Abstract
Poor growth is a significant problem in children with chronic renal failure. Poor
nutrition and metabolic abnormalities contribute to poor growth, and in addition
disturbances of growth hormone (GH) and its mediator insulin-like growth factor-I
(IGF-I) have been described. Growth rates usually decline further once dialysis is
required, and whilst growth rate may improve following renal transplantation in some
children, this is not universal, and may not be sustained. Final adult height is reduced in
children who require dialysis or transplantation during childhood.
It is on this background that recombinant human growth hormone (rhGH) is
being used more commonly in children with chronic renal failure. The basis of this
thesis is a multi-centre study looking at the safety and efficacy of the use of rhGH in
10 infants with chronic renal failure (CRF), 29 children with CRF, 14 children on
peritoneal dialysis (PD), 8 on haemodialysis (HD) and in 22 children following renal
transplantation. All of the children were followed during one year of rhGH treatment
except the transplanted children who were randomised either to receive 2 years of
rhGH treatment or to receive no treatment in the first year and rhGH in the second
year. RhGH treatment (liu/kg/week) improved short to medium term growth in all of
these groups of children. Comparison between groups and factors predictive of the
magnitude of response to rhGH are described, as are the effects of rhGH during the
pubertal years.
The main safety issues which are addressed are the effects of rhGH on renal
function, immune function, renal bone disease, and the effects on glucose and lipid
metabolism. Patients with acromegaly, where there is overproduction of GH, have
large kidneys that have an increased glomerular filtration rate (GFR). In a setting of
impaired renal function, a stimulus to increase GFR could result in hyperfiltration,
which is thought to be one mechanism for progression of chronic renal impairment.
Renal function was measured in the CRF and transplanted children; there was no
significant change in the CRF group, but an increase was seen in the transplanted
group after 1 week and 6 months which returned to baseline by one year. These
findings and the effects of rhGH on blood pressure, renal size and protein excretion are
discussed in detail.
There are well established links between GH and the immune system,
particularly in smaller mammals. In man, GH and IGF-I receptors are found on
peripheral blood lymphocytes, and in vitro studies indicate a role for GH in
lymphopoiesis and granulopoiesis. Minor changes in lymphocyte subsets have been
reported with GH replacement in children with GH deficiency. Children with renal
transplants are immunosuppressed, and any increase in immune activity could result in
rejection of the graft. Flow cytometry studies demonstrated little change in lymphocyte
subsets, and markers of T lymphocyte activation in the CRF and transplanted patients
during rhGH treatment. Overall there was no increase in the incidence of rejection
episodes in the transplanted children during rhGH treatment. These results are
decribed in detail.
Carbohydrate and lipid metabolism are already disturbed in chronic renal
failure, and could be altered further by rhGH treatment. Fasting glucose was
unchanged by rhGH treatment, but fasting insulin increased transiently. Fasting
cholesterol and triglyceride levels were already increased in many children before the
start of treatment, and with the exception of the CRF group, in whom a small but
significant increase in triglyceride was seen, there was little change during the study.
The implications of these findings are discussed, as are the effects of rhGH on bone
metabolism. Calcium was unchanged during treatment, but significant increases in
phosphate and alkaline phosphatase were seen. Parathyroid hormone increased during
rhGH treatment in the CRF groups.
Abnormalities of the GH / IGF-I axis are found in chronic renal failure; indeed
a state of GH resistance has been described. Detailed studies of GH, IGF-I and its
binding proteins (IGFBPs) were undertaken to investigate the mechanisms of GH
resistance and the effects of rhGH treatment both before and after renal
transplantation. Roles for different IGFBPs in the mechanism of short stature before
and after transplantation are discussed.
