William Dager and Jenana Halilovic
Three classification systems exist for staging severity of acute kidney injury (AKI): (a) Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease (RIFLE), (b) Acute Kidney Injury Network (AKIN), and (c) Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines. All three classification systems are based on separate criteria for serum creatinine (Scr) and urine output.
AKI is a common complication in hospitalized patients and is associated with high morbidity and mortality, especially in critically ill.
AKI is categorized based on three distinct types of injury: (a) prerenal—decreased renal blood flow, (b) intrinsic—structural damage within the kidney, and (c) postrenal—an obstruction is present within the urine collection system.
Conventional formulas used to determine estimated glomerular filtration rate (eGFR) and creatinine clearance should not be used to estimate renal function in patients with AKI. This may be especially true for medication dosing adjustments.
Prevention is of utmost importance since there are very few therapeutic options available for the treatment of established AKI.
Supportive management remains the primary approach to prevent or reduce the complications associated with AKI. Supportive therapies include renal replacement therapy (RRT), nutritional support, avoidance of nephrotoxins, and blood pressure and fluid management.
For those patients with prolonged or severe AKI, RRT is the cornerstone of support along with an aggressive approach to fluid, electrolyte, and waste management.
Drug dosing for AKI patients receiving continuous renal replacement therapy (CRRT) or sustained low-efficiency dialysis (SLED) is poorly characterized. Dosing regimens should be individualized and therapeutic drug monitoring utilized whenever possible.
Diuretic resistance is a common phenomenon in the patient with AKI and can be addressed with sodium restriction, combination diuretic therapy, or a continuous infusion of a loop diuretic.
Acute kidney injury (AKI) is a clinical syndrome generally defined by an abrupt reduction in kidney function as evidenced by changes in laboratory values, serum creatinine (Scr), blood urea nitrogen (BUN), and urine output. The consequences of AKI can be serious, especially in hospitalized patients, among whom complications and mortality are particularly high. Early recognition along with supportive therapy is the focus of management for those with established AKI, as there is no therapy that directly reverses the injury. Individuals at risk, such as those with history of chronic kidney disease (CKD), need to have their hemodynamic status carefully monitored and their exposure to nephrotoxins minimized. A thorough patient workup is often necessary and includes past medical and surgical history, medication use, physical examination, and multiple laboratory tests. Management goals include maintenance of blood pressure, fluid, and electrolyte homeostasis, all of which may be dramatically altered. Additional therapies designed to eliminate or minimize the insult that precipitated AKI include discontinuation of the offending drug (i.e., the nephrotoxin), aggressive hydration, maintenance of renal perfusion, and renal replacement therapy (RRT).
In this chapter, the definition, classification, epidemiology, and common etiologies of AKI are presented. Methods to recognize and assess the extent of kidney function loss are also discussed. Finally, preventive strategies for patients at risk and management approaches for those with established AKI are reviewed.
DEFINITION AND CLASSIFICATION OF ACUTE KIDNEY INJURY
Over the past 10 years, several efforts by a broad consensus of experts have been made to standardize the definition and classification of AKI. In 2004, the Acute Dialysis Quality Initiative (ADQI) group published a consensus-derived definition and classification system called the Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease (RIFLE) classification.1 In 2007, a modified version of RIFLE was developed by the Acute Kidney Injury Network (AKIN) and these criteria are presented in Table 28-12 (see Table 28-1 for an overview of all classification systems). Both classification systems are now widely accepted and have been validated to predict outcomes in thousands of patients worldwide.3,4 While generally similar, there are a few noteworthy differences: RIFLE defines AKI as an abrupt (1 to 7 days) but sustained (>24 hours) decrease in renal function from baseline while AKIN designates a 48-hour period for the decrease to occur. Also, AKIN removed RIFLE’s last two classification components (Loss of Kidney Function and End-Stage Kidney Disease [ESKD]) from the staging system and instead places all patients receiving RRT automatically into AKIN stage 3. Finally, AKIN removed all estimated glomerular filtration rate (eGFR) criteria from its staging system and lowered the absolute increase in Scr from 0.5 mg/dL (44 μmol/L) designated for RIFLE-Risk class to 0.3 mg/dL (27 μmol/L) for AKIN stage 1.1,2
TABLE 28-1 RIFLE, AKIN, and KDIGO Classification Schemes for Acute Kidney Injurya
Even though the initial aim of RIFLE and the AKIN modification was to provide a standardized definition of AKI, they resulted in two distinct definitions that were not consistently applied across studies and thus have provided somewhat different epidemiologic findings. In order to provide a single definition of AKI for practice, research, and public health, a second modification of RIFLE and AKIN criteria was recently published by the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines working group in 2012.5
KDIGO defines AKI as being present if any of the following three criteria are met: 1. Increase in Scr by at least 0.3 mg/dL (27 μmol/L) within 48 hours, 2. Increase in Scr by at least 1.5 times baseline within the prior 7 days, or 3. Decrease in urine volume to less than 0.5 mL/kg/h for 6 hours.
KDIGO staging of AKI is similar to the RIFLE and AKIN criteria with the notable addition of inclusion of pediatric patients (<18 years) to KDIGO Stage 3 for those with an estimated GFR of less than 35 mL/min/1.73 m2 (0.34 mL/s/m2) as determined by the Schwartz formula.5 Due to the very recent publication of KDIGO guidelines, it still remains to be seen if it will supersede RIFLE and AKIN criteria for the diagnosis and classification of AKI in the future.
Since all three staging systems depend on Scr and urine output as the main diagnostic criteria, they are associated with the same inherent weaknesses. An increase in Scr is usually evident about 1 or 2 days after development of AKI. This lag time in Scr rise may significantly delay diagnosis of AKI and adversely affect patient outcomes. Urine output reduction emerges earlier in AKI but is a very nonspecific marker because it may not always be present. In fact, patients with AKI can be anuric (urine output <50 mL/day), oliguric (urine output <500 mL/day), or nonoliguric (urine output >500 mL/day). Urine output will also vary with volume status, diuretic administration, and presence of obstruction.6 Further, since all criteria are based on detecting a decrease in Scr from its baseline, a patient’s renal function prior to the development of AKI needs to be known. If the baseline measure of Scr is not available and the patient has no history of renal dysfunction, the ADQI, a workgroup composed of experts in nephrology and critical care, has suggested estimating the baseline Scr value by using the four variable Modification of Diet in Renal Disease (MDRD) equation with an assumed normal GFR of 75 mL/min/1.73 m2 (0.72 mL/s/m2).1 However, this method needs to be interpreted with caution as it has been found to overestimate the incidence of AKI by as much as 40%.7,8
The epidemiology of AKI varies widely depending on the patient population, geographical location, and the criteria used to evaluate the patient. AKI is generally considered to be an uncommon condition in the community-dwelling population, with an annual incidence of 520 per 100,000 person-years for nondialysis requiring AKI and 30 per 100,000 person-years for dialysis-requiring injury9 (Table 28-2). AKI is more common in hospitalized individuals, with a reported incidence ranging from 2% to 20%.10,11 Intensive care unit (ICU) patients have the highest risk of developing AKI, with 20% to 60% of critically ill patients being affected.3,4
TABLE 28-2 Incidence and Outcomes of AKI
Increased mortality and morbidity are two well-recognized complications of AKI. In particular, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. Any degree of AKI is associated with an increased risk of death, and the odds increase with the severity of the insult.11,12 For survivors of AKI, the development of some degree of CKD and need for RRT are other important considerations.13 In addition, AKI is associated with increased length of hospital stay, ventilator days, and need for posthospitalization care.10,13
The etiology of AKI can be divided into broad categories based on the anatomic location of the injury associated with the precipitating factor(s). The management of patients presenting with this disorder is largely predicated on identification of the specific etiology responsible for the patient’s AKI (Fig. 28-1). Traditionally, the causes of AKI have been categorized as (a) prerenal, which results from decreased renal perfusion in the setting of undamaged parenchymal tissue, (b) intrinsic, the result of structural damage to the kidney, most commonly the tubule from an ischemic or toxic insult, and (c) postrenal, caused by obstruction of urine flow downstream from the kidney (Fig. 28-2).
FIGURE 28-1 Classification of acute kidney injury (AKI) based on etiology. (ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BPH, benign prostatic hyperplasia; HPI, history of present illness; HTN, hypertension; HUS, hemolytic uremic syndrome; NSAIDs, nonsteroidal antiinflammatory drugs; PMH, past medical history; TTP, thrombotic thrombocytopenic purpura.)
FIGURE 28-2 Physiologic classification of AKI. Blood flows through the afferent arteriole, to the glomerulus, and exits through the efferent arteriole. A decrease in blood flow and renal perfusion can lead to a prerenal reduction in renal function. Under conditions in which renal blood flow is diminished, the kidney maintains glomerular ultrafiltration by vasodilating the afferent arterioles and vasoconstricting the efferent arterioles. Medications that may interfere with these processes may result in an abrupt decline in glomerular filtration. Damage to the glomerular or tubular regions leads to intrinsic AKI. Obstruction of urine flow in the collecting tubule, ureter, bladder, or urethra is termed postrenal impairment.
Community-acquired AKI most commonly occurs secondary to renal hypoperfusion from volume depletion (dehydration, vomiting, and diarrhea), sepsis, or medications (angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and diuretics).9,14,15 The most common cause of hospital-and ICU-acquired AKI is intrinsic, occurring as the result of acute tubular necrosis (ATN).
The risk of AKI increases substantially with decreasing GFR and presence of underlying CKD.16 Other risk factors for developing AKI are age >65 years, septic shock, critical illness, chronic diseases (heart, lung, liver), recent exposure to nephrotoxic drugs, cardiac surgery, cancer, trauma, and African American race.5,15,17 History of AKI has also been associated with high risk for developing additional episodes of AKI and subsequent complications such as advanced CKD.18
The three main pathophysiologic processes involved in the development of AKI include prerenal AKI, intrinsic AKI, and postrenal AKI. As described below, pseudorenal kidney injury does not represent a true pathophysiologic process.
Pseudorenal Acute Kidney Injury
Pseudorenal AKI is characterized by a rise in either the BUN or the Scr, which misleadingly may suggest the presence of renal dysfunction, when in fact GFR is not diminished. This could be the result of cross-reactivity with the assay used to measure the BUN or Scr or selective inhibition of the secretion of creatinine into the proximal tubular lumen by certain medications (see eChap. 17). A similar problem exists when urine output data are unreliable. Urine output may be either inaccurate (particularly in noncatheterized patients) or not reported at all. Since the urine output criteria for AKI staging are weight-based, some obese individuals may meet the definition of AKI without truly having any kidney impairment. Thus, clinical judgment should always be applied when interpreting laboratory results.
Prerenal Acute Kidney Injury
Prerenal AKI or prerenal azotemia results from hypoperfusion of the renal parenchyma, with or without systemic arterial hypotension. Renal hypoperfusion with systemic arterial hypotension may be caused by a decline in either the intravascular volume or the effective circulating blood volume. Intravascular volume depletion may result from several conditions, including hemorrhage, excessive GI losses (severe vomiting or diarrhea), dehydration, extensive burns, and diuretic therapy. Effective circulating blood volume may be reduced in conditions associated with a decreased cardiac output and systemic vasodilation (e.g., sepsis). Renal hypoperfusion without systemic hypotension is most commonly associated with bilateral renal artery occlusion or unilateral occlusion in a patient with a single functioning kidney.
