Hereditary Causes of Nephrolithaisis and Kidney Failure

肾结石和肾衰竭的遗传原因

基本信息

批准号：
8538352
负责人：
Dawn Schmautz Milliner
金额：
$ 122.3万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2014-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538352
关键词：
Abdominal colic Accounting Address Adenine Adult Affect Age Alanine-glyoxylate aminotransferase Area Automobile Driving Biological Markers Calcium Oxalate Calculi Caring Case Study Cells Cellular biology Childhood Chloride Channels Clinic Clinical Clinical Research Clinical Trials Clinical Trials Cooperative Group Communication Communities Crystal Formation Cystine Cystinuria Data Data Collection Decision Making Defect Diagnosis Diagnostic Diagnostic tests Disease Disease Progression Drug Metabolic Detoxication Education Elements End stage renal failure Enrollment Enzymes European Event Excision Excretory function Familiarity Family Figs - dietary Functional disorder Funding Future Generations Glyoxylates Goals Health Care Costs Hepatic Hepatocyte Hydroxypyruvate reductase Hyperoxaluria Impaired Renal Function Inborn Errors of Metabolism Individual Infection Inflammatory Inflammatory Response Inherited Injury Injury to Kidney Interdisciplinary Study International International Cooperation Intervention Investigation Joints Kidney Kidney Failure Kidney Transplantation Knowledge Lead Life Liver Longitudinal Studies Mediating Medical Meta-Analysis Metabolic Metabolic Pathway Minerals Minority Modeling Natural History Needs Assessment Nephrocalcinosis Nephrolithiasis Nephrology Obstruction Online Systems Operative Surgical Procedures Outcome Oxalates Pain Patient Care Patients Physicians Pilot Projects Play Prevalence Primary Hyperoxaluria Procedures Process Proteins Proteome Proximal Kidney Tubules Quality of Care Quality of life Rare Diseases Reaction Recurrence Registries Renal function Renal tubule structure Research Research Infrastructure Research Personnel Research Training Resource Sharing Resources Risk Salts Science Scientist Secure Severity of illness Site Structure Symptoms System Time Time Study Tissue Banking Tissue Banks Tissues Toxic effect Training Programs Transferase Treatment outcome United States National Institutes of Health Urinary Calculi Urinary tract Urine Urologist Woman Work adenine phosphoribosyltransferase advanced disease autosomal recessive trait clinical research site cohort disease-causing mutation disorder risk effective therapy efficacy testing experience glyoxylate hypercalciuria improved infancy inhibitor/antagonist investigator training kidney cell liver transplantation male meetings member men middle age multidisciplinary neuronal cell body patient advocacy group patient registry prevent programs public health relevance response solute success tissue resource treatment strategy urinary

项目摘要

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.

描述（由申请人提供）：300字四种先天性代谢缺陷会导致尿液中不溶性矿物盐浓度过高，并导致严重的复发性肾结石。患有原发性高草酸尿症 (PH)、胱氨酸尿症、APRT 缺乏症（二羟基腺嘌呤尿症，DMA）和 Dent 病的患者从儿童时期就开始出现结石。所有患者均观察到肾组织中晶体沉积和肾功能丧失。疾病表现差异很大。例如，一些 PH 患者在婴儿期进展为终末期肾衰竭，而另一些患者则维持肾功能直至中年。人们对这种变异性知之甚少。如果确定了疾病表达的修饰因子，则有望成为潜在的新治疗策略。然而，有效治疗的进展缓慢。患者数量少、分布广泛，使得对疾病表现进行严格的表征和纵向评估变得困难。由于很少有患者可以参加临床试验，因此测试新疗法疗效的能力有限。为了解决这个问题，我们将在国际原发性高草酸尿登记处 (IPHR) 先前成功工作的基础上扩展 IPHR 并建立安全的、基于网络的胱氨酸尿症、DHA 和 Dent 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确定特征明确的患者群体以用于未来的临床试验。所有四种疾病似乎都是由晶体的肾沉积介导的，而细胞反应似乎又受到尿蛋白抑制剂的调节。因此，通过协同作用来了解尿蛋白质组和肾细胞生物学对疾病进展的影响具有巨大的潜力。一个由具有独特专业知识并能接触到患有这些诊断的患者的临床科学家组成的杰出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进行。