Natural History and Structural-Functional Relationships in Fabry Renal Dis(Mauer)

法布里肾病的自然史和结构功能关系(Mauer)

• 批准号: 8545236
• 负责人: MICHAEL S MAUER
• 金额: $ 8.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8545236
• 关键词: Accounting; Address; Adult; Age; Biopsy; Child; Childhood; Chronic Kidney Failure; Clinical; Clinical Trials; Complication; Country; Creatinine; Data; Deterioration; Dialysis patients; Disease; Disease Progression; Early Intervention; Early intervention trials; End stage renal failure; Endothelial Cells; Enzymes; Fabry Disease; Female; Filtration; Goals; Kidney; Kidney Diseases; Kidney Failure; Life; Measures; Methods; Natural History; Non-linear Models; Patient Recruitments; Patients; Pilot Projects; Prevalence; Primary Prevention; Proteinuria; Renal function; Research; Serum; Structural Models; Structure; Surrogate Endpoint; Time; base; cellular pathology; design; enzyme replacement therapy; functional outcomes; male; mesangial cell; podocyte; response; screening

Chronic renal failure is a major debilitating and life-threatening complication of Fabry disease known to account for 0.01% of end-stage renal disease in western countries. Enzyme screening studies in male dialysis patients suggest that this might be an underestimate of the true prevalence of the disease by 10- to 100-fold. Furthermore, the natural history of heterozygous females is even more unclear. Primary prevention, before the disease is clinically manifest, could be important to maximize the potential benefits of enzyme replacement therapy, but it will be important to evaluate such early intervention before consigning every child to life-long therapy. Understanding the cellular pathology, and the tempo of progression, will be crucial. However, the structural changes of Fabry renal disease responsible for glomular filtration rate (GFR) loss have not been systematically studied. Using quantitative morphometric stereologic methods we have recently demonstrated that podocyte GL-3 accumulation is progressive with age (time) while mesangial and endothelial cell accumulation is not. We will apply these systematic quantitative methods to 50-60 Fabry patients with a wide range of GFR with kidney biopsies performed prior to beginning enzyme replacement therapy. We will then develop a model of structural functional relationships which most closely predicts GFR loss. These data will be used for the power calculations needed to design early intervention trials based on those structural endpoints which are most closely related to important functional outcomes in Fabry disease.

慢性肾衰竭是法布里病的一种主要的衰弱和危及生命的并发症，已知在西方国家占终末期肾病的0.01%。男性透析患者的酶筛查研究表明，这可能低估了该疾病的真实患病率10至100倍。此外，杂合雌性的自然史更加不清楚。在疾病临床表现之前进行一级预防对于最大限度地发挥酶替代疗法的潜在益处可能很重要，但在将每个儿童交付终身治疗之前评估这种早期干预也很重要。了解细胞病理学和进展的克里思将是至关重要的。然而，负责肾小球滤过率（GFR）损失的法布里病肾病的结构变化还没有系统的研究。使用定量形态学体视学方法，我们最近证明，足细胞GL-3的积累是渐进的年龄（时间），而肾小球系膜和内皮细胞的积累不是。我们将这些系统的定量方法应用于50-60例GFR范围广泛的法布里病患者，在开始酶替代治疗前进行肾活检。然后，我们将开发一个模型的结构功能关系，最密切地预测GFR的损失。这些数据将用于设计早期干预试验所需的把握度计算，这些试验基于与法布里病重要功能结局最密切相关的结构性终点。