K CITRATE AND STONE RISK IN PATIENTS ON TOPIRAMATE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 托吡酯（TPM）是一种新型神经调节剂，常用于治疗癫痫发作和预防偏头痛。由于其主要的副作用肾结石形成，我们最近进行了一项全面的阐明结石的风险概况，其中32个TPM治疗的受试者进行了比较，50名健康，正常志愿者。本研究的结果表明，TPM治疗会导致全身性代谢性酸中毒、低柠檬酸尿症和尿pH值升高。这些变化会增加形成磷酸钙肾结石的倾向，因为柠檬酸盐是主要的结石抑制剂，尿pH值升高是磷酸钙盐结晶的重要决定因素。柠檬酸钾增加尿柠檬酸盐，因此可能有助于改善接受TPM治疗的患者的结石风险。然而，柠檬酸钾伴随的尿液pH值升高可能会抵消尿柠檬酸盐增加的有益作用。柠檬酸是一种非处方营养补充剂，在降低肾结石风险方面可能比柠檬酸钾更有利，因为柠檬酸已被证明可以增加尿柠檬酸盐排泄而不会增加尿pH值。除了对尿结石风险的影响外，TPM还对骨骼有潜在的有趣影响。尽管众所周知全身性代谢性酸中毒会增加骨吸收，但理论上有理由支持骨吸收碳酸酐酶抑制剂的概念，尽管发生了全身性代谢性酸中毒，但可防止骨吸收。

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. Topiramate (TPM) is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and migraine headache prophylaxis. Due to its major side effect of kidney stone formation, we recently have performed a comprehensive elucidation of stone risk profile in which 32 TPM-treated subjects were compared to 50 healthy, normal volunteers. The result of this study demonstrated that treatment with TPM causes systemic metabolic acidosis, hypocitraturia, and increased urinary pH. These changes increase the propensity to form calcium phosphate kidney stones, since citrate is a major stone inhibitor and the rise in urinary pH is an important determinant of crystallization of calcium phosphate salts. Potassium citrate increases urinary citrate and therefore may be beneficial in ameliorating stone risk in TPM-treated patients. However, a concomitant rise in urinary pH with potassium citrate may negate the beneficial effect of increased urinary citrate. Citric acid is an over-the-counter nutritional supplement that may be more advantageous than potassium citrate in reducing the risk of kidney stones as citric acid has been shown to increase urinary citrate excretion without increasing urinary pH. In addition to the effect on urinary stone risk, TPM also has potentially interesting effects on bone. Although systemic metabolic acidosis is well known to increase osteoclastic bone resorption, there are theoretically reasons to support the notion that osteoclastic carbonic anhydrase inhibition, despite the development of systemic metabolic acidosis, protects against bone resorption.