Prevention of Renal Damage in Primary Hyperoxaluria

描述(申请人提供)：原发性高草酸尿(PH)是一种罕见的常染色体隐性遗传病(估计发病率1：120,000新生儿)。虽然大多数患者在儿童时期经历了肾钙沉着和/或反复发作的尿石症，但一些人在婴儿时期就出现了肾功能衰竭，而另一些人则是在成年后才首次出现尿石症。造成这种差距的原因在很大程度上不得而知。然而，大多数(如果不是全部)的PH患者最终会失去肾功能，需要进行肾移植，而肝移植也是最需要的。迫切需要确定导致严重疾病表现的因素，并进行有效的治疗。高草酸尿症及其相关肾损伤的病理生理学研究进展和有效治疗方法的开发由于这种情况的罕见而进展缓慢。这笔赠款的总体目标是汇集患者经验，以确定与PH疾病进展相关的因素，在有风险的患者中使用特定的治疗策略来修改这些因素，并证明肾脏损伤的减少。我们聚集了一群对PH有长期兴趣的独特的内科医生和科学家。最近，我们开发了一个安全的、基于网络的登记处，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提高这些患者的诊断、治疗和生活质量：1)开发和扩大PH患者的国际疾病登记；2)确定PH患者的扩大代谢表型；3)利用创新的成像方法更准确地检测和量化疾病进展；4)确定尿视黄醇结合蛋白、α-1微球蛋白、转化生长因子(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受体拮抗剂减少；以及5)应用药物基因组学来指导PH的治疗。书记官处将能够制定协商一致的循证诊断和管理准则。通过注册中心完成的临床数据、样本和研究方案将允许快速测试假说，并促进全球合作，以推进对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.