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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 4 1007-1013
Copyright © 1997 by The Endocrine Society

Pediatric Endocrinology

Reduced Concentration of Serum Growth Hormone (GH)-Binding Protein in Children with Chronic Renal Failure: Correlation with GH Insensitivity

Burkhard Tönshoff, Michael J. Cronin, Marcel Reichert, Dieter Haffner, Anne-Margret Wingen, Werner F. Blum, Otto Mehls and The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood1 and Members of the German Study Group for Growth Hormone Treatment in Chronic Renal Failure,2

University Children’s Hospitals Heidelberg (B.T., D.H., O.M.), Essen (A.-M.W.) and Giesen (W.F.B.), Germany; and Genentech, Inc. (M.J.C., M.R.), South San Francisco, California 94080

Address all correspondence and requests for reprints to: Burkhard Tönshoff, M.D., Division of Pediatric Nephrology, University Children’s Hospital, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany. Burkhard Toenshoff{at}krzmail.krz.uni-heidelberg.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Growth retardation in children with chronic renal failure (CRF) despite normal or elevated GH levels indicates a peripheral insensitivity to the action of GH. One possible molecular mechanism is a reduced density of GH receptors in GH target organs. In humans, the circulating high affinity GH binding protein (GHBP) is thought to reflect GH receptor expression, because it is derived from the extracellular domain of the GH receptor by proteolytic cleavage. We, therefore, analyzed serum GHBP levels by ligand-mediated immunofunctional assay in 126 children with CRF compared to reference values obtained by analysis of 773 healthy children. In 77% of CRF patients, serum GHBP concentrations were below the mean for age- and gender-matched controls. The decrease in serum GHBP levels was related to the degree of renal dysfunction. In advanced CRF (glomerular filtration rate, <35 mL/min·1.73 m2), mean age- and gender-adjusted GHBP levels were -1.40 ± 0.18 SD score; 36% of patients had GHBP levels below the normal range (<-2 SD score). Children with end-stage renal disease (n = 26) had the lowest GHBP levels (-2.25 ± 0.22 SD score). Multiple linear regression analysis revealed that body mass index, rather than glomerular filtration rate, is the prevailing determinant of serum GHBP levels in CRF. GHBP levels correlated with both the spontaneous growth rate (r = 0.44; P < 0.0001) and the growth response to GH therapy (r = 0.48; P < 0.005), indicating decreased sensitivity to both endogenous and exogenous GH. Subcutaneous GH therapy did not consistently affect serum GHBP levels after 3 months of treatment. It is suggested that low GHBP levels in children with CRF represent a quantitative tissue GH receptor deficiency as one of the molecular mechanisms of GH insensitivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GROWTH FAILURE in the presence of normal or elevated GH levels in children with chronic renal failure (CRF) indicates a peripheral insensitivity to the action of GH (1). This concept is supported by the recent observation of reduced hepatic insulin-like growth factor I (IGF-I) gene expression in the setting of experimental CRF (2). One possible molecular mechanism is a reduced density of GH receptors in GH target organs in the uremic state. A direct measurement of GH receptors in human tissues is not readily available. However, tissue GH receptor density can be indirectly assessed by determination of the high affinity GH-binding protein (GHBP) concentrations in serum. GHBP appears to be produced by a limited proteolytic cleavage of the GH receptor and release of the extracellular domain into the circulation (3, 4, 5). Most patients with congenital GH insensitivity syndrome (Laron’s syndrome) lack GH receptor-binding activity in liver and have absent or very low GHBP activity in blood (6). Acquired disease states associated with GH insensitivity, such as acute fasting (7), chronic malnutrition (8), and insulin-dependent diabetes mellitus (9), also have reduced serum GHBP activity.

Previous studies in adults (10, 11, 12) and children (13) have described a reduced GHBP activity in CRF serum. However, the small number of patients in these studies did not allow determination of the possible causes or functional consequences of this alteration. Furthermore, the GH binding assay used in these previous studies required a correction for elevated endogenous GH levels, which reduced the precision of the assay. This problem is avoided by the ligand-mediated immunofunctional assay (LIFA) developed by Carlsson and colleagues (14). The LIFA requires that the GHBP is capable of binding GH, and thus, only functional GHBP is detected (14). Total GHBP concentrations remain relatively stable during a 24-h sampling period (15). Hence, single random blood samples provide a good estimate of the serum GHBP level of an individual.