Patients with a mild reduction in effective circulating blood volume or volume depletion are generally able to maintain a normal GFR by activating several compensatory mechanisms. Those initial physiologic responses by the body stimulate the sympathetic nervous and the renin–angiotensin–aldosterone system and release antidiuretic hormone if hypotension is present. These responses work together to directly maintain blood pressure via vasoconstriction and stimulation of thirst, which in conscious patients results in increased fluid intake, as well as sodium and water retention. Additionally, GFR may be maintained by afferent arteriole dilation (mediated by intrarenal production of vasodilatory prostaglandins, kallikrein, kinins, and nitric oxide) and efferent arteriole constriction (mainly mediated by angiotensin II). In concert, these homeostatic mechanisms are often able to maintain arterial pressure and renal perfusion, potentially averting the progression to AKI.19 If, however, the decreased renal perfusion is severe or prolonged, these compensatory mechanisms may be overwhelmed, and prerenal AKI will be clinically evident.
Patients at risk for prerenal AKI are particularly susceptible to changes in the afferent and efferent arteriolar tone, as they may not be able to compensate as readily. Certain drug classes can interfere with these renal adaptive responses that are normally responsible for maintaining adequate renal perfusion. The resulting reduction in the glomerular hydrostatic pressure precipitates an abrupt decline in GFR and is sometimes referred to as functional AKI. A common cause of this syndrome is a decrease in efferent arteriolar resistance as the result of initiation of an ACE inhibitor or ARB (see Chap. 31). For example, individuals with heart failure are often given an ACE inhibitor or ARB to help improve left ventricular function, but if the dose is titrated too rapidly, they may experience a decline in GFR. If the increase in the Scr is less than 30% from baseline, the medication can generally be continued. Another classic example is initiation of ACE inhibitors or ARBs in patients with renovascular disease. It is estimated that ACE inhibitor–induced renal failure occurs in 6% to 23% of patients with bilateral renal artery stenosis and in 38% of patients with unilateral stenosis who have a single kidney.20 As a result, administration of ACE inhibitor or ARB therapy in the presence of those conditions is contraindicated. Nonsteroidal antiinflammatory drugs (NSAIDs) may also initiate AKI in susceptible individuals. NSAIDs inhibit renal prostaglandin production and afferent arteriolar vasodilation, which some patients rely on to maintain renal perfusion and GFR. Patients at risk for NSAID-induced AKI include those with CKD, volume depletion, and decreased effective circulating blood volume.21
If the causes of renal hypoperfusion are promptly corrected, prerenal AKI can be reversed and renal function returned to baseline in a matter of days. Prolonged prerenal azotemia, in contrast, can cause direct (and potentially irreversible) injury to the renal parenchyma and lead to development of ischemic ATN.22
Intrinsic Acute Kidney Injury
Intrinsic AKI results from direct damage to the kidney and is categorized on the basis of the injured structures within the kidney: the renal vasculature, glomeruli, tubules, and interstitium.
Renal Vasculature Damage
Occlusion of the larger renal vessels resulting in AKI is not common but can occur if large atheroemboli or thromboemboli occlude the bilateral renal arteries or one vessel of the patient with a single kidney. Atheroemboli most commonly develop during vascular procedures that cause atheroma dislodgement, such as angioplasty and aortic manipulations. Thromboemboli may arise from dislodgement of a mural thrombus in the left ventricle of a patient with severe heart failure or from the atria of a patient with atrial fibrillation. Renal artery thrombosis may occur in a similar fashion to coronary thrombosis, in which a thrombus forms in conjunction with an atherosclerotic plaque.
Although smaller vessels can also be obstructed by atheroemboli or thromboemboli, the damage is limited to the vessels involved, and the development of significant AKI is unlikely. However, these small vessels are susceptible to inflammatory processes that lead to microvascular damage and vessel dysfunction when the renal capillaries are affected. Neutrophils invade the vessel wall, causing damage that can include thrombus formation, tissue infarction, and collagen deposition within the vessel structure. Diffuse renal vasculitis can be mild or severe, with severe forms promoting concomitant ischemic ATN. The Scr is usually elevated when the lesions are diffuse. Accelerated hypertension that is not treated may also compromise renal microvascular blood flow, causing diffuse renal capillary damage.
Only 5% of the cases of intrinsic AKI are of glomerular origin. The glomerulus is one of two capillary beds in the kidney. It serves to filter fluid and solute into the tubules while retaining proteins and other large blood components in the intravascular space. Because the glomerulus is a capillary system, similar damage observed in the renal vasculature can additionally occur by the same mechanisms. The pathophysiology and specific therapeutic approaches to glomerulonephritis are described in detail in Chapter 32.
Approximately 85% of all cases of intrinsic AKI are caused by ATN, of which 50% are a result of renal ischemia, often arising from an extended prerenal state. The remaining 35% are the result of exposure to direct tubule toxins, which can be endogenous (myoglobin, hemoglobin, or uric acid) or exogenous (contrast agents, aminoglycosides, etc.). The tubules located within the medulla of the kidney are particularly at risk for ischemic injury, as this portion of the kidney is metabolically active and thus has high oxygen requirements, yet, as compared with the cortex, receives relatively low oxygen delivery. Thus, ischemic conditions caused by severe hypotension or exposure to vasoconstrictive drugs preferentially affect the tubules more than any other portion of the kidney.
The clinical evolution of ATN is characterized by three distinct phases: initiation, maintenance, and recovery. The hallmarks of the initiation phase are ischemic injury and GFR reduction, both of which occur as a result of the interplay between several different pathophysiologic processes. Ischemic injury causes tubular epithelial cell necrosis or apoptosis and is followed by an extension phase with continued hypoxia and an inflammatory response involving the nearby interstitium. The loss of epithelial cells between the filtrate and the interstitium leaves the basement membrane denuded and unable to appropriately regulate fluid and electrolyte transfer across the tubular lumen. As a result, the glomerular filtrate starts leaking back into the interstitium and is reabsorbed into the systemic circulation. Additionally, urine flow is obstructed by accumulation of sloughed epithelial cells, cellular debris, and formation of casts. The onset of ATN can occur over hours to days, depending on the factors responsible for the damage. Regardless of the etiology, tubular injury, back leakage, and obstruction lead to decreased urine-concentrating ability, decreased urine output, and, ultimately, reduced GFR. Continued kidney hypoxia or toxin exposure after the original insult kills more cells and propagates the inflammatory response. It also can extend the injury and delay the recovery process. With prolonged ischemia, the tubular epithelial cells in the corticomedullary junction are damaged and die.22 When the toxin or ischemia is removed, a maintenance phase ensues and may last anywhere from a few weeks to several months. The maintenance phase is eventually followed by a recovery phase, during which new tubule cells are regenerated. The recovery phase is associated with a notable diuresis, which requires prompt attention to maintain fluid balance, or a secondary prerenal injury may occur. However, if the ischemia or injury is extremely severe or prolonged, cortical necrosis may occur, limiting tubule cell regrowth in the affected areas.20
If the renal interstitium becomes severely inflamed and edematous, it can lead to development of acute interstitial nephritis (AIN). AIN may be caused by drugs (see Chap. 31), infections, and, rarely, autoimmune idiopathic diseases. Whatever the inciting event, acute interstitial injury is characterized by lesions composed of monocytes, eosinophils, macrophages, B cells, or T cells, clearly identifying an immunologic response as the injurious process affecting the interstitium. If AIN is caused by a drug hypersensitivity reaction, most patients will regain normal renal function within several weeks if the offending drug is promptly discontinued. If symptoms of AIN remain unrecognized, and the exposure to the causative agent continues, persistent renal dysfunction associated with interstitial fibrosis and tubular atrophy may develop.23
Postrenal Acute Kidney Injury
Postrenal AKI accounts for less than 5% of all cases of AKI and may develop as the result of obstruction at any level within the urinary collection system22 (see Fig. 28-1). However, if the obstructing process is above the bladder, it must involve both kidneys (one kidney in a patient with a single functioning kidney) to cause clinically significant AKI, as one functioning kidney can generally maintain a near-normal GFR. Bladder outlet obstruction, the most common cause of obstructive uropathy, is often the result of a prostatic process (hypertrophy, cancer, or infection), producing a physical impingement on the urethra and thereby preventing the passage of urine. It may also be the result of an improperly placed urinary catheter. Blockage may also occur at the ureter level secondary to nephrolithiasis, blood clots, sloughed renal papillae, or physical compression by an abdominal process. Crystal deposition within the tubules from oxalate and some medications severe enough to cause AKI is uncommon, but it is possible in patients with severe volume contraction and in those receiving large doses of a drug with relatively low urine solubility (see Chap. 31). In these cases, patients have insufficient urine volume to prevent crystal precipitation in the urine. Extremely elevated uric acid concentrations from chemotherapy-induced tumor lysis syndrome can cause obstruction and direct tubular injury as well.24 Wherever the location of the obstruction, urine will accumulate in the renal structures above the obstruction and cause increased pressure upstream. The ureters, renal pelvis, and calyces all expand, and the net result is a decline in GFR. If renal vasoconstriction ensues, a further decrement in GFR will be observed.
The initiating signs or symptoms prompting the clinical suspicion of AKI is highly variable and largely dependent on the underlying etiology. It may be a change in urinary habits (e.g., decreased urine output or urine discoloration), sudden weight gain, or severe abdominal or flank pain. Early recognition and cause identification are critical, as they directly affect the outcome of AKI. One of the first steps in the diagnostic process is to determine if the renal complication is acute, chronic, or the result of an acute change in a patient with known CKD (also called acute-on-chronic renal failure). Patients should also be promptly evaluated for any changes in their fluid and electrolyte status. Patients presenting with AKI in the outpatient environment may have very nonspecific or seemingly unrelated symptoms so that the time of onset of the injury can be difficult to determine. On the other hand, AKI in hospitalized patients is often detected much earlier in its course due to frequent laboratory studies and daily patient assessment.
The assessment of a patient with AKI starts with a thorough review of his or her medical records, with a particular focus on chronic conditions, medication history, laboratory studies, procedures, and surgeries. An exhaustive review of prescription and nonprescription medicines, herbal products, and recreational drugs may help determine if AKI was potentially precipitated by drug ingestion.
During the initial patient evaluation, presumptive signs and symptoms of AKI need to be differentiated from a potential new diagnosis of CKD. A past medical history for renal disease–related chronic conditions (e.g., poorly controlled hypertension and diabetes mellitus), previous laboratory data documenting the presence of proteinuria or an elevated Scr, and the finding of bilateral small kidneys on renal ultrasonography suggest the presence of CKD rather than AKI. However, it is important to note that patients with CKD may develop episodes of AKI as well. In that case, an abrupt rise in the patient’s baseline Scr is one of the most useful indicators of the presence of an acute insult to the kidneys.
