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

慢性肾功能衰竭是Fabry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%。对男性透析患者进行的酶筛查研究表明，这可能将这种疾病的真实患病率低估了10-100倍。此外，杂合子雌性的自然历史更是不清楚。在疾病临床显现之前进行初级预防，对于最大限度地发挥酶替代疗法的潜在好处可能很重要，但在让每个儿童接受终身治疗之前，评估这种早期干预将是重要的。了解细胞病理以及进展的速度将是至关重要的。然而，导致肾小球滤过率(GFR)丧失的Fabry肾病的结构变化尚未得到系统的研究。我们最近用定量形态体视学方法证明，足细胞GL-3的积聚是随着年龄的增长而递增的，而系膜细胞和内皮细胞的积聚则不是这样。我们将把这些系统的定量方法应用于50-60名有广泛肾小球滤过率的Fabry患者，这些患者在开始酶替代治疗之前进行了肾脏活检。然后，我们将开发一个结构功能关系模型，该模型最接近地预测GFR的损失。这些数据将用于根据与Fabry病的重要功能结果最密切相关的结构终点来设计早期干预试验所需的功率计算。

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.