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Pulmonary Consequences of Acute Kidney Injury

      Summary: Mortality rates among critically ill patients with acute kidney injury (AKI) requiring renal replacement therapy typically exceed 50%, rates that have not improved significantly despite ongoing advancements in renal replacement therapy. A growing body of animal and human data have accumulated over the past 2 decades that have shown that AKI is associated with a series of distant organ effects that may contribute to the persistently high mortality of AKI. In this review, we describe the pulmonary sequelae of AKI, focusing on mechanisms of pulmonary edema in the context of traditional complications of AKI (eg, volume overload, acidosis) and nontraditional complications of AKI (eg, systemic inflammation). We review the complexities of volume management in patients with kidney and lung injury and subsequently delve into the clinical and basic science data on the mediators of lung injury after AKI. With an in-depth understanding of how the traditional and nontraditional effects of AKI can combine to produce pulmonary complications, effective management and therapeutic strategies may be developed.

      Keywords

      Despite advances in renal replacement therapy (RRT), mortality in patients with acute kidney injury (AKI) remains unacceptably high. In modern cohorts, the in-hospital mortality rates of patients with AKI are reported to be 9% to 28% overall,
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      Hospital mortality in the united states following acute kidney injury.
      The in-hospital mortality rate associated with severe AKI is higher, increasing to 28% to 33% for AKI requiring RRT,
      • Waikar SS
      • Curhan GC
      • Wald R
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      • Chertow GM.
      Declining mortality in patients with acute renal failure, 1988 to 2002.
      • Xue JL
      • Daniels F
      • Star RA
      • et al.
      Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001.
      and even higher for AKI in the intensive care unit (ICU), usually exceeding 50% with or without RRT.
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      • Angus DC
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      • Pinsky MR
      • Johnson JP.
      Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes.
      • Rocha E
      • Soares M
      • Valente C
      • et al.
      Outcomes of critically ill patients with acute kidney injury and end-stage renal disease requiring renal replacement therapy: a case-control study.
      • Ostermann M
      • Chang R
      Riyadh ICU Program Users Group
      Renal failure in the intensive care unit: acute kidney injury compared to end-stage renal failure.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      • Chertow GM
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      • Cleary PD
      • Munro C
      • Lazarus JM.
      Prognostic stratification in critically ill patients with acute renal failure requiring dialysis.
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      Refining predictive models in critically ill patients with acute renal failure.
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      Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.
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      Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients.
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      VA/NIH Acute Renal Failure Trial Network
      Intensity of renal support in critically ill patients with acute kidney injury.
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      RENAL Replacement Therapy Study Investigators
      Intensity of continuous renal-replacement therapy in critically ill patients.
      Although outcomes in AKI remain poor, AKI and respiratory failure are an especially deadly combination. Respiratory failure is common in patients with AKI, with mechanical ventilation being needed in 70% to 85% of patients with AKI in the ICU,
      • Uchino S
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      • Morimatsu H
      • et al.
      Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (B.E.S.T. kidney) investigators.
      • Metnitz PG
      • Krenn CG
      • Steltzer H
      • et al.
      Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients.
      • Uchino S
      • Kellum JA
      • Bellomo R
      • et al.
      Acute renal failure in critically ill patients: a multinational, multicenter study.
      • Bagshaw SM
      • Wald R
      • Barton J
      • et al.
      Clinical factors associated with initiation of renal replacement therapy in critically ill patients with acute kidney injury-a prospective multicenter observational study.
      ,
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      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
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      Initiation strategies for renal-replacement therapy in the intensive care unit.
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      • Chertow GM
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      • et al.
      Model to predict mortality in critically ill adults with acute kidney injury.
      and the need for mechanical ventilation has been shown repeatedly to be an independent risk factor for mortality in patients with AKI.
      • Ostermann M
      • Chang R
      Riyadh ICU Program Users Group
      Renal failure in the intensive care unit: acute kidney injury compared to end-stage renal failure.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      • Chertow GM
      • Christiansen CL
      • Cleary PD
      • Munro C
      • Lazarus JM.
      Prognostic stratification in critically ill patients with acute renal failure requiring dialysis.
      • Mehta RL
      • Pascual MT
      • Gruta CG
      • Zhuang S
      • Chertow GM.
      Refining predictive models in critically ill patients with acute renal failure.
      • Lins RL
      • Elseviers MM
      • Daelemans R
      • et al.
      Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.
      • Uchino S
      • Bellomo R
      • Morimatsu H
      • et al.
      Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (B.E.S.T. kidney) investigators.
      • Metnitz PG
      • Krenn CG
      • Steltzer H
      • et al.
      Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients.
      • Uchino S
      • Kellum JA
      • Bellomo R
      • et al.
      Acute renal failure in critically ill patients: a multinational, multicenter study.
      ,
      • Demirjian S
      • Chertow GM
      • Zhang JH
      • et al.
      Model to predict mortality in critically ill adults with acute kidney injury.
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      • Keener C
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      Biomarker enhanced risk prediction for adverse outcomes in critically ill patients receiving RRT.
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      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
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      • Horwitz RI.
      The effect of acute renal failure on mortality. A cohort analysis.
      One study showed that respiratory failure was associated with a two-fold increase in mortality of patients with AKI, with the combination of AKI and respiratory failure carrying a worse prognosis than the combination of AKI and failure of any other organ system.
      • Chertow GM
      • Christiansen CL
      • Cleary PD
      • Munro C
      • Lazarus JM.
      Prognostic stratification in critically ill patients with acute renal failure requiring dialysis.
      In another study, a cohort analysis of more than a thousand patients with AKI requiring RRT from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network (ATN) study, hypoxemia at the initiation of RRT (defined as the need for a fraction of inspired oxygen of ≥60%) and mechanical ventilation were the two factors, of a total of 21 variables with predictive value, that most strongly predicted mortality.
      • Demirjian S
      • Chertow GM
      • Zhang JH
      • et al.
      Model to predict mortality in critically ill adults with acute kidney injury.
      AKI complicating pre-existing respiratory failure has been associated with a prolonged need for mechanical ventilation, longer duration of weaning, and longer ICU stay.
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      Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients.
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      • Wang JH.
      Acute kidney injury on ventilator initiation day independently predicts prolonged mechanical ventilation in intensive care unit patients.
      Finally, AKI has been shown in multiple studies to be a risk factor for increased mortality in patients with respiratory failure,
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      • Castro I
      • Curvello-Neto A
      • et al.
      Effect of acute kidney injury on weaning from mechanical ventilation in critically ill patients.
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      • Glidden DV
      • Eisner MD
      • et al.
      Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury.
      with one study of acute respiratory distress syndrome (ARDS) patients documenting that AKI is associated with a doubling of mortality compared with non-AKI patients.
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      • et al.
      Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury.
      The relationship between kidney injury and lung injury may be bidirectional because mechanical ventilation appears to be a risk factor for the development of AKI. A recent systematic review of 31 observational studies estimated that invasive ventilation is associated with a three-fold increased risk of AKI in ICU patients.
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      • Groeneveld AB.
      Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis.
      The risk may be mediated specifically by mechanical ventilation rather than respiratory dysfunction per se because the risk of AKI appears to be higher in mechanically ventilated rather than noninvasively ventilated patients.
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      • Groeneveld AB.
      Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis.
      Both the hemodynamic effects of mechanical ventilation on renal blood flow and the inflammatory effects of ventilator-induced barotrauma have been proposed as possible mediators of the increased risk of AKI.
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      Mechanical ventilation and acute renal failure.
      Some limited animal data support a possible role of inflammatory mediators in ventilator-induced AKI.
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      Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome.
      However, in the systematic review of invasive ventilation, non-ARDS patients were at equal or higher risk of AKI as ARDS patients, leading the investigators to conclude that hemodynamic effects may be more important than barotrauma for inducing AKI in human beings.
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      • Groeneveld AB.
      Invasive mechanical ventilation as a risk factor for acute kidney injury in the critically ill: a systematic review and meta-analysis.

