Effect of Cytokines on Growth of Children With Chronic Kidney Failure

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.

Inclusion Criteria:

- Current height < 2SD (or < 3rd percentile) for chronological age

- Chronic renal failure (estimated creatinine clearance <75 mL/min/1.73m2) or ESRD (as
defined by receiving maintenance HD or PD)

- Age < 21 years and /or growth potential demonstrable by bone age

Exclusion Criteria:

- Unable or unwilling to adhere to the protocol

- Additional diagnoses that could impair responsiveness to GH, e.g. dwarfism syndromes,
significant extra-renal organ disease, e.g. chronic liver disease, or chronic
corticosteroid therapy