An acute change in urinary habits is another common and noticeable symptom associated with AKI. The presence of cola-colored urine is indicative of blood in the urine, a finding commonly associated with acute glomerulonephritis. In hospitalized patients, changes in urine output may be helpful in characterizing the cause of the patient’s AKI. Acute anuria is typically caused by either complete urinary obstruction or a catastrophic event (e.g., shock or acute cortical necrosis). Oliguria, which often develops over several days, suggests prerenal azotemia, whereas nonoliguric renal failure usually results from acute intrinsic renal failure or incomplete urinary obstruction.
Depending on the underlying cause of AKI, patients may present with a variety of symptoms affecting virtually any organ system of the body. Constitutional symptoms such as nausea, vomiting, fatigue, malaise, and weight gain are common but nonspecific. The onset of flank pain is suggestive of a urinary stone; however, if bilateral, it may suggest swelling of the kidneys secondary to acute glomerulonephritis or AIN. Complaints of severe headaches may suggest the presence of severe hypertension and vascular damage. The presence of fever, rash, and arthralgias may be indicative of drug-induced AIN or lupus nephritis.
A thorough physical examination is an important step in evaluating individuals with AKI, as clues regarding the etiology can be evident from the patient’s head (eye examination) to toe (evidence of dependent edema) assessment. Observations will either support or refute the cause as prerenal, intrinsic, or postrenal. Evaluation of the patient’s volume and hemodynamic status is critical as well, as it will guide management. For example, patients with prerenal AKI can present with either volume depletion or fluid overload. Volume depletion may be evidenced by the presence of postural hypotension, decreased jugular venous pressure (JVP), and dry mucous membranes. Fluid overload, on the other hand, is often reflected by elevated JVP, pitting edema, ascites, and pulmonary crackles.
Conventional Markers of Kidney Function
The commonly available laboratory tests used to evaluate the patient with renal insufficiency are described in eChapter 17. Over the past 3 decades, Scr has been the most widely used laboratory test for estimating creatinine clearance (CLcr) and GFR. However, there are several limitations associated with its use. Scr varies widely with a patient’s age, gender, muscle mass, diet, and hydration status. For example, patients with reduced creatinine production, such as those with low muscle mass, may have very low Scr values (<0.6 mg/dL [<53 μmol/L]); thus, the presence of a gradual Scr rise to normal values (0.8 to 1.2 mg/dL [71 to 106 μmol/L]) may actually suggest the presence of AKI. However, in the presence of improved nutrition and a large muscle mass, a Scr of 1.2 mg/dL (106 μmol/L) may be a true representation of a person’s current renal status. Instead of using fixed numbers to determine renal function, changes in the value from a patient’s baseline need to be considered. Scr is normally inversely proportional to GFR. However, rapid changes in GFR (as they occur in AKI) disrupt this equilibrium and make Scr a very insensitive marker. In fact, changes in Scr will lag behind the GFR’s decline by 1 to 2 days due to slow accumulation, increased tubular secretion, and increased extrarenal clearance.25 This can lead to a significant overestimation of the patient’s GFR in the early stages of AKI and consequently a potential delay in the diagnosis of the syndrome.
An example of this phenomenon is illustrated by an acute renal artery thrombus that results in abrupt cessation of GFR in one kidney as a consequence of the complete obstruction of blood flow to that kidney (Fig. 28-3). Although 5 minutes following the event GFR is decreased 50% (assuming the other kidney is functioning and unaffected), the Scr remains unchanged. Assuming a standard daily creatinine production of ~20 mg/kg of lean body weight, one can expect ~1.4 g of creatinine production in a 24-hour period in a 70-kg individual. In pharmacokinetic terms, daily creatinine production is analogous to a continuous infusion, and GFR determines the elimination rate of creatinine. In a patient with normal renal function (GFR of 120 mL/min [2 mL/s]), the half-life of creatinine is 3.5 hours, with 95% of steady state achieved in ~14 hours. If GFR declines to 50%, 25%, or 10% of normal, the half-life of creatinine increases, resulting in prolongation of the time to reach 95% of steady state, specifically taking 1, 2, and 4 days, respectively.
FIGURE 28-3 Glomerular filtration rate (GFR; mL/min) and serum creatinine (Scr; mg/dL) versus time following the insult that leads to acute kidney injury (AKI). Prior to the renal insult, a patient’s GFR and Scr are at stable levels. After the renal insult has occurred, GFR readily declines while Scr does not increase immediately, as it is dependent on creatinine production and attainment of steady-state serum concentrations. Novel biomarkers can detect AKI within a few hours after the injury has occurred while conventional biomarkers may take 1 to 2 days to detect a noticeable change. AKI can only be staged once Scr has increased to a significant level. Patients at risk may benefit from prevention strategies; however, once AKI is diagnosed, supportive care and potentially renal replacement therapy should be implemented. Patients with established AKI should undergo further testing to determine the most likely etiology of AKI and need to be continuously monitored for any changes in their renal function. (BUN, blood urea nitrogen; IL-18, interleukin-18; KIM-1, kidney injury molecule 1; NGAL, neutrophil gelatinase–associated lipocalin.)
Because Scr steady-state values are assumed when one uses several GFR calculation methods, such as the Cockcroft-Gault, MDRD, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, should not be used in AKI patients with unstable renal function. These equations will typically overestimate GFR when the AKI is worsening and underestimate it when the AKI is resolving. Instead, it may be useful to evaluate changes in Scrvalues from the patient’s baseline and also consider the Scr sequence values to determine if renal function is potentially improving (Scr values declining) or worsening (Scr values rising). The most recent Scr reflects the time-averaged kidney function over the preceding time period. Several mathematical approaches to estimate GFR in patients with unstable Scr that incorporate the principles of creatinine accumulation and elimination have been proposed and are discussed in detail in eChapter 17. However, these methods have not been extensively validated in the setting of acute alterations in renal function, and their value for adjusting medication dosing is questionable. Additionally, these equations are complex and are not commonly used in the clinical setting.
Two other widely available markers of renal function are BUN and urine output. BUN is widely used to assess hemodialysis adequacy in chronic hemodialysis patients. However, its use in AKI is very limited because urea’s production and renal clearance are heavily influenced by extrarenal factors such as critical illness, volume status, protein intake, and medications. Urine output measured over a specified period of time (e.g., 4 to 24 hours) allows for short-term assessment of kidney function, but its utility is limited to cases in which it is significantly decreased. The presence of anuria suggests complete kidney failure, whereas oliguria indicates some level of kidney damage. Urine output needs to be interpreted with caution, as it is dependent on several factors, such as hydration status and medications. As mentioned earlier in the chapter, a patient may have AKI and still maintain a normal urine output; this condition is referred to as nonoliguric AKI. Another approach to estimating renal function is to directly measure CLcr over a short period of time, for example, 4 to 12 hours.26 Although potentially precise and fairly simple to do, its accuracy is questionable if the urine output is low or the urine collection is incomplete.
In addition to BUN and Scr, selected blood tests, urinary chemistry, and urinary sediment are routinely used to differentiate the cause of AKI and guide patient management. For example, a complete blood cell count with differential can help rule out infectious causes of AKI. Serum electrolyte values may be abnormal because of the acute decline of the kidney’s ability to regulate electrolyte excretion. Particular attention should be paid to serum potassium and phosphorus values, which can be markedly elevated and cause life-threatening complications. In individuals with normal renal function, the ratio between BUN and Scr is usually less than 15:1 using conventional units (60:1 using SI units). In the presence of prerenal AKI, reabsorption of BUN exceeds that of creatinine; thus, one often sees a ratio greater than 20:1 (80:1 using SI units).
Given the limited usefulness of solely using Scr or BUN concentrations to differentiate the etiology of AKI, urinary electrolytes and osmolality should be determined, and both a microscopic and chemical analysis of the urine should be performed (Table 28-3). The finding of a high urinary specific gravity, in the absence of glucosuria or mannitol administration, suggests an intact urinary concentrating mechanism and that the cause of the patient’s AKI is likely prerenal azotemia. The presence of urinary protein is often difficult to interpret, especially in the setting of acute or chronic renal failure. A patient with CKD may have a baseline proteinuria, thus clouding the clinical presentation, unless this is known at the time of AKI assessment. Classically, proteinuria is a hallmark of glomerular damage. However, tubular damage can also result in proteinuria, as the tubules are responsible for reabsorbing small proteins that are normally filtered by all glomeruli. The presence of blood also results in a positive urine protein test, so this confounder must always be assessed when a positive urine protein is obtained. Hematuria suggests acute intrinsic AKI secondary to glomerular injury, infection, or a kidney stone. On microscopic examination, the key findings are cells, casts, and crystals, and the presence of one or more of these may suggest specific etiologies of the AKI (Table 28-4). The finding of urinary crystals may indicate nephrolithiasis and a postrenal obstruction. If red blood cells or red blood cell casts are present, one should consider the presence of a physical injury to the glomerulus, renal parenchyma, or vascular beds. The finding of white blood cells or white blood cell casts suggests interstitial inflammation (i.e., interstitial nephritis), which can be secondary to an allergic, granulomatous, or infectious process.
TABLE 28-3 Diagnostic Parameters for Differentiating Causes of AKIa
TABLE 28-4 Urinary Findings as a Guide to the Etiology of AKI
Simultaneous measurement of urine and serum electrolytes is also helpful in the setting of AKI (see Table 28-3). From these values, a fractional excretion of sodium (FENa) can be calculated. The equation for the calculation of the FENa is as follows:
where Uvol is urine volume; Ucr is urine creatinine concentration; UNa is urine sodium; Scr is serum creatinine concentration; SNa is serum sodium concentration, which usually does not vary much; GFR is the glomerular filtration rate; and t is the time period over which the urine is collected.
The FENa is one of the better diagnostic parameters to differentiate the cause of AKI. A low urinary sodium concentration (<20 mEq/L [<20 mmol/L]) and low FENa (<1%) in a patient with oliguria suggest that there is stimulation of the sodium-retentive mechanisms in the kidney and that tubular function is intact. These findings are most characteristic of prerenal azotemia. Unfortunately, diuretic use in the preceding days limits the usefulness of the FENa calculation by increasing natriuresis, even in hypovolemic patients. The fractional excretion of urea (FEUrea), which can be calculated like FENa, is sometimes used as an alternative means to assess tubular function. The inability to concentrate urine results in a high FENa (>2%), suggesting tubular damage as the primary cause of the intrinsic AKI. However, this is also not an absolute finding, as there are some intrinsic causes that can be associated with a low FENa (e.g., contrast nephropathy, myoglobinuria, and interstitial nephritis). Highly concentrated urine (>500 mOsm/kg [>500 mmol/kg]) suggests stimulation of antidiuretic hormone and intact tubular function. These findings are consistent with prerenal azotemia.
Novel Biomarkers of Kidney Function
Diagnostic delays associated with creatinine-based methods have stimulated the search for novel biomarkers that are able to detect renal injury before a clinically evident decline in GFR occurs. Biomarkers that can detect renal injury more sensitively than Scr would enable clinicians to identify AKI earlier and, as a result, initiate preventative strategies and other interventions more rapidly.
