Pediatric Nephrology

Pediatr Nephrol (1992) 6:433-438 9 IPNA 1992

Original article Insulin-like growth factor-l, growth hormone-dependent insulin-like growth factor-binding protein and growth in children with chronic renal failure Elisabeth M. Hodson 1, A. Shane Brown 2, L. Paul Roy 3, and Andrew R. Rosenberg 4 i Department 2 Department 3 Department 4 Department

of Paediatrics, Westmead Hospital, Westmead, New South Wales 2145, Australia of Endocrinology, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia of Neplirology, Royal Alexandra Hospital for Children, Camperdown, New South Wales 2050, Australia of Nephrology, Prince of Wales Children's Hospital, Randwick, New South Wales 2031, Australia

Received July 26, 1991; received in revised form December 17, 1991; accepted January 9, 1992

Abstract. Insulin-like growth factor-binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) levels were measured by specific radioimmunoassays in children with all degrees of chronic renal failure (CRF). Study group 1 comprised 29 children (10 on dialysis) who had been studied one to four times over 2 years to determine whether IGF-1 and IGFBP-3 levels differed from those in age-matched healthy children and to examine the relationship between these levels and heights. IGF-1 and IGFBP-3 levels did not differ from those in normal children. IGF-1 and IGFBP-3 were significantly correlated, increased with pubertal stage in all children and with age in non-dialysis patients. IGF-1, but not IGFBP-3, correlated with age in dialysis patients. There was no correlation between IGF-1 or IGFBP-3 levels (corrected for age) and height standard deviation score (SDS) in either non-dialysis or dialysis patients. Study group 2 comprised 19 children (7 on dialysis) who were studied prospectively for 1 - 2 years to examine the relationship between IGF-1 and IGFBP-3 levels, growth rates and nutritional parameters. Mean values of IGF-1 and IGFBP-3 (corrected for age) did not change over i-year periods, while height SDS fell by -0.38 _+0.21 SD/year in dialysis patients and by -0.11 _+0.29 SD/year in non-dialysis patients. No significant correlations were found between IGF-1 or IGFBP-3 levels and growth rates or nutritional parameters. Thus growth retardation in children with CRF is not related to circulating levels of IGF-1 or IGFBP-3. Key words" Insulin-like growth factor-1 - Insulin-like growth factor-binding protein-3 - Chronic renal failure Growth retardation

Introduction One of the major obstacles to satisfactory rehabilitation following successful renal transplantation in childhood is Correspondence to: E. M. Hodson

short stature. Growth rates, which may be reduced before end-stage renal failure occurs, fall during dialysis treatment and catch-up growth after transplant is uncommon [1]. Multiple factors including renal bone disease, protein and calorie intake and electrolyte disturbances have been implicated in the pathogenesis of growth retardation in uraemic children [2]. In addition, the findings of elevated growth hormone (GH) levels [3] and reduced insulin-like growth factor (IGF) activity [4] in uraemic children have suggested that a disorder in the balance between IGFs and their trophic hormone GH could contribute to growth retardation in chronic renal failure (CRF). In vivo, GH appears to regulate growth by direct action on growth plate chondrocytes [5] and by stimulating the hepatic [6] and local production of IGFs [6, 7]. It is not known to what extent each of these mechanisms contributes to normal growth in children. The most potent mediator of GH's growth-promoting effect is considered to be IGF-1 [8]. IGFs circulate complexed to specific binding proteins and unbound IGF is not detectable in serum [8]. The majority of serum IGF (75%-80%) is present in a GH-dependent 150-kDa binding protein complex (IGFBP-3) comprising IGF, an acid-stable 53-kDa protein subunit and an acid-labile 100- to 110-kDa protein subunit [9]. The remaining serum IGF is present in a GH-independent 30- to 50-kDa binding protein complex (IGFBP-1). IGFBP-1 is responsible for the major portion of circulating unsaturated IGF binding activity [8]. The functions of IGFBPs are incompletely delineated but IGFBP-3 may function as a reservoir for IGFs while IGFBP- 1 may modulate the actions of IGFs in the body [10]. Although IGF bioactivity is reduced in uraemia, measurements of IGF-1 by radioimmunoassay (RIA) have produced conflicting results, with low [11, 12], normal [13-15] and high [10] levels being reported. In addition, elevated levels of IGFBP-1 and IGFBP-3 have been found in uraemic children and have been postulated to interfere with IGF action and, therefore, with growth [15, 17-19]. In this study, IGF-1 and IGFBP-3 levels were measured by specific RIAs in children with all degrees of CRF. The aims of the study were to determine whether IGF-1 and

434 I G F B P - 3 l e v e l s w e r e a b n o r m a l in c o m p a r i s o n w i t h a g e m a t c h e d n o r m a l c h i l d r e n and tO e x a m i n e the r e l a t i o n s h i p o f t h e s e l e v e l s w i t h h e i g h t and h e i g h t v e l o c i t y .

