Hereditary Causes of Nephrolithaisis and Kidney Failure

描述(申请人提供)：300字四种先天代谢缺陷会导致尿液中大量的不溶性矿物质盐和严重的、反复出现的肾结石。患有原发性高草酸尿(PH)、胱氨酸尿症、APRT缺乏症(二羟腺苷尿症，DMA)和Dent病的患者从童年开始就有结石的经历。肾组织中可见结晶沉积，肾功能受损。疾病的表现差异很大。例如，一些PH患者在婴儿期进展为终末期肾功能衰竭，而另一些患者则将肾功能维持到中年。人们对这种可变性知之甚少。疾病表达的修饰物，如果被发现，将有望成为潜在的新治疗策略。然而，在有效治疗方面进展缓慢。少数广泛分散的患者使得对疾病表现的严格描述和纵向评估变得困难。由于可用于临床试验的患者寥寥无几，测试新疗法疗效的能力有限。为了解决这一问题，我们将在国际高草酸尿症登记处(IPHR)以前成功工作的基础上，扩大IPHR，并为胱氨酸尿症、DHA和Dent病建立安全的、基于网络的登记处和组织库。在每种疾病中对个别患者进行的纵向研究将强调产生可检验的假说，并为未来的临床试验确定具有良好特征的患者队列。所有这四种疾病似乎都是由肾脏晶体沉积和细胞反应介导的，而细胞反应似乎受到尿蛋白抑制物的调节。因此，在了解尿液蛋白质组和肾细胞生物学在疾病进展中的影响方面，有很大的潜力。一个由具有独特专业知识和接触这些诊断患者的杰出临床科学家组成的联盟将致力于这项工作。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交流以及与患者、医学界成员和科学家开放共享新开发的资源来实现。 公共卫生相关性：肾结石和肾功能衰竭遗传原因联合会非常适合完成所需的表征和纵向评估，以促进发现疾病风险、疾病活动性和对四种具有相似机制和严重疾病表现的罕见疾病的治疗反应的生物标记物。这项工作将通过积极的多学科合作来解决罕见疾病研究的障碍。

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.