We, therefore, analyzed serum GHBP levels by LIFA in a large cohort of children with CRF and a varying degree of residual renal function compared to that in normal controls. We sought to determine whether the reduction of serum GHBP levels is related to the degree of renal dysfunction. To test the hypothesis that the growth failure in children with CRF is due to GH insensitivity, as reflected by low GHBP/GH receptor status, age-related GHBP levels were correlated with spontaneous growth rates and those stimulated by GH therapy.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Children with CRF (creatinine clearance, <70 mL/min·1.73 m2) and well controlled conservative treatment were eligible for the present study. The study design was cross-sectional. Patient sera were obtained from two multicenter studies in children with CRF. The first group consisted of patients who were investigated before enrollment into the multicenter randomized study of the effect of a low protein diet on the progression of renal failure in childhood (16). The second group comprised patients with CRF-related growth retardation who were investigated before enrollment into a multicenter study for treatment with recombinant human GH (rhGH; kindly provided by Pharmacia Upjohn, Erlangen, Germany) (17, 18). The inclusion and exclusion criteria for these studies have been published (16, 17, 18). In particular, patients with additional thyroid, liver, or gastrointestinal disease; systemic diseases such as lupus erythematosus, amyloidosis, or oxalosis; or severe cardiac diseases or those who had received treatment with glucocorticoids or other immunosuppressive drugs during the previous 6 months were excluded from the study. In patients with growth retardation, no reason for short stature other than CRF was reported. For the present study, only patients between the age of 3–15 yr were analyzed, because for this age group GHBP reference values from 773 normal children were available for comparison (19). Characteristics of the 126 patients studied are listed in Table 1Go. Eighty-one percent of the patients were prepubertal. Adequate spontaneous energy and protein intake were monitored in the majority of patients (63%) by written dietary diaries, as described previously (20). Twenty-two patients had mild to moderate proteinuria (>0.07 g/kg·day). None of the patients had a nephrotic syndrome.


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  		Table 1. Patient characteristics

 
Patients with CRF received medications consisting of vitamin D or cholecalciferol, water-soluble vitamins, oral phosphate binders, oral sodium bicarbonate, and oral antibiotics for prophylaxis of urinary tract infection. Antihypertensive treatment was given in 47 patients; no patient received clonidine. Recombinant human (rh) erythropoietin was given to 20 patients with end-stage renal disease (ESRD). None of the patients included had previously received any form of GH therapy. Twenty-five patients with ESRD were treated with continuous peritoneal dialysis; 1 patient was treated with intermittent hemodialysis.

Serum was obtained under out-patient conditions in the morning after an overnight fast. The children were studied after informed parental consent was obtained. The study protocol was approved by the local ethics committee of each contributing center.

For analysis of the relationship between GHBP and growth parameters, only prepubertal children (n = 75; subgroup I, Table 1Go) were taken from the entire group of children with CRF because of the uncertainties arising from the timing of pubertal development. In these children, well documented height and height velocity data over the previous year before analysis of serum GHBP levels were available.

To analyze the usefulness of serum GHBP determinations to predict the growth response to rhGH, serum samples from 40 prepubertal patients with CRF-related growth retardation (subgroup II, TableGo I), who were treated with rhGH (28 IU/m2 body surface area·week in daily sc injections, corresponding to 0.05 mg/kg BW·day) for at least 1 yr were collected at baseline evaluation. All patients had a baseline height SD score of -2 or less. The patients remained prepubertal during the 1-yr treatment period. To study the regulatory effect of sc administered rhGH on serum GHBP levels, 27 patients were analyzed at baseline and after 3 months of therapy.

To study the relationship of GHBP levels with IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3, and serum insulin levels, 79 children (subgroup III, Table 1Go), whose serum IGF and IGFBP levels had been measured previously (21), were analyzed.

