Mechanical Ventilation and Lung–Kidney Interactions

It was not so long ago that the term “pulmonary-renal syndrome” was synonymous with the combination of immune alveolar hemorrhage and rapidly progressive glomerulonephritis caused by rare conditions such as Goodpasture's disease and Wegener's granulomatosis. Recent elucidation of the pathobiology of critical illness has led to a more basic mechanistic understanding of the complex interplay between injured organs in patients with multiple organ dysfunction syndrome; this has been aptly called the “slippery slope of critical illness” (1). Distant organ effects of apparently isolated injuries to the lungs, gut, and kidneys have all been discovered in recent years. In this article, we review the harmful bidirectional interaction between acute lung injury (ALI) and acute kidney injury (AKI), which appears to be a common clinical syndrome with routine clinical implications, rather than a rare autoimmune catastrophe. We will review the current understanding of lung–kidney interactions from both perspectives, including the renal effects of ALI and mechanical ventilation, the pulmonary sequelae of AKI, and the emerging evidence of deleterious bidirectional organ cross-talk between lung and kidney. Renal Effects of ALI and Mechanical Ventilation AKI is an independent predictor of mortality in intensive care unit (ICU) patients (2). Unfortunately, AKI often develops as a component of multiorgan system dysfunction in critically ill patients and may lead to mortality rates in excess of 60%, depending on the setting (2–5). Severe AKI in critically ill patients is typically part of a triad with shock and respiratory failure requiring positive pressure mechanical ventilation (6). The physiologic impact of positive pressure ventilation (PPV) and its effects on renal perfusion and function are well documented (7). Recent advances in critical care, including the implementation of lung-protective ventilatory strategies, have disclosed the role of inflammatory mediators of ALI and specifically ventilator-induced lung injury in the pathogenesis of AKI. Effects of Mechanical Ventilation and ALI on Renal Function Hemodynamic Effects of PPV In 1947, PPV was first shown to effect renal function and perfusion (7). Since this first study involving healthy individuals receiving continuous positive airway pressure, a variety of mechanisms have been shown to alter cardiac output and result in changes of renal perfusion and function (8). While a variety of animal and human studies have produced equivocal results, there are thought to be two main components contributing to the decrease in renal perfusion and function caused by PPV, broadly categorized as hemodynamic and neurohormonal (9–12). Increased intrathoracic pressure associated with PPV decreases the venous return to the heart (preload) and may result in decreased cardiac output (10). This may lead to hypotension and fluid-responsive shock, which is common in the initial postintubation period when PPV is initiated. The increase in intrathoracic pressure has been shown to correlate with a decrease in renal plasma flow, glomerular filtration rate (GFR) and urine output during PPV (9). This aspect of renal hemodynamics has in part been validated by the canine work performed by Qvist et al., who showed that a stable cardiac output in the setting of PPV is not associated with a decrease in GFR or urine output (13). There are other, clinically occult adverse hemodynamic effects of PPV in the pulmonary, systemic, and renal circulations. PPV has been shown to compress the mediastinal structures and pulmonary vasculature and may result in increased right ventricular afterload. This may result in a decreased cardiac output and a decline in renal perfusion independent of effects on venous return. Similarly, PPV in patients with increased intrathoracic pressure (injured, stiff lungs or chest wall) or intra-abdominal pressure (morbid obesity, abdominal compartment syndrome) may act to decrease renal blood flow by increasing renal venous pressure (which diminishes renal perfusion pressure) and by compressing the renal vasculature leading to AKI (14–16). However, because effects on cardiac output and renal perfusion are insufficient to fully explain the mechanism of PPV-induced oliguria and renal dysfunction, other mechanisms have been proposed. Neurohormonal Effects of PPV PPV has been shown to alter a variety of neurohormonal systems, including sympathetic outflow, the renin-angiotensin axis, nonosmotic vasopressin (antidiuretic hormone [ADH]) release and atrial natriuretic peptide (ANP) production. The end result of all of these neurohormonal pathways is diminished renal blood flow, decreased GFR, and fluid retention (salt and water) with oliguria. Despite conflicting data, there is some evidence that fluid retention is caused by PPV-induced production of