Feature

Acute Kidney Injury: Not Just Acute Renal Failure Anymore?

Susan Dirkes, RN, MSA, CCRN

Until recently, no uniform standard existed for diagnosing and classifying acute renal failure. To clarify diagnosis, the Acute Dialysis Quality Initiative group stated its consensus on the need for a clear definition and classification system of renal dysfunction with measurable criteria. Today the term acute kidney injury has replaced the term acute renal failure, with an understanding that such injury is a common clinical problem in critically ill patients and typically is predictive of an increase in morbidity and mortality. A classification system, known as RIFLE (risk of injury, injury, failure, loss of function, and end-stage renal failure), includes specific goals for preventing acute kidney injury: adequate hydration, maintenance of renal perfusion, limiting exposure to nephrotoxins, drug protective strategies, and the use of renal replacement therapies that reduce renal injury. (Critical Care Nurse. 2011;31[1]:37-50)

he development of acute renal failure (ARF) continues to be a problem that markedly affects outcome in critically ill patients. Despite advances in treatment, development of ARF continues to be associated with high mortality rates, ranging from 40% to 90%.1,2 In addition, ARF is a major

CEContinuing Education
This article has been designated for CE credit. A closed-book, multiple-choice examination follows this article, which tests your knowledge of the following objectives: 1. Define and discuss acute kidney injury (AKI) 2. Compare and contrast renal biomarkers for early detection of AKI 3. Understand the RIFLE classification system 4. Discuss prevention and treatment strategies for AKI 2011 American Association of CriticalCare Nurses doi: 10.4037/ccn2011946

risk factor for nonrenal complications.3 Factors that may influence the high mortality rates include the increasing age of the population of patients and the existence of comorbid conditions (eg, diabetes, heart disease, preexisting renal disease, preexisting vascular disease, and respiratory failure).3 Additional evidence4-7 indicates that even milder forms of acute kidney injury (AKI), not just ARF requiring renal replacement therapy, are associated with excess mortality. Numerous studies8-11 have shown that ARF in patients in the intensive care unit (ICU) is associated with high short- and long-term case fatality rates, dialysis dependence, and reduced quality of life. Until recently, no uniform standard for diagnosing and classifying

ARF was available. Kellum et al12 reported that more than 35 different definitions of acute renal failure were used in clinical practice. A need for clear definitions of renal injury and renal failure has led to the request for measurable criteria. A consensus on the need for a definition and a classification system to enable more accurate diagnosis of kidney injury was reached by the Acute Dialysis Quality Initiative group.6,11 AKI refers to a sudden decline in kidney function that causes disturbances in fluid, electrolyte, and acid-base balances because of a loss in clearance of small solutes and a decreased glomerular filtration rate (GFR).13 Therefore, the term AKI has replaced the term ARF, with the understanding that AKI has a broad spectrum and encompasses the entire syndrome in all patients, not just patients who require renal replacement therapy but also patients with minor changes in renal function.14 In this article, I review AKI, including causes, detection with conventional and new markers, impact on outcome in critically ill patients, and prevention.

AKI Classification
Classification criteria for AKI include assessment of 3 grades of

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Table 1

RIFLE classification system for acute kidney injury

Criteria

RIFLE category Grades of severity Risk Injury Failure Outcomes Loss End-stage kidney disease

Glomerular filtration rate

Urine output

Serum creatinine level increased 1.5 times or glomerular filtration rate decreased >25% Serum creatinine level increased 2 times or glomerular filtration rate decreased >50% Serum creatinine level increased 3 times or glomerular filtration rate decreased >75% or serum creatinine level >4 mg/dL

<0.5 mL/kg for 6 hours <0.5 mL/kg for 12 hours <0.5 mL/kg for 12 hours or anuria for 12 hours

Complete loss of renal function for >4 weeks Need for renal replacement therapy for >3 months

severity: risk of acute renal failure, injury to the kidney, and failure of renal function. The 2 outcome classifications are loss of kidney function and end-stage renal disease. This 5-point system (risk of injury, injury, failure, loss of function, and end-stage renal failure) is known as the RIFLE classification system6,12,15 (Table 1). In several investigations2,7,8,14,16-19 on use of the RIFLE system in different populations of patients, RIFLE criteria correlated with outcome (see Figure). Consequently, the RIFLE classification is being used to identify kidney injury and improve patients outcome.

