Preventive Tactics and Management of Acute Kidney Injury in the ICU
December 1, 2018
By Arnaldo Lopez Ruiz, MD, and Alexander Niven, MD
Dr. Lopez Ruiz is Clinical Fellow, Division of Pulmonary/Critical Care, Mayo Clinic, Rochester, MN.
Dr. Niven is Senior Associate Consultant, Division of Pulmonary/Critical Care Medicine, Mayo Clinic, Rochester, MN.
Drs. Lopez Ruiz and Niven report no financial relationships relevant to this field of study.
Acute kidney injury (AKI) is a sudden decline in renal function due to nephron dysfunction and/or damage that results in nitrogenous waste product accumulation and acid-base, electrolyte, and fluid disturbances. It is estimated to occur in 16-67% of critically ill patients admitted to the ICU. Common inciting causes include major surgery, iatrogenic interventions, and sepsis. Advanced age and comorbidities increase kidney susceptibility to various exposures and insults.1 Severe AKI requiring renal replacement therapy (RRT) is associated with a 10-fold increase in mortality and increases length of stay an average of 5.7 days.2 Preventive tactics and RRT remain the cornerstones of AKI management in critically ill patients.
Identify Higher-risk Patients
Prevention starts with identifying patients at higher risk for AKI. Common associated risk factors include age, gender, genetic predisposition, and multiple comorbid medical conditions, such as heart failure, diabetes, hypertension, and chronic kidney disease (CKD).3 Patients > 65 years of age are twice as likely to sustain AKIs as patients 50-64 years of age. Patients > 75 years of age sustain AKIs three times as often as others. Interestingly, this finding is much more strongly associated with male gender.4 Although ethnicity does not seem to affect AKI development, some studies suggest African Americans are at greater risk, perhaps because of the CKD prevalence in this population.3
Preexisting CKD or estimated glomerular filtration rate (eGFR) < 60 mL/min carries a high risk for AKI development.3,4 The effects of age, gender, and race appear to be attenuated in higher stages of CKD. It is unclear if these factors play less of a biological role or if the risk for AKI in patients with advanced CKD is so great that contributions from other factors become insignificant.5 Patients with CKD are more likely to experience progression of their disease after episodes of AKI. Those patients with a baseline eGFR < 45 mL/min were 30% more likely to die or progress to end-stage renal disease (ESRD).6 Patients with proteinuria (albuminuria > 300 mg/g creatinine) are at a 2.5-fold risk of AKI compared to patients with undetectable urine albumin levels.5
Chronic liver disease and heart failure with reduced ejection fraction also are associated with a higher risk of AKI. Rates of AKI in cirrhosis range from 20-50%, depending on aggravating factors such as hypotension, hypoalbuminemia (< 3 g/dL), and spontaneous bacterial peritonitis.7 AKI has been described in up to 60% of patients admitted with decompensated systolic heart failure and is associated with a greater need for renal replacement therapy.8 A history of hypertension increases the risk for AKI by an overall odds ratio of 2 and in various settings, including contrast administration, lung resection, severe aortic dissection, and abdominal surgery.9 Diabetes confers only a mild risk of developing AKI, but the contribution of this comorbidity is established most strongly in the setting of iodinated contrast administration and cardiovascular surgery. In comparison with nondiabetic subjects, patients with type 1 and type 2 diabetes undergoing coronary bypass graft surgery had an odds ratio of 4.9 and 1.3 to develop AKI, respectively.10
The risk of AKI and AKI progressing to ESRD after a major cardiac and vascular surgery is highest in patients with advanced CKD.11 The incidence of AKI requiring RRT following cardiac surgery can be 30% higher in CKD patients, especially in the setting of complex disease (i.e., left main coronary disease) and postsurgical cardiogenic shock.12 Longer cardiopulmonary bypass or cross-clamp time and “off-pump” procedures also strongly increase the risk of AKI.13 Vascular surgery may carry an even higher risk for AKI than cardiac surgery, with severe AKI rates from 15-75% in patients who require thoracic and abdominal aortic interventions (depending on baseline renal function).14
Risk assessment models have been developed and validated to predict AKI in specific populations. Using information from the National Cardiovascular Data Registry CathPCI Registry, Tsai et al identified 11 variables associated with AKI in patients undergoing cardiac catheterization. (See Table 1.) ST-elevation myocardial infarction presentation, cardiogenic shock, and severe baseline CKD were the strongest predictors for AKI.15 These variables were used to develop the risk prediction model that has demonstrated good subsequent performance to predict AKI incidence (C-statistic, 0.76) and need for dialysis (C-statistic, 0.92).16
