EFFECTS OF RENAL OSTEODYSTROPHY DURING GROWTH

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肾性骨营养不良症（ROD）是一种多因素的骨代谢紊乱与肾功能不全的个体。随着肾功能衰竭的进展，随之而来的甲状旁腺激素（PTH）分泌和钙代谢异常导致小梁骨硬化和皮质骨变薄。在儿童和青少年时期，骨骼生长通常以皮质尺寸的显著扩张和小梁密度的增加为特征。因此，生长中的骨骼可能特别容易受到肾性骨营养不良的结构影响。与全身炎症细胞因子水平升高相关的潜在肾脏疾病和肾治疗，如糖皮质激素，也可能损害骨增生。虽然这些威胁对肾功能衰竭儿童正常骨骼发育的影响尚不完全清楚，但它们可能导致不可逆转的骨骼结构发育失败和骨量峰值。即使面对肾移植，结构性功能不全也可能不会消退，这逆转了许多肾功能衰竭引起肾性骨营养不良的代谢影响。与传统的骨量密度测量不同，外周定量计算机断层扫描（pQCT）允许对小梁和皮质骨密度和尺寸进行离散评估，并且可以可靠地估计骨强度。因此，pQCT是研究生长过程中肾性骨营养不良的结构意义的理想工具。肾脏疾病儿童的结构性骨缺损和骨骼发育受损的危险因素尚未得到准确的描述，这是本研究的重点。假设是(a)与正常对照相比，患有肾衰竭的儿童和青少年皮质骨体积的扩张明显受损，导致骨强度大幅降低；(b)在患有肾脏疾病的儿童中，骨缺损的程度和进展与生长发育不良以及肾脏疾病（如全系统炎症性肾脏疾病）和治疗方法（如糖皮质激素）的可变性有关。(c)肾移植后骨结构的恢复和重建受移植时骨骼成熟、免疫抑制疗法、排斥反应和同种异体移植肾功能的调节。目的:1。进行骨量（尺寸、密度和强度）的横断面研究，比较慢性肾衰竭儿童和青少年与健康对照，随后比较慢性肾衰竭儿童亚组，以确定骨量减少的预测因素，如潜在的肾脏疾病、肾功能障碍的严重程度、生长状况不良、骨骼年龄延迟、肌肉力量下降、先前的免疫抑制治疗(如糖皮质激素、环孢素)、骨化三醇治疗和血清甲状旁腺激素水平。2. 进行骨矿物质增加速度（尺寸、密度和强度的变化）的纵向研究，将健康对照者与三组肾脏疾病患者进行比较：慢性肾衰竭儿童、透析儿童和肾移植后儿童。3. 比较双能x线吸收仪（DXA）和pQCT在评估儿童肾脏疾病期间骨骼结构和骨矿物质增加方面的作用，以证明肾性骨营养不良对骨大小和密度的明显影响不能很好地用DXA表征。4. 在慢性肾衰竭、透析和移植患者的随访期间，确定血清PTH基线水平和骨转换生物标志物是否可以预测随后的生长模式和骨矿物质增生（尺寸、密度和强度的变化）。

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.