Conventional Markers for AKI

The loss of kidney excretory function can be manifested by the accumulation of end products of

metabolism. The detection of changes in these end products, or what are currently the conventional renal markers (Table 2), is the impetus for the diagnosis of AKI. Markers commonly used now are measurement of serum levels of creatinine and urea nitrogen, fractional excretion of sodium to assess GFR, and changes in urine output.20 Changes in these markers have been used to assess renal function for decades, but each marker has limitations.21 Because AKI has such a poor prognosis and increases risk for death in critically ill patients, tests of kidney function that allow early diagnosis of kidney injury are desirable. In addition, the time required for abnormal accumulation of the markers to become detectable in the serum can cause a delay in the diagnosis and, potentially, the treatment of AKI.22

Creatinine

Author
Susan Dirkes is an educator in the progressive care unit, University of Michigan Health System, Ann Arbor, Michigan.
Corresponding author: Susan Dirkes, RN, MSA, CCRN, University of Michigan Health System, 6326 Sterling Dr, Newport, MI 48166 (e-mail: sdirkes@umich.edu). To purchase electronic or print reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 899-1712 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints@aacn.org.

Creatinine is released from the plasma at a relatively constant rate, is freely filtered at the glomerulus, and is not reabsorbed or metabolized by the kidneys. Measurement of the serum level of creatinine is the most widely used method of assessing renal function.23 The historical belief was that when the creatinine level becomes greater than the normal reference range of 0.5 to 1.0 mg/dL (to convert to micromoles per liter, multiply by 88.4), the GFR decreases.21 Thus, changes in the serum level of creatinine in an ideal situation should be directly proportional to changes in GFR. Unfortunately, critically ill patients do not represent an ideal situation. The serum level of creatinine may be a poor reflection of kidney function because the patients are not in a steady state and an increase in the creatinine level lags behind renal injury by as much as 12 hours to 2 days.22 Use of creatinine as a marker for renal function has additional limitations. Patients age, sex, dietary intake, and muscle mass all influence the baseline level of creatinine, as

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90 80 70 60 Mortality, % 50 40 30 20 10 0 Hoste and Kellum8 Uchino et al17 Ostermann and Chang2 Injury Abosaif et al16 Maccariello et al18

with chronic liver disease may have normal values of urea because of decreased urea production and protein restriction and normal levels of serum creatinine despite markedly reduced GFR.21 In patients with decreased circulating blood volume due to volume depletion or low cardiac output, resorption of urea increases because of the relationship between urea levels and water conservation mechanisms.26 Therefore, urea, like creatinine, can be influenced by multiple factors and does not represent real-time changes in GFR because the accumulation of urea requires, at a minimum, several hours or longer.23
Fractional Excretion of Sodium

Risk

Failure

Figure Mortality by RIFLE class.

do some disease states and drugs (eg, cimetidine).23 Sex and age are influences because men typically have greater muscle mass than women do. As a person becomes older, a decrease in muscle mass occurs. Such a decrease also occurs in patients taking corticosteroids.24 Excess intake of cooked meat also can elevate the creatinine level in the absence of renal failure. Cimetidine is known to enhance creatinine clearance, thereby changing the amount of creatinine that is secreted.25 Measurement of serum creatinine levels does not depict real-time changes in GFR that occur with acute reduction in kidney function.21
Urea

Urea is another commonly used marker for the diagnosis of renal

failure. Urea is a by-product of protein metabolism and is used as a marker in AKI for retention and elimination of uremic solutes.23 Like creatinine, urea is not produced at a constant rate, and the rate can be influenced by extrarenal factors. Urea production can be increased by diet, critical illness, burns, trauma, gastrointestinal bleeding, and sepsis and can be influenced by drugs, such as corticosteroids.20 Thus, patients being treated with steroids, such as transplant recipients, may have increases in the serum concentration of urea without increases in serum level of creatinine. Also, critically ill patients who receive corticosteroids have an increase in protein catabolism associated with the medications and the overall hypercatabolism of their illness.20 Patients such as those

Fractional excretion of sodium has also been used as a marker for renal function. Its use is based on the principle that filtered sodium is reabsorbed into the renal tubules from glomerular filtrate in prerenal azotemia, in which tubular function remains intact.27 In prerenal azotemia, fractional excretion of sodium in urine is less than 1%.28 Fractional excretion is often greater than 1% in patients receiving diuretics and can be less than 1% in conditions such as sepsis, rhabdomyolysis, and exposure to radiological contrast media.29,30 In summary, in the clinical setting, fractional excretion of sodium is not an accurate indicator of renal injury, and the level is influenced by numerous conditions that reflect injury of the renal parenchyma.31

Novel Biomarkers for AKI

Studies32-34 in which variables such as levels of urea and creatinine and urine output have been used as

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Table 2
Marker Urea

Conventional markers for acute kidney injury

Normal value 8-20 mg/dL Source Serum Information By-product of protein metabolism, used as a marker indicating solute retention and elimination Derived from creatine, excreted through filtration in glomerulus Limitations Affected by diet, critical illness, burns, gastrointestinal bleeding, and trauma; production rate not constant Critically ill patients not in a steady state, may not reflect severity of renal injury; serum value influenced by patients age, sex, dietary intake, and muscle mass, as well as drugs May be greater than 1% in patients receiving diuretics, and <1% in patients with parenchymal acute renal failure, sepsis, rhabdomyolysis, or exposure to radiological contrast media