Maximize Renal Perfusion
Intravascular volume expansion to maintain renal perfusion in high-risk patients is the best demonstrated tactic to prevent AKI. Fluid administration has been shown to decrease AKI risk in several clinical settings, including myoglobinuric or hemoglobinuric AKI, radiocontrast nephropathy, and aminoglycoside- and amphotericin-associated nephrotoxicity. Fluids also have been shown to decrease the risk of intratubular obstruction from crystal deposition in tumor lysis syndrome and drug-induced crystalline nephropathies.17 Isotonic crystalloids are preferred, as multiple clinical studies have proven synthetic colloids to be nephrotoxic.18 Recent evidence suggests the use of balanced crystalloids (Ringer’s lactate or PlasmaLyte) instead of saline is associated with a lower risk of AKI.19
As AKI progresses, one of the earliest consequences is the loss of normal autoregulation of renal blood flow during blood pressure fluctuations. Rapid hemodynamic stabilization, optimization of cardiac output, and maintenance of renal perfusion (generally by maintaining a mean arterial pressure > 65 mmHg) is essential to prevent further renal injury. However, once the injury is established, the potential benefit of further volume expansion must be balanced with the unwanted consequence of fluid accumulation and overload.20 A large randomized trial comparing dopamine to norepinephrine as initial vasopressors in patients with septic shock showed no significant differences between groups regarding renal function or mortality, although norepinephrine was associated with less arrhythmias and was superior regarding survival in patients with cardiogenic shock.21 In clinical trials, vasopressin increases blood pressure and enhances diuresis in hypotensive oliguric patients with sepsis, but it has not yet been proven to enhance survival nor been shown to prevent or ameliorate AKI.22
Minimize Nephrotoxic Medications and Iodinated Contast
Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and nonsteroidal anti-inflammatory medications increase the risk of AKI in critically ill patients. Their harmful effects are worse in the setting of advanced age, sepsis, volume depletion, eGFR < 45 mL/min, impaired systolic function, postcardiac surgery, and advanced cirrhosis. As their primary effect is on renal hemodynamics and only results in tubular damage with prolonged use, most patients recover renal function within three to five days after discontinuation of these agents.
Antibiotics such as vancomycin, aminoglycosides, and beta-lactams are associated with more selective damage to tubular and interstitial cells and have been associated with both severe AKI and the need for RRT. Elevated vancomycin trough levels (> 35 µg/mL) have been strongly associated with acute tubular necrosis and AKI.23 Aminoglycoside toxicity is related primarily to duration of therapy and typically develops after five to seven days of treatment (earlier in the presence of CKD). Preceding signs of renal toxicity include concentrating defects, low-grade proteinuria, granular casts in the urine sediment, elevated fractional excretion of sodium (FENa), and urinary loss of potassium and magnesium. Prolonged exposure to high-dose, broad-spectrum beta-lactams (e.g., piperacillin-tazobactam, cefepime, or ampicillin-sulbactam) have been associated with increased AKI risk. Several recent reports have raised concerns about the risk of AKI with the combination therapy of piperacillin-tazobactam and vancomycin. In our institution, a short course (< 72 hours) of piperacillin/tazobactam plus vancomycin was not associated with an increased risk of AKI or long-term adverse renal outcomes compared to other empiric broad-spectrum antibiotics commonly used in the ICU.24
The risk of contrast-induced nephropathy (CIN) ranges from 1-25%. The strongest predictor for CIN is kidney function at the time of exposure, but contrast (volume, osmolarity, arterial vs. venous infusion) and patient factors (hypotension, sepsis, diabetes, heart failure, advanced age, concomitant nephrotoxins) are additional strong contributors to severe CIN and the need for RRT. The authors of multiple studies have shown that administration of isotonic crystalloids prior to and following contrast exposure reduces the risk of AKI and is most beneficial in patients with an eGFR < 30mL/min.25 The authors of the recent PRESERVE trial, a comparison of commonly applied tactics to prevent CIN, showed there was no benefit of IV sodium bicarbonate vs. IV sodium chloride or oral acetylcysteine vs. placebo to prevent a composite outcome of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of CIN.26 Notably, higher-risk patients, including those undergoing emergency procedures more typical of the critically ill, were excluded from this trial.