      TRADITIONAL VERSUS NONTRADITIONAL COMPLICATIONS OF AKI

      As the link between AKI and pulmonary complications has emerged over the past several decades, so has the notion that AKI is a complex multisystem disorder resulting in a series of both traditional complications and nontraditional complications (Table 1).
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      • Shah PB.
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      This classification is useful when considering the potential mediators of and remedies for systemic complications of AKI, including respiratory complications of AKI (Table 2). The traditional complications of AKI include volume overload; electrolyte abnormalities such as hyperkalemia, metabolic acidosis, hyperphosphatemia, and hypocalcemia; and the clinical syndrome of uremia. These traditional complications of AKI all generally are correctable by RRT. However, AKI increasingly is recognized to result in multiple systemic derangements and a variety of nontraditional complications have been reported in human beings, animal models, or both, including increased susceptibility to sepsis,
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      • Viscoli CM
      • Horwitz RI.
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      • Mehta RL
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      • Soroko SB
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      Sepsis as a cause and consequence of acute kidney injury: Program to Improve Care in Acute Renal Disease.
      immune dysfunction,
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      • et al.
      Impaired monocyte cytokine production in critically ill patients with acute renal failure.
      and injury to or dysfunction of a variety of organs including the heart,
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      Distant effects of experimental renal ischemia/reperfusion injury.
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      • Tonnesen E
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      Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: a population-based cohort study.
      liver,
      • Kim M
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      • Kim M
      • D'Agati VD
      • Lee HT.
      Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction.
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      • et al.
      Paneth cell-mediated multiorgan dysfunction after acute kidney injury.
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      Prolonged acute kidney injury exacerbates lung inflammation at 7 days post-acute kidney injury.
      intestine,
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      • Lee HT.
      Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction.
      • Park SW
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      • et al.
      Paneth cell-mediated multiorgan dysfunction after acute kidney injury.
      and brain.
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      Acute kidney injury leads to inflammation and functional changes in the brain.
      It has been proposed that these multisystem nontraditional complications of AKI are responsible for its high mortality, which persists despite RRT.
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      • Viscoli CM
      • Horwitz RI.
      The effect of acute renal failure on mortality. A cohort analysis.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.
      Table 1Comparisons of the Traditional and Nontraditional Complications of AKI
      Traditional complications of AKINontraditional complications of AKI
      Recognized for >50 yearsNewly appreciated and studied in the past 20 years
      May contribute to increased mortality of AKIMay contribute greatly to AKI mortality
      Direct result of loss of renal functionTypically mediated by inflammatory distant organ cross-talk
      Complicate AKI and ESRDComplicate only AKI (not ESRD)
      Typically corrected by RRTNot corrected by RRT
      Include the following:Include the following:
       Fluid overload Respiratory complications/inflammatory lung injury
       Hyperkalemia Sepsis
       Acidosis Cardiac dysfunction or injury
       Hyperphosphatemia Intestinal injury
       Hypocalcemia Liver injury
       Uremia (eg, encephalopathy, pericarditis, platelet dysfunction) Immune dysfunction
      Adapted with permission from Faubel et al.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.
      Table 2Respiratory Complications of AKI
      Pulmonary edema
       Hydrostatic (ie, cardiogenic), from fluid overload and/or cardiac dysfunction
       Nonhydrostatic, from inflammatory endothelial injury and endothelial cell apoptosis
      Impaired lung fluid clearance
       Decreased lung epithelial sodium channels and lung aquaporins
      Respiratory failure requiring mechanical ventilation
       Increased incidence (70%-85% of critically ill patients with AKI)
       Prolonged duration and/or weaning
      Adapted with permission from Faubel et al.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.

      COMPARING AKI AND END-STAGE RENAL DISEASE: AKI IS NOT ACUTE END-STAGE RENAL DISEASE

      Although our ability to study the effects of AKI in human beings generally is limited to observational data, the specific effects of AKI, rather than a lack of renal function per se, can be gleaned from comparisons between acutely ill patients with AKI and those with end-stage renal disease (ESRD). ESRD patients are subjected to the same traditional consequences of renal failure as AKI patients including electrolyte abnormalities, fluid overload, and uremia. In contrast, only AKI patients are subject to the nontraditional systemic effects of AKI. As such, differences in outcomes between AKI and ESRD patients may be mediated by these nontraditional effects of kidney injury.
      Multiple studies have established that AKI in hospitalized patients carries a higher risk of mortality than ESRD.
      • Clermont G
      • Acker CG
      • Angus DC
      • Sirio CA
      • Pinsky MR
      • Johnson JP.
      Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes.
      • Rocha E
      • Soares M
      • Valente C
      • et al.
      Outcomes of critically ill patients with acute kidney injury and end-stage renal disease requiring renal replacement therapy: a case-control study.
      • Ostermann M
      • Chang R
      Riyadh ICU Program Users Group
      Renal failure in the intensive care unit: acute kidney injury compared to end-stage renal failure.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      For example, one study compared critically ill patients without renal failure, with ESRD, with AKI not requiring RRT, and with AKI requiring RRT, showing mortality rates of 5%, 11%, 23%, and 58%, respectively, despite similar illness severity (Acute Physiology And Chronic Health Evaluation [APACHE] III) scores in the ESRD and AKI patients.
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      • Acker CG
      • Angus DC
      • Sirio CA
      • Pinsky MR
      • Johnson JP.
      Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes.
      Another study showed that the increased mortality of AKI relative to ESRD occurred despite a significantly older age and rate of comorbid diabetes and hypertension in the ESRD cohort.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      Furthermore, three of these studies found that mechanical ventilation is needed in a higher percentage of AKI patients relative to ESRD patients, and in all three studies mechanical ventilation was found to be a risk factor for mortality.
      • Rocha E
      • Soares M
      • Valente C
      • et al.
      Outcomes of critically ill patients with acute kidney injury and end-stage renal disease requiring renal replacement therapy: a case-control study.
      • Ostermann M
      • Chang R
      Riyadh ICU Program Users Group
      Renal failure in the intensive care unit: acute kidney injury compared to end-stage renal failure.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      In one study, mechanical ventilation was the sole factor on multivariate analysis driving the increased mortality in AKI patients relative to ESRD patients.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      AKI was considered to contribute to respiratory failure via a combination of fluid overload, as shown by increased weight gain between ICU admission and continuous renal replacement therapy (CRRT) initiation, and increased inflammation, as evidenced by depressed serum albumin.
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      Significantly lower levels of serum albumin in AKI patients were observed,
      • Walcher A
      • Faubel S
      • Keniston A
      • Dennen P.
      In critically ill patients requiring CRRT, AKI is associated with increased respiratory failure and death versus ESRD.
      despite the fact that hypoalbuminemia is common and is associated with increased mortality and increased inflammation in ESRD patients.
      • Kaysen GA.
      Biological basis of hypoalbuminemia in ESRD.
      Thus, the poor outcomes of AKI versus ESRD patients with respiratory failure illustrate how nontraditional complications of AKI can combine with the traditional complications of AKI to produce harm.

      RESPIRATORY FAILURE AS A TRADITIONAL COMPLICATION OF AKI, A NONTRADITIONAL COMPLICATION OF AKI, OR BOTH?

