Mentored Patient Oriented Research Career Development Aw

以肠道钙吸收过多为特征的吸收性高钙尿症(AH)是肾结石的主要原因。虽然骨丢失在这种情况下是意想不到的，但几项骨密度研究表明，这种情况很常见，特别是在严重的疾病中。本项目的目标是更好地阐明严重吸收性高钙尿症(AH)中一次丢失和高钙尿的病理生理机制，以便制定更合理的治疗方案。我们的假说是：1)重度AH患者骨丢失的主要原因是骨吸收正常或轻度增加时骨形成减少，2)重度AH患者的高钙尿症主要是由肠道钙吸收过多引起的，但在某些患者中可能是骨骼引起的。在这个方案中，我们将通过将25名AH患者与两个匹配的对照组(25名正常志愿者和25名固定性高钙尿症患者(骨吸收增加所致的高钙尿症模型))进行比较来检验每个假设。假设1将使用骨组织形态计量学(终点：骨形成和吸收指数的差异)和骨周转标志物(终点：血清骨特异性碱性磷酸酶和尿中游离脱氧吡啶和N-端肽的差异)进行检验。假设二将通过两个不同的生理学挑战来探讨：1)磷酸纤维素钠(SCP)，一种吸收不良的粉末，阻止肠道钙吸收，将被用来评估肠道对尿钙的贡献(终点：尿钙减少，单位为mg/d)。2)阿仑磷酸钠可阻断骨吸收，用于检测骨骼对尿钙的贡献(终点：尿钙减少，单位为mg/d)。受试者将接受基线住院评估，同时摄入含有10 mmoL钙、100 mmoL Na和25.8 mmoP的恒定代谢饮食。评估将包括血清化学、甲状旁腺素、维生素D代谢物、骨周转标志物、24小时尿钙、直接和间接测量的钙吸收以及骨密度。在持续代谢饮食的SCP治疗3天期间，将在门诊销售中对它们进行重新评估。他们也将作为住院患者在2周后和3个月后接受阿伦磷酸钠治疗后进行持续代谢饮食的研究。

Absorptive hypercalciuria (AH), characterized by excess intestinal calcium absorption, is a major cause of nephrolithiasis. Although bone loss is unexpected in this condition, several bone density studies have demonstrated that it is common particularly in severe disease. The goal of this project is to better elucidate the pathophysiologic mechanisms for one loss and hypercalciuria in severe absorptive hypercalciuria (AH) to allow formulation of more rational treatment modalities. Our hypotheses are 1) the main cause of bone loss in subjects with severe AH is reduced bone formation in the setting of normal or slightly increased bone resorption, and 2) hypercalciuria in severe AH is primarily caused by excessive intestinal calcium absorption, but the bone may contribute to it in some subjects. In this protocol, we will test each hypothesis by comparing 25 AH patients with two matching control groups, 25 normal volunteers and 25 immobilized hypercalciuric patients (a model for hypercalciuria resulting from increased bone resorption). Hypothesis 1 will be tested using bone histomorphometry (endpoints: difference in bone formation and resorption indices) and bone turnover markers (endpoints: difference in serum bone specific alkaline phosphatase and urine free deoxypyridinoline and N-telopeptides). Hypothesis two will be probed via two separate physiologic challenges: 1) sodium cellulose phosphate (SCP), a poorly absorbed powder which blocks intestinal calcium absorption, will be used to assess the contribution of the intestine to urinary calcium (endpoint: decrement in urinary calcium in mg/d). 2) Alendronate, which blocks bone resorption, will be used to examine the contribution of the bone to urinary calcium (end point: decrement in urinary calcium in mg/d). Subjects will have baseline inpatient evaluation while consuming a constant metabolic diet containing 10 mmol Ca, 100 mmol Na and 25.8 mmol P. Evaluation will include serum chemistries, PTH, vitamin D metabolites, bone markers of turnover, 24-hour urinary calcium, calcium absorption by direct and indirect measures and bone mineral density. They will be reevaluated in an outpatient selling during 3 days of treatment with SCP on constant metabolic diet. They will also be studied as inpatients on constant metabolic diet after 2 weeks and after 3 months of treatment with alendronate.