毛细血管稀疏与顺铂、横纹肌溶解和缺血再灌注引起的急性肾损伤(AKI)后 CKD 进展的关系比肾纤维化更密切。

Capillary rarefaction is more closely associated with CKD progression after cisplatin, rhabdomyolysis, and ischemia-reperfusion-induced AKI than renal fibrosis.

机构信息

Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

出版信息

Am J Physiol Renal Physiol. 2019 Nov 1;317(5):F1383-F1397. doi: 10.1152/ajprenal.00366.2019. Epub 2019 Sep 11.

Abstract

Acute kidney injury (AKI) is a strong independent predictor of mortality and often results in incomplete recovery of renal function, leading to progressive chronic kidney disease (CKD). Many clinical trials have been conducted on the basis of promising preclinical data, but no therapeutic interventions have been shown to improve long-term outcomes after AKI. This is partly due to the failure of preclinical studies to accurately model clinically relevant injury and long-term outcomes on CKD progression. Here, we evaluated the long-term effects of AKI on CKD progression in three animal models reflecting diverse etiologies of AKI: repeat-dose cisplatin, rhabdomyolysis, and ischemia-reperfusion injury. Using transdermal measurement of glomerular filtration rate as a clinically relevant measure of kidney function and quantification of peritubular capillary density to measure capillary rarefaction, we showed that repeat-dose cisplatin caused capillary rarefaction and decreased renal function in mice without a significant increase in interstitial fibrosis, whereas rhabdomyolysis-induced AKI led to severe interstitial fibrosis, but renal function and peritubular capillary density were preserved. Furthermore, long-term experiments in mice with unilateral ischemia-reperfusion injury showed that restoration of renal function 12 wk after a contralateral nephrectomy was associated with increasing fibrosis, but a reversal of capillary rarefaction was seen at 4 wk. These data demonstrate that clear dissociation between kidney function and fibrosis in these models of AKI to CKD progression and suggest that peritubular capillary rarefaction is more strongly associated with CKD progression than renal fibrosis.

摘要

急性肾损伤 (AKI) 是死亡率的强有力独立预测因子,常导致肾功能不完全恢复,进而导致慢性肾脏病 (CKD) 进展。许多临床试验都是基于有前途的临床前数据进行的,但没有治疗干预措施被证明可以改善 AKI 后的长期结局。这在一定程度上是由于临床前研究未能准确模拟与临床相关的损伤和 CKD 进展的长期结局。在这里,我们评估了三种反映 AKI 不同病因的动物模型中 AKI 对 CKD 进展的长期影响:重复剂量顺铂、横纹肌溶解和缺血再灌注损伤。我们使用经皮肾小球滤过率测量作为反映肾脏功能的临床相关指标,并测量小管周毛细血管密度以衡量毛细血管稀疏,结果表明重复剂量顺铂导致毛细血管稀疏和小鼠肾功能下降,但间质纤维化无明显增加,而横纹肌溶解引起的 AKI 导致严重的间质纤维化,但肾功能和小管周毛细血管密度得到保留。此外,单侧缺血再灌注损伤小鼠的长期实验表明,对侧肾切除后 12 周肾功能恢复与纤维化增加相关,但在 4 周时观察到毛细血管稀疏逆转。这些数据表明,这些 AKI 向 CKD 进展的模型中,肾功能和纤维化之间存在明显的分离,并表明小管周毛细血管稀疏与 CKD 进展的相关性强于肾纤维化。

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