      When considering pulmonary complications of AKI, the most important traditional complication of AKI is volume overload. Volume overload from any cause, including severe renal failure with preserved cardiac function, has the potential to cause hydrostatic (often referred to as cardiogenic) pulmonary edema. Volume overload resulting from AKI was linked long ago to respiratory failure from pulmonary edema.
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      Studies in the 1950s showed that some patients with pulmonary edema and renal failure improve with fluid removal alone.
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      However, it has long been suspected that volume overload does not explain all cases of pulmonary edema in patients with AKI. For example, two historical case series collectively reported nine patients with pulmonary edema in the setting of severe renal dysfunction but in the absence of increased pulmonary capillary wedge pressure, suggesting that increased pulmonary capillary permeability was responsible for the edema.
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      Human autopsy studies, including a large study comparing more than 100 patients with AKI with more than 400 non-AKI controls,
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      Uremic pneumonitis.
      have shown that pulmonary edema in patients with AKI is associated with leukocyte infiltration,
      • Hopps HC
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      proteinaceous edema fluid,
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      ,
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      hyaline membrane formation,
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      and diffuse alveolar damage,
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      leading some investigators in that era (the 1950s–1980s) to consider “uremic pneumonitis”
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      a cause of ARDS.
      Establishing the precise mechanisms of pulmonary edema in human beings with AKI is challenging because of the complexities of assessing volume status, the frequent presence of multiple insults, and uncertainty regarding the onset of AKI. In this regard, animal models of AKI have been particularly informative to characterize the nature of lung injury after AKI and elucidate potential mechanisms. Notably, over the past 2 to 3 decades a large body of data (discussed later) has accumulated showing that AKI can induce inflammatory lung injury and nonhydrostatic pulmonary edema. Similar to the historical human case series and autopsy data, the majority of animal models of AKI-induced acute lung injury (ALI) are characterized by higher wet/dry lung weight ratios,
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      Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion.
      along with inflammatory changes such as neutrophilic infiltration,
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      Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.
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      Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.
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      The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
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      increased circulating levels of inflammatory mediators,
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      Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.
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      The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
      ,
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      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      increased bronchoalveolar lavage (BAL) fluid protein content,
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      Uremic pneumonitis. Evidence for participation of proteolytic enzymes.
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      Functions of aquaporin 1 and alpha-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury.
      ,
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      • et al.
      Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.
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      • Douglas IS
      • Faubel S.
      Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.
      • Doi K
      • Ishizu T
      • Tsukamoto-Sumida M
      • et al.
      The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
      • Kim DJ
      • Park SH
      • Sheen MR
      • et al.
      Comparison of experimental lung injury from acute renal failure with injury due to sepsis.
      ,
      • Kramer AA
      • Postler G
      • Salhab KF
      • Mendez C
      • Carey LC
      • Rabb H.
      Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability.
      As a result, a modern approach to respiratory dysfunction in the setting of AKI has been proposed in which pulmonary edema is considered to exist on a spectrum between pure hydrostatic pulmonary edema, which can be corrected through volume removal by diuresis or ultrafiltration, and nonhydrostatic edema, for which volume removal is ineffective (Figs. 1 and 2).
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.
      In any given patient, a combination of hydrostatic and nonhydrostatic pulmonary edema may co-exist; in such a patient, volume removal will improve oxygenation and lung function to a degree, beyond which further volume removal may be detrimental by potentially leading to decreased renal perfusion, hypotension, and prolongation of AKI.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.
      Figure 1.
      Figure 1Pulmonary edema in AKI. (A) Spectrum of pulmonary edema in AKI. Hydrostatic pulmonary edema (traditionally termed cardiogenic edema) is caused by fluid overload and/or cardiac dysfunction, leading to increased pulmonary capillary hydrostatic pressure and transudative edema. Patients may improve quickly with fluid removal via ultrafiltration or diuresis. Nonhydrostatic (noncardiogenic) pulmonary edema is caused by injury to the capillary membrane, leading to increased capillary permeability and leak of proteinaceous edema fluid. Patients improve little or not at all with fluid removal via ultrafiltration or diuresis. Many patients likely fall in the spectrum between hydrostatic and nonhydrostatic pulmonary edema. (B) Hydrostatic pulmonary edema is characterized by bilateral infiltrates visible on chest radiography and is generally without histologic or biochemical evidence of inflammation. Accurate measurements of CVP or pulmonary artery occlusion pressure typically are increased. (C) Histologic image showing interstitial edema (arrows). (D) Nonhydrostatic pulmonary edema also is characterized by bilateral infiltrates visible on chest radiography, but with histologic or biochemical evidence of inflammation. Accurate measurements of CVP of pulmonary artery occlusion pressure typically are normal or low. (E) Normal lung histology. (F) The histologic image shows proteinaceous edema (thick arrow) and interstitial edema (thin arrows). (G) The magnified histologic image shows neutrophils in the interstitial space (thick arrow) and interstitial edema (thin arrow), findings typical of nonhydrostatic pulmonary edema. Adapted with permission from Faubel et al.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.
      Figure 2.
      Figure 2The effects of kidney injury and kidney failure on the lung. The effects of AKI on the lung can be conceptually divided into factors that are associated with kidney injury and factors that are associated with loss of kidney function. Kidney injury leads to a robust inflammatory response, in part owing to cell death, that is characterized by increased production and release of inflammatory mediators such as TNF, IL6, and IL8, which are known mediators of lung injury after AKI. Other possible factors that might be present in the circulation owing to kidney injury and cell death include a variety of damage-associated molecular proteins, such as histones and other proteins, DNA, RNA, and microparticles. Loss of kidney function (modeled by bilateral nephrectomy in animals) results in the accumulation of factors normally excreted and metabolized by the kidney that could affect lung function. Loss of kidney function can affect the lung if reduced fluid excretion occurs resulting in fluid retention, volume overload, and hydrostatic (cardiogenic) pulmonary edema. Certain electrolyte abnormalities also can contribute, including acidosis, which might lead to hydrostatic pulmonary edema by impairing cardiac output. The role of typical uremic toxins, such as those that accumulate in ESRD, remains to be determined. Finally, because the kidney contributes to cytokine elimination, known inflammatory mediators (eg, IL6) might accumulate to a greater extent in patients with kidney failure than in patients with normal kidney function. Abbreviations: GFR, glomerular filtration rate; SIRS, systemic inflammatory response syndrome. Adapted with permission from Faubel et al.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.