Creatinine

0.7-1.5 mg/dL

Serum

Fractional excretion of sodium

<1%

Urine

Used to differentiate between prerenal and established renal failure Sodium is reabsorbed from glomerular filtrate in prerenal acute renal failure, resulting in level <1%; in tubular injury, level is >1%

indicators of kidney function or injury have not provided interventions that decrease the need for dialysis or reduce mortality. At the same time, the inability to diagnose AKI quickly and accurately places an enormous financial burden on society: AKI-associated medical expenses are estimated to be $8 billion annually in the United States.33,35,36 Therefore, the use of biomarkers that could be used to detect early renal injury may affect timely diagnosis and, possibly, outcomes in AKI. Desirable characteristics of biomarkers for detection of AKI are ease of use and noninvasiveness; usability at the bedside or in a conventional clinical laboratory with samples such as blood or urine; reliance on a rapid, reliable, and standard test; and a high sensitivity to facilitate early detection.37 These biomarkers should be highly specific for AKI. Biomarkers may be able to (1) indicate the location of the injury, the duration of kidney failure, causes of renal injury, and the duration and need for renal replacement therapy and (2) be used to monitor the response to interventions.37,38

Some of the newer biomarkers are interleukin 18 (IL-18) neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). These markers were discovered initially in studies on the pathophysiology of AKI in animal models.38-40 Use of these biomarkers for AKI may enable earlier detection of renal injury and aid in identifying the time of occurrence of the initial injury, the nature of the injury, and the duration of AKI. Use of these biomarkers may also provide a window of opportunity for interventions that may be of more benefit if provided early enough in the course of the disease. The markers also may be useful in predicting the overall prognosis and any potential dialysis requirements. Currently, they have only been tested in small studies and in limited clinical situations.
Interleukin 18

Urinary levels of IL-18 have been shown to increase in ischemic AKI.37,41 Parikh et al42 found that IL-18 was an early marker for AKI in patients with acute respiratory distress syndrome. Urinary IL-18 levels greater than 100 pg/mg were predictive of the development of AKI 24 hours before the level of creatinine increased. The level of urinary IL-18 on the day of initiation of mechanical ventilation was also predictive of mortality in patients with acute respiratory distress syndrome, independent of the severity of illness, urine level of creatinine, and urine output.
Neutrophil Gelatinin-Associated Lipocalin

IL-18 is a proinflammatory cytokine produced in the proximal tubule after AKI. The intracellular protease capsase-1 converts the cytokines interleukin 1b and IL-18 to their active forms. IL-18 then exits the cell and enters the urine.

NGAL is normally present at low levels in several human tissues, including the kidneys, lungs, stomach, and colon.37 NGAL expression is markedly elevated in injured epithelium, which occurs in acute bacterial infections, asthma, and pulmonary disease.39,43-45 NGAL was detected more often than conventional markers of AKI in the kidneys after ischemic or nephrotoxic injury in animals models and was easily detected in urine and blood.44,45

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Recently, Kmpers et al46 found that serum levels of NGAL at the start of renal replacement therapies were predictive of survival in critically ill patients with AKI. In a study42 of 20 children undergoing cardiopulmonary bypass, AKI (defined as a 50% increase in serum creatinine according to the injury item of RIFLE) occurred in 28% of the patients, but diagnosis based on the serum level of creatinine was possible only 1 to 3 days after surgery. In 8 patients, the increase in serum creatinine level occurred 24 to 48 hours after surgery; in the other 12, it occurred 48 to 72 hours postoperatively. Therefore, the diagnosis of AKI based on serum creatinine level could only be made days after the injury. In contrast, a 10-fold or greater increase in NGAL in the urine or plasma occurred within 2 to 6 hours after the surgery. NGAL has also been evaluated as a biomarker of AKI in transplantation. Mishra et al47 used NGAL as an indicator of injury in living-related donor kidneys and cadaveric kidneys. The cadaveric kidneys all had some cold ischemia time before transplantation. Immunohistochemical staining for NGAL was minimal to absent in the living-related kidneys and easily detectable in the cadaveric kidneys. Biopsies obtained 1 hour after vascular anastomosis in the kidneys revealed a significant correlation between NGAL staining intensity and the subsequent development of graft dysfunction.
Kidney Injury Molecule-1

in the proximal tubules in kidney biopsy specimens from patients with established AKI, and urinary KIM-1 could be used to distinguish ischemic AKI from prerenal azotemia and chronic diseases.50 In another study,51 KIM-1 was measured in adults undergoing cardiopulmonary bypass. AKI (defined by RIFLE as an increase in serum creatinine of 0.3 mg/dL) developed in 31%, and urinary KIM-1 levels increased by about 40% at 2 hours after surgery and by more than 100% by 24 hours. KIM-1 seems to be more specific to ischemic or nephrotoxic kidney injury and is not markedly altered by chronic kidney disease or urinary tract infections. Therefore, it could be used to identify subtypes of AKI.37

and caution in the prescribing and dosing of aminoglycosides and the use of radiological contrast agents are also important components to prevent AKI.4
Hydration