An ideal biomarker would be highly sensitive and specific for AKI, noninvasive, and reliably and easily measurable using standardized clinical assays. In addition, it would differentiate between different AKI etiologies, be unaffected by other comorbidities and biologic variables, and allow for monitoring of response to AKI interventions. Over the past 10 years, several biomarkers have been investigated in their ability to detect and predict the clinical outcomes of AKI.27 Since no single marker fulfills all the criteria to be deemed “ideal,” combining multiple biomarkers into a panel may serve as a future clinical application for early detection, differential diagnosis, prognosis, response, and recovery of AKI. Of note, since the area of biomarker research is still relatively novel, these tests are not routinely available at most clinical practice sites. Over the past 2 years, several clinical studies evaluated the diagnostic and prognostic value of AKI biomarkers in heterogeneous patient populations and overall demonstrated promising results. However, the transition to clinical application will still require further validation, standardization, and development of implementation strategies for their use in all practice settings. Table 28-5 summarizes the advantages and disadvantages of the four most promising biomarkers.
TABLE 28-5 Advantages and Disadvantages of Novel Clinical Biomarkers of AKI
One such biomarker, serum cystatin C (see eChap. 17), is an endogenous cysteine proteinase that is released into the plasma by all nucleated cells in the body at a relatively constant rate and is then freely filtered by the glomerulus. It does not undergo any significant secretion or reabsorption, but is instead completely metabolized by the proximal renal tubules and undetectable in urine in normal kidney tissue.28However, if tubular injury occurs, plasma cystatin C levels will rise and urinary levels will become detectable. Serum cystatin C has been extensively studied as a marker of estimated GFR in patients with stable renal function, and its measurements are readily available using standardized assays.29 Its performance in early detection and clinical outcome prediction for AKI has yielded varied results. While it does seem to outperform Scr, it has not generally outperformed other novel biomarkers.28 One of its main limitations is that, similarly to Scr, cystatin C is a marker of GFR and not a direct marker of tissue injury. Therefore, the rise in its concentrations may be delayed compared with other biomarkers and it lacks specificity in differentiating AKI from CKD.27 Also, cystatin C levels may be altered by certain disease states (e.g., thyroid dysfunction and systemic inflammation) and possibly patient demographics (age, weight, gender, etc.).30,31
Another relatively novel biomarker is neutrophil gelatinase–associated lipocalin (NGAL), a transporter protein found on cell surfaces of neutrophils and various epithelial cells. It is freely filtered by the glomeruli and reabsorbed by the proximal tubules.32 As a result, if proximal tubular injury occurs, urinary NGAL levels are expected to rise. Studies indicate that NGAL is a valuable biomarker of AKI development across a range of clinical settings, including both pediatrics and adults, patients with contrast-induced nephropathy (CIN), critically ill, and cardiac surgery patients.33 NGAL measurements may be elevated as early as 1 to 2 hours after renal injury in select populations and correlate well with the severity of AKI.34 Also, the recent development of two standardized clinical assays, a chemiluminescent microparticle assay for urine NGAL and a point-of-care kit for plasma NGAL, will help increase the availability of this measure to assess the risk of AKI.27 Although NGAL appears to be a very sensitive, specific, and early biomarker of AKI, its levels may be influenced by the presence of CKD and other comorbidities.35
Interleukin-18 (IL-18) is a proinflammatory cytokine produced by the proximal tubular epithelial cells in response to renal injury. It seems to be specific for ischemic ATN and can distinguish it from CKD, prerenal azotemia, nephrotic syndrome, and urinary tract infections.36 Urinary IL-18 levels begin increasing as early as 4 to 6 hours after an ischemic insult, peak at 12 hours, and remain elevated for up to 48 hours.37 Urinary IL-18 has been studied in several clinical settings with varied results. Its ability for early detection of AKI has proven more robust in patients with discrete ischemia reperfusion injury such as kidney transplantation or pediatric cardiopulmonary bypass and less favorable in critically ill patients or adults with comorbidities.27,38 This finding may, in part, be explained by the potential confounding impact of systemic inflammatory states on IL-18 levels, but the extent of this association still remains largely unknown.27 Even though the performance of IL-18 on early AKI detection has been inconsistent, recent studies suggest that IL-18 may be more useful as a prognostic marker of poor renal outcomes, including mortality.
Kidney injury molecule 1 (KIM-1) is a membrane glycoprotein expressed by the proximal tubular epithelial cells and released into the urine in response to ischemic renal injury. One advantage of KIM-1 is that it is not expressed in healthy kidney tissue or detected in plasma.39 While KIM-1 does have detectable levels in patients with other renal diseases such as CKD and CIN, these concentrations are significantly lower compared with ischemic AKI.27,32This finding suggests that KIM-1 may be useful in differentiating ischemic AKI from other types of renal injury. Studies indicate that KIM-1 is a promising biomarker for early detection as its levels are elevated as early as 2 hours after renal injury.40 In addition, a rapid urine dipstick test for KIM-1 is now available that provides semiquantitative results in 15 minutes and may serve as an additional tool for rapid and early diagnosis of AKI.41
When the source of renal injury is unclear after a history, physical examination, and assessment of laboratory values, imaging techniques such as abdominal radiography, including the kidneys, ureters, and bladder (KUB), computed tomography (CT), and ultrasonography may be helpful. These may reveal small, shrunken kidneys indicative of CKD. Postrenal obstruction can often be identified with a renal ultrasonogram and/or CT scan. Renal ultrasonography is also useful in detecting obstruction or hydronephrosis. Nephrolithiases as small as 5 nm or a narrowing of the ureteral tract can be detected by ultrasonography or more sensitive tests, such as KUB and CT.
In cases in which the cause of AKI is not evident, renal biopsies are useful in determining the cause in the majority of patients. Because of the associated risk of bleeding, a renal biopsy is rarely undertaken and should only be performed in those circumstances when a definitive diagnosis is needed to guide therapy, such as the precise etiology of glomerulonephritis (see Chap. 32).
PREVENTION OF AKI
The preventive strategy will depend on the type of renal insult. Clearly, complete avoidance of all potential causes of injury is the most effective preventive method; however, it may not always be possible to implement. Sometimes, the risk of renal injury is predictable, such as decreased perfusion secondary to coronary bypass surgery or secondary to the administration of a radiocontrast dye prior to a diagnostic procedure. In these situations, the potential insult to the kidneys cannot be avoided but may be preventable with aggressive hydration and removal of any additional insults. In the outpatient setting, all healthcare professionals should educate the patient on preventive measures for AKI. Patients should receive counseling regarding their optimal daily fluid intake (~2 L/day) to avoid dehydration, especially if they are to receive a potentially nephrotoxic medication. In the inpatient setting, adequate hydration, standardized hemodynamic support in the critically ill, and avoidance of nephrotoxic medications are commonly recommended strategies for the prevention of AKI. Table 28-6 summarizes the recommendations published by KDIGO clinical practice guidelines regarding recommended and not recommended therapies for the prevention of AKI.5,24
TABLE 28-6 KDIGO Recommendations for Prevention and Treatment of AKI
The goals of AKI prevention are to (a) screen and identify patients at risk, (b) monitor high-risk patients until the risk has subsided, and (c) implement prevention strategies when appropriate.
Several nonpharmacologic therapies have been explored for the prevention of AKI, including hydration and RRT.
Hydration is one of the primary interventions that has consistently shown benefit and is routinely used in the prevention of AKI. Fluids have largely been studied in association with hemodynamic instability secondary to intravascular volume depletion as well as contrast administration before a radiologic procedure.
Hemodynamic instability increases the risk of AKI as it can lead to decreased renal perfusion and subsequent renal injury. Both isotonic crystalloids and colloid-containing solutions have been studied as means to replace intravascular volume. Among colloids, synthetic products such as hyperoncotic hydroxyethyl starch have been associated with renal dysfunction and should generally be avoided in patients at risk for AKI.42 Albumin appears to be safe for the kidneys; however, it is more costly and does not provide better patient outcomes compared with isotonic saline.43 As a result, KDIGO guidelines recommend isotonic crystalloids over colloids for intravascular volume expansion in patients at risk for AKI.5
CIN is a common cause of ATN in the inpatient setting (see Chap. 31 for a detailed discussion of CIN) and is typically characterized by an increase in Scr starting at 12 hours to up to 5 days after the radiologic procedure.5 It is associated with increased mortality especially in individuals with CKD, diabetes, volume depletion, concurrent nephrotoxic drug therapy, or hemodynamic instability.44 Hydration is thought to counterbalance some of the deleterious effects of radiocontrast dyes by diluting the contrast media, preventing renal vasoconstriction that contributes to hypoxia and ischemia, and minimizing tubular obstruction.45 Sodium bicarbonate infusion has also been evaluated for the prevention of CIN. The hypothesized mechanism for protection is that sodium bicarbonate may reduce the formation of oxygen free radicals by alkalinizing renal tubular fluid.46 There is currently no agreement on which hydration regimen is more effective as some studies indicate lower incidences of CIN with sodium bicarbonate while others show lower CIN rates with isotonic saline.47,48 The KDIGO guidelines currently recommend using either sodium bicarbonate or isotonic saline in high-risk individuals receiving radiocontrast media.5
Since there is no consensus on the optimal rate and duration of fluid infusions, CIN hydration protocols may vary slightly across different institutions. A common sodium bicarbonate regimen is 154 mEq/L (154 mmol/L) infused at 3 mL/kg/h for 1 hour before the procedure and at 1 mL/kg/h for 6 hours after the procedure.46,48 The rate and duration of normal saline infusion vary, but one frequently cited regimen is 1 mL/kg/h for 12 hours before and 12 hours after the procedure.48 The rate of administration may need to be adjusted depending on the patient’s cardiopulmonary and volume status.
Renal Replacement Therapy
Prophylactic administration of RRT has been explored as another potential approach to prevent CIN in high-risk patients. Radiocontrast media are eliminated by the kidneys, but their clearance is delayed in patients with renal dysfunction, thereby increasing their risk for nephrotoxicity. RRT use is based on its ability to enhance radiocontrast dye clearance and thus potentially prevent nephrotoxicity. So far, there seems to be no overall benefit of RRT in decreasing the incidence of CIN.43,49 In fact, there seems to be a significantly higher risk of harm among studies using prophylactic hemodialysis versus other RRT modalities such as hemofiltration.43,49 There also may be a difference in renal outcomes based on the timing of RRT relative to contrast administration as well as the patients’ degree of renal impairment. RRT has demonstrated most promising clinical benefit when hemofiltration was initiated both before and after the procedure in patients with advanced CKD (stage 4 or higher).48,50 Other, more practical issues associated with using prophylactic RRT are cost and the labor-intensive and invasive nature of the procedure itself. Overall, due to a relatively uncertain benefit, KDIGO guidelines do not currently recommend RRT for prevention of CIN.5 However, further investigation is needed to elucidate the mechanisms and timing of different RRT modalities and clarify the effect of underlying CKD on renal outcomes.
Several pharmacologic therapies have been investigated for the prevention of AKI with variable results.