      TRADITIONAL VERSUS NONTRADITIONAL COMPLICATIONS OF AKI: COMPLEXITIES OF VOLUME OVERLOAD

      Although conceptually straightforward, the impact of volume resuscitation or volume removal in a given patient with AKI and respiratory failure remains a clinically problematic issue, far more complicated than the truism that dry lungs are happy lungs. There is a paucity of data informing clinicians on when to give fluid or when to stop giving fluid to patients with AKI.
      • Perner A
      • Prowle J
      • Joannidis M
      • Young P
      • Hjortrup PB
      • Pettila V.
      Fluid management in acute kidney injury.
      • Prowle JR
      • Kirwan CJ
      • Bellomo R.
      Fluid management for the prevention and attenuation of acute kidney injury.
      Although a full discussion of fluid management in the setting of AKI and respiratory failure is beyond the scope of this review, a few salient points can be made.
      First, appropriate volume resuscitation in the setting of AKI may be beneficial to both the kidneys and the lungs. For example, a study comparing differing amounts of fluid administration in the first 7 days after ischemic AKI in mice showed that mice that received adequate fluid resuscitation recovered from ischemic AKI sooner and this recovery was accompanied by more rapid resolution of lung inflammation; in contrast, under-resuscitated mice with ischemic AKI had a prolongation of both AKI and inflammatory lung injury.
      • Andres-Hernando A
      • Altmann C
      • Bhargava R
      • et al.
      Prolonged acute kidney injury exacerbates lung inflammation at 7 days post-acute kidney injury.
      However, despite these animal data and general consensus that, in many patients, adequate volume resuscitation is essential for the prevention of or for shortening the course of AKI, data supporting this notion are limited.
      • Perner A
      • Prowle J
      • Joannidis M
      • Young P
      • Hjortrup PB
      • Pettila V.
      Fluid management in acute kidney injury.
      • Prowle JR
      • Kirwan CJ
      • Bellomo R.
      Fluid management for the prevention and attenuation of acute kidney injury.
      In contrast, there is a large and increasing number of studies showing that volume overload in AKI is associated with poor outcomes, including an increased risk of death; although the observational nature of these studies subject the data to the risk of residual confounding, in all these studies fluid overload remained an independent predictor of mortality after adjustment for other covariates including severity of illness.
      • Bagshaw SM
      • Wald R
      • Barton J
      • et al.
      Clinical factors associated with initiation of renal replacement therapy in critically ill patients with acute kidney injury-a prospective multicenter observational study.
      • Payen D
      • de Pont AC
      • Sakr Y
      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
      ,
      • Bouchard J
      • Soroko SB
      • Chertow GM
      • et al.
      Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
      • Vaara ST
      • Korhonen AM
      • Kaukonen KM
      • et al.
      Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study.
      • Bellomo R
      • Cass A
      • et al.
      RENAL Replacement Therapy Study Investigators
      An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial.
      • Grams ME
      • Estrella MM
      • Coresh J
      • et al.
      Fluid balance, diuretic use, and mortality in acute kidney injury.
      More importantly, prevention of volume overload has been associated with a decreased duration of mechanical ventilation in settings ranging from adults with ARDS treated with diuretics
      • Wiedemann HP
      • Wheeler AP
      • Bernard GR
      • Thompson BT
      • Hayden D
      • et al.
      National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network1
      Comparison of two fluid-management strategies in acute lung injury.
      to infants started pre-emptively on peritoneal dialysis (PD) after congenital heart surgery.
      • Kwiatkowski DM
      • Menon S
      • Krawczeski CD
      • et al.
      Improved outcomes with peritoneal dialysis catheter placement after cardiopulmonary bypass in infants.
      • Sasser WC
      • Dabal RJ
      • Askenazi DJ
      • et al.
      Prophylactic peritoneal dialysis following cardiopulmonary bypass in children is associated with decreased inflammation and improved clinical outcomes.
      The former study, the Fluid and Catheter Treatment Trial (FACTT), showed, via randomization of 1,000 patients to one of two different fluid strategies, that maintaining an approximately net even fluid balance over 1 week (compared with an approximately net positive balance of 1 L/d in the control group) led to improved oxygenation and decreased severity of lung injury and shortened the duration of mechanical ventilation and ICU stay by more than 2 days each.
      • Wiedemann HP
      • Wheeler AP
      • Bernard GR
      • Thompson BT
      • Hayden D
      • et al.
      National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network1
      Comparison of two fluid-management strategies in acute lung injury.
      There were no differences in overall mortality or in the rates of shock, AKI, or other nonpulmonary organ failure, but there was a nonsignificant trend toward decreased need for RRT in the conservative management group compared with the control.
      • Wiedemann HP
      • Wheeler AP
      • Bernard GR
      • Thompson BT
      • Hayden D
      • et al.
      National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network1
      Comparison of two fluid-management strategies in acute lung injury.
      Less intuitively, similar benefits of fluid restriction recently were found in patients with sepsis rather than ARDS. One trial of 150 patients with septic shock showed a benefit from implementation, after an initial resuscitation period, of a restrictive fluid strategy, with a trend toward decreased mortality and a statistically significant decrease in AKI rates.
      • Hjortrup PB
      • Haase N
      • Bundgaard H
      • et al.
      Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial.
      In addition, a meta-analysis of 11 trials of adults and children with ARDS, sepsis, and/or systemic inflammatory response syndrome (including FACTT) had similar results, with a conservative or “de-resuscitation” strategy of fluid management resulting in reduced ICU length of stay and more ventilator-free days without a significant effect on mortality.
      • Silversides JA
      • Major E
      • Ferguson AJ
      • et al.
      Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis.
      Four recent, large, multicenter trials of protocolized resuscitation of patients, including three
      • Peake SL
      • Delaney A
      • Bailey M
      • Bellomo R
      • et al.
      ARISE Investigators; ANZICS Clinical Trials Group
      Goal-directed resuscitation for patients with early septic shock.
      • Pro CI
      • Yealy DM
      • Kellum JA
      • et al.
      A randomized trial of protocol-based care for early septic shock.
      • Mouncey PR
      • Osborn TM
      • Power GS
      • et al.
      Trial of early, goal-directed resuscitation for septic shock.
      of early septic shock treated with 6-hour protocols similar to the original early goal-directed therapy (GDT) of Rivers et al,
      • Rivers E
      • Nguyen B
      • Havstad S
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      and one using a cardiac output–guided hemodynamic algorithm after major surgery,
      • Pearse RM
      • Harrison DA
      • MacDonald N
      • et al.
      Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review.
      all failed to show improvement in either renal outcomes or mortality relative to usual care, emphasizing the need to carefully individualize fluid therapy to every patient rather than applying a blanket approach to all patients with a given diagnosis. However, of the trials that have shown benefit to protocolized fluid administration in the past 20 years, a few themes can be gleaned. First, the older trials showing improvement in renal or overall outcomes of GDT in adults or children with septic shock generally have resulted in increased fluids given early (ie, the first 6 hours), with differences in amounts of fluid administered largely equal in the intervention and usual care groups by 72 hours.
      • Rivers E
      • Nguyen B
      • Havstad S
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      • de Oliveira CF
      • de Oliveira DS
      • Gottschald AF
      • et al.
      ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation.
      Similarly, a review of 24 trials of postoperative GDT showed a significant reduction in rates of postoperative AKI, but the overall difference between the groups in fluid administered was ultimately quite modest, averaging less than an additional 600 mL.
      • Prowle JR
      • Chua HR
      • Bagshaw SM
      • Bellomo R.
      Clinical review: volume of fluid resuscitation and the incidence of acute kidney injury - a systematic review.
      Furthermore, the overall benefit of postoperative GDT was driven primarily by the trials in which fluid balance was near equal and/or inotropic support was used, rather than those trials that used significantly more fluid administration.
      • Prowle JR
      • Chua HR
      • Bagshaw SM
      • Bellomo R.
      Clinical review: volume of fluid resuscitation and the incidence of acute kidney injury - a systematic review.
      Finally, the interventions in nearly all the studies were limited to the first 24 postoperative hours or less.
      • Prowle JR
      • Chua HR
      • Bagshaw SM
      • Bellomo R.
      Clinical review: volume of fluid resuscitation and the incidence of acute kidney injury - a systematic review.
      Coupled with the more limited sepsis data, these findings suggest that fluid resuscitation to prevent AKI is most effective if given early and in a targeted manner to prevent excessive fluid administration and should be followed, outside the initial 24 hours of critical illness, by the maintenance of a net even fluid balance.
      • Perner A
      • Prowle J
      • Joannidis M
      • Young P
      • Hjortrup PB
      • Pettila V.
      Fluid management in acute kidney injury.
      • Prowle JR
      • Kirwan CJ
      • Bellomo R.
      Fluid management for the prevention and attenuation of acute kidney injury.
      With these data in mind, it is clear that accurate assessment of volume status in patients with AKI and respiratory failure, although often elusive, remains of pre-eminent importance because nephrologists frequently are faced with the dilemma of whether to administer volume or attempt, with diuresis or ultrafiltration, to remove volume.
      Unfortunately, traditional measures of volume status or fluid responsiveness in patients with hypotension and/or renal failure have been shown to have only marginal clinical utility. For example, central venous pressure (CVP), once the mainstay for guiding resuscitation in sepsis,
      • Rivers E
      • Nguyen B
      • Havstad S
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      has been shown to be a very poor determinant of fluid responsiveness, with one systematic review reporting an area under the receiver operating characteristic curve for CVP for predicting improvement in cardiac index with fluids as only 0.56 (ie, only slightly better than a coin flip).
      • Marik PE
      • Cavallazzi R.
      Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense.
      In fact, consistent with the poor overall outcomes associated with volume overload in AKI,
      • Bagshaw SM
      • Wald R
      • Barton J
      • et al.
      Clinical factors associated with initiation of renal replacement therapy in critically ill patients with acute kidney injury-a prospective multicenter observational study.
      • Payen D
      • de Pont AC
      • Sakr Y
      • et al.
      A positive fluid balance is associated with a worse outcome in patients with acute renal failure.
      ,
      • Bouchard J
      • Soroko SB
      • Chertow GM
      • et al.
      Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.
      • Vaara ST
      • Korhonen AM
      • Kaukonen KM
      • et al.
      Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study.
      • Bellomo R
      • Cass A
      • et al.
      RENAL Replacement Therapy Study Investigators
      An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial.
      • Grams ME
      • Estrella MM
      • Coresh J
      • et al.
      Fluid balance, diuretic use, and mortality in acute kidney injury.
      data continue to emerge that higher CVP in AKI is associated with worse renal and overall outcomes.
      • Legrand M
      • Dupuis C
      • Simon C
      • et al.
      Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study.
      • Van Biesen W
      • Yegenaga I
      • Vanholder R
      • et al.
      Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis.
      Specifically, multiple recent reports have correlated higher CVP with worsening AKI or higher AKI-related mortality in not only heart failure
      • Mullens W
      • Abrahams Z
      • Francis GS
      • et al.
      Importance of venous congestion for worsening of renal function in advanced decompensated heart failure.
      or ARDS,
      • Grams ME
      • Estrella MM
      • Coresh J
      • et al.
      Fluid balance, diuretic use, and mortality in acute kidney injury.
      as might be expected, but also in sepsis
      • Legrand M
      • Dupuis C
      • Simon C
      • et al.
      Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study.
      • Van Biesen W
      • Yegenaga I
      • Vanholder R
      • et al.
      Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis.
      and in ICU patients as a whole.
      • Chen KP
      • Cavender S
      • Lee J
      • et al.
      Peripheral edema, central venous pressure, and risk of AKI in critical illness.
      This effect has been attributed to the harmful effects of venous congestion and reduced renal blood flow and glomerular filtration rate resulting from increased renal subcapsular and interstitial pressure.
      • Prowle JR
      • Kirwan CJ
      • Bellomo R.
      Fluid management for the prevention and attenuation of acute kidney injury.
      • Chen KP
      • Cavender S
      • Lee J
      • et al.
      Peripheral edema, central venous pressure, and risk of AKI in critical illness.
      In sepsis, higher CVP, even within the target range of range of 8 to 12 mm Hg originally proposed by Rivers et al,
      • Rivers E
      • Nguyen B
      • Havstad S
      • et al.
      Early goal-directed therapy in the treatment of severe sepsis and septic shock.
      is associated independently with an increased risk of AKI.
      • Legrand M
      • Dupuis C
      • Simon C
      • et al.
      Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study.
      • Van Biesen W
      • Yegenaga I
      • Vanholder R
      • et al.
      Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis.
      Similarly, in a post hoc analysis of more than 300 patients in the FACTT trial who developed AKI in the context of ARDS, CVP was statistically higher (at approximately 13 versus 11 mm Hg) in those who died relative to survivors, and higher mean CVP was associated independently in a multivariate model with a higher risk of death.
      • Grams ME
      • Estrella MM
      • Coresh J
      • et al.
      Fluid balance, diuretic use, and mortality in acute kidney injury.
      Likewise, in a study of more than 4,500 medical, cardiac, and surgical ICU patients, progressively higher CVP at admission was associated with a progressively higher risk of AKI.
      • Chen KP
      • Cavender S
      • Lee J
      • et al.
      Peripheral edema, central venous pressure, and risk of AKI in critical illness.
      Together, these data suggest that increased CVP is associated with worse outcomes, and some have proposed that the primary utility of CVP is to identify patients with increased CVP at risk of harm from volume overload in whom further fluid administration may be harmful or fluid removal may be beneficial.
      • De Backer D
      • Vincent JL.
      Should we measure the central venous pressure to guide fluid management? Ten answers to 10 questions.
      However, this approach has not been prospectively tested in clinical trials.
      Even more basic assessments of fluid balance such as daily weight and charted fluid balance have significant limitations, with recent studies showing poor day-to-day correlation between each other in ICU patients in general
      • Schneider AG
      • Baldwin I
      • Freitag E
      • Glassford N
      • Bellomo R.
      Estimation of fluid status changes in critically ill patients: fluid balance chart or electronic bed weight?.
      or in patients specifically on CRRT,
      • Davies H
      • Leslie GD
      • Morgan D
      • Dobb GJ.
      A comparison of compliance in the estimation of body fluid status using daily fluid balance charting and body weight changes during continuous renal replacement therapy.
      even after correcting for insensible fluid losses.
      • Schneider AG
      • Baldwin I
      • Freitag E
      • Glassford N
      • Bellomo R.
      Estimation of fluid status changes in critically ill patients: fluid balance chart or electronic bed weight?.
      Considering that insensible losses are not accounted for routinely, reliance on charted fluid balance has the potential to induce significant hypovolemia even if RRT is used to maintain seemingly even fluid balance over a prolonged period.
      A variety of dynamic measures of fluid responsiveness, such as pulse pressure variation, passive leg raise, or ultrasonographic inferior vena cava collapsibility, have been developed and reported to be superior to static measures of fluid status in caring for ICU patients,
      • Marik PE
      • Monnet X
      • Teboul JL.
      Hemodynamic parameters to guide fluid therapy.
      • Schmidt GA.
      POINT: should acute fluid resuscitation be guided primarily by inferior vena cava ultrasound for patients in shock? Yes.
      although whether they are useful in guiding fluid therapy specifically in AKI is not as clear.
      Furthermore, these dynamic measures of fluid responsiveness have been primarily validated for deciding whether to give fluid, not whether to remove fluid, with only a few small studies specifically addressing fluid removal in AKI.
      • Monnet X
      • Cipriani F
      • Camous L
      • et al.
      The passive leg raising test to guide fluid removal in critically ill patients.
      • Guiotto G
      • Masarone M
      • Paladino F
      • et al.
      Inferior vena cava collapsibility to guide fluid removal in slow continuous ultrafiltration: a pilot study.
      • Huber W
      • Fuchs S
      • Minning A
      • et al.
      Transpulmonary thermodilution (TPTD) before, during and after sustained low efficiency dialysis (SLED). A prospective study on feasibility of TPTD and prediction of successful fluid removal.
      The first such study involved 39 hemodynamically stable ICU patients with renal failure, including 85% with AKI, in which the passive leg raise was shown to accurately predict subsequent intradialytic hypotension with attempted ultrafiltration with intermittent RRT.
      • Monnet X
      • Cipriani F
      • Camous L
      • et al.
      The passive leg raising test to guide fluid removal in critically ill patients.
      The second was a pilot study of 24 patients with decompensated CHF and diuretic resistance, in which inferior vena cava collapsibility similarly was shown to predict hypotension during attempted slow continuous ultrafiltration.
      • Guiotto G
      • Masarone M
      • Paladino F
      • et al.
      Inferior vena cava collapsibility to guide fluid removal in slow continuous ultrafiltration: a pilot study.
      More recently, a feasibility trial was performed in 32 ICU patients on the use of transpulmonary thermodilution to estimate cardiac index and related measures and found it moderately useful (with areas under the receiver operating characteristic curves of 0.65-0.75) to predict the ability to achieve ultrafiltration goal during sustained low-efficiency dialysis without a significant increase in vasopressor requirement.
      • Huber W
      • Fuchs S
      • Minning A
      • et al.
      Transpulmonary thermodilution (TPTD) before, during and after sustained low efficiency dialysis (SLED). A prospective study on feasibility of TPTD and prediction of successful fluid removal.
      None of these studies reported outcomes beyond short-term hypotension or tolerance of fluid removal. A variety of other technologies have been proposed to guide volume removal during dialysis of patients with AKI, but either have been found to be unhelpful, as with continuous blood volume monitoring,
      • Tonelli M
      • Astephen P
      • Andreou P
      • Beed S
      • Lundrigan P
      • Jindal K.
      Blood volume monitoring in intermittent hemodialysis for acute renal failure.
      are promising but as-of-yet unproven, as with the use of biomarkers to assess for recurrent or additional renal injury from excess volume removal,
      • Prowle JR
      • Kirwan CJ
      • Bellomo R.
      Fluid management for the prevention and attenuation of acute kidney injury.
      or, as in the case of bioimpedance or lung ultrasonography, have not yet been studied in AKI apart from prognostication or as adjunctive measures of impaired oxygenation.
      • Rhee H
      • Jang KS
      • Shin MJ
      • et al.
      Use of multifrequency bioimpedance analysis in male patients with acute kidney injury who are undergoing continuous veno-venous hemodiafiltration.
      • Ciumanghel A
      • Siriopol I
      • Blaj M
      • Siriopol D
      • Gavrilovici C
      • Covic A.
      B-lines score on lung ultrasound as a direct measure of respiratory dysfunction in ICU patients with acute kidney injury.
      A study of the use of bioimpedance with lung ultrasound to guide fluid removal with CRRT in AKI currently is underway (ClinicalTrials.gov identifier: NCT02384525). As it currently stands, no one method—dynamic or static, traditional or novel—for diagnosing fluid overload or any one strategy for determining when to start or stop removing fluid, whether by diuretics or ultrafiltration, has been proven superior to any other.
      • Rosner MH
      • Ostermann M
      • Murugan R
      • et al.
      Indications and management of mechanical fluid removal in critical illness.
      Thus, further study is needed to help determine which measures of fluid status are most useful to guide fluid removal and to correlate them with not only short-term risk of hypotension or tolerance of fluid removal, but more meaningful long-term outcomes such as renal recovery or overall survival.