Urine Biomarkers
Creatinine is recognized as an insensitive biomarker for AKI. Recently, the FDA approved the NephroCheck Test, a quick, quantitative measurement of the cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7. These urinary biomarkers increase in response to renal tubule cell stress or early injury due to exposures known to cause AKI. A primary clinical cutoff value (0.3) for the NephroCheck Test is both specific to AKI (i.e., not caused by other comorbidities such as CKD or sepsis) and identifies critically ill patients at imminent risk of developing moderate to severe AKI in the next 12 hours.27 A second, high-specificity cutoff (2.0) was selected and verified in patients at the highest risk of AKI. Both cutoff values underwent confirmatory validation in a multisite study that used clinical adjudication to determine the primary endpoint of moderate-severe AKI. A positive test identifies patients who may be candidates for kidney-sparing management tactics that are outlined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines for high-risk patients.28,29
Electronic Medical Record Decision Support
Consistently applying best evidence-based practices to bedside practice is a challenge for many common critical care conditions, and AKI is no exception. Electronic alert systems to notify intensivists about nephrotoxic side effects of drugs prescribed for septic patients and to recommend hydration protocols in at-risk patients undergoing contrast studies have demonstrated impressive reductions in the development of AKI.30 More recently, a clinical decision support system that alerts physicians of creatinine changes and/or early stages of AKI using KDIGO criteria with a suggested management approach has been shown to reduce the need for RRT, hospital length of stay, and mortality.31
Diagnostic Approach
Urine analysis is a priority in any suspected case of AKI. A normal urine sediment suggests either a prerenal or postrenal etiology, although hematuria, pyuria, or crystalluria also may be seen in obstructive uropathy. Proteinuria and urinary sediment containing abundant cells or casts suggests an intrinsic process. The presence of many renal tubular epithelial cells, epithelial cell casts, or pigmented (muddy brown) granular casts suggests the diagnosis of acute tubular necrosis (ATN) and a higher risk for severe AKI and RRT.
In the appropriate clinical setting, the presence of white blood cells (WBCs) and WBC casts suggests acute interstitial nephritis.32 Although eosinophiluria also may be seen in association with interstitial nephritis, the specificity and sensitivity of this finding is very limited (< 40%). Urine eosinophils can be seen with ATN, atheroembolic disease, and urinary tract infections.33 The use of FENa or urine Na excretion to help distinguish the etiology of AKI carries poor specificity and sensitivity. Such use should be considered only in the setting of oliguria without recent loop diuretics, radiocontrast, glomerulonephritis, myoglobinuria, or sepsis. FE-urea (< 35% for prerenal and > 65% for ATN) and FE-uric acid (< 7% for prerenal AKI and > 20% for ATN) both offer better sensitivity and specificity. Injury biomarkers detect AKI 36-48 hours earlier than serum creatinine and urine output.
Although not validated for clinical use, urine and/or plasma neutrophil gelatinase-associated lipocalin (NGAL) has been reported to be an effective early marker of AKI in sepsis, postcardiac surgery, and drug-induced renal damage. Plasma NGAL > 150-200 ng/dL has been used in numerous AKI trials as an early and specific marker for AKI and has shown a good correlation with impaired renal recovery, need for RRT, and increased mortality.34-36 The furosemide stress test is another important functional evaluation tool. A positive test (< 200 mL urine two hours after IV furosemide 1-1.5 mg/kg) in patients with AKI stage 1 is highly predictive of progression to AKI stage 3 (area under the curve, 0.87).37
Starting Renal Replacement Therapy
The decision to start RRT should be individualized, integrating baseline clinical information (i.e., CKD, injury and functional biomarkers, renal reserve), acute diagnosis, illness severity, nonrenal organ dysfunction, and physiologic and laboratory data to determine the patient trajectory in the dynamic setting of critical illness.
Among patients facing life-threatening AKI complications, the decision to start RRT generally is clear. Severe hyperkalemia refractory to medical therapy, marked metabolic acidosis with a persistent bicarbonate < 12 mEq/L or pH < 7.15, symptoms of uremia and/or blood urea nitrogen > 110-120 mg/dL, and/or fluid overload > 10% of basal body weight or resulting in high FiO2 that is difficult to wean are commonly accepted indications to initiate RRT treatment.17
Unfortunately, outside these urgent indications, the best method and timing of RRT remains elusive. There are many postulated benefits of continuous RRT (CRRT) in the critically ill. CRRT does not affect blood pressure as much, reducing the need for escalation in vasopressors in critically ill patients. CRRT may confer more rapid correction of electrolyte and acid-base derangements, better control of azotemia, and improved fluid balance homeostasis when initiated early.
