Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy
Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy
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DOI：
10.1093/ndt/gfaa298
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发表时间：
2022-01-01
影响因子：
6.1
通讯作者：
Isaka, Yoshitaka
中科院分区：
文献类型：
--
作者：
Yonishi, Hiroaki;Namba-Hamano, Tomoko;Isaka, Yoshitaka
背景。在蛋白尿 >1 g/天的情况下，酶替代疗法 (ERT) 无法预防法布里肾病 (FN) 的进展，这凸显了识别有效生物标志物以早期诊断蛋白尿之前的 FN 的必要性。在这里，我们尝试识别用于早期检测 FN 的生物标志物。方法。纳入了 51 名法布里病 (FD) 患者。对尿桑葚体 (uMB) 进行免疫染色，检测三酰神经酰胺 (Gb3) 和肾细胞标记物，以确定其来源。使用空泡足细胞与肾小球平均面积比对 7 名患者进行半定量 uMB 排泄与足细胞空泡形成的组织学严重程度之间的关联进行研究。分析了 uMB 排泄的半定量估计值与 ERT 持续时间之间的关联。进行了一项纵向研究来评估 ERT 对 uMB 排泄的影响。结果。 32 名患者 (63%) 出现 uMB，而只有 31% 的患者出现蛋白尿。 uMB 的 Gb3、溶酶体相关膜蛋白 1 和足萼蛋白呈阳性，表明它们源自足细胞中 Gb3 积累的溶酶体。我们观察到随着 uMB 排泄的增加，足细胞空泡化更加严重（趋势 P = 0.03）；然而，蛋白尿增加却没有观察到同样的情况。随着 ERT 持续时间的缩短，大量 uMB 排泄的患者百分比增加 (P = 0.018)。十八个月的 ERT 减少了 uMB 排泄（P = 0.03），但不影响蛋白尿。结论。大多数患者出现蛋白尿之前就会出现 uMB 排泄，这意味着足细胞持续损伤。半定量 uMB 估计值可以作为早期 FN 诊断和监测 FD 特异性疗法疗效的新型生物标志物。
Background. The inability of enzyme replacement therapy (ERT) to prevent progression of Fabry nephropathy (FN) in the presence of >1 g/day proteinuria underscores the necessity of identifying effective biomarkers for early diagnosis of FN preceding proteinuria. Here we attempted to identify biomarkers for early detection of FN.Methods. Fifty-one Fabry disease (FD) patients were enrolled. Urinary mulberry bodies (uMBs) were immunostained for globotriaosylceramide (Gb3) and renal cell markers to determine their origin. The association between semiquantitative uMB excretion and the histological severity of podocyte vacuolation was investigated in seven patients using the vacuolated podocyte:glomerular average area ratio. The association between the semiquantitative estimate of uMB excretion and duration of ERT was analyzed. A longitudinal study was conducted to assess the effect of ERT on uMB excretion.Results. Thirty-two patients (63%) had uMBs, while only 31% showed proteinuria. The uMBs were positive for Gb3, lysosomal-associated membrane protein 1 and podocalyxin, suggesting they were derived from lysosomes with Gb3 accumulation in podocy les. We observed more severe podocyte vacuolation with increased uMB excretion (P = 0.03 for trend); however, the same was not observed with increased proteinuria. The percentage of patients with substantial uMB excretion increased with shorter ERT duration (P = 0.018). Eighteen-month-long ERT reduced uMB excretion (P = 0.03) without affecting proteinuria.Conclusions. uMB excretion, implying ongoing podocyte injury, preceded proteinuria in most patients. Semiquantitative uMB estimates can serve as novel biomarkers for early FN diagnosis and for monitoring the efficacy of FD-specific therapies.