Aguiar Patrício, Azevedo Olga, Pinto Rui, Marino Jacira, Baker Robert, Cardoso Carlos, Ducla Soares José Luís, Hughes Derralynn
Medicine 1 Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
Department of Cardiology, Reference Center on Lysosomal Storage Disorders, Hospital Senhora da Oliveira, Guimarães, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, ICVS/3Bs PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Mol Genet Metab. 2017 Jun;121(2):162-169. doi: 10.1016/j.ymgme.2017.05.007. Epub 2017 May 13.
Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage≥2.
In this multicentre, prospective, cross-sectional and diagnostic test study, a cohort of 78 Fabry patients and 25 healthy controls was consecutively recruited. Patients were grouped by severity of nephropathy: 1) albuminuria<30mg/g; 2) albuminuria 30-299mg/g; 3) albuminuria>300mg/g; 4) glomerular filtration rate (GFR)<60mL/min/1.73m. Several index tests, namely biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-β-glucosaminidase and alanine aminopeptidase) dysfunction were compared with the reference standard (albuminuria).
Significant increase of all tested biomarkers in Fabry patients, even in the subgroup of patients without evidence of nephropathy. We also found inverse significant correlations between estimated GFR and collagen type IV (ρ=-0.289; p=0.003) or N-acetyl-β-glucosaminidase (ρ=-0.448; p<0.001), which were stronger than with albumin (ρ=-0.274; p=0.019). There was also better diagnostic accuracy of N-acetyl-β-glucosaminidase to predict CKD stage≥2.
These results suggest that studied biomarkers may overcome the limitations of albuminuria as sensitive marker of early renal dysfunction and as marker for CKD progression risk. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage.
法布里病的肾脏受累是疾病总体预后的主要决定因素，早期酶替代疗法似乎对预防肾损伤进展有效。在标准肾脏检查中，即使变化极小或无变化，也可能出现Globotriaosylceramide（Gb3）蓄积、肾小球硬化和肾小管间质纤维化，因此肾功能不全的替代标志物至关重要。在本研究中，我们比较了几种生物标志物与蛋白尿在早期法布里肾病诊断中的作用及其对慢性肾脏病（CKD）≥2期的诊断准确性。
在这项多中心、前瞻性、横断面诊断试验研究中，连续招募了78例法布里病患者和25例健康对照。患者按肾病严重程度分组：1）蛋白尿<30mg/g；2）蛋白尿30 - 299mg/g；3）蛋白尿>300mg/g；4）肾小球滤过率（GFR）<60mL/min/1.73m²。将几种指标检测，即肾小球功能障碍的生物标志物（转铁蛋白和IV型胶原）和肾小管功能障碍的生物标志物（α1 - 微球蛋白、N - 乙酰 - β - 氨基葡萄糖苷酶和丙氨酸氨基肽酶）与参考标准（蛋白尿）进行比较。
法布里病患者中所有检测的生物标志物均显著升高，即使在无肾病证据的患者亚组中也是如此。我们还发现估计的GFR与IV型胶原（ρ = - 0.289；p = 0.003）或N - 乙酰 - β - 氨基葡萄糖苷酶（ρ = - 0.448；p < 0.001）之间存在显著负相关，其相关性强于与白蛋白的相关性（ρ = - 0.274；p = 0.019）。N - 乙酰 - β - 氨基葡萄糖苷酶对预测CKD≥2期也具有更好的诊断准确性。
这些结果表明所研究的生物标志物可能克服蛋白尿作为早期肾功能不全敏感标志物以及CKD进展风险标志物的局限性。这些生物标志物还可能定义以系膜扩张和/或肾小管损伤为特征的新型肾病早期阶段。
