CALCIUM NEPHROLITHIASIS IN POSTMENOPAUSAL WOMEN: REGULATION OF RENAL CALCIUM...

在整个成年生活中，女性肾结石的发病率低于男性。然而，据报道，结石发病率在女性的第六个十年期间有所增加，而男性的发病率开始下降。对在P01之前的资助周期中获得的患者数据的回顾分析显示，在第六个十年期间，女性结石患者的尿钙排泄量显著增加。在许多女性中，这个时间对应于更年期的开始。此外，接受雌激素治疗的绝经后妇女的尿钙排泄量显著低于未接受雌激素治疗的妇女，这与尿草酸钙饱和度的下降类似。这些发现与雌激素缺乏增加结石形成风险的可能性是一致的。我们的中心假设是，绝经后结石形成率的明显增加部分是由于雌激素缺乏对肾小管钙重吸收的损害。这一假说将通过四个具体目标进行检验，这些目标代表了一种揭示肾脏钙泄漏机制的翻译方法(S)。具体目的是：(1)评估短期雌激素治疗对正常绝经后妇女和绝经后肾结石妇女肾脏钙处理和结石形成倾向的影响；(2)量化雌激素替代治疗对钙的影响。 通过清除研究以及体内微灌流对去卵巢(OVX)大鼠近端小管、Henle环和远端曲管的转运进行研究；(3)研究雌激素依赖对肾小管细胞calbindin-D28K基因表达的调节；(4)研究calbindin-D28K通过上皮钙通道(ECAC)调节钙内流的机制。这些拟议的研究代表了一种翻译方法，将使用临床、整体动物和分子模型来表征雌激素对肾脏钙处理的影响。预计这些发现将扩大我们对 这项研究旨在研究激素对肾脏钙转运的调节作用，为绝经后女性结石倾向的增加提供一种机制，并为研究潜在的结石形成对策开辟了新的途径，不仅适用于这一特定的患者组，也适用于一般的结石形成人群。

The incidence of kidney stones in women is lower than in men throughout adult life. However, stone incidence has been reported to increase in women during the 6th decade of life, while for men it begins to decrease. A retrospective analysis of patient data obtained during previous funding cycles of this P01 has disclosed a significant increase in urinary calcium excretion during the 6th decade in women stone-formers. This time corresponds to the onset of menopause in many women. Moreover, udnary calcium excretion was substantially lower in postmenopausal women treated with estrogen than in those who were not, commensurate with a similar decline in urinary saturation of calcium oxalate. These findings are consistent with the possibility that estrogen deficiency increases the risk of stone formation. Our central hypothesis to be tested in this proposal is that the apparent increase in stone formation rate following menopause is in part due to pdmary impairment of renal tubular calcium reabsorption from estrogen lack. This hypothesis will be tested through four specific aims representing a translational approach to uncover the mechanism(s) of renal calcium leak. The specific aims are: (1) evaluate the effects of short-term estrogen treatment on the renal handling of calcium and the propensity for stone formation in normal postmenopausal women as well as postmenopausal women with kidney stones: (2) quantitate the effect of estrogen replacement on calcium transport via clearance studies as well as in vivo microperfusion of the proximal tubule, loop of Henle and distal convoluted tubule in the ovariectomized (OVX) rat; (3) characterize estrogen-dependent regulation of calbindin-D28K gene expression in renal tubular cells; and (4) examine the mechanism for calbindin-D28K regulation of calcium entry via epithelial calcium channel (ECaC). These proposed studies represent a translational approach that will characterize the effect of estrogen on renal calcium handling using clinical, whole animal, and molecular models. It is anticipated that the findings will expand our understanding of hormonal regulation of renal calcium transport, offer a mechanism for increased stone propensity in postmenopausal women, and open new avenues for investigation of potential countermeasures to stone formation not only for this select group of patients but for the stone-forming population in general.