Methods

Height and weight were measured in all subjects with standardized equipment and techniques. To estimate the nutritional status of the patients, body mass index (BMI) was calculated using the formula: weight (kilograms)/height (meters)2 (Quetelet index). To obtain age-independent estimates of body size and mass, height and BMI (after logarithmic transformation to obtain normally distributed data) were converted to SD scores related to age- and gender-specific means and SDs of European reference populations (22, 23). The stage of puberty was assessed by the method of Tanner (24). The glomerular filtration rate (GFR) was calculated with the formula reported by Schwartz et al. (25): GFR = 0.55 x height (centimeters)/serum creatinine concentration (milligrams per dL). In patients with ESRD receiving dialysis treatment, no attempt was made to measure residual GFR, which is usually in the very low range, between 5–10 mL/min·1.73 m2. Therefore, a value of 7 mL/min·1.73 m2 was arbitrarily entered.

Assays

GHBP was assayed with the LIFA, as previously described (14). The detection range in the LIFA was 15.6–1000 pmol/L. The intra- and interassay coefficients of variation (CVs) were approximately 7% and 11%, respectively. All samples were measured in duplicate.

IGF-I was measured by RIA after acid-ethanol extraction or acidic gel chromatography of serum samples, as described previously (26). The intra- and interassay CVs were 3.5% and 6.7%, respectively. IGF-II (CV, 3.6% and 12.2%) was measured by RIA after acid-ethanol extraction and blocking residual IGFBP in the extract with an excess of IGF-I, as described previously (27). IGFBP-1 (CV, 3% and 11%) (28), IGFBP-2 (CV, 3.7% and 9.6%) (29), and IGFBP-3 (CV, 3.5% and 7.3%) (30) were analyzed by specific RIAs, as described previously. Serum insulin levels (CV, 3.7% and 8.5%) were determined using a solid phase RIA (Biermann, Bad Nauheim, Germany).

Statistical analyses

Reference values for GHBP in 773 healthy children between the age of 3–15 yr have been published previously (19). The distribution of normal serum GHBP levels was log normal (19). Measured values were, therefore, transformed to their logarithms before calculating the SD score to obtain age-independent values for comparison. The calculation of standardized GHBP levels (SD score) was based on the means and associated SDs from the control subject data grouped by gender and age, using the equation: SD score = {log (GHBP) - mean [log (GHBP for age and gender)]}/SD [log(GHBP) for age and gender], where mean [log (GHBP for age and gender)] is the average log value of GHBP for control subjects of the same age and gender as the individual, and SD [log(GHBP for age and gender)] is the associated SD.

Reference values for IGF-I (31), IGF-II (31), IGFBP-1 (21), IGFBP-2 (21), and IGFBP-3 (31) have been reported previously. The distribution of normal IGF and IGFBP serum levels was log normal. Measured values were, therefore, transformed to their logarithms before calculating the SD score to obtain age-independent values for comparison.

Data are given as the mean ± SEM. Data were examined for normal and non-Gaussian distribution by the Shapiro-Wilk test (32). For comparison between two normally distributed groups, an unpaired or paired Student’s t test (two-tailed) was used, as appropriate. Correlations between variables were assessed using univariate linear regression analysis and multiple linear regression analysis. P < 0.05 was accepted as statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum GHBP levels

Serum GHBP levels in individual children with CRF (n = 126) are depicted in Fig. 1Go in relation to the age- and gender-dependent normal range. Similar to that in normal controls, there was a broad variation in serum GHBP levels in patients with CRF. However, there was a consistent tendency toward serum GHBP levels in the low normal or subnormal range, particularly in patients with ESRD. In 97 (77%) of CRF patients, serum GHBP concentrations were below the mean for age- and gender-matched controls. Thirty-six subjects had decreased serum GHBP levels below the normal range (<-2 SD).



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  		Figure 1. Serum GHBP concentrations in 75 male (left panel) and 51 female (right panel) children with CRF related to the age- and gender-dependent normal range (-2 to +2 SD score). The bold line indicates the normal means for age and gender. Open symbols represent children with preterminal CRF; closed symbols indicate children with ESRD receiving dialysis.

