Physiologic and Molecular Mechanisms of Ventilator Induced Kidney Injury

Va San Diego Healthcare System, San Diego CA

Investigators

Abstract

Mechanical ventilation is the most utilized form of life support in Veterans suffering from critical illnesses. While mechanical ventilation may be lifesaving, it is also associated with an increased risk of acute kidney injury (AKI). Concurrent illnesses, such as sepsis and shock, contribute to AKI in the critically ill, but recent data suggest that mechanical ventilation itself is an independent risk factor. The mortality associated with AKI during mechanical ventilation is unacceptably high at over 50%, and preventative treatment options are limited. The overall goal of this proposal is to fill current gaps in our knowledge of the mechanisms involved in AKI due to mechanical ventilation and identify novel pathways that may be modifiable. Pre-clinical models have demonstrated that mechanical ventilation is associated with an instantaneous decrease in glomerular filtration rate (GFR) and an increase in sodium retention. Lack of understanding of the mechanisms involved in these physiological changes have precluded the development of novel treatments that could be used to mitigate the exact alterations in kidney function that lead to AKI. For example, we do not know the physical changes in glomerular function that lead to decreased GFR, or the alterations in tubule function across the nephron segments that contribute to a decrease in natriuresis. Understanding the mechanisms of these functional changes in kidney physiology and how they relate to the development of structural kidney injury (i.e., cell injury and death) is imperative to the development of novel treatments that may be lifesaving. In this proposal, we combine renal micropuncture, a gold standard method for evaluating kidney physiology in real-time, with a flexiVent rodent ventilator (SCIREQ) to perform the first thorough assessment of glomerular and tubule function during mechanical ventilation. We will use this model to identify the alterations in kidney function that contribute to AKI and test the hypothesis that increased proximal tubule transport work relative to renal blood flow leads to hypoxia, mitochondrial dysfunction, and AKI via mitochondrial DNA (mtDNA)-mediated inflammation. We have assembled a multidisciplinary team of investigators at the VA San Diego Healthcare System with combined expertise in clinical care of critical illnesses and AKI, in addition to scientific expertise in kidney physiology, molecular mechanisms of AKI and lung injury, and mitochondrial biology to complete the aims proposed. The first aim will define the physical determinants of decreased GFR and the apportioning of electrolyte reabsorption along the nephron segments in rats treated with standard ventilator settings utilized in the critically ill. We will also determine the association between observed physiological changes and markers of mitochondrial injury and structural AKI. Renal nerve ligation and renin angiotensin system inhibition will be used to determine the mechanistic role of these respective pathways. The second aim will test the glucagon like peptide-1 agonist, exenatide, as a novel treatment to counteract the physiological changes that occur during mechanical ventilation and prevent AKI. Finally, systemic inflammatory mediators released during ventilator induced lung injury have been shown to contribute to AKI in pre-clinical models, but the exact mediators involved are unknown. Importantly, many patients still develop ventilator induced lung injury despite lung protective ventilation with low tidal volumes. In our third aim, we will stimulate ventilator induced lung injury via high tidal volume ventilation to determine the physiological impact on the kidney and define the role of mtDNA as a novel mediator of AKI due to ventilator induced lung injury that may be modifiable. All the aims proposed will combine micropuncture with assessments of renal blood flow and oxygenation, mitochondrial structure and function, AKI biomarkers, histology, and key mtDNA inflammatory pathways. Successful completion of these aims will provide a rationale for translational studies investigating novel pharmacologic therapies targeting intrarenal hemodynamics and tubule function, kidney metabolism, and mtDNA to prevent AKI in critically ill Veterans who require mechanical ventilation.