Prevention of Kidney Injury

Studies14-17 of renal failure, as defined by RIFLE, indicate that AKI, even in milder forms and not just severe AKI requiring renal replacement therapy, is associated with mortality rates of 28% to 85%. Only a few therapeutic interventions affect the clinical course and outcome for critically ill patients once AKI is established.52 Some interventions have been successful in smaller studies of AKI, and but no intervention improved clinical end points such as need for dialysis or mortality.15,52 The goals of a preventive strategy for AKI are to preserve renal function and to prevent complications such as volume overload, electrolyte abnormalities, the need for chronic dialysis, and death. Conservative strategies to prevent AKI include prevention of dehydration, hypotension, and exposure to nephrotoxins. Adequate fluid administration, maintenance of mean arterial pressure,

KIM-1 is a protein that is highly overexpressed in proximal tubular cells after ischemic or nephrotoxic AKI in animal models.48 In a small study,49 KIM-1 was markedly present

Intravascular volume depletion is an important risk factor for AKI. In a study53 of outcomes in patients given fluids, the results suggested that use of fluids in combination with other treatments might be beneficial. Aggressive use of fluids in patients with rhabdomyolysis was beneficial.54 When patients with AKI have oliguria, defined as urine output less than 200 to 500 mL in 24 hours,21 fluids are commonly used to expand fluid volume. Of note, however, oliguria is not necessarily an indication for volume expansion. The clinical picture must be considered. Even though added fluids may increase urine flow, no evidence indicates that this increase will improve renal recovery and patients outcomes.55 Van Biesen et al56 found that liberal use of fluidsmean overall higher fluid intake of 2037 mL (SD, 1681) versus 1116 mL (SD, 1220)for the first 3 days of treatment of patients with ARF in the ICU could be harmful. In patients with acute respiratory distress syndrome, a positive fluid balance can be predictive of hospital mortality.57,58 Continuing to provide additional fluid therapy to improve urine output when hydration is adequate contributes to a grossly positive fluid balance, which in turn can adversely affect lung function and oxygenation.56,58-61 Therefore, although the use of fluids in AKI with oliguria can be beneficial initially, the decision to

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continue hydration should be carefully considered according to the patients weight, blood pressure, central venous pressure, and the use of any vasoactive drugs.
Maintaining Renal Perfusion Pressure

Abdominal Compartment Syndrome

Maintenance of fluid volume on the basis of mean arterial pressure is standard practice in the ICU. Sepsis, trauma, major surgery, and the use of certain drugs can cause systemic hypotension.62 Expansion and maintenance of fluid volume should be tailored to the achievement of targets such as cardiac output, central venous pressure, and urine output. Early goal-directed therapy with volume expansion for rapid fluid replacement is now a cornerstone in the management of sepsis.63 The result of this therapy is a vigorous replacement of fluid volume in the vascular space. In patients with hypotension and capillary leak, this increased fluid volume can lead to abdominal organ edema and pulmonary complications.64 Edema of solid organs and the visceral wall causes an increase in intraperitoneal pressure. This pressure can compress abdominal organs and cause organ and tissue ischemia. As abdominal ischemia progresses, ascities occurs, leading to a loss of fluids, electrolytes, and proteins through leaky capillaries and a loss of membrane integrity.65 The result is increased intra-abdominal pressure (IAP), which is associated with abnormalities in many organ systems. The overall increase in IAP causes compression of renal veins, and inadequate cardiac output diminishes renal blood flow.66

According to the World Society of Abdominal Compartment Syndrome,67 normal IAP in healthy persons is less than 5 to 7 mm Hg. The upper limit of nonpathological IAP is 12 mm Hg, and sustained increased pressure greater than 12 mm Hg is defined as intra-abdominal hypertension.68 Similar to the situation in cerebral perfusion pressure, a relationship exists between mean arterial pressure and IAP that is related to abdominal perfusion pressure.69 Increased IAP compromises venous return, cardiac output, and systemic oxygen delivery. As IAP increases, oliguria and renal injury occur despite continued fluid replacement.70 Unfortunately, once intraabdominal hypertension has occurred, relieving this pressure (ie, abdominal compartment syndrome) does not stop the renal injury. The goal is to detect the onset of renal injury by using new biomarkers.38 Currently, relief of abdominal compartment syndrome by laparotomy is the standard of care to prevent further renal injury.66 The primary strategy to prevent AKI is to minimize the risk of kidney injury by monitoring IAP before the onset of abdominal compartment syndrome.
Exposure to Nephrotoxins

