Growth failure is common in children with chronic renal failure (CRF); CRF must interfere with the hormonal control of statural growth. Statural growth depends on the growth hormone (GH)-stimulated production of insulin-like growth factor (IGFs), primarily IGF-1. These growth factors then circulate in blood bound to carrier proteins and act to produce growth by stimulating mitogenic pathways in growth plate chrondrocytes of long bones. GH levels are high and immunoreactive IGF-1 levels are normal in children with CRF and growth failure. Growth failure may be due either to immunoreactive but biologically inactive IGF-1 in CRF serum or to end organ resistance to IGF-1 action, perhaps caused by circulating inhibitors. This proposal outlines an evaluation of IGF-1 bioactivity in CRF. Studies will evaluate whether structural variants or metabolic fragments of IGF-1 are immunoreactive but biologically inactive in CRF, and will concentrate on IGF-1 prohormone which is elevated in CRF serum. In addition to IGF-1 prohormone, IGF carrier proteins and small molecular weight inhibitors of cell metabolism also accumulate in CRF serum; studies will evaluate these three for their ability to block IGF-1 mediated mitogenic effects in fibroblasts and chondrocytes in vitro. Studies are also outlined which will investigate the role of protein intake on growth and levels of growth factors and their inhibitors in infants with CRF. A final study will evaluate whether long-term GH therapy is associated with improved growth, elevated IGF-1 levels, insulin resistance and/or accelerated decline in renal function in a rat model of CRF. Dr. David Powell, the principal investigator, gained familiarity with the areas of growth and nutrition in children with CRF while training with Dr. Malcolm Holliday at UCSF. Dr. Powell later gained experience in HPLC, radioimmunoassay and cell culture methodologies in the Stanford laboratory of Dr. Raymond Hintz, who is a secondary sponsor and an authority in the measurement and cell physiology of IGF peptides. The work will be performed at the Baylor School of Medicine laboratory of Dr. Ken Gabbay, an authority in the physiology and molecular biology of IGF peptides. Dr. Gabbay and others in his laboratory are well qualified to critically evaluate the cell culture, RIA and protein purification methodologies which are necessary to perform the above studies. Dr. Powell and his sponsors hope that these studies will improve both understanding and treatment of the growth failure of children with chronic renal failure.
