Role of Parathyroid Hormone in Renal Osteodystrophy

描述(申请人提供)：肾性骨营养不良的谱系在接受透析治疗的患者中通过骨组织形态计量学得到了很好的特征。然而，只有随着第一代免疫甲状旁腺激素测定(1PTH-IMA)的出现，这种测量才成为肾性骨病骨骼病变的相对准确的预测指标。然而，间歇性骨化三醇治疗改变了甲状旁腺激素和骨形成的关系。20多年来，没有对慢性肾病(CKD)儿童进行过类似的研究。 尽管缺乏数据，甲状旁腺激素的测定通常被用作骨形成和转换的替代标志，建议这些患者使用骨化三醇治疗，以防止生长迟缓和骨畸形。此外，骨转换的预测更加复杂，因为它们的解释被CKD的分期混淆了，而且它似乎可能反映了骨骼对甲状旁腺激素抵抗状态的进展。目前已知，1PTH-IMA不仅检测PTH(1-84)，而且检测大的氨基端截短的PTH片段，其中一些片段被证明在体内具有降钙特性，并减少骨转换。相反，最近开发的第二代免疫计量甲状旁腺激素(第二代甲状旁腺激素-IMA)只识别甲状旁腺素(1-84)，而不识别自然产生的完整激素片段。 目前的建议将确定：1)第二次PTH-IMA测量的甲状旁腺素浓度是否比第一次PTH-IMA在透析前和接受慢性血液透析的CKD儿童、青少年和年轻人中提供了更准确的骨形成和转换评估。2)评估肾和骨骼对甲状旁腺素抵抗的程度和进展，并确定甲状旁腺激素(1-84)氨基端截短片段的丰度是否与此类患者的抵抗状态有关。松质骨中的骨形成将通过定量组织形态计量学来评估，肾脏和骨骼对甲状旁腺素的抵抗力将通过甲状旁腺素(1-34)的输注来评估。这项研究结果将为CKD患者甲状旁腺激素与骨形成的关系提供新的信息，并可能对肾性骨营养不良的诊断和治疗具有重要意义。

DESCRIPTION (provided by applicant): The spectrum of renal osteodystrophy has been very well characterized by bone histomorphometry in patients treated with dialysis. However, it was only with the availability of the first generation immunometric PTH assay (1st PTH-IMA) that such measurements have emerged as relatively accurate predictors of the skeletal lesion of renal osteodystrphy. However, the relationship between PTH and bone formation was altered by intermittent calcitriol therapy. Similar studies have not been carried out in children with chronic kidney disease (CKD) before dialysis for more than two decades. Despite this lack of data, PTH determinations are commonly used as surrogate markers of bone formation and turnover, and therapy with calcitriol is recommended to those patients to prevent growth retardation and bone deformities. Furthermore, the prediction of bone turnover is further complicated because their interpretation is confounded by the stage of CKD and that it appears likely to reflect progression of the state of skeletal resistance to PTH. It is now known that 1st PTH-IMA detect not only PTH(1-84), but also large amino-terminally truncated PTH fragments, some of which were shown to have hypocalcemic properties in vivo and diminish bone turnover. In contrast, recent developed second generation immunometric PTH (2nd PTH-IMA) that recognize only PTH(1-84), but not naturally occurring fragments of the intact hormone. The current proposal will determine: 1) whether PTH concentrations measured by 2nd PTH-IMA provide a more accurate assessment of bone formation and turnover than 1st PTH-IMA in children, adolescents and young adults with CKD prior to dialysis and those undergoing chronic hemodialysis. 2) To assess the magnitude and progression of renal and skeletal resistance to PTH and to determine whether the abundance of amino-terminally truncated PTH (1-84) fragments contribute to the state of resistance in such patients. Bone formation will be evaluated in cancellous bone by quantitative histomorphometry, renal and skeletal resistance to PTH will be assessed by PTH(1-34) infusions. The results of the study should provide new information on the relationship between PTH and bone formation in CKD and they are likely to have important implications for the diagnosis and treatment of renal osteodystrophy.