      MECHANISMS OF INFLAMMATORY LUNG INJURY AFTER AKI: OVERVIEW

      The nontraditional effects of AKI on the lung appear to involve a complex inflammatory cascade, of which four components have been best studied, including increases in levels of circulating cytokines, most prominently interleukin 6 (IL6) and IL8, pulmonary endothelial cell apoptosis, renal necroinflammation, and T-lymphocyte recruitment and activity.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      These inflammatory processes have been shown most clearly in animal models to be important in bringing about the neutrophil recruitment, endothelial cell injury, and increased capillary permeability characteristic of inflammatory pulmonary edema (Fig. 3). Each is discussed separately in detail later.
      Figure 3.
      Figure 3Cascade of events leading from AKI to ALI. T cells are recruited to the lung and initiate caspase‑3–mediated apoptosis of lung endothelial cells, which results in increased lung capillary permeability and nonhydrostatic (noncardiogenic) pulmonary edema (1). TNF acts via TNFR1 on lung endothelial cells, resulting in endothelial cell apoptosis via caspase‑3 activation, which causes increased lung capillary permeability and nonhydrostatic pulmonary edema (2). TNF also activates nuclear factor-κB (NF-κB), which then increases both inflammation and apoptosis, leading to endothelial injury, increased lung capillary permeability, and nonhydrostatic pulmonary edema. AKI is associated with an increase in serum levels of proinflammatory cytokines such as IL6, IL8, and TNF, which is consistent with a systemic inflammatory response syndrome (SIRS) response (3). Proinflammatory cytokines are increased in AKI owing to their increased renal production, increased extrarenal production (eg, in the monocytes, liver, and spleen), decreased renal clearance, and decreased renal metabolism. Circulating IL6 binds to circulating soluble IL6R (sIL6R) and engages gp130 on endothelial cells, resulting in an increase in both lung production and serum levels of IL8. IL8 causes lung injury by facilitating neutrophil accumulation, which leads to endothelial injury, increased lung capillary permeability, and nonhydrostatic pulmonary edema. HMGB1 leads to TLR4 activation (4). The net effect is inflammation, neutrophil accumulation, endothelial injury, increased lung capillary permeability, and nonhydrostatic edema. Abbreviations: HMGB1, high mobility group box 1 protein; TLR4, toll-like receptor 4. Adapted with permission from Faubel et al.
      • Faubel S
      • Edelstein CL.
      Mechanisms and mediators of lung injury after acute kidney injury.

