MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Department of Electrical Engineering, Technical University of Denmark, Kgs Lyngby, Denmark.
Sci Rep. 2017 Jan 17;7:40812. doi: 10.1038/srep40812.
Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), and at present, there is a lack of reliable biomarkers that can diagnose AKI and measure early progression because the commonly used methods cannot evaluate single-kidney IRI. Hyperpolarized [1,4-C]fumarate conversion to [1,4-C]malate by fumarase has been proposed as a measure of necrosis in rat tumor models and in chemically induced AKI rats. Here we show that the degradation of cell membranes in connection with necrosis leads to elevated fumarase activity in plasma and urine and secondly that hyperpolarized [1,4-C]malate production 24 h after reperfusion correlates with renal necrosis in a 40-min unilateral ischemic rat model. Fumarase activity screening on bio-fluids can detect injury severity, in bilateral as well as unilateral AKI models, differentiating moderate and severe AKI as well as short- and long-term AKI. Furthermore after verification of renal injury by bio-fluid analysis the precise injury location can be monitored by in vivo measurements of the fumarase activity non-invasively by hyperpolarized [1,4-C]fumarate MR imaging. The combined in vitro and in vivo biomarker of AKI responds to the essential requirements for a new reliable biomarker of AKI.
肾缺血/再灌注损伤 (IRI) 是急性肾损伤 (AKI) 的主要原因，目前缺乏可靠的生物标志物来诊断 AKI 和衡量早期进展，因为常用的方法无法评估单肾 IRI。先前有研究提出，通过延胡索酸酶将[1,4-C]延胡索酸转化为[1,4-C]苹果酸，可作为评估大鼠肿瘤模型和化学诱导 AKI 大鼠中坏死的指标。本研究表明，与坏死相关的细胞膜降解会导致血浆和尿液中延胡索酸酶活性升高；其次，再灌注后 24 小时的[1,4-C]苹果酸产生与 40 分钟单侧缺血大鼠模型中的肾坏死相关。生物液中的延胡索酸酶活性筛查可以检测损伤严重程度，无论是在双侧还是单侧 AKI 模型中，都可以区分中度和重度 AKI 以及短期和长期 AKI。此外，通过生物液分析验证肾损伤后，可通过非侵入性的极化[1,4-C]延胡索酸磁共振成像来测量体内延胡索酸酶活性，从而对损伤部位进行精准监测。AKI 的这种联合体内外生物标志物符合 AKI 新型可靠生物标志物的基本要求。
