Department of Pediatrics, University of Colorado, Aurora, Colorado.
Department of Pediatrics, Washington University, St. Louis, Missouri.
Am J Physiol Renal Physiol. 2022 Jul 1;323(1):F20-F32. doi: 10.1152/ajprenal.00039.2022. Epub 2022 May 9.
Acute kidney injury (AKI) is a common cause of morbidity after congenital heart disease surgery. Progress on diagnosis and therapy remains limited, however, in part due to poor mechanistic understanding and a lack of relevant translational models. Metabolomic approaches could help identify novel mechanisms of injury and potential therapeutic targets. In the present study, we used a piglet model of cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB/DHCA) and targeted metabolic profiling of kidney tissue, urine, and serum to evaluate metabolic changes specific to animals with histological acute kidney injury. CPB/DHCA animals with acute kidney injury were compared with those without acute kidney injury and mechanically ventilated controls. Acute kidney injury occurred in 10 of 20 CPB/DHCA animals 4 h after CPB/DHCA and 0 of 7 control animals. Injured kidneys showed a distinct tissue metabolic profile compared with uninjured kidneys ( = 0.93, = 0.53), with evidence of dysregulated tryptophan and purine metabolism. Nine urine metabolites differed significantly in animals with acute kidney injury with a pattern suggestive of increased aerobic glycolysis. Dysregulated metabolites in kidney tissue and urine did not overlap. CPB/DHCA strongly affected the serum metabolic profile, with only one metabolite that differed significantly with acute kidney injury (pyroglutamic acid, a marker of oxidative stress). In conclusion, based on these findings, kidney tryptophan and purine metabolism are candidates for further mechanistic and therapeutic investigation. Urine biomarkers of aerobic glycolysis could help diagnose early acute kidney injury after CPB/DHCA and warrant further evaluation. The serum metabolites measured at this early time point did not strongly differentiate based on acute kidney injury. This project explored the metabolic underpinnings of postoperative acute kidney injury (AKI) following pediatric cardiac surgery in a translationally relevant large animal model of cardiopulmonary bypass with deep hypothermic circulatory arrest. Here, we present novel evidence for dysregulated tryptophan catabolism and purine catabolism in kidney tissue and increased urinary glycolysis intermediates in animals who developed histological AKI. These pathways represent potential diagnostic and therapeutic targets for postoperative AKI in this high-risk population.
急性肾损伤（AKI）是先天性心脏病手术后发病率高的常见原因。然而，在诊断和治疗方面的进展仍然有限，部分原因是对发病机制的理解不足，以及缺乏相关的转化模型。代谢组学方法可以帮助确定新的损伤机制和潜在的治疗靶点。在本研究中，我们使用了一种心肺旁路（CPB）与深低温循环停止（DHCA）的小猪模型，并对肾脏组织、尿液和血清进行了靶向代谢谱分析，以评估与组织学急性肾损伤相关的特定代谢变化。CPB/DHCA 后 4 小时，将急性肾损伤的动物与无急性肾损伤和机械通气的对照组进行比较。CPB/DHCA 动物中，有 10 例发生 AKI，而对照组 7 例均无 AKI。与未受伤的肾脏相比，受伤的肾脏显示出明显的组织代谢谱（ = 0.93， = 0.53），表明色氨酸和嘌呤代谢失调。9 种尿液代谢物在 AKI 动物中差异显著，提示有氧糖酵解增加。肾脏组织和尿液中的失调代谢物没有重叠。CPB/DHCA 强烈影响血清代谢谱，只有一种代谢物与 AKI 差异显著（焦谷氨酸，氧化应激的标志物）。总之，基于这些发现，肾脏色氨酸和嘌呤代谢是进一步进行机制和治疗研究的候选者。尿液中糖酵解的生物标志物有助于在 CPB/DHCA 后早期诊断 AKI，并值得进一步评估。CPB/DHCA 后早期时间点测量的血清代谢物在基于 AKI 方面没有强烈区分。本项目在心肺旁路与深低温循环停止的转化相关大动物模型中探索了小儿心脏手术后术后急性肾损伤（AKI）的代谢基础。在这里，我们提出了新的证据，表明在发生组织学 AKI 的动物中，肾脏组织中色氨酸分解代谢和嘌呤分解代谢失调，以及尿液中糖酵解中间产物增加。这些途径代表了高危人群术后 AKI 的潜在诊断和治疗靶点。