 
To obtain age- and gender-independent data, GHBP values were referred to the normal range by calculating the SD score. The mean GHBP in females (-0.85 ± 0.24 SD score) and that in males (-1.23 ± 0.20 SD score) were significantly lower than the control value (P < 0.001). The decrease in serum GHBP levels was related to the degree of renal dysfunction. There was a significant positive correlation of age-related GHBP levels with residual GFR (r = 0.31; P < 0.001; Fig. 2Go). In advanced CRF (GFR, <35 mL/min·1.73 m2; n = 95), mean age-related GHBP levels were -1.40 ± 0.18 SD score; 34 children (36%) had GHBP levels below the normal range (<-2 SD score). Children with end-stage renal failure receiving dialysis (n = 26) had the lowest GHBP levels (-2.25 ± 0.22 SD score).



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  		Figure 2. Age- and gender-related serum GHBP levels (SD score) as a function of the GFR. The GFR in children with ESRD, which usually varies between 5–10 mL/min·1.73 m2, was arbitrarily entered as 7 mL/min·1.73 m2. There was a significant positive correlation (r = 0.31; P < 0.001).

 
Relationship to anthropometric parameters

As observed under normal conditions (33), age-related GHBP levels were correlated with age-related BMI (r = 0.43; P < 0.0001; Fig. 3Go). The BMI SD score was also weakly correlated with GFR (r = 0.23; P < 0.05). To determine whether GFR and the BMI SD score were independent predictor variables of the GHBP SD score, multiple linear regression analysis was performed. GHBP SD scores could be expressed by the following function: GHBP SD score = -1.44 + (0.02 x GFR) + (0.456 x BMI SD score) (r = 0.48; adjusted r <= 0.22). In this equation, GFR did not appear necessary to account for the ability to predict the GHBP SD score. Hence, BMI appears to be the prevailing determinant of serum GHBP levels in children with CRF, at least statistically.



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  		Figure 3. Age- and gender-related serum GHBP levels (SD score) as a function of age- and gender-related BMI (SD score). There was a significant positive correlation (r = 0.43; P < 0.001).

 
To test the hypothesis that reduced serum concentrations of GHBP reflect a decreased sensitivity to GH in children with CRF, the relationship of age-related GHBP levels with growth parameters was examined. Only prepubertal children (n = 75) were taken from the entire group of children with CRF because of the uncertainties arising from the timing of pubertal development. There was a moderate linear correlation between the GHBP SD score and spontaneous growth rates (r = 0.44; P < 0.0001; Fig. 4Go). Within the normal range of serum GHBP levels, height velocity varied considerably (Fig. 4Go), indicating that factors other than GHBP/GH receptor status influence growth in these children. The GHBP SD score was not correlated with age-related height. There was also a weak correlation of height velocity with age-related BMI (r = 0.33; P < 0.005). Multiple linear regression analysis revealed that only the GHBP SD score accounted for the statistical prediction of height velocity.



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  		Figure 4. Spontaneous height velocity in 75 prepubertal children with CRF as a function of age- and gender-related serum GHBP levels (SD score). The normal range for GHBP (-2 to +2 SD score) is given by a dotted line. There was a significant positive correlation (r = 0.44; P < 0.0001).

 
Next, we tested the hypothesis that GHBP levels in children with CRF might predict the growth response to exogenous rhGH. A group of 40 growth-retarded prepubertal children treated with rhGH for at least 1 yr who remained prepubertal during this study period was analyzed. Growth rate increased from a baseline of 3.6 ± 0.3 cm/yr to 8.1 ± 0.4 cm/yr during the first year of rhGH therapy. In this group of stunted children, height velocity at baseline was not significantly correlated with the GHBP SD score (r = 0.24; P = 0.14). However, there was a significant positive correlation of age-related serum GHBP levels with the increase in height SD after 1 yr of rhGH therapy (r = 0.57; P < 0.0001; Fig. 5AGo). This correlation remained significant (r = 0.41; P < 0.02) when the two patients with the lowest and highest growth responses to rhGH were excluded from the analysis. Age-related GHBP levels were also correlated with height velocity after 1 yr of rhGH therapy (r = 0.48; P < 0.005; Fig. 5BGo). Hence, GHBP levels appear to predict 23–32% of the growth response to rhGH in children with CRF. The growth response to rhGH was not correlated with the age-related BMI.