Patients and methods Patients. Two groups of children with CRF were studied. No child was nephrotic or was receiving corticosteroid therapy. Study group 1 comprised 29 children (22 boys, 7 girls) who were studied retrospectively to examine the relationship between cuncent height and IGF-1 or IGFBP-3 levels and to determine whether levels differed from those in agematched healthy children. The median age was 11.6 years (range 1.5-15 years). Ten children were receiving dialysis treatment (peritoneal dialysis 8, haemodialysis 2); the mean glomerular filtration rate (GFR) in the remaining children was 27_+16 ml/min per 1.73 m2 (range 6 - 6 0 ml/min per 1.73 m2). Eleven children (5 on dialysis) were in stages 2 - 4 of puberty. Non-fasting blood specimens for IGF-1 and IGFBP-3 levels had been obtained from these children over 2 years at approximately 6-monthly intervals. A total of 52 measurements were obtained; 14 children had t measurement, 10 children 2 measurements, 2 children 3 measurements and 3 children 4 measurements. Serum creatinine levels, growth data and bone ages were obtained from hospital records. The GFR in group 1 patients was determined from the creatinine clearance using the formula: creatinine clearance (ml/min per 1.73 m 2) = 48.6 x height (cm)lPlasma creatinine (gmol/l). This formula was adapted for use with SI units from the formula of Schwartz et al. [20]. Heights were expressed as standard deviation scores (SDS) for chronological or bone age using normal data from Tanner etal. [21]. Children in study group 2 were studied to examine the relationship between growth rates, nutritional parameters and IGF-1 or IGFBP-3 levels. The group comprised 19 children (16 boys, 3 gifts) who were studied prospectively for 1 year (16 children) and 2 years (3 children) to provide 22 sets of data over 1-year periods. The median age was 6 years (range 1 - 14 years); children were not entered into the prospective study if their bone age exceeded 11 years in girls or 13 years in boys. Seven children were on continuous ambulatory peritoneal dialysis (CAPD); the mean GFR of non-dialysis patients was 25 _+14 mllmin per 1.73 m 2 (range 13-61 ml/min per 1.73 m2). Four children (all on CAPD) were in stage 2 of puberty at the start of the study and did not progress through puberty during follow-up. Measurements of height, weight, triceps skinfold thickness (TSF) and mid-arm circumference (MAC) and determination of pubertal status were carried out annually, within 1 month of the child's birthday, by a single observer (E. M. H.). On the same day, a fasting blood specimen was collected for IGF-1 and IGFBP-3 levels. GFR was determined in non-dialysis patients from the disappearance of 99mtechnetium-diaminotetraethylpentacetic acid [22], and a radiograph of the left hand was obtained for bone age determination. Bone ages were determined using the standards of Gruelich and Pyle [23] by two radiologists at each of the children's hospitals. Informed consent was obtained from the children's parents or guardians. The study was approved by the research and ethics committees of the hospitals involved. Growth measurements. In study group 2, standing heights in children aged 2 years and above and recumbent length in younger children were measured using a Holtain stadiometer (Crosswelt, Crymmch, Dyfed, UK) or Holtaln infantometer, respectively. Children were weighed in light underclothes on a beam balance. Children on CAPD were weighed following drainage of dialysis fluid. TSF and MAC were measured midway between the tip of the acromion and the olecranon process of the left arm using Holtain skinfold calipers [24] and a non-stretched tape measure, respectively. Mid-arm muscle circumference (MAMC) was calculated according to the formula: MAMC (cm) = MAC (cm) (0.314) TSF (ram). Pubertal stage was determined using the staging system of Tanner [251. Height velocities, calculated over 1-year periods, were expressed as SDS for chronological or bone age. Weights were expressed as weightfor-height index (WIll) according to the formula: WHI = actual weight/ideal weight for 50th percentile of height age [26]. A WHI below