Loop diuretics are frequently used for the management of fluid overload in patients at risk for AKI as well as those with established renal injury. Early experimental studies proposed that loop diuretics had the following theoretical advantages: decreased risk of tubular obstruction secondary to an increased urine flow and flushing out of debris; increased urine output that may be beneficial in itself, as nonoliguric AKI is associated with better outcomes than oliguric AKI; decreased risk of ischemic injury as the result of inhibition of the sodium/potassium chloride cotransporter and thus a reduction in oxygen demand; and enhanced renal blood flow due to increased availability of renal prostaglandins.28 However, clinical studies have found that even though the loop diuretics increase urine output, they neither reduce the incidence of AKI nor improve patient outcomes, such as mortality, need for RRT, and renal recovery.28,51 There is even some evidence of potential harm associated with their use, in particular, ototoxicity and possibly mortality in certain clinical settings.51 Proposed explanations for such lack of benefit are twofold. Loop diuretics may not be reaching the proximal tubule, their site of action, due to tubular obstruction from debris, increased extrarenal clearance secondary to hypoalbuminemia, and increased urinary protein binding due to albuminuria. Also, loop diuretics may actually decrease renal blood flow by reducing effective circulating arterial volume, which, in turn, may stimulate the adrenergic and the renin–angiotensin systems.28 Therefore, the KDIGO guidelines recommend limiting the use of loop diuretics to the management of fluid overload and avoiding their use for the sole purpose of prevention or treatment of AKI.5
Vasodilators studied for the prevention and treatment of AKI include dopamine, fenoldopam, anaritide, and nesiritide.
Dopamine Dopamine is a nonselective dopamine receptor agonist that, in high doses, also stimulates the adrenergic receptors. Low doses of IV dopamine (1 to 3 mcg/kg/min) increase renal blood flow, induce natriuresis and diuresis, and might be expected to increase GFR. Theoretically, this could be considered beneficial, as an increase in renal perfusion and oxygenation might limit ischemic cell injury, inhibition of sodium transport might reduce oxygen demand, and an enhanced GFR might flush nephrotoxins and casts from the tubules. Despite these theoretical suggestions, controlled studies have found that low-dose dopamine did not prevent AKI, need for dialysis, or mortality compared with placebo.52 Thus, current evidence and KDIGO guidelines do not support the use of low-dose dopamine for prevention or treatment of noncardiogenic AKI.5
Fenoldopam Fenoldopam mesylate is a selective dopamine A1 receptor agonist that increases renal blood flow, natriuresis, and diuresis without systemic α- or β-adrenergic stimulation. Fenoldopam has largely been studied in critically ill and/or cardiac surgery patients. Some studies have demonstrated decreased inpatient mortality and need for RRT while others have not found any benefit.53 Due to a lack of large multicenter trials as well as risk of hypotension, current KDIGO guidelines do not recommend the use of fenoldopam for the prevention and treatment of AKI.5
Natriuretic Peptides Natriuretic peptides, specifically atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), mediate vasodilation, diuresis, and natriuresis. ANP, which is released from the atrium in response to a rise in atrial stretch, dilates the afferent renal arteriole and constricts the efferent renal arteriole resulting in an increase in renal perfusion and GFR. Clinical studies on human recombinant ANP (anaritide) have varied in their findings, depending on the patient population and the anaritide dose under study. There is some evidence that anaritide may be beneficial in reducing the need for RRT in cardiac surgery patients but not in other patient populations.54 Also, anaritide at low doses (50 to 100 ng/kg/min) seems to be associated with improved outcomes while doses above 100 ng/kg/min increase the risk of hypotension and arrhythmias.5,54 On the other hand, studies using BNP (nesiritide) have largely demonstrated no benefit on the long-term survival and renal outcomes in patients at risk for AKI.55 Due to the need for further research on appropriate dosing and duration as well as risk of adverse effects, both ANP and BNP are currently not recommended for prevention or treatment of AKI by the KDIGO Work Group.5
Ascorbic acid and N-acetylcysteine (NAC) are two antioxidants that have been studied for the prevention of AKI.
Ascorbic Acid Ascorbic acid has mainly been studied in the prevention of CIN, as its antioxidant properties are thought to alleviate oxidative stress caused by CIN-associated ischemia reperfusion injury.56While its excellent safety profile and low cost make it an attractive option, clinical studies have reported inconsistent results on its protective effect against CIN.57–59 One randomized, double-blind, placebo-controlled trial demonstrated that ascorbic acid, 3 g orally before the procedure and 2 g orally twice daily for two doses after the procedure, significantly diminished the incidence of CIN in patients undergoing coronary angiography/intervention.58 However, several subsequent studies were unable to reproduce the same results and have largely found no difference from placebo.57,59 While the KDIGO Work Group does not specifically provide recommendations on ascorbic acid, majority of studies indicate that ascorbic acid is expected to have little, if any, therapeutic benefit for the prevention of CIN.
N-Acetylcysteine NAC is another antioxidant that has been widely studied in the prevention of CIN. However, a therapeutic benefit is thought to be quite modest and has not been consistently demonstrated.47,60 When compared with ascorbic acid, NAC seemed to be more beneficial in preventing CIN, particularly in diabetic patients with preexisting CKD.61 The recommended dosing regimen for prevention of CIN is 600 to 1,200 mg orally every 12 hours for 2 to 3 days, with the first two doses administered prior to contrast exposure. This dosing regimen is generally well tolerated and expected to have little adverse effects. NAC has also been evaluated for the prevention of AKI in postoperative setting as well as in critically ill patients with hypotension, but studies have failed to demonstrate any protective effect on renal function.5,62
Glycemic control in critically ill patients is of utmost importance, as stress hyperglycemia and insulin resistance are common during critical illness. The causes of insulin resistance are multifactorial but include impaired glucose homeostasis due to loss of the kidney’s metabolic function, and decreased hepatic and peripheral glucose uptake secondary to uremia. Hyperglycemia has also been associated with an increased risk of renal injury, but the exact mechanisms by which glucose may contribute to renal toxicity are not fully elucidated.63 Experimental studies indicate increased sensitivity to renal ischemia reperfusion injury, glucose overload in the kidney causing tissue damage, and increased inflammation.64 Patients may also be at higher risk for hypoglycemia, as the kidneys are the primary metabolic site of insulin.
Contrary to earlier findings, recent studies conducted in critically ill patients now indicate that intensive insulin therapy to maintain blood glucose of 80 to 110 mg/dL (4.4 to 6.1 mmol/L) is associated with more adverse effects compared with conventional insulin therapy (180 to 200 mg/dL [10 to 11.1 mmol/L] blood glucose).65,66 The Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, a large multicenter randomized study conducted in medical and surgical ICU patients, revealed that intensive glucose control was associated with significantly greater 90-day mortality rates and higher risk of hypoglycemia compared with conventional insulin therapy (144 to 180 mg/dL [8 to 10 mmol/L]). Although the study did not report the incidence of ICU-acquired AKI, no significant difference in the need for RRT between the two groups was noted.65 A subsequent meta-analysis of 26 published trials conducted in ICUs found that intensive insulin therapy increased the risk of hypoglycemia by sixfold and did not provide an overall mortality benefit.67 As a way to balance potential benefit and harm, current KDIGO guidelines suggest using insulin therapy to target plasma glucose of 110 to 149 mg/dL (6.1 to 8.3 mmol/L).5
Adenosine Receptor Antagonists
Adenosine is generated at enhanced rates in response to increased tubular sodium chloride transport or hypoxia. It subsequently binds to glomerular adenosine A1 receptors to lower GFR by constricting the afferent arteriole. Theophylline is a nonselective adenosine receptor antagonist and has mainly been studied for the prevention of CIN. Two systematic reviews reported a nonsignificant trend toward reduced incidence of CIN.68,69 It is important to note that theophylline may have significant adverse effects such as tachycardia and tremor as well as a high potential for drug interactions. Due to the risk of adverse effects as well as a relatively small benefit, KDIGO guidelines suggest against using theophylline for prevention of CIN.5
Erythropoietin is a primary regulator of red blood cell production and is widely used to treat anemia in patients with CKD and cancer. Experimental models have demonstrated the tissue-protective role of erythropoietin against ischemic renal injury.70 However, a subsequent double-blind, placebo-controlled trial found no difference in the outcome of AKI among ICU patients.71 As a result, the KDIGO Work Group recommends against the use of erythropoietin for prevention and treatment of AKI.5
TREATMENT OF AKI
Identification and management of AKI should be prompt. Prerenal sources of AKI should be managed with hemodynamic support and volume replacement.72 Postrenal therapy focuses on removing the cause of the obstruction. It is important to approach the treatment of established AKI with an understanding of the patient’s comorbidities and baseline renal function. Loss of kidney function combined with other clinical conditions, such as cardiac and liver failure, is associated with higher mortality than that associated with the development of AKI alone.73 At times, the most efficacious remedy for AKI is management of the comorbid precipitating event. Appreciation of the baseline renal function is also important at the outset of AKI management, because the preexisting level of renal function indicates the highest degree of recovery that can be attained. Presence of CKD indicates that the kidneys have less reserve, and there is a greater likelihood that full recovery may not occur.
The desired outcome in patients with AKI is to facilitate renal recovery and minimize injury. Renal recovery is facilitated by ensuring that hemodynamic parameters and blood chemistries are monitored daily and maintained within normal range. Fluid status should be monitored by following fluid ins and outs and patient weight as both excessive and insufficient fluid administration can be detrimental to patient recovery. Renal injury can be minimized by careful daily review of patient medications with the goal of avoiding nephrotoxic drugs and adjusting the dosing of renally eliminated medications. Patients receiving RRT need to have their medication administration and serum concentration measurement times adjusted appropriately with regards to the timing and duration of their RRT.
Supportive care is the mainstay of AKI management regardless of etiology. RRT may be necessary to maintain fluid and electrolyte balance while removing accumulating waste products or toxins.72 The slow process of renal recovery cannot begin until insults are eliminated. The recovery process for ATN typically occurs within 10 to 14 days after insult resolution. This may be prolonged if the kidney is exposed to repeated insults.
Short-term goals of AKI management include minimizing the degree of insult to the kidney, reducing extrarenal complications, and expediting the patient’s recovery of renal function. The ultimate goal is to have the patient’s renal function restored to his or her pre-AKI baseline. Table 28-6 summarizes the recommendations published in the KDIGO clinical practice guidelines regarding recommended and not recommended therapies for the treatment of AKI.5
Initial modalities to reverse or minimize prerenal AKI include eliminating medications associated with kidney damage and improving cardiac output and renal blood flow. If dehydration is evident, then appropriate fluid replacement therapy should be initiated. Moderately volume-depleted patients can be given oral rehydration fluids; however, if IV fluid is required, isotonic saline is preferred, and large volumes may be necessary for adequate fluid resuscitation. In septic patients, IV fluid challenges are initiated with up to 1,000 mL of isotonic saline over 30 minutes if tolerated with an assessment of the volume status after each challenge.74 The patient should be monitored for pulmonary edema, peripheral edema, adequate blood pressure (target mean arterial pressure ≥65 mm Hg), normoglycemia, and electrolyte balance. Urine output ≥0.5 mL/kg/h is generally targeted during the initial fluid resuscitation phase.74
In patients with anuria or oliguria, slower rehydration, such as 250 mL boluses or 100 mL/h infusions of isotonic saline or a balanced crystalloid solution, should be considered to reduce the risk for pulmonary edema, especially if heart failure or pulmonary insufficiency exists. Isotonic saline has been associated with hyperchloremic metabolic acidosis and acid–base imbalance if the dehydration is accompanied by a severe electrolyte imbalance amenable to large and relatively rapid infusions. For example, dehydration resulting from severe diarrhea is often accompanied by metabolic acidosis caused by bicarbonate losses. A reasonable IV rehydration fluid in this situation would be 5% dextrose with 0.45% sodium chloride plus 50 mEq (50 mmol) of sodium bicarbonate per liter, administered as boluses as described above, followed by a brisk continuous infusion (200 mL/h) until rehydration is complete, acidosis corrected, and diarrhea resolved. This fluid will remain mostly in the intravascular space, providing the necessary perfusion pressure to the kidneys, as well as a substantial amount of bicarbonate to correct the acidosis.
