Prevention of Renal Damage in Primary Hyperoxaluria

描述（由申请人提供）：原发性高尿酸（PH）是一种罕见的常染色体隐性遗传疾病（估计发病率为1：120，000出生）。虽然大多数患者在儿童时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人时仅出现尿石症。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，大多数还需要肝移植。目前迫切需要鉴定导致严重疾病表达的因素，以及有效的治疗方法。由于这种疾病的罕见性，在了解高尿症和相关肾损伤的病理生理学以及开发有效治疗方法方面的进展已经放缓。该基金的总体目标是汇总患者经验，以确定与PH疾病进展相关的因素，在风险患者中使用特定治疗策略对其进行修改，并证明肾损伤的减少。我们已经召集了一组对PH长期感兴趣的医生和科学家。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来改善这些患者的诊断、治疗和生活质量：1）开发和扩展PH患者的国际疾病登记; 2）定义PH患者的扩展代谢表型; 3）采用创新的成像模式来更准确地检测和量化疾病进展; 4）测定尿中视黄醇结合蛋白、α-1微球蛋白、转化生长因子（TGF）β 1和γ-谷氨酰转移酶（GGT）是进行中的肾损伤的敏感标志物，可以作为疾病进展的替代标志物，并且通过血管紧张素阻断而降低;和5）应用药物基因组学指导PH治疗。登记处将允许制定共识、循证诊断和管理指南。通过注册完成的临床数据、样本和研究方案将允许快速测试假设，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.