Growth hormone
binding protein in patients with renal failure
Hiralal G Maheshwari, Ian Rifkin, Joan Butler and Michael Norman Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, London and
Renal
Unit'. Dulwich Hospital. London,
UK
Maheshwari HG, Rifkin I, Butler J, Norman M. Growth hormone binding protein in patients with renal failure. Acta Endocrinol 1992;127:485-8. ISSN 0001-5598
investigate changes in the growth hormone binding protein (GH-BP) in renal disease, gel chromatography was used to separate free and bound hormone after incubation with 125I-GH, the results being expressed as a percentage of radioactive GH eluting in a high molecular weight (70\p=n-\80 kD) peak. In 26 normal individuals, binding was 39.3 \m=+-\8.0%, while in 11 patients with renal disease who were off dialysis binding was reduced to 16.8\m=+-\5.6%. Similarly, in 9 patients undergoing hemodialysis binding was reduced to 24.6 \m=+-\6.8%, in 8 patients undergoing chronic ambulatory peritoneal dialysis binding was reduced to 25.7\m=+-\7.6%,and in 9 patients within three months of a renal transplant binding was reduced to 25.1 \m=+-\8.6%. Scatchard analysis showed that these changes were not a result of decreased affinity of GH-BP for GH, and receptor binding studies showed that uremic serum was not inhibiting binding. The decreased concentration of GH-BP may indicate decreased expression of the GH To
receptor in target tissues, and hence diminished responsiveness MR Norman,
to GH in
renal failure.
Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, Denmark
Hill, London SE 5 8PJ, UK
The growth failure which is frequently associated with chronic renal failure in children ( 1 ) has focused atten¬ tion on possible changes in the release and function of growth hormone. More recently, it has become apparent that GH may also be important for maintenance of muscle mass in adults (2), so that the relevance of any alteration in GH may not be limited to children with renal failure. Several studies have shown that renal disease is associated with abnormalities in the regulation of GH release, but in general plasma GH concentrations are normal or increased. Measurement of insulin-like growth factor I (IGF-I) has been used to assess the biological effect of GH on target tissues. Immunoreactive IGF-I concentrations are generally found to be normal or increased (3), while bioactive IGF-I is decreased (4-6). An explanation for this discrepancy may lie in increased concentrations of IGF-I binding proteins or other inhibi¬ tors of IGF-I action (7, 8), but in any case the majority of serum IGF-I is probably derived from liver and may not reflect direct actions of GH on other tissues, such as chondrocytes and muscle (9). Direct evidence that cellular responsiveness to GH is defective in renal failure has been obtained by Finidori et al. (10), who showed that sub-total nephrectomy caused a marked reduction in the number of hepatic GH receptors in rats. The increased growth rate of children with renal failure who were treated with recombinant GH (11) has been taken as further evidence that partial resistance to GH may be a contributing factor to their poor growth. The specific binding protein for GH (GH-BP), first discovered in mouse (12), then rabbit (13), and human (14, 15) serum, is derived from the GH receptor gene,
either by proteolysis of the GH receptor (16) or by alternative splicing of the GH receptor mRNA (17). The function of this protein is unclear, but it has been shown to increase the half-life of GH in serum (18) and also to decrease availability of GH to cellular receptors (19, 20). Since the concentration of GH-BP in serum may be determined by the level of GH receptor expression, we decided to investigate the effects of renal failure on serum GH-BP.
