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

慢性肾衰竭是法布里病的主要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选研究表明，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不清楚。初级预防，在疾病临床表现出来之前，对于最大化酶替代疗法的潜在益处可能是重要的，但在让每个孩子接受终身治疗之前，评估这种早期干预将是重要的。了解细胞病理和进展的速度将是至关重要的。然而，Fabry肾病引起肾小球滤过率（GFR）损失的结构改变尚未得到系统的研究。我们最近使用定量形态测量体视学方法证明足细胞GL-3的积累是随着年龄（时间）而进行性的，而系膜细胞和内皮细胞的积累则不是。我们将把这些系统的定量方法应用于50-60名在开始酶替代治疗之前进行肾脏活检的大范围GFR的Fabry患者。然后，我们将开发一个最接近预测GFR损失的结构功能关系模型。这些数据将用于设计早期干预试验所需的功率计算，这些试验基于与Fabry病重要功能结局最密切相关的结构终点。

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.