      MECHANISMS OF INFLAMMATORY LUNG INJURY AFTER AKI: CIRCULATING FACTORS

      AKI in human beings is associated with increased serum levels of IL6,
      • Himmelfarb J
      • Le P
      • Klenzak J
      • et al.
      Impaired monocyte cytokine production in critically ill patients with acute renal failure.
      ,
      • Liu KD
      • Altmann C
      • Smits G
      • et al.
      Serum interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study.
      • Simmons EM
      • Himmelfarb J
      • Sezer MT
      • et al.
      Plasma cytokine levels predict mortality in patients with acute renal failure.
      • Chawla LS
      • Seneff MG
      • Nelson DR
      • et al.
      Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis.
      IL8,
      • Zarbock A
      • Kellum JA
      • Schmidt C
      • et al.
      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
      • Pike F
      • Murugan R
      • Keener C
      • et al.
      Biomarker enhanced risk prediction for adverse outcomes in critically ill patients receiving RRT.
      ,
      • Liu KD
      • Altmann C
      • Smits G
      • et al.
      Serum interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study.
      • Murugan R
      • Wen X
      • Shah N
      • et al.
      Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy.
      and tumor necrosis factor (TNF).
      • Simmons EM
      • Himmelfarb J
      • Sezer MT
      • et al.
      Plasma cytokine levels predict mortality in patients with acute renal failure.
      Increased serum levels of IL6 and IL8 after cardiac surgery in children can be detected as soon as 2 hours after surgery, well before AKI is appreciated by an increase in serum creatinine concentration; furthermore, these early increases in serum IL6 and IL8 are associated with both subsequent AKI development and a prolonged need for mechanical ventilation.
      • Liu KD
      • Altmann C
      • Smits G
      • et al.
      Serum interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study.
      IL6 likewise has been shown to predict AKI in patients with severe sepsis.
      • Chawla LS
      • Seneff MG
      • Nelson DR
      • et al.
      Elevated plasma concentrations of IL-6 and elevated APACHE II score predict acute kidney injury in patients with severe sepsis.
      In adult ICU patients, AKI, in comparison with ESRD or non–renal failure controls, is associated with increased levels of IL6 and IL8, which in turn predict a higher risk of mortality.
      • Simmons EM
      • Himmelfarb J
      • Sezer MT
      • et al.
      Plasma cytokine levels predict mortality in patients with acute renal failure.
      In animal models, IL6 has been shown to be particularly important among the factors involved in lung injury. In mice subjected to ischemic AKI or bilateral nephrectomy, IL6 has been found to mediate lung injury characterized by neutrophil infiltration, increased neutrophil chemokine production, and capillary leak.
      • Klein CL
      • Hoke TS
      • Fang WF
      • Altmann CJ
      • Douglas IS
      • Faubel S.
      Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.
      • Ahuja N
      • Andres-Hernando A
      • Altmann C
      • et al.
      Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
      ,
      • Bhargava R
      • Janssen W
      • Altmann C
      • et al.
      Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice.
      These effects have been attributed specifically to circulating IL6 rather than pulmonary IL6.
      • Ahuja N
      • Andres-Hernando A
      • Altmann C
      • et al.
      Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
      The primary source of the circulating IL6 in models of AKI-induced ALI had been presumed to be the injured kidney, and indeed renal IL6 messenger RNA and protein expression have been shown to be induced by both ischemic and nephrotoxic AKI.
      • Faubel S
      • Lewis EC
      • Reznikov L
      • et al.
      Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.
      • Kielar ML
      • John R
      • Bennett M
      • et al.
      Maladaptive role of IL-6 in ischemic acute renal failure.
      ,
      • Andres-Hernando A
      • Altmann C
      • Ahuja N
      • et al.
      Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice.
      However, both decreased renal clearance and increased extrarenal production by the spleen and liver and by macrophages have been shown also to contribute to increased IL6 levels after bilateral nephrectomy.
      • Andres-Hernando A
      • Dursun B
      • Altmann C
      • et al.
      Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy.
      Renal clearance of IL6, similar to other small proteins, appears to be mediated by metabolism by proximal tubular cells and is inhibited by tubular injury but not prerenal azotemia.
      • Dennen P
      • Altmann C
      • Kaufman J
      • et al.
      Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery.
      A study using functional genomic analyses of the inflammatory transcriptome, which included more than 100 inflammatory genes, identified the IL6 signaling pathway as a mediator of ALI after ischemic AKI.
      • Grigoryev DN
      • Liu M
      • Hassoun HT
      • Cheadle C
      • Barnes KC
      • Rabb H.
      The local and systemic inflammatory transcriptome after acute kidney injury.
      IL8 is a cytokine and neutrophil chemokine that also has been shown in animal studies to have a key role in the development of AKI-induced lung injury. Both lung and serum IL8 levels are increased in AKI, and, in models of AKI-induced lung injury, a reduction in IL8 results in decreased lung neutrophil infiltration and activity and decreased lung permeability.
      • Andres-Hernando A
      • Altmann C
      • Bhargava R
      • et al.
      Prolonged acute kidney injury exacerbates lung inflammation at 7 days post-acute kidney injury.
      • Klein CL
      • Hoke TS
      • Fang WF
      • Altmann CJ
      • Douglas IS
      • Faubel S.
      Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.
      ,
      • Doi K
      • Ishizu T
      • Tsukamoto-Sumida M
      • et al.
      The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
      • Ahuja N
      • Andres-Hernando A
      • Altmann C
      • et al.
      Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
      ,
      • Andres-Hernando A
      • Altmann C
      • Ahuja N
      • et al.
      Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice.
      The most definitive demonstration of the role of IL8 in AKI-induced lung injury comes from an additional experiment performed using the previously referenced mouse model that showed the role of circulating IL6.
      • Ahuja N
      • Andres-Hernando A
      • Altmann C
      • et al.
      Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
      The investigators were able to show that IL6 acts via up-regulation of the chemokine C-X-C motif ligand 1 (CXCL1), the mouse functional analog of human IL8, on lung endothelial cells to promote neutrophil accumulation.
      • Ahuja N
      • Andres-Hernando A
      • Altmann C
      • et al.
      Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
      In mice that were treated with either anti-CXCL1 antibodies or were deficient in CXCL1′s receptor (C-X-C motif chemokine receptor 2), AKI or bilateral nephrectomy resulted in significantly less neutrophil infiltration than in the respective untreated or wild-type controls.
      • Ahuja N
      • Andres-Hernando A
      • Altmann C
      • et al.
      Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.
      A third cytokine shown to mediate lung injury after bilateral nephrectomy or renal ischemia-reperfusion is the high-mobility group B 1 protein, which was shown to produce its effects both via and independently of its receptor, Toll-like receptor 4.
      • Doi K
      • Ishizu T
      • Tsukamoto-Sumida M
      • et al.
      The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
      Finally, in addition to IL6 and IL8, other inflammatory mediators increased in the lung or alveolar fluid after ischemic AKI include adhesion molecules such as intercellular adhesion molecule 1,
      • Gu J
      • Chen J
      • Xia P
      • Tao G
      • Zhao H
      • Ma D.
      Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice.
      • Deng J
      • Hu X
      • Yuen PS
      • Star RA.
      Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion.
      ,
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.
      other chemokines such as macrophage inflammatory protein 2
      • Faubel S
      • Lewis EC
      • Reznikov L
      • et al.
      Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.
      • Klein CL
      • Hoke TS
      • Fang WF
      • Altmann CJ
      • Douglas IS
      • Faubel S.
      Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy.
      and cytokine-induced neutrophil chemoattractant 2,
      • Kim DJ
      • Park SH
      • Sheen MR
      • et al.
      Comparison of experimental lung injury from acute renal failure with injury due to sepsis.
      chemokine receptors such as C-X-C motif chemokine receptor 2,
      • Kim DJ
      • Park SH
      • Sheen MR
      • et al.
      Comparison of experimental lung injury from acute renal failure with injury due to sepsis.
      and the signaling complex nuclear factor-κB.
      • Deng J
      • Hu X
      • Yuen PS
      • Star RA.
      Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion.
      • White LE
      • Santora RJ
      • Cui Y
      • Moore FA
      • Hassoun HT.
      TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.
      As an extension of these human and animal data showing the role of IL6 and IL8 in mediating AKI-induced lung injury, four studies have been published within the past few years investigating the effects of RRT on cytokine levels and related outcomes.
      • Zarbock A
      • Kellum JA
      • Schmidt C
      • et al.
      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
      • Sasser WC
      • Dabal RJ
      • Askenazi DJ
      • et al.
      Prophylactic peritoneal dialysis following cardiopulmonary bypass in children is associated with decreased inflammation and improved clinical outcomes.
      ,
      • Altmann C
      • Ahuja N
      • Kiekhaefer CM
      • et al.
      Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.
      • Murugan R
      • Wen X
      • Keener C
      • et al.
      Associations between intensity of RRT, inflammatory mediators, and outcomes.
      The most comprehensive of these was an animal study that evaluated the effect of RRT on both inflammatory mediators and on lung inflammation after ischemic AKI or bilateral nephrectomy.
      • Altmann C
      • Ahuja N
      • Kiekhaefer CM
      • et al.
      Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.
      By using a novel model of PD in mice with AKI, the investigators were able to show that high-dose PD resulted in decreased serum IL6 levels, lung CXCL1 levels, lung neutrophil count and activity, and lung interstitial macrophage number without a change in the wet/dry lung weight ratio.
      • Altmann C
      • Ahuja N
      • Kiekhaefer CM
      • et al.
      Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.
      By infusing and tracking recombinant IL6, this experiment directly showed that IL6 is cleared effectively by PD, consistent with prior human data,
      • Dittrich S
      • Aktuerk D
      • Seitz S
      • et al.
      Effects of ultrafiltration and peritoneal dialysis on proinflammatory cytokines during cardiopulmonary bypass surgery in newborns and infants.
      and that peritoneal IL6 is in equilibrium with serum IL6.
      • Altmann C
      • Ahuja N
      • Kiekhaefer CM
      • et al.
      Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.
      Two recent human studies have shown that RRT is associated with decreased plasma IL6 levels and with improved clinical outcomes, possibly owing to IL6 removal. In one of the previously referenced case-matched cohort studies of prophylactic PD use in infants at high risk of fluid overload after cardiopulmonary bypass for congenital heart disease, the use of PD was shown to be associated with lower serum levels of both IL6 and IL8 within 24 hours, and with more negative fluid balance, less inotrope use, and earlier sternal closure, with a trend toward a shorter duration of mechanical ventilation.
      • Sasser WC
      • Dabal RJ
      • Askenazi DJ
      • et al.
      Prophylactic peritoneal dialysis following cardiopulmonary bypass in children is associated with decreased inflammation and improved clinical outcomes.
      Although PD use was associated with a statistically significant decrease of the serum IL6 and IL8 levels, implying clearance of the cytokines, cytokine clearance (ie, cytokine levels in the PD effluent) was not measured directly.
      • Sasser WC
      • Dabal RJ
      • Askenazi DJ
      • et al.
      Prophylactic peritoneal dialysis following cardiopulmonary bypass in children is associated with decreased inflammation and improved clinical outcomes.
      A later similar cohort study of prophylactic PD after infant cardiac surgery did not measure cytokine levels, but did report a statistically significant shortening of ventilation time.
      • Kwiatkowski DM
      • Menon S
      • Krawczeski CD
      • et al.
      Improved outcomes with peritoneal dialysis catheter placement after cardiopulmonary bypass in infants.
      The second trial to report on the effect of RRT on cytokine levels in human beings was the highly publicized Early versus Late Initiation of Renal Replacement Therapy in Critically Ill Patients with Acute Kidney Injury (ELAIN) trial,
      • Zarbock A
      • Kellum JA
      • Schmidt C
      • et al.
      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
      one of two recent randomized controlled trials comparing the timing of RRT initiation in ICU patients with AKI. The trial, in a secondary exploratory analysis, measured levels of various proinflammatory cytokines including IL6 and IL8. The modality used at RRT initiation in both sets of patients was continuous venovenous hemodiafiltration, with a 1:1 ratio of dialysate and replacement fluid. Hemofiltration has been shown in a different setting to effectively clear IL6 and IL8 in human beings.
      • Dittrich S
      • Aktuerk D
      • Seitz S
      • et al.
      Effects of ultrafiltration and peritoneal dialysis on proinflammatory cytokines during cardiopulmonary bypass surgery in newborns and infants.
      In the ELAIN trial, early RRT resulted in a significant decrease in both the primary outcome of 90-day mortality, with an absolute risk reduction of more than 15%, and in the median duration of mechanical ventilation, by more than 48 hours, despite no significant difference in fluid balance between the groups.
      • Zarbock A
      • Kellum JA
      • Schmidt C
      • et al.
      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
      With regard to cytokines, early RRT was associated with a reduction in serum IL6 and IL8 levels by 24 hours after randomization, and, in turn, lower day 1 IL6 and IL8 levels were found to be associated with a lower risk of mortality.
      • Zarbock A
      • Kellum JA
      • Schmidt C
      • et al.
      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
      Again, similar to the human PD study referenced earlier, although cytokine clearance was implied by the decreased serum levels in the early RRT group, cytokine clearance (ie, effluent levels of cytokines) was not measured directly.
      • Zarbock A
      • Kellum JA
      • Schmidt C
      • et al.
      Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial.
      Although promising, the overall benefit from early RRT initiation in the ELAIN trial, whether mediated by cytokine clearance or not, must be interpreted with caution given the discrepant results of two other studies. First, the contemporaneous Artificial Kidney Initiation in Kidney Injury (AKIKI) trial, in contrast to the single-center ELAIN trial, was a larger multicenter trial of RRT timing in ICU patients with AKI, which did not show any benefit to earlier initiation of RRT (although, of note, the definitions of early versus late initiation differed significantly in the two trials).
      • Gaudry S
      • Hajage D
      • Schortgen F
      • et al.
      Initiation strategies for renal-replacement therapy in the intensive care unit.
      The AKIKI trial did not measure cytokine levels. Second, a third report of the effect of RRT in human beings on cytokine levels, a substudy
      • Murugan R
      • Wen X
      • Keener C
      • et al.
      Associations between intensity of RRT, inflammatory mediators, and outcomes.
      of the Veterans Affairs/National Institutes of Health ATN trial on dose intensity of RRT for AKI in the ICU, had differing results than the earlier-described studies. Specifically, serum levels of a variety of cytokines and apoptosis biomarkers, including IL6 and TNF receptor 1 (TNFR1), were measured on day 1 and day 8 of AKI in more than 800 patients.
      • Murugan R
      • Wen X
      • Keener C
      • et al.
      Associations between intensity of RRT, inflammatory mediators, and outcomes.
      Higher-dose RRT was associated with no overall change in the serum levels of these biomarkers in those surviving to day 8, with a reduction noted in those with high baseline levels on day 1, but an increase noted in those with low baseline levels.
      • Murugan R
      • Wen X
      • Keener C
      • et al.
      Associations between intensity of RRT, inflammatory mediators, and outcomes.
      Higher levels of day-8 biomarkers were associated with an increased risk of death and RRT dependence, but the dose of RRT did not modulate the rates of death or renal recovery even when adjusting for baseline biomarker levels.
      • Murugan R
      • Wen X
      • Keener C
      • et al.
      Associations between intensity of RRT, inflammatory mediators, and outcomes.
      Of note, in contrast to the ELAIN trial, both the AKIKI and ATN trials used a mix of intermittent hemodialysis and CRRT, in roughly equal proportions.
      • Palevsky PM
      • Zhang JH
      • et al.
      VA/NIH Acute Renal Failure Trial Network
      Intensity of renal support in critically ill patients with acute kidney injury.
      • Gaudry S
      • Hajage D
      • Schortgen F
      • et al.
      Initiation strategies for renal-replacement therapy in the intensive care unit.
      In AKIKI, the CRRT patients underwent either hemofiltration or hemodialysis (with the proportion not reported); in the ATN trial most of the patients on CRRT were prescribed hemodiafiltration (with, as in ELAIN, a 1:1 ratio of dialysate and replacement fluid), although a minority (<10%) of the CRRT treatments were delivered as sustained low-efficiency dialysis.
      • Palevsky PM
      • Zhang JH
      • et al.
      VA/NIH Acute Renal Failure Trial Network
      Intensity of renal support in critically ill patients with acute kidney injury.
      • Gaudry S
      • Hajage D
      • Schortgen F
      • et al.
      Initiation strategies for renal-replacement therapy in the intensive care unit.
      Given that many cytokines are middle-weight molecules greater than 20 kDa (eg, IL6 is approximately 26 kDa), the overall clearance of cytokines via hemofiltration is likely greater than with hemodialysis because the molecular weight cut-off of modern high-flux dialyzers is typically approximately 10 kDa.
      • Altmann C
      • Ahuja N
      • Kiekhaefer CM
      • et al.
      Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.
      • Friedrich JO
      • Wald R
      • Bagshaw SM
      • Burns KE
      • Adhikari NK.
      Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis.
      As such, it is possible that the different outcomes between the AKIKI and the ATN trials and the ELAIN trial could relate to the higher overall proportion of the RRT being provided as hemodialysis rather than hemofiltration, but the limited data available directly comparing the CRRT modalities suggest no difference between hemofiltration and hemodialysis on clinical outcomes in AKI.
      • Friedrich JO
      • Wald R
      • Bagshaw SM
      • Burns KE
      • Adhikari NK.
      Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis.

