Pharmacological Therapy for Calcium Phosphate Urolithiasis

描述(由申请人提供)：在过去的三十年里，磷酸钙(CAP)肾结石的发病率显著增加。患有头状尿石症的患者经常会经历结石复发，尽管进行了药物干预，这表明当前医疗方案的性质并不理想。易导致帽状结石形成的主要代谢危险因素是高钙尿、高尿酸和低柠檬酸尿。柠檬酸钾(KCit)经常被开给钙结石患者，因为它增加了尿柠檬酸盐，降低了尿钙。然而，一个令人担忧的问题是，在帽状结石患者中，KCit引起的尿液pH进一步升高可能会抵消这些有益作用，而KCit在帽状结石患者中的净效果仍有待确定。另一种基于生理但未经临床测试的策略是柠檬酸(CITA)给药，它可以在不提高尿液pH的情况下潜在地增加尿柠檬酸盐。基于上述知识和原理以及我们的初步研究，我们假设KCit和/或柠檬酸是降低帽状结石患者复发结石形成风险的潜在对策。为了验证这一假设，我们将在一项短期的安慰剂控制的交叉代谢研究中检验CITA或KCit是否可以降低帽状石形成者的尿帽饱和度(作为刷石)。除了基于计算机的结石风险预测程序外，还将应用物理化学分析来评估结石复发的风险。这项小规模的临床试点研究将使用替代措施来测试两种简单的方案。它解决了一个极其重要的临床问题，因为我们迫切需要一种有效的疗法来治疗复发的帽状结石患者，这是一组在过去的临床试验中没有得到具体评估的结石形成者。结果 这项先导性研究可能导致全面的随机临床试验，得出预防和治疗复发性头状尿石症的临床结果，这是一种在临床实践中越来越多遇到的情况。 与公共卫生相关：在临床实践中，磷酸钙肾结石越来越多地出现，并且高度复发且难以治疗。这项建议将测试柠檬酸钾或柠檬酸的药物治疗是否降低了磷酸钙结石患者复发结石形成的风险。这项先导性研究的结果可能导致预防和治疗复发性磷酸钙肾结石的全面随机临床试验。

DESCRIPTION (provided by applicant): The incidence of calcium phosphate (CaP) kidney stone disease has increased significantly over the last three decades. Patients suffering from CaP urolithiasis often experience stone recurrence despite pharmacological interventions, an indication to the suboptimal nature of the current medical regimen. The major metabolic risk factors predisposing to CaP stone formation are hypercalciuria, high urine pH, and hypocitraturia. Potassium citrate (KCit) is frequently prescribed to calcium stone formers because it increases urine citrate and lowers urine calcium. However, a concern is that, in CaP stone formers, these beneficial effects may be negated by a further rise in urine pH induced by KCit, and the net effect of KCit in CaP stone formers remains to be determined. An alternative strategy that is physiologically-based but not clinically-tested is citric acid (CitA) administratin that can potentially increase urine citrate without raising urine pH. Based on the knowledge and rationale stated above and our preliminary studies, we hypothesize that KCit and/or citric acid are potential countermeasures that attenuate the risk of recurrent stone formation in CaP stone formers. To test this hypothesis, we will examine in a short-term placebo-controlled cross-over metabolic study whether CitA or KCit can reduce CaP saturation (as brushite) in urine of CaP stone formers. Physicochemical assays will be applied in addition to computer-based stone risk prediction programs to assess risk of stone recurrence. This small scale clinical pilot study will use surrogate measures to test two simple regimens. It addresses a clinical question of utmost importance as we are in dire need of an effective therapy for patients with recurrent CaP stones, a group of stone formers that have not been specifically evaluated in past clinical trials. Results from this pilot study are likely to lead to full-scale randomized clinical trials with clinical outcomes for the prevention and treatment of recurrent CaP urolithiasis, an increasingly encountered condition in clinical practice. PUBLIC HEALTH RELEVANCE: Calcium phosphate kidney stones are increasingly encountered in clinical practice, and are highly recurrent and difficult to treat. This proposal wil test whether pharmacological therapy with potassium citrate or citric acid reduces the risk of recurrent stone formation in calcium phosphate stone formers. Results from this pilot study are likely to lead to full-scale randomized clinical trials for the prevention and treatment of recurret calcium phosphate kidney stones.