Critically ill patients are often exposed to nephrotoxic materials, including, but not limited to, aminoglycosides, amphotericin B, and radiological contrast agents. In the ICU, nephrotoxic effects, either alone or more commonly associated with ischemia, have been a factor in the development of AKI in almost one-half of the cases.71,72 Because the

kidneys are responsible for the excretion of many drugs, the most common mechanism of nephrotoxic injury is the toxic effect on the renal tubules, causing cellular injury and death or inflammation.73 Aminoglycosides. Aminoglycosides are used often in critical care and are a contributing factor in 19% to 25% of cases of severe renal failure.7 Aminoglycosides are eliminated by glomerular filtration, but a fraction of the dose given is reabsorbed in the proximal tubule.74,75 After glomerular filtration, part of the aminoglycoside is transported to the intracellular compartment. Intracellular accumulation of the aminoglycoside is thought to interfere with cellular function, eventually leading to cell death and a decreased GFR.76 Nephrotoxic effects due to aminoglycosides are common in high-risk patients such as the elderly; renal dysfunction develops in 15% of elderly patients treated with these drugs.77 Once the nephrotoxic effects develop, the impaired renal function prevents the kidneys from excreting the dose of aminoglycoside within the dosing interval. Currently, the only clinical approach used to prevent the nephrotoxic effects is decreasing the dosage schedule to prevent further damage of the kidneys.78 In a meta-analysis79 of multiple and single daily dosing of aminoglycosides, the overall rate of nephrotoxic effects was 5.5% for a single daily dose and 7.7% for multiple daily doses. In other studies,78,80,81 once-daily dosing and multiple daily doses had similar efficacy in treating infections, but a trend favoring oncedaily dosing in reducing nephrotoxic effects was noted. Current

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recommendations are to consider alternative antimicrobial agents in patients such as elderly persons who are at high risk for nephrotoxic effects due to aminoglycosides.73 Amphotericin B. Amphotericin B is an extremely nephrotoxic drug.82 AKI associated with conventional use of amphotericin B occurs in 25% to 30% of patients treated with the drug, and the risk increases with cumulative doses.83 Amphotericin B directly binds to the tubular epithelial cells in the collecting duct, causing altered cell permeability, which in turn causes sodium, potassium, and magnesium wasting. The medication then directly causes vasoconstriction of the intrarenal arteries and arterioles.84-86 Renal function can improve when treatment with the drug is discontinued; other strategies to reduce the nephrotoxic effects of amphotericin B include sodium loading87 and longer infusion times, up to 24 hours.82 In a comparison82 of patients given a rapid infusion (over 4 hours) of amphotericin B and patients given a 24-hour infusion, patients in the rapid infusion group had significantly more nephrotoxic effects. Although this study82 and other studies83,84,87 showed a reduction in nephrotoxic effects when the drug was given by continuous infusion, all the studies had small sample sizes and were done in low-risk patients. New drugs have been approved for treatment of fungal infections, but because of its low cost and broad spectrum of activity, amphotericin B is still widely used.73 Vancomycin. Vancomycin is commonly used in the ICU for methicillinresistant Staphylococcus aureus and gram-positive bacterial infections.88

It is widely used in conjunction with other aminoglycosides, and the reported frequency of ARF in patients treated with vancomycin plus an aminoglycoside is 20% to 30%.89 Vancomycin is excreted by glomerular filtration; 80% to 90% is eliminated in an unaltered form. The mechanism of the nephrotoxic effects is unknown, but risk factors include age, use of other nephrotoxic agents, duration of therapy, and drug levels achieved.90,91 Standards of care to prevent the risk of nephrotoxic effects due to vancomycin include monitoring of trough levels of the drug and attention to dosing frequency. Radiological Contrast Media. The multiple types of radiological imaging for critically ill patients often involve use of contrast agents. At the same time, critically ill patients are likely to have compromised renal function and are often elderly.92 Contrast mediuminduced nephropathy (CIN) is a serious complication; it is associated with increases in hospital length of stay, requirement for dialysis, and risk for death.15,93 CIN is defined as an increase in serum creatinine that occurs within the first 24 hours after exposure to contrast medium and peaks within 3 days after the exposure.94 In a large study,14 the risk of death in patients with CIN was 34% compared with 7% in matched controls. Specific risk factors for CIN in hospitalized patients include diabetes mellitus,95 heart failure, volume depletion,96 nephrotoxic drugs, and unstable hemodynamic status.97,98 When radiological contrast material is used, the type and volume of the material administered may influence the risk for nephrotoxic effects.99