If the prerenal AKI is a result of blood loss or is complicated by symptomatic anemia, red blood cell transfusion to a hematocrit no higher than 30% (0.30) is the treatment of choice.74 Although albumin is sometimes used as a resuscitative agent, its use should be limited to individuals with severe hypoalbuminemia (e.g., liver disease and nephritic syndrome) who are resistant to crystalloid therapy. These patients have severe hypoalbuminemia-associated third spacing that complicates fluid management, and albumin may be useful in this setting.75
The most common interventions that must be made when treating patients with intrinsic or postobstructive AKI involve fluid and electrolyte management. Fluid and electrolyte status will need to be assessed regularly and individualized. At times, drug infusions and nutrition solutions may need to be maximally concentrated. Maintenance IV infusions should be minimized unless the patient is euvolemic or is receiving RRT to maintain fluid balance. Supportive care goals include maintenance of adequate cardiac output and blood pressure to allow adequate tissue perfusion. However, a fine balance must be maintained in anuric and oliguric patients unless the patient is hypovolemic or is able to achieve fluid balance via RRT. If fluid intake is not minimized, edema may rapidly develop, especially in hypoalbuminemic patients. Excessive fluid administration can also impair the function of other organ systems and reduce outcomes.76 In critically ill patients with vasomotor shock, vasopressors such as norepinephrine, vasopressin, or dopamine may be used in conjunction with fluids in order to maintain adequate hemodynamics and renal perfusion.5
Renal Replacement Therapy
RRT can be administered either intermittently or continuously. The optimal mode for hemodialysis is unclear and varies depending on the clinical presentation of the patient.5 Some recent data suggest that more aggressive approaches using RRT in a more liberal fashion or use of a bioartificial membrane consisting of renal proximal tubule cells may improve survival in critically ill patients with AKI.77Early RRT should be considered when life-threatening changes in fluid, electrolyte, and acid–base balance are present.5,78 The choice of continuous versus intermittent RRTs is a matter of considerable debate and usually depends on physician preference and the resources available at the hospital. The most common indications for initiation of RRT are summarized in Table 28-7.
TABLE 28-7 Common Indications for Renal Replacement Therapy
Controversy exists as to what is the optimal RRT modality for patients with AKI. As a result, selection of a particular type of RRT is largely determined by physician preference and/or hospital resources.
Intermittent Hemodialysis Intermittent hemodialysis (IHD) is the most frequently used RRT. IHD machines are readily available in most acute care facilities, and healthcare workers are commonly familiar with their use. Hemodialysis treatments usually last 3 to 4 hours, with blood flow rates to the dialyzer typically ranging from 200 to 400 mL/min. Advantages of IHD include rapid removal of volume and solute and correction of most of the electrolyte abnormalities associated with AKI. IHD can be scheduled to allow multiple treatments per day per machine. The primary challenge is hypotension, typically caused by rapid removal of intravascular volume over a short period of time. Venous access for dialysis can be difficult in hypotensive patients and can limit the effectiveness of IHD, leading to ineffective solute clearance, lack of acidosis correction, continued volume overload, and delayed recovery because of further ischemic insults to the kidneys. If hemodialysis is carefully monitored and hypotension avoided, better patient outcomes can be achieved.79 Patients with CKD stage 5 generally achieve adequate solute and volume control with three times weekly dialysis, but hypercatabolic, fluid-overloaded patients with AKI may require daily hemodialysis treatments. The use of daily versus three times weekly IHD in the setting of AKI has been associated with a reduction in dialysis-related hypotension and a shorter period of time to full recovery of kidney function.80 Chapter 30 provides a detailed explanation of the principles and processes of IHD.
Continuous Renal Replacement Therapy Continuous renal replacement therapy (CRRT) is a viable approach to manage hemodynamically unstable patients with AKI. Several CRRT variants have been developed, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF). They differ in the degree of solute and fluid clearance that can be clinically achieved as a result of the use of diffusion, convection, or a combination of both. A greater amount of solute removal and higher mean arterial pressures are observed during CCRT compared with IHD in critically ill patients with AKI.81 In CVVH, solute and fluid clearance is primarily a result of convection, in which passive diffusion of fluids containing solutes is removed, while volume absent of the solutes is replaced (Fig. 28-4). CVVHD provides extensive solute removal primarily by diffusion, in which solute molecules at a higher concentration (plasma) pass through the dialysis membrane to an area of lower concentration (dialysate). Also, some fluid is removed as a function of the ultrafiltration coefficient of the dialyzer. CVVHD potentially has a lower risk of clotting than CVVH because of reduced hemoconcentration, as there is less fluid removal during the process. CVVHDF combines both convection or hemofiltration and hemodialysis, achieving even higher solute and fluid removal rates (Fig. 28-4). The ultrafiltration rate is an important determinant of the effectiveness of all three forms of CRRT. In direct comparisons of ultrafiltration rates of 25 to 40 mL/kg/h or higher, no difference in mortality has been observed, and there was a tendency toward prolonged need for renal replacement in those who received the higher ultrafiltration rate.82,83 Therefore, current KDIGO guidelines recommend an ultrafiltration rate of no more than 20 to 25 mL/kg/h during CRRT.5
FIGURE 28-4 Several renal replacement therapies are commonly used in patients with AKI, including one of the three primary continuous renal replacement therapy (CRRT) variants: (a) continuous venovenous hemofiltration (CVVH), (b) continuous venovenous hemodialysis (CVVHD), (c) continuous venovenous hemodiafiltration (CVVHDF), and the hybrid intermittent hemodialysis therapy (d) sustained low-efficiency dialysis (SLED). The blood circuit in each diagram is represented in red, the hemofilter/dialyzer membrane is yellow, and the ultrafiltration/dialysate compartment is brown. Excess body water and accumulated endogenous waste products are removed solely by convection when CVVH is employed. With CVVHD, waste products are predominantly removed as the result of passive diffusion from the blood, where they are in high concentration to the dialysate. The degree of fluid removal that is accomplished by convection is usually minimal. CVVHDF uses convection to a degree similar to that employed during CVVH as well as diffusion, and thus is often associated with the highest clearance of drugs and waste products. Finally, SLED employs lower blood and dialysate flow rates than intermittent hemodialysis (IHD), but because of its extended duration, it is a gentler means of achieving adequate waste product and fluid removal.
Because of the reduced blood flow rates relative to IHD, CRRT-related thrombosis is a significant concern; thus, some form of anticoagulation during RRT is generally necessary for almost all patients. Typical anticoagulation is achieved by the administration of parenteral agents such as regional citrate (preferred if increased risk for bleeding is present), unfractionated heparin, low-molecular-weight heparin in some cases, or a direct thrombin inhibitor when other therapies are contraindicated.5,84 Replacement fluids can be infused either just before or after the dialyzer/hemofilter. Infusing fluids after the hemofilter can result in hemoconcentration within the filter, a factor associated with an increased risk of thrombosis of the dialyzer. Replacing fluids before the filter reduces thrombosis risk, but it also reduces solute clearance.
Disadvantages of CRRT may include limited availability of the special equipment necessary to provide these treatments or the need for intensive nursing care, and the need to individualize the IV replacement, dialysate fluids, and drug therapy adjustments. There is also very little known about drug-dosing requirements for patients who are receiving CRRT.85 CRRT use is most commonly considered for those patients with higher acuity because of their intolerance of IHD-associated hypotension. Current KDIGO guidelines suggest using CRRT over IHD in hemodynamically unstable patients.5
Hybrid Dialysis Therapies Another alternative to CRRT is the hybrid extended-duration IHD that is also utilized in critically ill patients with AKI. Hybrid IHD therapies have a variety of names, with the two most common being sustained low-efficiency dialysis (SLED)79 and slow, extended, daily dialysis (see Fig. 28-4).86 These therapies use lower blood (150 to 200 mL/min) and dialysate (300 to 400 mL/min) flow rates with extended treatment periods of 6 to 12 hours. For critically ill patients with AKI, SLED appears comparable to CRRT for hemodynamic control.79 Anticoagulation is still required, but the amount necessary compared with CRRT is lower.86 Although the use of hybrid hemodialysis therapies is increasing, our knowledge of their impact on drug removal remains limited.87 Daily delivery of SLED presents challenges to clinicians prescribing drug and nutrition therapy, as most of the dosing guidelines are based on IHD given three times per week in CKD patients. Thus, application of these guidelines in patients with AKI may potentially yield suboptimal outcomes.
IHD Compared with CRRT In addition to patient-specific differences, there are marked differences between IHD and the three primary types of CRRT—CVVH, CVVHD, and CVVHDF—with regard to drug removal.85,87,88
During CVVH, drug removal primarily occurs via convection/ultrafiltration (the passive transport of drug molecules at the concentration at which they exist in plasma water into the ultrafiltrate). Convective removal is most efficient for smaller agents, typically less than 15,000 Da (15 kDa) in size, and those that are primarily unbound in the plasma. The clearance of a drug by either of these methods is thus a function of the membrane permeability for the drug, which is called the sieving coefficient (SC), and the rate of ultrafiltrate formation (UFR). Alteration in the pore size of the filter and surface charge relative to the molecule being removed may vary between different dialyzers. If diffusion of the drug is not dependent on the filter pore size, then the SC can be calculated as follows:
where Ca and Cv are the concentrations of the drug in the plasma going into and returning from the dialyzer/hemofilter, respectively, and CUF is the concentration in the ultrafiltrate. The SC is often approximated by the fraction unbound (fu) because this information may be more readily available. Thus, the clearance by CVVH can be calculated as
or approximated as
In CVVHDF, clearance is a combination of both diffusion and convection. The ClCVVHDF can be mathematically approximated, providing the blood flow rate is greater than 100 mL/min and the dialysate flow rate (DFR) is between 8 and 33 mL/min, as
where Cldiffusion is the clearance via diffusion from plasma water to the dialysate. In the clinical setting, it is not possible to separate these two components (UFR and DFR) of ClCVVHDF. In essence, the ClCVVHDF is calculated as the product of the combined ultrafiltrate and dialysate volume (Vdf) and the concentration of the drug in this fluid (Cdf) divided by the plasma concentration () at the midpoint of the Vdf collection period.