0.95 was considered abnormally low. Normal data for height velocities and for ideal weights were obtained from the data of Tanner et al. [21]. Normal data for TSF, MAC and MAMC were obtained from the data of Frisancho [27]. IGF-1 and IGFBP-3 measurements. IGF-1 was measured by RIA as previously described [28] using an antiserum raised in rabbits against an IGF-1 preparation [29]. Plasma samples were extracted with acid-ethanol to release IGFs from their binding proteins and to remove binding proteins from the plasma extracts [30]. An acid-ethanol extract of a normal human plasma pool, assigned a potency of 1.0 unit/ml, was used as a standard and radioiodinated IGF- 1 as the tracer. The working range of the assay was 0.1-10 units/ml. The between-assay and within-assay coefficients of variation were 8.7% at 1.21 unit/ml and 11.8% at 1.06 unit/ml, respectively. The cross-reactivity with IGF-2 in this assay was less than 1%. Age-standardised normal ranges were obtained from 160 healthy children aged less than 16 years. IGFBP-3 was measured by RIA as previously described [31] in unextracted plasma samples using an antiserum raised in rabbits against the 53-kDa acid-stable binding protein component of IGFBP-3, a covalent mixture of IGF-1 and 53-kDa binding protein as tracer and a normal human plasma pool as standard. The coefficients of variation for the assay were; between assay 14.5% at 6.3 gg/ml, within-assay 5.5% at 5.7 gg/ml. The cross-reactivity with IGFBP-1 was 0.16%. Age-related normal ranges were obtained from 119 children aged below 16 years. Statistical methods. Data were analysed using standard statistical packages. Descriptive statistics were expressed as mean + SD. Correlations of variables within groups were calculated by regression analysis. To avoid incorrect assessment of significance where multiple tests of correlation were performed, only values for r exceeding 0.49 were regarded as significant. Differences between paired data were analysed using paired Student's t-test, and differences between dialysis and non-dialysis patients were analysed using the Mann-Whitney U-test P values for these tests of less than 0.05 were considered significant. IGF- 1 values in normal children were demonstrated to conform to a log-normal distribution. On the basis of this finding, values were logtransformed to permit regression analysis against chronological and bone age. The normal range for IGF-I, derived from the log-transformed data, is expressed as geometric mean with 95% confidence limits. Log-normalisation of IGFBP-3 levels did not effect regression analysis against chronological and bone age. The normal range for IGFBP-3 is expressed as mean + 2 SD. To allow comparison of data between children of different ages, IGF-1, IGFBP-3, TSF, MAC and MAMC levels were expressed as lOgl0 observed value/expected value for age rather than as SDS, since levels were not normally distributed.

Results Study group 1 IGF-1 levels increased significantly with chronological age (Fig. 1), b o n e age and p u b e r t a l stage in dialysis and n o n - d i a l y s i s patients ( T a b l e 1). O n l y 2 v a l u e s (2 c h i l d r e n ) o f I G F - 1 w e r e b e l o w a g e - r e l a t e d n o r m a l v a l u e s ; subs e q u e n t v a l u e s in 1 girl n o r m a l i s e d as s h e e n t e r e d p u b e r t y . IGFBP-3 levels increased significant LY with chronological a g e (Fig. 2), b o n e a g e and p u b e r t a l stage in n o n - d i a l y s i s patients ( T a b l e 1). H o w e v e r , in d i a l y s i s patients I G F B P - 3 l e v e l s c o r r e l a t e d o n l y w i t h p u b e r t a l stage. T h r e e v a l u e s o f I G F B P - 3 in 3 c h i l d r e n w e r e b e l o w n o r m a l v a l u e s and 6 v a l u e s in 5 c h i l d r e n w e r e a b o v e n o r m a l v a l u e s ; further v a l u e s w e r e a v a i l a b l e in 6 children, and all w e r e w i t h i n the n o r m a l range. I G F - 1 and I G F B P - 3 l e v e l s (Fig. 3) w e r e s i g n i f i c a n t l y c o r r e l a t e d in n o n - d i a l y s i s (r = 0.76, P < 0 . 0 0 0 1 ) and in d i a l y s i s patients (r = 0.61, P

Insulin-like growth factor-1, growth hormone-dependent insulin-like growth factor-binding protein and growth in children with chronic renal failure.

Insulin-like growth factor-binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) levels were measured by specific radioimmunoassays in ...
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