Cytokines and Growth in Children With CRI and ESRD

Children with chronic renal failure (CRF; estimated creatinine clearance less than 75ml/min/1.73 m2) and end-stage renal disease (ESRD; dialysis dependent) have marked growth retardation and often do not achieve their expected height based on genetic potential despite adequate caloric supplementation, and more recently, rhGH treatment. Resistance to both endogenous and rhGH has been proposed to account for much of this growth failure, although the specific mechanisms remain unknown. Possibilities include insensitivity to GH and an inappropriate production of IGF-I and/or a reduced bioavailability secondary to an altered GH-IGF axis. Abnormalities in the GH/IGF-I axis may result in an inability of the growth plate chondrocyte to respond appropriately. Studies combining data on nutritional parameters, changes in body composition and bone density, bone turnover and the GH-IGF axis-related proteins in children with CRF and ESRD are lacking. We propose to further characterize the specific mechanisms underlying impaired growth in pre-pubertal and pubertal children with CRF or ESRD and growth failure prior to and after the initiation of rhGH therapy. The Specific Aims of this proposal are designed to allow a more efficacious use of rhGH in maximizing growth in these children. In this study measurements of total body composition, i.e., lean body mass, fat mass and bone mineral content will be made using dual photon X-ray absorptiometry. Bone mineral density will also be determined. These studies will be correlated with anthropometric, biochemical and nutritional assessments of patients before and during rhGH treatment. Letin and cytokines will be concomitantly measured. Bone collagen turnover will be quantitated using pyridinoline and deoxypyridinoline cross-links excretion (in CRF patients) and serum levels of collagen type I C-terminal propeptide (CICP) concomitant with the above measurements. Bone turnover will be further assessed by looking at additional biochemical markers of bone metabolism such as osteocalcin and bone alkaline phosphatase. Serum levels of IGF-I, IGF-II, intact and fragmented IGFBP-1, -2,-3, and GH and GH-binding activity will be determined before and during rhGH therapy and correlated to measurements made in the other studies. These studies will help elucidate the differences in rhGH responsiveness in this population. Taken together, the above studies will substantially advance our understanding of how rhGH improves growth in children with CRF and ESRD.