Lithium in Acute Kidney Injury (LSCAKI)

A growing body of pre-clinical evidence suggests that glycogen synthase kinase 3β (GSKβ) is implicated in the development and progression of acute kidney injury (AKI). Lithium is a naturally occurring standard inhibitor of GSKβ. The purpose of this study is to examined if low dose lithium carbonate is able to reduce the incidence of AKI in patients undergoing cardiac surgery who are placed on cardiopulmonary bypass during surgery. We hypothesize that low dose lithium might reduce the incidence and duration of AKI in patients undergoing cardiac surgery who are on cardiopulmonary bypass.

Cardiac surgery associated acute kidney injury (CSA-AKI) is a significant problem. The prevalence varies from 0.3% to 22.9% depending on the definition of AKI. The pathogenesis of AKI in this population is multifactorial. Factors associated with AKI in such patients include increased age, preoperative elevated creatinine, presence of diabetes, reduced ejection fraction, increased body weight, and presence of carotid artery bruit, duration of cardiopulmonary bypass, aortic cross clamp time, and duration of surgery. CSA-AKI is an independent predictor of mortality, morbidity, increased length of stay and hospitalization costs. Moreover these patients are also at increased risk of chronic kidney disease and end stage renal failure in the future. Various pharmacologic approaches that have been tried to prevent early CSA-AKI such as diuretics, vasodilators, and anti-inflammatory drugs. Fenoldopam, atrial natriuretic peptide, and brain natriuretic peptide have shown little renoprotection. However these strategies lack high quality evidence to support their use and are not standard of care. There is no strong evidence to suggest any single or multiple pharmacotherapy that significantly impacts in reducing CAS-AKI. Thus the current best therapy for CSA-AKI is prevention, supportive care, hemodynamic optimization and renal replacement therapy. AKI is an extremely complex process involving multiple pathophysiologic pathways. Glycogen synthase kinase 3β (GSK3β) is implicated in many pathways beyond glycogen metabolism and has been shown to be an important player in the development of AKI . Lithium is a US Food and Drug Administration (FDA)-approved drug which has been used for over 50 years as first line agent to treat mood disorders. It is a standard inhibitor for GSK3β. Latest evidence in murine models of cisplatin-induced AKI and ischemia/reperfusion-induced AKI suggests that lithium treatment may attenuated kidney dysfunction and kidney histologic injury following AKI. Lithium was able to promote kidney tubular cell repair hence improvement of AKI in murine models. In addition, lithium has also been found to exert an anti-proteinuric and renal reparative effect. On this background we want to explore the potential preventive and therapeutic role of lithium carbonate in CSA- AKI.

Patients will be randomized to lithium versus placebo and rates of acute kidney injury will be measured

Patients will be identified by chart review and be explained the purpose of the study and informed consent taken

Patients will be identified by chart review and be explained the purpose of the study and informed consent taken

On day 0, the day of the cardiac surgery placebo will be given once On day 1, one day after cardiac surgery placebo will be given once On day 2, two days after cardiac surgery placebo will be given once

On day 0, the day of the cardiac surgery oral lithium will be given at dose 900mg once On day 1, one day after cardiac surgery oral lithium will be given at dose 900mg once On day 2, two days after cardiac surgery oral lithium will be given 900mg once

Inclusion Criteria: A male or female greater than 18 years Stable renal function with creatinine change <0.3mg/dl in the preceding 1 month prior to scheduled surgery Procedure such as aortic valve surgery, mitral valve surgery, coronary artery bypass grafting, or combination of the above mentioned procedures Have estimated glomerular filtration rate greater than or equal to 15ml/min/ 1.73m2 as calculated by chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula Exclusion Criteria: Subjects who: Are taking lithium prior to surgery for any reason Have ejection fraction of <30% prior to surgery Have estimated glomerular filtration rate <15ml/min/ 1.73m2 as calculated by chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula Having cardiac surgery to be performed without using cardiopulmonary bypass Has ongoing sepsis or history of sepsis in the last 2 weeks, defined as having 2 of the following criteria T >38C or <36C, pulse rate >90/min, RR >20/min, WBC >12 or >10% polymorphonuclear cells plus a documented source Has documented rise in creatinine ≥ 0.3mg/dl in the preceding one month prior to surgery

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