Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Alder Hey Children's Hospital, Liverpool, UK.
Physiol Rep. 2022 Mar;10(5):e15211. doi: 10.14814/phy2.15211.
Renal ischemia reperfusion injury (R-IRI) can cause acute kidney injury (AKI) and chronic kidney disease (CKD), resulting in significant morbidity and mortality. To understand the underlying mechanisms, reproducible small-animal models of AKI and CKD are needed. We describe how innovative technologies for measuring kidney function noninvasively in small rodents allow successful refinement of the R-IRI models, and offer the unique opportunity to monitor longitudinally in individual animals the transition from AKI to CKD.
Male BALB/c mice underwent bilateral renal pedicle clamping (AKI) or unilateral renal pedicle clamping with delayed contralateral nephrectomy (CKD) under isoflurane anesthetic. Transdermal GFR monitoring and multispectral optoacoustic tomography (MSOT) in combination with statistical analysis were used to identify and standardize variables within these models.
Pre-clamping anesthetic time was one of the most important predictors of AKI severity after R-IRI. Standardizing pre-clamping time resulted in a more predictably severe AKI model. In the CKD model, MSOT demonstrated initial improvement in renal function, followed by significant progressive reduction in function between weeks 2 and 4. Performing contralateral nephrectomy on day 14 enabled the development of CKD with minimal mortality.
Noninvasive monitoring of global and individual renal function after R-IRI is feasible and reproducible. These techniques can facilitate refinement of kidney injury models and enable the degree of injury seen in preclinical models to be translated to those seen in the clinical setting. Thus, future therapies can be tested in a clinically relevant, noninvasive manner.
肾缺血再灌注损伤（R-IRI）可导致急性肾损伤（AKI）和慢性肾病（CKD），从而导致发病率和死亡率显著增加。为了了解其潜在机制，需要建立可重现的小型动物 AKI 和 CKD 模型。我们描述了如何创新地使用非侵入性测量小型啮齿动物肾功能的技术来成功改进 R-IRI 模型，并为在个体动物中进行从 AKI 到 CKD 的纵向监测提供了独特的机会。
雄性 BALB/c 小鼠在异氟烷麻醉下接受双侧肾蒂夹闭（AKI）或单侧肾蒂夹闭加延迟对侧肾切除术（CKD）。透皮肾小球滤过率监测和多光谱光声断层扫描（MSOT）结合统计分析用于确定和标准化这些模型中的变量。
再灌注前的麻醉时间是 R-IRI 后 AKI 严重程度的最重要预测因素之一。标准化再灌注前的时间导致更可预测的严重 AKI 模型。在 CKD 模型中，MSOT 显示肾功能最初有所改善，然后在第 2 至第 4 周之间肾功能显著持续下降。在第 14 天进行对侧肾切除术可使 CKD 发展，且死亡率最低。
R-IRI 后对整体和个体肾功能进行非侵入性监测是可行且可重现的。这些技术可以促进肾脏损伤模型的改进，并使临床前模型中观察到的损伤程度转化为临床观察到的损伤程度。因此，未来的治疗方法可以以一种具有临床相关性的非侵入性方式进行测试。