Once administered, iodinated contrast material collects and dwells in the urinary space of the glomerulus and renal tubules, where it has a direct cytotoxic effect on the renal tubular cells.100 Some research99 indicates the risk for CIN is less when low-osmolality agents are used, although use of lowosmolality agents did not influence the development of AKI or the need for dialysis. Other studies have had conflicting results. Strategies to reduce the incidence of CIN include volume expansion with isotonic crystalloid,101 hemofiltration,102,103 and use of N-acetylcysteine.104

Pharmacological Strategies to Prevent AKI

Table 3 lists pharmacological strategies for prevention of AKI.
Loop Diuretics

Oliguria develops in many ICU patients. Therapeutic options for these patients include ruling out urinary tract obstruction, restoration and maintenance of fluid balance, and restoration of urine flow.120 Loop diuretics have long been used to treat ICU patients with AKI. These agents act in the kidney in the loop of Henle to prevent the reabsorption of water.55 Loop diuretics aid in the management of fluid volume overload by augmenting diuresis and help maintain homeostasis.120 In a multinational study,121 furosemide was by far the most common diuretic used, but most clinicians did not actually think use of this diuretic would lead to improved clinical outcomes. Although use of furosemide in animal models of AKI has shown it can reduce injury and improve renal

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Table 3
Method Loop

Pharmacological strategies for acute kidney injuries

Method of action Act in loop of Henle to prevent reabsorption of water Effective in volume overload by augmenting diuresis Increases renal blood flow by splanchnic vasodilatation, increasing cardiac output and perfusion pressure Increases renal blood flow and glomerular filtration rate Summary Adverse effects include risk of temporary deafness and tinnitus with use of high doses No data indicate that loop diuretics decrease need for renal replacement or number of dialysis sessions Use may be associated with increased risk of death or nonrecovery of renal function In studies on the role of dopamine in the prevention of deterioration of renal function in intensive care units, dopamine did not prevent onset of acute renal failure, need for dialysis, or mortality Use decreases incidence of acute renal failure in intensive care patients Use significantly reduces the risk for acute kidney injury, need for renal replacement therapy, and in-hospital death in intensive care patients and patients undergoing major surgery Currently, used alone, fenoldopam has no role in the prevention of contrastinduced nephropathy

diureticsa

Dopamineb

Fenoldopamc

Natriuretic peptidesd

Maintain pressure and homeo- Oliguric patients (urine ouptut <400 mL/day) given atrial natriuretic peptide (Anaritide) had better dialysis-free survival than did the placebo group; nonoliguric stasis by modulating cardiac patients had worse dialysis-free survival with Anaritide and renal function Atrial natriuretic peptide associ- Compared with placebo, use of a continuous infusion of low-dose human recombinant natriuretic peptide was associated with a decreased use of dialysis and ated with an increase in improved dialysis-free survival glomerular filtration rate No large trials have been done to validate the effectiveness of using natriuretic peptides One study indicated that N-acetylcysteine significantly reduced the incidence of contrast mediuminduced nephropathy (CIN) Other current data do not show consistent results in the prevention of CIN; however, N-acetylcysteine is low cost and may help prevent CIN in high-risk patients

N-acetylcysteinee Antioxidant and free-radical scavenger with vasodilating properties

a

Based on data from Marenzi et al,102 Bagshaw et al,105 and Mehta et al.106 Based on data from Kellum and Decker,107 Marik,108 Friedrich et al,109 and Bellomo et al.110 c Based on data from Halpenny et al,111 Morelli et al,112 and Landoni et al.113 d Based on data from Ricksten and Swrd,114 Allgren et al,115 and Swrd et al.116 e Based on data from Singbartl and Zarbock,117 Pannu et al,118 and Hoffman et al.119
b

hemodynamics, these results were not universal.105,121-124 In contrast, in vitro studies125 with peripheral blood mononuclear cells stimulated with lipopolysaccharide have shown that high concentrations of furosemide have cytotoxic and immunosupressive effects. Other evidence106 indicates that furosemide does not improve outcome in AKI. Therefore, an accurate assessment of each patient and the patients clinical feature should guide the use of loop diuretics.
Dopamine

Several investigators108-110 have evaluated the role of dopamine in preventing the deterioration of renal function in ICU patients. The results indicated that the drug did not prevent the onset of ARF or the need for dialysis or improve mortality,108,109 and Bellomo et al110 concluded that dopamine has no role in the prevention of AKI.
Natriuretic Peptides

by Swrd et al,116 compared with continuous infusion of a placebo, continuous infusion of low-dose human recombinant natriuretic peptide was associated with a decrease in use of dialysis and an improvement in dialysis-free survival.
N-Acetylcysteine

