Sudhindar Praveen Dhondurao, Orr Sarah E, Miller-Hodges Eve, Molinari Elisa, Wood Katrina, Srivastava Shalabh, Miles Colin G, Mabillard Holly R, Sentell Zachary T, Trevisan-Herraz Marco, Arcila-Galvis Juliana E, Sayer John A
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Central Parkway, Newcastle upon Tyne, United Kingdom.
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Clin Sci (Lond). 2025 Jul 28;139(14):791-808. doi: 10.1042/CS20255570.
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Renal involvement is a major complication, yet diagnosis often requires an invasive kidney biopsy, and follow-up relies on indirect biomarkers or imaging, which lack specificity. Here, we present human urine-derived renal epithelial cells (hURECs) as a minimally invasive alternative for phenotyping renal Fabry disease and monitoring treatment response. Using hURECs from a newly diagnosed male Fabry disease patient, transmission electron microscopy (TEM) revealed lysosomal inclusions consistent with native kidney biopsy findings. Bulk RNA sequencing (RNA-seq) identified a transcriptomic disease signature, including dysregulated pathways involved in lipid metabolism homeostasis, ion transport, endoplasmic reticulum stress response, and collagen processing. Following systemic treatment of the patient with chaperone therapy, partial amelioration of the hUREC transcriptomic signature was observed during the first few months. However, by nine months, the signature began reverting toward baseline, correlating with continued kidney function decline. This prompted a transition to enzyme replacement therapy, with early evaluations showing transcriptomic stabilization. Our findings demonstrate that hURECs replicate key structural and molecular markers of renal Fabry disease and offer a non-invasive platform for longitudinal assessment of treatment response. TEM of hURECs provides a diagnostic alternative to biopsy, while RNA-seq-based transcriptomic profiling offers a sensitive and dynamic view of molecular changes, including key dysregulated pathways. This dual utility positions hURECs as a novel tool for improving the diagnosis, monitoring, and personalized management of kidney involvement in Fabry disease.
法布里病是一种X连锁溶酶体贮积症，由α-半乳糖苷酶A缺乏引起，导致糖鞘脂蓄积和进行性器官损害。肾脏受累是主要并发症，但诊断通常需要进行侵入性肾活检，随访依赖于缺乏特异性的间接生物标志物或影像学检查。在此，我们提出将人尿液来源的肾上皮细胞（hURECs）作为一种微创替代方法，用于对肾法布里病进行表型分析和监测治疗反应。使用一名新诊断的男性法布里病患者的hURECs，透射电子显微镜（TEM）显示溶酶体包涵体与天然肾活检结果一致。批量RNA测序（RNA-seq）确定了一种转录组疾病特征，包括参与脂质代谢稳态、离子转运、内质网应激反应和胶原蛋白加工的失调途径。在对该患者进行伴侣疗法全身治疗后，最初几个月观察到hUREC转录组特征有部分改善。然而，到九个月时，该特征开始恢复到基线水平，与肾功能持续下降相关。这促使转而采用酶替代疗法，早期评估显示转录组稳定。我们的研究结果表明，hURECs复制了肾法布里病的关键结构和分子标志物，并为纵向评估治疗反应提供了一个非侵入性平台。hURECs的TEM为活检提供了一种诊断替代方法，而基于RNA-seq的转录组分析提供了分子变化的敏感和动态视图，包括关键的失调途径。这种双重用途使hURECs成为改善法布里病肾脏受累的诊断、监测和个性化管理的一种新工具。
