A Multicenter Study of the Effect of Recombinant Human Growth Hormone on Leptin and Cytokines in Relation to Body Composition in Pediatric Patients With Growth Failure Due to Chronic Kidney Disease (CKD)
Hypothesis: The energy cost of growth is increased in experimental CKD. Caloric intake has
been shown to correlate with height velocity in children with CKD, and calorie
supplementation has been clearly shown to improve height velocity in children on dialysis.
However, when energy intake exceeds 75% of the recommended allowance, further growth
improvement does not occur. Circulating concentrations of cytokines, such as leptin, tumor
necrosis factor-alpha and interleukins 1 and 6 are increased in patients with CKD. In light
of the increasing recognition that growth hormone receptor signaling involves cytokine
pathway activation, we hypothesize that maladaptation of cytokine regulation in CKD may
underlie growth failure. Secondly, we hypothesize that administration of recombinant human
growth hormone (rhGH) will result in growth rate stimulation in pre-pubertal children with
growth impairment due to CKD by down regulation of the cytokine pathways.
Specific Aims: This investigation's primary objective will be to evaluate
biochemical/metabolic, and immunologic parameters in relation to body composition pre- and
post-rhGH therapy. The secondary objective is to examine the efficacy of rhGH to improve
growth velocity in prepubertal, rhGH naïve, children with growth failure secondary to CKD.
The safety of rhGH will be assessed by measuring the above parameters, in addition to
identifying if there is an increase in the incidence of slipped capital femoral epiphyses,
and an increase in progression of the underlying renal disease.
Methods of Procedure: This is an open-label study to evaluate the efficacy and safety of
recombinant human growth hormone in children with chronic kidney disease and growth failure.
The study involves obtaining the following:
1. Medical History and Physical Examination: Subjects will have a complete medical history
for any potential conditions/medications, which might affect linear growth, growth
velocity, or responsiveness to rhGH. A complete physical examination will be performed,
including Tanner Staging, accurate measurement of standing height (or recumbent length,
if < 3 years of age) using a stadiometer (in triplicate), weight (in triplicate), blood
pressure and funduscopic examination at each referring Center. Anthropometric
measurements will be made at the Body Composition Unit at St. Luke's-Roosevelt Medical
Center, New York, NY.
2. Routine labs will include a CBC (Hgb/ Hct), BUN, creatinine, liver function studies,
3. Bone Age
5. Cytokines that will be measured include IL-6, TNF alpha, TNFsR, Rp55 (type1), IL-1beta,
and IL-1Ra. The ratio of IL-1 to IL-1Ra will be measured as intracellular and
extracellular IL-1b compared to extracellular IL-Ra measured in circulation and as
produced in vitro, both spontaneously and in response to activation. TNF alpha levels
and production both intracellularly and extracellularly will be compared to TNFsRp55
7. GH-IGF Axis Proteins
8. Body Composition by DXA
During the two years of the study, we anticipate that 15 eligible subjects will receive rhGH
at 0.05 mg/kg daily by subcutaneous injection. This estimate of patient enrollment is based
upon our preliminary data and our experience with the incidence, age of onset of CKD, and
the anticipated change in therapy as some of these patients receive transplants. The dose
will be calculated based on the initial weight and will be adjusted as needed every three
months according to weight. A parent or legal guardian will administer all doses at home
after appropriate training. Following treatment for 6 months and termination from the study,
patients who remain eligible due to persistent growth retardation, will receive daily rhGH
as standard of care therapy at their institution and their growth rates will be followed.
During the course of the study all study subjects will continue medical management and
follow-up of their CKD as prescribed by their Pediatric Nephrologist. Subjects may require
concomitant medications such as erythropoietin, calcium supplements, sodium
bicarbonate/sodium citrate, phosphate binders, calcitriol, and/or antihypertensives as part
on their on-going management.
After baseline assessment (Time 0), all study subjects will enter a six-month observation
phase. Medical history, physical examination, biochemical studies, creatinine clearance for
glomerular filtration rate (GFR), Hgb/Hct, Glucose Tolerance testing (GTT) with insulin
measurements, GH-IGF axis proteins, cytokine and leptin studies will be obtained at Time 0,
+3 months, and +6 months. At Time 0 and at the end of six months of observation, study
subjects will also undergo body composition evaluation (DXA) for a total of two sets of
studies. Bone age will be assessed at these time points as well. Each patient will serve as
his/her own control at Time 0 for all these measurements. Historical growth data will be
obtained back as far as six months, and further, if possible.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary objective will be to evaluate biochemical/metabolic, and immunologic parameters in relation to body composition.
pre- and post-rhGH therapy
Valerie L Johnson, MD, PhD
Weill Medical College of Cornell University
United States: Institutional Review Board
|Weill Medical College of Cornell University||New York, New York 10021|