Pharmacological Therapy for Calcium Phosphate Urolithiasis

描述（由申请人提供）：磷酸钙（CaP）肾结石疾病的发病率在过去三十年中显著增加。尽管药物干预，患有CaP尿石症的患者经常经历结石复发，这表明当前医疗方案的次优性质。导致CaP结石形成的主要代谢危险因素是高钙尿、高尿pH值和低尿。柠檬酸钾（KCit）经常用于钙结石患者，因为它能增加尿液中的柠檬酸盐，降低尿液中的钙。然而，值得关注的是，在CaP结石患者中，这些有益作用可能会被KCit引起的尿液pH值进一步升高所抵消，KCit对CaP结石患者的净效应仍有待确定。另一种基于生理但未经临床试验的策略是使用柠檬酸（CitA），它可以潜在地增加尿液中的柠檬酸盐而不提高尿液ph值。基于上述知识和基本原理以及我们的初步研究，我们假设KCit和/或柠檬酸是降低CaP结石患者复发性结石形成风险的潜在对策。为了验证这一假设，我们将在一项短期安慰剂对照交叉代谢研究中检验CitA或KCit是否能降低CaP结石患者尿液中的CaP饱和度（如毛石）。除了基于计算机的结石风险预测程序之外，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。它解决了一个至关重要的临床问题，因为我们迫切需要一种有效的治疗复发性CaP结石患者的方法，这是一组在过去的临床试验中没有特别评估的结石形成者。结果

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.