MicroRNA levels, hypoxia and cardiopulmonary bypass in the development of acute kidney injury

Author: Annette Mazzone

Mazzone, Annette, 2020 MicroRNA levels, hypoxia and cardiopulmonary bypass in the development of acute kidney injury, Flinders University, College of Medicine and Public Health

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Acute kidney injury (AKI) is a frequent and important complication of cardiac surgery and is associated with increased complications, length of hospital stay and mortality. During cardiac surgery procedures, cardiopulmonary bypass (CPB) is used to support the function of the heart and lungs. A number of modifiable factors of CPB, resulting in oxygen supply/demand mismatch have been investigated in playing a potential role in the development AKI. The challenge with managing AKI following cardiac surgery is that there is no effective intervention once AKI has been diagnosed.

Efforts to prevent cardiac surgery associated AKI are limited by the ability to predict which patients will develop AKI due to the inability to monitor the risk of its development intraoperatively. Traditional biomarkers, including serum creatinine, provide prognostic information that damage has occurred and do not reflect real time change in renal function. Due to the number of potential known modifiable risk factors of CPB, the time on CPB provides an ideal opportunity to investigate the development of AKI as intervention during this known period of insult is feasible.

The potential application of microRNAs (miRNAs) as disease biomarkers has been of considerable recent interest due to the vital role miRNAs play in biological process, with altered expression associated with altered physiological states including hypoxia. The expanding roles of miRNAs, not only as biomarkers, but their involvement in the control and progression of disease processes, including AKI, makes them ideal to study.

The specific aims of this thesis were to successfully isolate and measure circulating and urinary miRNAs, such as miRNAs associated with hypoxia and haemolysis to gain a greater understanding of the molecular response to CPB; and to elucidate the molecular mechanisms involved in the development of AKI following CPB potentially identifying a predictive marker of AKI during cardiac surgery. The results of this thesis present the first comprehensive investigation into miRNAs expression levels during cardiac surgery with CPB, with differential patterns of miRNA release observed. Hypoxically regulated miR-210 levels were found to be increased during CPB and into the early postoperative period. Investigation in a cohort of patients who developed AKI found levels of miR-210 to be increased compared to patients who did not develop AKI. Levels of miR-210 measured during CPB also significantly correlated with levels of urinary PO2, a predictive marker of AKI, suggesting a hypoxic release of miR-210 release during CPB.

This thesis provides evidence of hypoxically regulated miRNA release, dysregulation of hypoxia related molecular pathways and provide evidence of a potential hypoxia response to CPB which has not be previously shown. The results of this thesis provide ground work for a greater understanding of the molecular effects of CPB and may help guide future directions of CPB conduct and management serving as a tool for examining effects of changes in management, leading to improved outcomes.

Keywords: Acute kidney injury, hypoxia, cardiopulmonary bypass, cardiac surgery

Subject: Medical Science thesis

Thesis type: Doctor of Philosophy
Completed: 2020
School: College of Medicine and Public Health
Supervisor: Professor Jonathan Gleadle