Effect of Pyridoxamine in Oxalate excretion in Stone Disease and Hyperoxaluria

描述（由申请人提供）：肾结石是一种多发病，且呈上升趋势，复发率不可接受的疾病。大多数结石是由草酸钙（CaOx）组成的，尿液中的草酸是一个主要的危险因素。目前还没有针对尿草酸盐的有效治疗结石的方法。我们的长期目标是找到一种方法来预防常见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。吡哆沙明（PM）是维生素B6的衍生物，在正常人体内存在少量。它的化学性质允许它捕获草酸生物合成的前体（乙醛酸酯和乙醇醛）。这一过程在体外得到了很好的证明。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血氧大鼠的草酸盐排泄；(2) PM能显著降低高血氧大鼠钙化的发生。其他临床试验表明，吡哆沙明对人体无毒。我们建议PM将减少人类草酸盐合成，草酸合成主要发生在人类肝细胞的解毒室（过氧化物酶体）中。这将减少草酸盐的排泄，从而减少肾结石形成的危险因素。提出的研究的主要目的是表明，它是可行的，以减少尿草酸盐排泄在人类使用PM。该研究的具体目的是(1)评估PM对无高血氧血症肾结石患者的治疗效果。这是一个安慰剂对照，双盲，交叉设计。我们希望在其他因素不变的情况下，发现尿草酸降低。因此，强烈影响石材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，并且积极性很高。(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盐的可行性。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盐、乙醛酸盐和乙醇醛前体形成复合物的方式。这项研究的公共卫生意义在于它对预防常见肾结石疾病和预防原发性高草酸尿症孤儿疾病肾衰竭的贡献。

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.