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  		Figure 5. Change ({Delta}) in height SD score (A) and height velocity (B) after 1 yr of rhGH therapy as a function of baseline age- and gender-related serum GHBP levels (SD score) in 40 prepubertal children with CRF treated with 28 IU rhGH/m2 body surface area in daily sc injections. There was a significant positive correlation (A: r = 0.57; P < 0.0001; B: r = 0.48; P < 0.005).

 
In Fig. 6Go, growth data were stratified according to children with low (<=-2 SD score) or normal (>-2 SD score) serum GHBP levels. In subgroup I (Table 1Go), the spontaneous growth rate (3.5 ± 0.5 cm/yr) in children with decreased GHBP levels (n = 54) was markedly lower than the growth rate (6.1 ± 0.4 cm/yr) in children with normal GHBP levels (n = 21). The two groups were of comparable age (8.0 ± 0.4 and 8.6 ± 0.6 yr, respectively). In GH-treated children (subgroup II, Table 1Go), the difference in growth rate between children with low vs. normal serum GHBP levels was less apparent, yet still statistically significant, indicating that the hyporesponsiveness to GH in children with CRF can only partially be overcome by this supraphysiological dose of rhGH (Fig. 6Go). Also these two groups were of comparable age (7.3 ± 0.7 and 8.5 ± 0.7 yr, respectively).



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  		Figure 6. Left panel, Spontaneous growth rate in 75 children with CRF, stratified according to decreased (<=-2 SD score; open bars; n = 21) or normal (>-2 SD score; hatched bars; n = 54) age- and gender-related GHBP levels. Right panel, First year growth rate during rhGH therapy in 40 children with CRF, stratified according to decreased (<=-2 SD score; open bars; n = 18) or normal (>2 SD score; hatched bars; n = 22) age- and gender-related GHBP levels. *, P < 0.05; **, P < 0.001.

 
Relationship to hormonal and metabolic parameters

To investigate whether the growth-stimulating effect of rhGH is mediated by an up-regulation of tissue GH receptors, as estimated by circulating GHBP levels, 12 patients with preterminal CRF and 15 patients with ESRD were investigated before and after 3 months of sc rhGH treatment. Treatment with exogenous GH had no consistent effect on serum GHBP levels after 3 months of therapy in any of the groups, indicating the relative constancy of GHBP levels in the same subject (Fig. 7Go).



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  		Figure 7. Serum GHBP levels at baseline and after 3 months of rhGH therapy in 12 children with preterminal CRF (A) and 15 patients with ESRD receiving dialysis (B). Square symbols indicate the mean ± SEM. There was no consistent effect of GH therapy on serum GHBP levels.

 
Correlation analyses with other hormones of the somatotropic hormone axis were performed in 78 children with preterminal CRF. Age-related IGF-I levels in this group of children were in the low normal range (-0.16 ± 0.17 SD score). There was no correlation between serum GHBP levels and IGF-I, IGF-II, IGFBP-1, IGFBP-3, or serum insulin, irrespective of whether absolute or age-related values were taken. However, there was a weak inverse correlation between age-related GHBP and IGFBP-2 levels (r = -0.29; P < 0.01).

