Rationale and Design of Assessing the Effectiveness of Short-Term Low-Dose Lithium Therapy in Averting Cardiac Surgery-Associated Acute Kidney Injury: A Randomized, Double Blinded, Placebo Controlled Pilot Trial

Abstract

Background: Burgeoning pre-clinical evidence suggests that therapeutic targeting of glycogen synthase kinase 3β (GSK3β), a convergence point of multiple cellular protective signaling pathways, confers a beneficial effect on acute kidney injury (AKI) in experimental models. However, it remains unknown if GSK3β inhibition likewise mitigates AKI in humans. Cardiac surgery associated acute kidney injury (CSA-AKI) poses a significant challenge for clinicians and currently the only treatment available is general supportive measures. Lithium, an FDA approved mood stabilizer, is the best-known GSK3β inhibitor and has been safely used for over half a century as the first line regimen to treat bipolar affective disorders. This study attempts to examine the effectiveness of short term low dose lithium on CSA-AKI in human patients. Methods/Design: This is a single center, prospective, randomized, double blinded, placebo controlled pilot study on patients undergoing cardiac surgery with cardiopulmonary bypass. Patients will be randomized to receive a small dose of lithium or placebo treatment for three consecutive days. Renal function will be measured via creatinine as well as novel AKI biomarkers. The primary outcome is incidence of AKI according to Acute Kidney Injury Network (AKIN) criteria, and secondary outcomes include receipt of new dialysis, days on dialysis, days on mechanical ventilation, infections within 1 month of surgery, and death within 90 days of surgery. Discussion: As a standard selective inhibitor of GSK3β, lithium has been shown to exert a beneficial effect on tissue repair and regeneration upon acute injury in multiple organ systems, including the central nervous system and hematopoietic system. In experimental AKI, lithium at small doses is able to ameliorate AKI and promote kidney repair. Successful completion of this study will help to assess the effectiveness of lithium in CSA-AKI and could potentially pave the way for large-scale randomized trials to thoroughly evaluate the efficacy of this novel regimen for preventing AKI after cardiac surgery. Trial Registration: This study was registered prospectively on the 17th February 2017 at ClinicalTrials.gov (NCT03056248, https://ichgcp.net/clinical-trials-registry/NCT03056248?term=NCT03056248&draw=2&rank=1).

Keywords: acute kidney injury; cardiac surgery associated acute kidney injury; cardiopulmonary bypass surgery; glycogen synthase kinase 3β; lithium.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Sharif, Chen, Brewster, Chen, Dworkin and Gong.

Figures

Figure 1

Schematic diagram depicting pathways leading to cardiovascular surgery-associated acute kidney injury (CSA-AKI) and role of GSK3β in the pathogenesis. There are multiple, complicated pathways mediating CSA-AKI. Cardiovascular surgery is a state of low blood flow, there is hypothermia, blood loss, activation of renin angiotensin aldosterone system (RAAS). Additionally due to CPB there is hemolysis, systemic inflammatory response syndrome (SIRS) and microemboli formation. Together these lead to reduced renal perfusion, ischemia, increase in oxidative and inflammatory injury, which in turn overactivate GSK3β. GSK3β increases proinflammatory NFκB activation, potentiates mitochondrial dysfunction as well as impairs Nrf2 antioxidant response, culminating in CSA-AKI. As an FDA-approved mood stabilizer, lithium is a standard and effective inhibitor of GSK3β and is able to ameliorate diverse types of AKI in pre-clinical models. Its efficacy in preventing CSA-AKI will be tested by this prospective, randomized, double blinded, placebo-controlled pilot clinical trial.

Figure 2

Flow diagram depicting the design of this single center, randomized, double blinded, placebo controlled pilot trial. Patients scheduled to undergo cardiovascular surgeries with cardiopulmonary bypass (CPB) will be subjected to eligibility assessment for inclusion in this trial to test the potential of short-term use of microdose lithium for protecting against CSA-AKI. This will include patients in the emergency department, general floors, critical care units, coronary care unit and step down/ telemetry units.

Figure 3

Scheme diagram depicting study interventions to be given in this trial. Patients will receive microdose lithium carbonate or placebo treatment on day 0, 1, and 2 after the cardiovascular surgery. *Biomarkers that will be sent include urinary NGAL, KIM1, tissue inhibitor of metalloproteinases-2 (TIMP-2), and insulin-like growth factor-binding protein 7 (IGFBP-7).