EFFECTS OF RENAL OSTEODYSTROPHY DURING GROWTH

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Renal osteodystrophy (ROD) is a multifactorial disorder of bone metabolism in individuals with renal insufficiency. As renal failure progresses, ensuing abnormal parathyroid hormone (PTH) secretion and calcium metabolism result in sclerosis of trabecular bone and thinning of cortical bone. During childhood and adolescence, skeletal growth is normally characterized by marked expansion of cortical dimensions and increases in trabecular density. Therefore, the growing skeleton may be particularly vulnerable to the structural effects of renal osteodystrophy. Underlying renal disorders associated with elevated systemic levels of inflammatory cytokines and renal therapies, such as glucocorticoids, also may impair bone accretion. Although the impact of these threats to normal bone development among children with renal failure is not fully known, they plausibly may lead to an irreversible failure to develop normal skeletal architecture and peak bone mass. Structural insufficiency may not regress even in the face of kidney transplantation, which reverses many of the metabolic effects of kidney failure that induce renal osteodystrophy. Unlike traditional densitometric measures of bone mass, peripheral quantitative computed tomography (pQCT) permits the discrete assessment of trabecular and cortical bone density and dimensions, and bone strength can be reliably estimated. Therefore, pQCT is an ideal tool to study the structural implications of renal osteodystrophy during growth. Accurate characterization of the structural bone deficits and the risk factors for impaired skeletal development in children with renal disease has not yet been performed and is the focus of this proposed investigation. The hypotheses are that (a) compared to normal controls, expansion of cortical bone volume is significantly impaired in children and adolescents with renal failure, resulting in substantial reduction of bone strength, (b) among children with renal disease, the magnitude and progression of the bone deficit is associated with poor growth and development, and with variability in the renal diseases (e.g., systemic inflammatory renal diseases) and therapies (e.g., glucocorticoids), and (c) the recovery and reconstitution of bone structure following renal transplantation is modulated by skeletal maturation at the time of transplantation, immunosuppressive therapies, rejection episodes, and allograft renal function. AIMS: 1. To perform a cross-sectional study of bone mass (dimensions, density, and strength) comparing children and adolescents with chronic renal failure to healthy controls and subsequently compare subgroups of children with chronic renal failure to identify predictors of decreased bone mass, such as the underlying renal disease, the severity of renal dysfunction, poor growth status, delayed skeletal bone age, decreased muscle strength, prior immunosuppressive therapies (e.g., glucocorticoids, cyclosporine), calcitriol therapy, and serum PTH levels. 2. To perform a longitudinal study of bone mineral accretion velocity (changes in dimensions, density, and strength) comparing healthy controls to each of three groups with renal disease: children with chronic renal failure, children on dialysis, and children following renal transplantation. 3. To compare dual energy x-ray absorptiometry (DXA) and pQCT in the assessment of skeletal structure and bone mineral accretion during childhood renal disease in order to demonstrate that the distinct effects of renal osteodystrophy on bone size and density are not well-characterized by DXA. 4. To determine if baseline levels of serum PTH and biomarkers of bone turnover can predict the subsequent pattern of growth and bone mineral accretion (changes in dimensions, density, and strength) over the follow-up interval among the chronic renal failure, dialysis, and transplantation subjects.