Prevention of Renal Damage in Primary Hyperoxaluria

描述（由申请人提供）：原发性高草酸尿症（PH）是一种罕见的常染色体隐性遗传病（估计发病率为1:12万）。虽然大多数患者在儿童期经历肾钙质沉着症和/或反复发作的尿石症，但有些患者早在婴儿期就出现肾衰竭，而另一些患者则在成年后首次出现尿石症。造成这种差异的原因在很大程度上是未知的。然而，大多数（如果不是全部的话）PH患者最终会丧失肾功能，需要肾移植，大多数患者也需要肝移植。迫切需要确定导致严重疾病表达的因素，并进行有效的治疗。由于这种疾病的罕见性，对高血氧血症和相关肾损伤的病理生理学和有效治疗方法的研究进展缓慢。该资助的总体目标是收集患者经验，以确定与PH疾病进展相关的因素，对有风险的患者使用特定的治疗策略进行修改，并证明肾损伤的减少。我们召集了一群长期对博士感兴趣的独特的医生和科学家。最近，我们开发了一个安全的、基于网络的注册表，作为促进这项工作的关键工具。我们的目标是通过以下具体目标改善这些患者的诊断、治疗和生活质量：1)为PH患者建立和扩大国际疾病登记；2)定义PH患者的扩展代谢表型；3)采用创新的成像方式，更准确地检测和量化疾病进展；4)确定尿中视黄醇结合蛋白、a- 1微球蛋白、转化生长因子（TGF）（31）和v-谷氨酰转移酶（GGT）水平是否为持续肾损害的敏感标志物，可作为疾病进展的替代标志物，并可通过血管紧张素阻断降低；5)应用药物基因组学指导PH治疗。书记官处将有助于形成共识、基于证据的诊断和管理准则。通过注册中心完成的临床数据、样本和研究方案将允许对假设进行快速测试，并促进全球合作，以推进PH患者的护理。

DESCRIPTION (provided by applicant): Primary hyperoxaluria (PH) is a rare autosomal recessive disorder (estimated incidence 1:120,000 births). While most patients experience nephrocalcinosis and/or repeated episodes of urolithiasis in childhood, some develop renal failure as early as infancy while others first present as adults with urolithiasis only. The reasons for such disparity are largely unknown. However, the majority, if not all, PH patients eventually lose renal function and require renal transplantation with liver transplantation also needed in most. There is an urgent need for identification of factors responsible for severe disease expression, and for effective treatments. Progress in understanding the pathophysiology of hyperoxaluria and associated renal injury and in development of effective treatments, has been slowed by the rarity of this condition. The overall objective of this grant is to pool patient experience in order to identify factors associated with disease progression in PH, modify them using specific treatment strategies in patients at risk, and demonstrate reduction in renal injury. We have assembled a unique group of physicians and scientists with longstanding interest in PH. Recently we developed a secure, web-based registry as a key tool to facilitate this work. Our goal is to improve diagnosis, treatment, and quality of life for these patients by the following SPECIFIC AIMS: 1) Develop and expand an international disease registry for patients with PH; 2) Define an expanded metabolic phenotype of PH patients; 3) Employ innovative imaging modalities to more accurately detect and quantify disease progression; 4) Determine if urinary levels of retinol binding protein, a- 1 microglobulin, transforming growth factor (TGF)(31, and v-Glutamyltransferase (GGT) are sensitive markers of ongoing renal damage, can serve as surrogate markers of disease progression, and are reduced by angiotensin blockade; and 5) Application of pharmacogenomics to guide PH treatment. The Registry will allow development of consensus, evidence-based diagnosis and management guidelines. Clinical data, samples, and research protocols completed via the Registry will allow rapid testing of hypotheses and promote worldwide collaboration to advance the care of PH patients.