Effect of Pyridoxamine in Oxalate excretion in Stone Disease and Hyperoxaluria

吡哆胺对结石病和高草酸尿症草酸盐排泄的影响

• 批准号: 7144077
• 负责人: Jon I Scheinman
• 金额: $ 27.03万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7144077
• 关键词: acute renal failure; biosynthesis; blood chemistry; clinical research; clinical trials; detoxification; disease /disorder proneness /risk; excretion; human subject; human therapy evaluation; kidney disorder chemotherapy; nephrocalcinosis; nephrolithiasis; orphan disease /drug; oxalates; patient oriented research; peroxisome; primary hyperoxalurias; urinalysis; urine; vitamin B6

DESCRIPTION (provided by applicant): Kidney stone disease is frequent, and increasing, and has an unacceptable recurrence rate. Most stones are made of calcium oxalate (CaOx), and urinary oxalate is a major risk factor. There is not yet an effective treatment for stone disease that can target urinary oxalate. Our long-term goal is to find a way to prevent stone formation in common idiopathic stone disease, and kidney calcification in the rare but most malignant form of stone disease, primary hyperoxaluria (PH). Pyridoxamine (PM) is a derivative of vitamin B6 that is present in small amounts in normal humans. Its chemical nature allows it to trap the precursors of oxalate biosynthesis (glyoxylate and glycolaldehyde). This process is well demonstrated in vitro. In our preliminary animal data, we showed (1) that PM can significantly lower oxalate excretion in normal and hyperoxaluric rats; and (2) that PM can dramatically decrease the development of CaOx calcification in these hyperoxaluric rats. Other clinical trials have shown that pyridoxamine is non-toxic in humans. We propose that PM will reduce human oxalate synthesis that occurs primarily in the detoxification compartment of liver cells (the peroxisome) in humans. This will decrease oxalate excretion, and therefore reduce a risk factor for kidney stone formation. The primary goal of the proposed study is to show that it is feasible to reduce urinary oxalate excretion in humans by using PM. The Specific Aims of the study will be (1) to evaluate PM treatment in people with kidney stones without hyperoxaluria. This is a placebo- controlled, double-blinded, crossover design. We expect to find that urinary oxalate will be reduced while other factors will not change. Therefore, the supersaturation state, which strongly influences stone formation, will be significantly improved. Patients from stone clinics are available for this study and are highly motivated to participate. (2) We will also study patients with Primary Hyperoxaluria (PH), a genetic disease that usually results in kidney failure at an early age. Here, we will explore the feasibility of lowering the massive oxalate generation derived from endogenous synthesis. If it is successful, PM will offer the first significant non-transplant treatment for this frequently fatal disease. To directly test the model of PM action we also plan (3) to characterize the way that PM forms complexes with the precursors of oxalate, glyoxylate and glycolaldehyde, in urine and serum of these patients. The public health implications of this study are in its contributions to preventing common kidney stone disease, and preventing kidney failure in an orphan disease, Primary Hyperoxaluria.

描述(申请人提供)：肾结石疾病是常见的，而且还在增加，复发率令人无法接受。大多数结石是由草酸钙(CaOx)组成的，尿草酸是一个主要的危险因素。目前还没有针对尿草酸的结石疾病的有效治疗方法。我们的长期目标是找到一种方法来预防常见的特发性结石疾病的结石形成，以及罕见但最恶性的结石疾病--原发性高草酸尿症(PH)的肾脏钙化。吡哆胺(PM)是维生素B6的一种衍生物，在正常人中以少量存在。它的化学性质使其能够捕获草酸生物合成的前体(乙醛和乙醇醛)。这一过程在体外得到了很好的演示。在我们的初步动物数据中，我们发现(1)PM可以显著降低正常和高草酸尿大鼠的草酸排泄量；(2)PM可以显著减少这些高草酸尿大鼠CaOx钙化的发展。其他临床试验表明，吡哆胺对人体无毒。我们认为PM将减少人类草酸的合成，而人类草酸的合成主要发生在人类肝细胞(过氧化物酶)的解毒部分。这将减少草酸的排泄，从而减少肾结石形成的风险因素。这项拟议研究的主要目标是证明使用PM减少人类尿中草酸排泄是可行的这项研究的具体目标将是(1)评估无高草酸尿的肾结石患者的PM治疗。这是一种安慰剂对照、双盲、交叉设计。我们预计会发现，在其他因素不变的情况下，尿草酸将会减少。因此，强烈影响结石形成的过饱和状态将得到显著改善。来自结石诊所的患者可以参加这项研究，他们参与的积极性很高。(2)我们还将研究原发性高草酸尿症(PH)患者，这是一种遗传性疾病，通常会导致早期肾衰竭。在这里，我们将探索降低内源合成产生的大量草酸的可行性。如果成功，PM将为这种经常致命的疾病提供第一个重要的非移植治疗。为了直接测试PM的作用模型，我们还计划(3)表征PM在这些患者的尿液和血清中与草酸、乙醛和乙醇醛前体形成络合物的方式。这项研究的公共卫生意义在于它对预防常见的肾结石疾病和预防一种孤儿疾病--原发性高草酸尿症--的肾衰竭做出了贡献。