vasoactive substances. These mediators shift intrarenal blood flow from the cortex to the medulla, resulting in greater fluid retention at any level of renal perfusion (10,17,18). ADH release in the setting of PPV is likely multifactorial. While some evidence suggests that decreased atrial stretch due to the absolute or relative intravascular volume depletion associated with mechanical ventilation plays a role in the increased ADH secretion (19), it is clear that there are more factors at play (20). Several experimental denervation procedures (cervical, carotid sinus) in animals have blunted the ADH response, but none has been able to abolish it (20,21). Taken together with evidence that an increase in urine osmolarity is not commonly found as a direct effect of PPV, this suggests that ADH release is not the primary mechanism responsible for the decrease in urine output during PPV. It should come as no surprise that the renin-angiotensin-aldosterone axis is affected by PPV. PPV has been shown to increase renin activity in both animal models and humans (9,21,22). Animal denervation studies have shown that increased sympathetic flow indirectly leads to the increase in renin activity (20). Thus, PPV leads to increased sympathetic tone, secondary activation of the renin-angiotensin axis, and decreased renal plasma flow, GFR, and urine output. Of course, downstream stimulation of aldosterone production is among the salt-retaining effects of PPV. The limited studies investigating catecholamine levels and PPV have not provided a clear correlation between mechanical ventilation and hormone concentrations (23). Suppression of ANP release has been proposed as a source of the decreased urine volume and sodium content associated with PPV. Using a canine model, Ramamoorthy et al. showed that plasma ANP levels correlated with right atrial filling pressures and decreased with the initiation of PPV (P < 0.05) (24). While some animal and human studies have supported these data, other human studies have refuted it (22,25). Of course, even if ANP suppression does play a role in causing PPV-induced sodium retention and oliguria, it may not explain the reported decrease in GFR caused by PPV. There are no definitive therapeutic trials for the treatment of PPV- and positive end expiratory pressure (PEEP)-induced renal hypoperfusion and AKI. Several small trials have shown that fluid administration and the use of vasoactive drugs (dopamine at 5 μg/kg per min or fenoldopam) may improve renal function (24,26,27), but results are not consistently positive (for example, no benefit of dopamine at 2 μg/kg per min) (28). It is unlikely that approaches focused solely on the hemodynamic and neurohormonal mechanisms of ALI-induced AKI will be clinically effective in preventing or treating this multifactorial problem, and the development of optimal interventional strategies will require more research into the molecular and cellular mechanisms involved (29). Inflammatory Mediators and Ventilator-induced Lung and Kidney Injury ALI is the syndrome of respiratory distress characterized by acute onset, severe hypoxemia, and bilateral radiographic infiltrates in the absence of left atrial hypertension (30). Acute respiratory distress syndrome (ARDS) is the most severe form of ALI, an inflammatory condition characterized by injury to the pulmonary endothelium and epithelium (31). Mounting evidence points to the role of cytokines and chemokines in the pathogenesis of ARDS (30,32,33). Emerging data further suggest that the pro-inflammatory effects of PPV may be a source of AKI, especially in the setting of mechanical ventilation and lung-injurious ventilator strategies (higher tidal volumes and lower PEEP) (34–37). Douillet et al. showed that mechanical ventilation itself can alter the nucleotide and purinoceptor expression in the kidney (38). They used a 4-way rodent model (altering tidal volume and PEEP, as well as the use of a placebo) to show that expression of these stress-responsive molecules is altered even in the presence of lung protective mechanical ventilation strategies (38). Since these extracellular ligands, which help control vascular tone and epithelial/endothelial permeability, are altered by ventilatory strategy, others have looked at the cellular and molecular effects of similar measures. Imai et al. used a rabbit model of ALI (acid aspiration) with both injurious and noninjurious ventilator strategies and variable oxygen and carbon dioxide levels to demonstrate that injurious ventilator strategies precipitate AKI (34). They demonstrated that injurious mechanical ventilation strategies induced production of a variety of inflammatory cytokines (IL-8 and monocyte-chemotactic protein-1, among others). They further demonstrated that this injurious strategy induced epithelial cell apoptosis in both the kidneys and intestines, providing concrete evidence