In select patients at high risk for worsening AKI, early CRRT could prevent overt complications of fluid overload, which may be independently associated with mortality. CRRT may unload a damaged kidney by providing added solute clearance, reducing metabolic demand, limiting exposure to nephrotoxins or unnecessary diuretics, and perhaps facilitating repair and recovery. CRRT also may modulate inflammation/immune function in sepsis and attenuate subsequent cardiac complications, platelet dysfunction, and lung injury.
Unfortunately, these theoretical benefits have not been demonstrated consistently in trials comparing CRRT to intermittent hemodialysis. The ELAIN trial is the most recent to suggest significant improvements in mortality, renal recovery, inflammatory markers, days free of mechanical ventilation, and length of stay in ICU.36
A conservative tactic consisting of supportive management resulted in spontaneous recovery of renal function without RRT in 25-49% of patients with AKI stage 3 who were randomized to standard or delayed initiation of RRT for acute indications.38-40 Late RRT initiation in the AKIKI39 and IDEAL-ICU40 trials showed no difference in mortality at 28-90 days, length of ICU stay, days free of vasopressor or mechanical ventilation support, and dependence on RRT at 30 days vs. patients who received early RRT initiation. Patients who received conservative management or delayed initiation of CRRT demonstrated earlier spontaneous diuresis, a lower risk of catheter related-bloodstream infections, thrombosis, iatrogenic episodes of hemodynamic instability, less hypophosphatemia and hypocalcemia, and reduced lower muscle weakness because of fewer barriers to mobilization.38-40 RRT also can remove metabolic and nutritional factors such as hydrosoluble vitamins, microelements (copper, zinc, selenium), amino acids, and free-unbound hormones. The impact of this effect on outcomes of critical illness is still unknown.
Summary
There is a frustrating patchwork of conflicting clinical studies in this area. Best critical care practices must focus on systematic efforts and computer-based decision support to identify patients at high risk for AKI. Further, these practices must minimize the risk of this common and significant disorder through diligent efforts to maximize renal perfusion, minimize unnecessary exposure to nephrotoxins, and judiciously administer balanced crystalloid solutions, especially prior to contrast exposure. When AKI occurs, urine sediment analysis, FE-urea, FE-uric acid, the furosemide stress test, and the NephroCheck Test all can help identify individuals at a higher risk of progressing to severe disease and RRT.
Although there are many hypothetical benefits to CRRT in the critically ill, evidence supporting the best mode and timing of RRT remains elusive. Treatment is individualized in the absence of life-threatening indications that have failed medical management.
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- Schreier DJ, Kashani KB, Sakhuja A, et al. Incidence of acute kidney injury among critically ill patients with brief empiric use of anti-pseudomonal beta-lactams with vancomycin. Clin Infect Dis 2018; Aug 24. doi: 10.1093/cid/ciy724. [Epub ahead of print].
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- Honore PM, Nguyen HB, Gong M, et al. Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 for risk stratification of acute kidney injury in patients with sepsis. Crit Care Med 2016;44:1851-1860.
- Sutherland SM, Chawla LS, Kane-Gill SL, et al. Utilizing electronic health records to predict acute kidney injury risk and outcomes: Workgroup statements from the 15(th) ADQI Consensus Conference. Can J Kidney Health Dis 2016;3:11.
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Table 1: Variables Associated With Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention |
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Acute kidney injury (AKI) is a sudden decline in renal function due to nephron dysfunction and/or damage that results in nitrogenous waste product accumulation and acid-base, electrolyte, and fluid disturbances. It is estimated to occur in 16-67% of critically ill patients admitted to the ICU. Common inciting causes include major surgery, iatrogenic interventions, and sepsis. Advanced age and comorbidities increase kidney susceptibility to various exposures and insults. Severe AKI requiring renal replacement therapy (RRT) is associated with a 10-fold increase in mortality and increases length of stay an average of 5.7 days. Preventive tactics and RRT remain the cornerstones of AKI management in critically ill patients.
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