girls. Boys had significantly lower mean GH levels compared to healthy controls. Forty per cent of the children met our criteria for a normal 24-hour GH profile (group A; n = 16) and 60% (n = 24) did not. We subdivided these 24 children into two groups: group B (n = 14) (children with either mean GH levels less than controls but with at least one spontaneous GH peak above 20 mU/l and children with normal mean GH levels but with no GH peak above 20 mU/l (subnormal 24-hour GH profile)) and group C (n = 10) (children with mean GH levels less than controls and no GH peak above 20 mU/l (low 24-hour GH profile)). The GH secretory abnormalities were due to a decrease in pulse amplitude, not in pulse frequency. Mean (SD) maximal GH response during ATT was 22.3 (12.1) mU/l. Nineteen children (47.5%) had a maximal GH value < 20 mU/l. Moderate, but significant, correlations were found between several 24-hour GH profile characteristics and the maximal GH response during ATT (r = 0.31-0.35; P < 0.05). Mean (SD) overnight urinary GH excretion was 3.8 (2.1) and 4.4 (3.5) microU/night for boys and girls, respectively. Compared to healthy schoolchildren, overnight urinary GH was lower in boys, but not in girls. Mean (SD) IGF-I and IGF-II SDS levels for chronological age were -0.88 (1.40) and -0.64 (1.48), respectively. Plasma IGF-I and IGF-II levels were significantly reduced compared to controls. Height SDSCA or height velocity SDSCA did not correlate with either spontaneous or stimulated GH secretion, urinary GH excretion or plasma IGF-I or IGF-II levels.
Our study indicates that 50-60% of children with short stature after intrauterine growth retardation have 24-hour GH profile abnormalities and/or subnormal responses to arginine provocation, while mean plasma IGF-I and IGF-II levels are significantly reduced, indicating GH insufficiency. Urinary GH excretion is lower in boys, but not in girls. The precise mechanism of the failure to catch up growth needs further elucidation. It seems justified to start clinical trials in order to investigate whether treatment with exogenous GH might be beneficial for these children.
Clinical Endocrinology 12/1994; 41(5):621-30. · 3.17 Impact Factor
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ABSTRACT: 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.
Journal of Clinical Endocrinology & Metabolism 11/1994; 79(4):1185-90. · 6.50 Impact Factor
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ABSTRACT: A retrospective study is reported assessing final height (FH) and its predictive factors in 52 patients (31 male, 21 female) who underwent renal transplantation (RTx) before the age of 15 y. They received prednisone daily or on alternate days as well as azathioprine. The study period covered 20 y. FH remained below the third height percentile [height standard deviation score for chronologic age (hSDSCA) < -1.88] for most of these patients (77% males, 71% females). Median (range) FH was 165.0 (143.0-176.8) cm in males and 153.0 (135.0-168.4) cm in females. Median difference between FH and target height was 15.0 and 15.4 cm for males and females, respectively. For both sexes, the median hSDSCA was already below -1.88 at the start of the first hemodialysis, after which it decreased significantly until the first RTx. After RTx, there was no significant improvement of hSDSCA. The predictive factors for FH were determined by evaluating various factors simultaneous in a multiple regression analysis. This analysis provided a regression equation for predicting FH. A higher hSDSCA at the time of the first RTx and alternate-day versus daily prednisone therapy both had a significantly positive influence on FH, whereas a longer duration of reduced GFR (< 50 mL/min/1.73 m2) had a significantly negative effect on FH. Other factors such as age or bone age at first RTx, primary renal disease, duration of initial dialysis, repeat RTx, and the cumulative dose of prednisone did not influence FH significantly. In conclusion, 71-77% of patients that received their first renal transplant before the age of 15 ended up with severely short adult stature. Optimization of the hSDSCA at first RTx appears very important. Long-term administration of prednisone on alternate days would then result in optimal FH, particularly if the GFR remains above 50 mL/min/1.73 m2.
Pediatric Research 10/1994; 36(3):323-8. · 2.70 Impact Factor
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ABSTRACT: 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.
The Lancet 05/1994; 343(8909):1313-7. · 38.28 Impact Factor