of distant organ cross-talk initiated by ALI. They then showed that plasma from the injurious strategy rabbits induced apoptosis when it was incubated with fresh, healthy rabbit proximal tubular cells (34). Similarly, limited human studies suggest that ALI and PPV play a major role in AKI development. In the ARDS Network tidal volume trial, the low tidal volume group had improved survival and ventilator-free days, along with more days without circulatory, coagulation and renal failure (renal: 20 ± 11 versus 18 ± 11 d, P = 0.005) (37). Furthermore, Ranieri et al. showed in a randomized controlled trial of 44 patients with ARDS that a lung protective mechanical ventilation strategy (lower tidal volumes and higher PEEP) induced a lesser systemic and intrapulmonary inflammatory response (as measured by serum and bronchoalveolar lavage fluid levels of TNF-α, IL-6, and IL-8) than standard of care ventilation (35). Additionally, they were able to show that this same lung protective strategy led to fewer patients with organ system failure, with a greater decrease in the incidence of renal failure (P < 0.04) than any other organ dysfunction (36). The precise pathways and mediators responsible for ventilator-induced injury to the kidneys and other organs have not been elucidated. In to a variety of inflammatory the has been in this a have been shown to systemic and renal effects has been shown to play in a variety of cellular including vascular and epithelial and apoptosis It is well documented that of leads to systemic blood pressure and renal Using a rodent model of ventilator-induced lung et al. showed that PPV with injurious tidal volumes induced expression in both the lung and the kidney. the same an increase in systemic was in both This response was blunted when the animals PPV were fluid and the in renal function was the In to changes in and its they showed that serum vascular levels were increased in animals receiving the lung-injurious it is that vascular extracellular and 2 and vascular Thus, it appears that increased vascular and associated release are to the development of AKI in the setting of PPV. In the decreased and mortality of patients with ALI with lung-protective strategies for mechanical ventilation are not by of ventilator-induced lung injury and but by diminished and injury to distant including the Effects of is a commonly mechanical ventilation in which tidal volumes and alveolar ventilation are to decrease ventilator-induced lung injury treating ALI. it has been that the effects of this lung-protective ventilatory strategy are the result of decreased lower pressure, and mechanical to injured emerging data suggest an independent lung-protective effect of there are no to the to mechanical ventilation in patients with use the that was in the ARDS Network trial of lower tidal volume ventilation (37). This use of a tidal volume of of and to airway pressure requiring as to ventilator-induced lung the use of this in clinical and in ARDS Network the to and associated an of clinical and and other commonly with such is and should with or renal The ARDS Network low tidal volume trial and approaches to the of and as with an of decrease ventilator if of < ventilator rate to a of or or < ventilator rate = or < then may be of severe < ventilator rate to ventilator rate = and < and has been or then tidal volume may be increased by these pressure may be Unfortunately, of the and to which these were in this trial have not been While the data not an of any impact of the use and of on we can from the that severe was not commonly The for receiving low tidal volumes were ± ± ± for the tidal volume group were ± ± the the of the d, there was not an to use during the of this the to used in this trial and was associated with improved We suggest that this should be used in clinical further research in this Of course, this is for patients with ALI, not with of pulmonary such as pulmonary such patients have respiratory with should be used to plasma at level to from mechanical ventilation when acute respiratory failure has has a variety of some others In both animal models and human has been shown to have hemodynamic effects that are well and In both canine and human these effects have a decrease in systemic vascular and increased cardiac output a decrease in cardiac these are not in all studies human study the effects of for et al. the use of a that does not for this In this human they found that cardiac and pressure pulmonary vascular which is harmful in patients with right ventricular dysfunction, including with pulmonary hypertension caused by ARDS pulmonary may have effects on and result in increased intrapulmonary with in ARDS the other a shift of the and oxygen in Thus, may or in critically ill it is well and should be for patients with severe should be in the use of in patients with pulmonary hypertension and right heart