      MECHANISMS OF LUNG INJURY AFTER AKI: LUNG ENDOTHELIAL APOPTOSIS

      A series of key animal studies have shown the role of pulmonary endothelial cell apoptosis in AKI-induced lung injury, with the apoptosis mediated by TNFR1 and carried out by the caspase pathway.
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.
      ,
      • White LE
      • Santora RJ
      • Cui Y
      • Moore FA
      • Hassoun HT.
      TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.
      • White LE
      • Cui Y
      • Shelak CM
      • Lie ML
      • Hassoun HT.
      Lung endothelial cell apoptosis during ischemic acute kidney injury.
      Collectively, these studies show that apoptosis begins in the lung at some point after 4 hours of AKI onset but is readily detectable in all reports by 24 hours after AKI.
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.
      ,
      • White LE
      • Santora RJ
      • Cui Y
      • Moore FA
      • Hassoun HT.
      TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.
      • White LE
      • Cui Y
      • Shelak CM
      • Lie ML
      • Hassoun HT.
      Lung endothelial cell apoptosis during ischemic acute kidney injury.
      These studies documented increased activity and gene expression of various elements of the caspase cascade, including the initiator caspase-8 and the executioner caspase-3.
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.
      ,
      • White LE
      • Santora RJ
      • Cui Y
      • Moore FA
      • Hassoun HT.
      TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.
      • White LE
      • Cui Y
      • Shelak CM
      • Lie ML
      • Hassoun HT.
      Lung endothelial cell apoptosis during ischemic acute kidney injury.
      Likewise, caspase inhibition prevents the increase in BAL fluid protein that is otherwise produced by renal ischemia-reperfusion.
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      Co-localization experiments have shown the apoptotic cells to be lung endothelial rather than epithelial cells.
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      The factor(s) required to induce apoptosis appear to be present in serum because isolated lung microvascular cells incubated in vitro with serum from animals with AKI undergo apoptosis.
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.
      TNF appears to be a likely candidate for such a factor. Prior studies have shown lung TNF messenger RNA expression or alveolar fluid levels of TNF increase after AKI.
      • Gu J
      • Chen J
      • Xia P
      • Tao G
      • Zhao H
      • Ma D.
      Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice.
      • Ma T
      • Liu Z.
      Functions of aquaporin 1 and alpha-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury.
      • Deng J
      • Hu X
      • Yuen PS
      • Star RA.
      Alpha-melanocyte-stimulating hormone inhibits lung injury after renal ischemia/reperfusion.
      ,
      • Doi K
      • Ishizu T
      • Tsukamoto-Sumida M
      • et al.
      The high-mobility group protein B1-Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy.
      Its specific role in induction of apoptosis was shown in models of AKI-induced lung injury in which blockade of TNF, by either etanercept
      • White LE
      • Santora RJ
      • Cui Y
      • Moore FA
      • Hassoun HT.
      TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.
      or TNFR-1 deficiency,
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      • White LE
      • Santora RJ
      • Cui Y
      • Moore FA
      • Hassoun HT.
      TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.
      resulted in decreased apoptosis and decreased BAL fluid protein. Two of these studies
      • Hassoun HT
      • Lie ML
      • Grigoryev DN
      • Liu M
      • Tuder RM
      • Rabb H.
      Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.
      included lung gene array analyses that showed activation of dozens of genes involved in apoptosis and inflammation, prominently including genes from the TNFR superfamily and the TNFR pathway, collectively suggesting a “transition to an activated proinflammatory and proapoptotic [lung] endothelial cell phenotype during AKI.”
      • Feltes CM
      • Hassoun HT
      • Lie ML
      • Cheadle C
      • Rabb H.
      Pulmonary endothelial cell activation during experimental acute kidney injury.