Patients and methods A total of 3 7 patients with renal disease who had a mean age of 5 9 years (range 2 5-84) were studied. Of these, 11 patients (age range 38 to 84 years including 4 females) had been off dialysis for ten days or more at the time samples were taken. A further 9 patients (age range 26 to 74 years, 3 females) were undergoing hemodialysis, 8 patients (age range 34 to 70 years, 2 females) were undergoing chronic ambulatory peritoneal dialysis and 9 patients (age range 25 to 74 years, 2 females) had undergone renal transplantation within the previous three months. Apart from the post-transplant patients
(who were treatment),
on
steroid, azathioprine and cyclosporin of the patients had been treated with
none
drugs likely to affect GH-BP. The mean BMI (body mass index, reference range 20-25) for the latter group
was
26 (range 19 to 35). Blood was taken after the patients had given informed consent. The 26 control subjects were healthy working or retired laboratory personnel and were not taking medication (mean age 39, range 2 5 to 76 years, 9 females). Serum GH concentrations in the
486 Hiralal G Maheshwari et al. Table 1. Effect of renal disease
ACTA ENDOCRINOLOGICA 1992, 127
on serum
GH-BP activity and
affinity.*
Creatinine
GH
(/jmol/1)
Group
(range)
Mean ± sd
Controls (N
=
80±19
2 6)
(mU/1)
Median 0.9
%GH
Affinity of
binding
GH-BP
MeaniSD
(
binding protein in patients with renal failure
Hiralal G Maheshwari, Ian Rifkin, Joan Butler and Michael Norman Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, London and
Renal
Unit'. Dulwich Hospital. London,
UK
Maheshwari HG, Rifkin I, Butler J, Norman M. Growth hormone binding protein in patients with renal failure. Acta Endocrinol 1992;127:485-8. ISSN 0001-5598
investigate changes in the growth hormone binding protein (GH-BP) in renal disease, gel chromatography was used to separate free and bound hormone after incubation with 125I-GH, the results being expressed as a percentage of radioactive GH eluting in a high molecular weight (70\p=n-\80 kD) peak. In 26 normal individuals, binding was 39.3 \m=+-\8.0%, while in 11 patients with renal disease who were off dialysis binding was reduced to 16.8\m=+-\5.6%. Similarly, in 9 patients undergoing hemodialysis binding was reduced to 24.6 \m=+-\6.8%, in 8 patients undergoing chronic ambulatory peritoneal dialysis binding was reduced to 25.7\m=+-\7.6%,and in 9 patients within three months of a renal transplant binding was reduced to 25.1 \m=+-\8.6%. Scatchard analysis showed that these changes were not a result of decreased affinity of GH-BP for GH, and receptor binding studies showed that uremic serum was not inhibiting binding. The decreased concentration of GH-BP may indicate decreased expression of the GH To
receptor in target tissues, and hence diminished responsiveness MR Norman,
to GH in
renal failure.
Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, Denmark
Hill, London SE 5 8PJ, UK
The growth failure which is frequently associated with chronic renal failure in children ( 1 ) has focused atten¬ tion on possible changes in the release and function of growth hormone. More recently, it has become apparent that GH may also be important for maintenance of muscle mass in adults (2), so that the relevance of any alteration in GH may not be limited to children with renal failure. Several studies have shown that renal disease is associated with abnormalities in the regulation of GH release, but in general plasma GH concentrations are normal or increased. Measurement of insulin-like growth factor I (IGF-I) has been used to assess the biological effect of GH on target tissues. Immunoreactive IGF-I concentrations are generally found to be normal or increased (3), while bioactive IGF-I is decreased (4-6). An explanation for this discrepancy may lie in increased concentrations of IGF-I binding proteins or other inhibi¬ tors of IGF-I action (7, 8), but in any case the majority of serum IGF-I is probably derived from liver and may not reflect direct actions of GH on other tissues, such as chondrocytes and muscle (9). Direct evidence that cellular responsiveness to GH is defective in renal failure has been obtained by Finidori et al. (10), who showed that sub-total nephrectomy caused a marked reduction in the number of hepatic GH receptors in rats. The increased growth rate of children with renal failure who were treated with recombinant GH (11) has been taken as further evidence that partial resistance to GH may be a contributing factor to their poor growth. The specific binding protein for GH (GH-BP), first discovered in mouse (12), then rabbit (13), and human (14, 15) serum, is derived from the GH receptor gene,
either by proteolysis of the GH receptor (16) or by alternative splicing of the GH receptor mRNA (17). The function of this protein is unclear, but it has been shown to increase the half-life of GH in serum (18) and also to decrease availability of GH to cellular receptors (19, 20). Since the concentration of GH-BP in serum may be determined by the level of GH receptor expression, we decided to investigate the effects of renal failure on serum GH-BP.
Patients and methods A total of 3 7 patients with renal disease who had a mean age of 5 9 years (range 2 5-84) were studied. Of these, 11 patients (age range 38 to 84 years including 4 females) had been off dialysis for ten days or more at the time samples were taken. A further 9 patients (age range 26 to 74 years, 3 females) were undergoing hemodialysis, 8 patients (age range 34 to 70 years, 2 females) were undergoing chronic ambulatory peritoneal dialysis and 9 patients (age range 25 to 74 years, 2 females) had undergone renal transplantation within the previous three months. Apart from the post-transplant patients
(who were treatment),
on
steroid, azathioprine and cyclosporin of the patients had been treated with
none
drugs likely to affect GH-BP. The mean BMI (body mass index, reference range 20-25) for the latter group
was
26 (range 19 to 35). Blood was taken after the patients had given informed consent. The 26 control subjects were healthy working or retired laboratory personnel and were not taking medication (mean age 39, range 2 5 to 76 years, 9 females). Serum GH concentrations in the
486 Hiralal G Maheshwari et al. Table 1. Effect of renal disease
ACTA ENDOCRINOLOGICA 1992, 127
on serum
GH-BP activity and
affinity.*
Creatinine
GH
(/jmol/1)
Group
(range)
Mean ± sd
Controls (N
=
80±19
2 6)
(mU/1)
Median 0.9
%GH
Affinity of
binding
GH-BP
MeaniSD
(