Individualization of therapy for a patient receiving CRRT is dependent on the patient’s residual renal function and the clearance of the drug by the mode of CRRT. There are differences in the rate of drug removal, not only between the three primary modes of CRRT but also within each mode.85,88 This is a result of differences in the filter membrane composition, variable degrees of drug binding to the membrane, and permeability characteristics of the membrane.89–91 Primary factors that influence drug clearance during CRRT are thus the ultrafiltration rate, blood flow rate, and DFR. For example, clearance in CVVH is directly proportional to the ultrafiltration rate, whereas clearance during CVVHDF, which depends on both the ultrafiltration rate and the DFR, increases as either flow rate increases. An increase in the ultrafiltration flow rate (5 to 45 mL/min) and DFR (8.3 to 33.3 mL/min), however, can have dramatic effects on the clearance of agents such as ceftazidime during CVVH and CVVHD, respectively (Fig. 28-5).91 Further, CRRT can rapidly remove excess fluid from edematous patients, thereby changing the volume of distribution (VD) of drugs with limited distribution (low VD suggesting a greater proportion in the plasma or extracellular fluid) fairly rapidly.88 Drug clearances attained by IHD, CRRTs, and hybrid RRTs all differ from each other and must be added to any endogenous drug clearance that the patient generates.
FIGURE 28-5 The effect of increasing ultrafiltration rate (UFR in milliliters per minute) and dialysate flow rate (DFR in milliliters per minute) on the clearance of ceftazidime. (Adapted from reference 91.)
Limitations of IHD-based dosing charts include variability in the patient’s individual pharmacokinetic parameters, differences in the dialysis prescription, such as dialyzer blood flow or duration, and the use of new IHD dialyzers. The approach to hemodialysis may also change on a daily basis, especially in hemodynamically unstable individuals with AKI. This could include, for example, the type of dialyzer/filter used, the duration, the degree of hemofiltration compared with convection, and the blood flow rate. Individualization of a dosing regimen may require daily assessment of the clinical status of the patient and any planned or recently administered hemodialysis.
Overall, there are numerous potential pharmacokinetic and pharmacodynamic alterations to be aware of in the patient with AKI. Unfortunately, there is a dearth of data to quantify these changes, and even less evidence demonstrating that if one incorporates these considerations into patient care, the associated outcomes will be improved.
Once the kidney has been damaged by an acute insult, initial therapies should be directed to prevent further insults to the kidney, thereby minimizing extension of the injury.5 Dosing considerations should include the drugs’ volume of distribution and the volume status of the patient. If sepsis is present, antibiotic therapy regimens should be adjusted for decreased renal elimination. Diuretics or ultrafiltration may be considered in patients with acute decompensated heart failure leading to prerenal AKI. Initial therapies should be aggressive if the agent has a relatively wide therapeutic range and low risk of toxicity. Renally eliminated drugs with narrow therapeutic ranges such as vancomycin or aminoglycosides may require an initial loading dose.88 The time to recovery from AKI is determined from the most recent insult to the kidney, not the first insult.
Hospitalized patients with AKI are at high risk for additional episodes of kidney injury as the result of repeated exposures to nephrotoxic agents and hypotensive episodes, among other problems. To date, no pharmacologic approach to reverse the decline or accelerate the recovery of renal function has been proven to be clinically useful. Many drugs have looked promising in animal trials, only to be found ineffective in human trials. Other agents have been investigated and shown no benefit in the treatment of established AKI.28,51 For example, loop diuretics are very effective in reducing fluid overload but can also worsen AKI.5 Prevention of pulmonary edema is an important goal, and it is preferable that it be accomplished with diuretics instead of more invasive RRTs, despite the previously mentioned finding that diuretic use may be associated with diminished outcomes.5,28
DIURETICS AND MANNITOL
The most effective drugs in producing diuresis in the patient with AKI, mannitol and the loop diuretics, have distinct advantages and disadvantages. Mannitol, which works as an osmotic diuretic, can only be given parenterally. A typical starting dose of mannitol (20%) is 12.5 to 25 g infused IV over 3 to 5 minutes. It has little nonrenal clearance, so when given to anuric or oliguric patients, mannitol can potentially cause a hyperosmolar state. Additionally, mannitol may cause AKI itself, so its use in AKI must be monitored carefully by measuring urine output and serum electrolytes and osmolality.5,92 Furosemide is the most commonly used loop diuretic because of its lower cost, availability in oral and parenteral forms, and reasonable safety and efficacy profiles. A disadvantage of furosemide is its variable oral bioavailability and potential for ototoxicity with high serum concentrations attained with rapid, high-dose bolus infusions. Consequently, initial IV furosemide doses should not exceed 40 to 80 mg and should include close followup assessment of any response. Torsemide and bumetanide have more predictable oral bioavailability and are more potent, 4:1 and 40:1, respectively, compared with furosemide. Torsemide has a longer duration of activity than the other loop diuretics, which allows for less-frequent administration but may also make it more difficult to titrate the dose. Ethacrynic acid is typically reserved for patients who are allergic to sulfa compounds. Loop diuretics all work equally well provided that they are administered in equipotent doses. In a patient who is unresponsive to aggressive IV loop diuretic therapy, switching to another loop diuretic is unlikely to be beneficial.
The inability to respond to diuretics is common in AKI and is associated with poor patient outcomes.28 An effective technique to overcome diuretic resistance is to administer loop diuretics via continuous infusion instead of intermittent boluses. Less natriuresis occurs when equal doses of loop diuretics are given as a bolus instead of as a continuous infusion. Furthermore, adverse reactions from loop diuretics (myalgia and hearing loss) occur less frequently in patients receiving continuous infusion compared with those receiving intermittent boluses, ostensibly because higher serum concentrations are avoided. An initial loading dose (equivalent to furosemide 40 to 80 mg) should be given prior to the initiation of a continuous infusion at 10 to 20 mg/h of furosemide or its equivalent. Patients with low CLcrmay have much lower rates of diuretic secretion into the tubular fluid; consequently, higher doses are generally used in patients with renal insufficiency.28
There are several reasons why certain patients develop diuretic resistance. Excessive sodium intake may override the ability of the diuretics to eliminate sodium. Patients with ATN have a reduced number of functioning nephrons on which the diuretic may exert its action. Other clinical states, such as glomerulonephritis, are associated with heavy proteinuria. Intraluminal loop diuretics cannot exert their effect in the loop of Henle because they are extensively bound to proteins present in the urine. Still other patients may have greatly reduced bioavailability of oral furosemide because of intestinal edema, often associated with high preload states, which further reduces oral furosemide absorption. Table 28-8 includes possible therapeutic options to counteract each form of diuretic resistance.
TABLE 28-8 Common Causes of Diuretic Resistance in Patients with Acute Kidney Injury
Combination therapy of loop diuretics plus a diuretic from a different pharmacologic class may be an alternative approach in the setting of AKI.93,94 Loop diuretics increase the delivery of sodium chloride to the distal convoluted tubule and collecting duct. With time, these areas of the nephron compensate for the activity of the loop diuretic and increase sodium and chloride resorption. Diuretics that work at the distal convoluted tubule (chlorothiazide and metolazone) or the collecting duct (amiloride, triamterene, and spironolactone) may have a synergistic effect when administered with loop diuretics by blocking the compensatory increase in sodium and chloride resorption.94 Of these combinations, oral metolazone is used most frequently because, unlike other thiazides, it produces effective diuresis at a GFR <20 mL/min (<0.33 mL/s). IV chlorothiazide (500 mg) has been used when oral metolazone is not feasible but is associated with notably higher cost. The combination of metolazone and a loop diuretic has been used successfully in the management of fluid overload in patients with heart failure, cirrhosis, and nephrotic syndrome.
Drug Dosing Considerations in AKI
Optimization of drug therapy for patients with AKI is often challenging. The multiple variables influencing responses to the drug regimen include the patient’s residual drug clearance, fluid accumulation, and delivery of RRT. For renally eliminated drugs, particularly for agents with a narrow therapeutic range, serum drug concentration measurements and assessment of pharmacodynamic responses are likely to be necessary. If hepatic function is intact, choosing an agent eliminated primarily by the liver may be preferred. However, any renally eliminated active metabolites may accumulate to a point where they can elicit an undesired pharmacologic effect. Renal failure can also independently impair nonrenal drug elimination including metabolism.95 Unfortunately, pharmacokinetic studies in patients with established AKI are fairly limited. Further, the use of dosing guidelines based on data derived from patients with stable CKD may not reflect the clearance and volume of distribution in critically ill AKI patients (see Chap. 33).85 The inability to adequately dose drugs in critically ill patients with AKI requiring RRT may be one factor contributing to the lack of improving outcomes with newer RRT approaches.
Edema, which is common in AKI, can significantly increase the volume of distribution of many drugs, particularly water-soluble ones with relatively small volumes of distribution. Increased fluid distribution into the tissues (i.e., sepsis and anasarca in heart failure) can also contribute to a larger volume of distribution for many drugs and thereby reduce the proportion of drug in the plasma that is available to be removed by RRT. Because AKI frequently occurs in critically ill patients, multisystem organ failure is often an accompanying problem. In addition to volume overload, reductions in cardiac output or liver function can significantly alter the pharmacokinetic profile of many drugs, such as vancomycin, aminoglycosides, and low-molecular-weight heparins.85,96,97
If rapid onset of activity is desired, a loading dose may be necessary to promptly achieve desired serum concentrations because the expanded volume of distribution and the prolonged elimination half-life reextend the time (3.5 times the half-life) needed to reach steady-state concentrations. Maintenance dosing regimens should be reassessed frequently and be based on the patient’s most current renal function. A dose that provides the desired serum concentration on one day may be inappropriate a few days later if the patient’s fluid status, RRT prescription, or renal function has changed dramatically.
Drug therapy individualization for the AKI patient who is receiving any form of RRT is complicated by the fact that patients with AKI may have a higher residual nonrenal clearance than patients with CKD who have a similar CLcr.85 This has been reported with some drugs, such as ceftriaxone, imipenem, and vancomycin.98–100 Alterations in the activity of some, but not all, cytochrome P450 enzymes have been demonstrated in patients with CKD.95 The nonrenal clearance of imipenem in patients with AKI (91 mL/min [1.52 mL/s]) is between the values observed in stage 5 CKD patients (50 mL/min [0.84 mL/s]) and those with normal renal function (120 mL/min [2 mL/s]).100 This may be the result of less accumulation of uremic waste products that may alter hepatic function. If a patient with AKI has higher than anticipated nonrenal clearance, this would result in lower than expected, possibly subtherapeutic, serum concentrations. For example, to maintain comparable serum concentrations, the imipenem dose requirement in patients with AKI would be 2,000 mg daily as compared with the recommended dosage for patients with ESRD of 1,000 mg daily.100 As AKI persists, the nonrenal clearance values appear to approach those observed in patients with CKD.99,100 Finally, the clearance of aminoglycosides has been reported to be higher and the elimination half-life shorter in those with severe AKI compared with ESRD patients requiring hemodialysis.96 Another challenge is that much of the dosing-related data were acquired in patients with CKD, with initial pharmacokinetic assessments done after single-dose administration. The determination of pharmacokinetic parameters using a single-dose model may result in more rapid initial drug removal estimates secondary to distribution from the plasma to the tissue as well. Thus, application of dosing regimens derived from studies in patients with CKD and ESRD in addition to the use of more aggressive RRT approaches may result in underdosing of certain drugs and thereby contribute to less than optimal clinical outcomes.