failure, in associated pulmonary may have adverse hemodynamic it be that the use of is in patients with pressure because of associated and increased are the effects of Recent of the ARDS Network tidal volume study an benefit from independent of the of ventilation and airway pressures et al. showed that the for mortality rate associated with as < and a was P = for receiving tidal volumes the injurious ventilation for of lung injury and who the lung protective strategy had an of (P = not that was not of benefit in with lung-protective tidal The decrease in mortality for with respiratory in the tidal volume of the trial is with other emerging data an independent protective effect of in the setting of ALI and in experimental injury and shock Several studies have shown that experimental ALI and ventilator-induced lung injury Similarly, in isolated animal has been shown to have a protective effect injury of not the same level of from injury as respiratory The protective effect of may result from the of to a in cellular oxygen or effects can decrease the rate of of to and decrease the release of cytokines (IL-8 and that are in the pathogenesis of ALI and AKI Similarly, and associated decrease the release of other cytokines and by of In a variety of may the of ALI, associated lung and organ cross-talk between the injured lung and other leading to a protective effect the development of AKI. Of course, these experimental data deleterious effects of the common of sodium or renal to for respiratory in patients with ALI. However, there is no clinical of the protective effects of in ALI patients with low tidal so the current to of these complex patients to when severe We suggest that the for used in the ARDS Network low tidal volume trial is an Effects of AKI on Function AKI in the setting is associated with ALI and more specifically and the mortality rate of this group is Despite this mortality and the clear clinical studies have the role of the kidney in the pathogenesis and development of ALI. There are both experimental animal data and limited human study results that effects of AKI and the use of renal on pulmonary including the development of ALI as a of AKI, and the effects of on the and of patients with ALI with renal Effects of AKI of the effects of AKI are to and but experimental data are the effects of AKI on distant organ function It is that such as pulmonary or such as are to AKI when they in the may have or may be occult of other and dysfunction with and In to the emerging data that to an independent role of AKI in increasing mortality in the it is clinically that AKI is a of and It is clear that the inflammatory response and that in the setting of AKI play a role in the development of ALI. et al. have the mechanisms of the of AKI and ALI. They in a 4-way rodent model bilateral bilateral and that AKI leads to in pulmonary expression bilateral AKI the pulmonary expression of all of the epithelial sodium and It should be that injury not lead to of the pulmonary expression of these in to bilateral renal or Thus, the increase of lung is likely by a systemic effect of AKI, rather than the effect of the of renal injury a variety of animal models have shown that pulmonary expression of these and play in the and and of alveolar and of these mechanisms may result in the development of ARDS in humans In et al. used a similar experimental renal bilateral renal and bilateral and demonstrated that AKI leads to altered pulmonary expression to the they showed that bilateral injury and bilateral were associated with with injury and in serum levels IL-6, and Of there were other cytokines that increased in the setting of bilateral injury or bilateral but not with the same and Thus, both models for the acute absence of renal function similar but of Using a similar but not et al. demonstrated that the from lungs to AKI caused by or bilateral the bilateral model, et al. the they found with decreased the of the inflammatory induced by Similarly, a rodent model was used to show that the administration of hormone both kidney and lung In this the activation of kidney and lung factors and decreased the expression of response and lung It is thought that hormone by of the activation of factors and response This emerging data further of the use of and other as therapeutic for AKI. Emerging data to the of interaction in AKI. et al. in a rodent model that ALI is from ALI caused by experimental both the and models lead to increased pulmonary vascular and pulmonary with they were in that the AKI was associated with lower levels of pulmonary inflammatory cell and animal model had expression of a variety of Furthermore, pulmonary expression of a variety of cytokines and pro-inflammatory between animal models of lung that inflammatory were involved in the injury mechanisms the of distant organ injury resulting in ALI is not to renal as has been shown to alter