Use of recombinant human growth hormone in children with chronic renal failure

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