Dopamine increases renal blood flow by splanchnic vasodilatation, increasing cardiac output and improving perfusion pressure.107

Low-dose human recombinant natriuretic peptides have been evaluated for prevention of AKI in cardiac surgery patients.115,116,126 The studies had small sample sizes and did not show any benefit of use of the peptides. However, in the study

N-acetylcysteine is an antioxidant.117 In several studies with small sample sizes, treatment with this antioxidant decreased CIN.118,127 N-acetylcysteine has a low cost, and may prevent CIN in patients at high risk for this nephropathy.1 N-acetylcysteine has also been used in conjunction with fenoldopam, a selective stimulator of the D1

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dopamine receptor that increases renal blood flow. The effects of N-acetylcysteine plus fenoldopam on morbidity and mortality, treatment, and length of hospital stay have been studied in cardiac surgical patients with moderate to severe preoperative renal dysfunction.118,127 Barr and Kolodner128 found that use of the 2 medications together had some renal-protective effects in the immediate postoperative period for patients with moderate to severe renal dysfunction but had no significant effect on length of stay, use of dialysis, or mortality.

Renal Replacement Therapies for AKI

Historically, the treatment of ARF has been supportive care. The most commonly used renal replacement therapy has been intermittent hemodialysis (IHD), for both patients with chronic renal failure and critically ill patients.129 Conventional indications for renal replacement therapy in AKI include fluid volume excess, hyperkalemia, metabolic acidosis, and uremia. This therapy also can be used for drug overdose.130 The focus of dialysis is removal of excess water and wastes via a dialysis machine and a dialyzer. IHD is intended to be used for short periods, typically 3 to 4 hours, to aggressively change fluid volume and remove wastes.131 A well-known consequence of this therapy is unstable hemodynamic status.132,133 IHD may be more suited to patients who are

To learn more about acute kidney failure, read Residual Urine Output and Postoperative Mortality in Maintenance Hemodialysis Patients, by Lin et al in the American Journal of Critical Care, 2009;18:446-455. Available at www.ajcconline.org.

not critically ill, because less ill patients typically have a more stable hemodynamic status and may tolerate sudden shifts in water volume and electrolyte levels.134 Research has shown that the rapid changes in fluid status and plasma osmolality associated with IHD may cause renal ischemia and delay renal recovery even after transient periods of hypotension.135 Episodes of renal hypoperfusion causing ischemia limit not only blood flow to the kidney but also the delivery of oxygen. Compared with cells in other organs, the tubular cells also depend on large amounts of oxygen.136 Small changes in oxygen delivery may exacerbate tissue hypoxia. When renal hypoperfusion occurs, the return of blood flow causes a series of events, including cytokine synthesis, altered cell adhesion, leukocyte migration, and leukocyte-mediated cell damage, causing physical blockage of renal microcirculation.137,138 With more severe injury, tubular cells die, causing the loss of tubular integrity and loss of renal function.139 Because of the renal abnormalities associated with IHD, the standard of care for patients who have this treatment may not be applicable to critical care patients, who differ in the nature of their illness, their catabolic state, the presence of systemic inflammatory syndrome with or without sepsis, and the presence of other organ failure.140 Therefore, other types of renal replacement therapies have been used in critically ill patients; the goals are to prevent further renal injury and preserve renal function. Continuous renal replacement therapy (CRRT) is currently used in

critically ill patients because of its many advantages compared with IHD: no abrupt variations in fluid removal or osmolality, good clearance of solutes, and better hemodynamic tolerance.141 Similar to IHD, CRRT requires an extracorporeal circuit, but the dialysis is continuous, 24 hours a day for several days. Compared with IHD, CRRT removes plasma water and wastes more slowly but still provides effective clearance of water and wastes.134 Removing water at a slower rate helps prevent hemodynamic complications. Despite the apparent advantages of CRRT versus IHD, no definitive studies comparing morbidity associated with the 2 methods have been done.141-144 Only a few studies145,146 have shown improved return of renal function with CRRT. In the Beginning and Ending Supportive Therapy for the Kidney study,147 investigators examined the effect of treatment choice on survival and renal recovery. Their results suggest that among survivors, IHD may increase dialysis dependence in AKI more than CRRT does. In a study to determine which method was better, Vinsonneau et al148 found no difference in mortality, ICU or hospital length of stay, or rate and time to renal recovery. In a recent study149 of intensive versus less intensive treatment strategies in IHD and CRRT, investigators compared standard dialysis 3 times per week with intensive dialysis 6 times per week, and CRRT at a standard effluent flow of 20 mL/kg per hour versus 35 mL/kg per hour. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy. The 2

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groups did not differ significantly in the duration of renal replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the 2 groups.

