Hereditary Causes of Nephrolithaisis and Kidney Failure

描述（由申请人提供）：300字四种先天性代谢错误导致尿中不溶性矿物盐浓度高和严重的复发性肾结石。原发性高草酸尿（PH）、胱氨酸尿、APRT缺乏症（二羟基腺嘌呤尿，DMA）和Dent疾病的患者在儿童时期开始经历结石。肾组织结晶沉积，肾功能丧失。疾病表现差异很大。例如，一些PH患者在婴儿期发展为终末期肾衰竭，而另一些患者则保持肾功能直到中年。人们对这种可变性知之甚少。疾病表达修饰因子，如果被确定，将有望成为潜在的新治疗策略。然而，有效治疗的进展一直很缓慢。由于患者数量少，分布广泛，因此难以对疾病表现进行严格的表征和纵向评估。由于很少有患者可用于临床试验，因此测试新疗法疗效的能力有限。为了解决这一问题，我们将在国际原发性高草酸尿症登记处（International Primary hyperoxaluia Registry， IPHR）之前成功工作的基础上，扩大IPHR，建立安全的、基于网络的胱氨酸尿症、DHA和Dent疾病登记处和组织库。对每种疾病的个体患者进行的纵向研究将强调产生可检验的假设，并为未来的临床试验确定具有良好特征的患者队列。这四种疾病似乎都是由肾脏结晶沉积介导的，而细胞反应反过来又由尿蛋白抑制剂调节。因此，了解尿蛋白组和肾细胞生物学在疾病进展中的影响有很大的协同潜力。一个杰出的临床科学家联盟，拥有独特的专业知识，并能接触到这些诊断的患者，将解决这项工作。多学科合作将通过与相关患者支持组织的联合活动、联盟成员之间的定期沟通以及与患者、医学界成员和科学家开放共享新开发的资源来实现。

DESCRIPTION (provided by applicant): 300 words Four inborn errors of metabolism lead to high concentrations of insoluble mineral salts in the urine and severe, recurrent nephrolithiasis. Patients with primary hyperoxaluria (PH), cystinuria, APRT deficiency (dihydroxyadeninuria, DMA), and Dent disease experience stones beginning in childhood. Deposition of crystals in kidney tissue and loss of kidney function is observed in all. Disease expression varies widely. Some PH patients, for example, progress to end stage renal failure during infancy, while others maintain kidney function until middle age. This variability is poorly understood. Modifiers of disease expression, if identified, offer promise as potential new treatment strategies. Yet progress toward effective treatment has been slow. Small numbers of widely scattered patients make rigorous characterization and longitudinal assessment of disease expression difficult. The ability to test efficacy of new treatments is limited since few patients are available for clinical trials. To address this problem, we will build on previous, successful work of the International Primary Hyperoxaluria Registry (IPHR) to expand the IPHR and establish secure, web-based registries and tissue banks for cystinuria, DHA, and Dent disease. Longitudinal studies of individual patients conducted in each disease will emphasize generation of testable hypotheses and identification of well characterized cohorts of patients for future clinical trials. All four diseases appear mediated by renal deposition of crystals, and the cellular response, which in turn, appears modulated by urinary protein inhibitors. Therefore, there is great potential for synergy to understand the impact of the urinary proteome and renal cell biology in disease progression. An outstanding consortium of clinical scientists with unique expertise and access to patient with these diagnoses will address this work. Multidisciplinary collaboration will occur through joint activities with the relevant patient support organizations, regular communications among Consortium members, and open sharing of newly developed resources with patients, members of the medical community and scientists. PUBLIC HEALTH RELEVANCE: The Consortium for Hereditary Causes of Nephrolithiasis and Renal Failure is highly suited to accomplish the characterization and longitudinal assessment needed to facilitate discovery of biomarkers of disease risk, disease activity, and response to therapy for four rare diseases that share similar mechanisms and severe disease manifestations. This work will address barriers of rare diseases research through vigorous multidisciplinary cooperation.