There was no correlation between age- and gender-related GHBP levels and serum albumin concentrations (43.0 ± 0.66 mg/L; range, 30.0–59.0) or serum bicarbonate levels (22.2 ± 0.34 mmol/L; range, 12–30).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our analysis in this large group of children with CRF shows a decrease in serum GHBP levels in relation to the degree of renal dysfunction. Because the high affinity GHBP is derived from the extracellular domain of the GH receptor by proteolytic cleavage, low GHBP levels in CRF are likely to indicate a quantitative reduction of GH receptor density in GH target organs, in particular in liver, because circulating GHBP is believed to derive mainly, but not exclusively, from liver tissue. This concept is supported by experimental data that demonstrate a nutrition-independent reduction of hepatic GH receptor gene expression in a rat model of CRF (34). The specific metabolic signal of the uremic milieu responsible for low GHBP/GH receptor status in CRF remains to be elucidated. The GH receptor underlies a complex regulation by hormonal and nutritional factors. Under experimental conditions, 24-h fasting in rats led to a 50% reduction in somatogenic binding to liver tissue (7). Similarly in humans, severe dietary restriction was associated with a decrease in serum GHBP levels (8, 35). However, severe malnutrition is rarely seen in children with CRF and was not apparent in our study population, because the vast majority (91%) of patients had an age-related BMI above the lower limit of normal. In addition, adequate spontaneous energy and protein intake were monitored in all patients by written dietary diaries. As observed under normal conditions (33), we report a positive correlation between GHBP levels and BMI in children with CRF, indicating that variations in nutritional status within the normal range are an important determinant of GH receptor status in tissues. The lack of a correlation between serum GHBP and serum bicarbonate levels in our study argues against a pathogenic role of metabolic acidosis on tissue GH receptor density.

Under normal conditions, there is an inverse correlation between the GH secretion rate and serum GHBP levels (33). In children with CRF, serum GH levels are normal or elevated depending on the extent of renal failure (36). An important question is whether low tissue GH receptor density in CRF is the reason for or the consequence of high GH plasma levels in advanced CRF. The isolated increase in GH secretion in normal puberty in the presence of unchanged GHBP levels (37) argues against a direct regulation of GH receptors by endogenous GH in vivo. In the majority of studies, children and adults with GH deficiency have normal serum GHBP levels (19, 38, 39, 40, 41), and these levels do not change during sc GH replacement therapy (38, 39, 40), whereas two smaller studies have suggested that GH-deficient children have low GHBP levels that rise after GH treatment (42, 43). On the other hand, some patients with idiopathic short stature exhibit clearly decreased serum GHBP levels in the presence of normal GH secretion (19). These results argue against a direct regulation of GHBP/GH receptors by GH. This concept is supported by the lack of effect of exogenous GH on serum GHBP levels in the present study. More likely is a direct suppressive effect of the uremic milieu on tissue GH receptor density, which leads to an adaptive increase in pituitary GH secretion in addition to the diminished feedback down-regulation of GH secretion by decreased IGF bioactivity (36, 44).

The interpretation of peptide hormone concentrations in CRF serum requires one to consider a reduced metabolic clearance by the diseased kidneys. The high affinity GHBP in humans is a heavily glycosylated protein with a molecular mass of approximately 60,000 kDa (45). In principal, one GH molecule is capable of binding two GHBP molecules with two different binding sites (46). In plasma, however, a 1:1 stoichiometry prevails because of the relatively low concentration of GHBP (47). The GH/GHBP complex, therefore, has a molecular mass between 80,000–85,000 kDa and is thus too large to undergo substantial renal filtration (48). Also, free GHBP, with a molecular mass of 60,000 kDa, is unlikely to undergo renal filtration in the absence of a nephrotic syndrome. In any event, reduced renal filtration of GHBP in CRF would, instead, lead to an underestimation of the quantitative deficiency of tissue GH receptors in CRF. Noteworthy, the minimal peritoneal losses of GHBP that occur during continuous peritoneal dialysis do not effect their respective serum concentrations (12).

In the present study, we also tried to determine the functional relevance of a decreased GHBP/GH receptor status in CRF with respect to growth. The correlation between age-related serum GHBP levels and the spontaneous growth rate as well as the growth response to GH therapy suggests that low GH receptor density in GH target organs is one of the molecular mechanisms of GH insensitivity in the uremic state. Notably, these correlations were only modest, indicating that low GHBP/GH receptor status cannot explain as a single factor the growth failure in children with CRF. Complex alterations of the IGF-IGFBP axis in children with CRF (21, 49, 50) as well as other hormonal and metabolic disturbances (51) contribute to the pathophysiological mechanism of CRF-associated growth retardation. Nevertheless, baseline GHBP levels predicted 23–32% of the growth response to rhGH in children with CRF in the present study, suggesting that GHBP may be a helpful clinical parameter to partially predict the growth response to rhGH. A modest correlation between pretreatment GHBP levels and first year growth rates in response to exogenous GH was also reported in 43 GH-deficient children (39), but not in children with idiopathic short stature (52). Our data help to explain the previously reported lower growth response to exogenous GH in children with ESRD compared to that in children with remnant renal function (18), because in the former group, serum GHBP levels were suppressed the most.

