Mechanisms of acute kidney injury due to mechanical ventilation - Mechanical ventilation (MV) is a lifesaving treatment in the critically ill. However, MV also increases the risk of acute kidney injury (AKI) 3-fold, independent of concurrent illnesses. The mortality associated with AKI during MV is unacceptably high at over 50%, and treatment options are limited. The overall goal of this proposal is to fill current gaps in knowledge of the mechanisms involved in AKI due to MV to identify novel pathways that may be targets for future therapies. Pre-clinical models have demonstrated that MV leads to an instantaneous decrease in glomerular filtration rate (GFR) and an increase in sodium retention. However, the exact mechanisms that contribute to these alterations in kidney function have not been well described. For example, we do not know the physical changes in glomerular function that lead to decreased GFR, or the alterations in tubule function 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, a multi-disciplinary team of pulmonary and nephrology physician-scientists will conduct the first thorough renal micropuncture assessment of glomerular and tubule function during MV to identify the physiological changes that contribute to AKI. The first aim will identify the physical determinants of decreased GFR during MV with and without lung injury induced by surfactant depletion. Renal nerve ligation will be used to determine the mechanistic role of renal nerve stimulation as a target for future translational therapies. In the second aim, the investigative team will evaluate the changes in sodium and electrolyte transport across the nephron segments that contribute to sodium retention and volume overload during MV. Importantly, volume overload is associated with high morbidity and mortality in patients treated with MV, and we hypothesize that volume overload is in part driven by increased proximal tubule reabsorption of sodium via increased Na+/H+ exchanger 3 (NHE3) activity. Thus, we will compare the effects of NHE3 inhibition to standard treatments with volume expansion and loop diuretics on sodium reabsorption and volume overload during MV. Finally, the relationship between functional changes in glomerular and tubule function during MV and structural AKI remain unclear. Structural AKI often occurs in the setting of low oxygen delivery relative to oxygen consumption, and our pilot data suggest that increased oxygen consumption/GFR contributes to mitochondrial injury and AKI. In the third aim, we will determine the effects of MV on kidney oxygenation, mitochondrial structure and function, and structural AKI, including the effects of renal denervation, volume expansion, loop diuretics, and NHE3 inhibition. Successful completion of these aims will provide a rationale for translational studies investigating therapies targeting intrarenal hemodynamics and kidney tubule function and metabolism to prevent AKI during MV.