References
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Summary
AKI is a serious and common clinical problem in the ICU; even mild forms of AKI are associated with high mortality rates. The term AKI has replaced ARF, with the understanding that the spectrum of AKI is broad and includes different degrees of severity. A new classification system, known as the RIFLE system, can be used to identify kidney injury and outcome. New biomarkers are being studied to replace conventional markers such as urea and creatinine, but although the markers appear to hold promise in identifying kidney injury, they still are not commonly available and require more study. Methods to prevent AKI include maintenance of fluid volume, renal perfusion pressure, avoidance of nephrotoxic agents, and treatment of AKI by dialysis methods after careful assessment of the patient and the clinical picture. Use of a variety of methods to prevent AKI, including renal replacement therapies, may improve the outcome from AKI. CCN
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Financial Disclosures
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CriticalCareNurse Vol 31, No. 1, FEBRUARY 2011 49

CE Test Test ID C113: Acute Kidney Injury: Not Just Acute Renal Failure Anymore? Learning objectives: 1. Define and discuss acute kidney injury (AKI) 2. Compare and contrast renal biomarkers for early detection of AKI 3. Understand the RIFLE classification system 4. Discuss prevention and treatment strategies for AKI
1. Acute kidney injury (AKI) differs from acute renal failure (ARF) for which of the following reasons? a. AKI refers to a syndrome of clinical events. b. AKI has a higher mortality than ARF. c. AKI is more easily detected than ARF. d. AKI is limited to critically ill patients. 2. Which of the following is not a limitation of conventional biomarkers such as serum urea nitrogen and creatinine? a. Increased length of time for markers to accumulate b. Levels may be influenced by diet or medications c. Do not provide a true reflection of the glomerular filtration rate d. Inability to detect changes in metabolic end products 3. Which of the following biomarkers provides the earliest indication of AKI? a. Serum urea nitrogen b. Creatinine c. Interleukin 18 d. Fractional excretion of sodium 4. Which of the following factors does not influence higher mortality rates from AKI? a. Increasing age b. Preexisting renal disease c. Comorbid conditions d. Gender 5. Which of the following is a current recommendation to decrease nephrotoxicity from aminoglycosides? a. Consider once-daily dosing b. Consider alternative antimicrobial agents in high-risk patients c. Consider decreasing the dosage d. Consider alternate-day dosing 6. Which of the following statements regarding administration of fluids to expand volume in the presence of AKI is correct? a. Oliguria is an indication for volume expansion. b. Increased fluid volume will improve renal recovery. c. High fluid intake is necessary for the first 3 days of treatment. d. Fluids should be given based on physiologic parameters such as blood pressure and central venous pressure. 1. K a Kb Kc Kd 2. K a Kb Kc Kd 3. K a Kb Kc Kd 4. K a Kb Kc Kd 5. K a Kb Kc Kd 6. K a Kb Kc Kd 7. Which of the following is not a desirable characteristic of biomarkers for detection of AKI? a. Ease of use b. Ability to detect injury of the renal parenchyma c. High specificity for AKI d. Noninvasiveness 8. Which of the following individual variables was predictive of mortality in patients with acute respiratory distress syndrome at the onset of mechanical ventilation? a. Urinary interleukin 18 levels b. Creatinine c. Severity of illness d. Urine output 9. Which of the following pharmacological strategies for AKI has been associated with a decreased use of dialysis? a. Loop diuretics b. Dopamine c. N-acetylcysteine d. Natriuretic peptides 10. The RIFLE classification system is used for which of the following reasons? a. To assess grades of severity and risk of failure b. To assess likelihood of requiring renal replacement therapy c. To determine onset of AKI d. To determine optimal treatment for AKI 11. Which of the following is a conservative strategy to prevent AKI? a. Early implementation of renal replacement therapy b. Maintenance of renal perfusion pressure c. Maintenance of a positive fluid balance in the presence of acute respiratory distress syndrome d. Administration of dopamine 12. Benefits of continuous renal replacement therapy compared to intermittent hemodialysis include which of the following? a. Increased removal of solutes b. Rapid changes in fluid status c. Better hemodynamic tolerance d. Decreased mortality 7. K a Kb Kc Kd 8. K a Kb Kc Kd 9. K a Kb Kc Kd 10. K a Kb Kc Kd 11. K a Kb Kc Kd 12. K a Kb Kc Kd

Test answers: Mark only one box for your answer to each question. You may photocopy this form.

Test ID: C113 Form expires: February 1, 2013 Contact hours: 1.0 Fee: AACN members, $0; nonmembers, $10 Passing score: 9 correct (75%) Synergy CERP: Category A Test writer: Devin Carr, RN, MSN, ACNS-BC

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