systemic levels and inflammatory ALI a rodent model of a increase of systemic at by similar in lung The pulmonary associated with can be by the administration of This research is all the more when that has been shown to be an for AKI in patients with ARDS and cardiac Effects of and Renal on Function and ALI pulmonary and in patients with cardiac dysfunction, ALI, renal failure, or other of pulmonary studies have shown that a fluid in patients with ALI and pulmonary increased the of ventilator-free days It is thought to be that decreased pulmonary pressure and alveolar fluid leads to improved and lung data from a randomized controlled trial of found of mechanical ventilation and in patients with ALI with fluid to lung et al. found that and decreased pressures in the setting of ARDS They demonstrated that the use of a to fluid and improve is more effective with the use of this combination plasma levels and pressure more than the However, of these trials was = and to an effect on were they able to show a in ventilator-free The trial, which is in this of used a 2 2 to two trials in patients with ALI receiving low tidal volume mechanical The of these trials the effects of a fluid versus fluid the fluid strategy not improve the of ventilator was increased of this trial are by and in this but is should be that renal failure requiring was an in this trial, and the fluid and trial was if AKI the to the use of to control is by controlled trials However, the to use of to control fluid or respiratory respiratory is not by emerging experimental evidence suggests that respiratory may have protective effects in ALI, and with may be but such is commonly with continuous in patients with ALI and AKI Of course, with renal has effects with patients with AKI and ALI. from the effects of fluid in ALI, the use of or continuous to control fluid should have benefit in this However, there is a of clinical trial data to this trials of to patients with ALI have focused on approaches to rather than fluid with a or fluid has a therapeutic benefit in patients with ALI because of its to inflammatory and mediators of AKI from the In patients some therapeutic benefit from fluid resulting in decrease pulmonary vascular (lower cardiac filling if the even fluid positive fluid or fluid Several animal models and have reported in pulmonary these mechanisms The models used in these studies have but ALI ALI and experimental models of of these studies have documented both clinically as well as plasma levels of a variety of inflammatory including and Similarly, et al. in a controlled study of canine shock of that intensive continuous was able to the serum of and the hypotension (as measured by pressure) associated with human continuous have conflicting Several studies performed in the and had conflicting results and of patients with ALI receiving but some more recent trials have been et al. a interventional trial to the effects of on 20 patients with shock It should be that this trial of an initial period during which of was and and a fluid was the patients then on to of This study found that patients who a of clinical and venous oxygen cardiac the initial period were more likely to have improved should be used when these data as the study was it was in patients with shock, and of the study had ALI. recent studies investigating the role of specifically in ARDS have had results, in part because of study et al. of shock associated with ARDS They individuals who with individuals who They found that improved (as measured by pressure of oxygen in blood of oxygen (P < 0.05) and hemodynamic (as measured by pressure and (P < In the receiving the had (P < and improved survival versus P < 0.05) of these were supported by a study of with ARDS associated with In this trial, of the had AKI, but all continuous to a or fluid of the of with of the patients at the the other et al. a study of patients with AKI and ALI, all of continuous They found no benefit when hemodynamics pressure, venous mechanical ventilation or pressure of oxygen in pressure of carbon dioxide in from initiation with from the first Unfortunately, this study not optimal with blood flow rates at and flow at It is clear that trials are to the optimal to of in the treatment of patients with AKI and ALI It is that there is a between the AKI and ALI. evidence points to cross-talk between these two distant organs and that injury to organ may and injury to the Recent data show that the kidneys play an role in the production and of mediators of and ALI. to the inflammatory of ALI and associated ventilator-induced lung injury may precipitate the of AKI. While there have been recent advances in approaches to ventilator-induced lung injury and decrease the of mechanical ventilatory the effect of these advances on the incidence and of AKI in critically ill patients to be between and is to and improve of this “pulmonary-renal