School of Medicine, Department of Pediatrics, Division Nephrology, University of Virginia, Box 800386, Charlottesville, VA, 22903, USA.
Department of Computer Science, School of Computing and Augmented Intelligence, Arizona State University, Tempe, AZ, USA.
BMC Nephrol. 2023 Jun 19;24(1):178. doi: 10.1186/s12882-023-03196-0.
A significant barrier to biomarker development in the field of acute kidney injury (AKI) is the use of kidney function to identify candidates. Progress in imaging technology makes it possible to detect early structural changes prior to a decline in kidney function. Early identification of those who will advance to chronic kidney disease (CKD) would allow for the initiation of interventions to halt progression. The goal of this study was to use a structural phenotype defined by magnetic resonance imaging and histology to advance biomarker discovery during the transition from AKI to CKD.
Urine was collected and analyzed from adult C57Bl/6 male mice at four days and 12 weeks after folic acid-induced AKI. Mice were euthanized 12 weeks after AKI and structural metrics were obtained from cationic ferritin-enhanced-MRI (CFE-MRI) and histologic assessment. The fraction of proximal tubules, number of atubular glomeruli (ATG), and area of scarring were measured histologically. The correlation between the urinary biomarkers at the AKI or CKD and CFE-MRI derived features was determined, alone or in combination with the histologic features, using principal components.
Using principal components derived from structural features, twelve urinary proteins were identified at the time of AKI that predicted structural changes 12 weeks after injury. The raw and normalized urinary concentrations of IGFBP-3 and TNFRII strongly correlated to the structural findings from histology and CFE-MRI. Urinary fractalkine concentration at the time of CKD correlated with structural findings of CKD.
We have used structural features to identify several candidate urinary proteins that predict whole kidney pathologic features during the transition from AKI to CKD, including IGFBP-3, TNFRII, and fractalkine. In future work, these biomarkers must be corroborated in patient cohorts to determine their suitability to predict CKD after AKI.
急性肾损伤（AKI）领域标志物开发的一个重大障碍是使用肾功能来鉴定候选者。成像技术的进步使得在肾功能下降之前检测早期结构变化成为可能。早期识别那些将进展为慢性肾脏病（CKD）的患者，可以进行干预以阻止进展。本研究的目的是使用磁共振成像和组织学定义的结构表型，在 AKI 向 CKD 过渡期间推进标志物的发现。
在叶酸诱导的 AKI 后 4 天和 12 周时，从成年 C57Bl/6 雄性小鼠收集并分析尿液。在 AKI 后 12 周处死小鼠，并从阳离子铁蛋白增强磁共振成像（CFE-MRI）和组织学评估中获得结构指标。组织学上测量近端肾小管的分数、无管肾小球（ATG）的数量和瘢痕面积。使用主成分分析单独或与组织学特征结合，确定 AKI 或 CKD 时的尿生物标志物与 CFE-MRI 衍生特征之间的相关性。
使用结构特征衍生的主成分，在 AKI 时鉴定出 12 种尿蛋白，这些蛋白可预测损伤后 12 周的结构变化。IGFBP-3 和 TNFRII 的原始和归一化尿浓度与组织学和 CFE-MRI 的结构发现强烈相关。CKD 时尿 fractalkine 浓度与 CKD 的结构发现相关。
我们已经使用结构特征鉴定了几种候选尿蛋白，这些蛋白可预测 AKI 向 CKD 过渡期间的整个肾脏病理特征，包括 IGFBP-3、TNFRII 和 fractalkine。在未来的工作中，必须在患者队列中验证这些生物标志物，以确定它们在预测 AKI 后 CKD 方面的适用性。