      MECHANISMS OF LUNG INJURY AFTER AKI: NECROINFLAMMATION

      Lung injury after AKI also has been shown to be mediated in part via a relatively novel concept of necroinflammation.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      Renal necroinflammation is an autoamplification loop in which tubular cell necrosis in AKI leads to the release from the necrotic cells of damage-associated molecular patterns, which drive intrarenal inflammation and further renal injury. Among these damage-associated molecular patterns are histones, which appear to specifically play a role in remote lung injury via a form of neutrophil death called neutrophil extracellular trap (NET) formation.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      It is specifically citrullinated histones, formed in the process of chromatin denaturation, that are capable of inducing NET formation.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      In a mouse model of ischemic AKI, serum concentrations of histones and NETs were found to increase along with serum levels of IL6 and TNF.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      The NETs and histones were found to amplify kidney tissue damage in this model.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      Regarding the lungs, these mice were found to have increased lung tissue levels of NETs and citrullinated histones and increased NET BAL levels.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      Furthermore, lung neutrophil infiltration and apoptosis were increased, with the levels of NETs in the lung tissue correlating with the degree of apoptosis and with BAL leukocyte count.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.
      Finally, the levels of lung NETs and lung apoptosis were decreased by use of a necrosis-inhibiting cocktail, an inhibitor of specifically NET formation, and, most prominently, by antihistone antibodies, implying that NETs and circulating histones play an important role in mediating remote lung injury after AKI.
      • Nakazawa D
      • Kumar SV
      • Marschner J
      • et al.
      Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI.

      MECHANISMS OF LUNG INJURY AFTER AKI: T LYMPHOCYTES

      Of the cellular mediators that appear to be involved in AKI-induced lung injury, T lymphocytes are the cell type that have been shown most convincingly to play an essential role.
      • Lie ML
      • White LE
      • Santora RJ
      • Park JM
      • Rabb H
      • Hassoun HT.
      Lung T lymphocyte trafficking and activation during ischemic acute kidney injury.
      In a mouse model of ischemic AKI, activated T cells, primarily of the CD8-positive phenotype, were found to traffic to the lungs by 24 hours after AKI.
      • Lie ML
      • White LE
      • Santora RJ
      • Park JM
      • Rabb H
      • Hassoun HT.
      Lung T lymphocyte trafficking and activation during ischemic acute kidney injury.
      Furthermore, both pulmonary apoptosis (as measured by caspase-3 activity) and increased pulmonary permeability (as measured by BAL fluid total protein) were found to be T-cell–dependent, because both findings were found to be present in wild-type mice, absent in T-cell–depleted mice, and then restored by re-injection of wild-type T lymphocytes.
      • Lie ML
      • White LE
      • Santora RJ
      • Park JM
      • Rabb H
      • Hassoun HT.
      Lung T lymphocyte trafficking and activation during ischemic acute kidney injury.
      In contrast, although neutrophils and macrophages appear to play roles in lung injury induced by AKI, whether they are simply markers of inflammation rather than essential components of the lung injury remains unclear. Neutrophils clearly are recruited early in the process of AKI-induced lung injury because animal studies have shown that marked neutrophil margination occurs in the lungs within 2 hours of renal ischemia-reperfusion.
      • Awad AS
      • Rouse M
      • Huang L
      • et al.
      Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury.
      However, there are no studies on the impact of neutrophil depletion. In the case of macrophages, the available data suggest they play a role in lung inflammation after AKI but are too inconsistent to draw definitive conclusions.
      • Kramer AA
      • Postler G
      • Salhab KF
      • Mendez C
      • Carey LC
      • Rabb H.
      Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability.
      • Altmann C
      • Andres-Hernando A
      • McMahan RH
      • et al.
      Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury.

      MECHANISMS OF LUNG INJURY AFTER AKI: WATER AND SODIUM HANDLING

      In addition to the earlier-described inflammatory changes, animal models have shown that AKI can predispose to pulmonary edema via impaired lung fluid clearance via changes in lung water and sodium channels. Specifically, lung expression of aquaporin-1,
      • Ma T
      • Liu Z.
      Functions of aquaporin 1 and alpha-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury.
      aquaporin-5,
      • Rabb H
      • Wang Z
      • Nemoto T
      • Hotchkiss J
      • Yokota N
      • Soleimani M.
      Acute renal failure leads to dysregulation of lung salt and water channels.
      epithelial sodium channel,
      • Ma T
      • Liu Z.
      Functions of aquaporin 1 and alpha-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury.
      • Rabb H
      • Wang Z
      • Nemoto T
      • Hotchkiss J
      • Yokota N
      • Soleimani M.
      Acute renal failure leads to dysregulation of lung salt and water channels.
      and Na-K adenosine triphosphatase
      • Rabb H
      • Wang Z
      • Nemoto T
      • Hotchkiss J
      • Yokota N
      • Soleimani M.
      Acute renal failure leads to dysregulation of lung salt and water channels.
      all have been shown to be decreased in animal models of AKI-induced lung injury.

      IMPLICATIONS FOR CLINICAL PRACTICE AND FUTURE RESEARCH

      Despite significant advances in the provision of RRT and supportive care, outcomes for AKI remain poor. The combination of AKI and respiratory failure is particularly devastating. AKI increases the risk of lung injury and significantly aggravates its course, increasing the duration of mechanical ventilation and overall mortality of respiratory failure. The evidence that AKI leads to inflammatory injury to a variety of organs, prominently including the lungs, continues to accumulate, strengthening the argument that these nontraditional effects of AKI mediate the excess mortality of AKI. However, until we develop interventions to either prevent or consistently mitigate both the traditional and nontraditional complications of AKI, recognition that AKI is a systemic disorder that is associated not only with mortality, but is a cause of such mortality, likely will remain limited.
      Furthermore, although RRT is an effective means of treating volume overload, many of the practical aspects of volume management in patients with kidney and lung injury remain problematic. Appreciation of the spectrum of hydrostatic and nonhydrostatic pulmonary edema complicating AKI will allow for more nuanced care of patients with acute lung and kidney injury via the understanding that not all pulmonary edema in patients with AKI and ALI can be corrected with volume removal alone and that excess ultrafiltration may impair organ perfusion or recovery from AKI. However, further studies are needed to identify and validate measures of volume status to more precisely guide fluid administration or fluid removal in patients with kidney and lung injury.
      To further translate our understanding of the nontraditional effects of AKI into clinically useful applications, we also must focus our future basic science experiments on the later pulmonary and systemic consequences of AKI. Currently, only a single study has examined the effects of AKI on the lung in an animal model beyond 48 hours.
      • Andres-Hernando A
      • Altmann C
      • Bhargava R
      • et al.
      Prolonged acute kidney injury exacerbates lung inflammation at 7 days post-acute kidney injury.
      Given our current dependence on serum creatinine increase to diagnose AKI, an increase that typically is evident only 24 to 48 hours after an initial insult, we must extend our understanding of the distant organ effects of AKI beyond the first 24 hours of AKI. Alternatively, we need to be able to diagnose the inflammatory consequences of AKI earlier, possibly via the adoption and clinical validation of renal biomarkers.

      CONCLUSIONS

      Both traditional and nontraditional effects of AKI on the lungs conspire to produce mortality rates exceeding 50% in patients with AKI and respiratory failure. As we strive to more adeptly manage the challenging traditional effects of AKI that are amenable to RRT, especially optimization of volume status, a better understanding of the nontraditional effects of AKI on the lungs, the immune system, and other remote organs has the potential to translate into a reduction in the unacceptably high mortality rate of AKI.

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