EFFECTS OF RENAL OSTEODYSTROPHY DURING GROWTH

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。肾性骨营养不良(Rod)是肾功能不全患者的一种多因素的骨代谢紊乱。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骨小梁硬化和皮质骨变薄。在儿童期和青春期，骨骼生长的特征通常是皮质面积显著扩大和骨小梁密度增加。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性影响。与全身炎症细胞因子水平升高相关的潜在肾脏疾病和肾脏治疗，如糖皮质激素，也可能损害骨吸收。尽管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，但它们可能会导致不可逆转的失败，无法形成正常的骨骼结构和峰值骨量。即使在肾移植的情况下，结构性功能不全也可能不会消退，这会逆转导致肾性骨营养不良的肾功能衰竭的许多代谢影响。与传统的骨量密度测量不同，外周定量计算机断层扫描(PQCT)允许对骨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是研究肾性骨营养不良在生长过程中的结构含义的理想工具。肾脏疾病儿童的结构性骨缺陷和骨骼发育受损的危险因素的准确特征尚未完成，这是这项拟议调查的重点。假说是：(A)与正常对照组相比，患有肾功能衰竭的儿童和青少年的皮质骨体积的扩张明显受损，导致骨强度大幅下降；(B)在患有肾脏疾病的儿童中，骨缺陷的程度和进展与生长发育不良、肾脏疾病(如全身炎症性肾脏疾病)和治疗方法(如糖皮质激素)的变化有关；以及(C)肾移植后骨结构的恢复和重建受移植时的骨骼成熟、免疫抑制治疗、排斥反应和移植肾肾功能的调节。目的：1.进行一项横断面研究，比较慢性肾功能衰竭儿童和青少年与健康对照儿童和青少年的骨量(尺寸、密度和强度)，并随后比较慢性肾功能衰竭儿童亚组，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、生长状况差、骨骼骨龄延迟、肌肉力量下降、既往免疫抑制治疗(如糖皮质激素、环孢素)、骨化三醇治疗和血清甲状旁腺素水平。2.对慢性肾功能衰竭儿童、透析儿童和肾移植后儿童的骨矿物质积累速度(大小、密度和强度的变化)进行纵向研究，比较健康对照组和肾脏疾病组的骨矿物质积累速度。3.比较双能X线骨密度仪(DXA)和pQCT在评价儿童肾脏疾病骨结构和骨矿沉积方面的差异，以说明DXA不能很好地反映肾性骨营养不良对骨大小和骨密度的明显影响。4.确定血清甲状旁腺素的基线水平和骨转换的生物标志物是否可以预测慢性肾功能衰竭、透析和移植受试者在随后的随访期间的生长和骨矿积累的模式(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.