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，女性在60岁时结石发病率增加，而男性则开始下降。对本P01之前资助周期中获得的患者数据进行的回顾性分析显示，在第6个十年期间，女性结石形成者的尿钙排泄显著增加。这个时间对应于许多女性更年期的开始。此外，绝经后妇女经雌激素治疗后尿钙排泄量明显低于未治疗者，与草酸钙尿饱和度下降相似。这些发现与雌激素缺乏增加结石形成风险的可能性一致。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导致肾小管钙重吸收障碍。将通过四个具体目标对该假设进行检验，这四个目标代表了揭示肾钙渗漏机制的转化方法。具体目标是：（1）评价短期雌激素治疗对正常绝经后妇女以及绝经后肾结石妇女肾脏钙处理和结石形成倾向的影响：（2）定量雌激素替代对钙的影响 通过清除研究以及在卵巢切除（OVX）大鼠中近端小管、Henle袢和远端曲小管的体内微灌注来进行转运;（3）表征肾小管细胞中钙结合蛋白-D28 K基因表达的雌激素依赖性调节;和（4）检查钙结合蛋白-D28 K通过上皮钙通道（ECaC）调节钙进入的机制。这些拟议的研究代表了一种转化方法，将使用临床、整体动物和分子模型表征雌激素对肾钙处理的影响。预计这些发现将扩大我们对 肾钙转运的激素调节提供了绝经后妇女结石倾向增加的机制，并为研究结石形成的潜在对策开辟了新的途径，不仅适用于这一选定的患者群体，而且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.