It is not known whether GHBP, in addition to serving as an accessible tool for assessment of GH receptor status, plays an active role in the regulation of growth. In vitro studies suggest that GHBP within the physiological range of serum GHBP concentrations decreases the binding of GH to its membrane-anchored receptor and thereby inhibits GH activity (53). In vivo, however, the growth-promoting effects of GH can be enhanced when GH is given together with GHBP to GH-deficient rats (54), probably by prolongation of the GH half-life. Whether low GHBP levels in children with CRF, in whom the GH half-life is prolonged (36), play a pathogenic role in growth failure independent of their indicative role for GH receptor status is difficult to assess.

In some clinical conditions, such as severe malnutrition, the reduced GHBP/GH receptor status is associated with a parallel decrease in circulating IGF-I levels (8, 35). In children with idiopathic short stature, a weak correlation between age-related GHBP and IGF-I levels was observed (52). The lack of a correlation in our study can be explained by the increased IGF-binding capacity in serum CRF, which does not allow interpretation of normal IGF-I levels as an indication of normal IGF-I production rates (55). Indeed, recent experimental data from our group indicate that reduced hepatic GH receptor gene expression is associated with a specific nutrition-independent reduction of IGF-I gene expression in liver tissue (2).

In conclusion, GHBP levels are decreased in children with CRF in relation to the degree of renal dysfunction, suggesting a quantitative GH receptor deficiency in GH target organs. We demonstrate that this alteration correlates with decreased sensitivity to both endogenous and exogenous GH in children with CRF. It is suggested that reduced GHBP/GH receptor status represents one of the molecular mechanisms of GH insensitivity in the uremic state.


   Acknowledgments
 
Recombinant human GH was kindly provided by Pharmacia Upjohn (Stockholm, Sweden). We thank Dr. G. Cimander, Pharmacia Upjohn (Erlangen, Germany), for help with organization of the serum samples.


   Footnotes
 
1 Contributing investigators (in alphabetical order of the centers): I. Rätsch (Ancona); K. Michelis and T. Kapogiannis (Athens); T. Lennert and F. Jung (Berlin I); S. Gellert (Berlin II); T. Tulassay and P. Sallay (Budapest); T. von Lilien and U. Querfeld (Cologne); M.-A. von Wendt-Göknur (Erlangen); K. E. Bonzel (Essen); R. Gusmano and E. Verrina (Genova); G. Offner (Hannover); O. Mehls, A.-M. Wingen, and C. Fabian-Bach (Heidelberg, coordinators); A. Appiani and A. Bettinelli (Milan); J. Feber (Prague); S. Picca and G. Rizzoni (Rome); H. J. Stolpe and W. Wigger (Rostock); J. Kist-van Holthe and E. Wolff (Rotterdam, coordinators for the centers at Amsterdam, Antwerp, Groningen, Nijmegen, and Rotterdam); U. Berg (Stockholm); M. Fischbach (Strasbourg); E. Dobos (Szeged); E. Balzar (Vienna); and T. Neuhaus (Zurich). Back

2 H. Ruder (Erlangen); K. E. Bonzel and B. Scheller (Essen); J. Dippell (Frankfurt); L. B. Zimmerhackl (Freiburg); and D. Haffner, O. Mehls, B. Tönshoff, and E. Wühl (Heidelberg, coordinators). Back

Received October 2, 1996.

Revised December 12, 1996.

Accepted January 6, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Tönshoff B, Mehls O. 1995 Growth retardation in children with chronic renal insufficiency: current aspects of pathophysiology and treatment. J Nephrol. 8:133–142.
  2. Tönshoff B, Powell DR, Zhao D, et al. Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein (IGFBP)-1 and -2 gene expression in experimental uremia. Endocrinology, in press.
  3. Leung DW, Spencer SA, Cachianes G, et al. 1987 Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature. 330:537–543.[CrossRef][Medline]
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