Translational Cardiovascular and Renal Research Group
Sepsis and heart surgery both pose great danger for patients, as both can lead to brain injury and kidney injury. Our group aims to offer solutions to these major unresolved health complications. We want to deconstruct the pathological changes that happens in the brain and kidneys during sepsis and heart surgery and ensure the safety and efficacy of new mechanism-guided treatments for future clinical use. Through this, we hope to have a true breakthrough in our ability to avoid brain and kidney injury arising from heart surgery and sepsis, and greatly improve patient-centered health outcomes.
About our research
Each year ~49 million people globally are diagnosed with severe infections (sepsis), which causes brain injury in ~70% of patients and kidney injury in ~50% of patients. Each year ~2 million people worldwide undergo heart surgery requiring the use of a heart-lung machine (cardiopulmonary bypass), which causes brain injury in ~50% of patients and kidney injury in ~30% of patients. Our research program aims to offer solutions to these major unresolved health complications.
In partnership with clinicians who routinely care for patients, we have developed world-first clinically relevant large animal models, where brain and kidney health can be continually assessed before, during and after sepsis or cardiopulmonary bypass.
Our vision is to deconstruct the pathological changes occurring in the brain and kidneys during sepsis and heart surgery, and then validate the safety and efficacy of novel mechanism-guided diagnostics and therapies for future clinical use. This would represent a true breakthrough in our ability to avoid brain and kidney injury arising from heart surgery and sepsis, and greatly improve patient-centered health outcomes.
Significance: Our research program aims to provide the scientific rationale for designing mechanism-guided clinical trials to reduce the incidence of acute brain and kidney injury arising in patients diagnosed with sepsis and in those undergoing heart surgery requiring cardiopulmonary bypass. The absence of appropriate animal models has thus far hindered our ability to understand the pathophysiology of sepsis- and cardiopulmonary bypass-induced brain and kidney injury. In partnership with clinicians that routinely care for patients, we have established world-first large animal models of sepsis and cardiopulmonary bypass, along with pioneered surgical techniques for continuously assessing the pathophysiology of brain and kidney injury. This places us at the vanguard to develop novel targeted diagnostics and therapies to avoid these life-threatening brain and kidney-related health complications.
- Cardiopulmonary bypass
- Heart failure
- Acute brain injury (i.e., delirium, cognitive dysfunction)
- Acute kidney injury
We propose that hypotension (i.e., low blood pressure) and tissue hypoxia (i.e., reduced oxygen levels) are critical drivers of sepsis-induced brain and kidney injury. We have strong evidence that mega-doses of a pH-balanced formulation of vitamin C, sodium ascorbate, can improve blood pressure control and reverse brain and kidney tissue hypoxia in sepsis.
Outcomes: This research program will focus on performing minimum therapeutic dose finding studies to determine the optimal dosing regimen of sodium ascorbate and elucidate its mechanisms-of-action on the brain, kidney, and blood vessels. In this research program, we will also validate new reliable biomarkers to detect the risk of sepsis-induced acute brain and kidney injury transitioning to dementia and chronic kidney disease.
We propose that inflammation and tissue hypoperfusion (i.e., reduced blood perfusion) in the brain and kidneys during cardiopulmonary bypass are critical drivers of heart surgery-associated brain and kidney injury. Preexisting heart disease (heart failure) is common in patients undergoing cardiopulmonary bypass that further increases their likelihood of developing brain and kidney-related complications after surgery. We have strong evidence intracellular zinc plays a critical role in reducing inflammation and in mediating vasodilation of blood vessels.
Outcomes: We will examine novel compounds, capable of delivering intracellular zinc, to reduce inflammation and hypoperfusion in the brain and kidneys during and after cardiopulmonary bypass in the presence and absence of preexisting heart failure. Within this research program, we will also validate new reliable biomarkers to detect the risk of cardiopulmonary bypass-induced acute brain and kidney injury transitioning to dementia and chronic kidney disease.
- Surgical techniques to implant probes, electrodes, and catheters to assess brain, heart, and kidney health.
- Implementation of the heart-lung machine (i.e., cardiopulmonary bypass).
- Wire myography for in vitro functional studies in blood vessels isolated from the brain and kidneys.
- Assay techniques for validating new biomarkers of brain, heart and kidney injury.
- Western blot analysis for elucidating molecular mechanisms in brain and kidney tissue.
- Immunohistochemistry to assess neuroinflammation in brain tissue.
- Implementation of renal replacement therapy (i.e., a form of dialysis routinely used in intensive care units)
‘Our research group vision is to: (1) understand pathogenesis of brain and kidney injury arising from sepsis and heart surgery in pursuit of targeted therapies, (2) trial candidate disease modifying drugs to mitigate brain- and kidney-related complications, and (3) build an enduring collaboration between scientists and clinicians to enact long-term transformative health changes for patients.’
- Dr Taku Furukawa
- Alemayehu Jufar
- Rachel Peiris
- Anton Trask-Marino
- Victoria Stock
- Mahek Shah
- Lier Deng
- Lankadeva, YR, Peiris, RM, Okazaki, N, Birchall, IE, Trask-Marino, A, Dornom, A, Vale, TAM, Evans, RG, Yanase, F, Bellomo, R & May, CN 2020, ‘Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C’, Critical Care Medicine, vol. 49, no. 2, pp. e179–e190.
- Lankadeva, Y.R., Cochrane, A.D., Marino, B., Iguchi, N., Hood, S.G., Bellomo, R., May, C.N. and Evans, R.G. (2019). Strategies that improve renal medullary oxygenation during experimental cardiopulmonary bypass may mitigate postoperative acute kidney injury. Kidney International, 95(6), pp.1338–1346. doi:https://doi.org/10.1016/j.kint.2019.01.032.
- Lankadeva, Y.R., Kosaka, J., Evans, R.G., Bellomo, R. and May, C.N. (2018). Urinary Oxygenation as a Surrogate Measure of Medullary Oxygenation During Angiotensin II Therapy in Septic Acute Kidney Injury. Critical Care Medicine, 46(1), pp.e41–e48. doi:https://doi.org/10.1097/ccm.0000000000002797.
- Khalid Elsaafien, Sloan, J.M., Evans, R.G., Cochrane, A.D., Marino, B., McCall, P.R., Hood, S.G., Yao, S.T., Korim, W.S., Bailey, S.R., Alemayehu Hailu Jufar, Peiris, R.M., Bellomo, R., Miles, L.F., May, C.N. and Lankadeva, Y.R. (2023). Associations Between Systemic and Cerebral Inflammation in an Ovine Model of Cardiopulmonary Bypass. Anesthesia & Analgesia, 136(4), pp.802–813. doi:https://doi.org/10.1213/ane.0000000000006379.
- Alemayehu Hailu Jufar, Evans, R.G., May, C.N., Hood, S.G., Betrie, A.H., Trask-Marino, A., Bellomo, R. and Lankadeva, Y.R. (2023). The effects of recruitment of renal functional reserve on renal cortical and medullary oxygenation in non‐anesthetized sheep. Acta Physiologica, 237(4). doi:https://doi.org/10.1111/apha.13919.