Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
Am J Physiol Renal Physiol. 2019 Oct 1;317(4):F1068-F1080. doi: 10.1152/ajprenal.00305.2019. Epub 2019 Aug 14.
Severe acute kidney injury has a high mortality and is a risk factor for progressive chronic kidney disease. None of the potential therapies that have been identified in preclinical studies have successfully improved clinical outcomes. This failure is partly because animal models rarely reflect the complexity of human disease: most preclinical studies are short term and are commonly performed in healthy, young, male mice. Therapies that are effective in preclinical models that share common clinical features seen in patients with acute kidney injury, including genetic diversity, different sexes, and comorbidities, and evaluate long-term outcomes are more likely to predict success in the clinic. Here, we evaluated susceptibility to chronic kidney disease after ischemia-reperfusion injury with delayed nephrectomy by monitoring long-term functional and histological responses to injury. We defined conditions required to induce long-term postinjury renal dysfunction and fibrosis without increased mortality in a reproducible way and evaluate effect of mouse strains, sexes, and preexisting diabetes on these responses.
严重的急性肾损伤具有很高的死亡率，是进展性慢性肾脏病的一个风险因素。在临床前研究中确定的潜在治疗方法都没有成功改善临床结果。这种失败部分是因为动物模型很少反映人类疾病的复杂性：大多数临床前研究是短期的，并且通常在健康、年轻、雄性小鼠中进行。在临床前模型中有效的治疗方法与急性肾损伤患者的共同临床特征相似，包括遗传多样性、不同性别和合并症，并评估长期结果，更有可能预测临床成功。在这里，我们通过监测对损伤的长期功能和组织学反应，评估了延迟性肾切除术后缺血再灌注损伤引起的慢性肾脏病易感性。我们以可重复的方式定义了在不增加死亡率的情况下诱导长期损伤后肾功能障碍和纤维化所需的条件，并评估了小鼠品系、性别和预先存在的糖尿病对这些反应的影响。
