An Observational Case Control Study to Identify the Role of MV and MV Derived Micro-RNA in Post CArdiac Surgery AKI

An Observational Case Control Study to Identify the Role of MV and MV Derived Micro-RNA in Post CArdiac Surgery Acute Kidney Injury: The MaRACAS Study

Acute kidney injury (AKI) complicates over 25% of cardiac surgical procedures where it increases mortality up to fourfold. The incidence of AKI is increasing, the pathogenesis is poorly understood, current diagnostic tests lack specificity and sensitivity, and there is no effective treatment. Improving outcomes in patients at risk of AKI has recently been defined as an NHS priority. The primary aim of this study is to determine how plasma derived microvesicles (MV) or more specifically MV associated microRNAs (miRNA) regulate survival and signalling in post cardiac surgery AKI. The study involves a clinical and experimental research project that will combine laboratory analyses of circulating MV and miRNA from clinical studies. The study will specifically consider how MV and miRNA alter inflammatory signaling in kidneys after cardiac surgery, how these are modified by important clinical risk factors, and whether they may serve as early biomarkers of injury.

AKI is characterised by upregulation of competing pro-survival and pro- inflammatory/ apoptotic signaling pathways whereby processes associated with renal recovery; tubular epithelial phenotypic change and proliferation occur simultaneously with those associated with diminished GFR, vascular inflammation, tubular dysfunction and epithelial apoptosis. Protection from AKI can be achieved by altering the balance of these pathways; for example upregulation of the pivotal phosphatidylinositol 3-kinase - serine-threonine protein kinase B (PI3K-Akt) pro-survival pathway following the administration of erythropoietin or insulin like growth factor inhibits experimental AKI following renal ischaemia and reperfusion in rodents and swine. In our own work we have shown that post cardiopulmonary bypass (CPB) AKI in swine can be prevented by the administration of either a phosphodiesterase type 5 (PDE-5) inhibitor which promotes cell survival and endothelial homeostasis via augmentation of endogenous nitric oxide (NO) signalling, or by the inhibition of endothelin-1 (ET-1), an important pro-inflammatory mediator and promoter of oxidative stress in renal injury How these competing pathways are regulated in patients at risk of AKI is poorly understood however, and it is our belief that the identification of these processes will facilitate the development of new and effective prevention and treatment strategies for AKI and improved outcomes for patients

Inclusion Criteria:

1. Adult cardiac surgery patients (>16 years) undergoing coronary artery bypass grafting or valve surgery with moderately hypothermic CPB (32-34°C) blood cardioplegia.
2. Identified as being at increased risk for AKI from a modified risk score.

Exclusion Criteria:

1. Patients with pre-existing inflammatory state: sepsis undergoing treatment, acute kidney injury within 5 days, chronic inflammatory disease, congestive heart failure,
2. Emergency or salvage procedure,
3. Ejection fraction <30 %,
4. Patient in a critical preoperative state (Kidney Disease: Improving Global Outcomes (KDIGO) Stage 3 AKI or requiring ionotropes, ventilation or intra-aortic balloon pump).
5. Pregnancy.