There is a scarcity of data on how to appropriately dose medications in patients receiving CRRT or SLED. Some clinicians use dosing recommendations extrapolated from IHD data, while others believe that more aggressive dosing regimens are warranted.
Hypernatremia and fluid retention are frequent complications of AKI. Total daily sodium intake should be monitored since excessive amounts may be a reason for diuretic therapy failure. Further, commonly administered IV antibiotics such as metronidazole, ampicillin, piperacillin, and fluconazole may contain significant amounts of sodium. As a result, the cumulative effect of a few sodium-containing medications and fluids can be significant.
In continuous and intermittent RRTs, there usually is less concern about hypernatremia developing because these therapies often incorporate isonatremic (135 to 140 mEq/L [135 to 140 mmol/L] of sodium) solutions as the dialysate or ultrafiltrate replacement solutions. Serum sodium concentrations should be monitored daily. Hyperkalemia, hyperphosphatemia, and, to a lesser extent, hypermagnesemia are electrolyte disorders that are frequently seen in patients with AKI. Higher ultrafiltration rates can potentially increase the risk for hyperphosphatemia. The shift in electrolytes is generally not a serious concern in those who are receiving RRT, but electrolytes should be monitored closely in all patients with AKI.
The most common electrolyte disorder encountered in AKI patients is hyperkalemia, as >90% of potassium is renally eliminated. Life-threatening cardiac arrhythmias may occur with serum potassium concentrations >6 mEq/L (>6 mmol/L), so frequent monitoring of potassium is essential. Some foods and medications such as oral phosphorous replacement powders (e.g., Neutra-Phos and Neutra-Phos-K) and alkalinizers (Polycitra) contain substantial amounts of potassium (see Chap. 36). Some medications may promote potassium retention by the kidneys and should also be avoided or closely monitored (see Chaps. 31 and 37).
Other electrolytes that require monitoring are phosphorus and magnesium. Both are eliminated by the kidneys and are not removed efficiently by dialysis. In the early stages of AKI, hyperphosphatemia may be more common than hypophosphatemia. Patients with significant tissue destruction (e.g., trauma, rhabdomyolysis, and tumor lysis syndrome) may have substantial amounts of phosphorus released from the destroyed tissue. Calcium-containing antacids should be avoided to prevent precipitation of calcium phosphate in the soft tissues. Typically, the dietary intake of phosphorus and magnesium needs to be restricted. However, patients receiving prolonged RRT can develop deficiency states, particularly pediatric patients as a result of reduced body stores. In contrast to the patient with CKD, AKI patients do not usually develop calcium imbalance secondary to the limited duration of the illness. One exception to this is seen in patients who are receiving CRRT with citrate as the anticoagulant. Citrate binds to serum calcium and is typically infused before the dialyzer/hemofilter. Calcium chloride or calcium gluconate is administered prior to returning the blood to the patient, while the citrate that reaches the systemic circulation is subsequently metabolized by the liver. The goals of citrate anticoagulation are to maintain the circuit ionized calcium between 0.8 and 1.6 mg/dL (0.2 and 0.4 mmol/L), and the patient’s systemic ionized calcium between 4.4 and 5.2 mg/dL (1.1 to 1.3 mmol/L).5 Since severe hypocalcemia can result in arrhythmias or even death, frequent monitoring of unbound serum calcium concentrations is essential.
Nutritional Considerations in AKI
Nutritional management of critically ill patients with AKI can be extremely complex, as it needs to account for metabolic derangements resulting from both renal dysfunction and underlying disease processes, as well as the effects of RRT on nutrient balance. Stress, inflammation, and injury lead to hypermetabolic and hypercatabolic states and may alter the nutritional requirements. In addition, severe malnutrition found in up to 42% of patients with AKI is a risk factor for increased hospital mortality and length of stay.74 Thus, patient outcomes can be significantly improved if the nutritional status is optimized.
Loss of the normal physiologic and metabolic functions of the kidney and the hypercatabolic response to stress and injury will have a significant impact on the metabolism of nutrients. Derangements in glucose, lipid, and protein metabolism result in hyperglycemia and insulin resistance, hypertriglyceridemia, protein catabolism, and negative nitrogen balance. The latter, in particular, is problematic to manage, as increased amino acid turnover and skeletal muscle breakdown lead to muscle wasting and malnutrition and do not respond well to increasing exogenous protein supplementation. KDIGO guidelines currently recommend a caloric intake goal of 20 to 30 kcal/kg/day (84 to 126 kJ/kg/day) irrespective of the stage of renal impairment and preferentially through the enteral route.5 In the setting of noncatabolic AKI without need for dialysis, 0.8 to 1 g/kg/day of protein is suggested and 1 to 1.5 g/kg/day if patient is receiving RRT.5 CRRT is associated with an increased removal of small water-soluble molecules such as amino acids and certain nutrients. As a result, hypercatabolic patients receiving CRRT will typically have higher protein requirements up to a maximum of 1.7 g/kg/day.5
Another nutritional consideration for patients receiving CRRT is the heat loss as a consequence of the cooling of the patient’s blood as it traverses the extracorporeal circuit.101 Even though the blood cooling effect by CRRT is widely recognized in clinical practice, its prevention and effect on energy and nutritional requirements have not been well studied. The blood cooling effect is reported to occur more frequently with venovenous modalities, higher dialysate, and lower blood flow rates. Also, certain patient characteristics, such as female gender, low normal baseline temperature, and low body weight, have been identified as risk factors for hypothermia.101,102 Overall, CRRT should be recognized as a potential source of heat loss. However, no recommendations are currently available for prevention or define the nutritional supplementation that may be necessary as the result of CRRT-induced blood cooling.
In the presence of AKI, several processes may exist that can alter drug response such as impaired elimination, RRT-related drug removal, or physiologic alterations in pharmacodynamic response. Guidance from clinical trials on how to appropriately adjust drug regimens is limited. Thus, continuous assessment is required when optimizing pharmacotherapeutic regimens. Changes in the patient’s clinical presentation including renal replacement regimens may require clinicians to make frequent adjustments. Information from yesterday’s medical record review may not reflect what is happening today or is being planned for tomorrow. Physiologic processes or metabolites that may have limited expression in normal renal function may elicit greater influence in AKI. Treating the patient may require more aggressive pharmacotherapy regimens initially that can be subsequently tapered back. Clinicians should keep the overall clinical status of the patient in mind when developing management plans. Key to optimal patient outcomes includes maximizing prevention, early identification of AKI, implementation of supportive therapies, and frequent assessments until the AKI has resolved.
EVALUATION OF THERAPEUTIC OUTCOMES
Vigilant monitoring of patients with AKI is essential, particularly in those who are critically ill. Table 28-9 summarizes the main monitoring parameters for patients with established AKI.
TABLE 28-9 Key Monitoring Parameters for Patients with Established Acute Kidney Injury
Once the laboratory-based tests (e.g., urinalysis and FENa calculations) have been conducted to diagnose the cause of AKI, they usually do not have to be repeated. In established AKI, daily measurements of urine output, fluid intake, and weight should be performed. Vital signs should be monitored at least daily, more often if the acuity of illness is high. Daily blood tests for electrolytes, BUN, and a complete blood cell count should be considered routine for hospitalized patients.
Therapeutic drug monitoring should be performed for drugs that have a narrow therapeutic window that can be measured by the hospital laboratory. If results from these serum drug concentrations cannot be obtained in a timely fashion (<24 hours), then their value is limited. When considering approaches to measuring serum concentrations, consensus is limited. Measuring a serum drug concentration prior to hemodialysis has the advantage of allowing time for the result to be reported and redosing done shortly after dialysis with minimal delay. This is especially important if the desired pharmacologic effects are lost during or after hemodialysis is complete because the serum concentrations have become subtherapeutic. Knowledge based on previous observations of how a particular agent is removed for a given dialysis approach and a prehemodialysis serum concentration can assist in estimating the amount of the drug removed and predict the need for any postdialysis doses. Serum concentrations drawn after hemodialysis may reflect plasma concentrations that are transiently depressed until the drug can reequilibrate from the tissues (plasma rebound effect). The advantage with an after-dialysis level is the greater accuracy in determining how much drug was cleared during hemodialysis, but this may delay reestablishing target effects. Greater therapeutic drug monitoring may be necessary in patients with AKI than what is done routinely for other patients because of the potential changes in hemodynamic status.
CLINICAL BOTTOM LINE
The unique characteristics of AKI compared with CKD can lead to notable differences in how renal function is measured and how treatment regimens are developed. Most management approaches involve both prevention and support strategies, so as to minimize the potential for additional harm to the kidney. Understanding the constantly changing status inherent to AKI and how to adjust management regimens is a key component to optimizing therapy.
1. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204–R212.
2. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
3. Bagshaw SM, George C, Dinu I, Bellomo R. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1203–1210.
4. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Crit Care 2006;10:R73.
5. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Workgroup. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1–138.
6. Ricci Z, Ronco C. Year in review 2007: Critical Care—Nephrology. Crit Care 2008;12:230.
7. Siew ED, Matheny ME, Ikizler TA, et al. Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int 2010;77:536–542.
8. Zavada J, Hoste E, Cartin-Ceba R, et al. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transplant 2010;25:3911–3918.
9. Hsu CY, McCulloch CE, Fan D, et al. Community-based incidence of acute renal failure. Kidney Int 2007;72:208–212.
10. Liangos O, Wald R, O’Bell JW, et al. Epidemiology and outcomes of acute renal failure in hospitalized patients: A national survey. Clin J Am Soc Nephrol 2006;1:43–51.
11. Uchino S, Bellomo R, Goldsmith D, et al. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006;34:1913–1917.
12. Liano F, Felipe C, Tenorio MT, et al. Long-term outcome of acute tubular necrosis: A contribution to its natural history. Kidney Int 2007;71:679–686.
13. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: A systematic review and meta-analysis. Kidney Int 2012;81:442–448.
14. Kaufman J, Dhakal M, Patel B, Hamburger R. Community-acquired acute renal failure. Am J Kidney Dis 1991;17:191–198.
15. Lameire N, Van Biesen W, Vanholder R. The changing epidemiology of acute renal failure. Nat Clin Pract Nephrol 2006;2:364–377.
16. Pannu N, James M, Hemmelgarn BR, et al. Modification of outcomes after acute kidney injury by the presence of CKD. Am J Kidney Dis 2011;58:206–213.
17. Pisoni R, Wille KM, Tolwani AJ. The epidemiology of severe acute kidney injury: From BEST to PICARD, in acute kidney injury: New concepts. Nephron Clin Pract 2008;109:c188–c191.
18. Thakar CV, Christianson A, Himmelfarb J, Leonard AC. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephrol 2011;6:2567–2572.
19. Badr KF, Ichikawa I. Prerenal failure: A deleterious shift from renal compensation to decompensation. N Engl J Med 1988;319:623–629.
20. Lameire N. The pathophysiology of acute renal failure. Crit Care Clin 2005;21:197–210.
21. Gambaro G, Perazella MA. Adverse renal effects of anti-inflammatory agents: Evaluation of selective and nonselective cyclooxygenase inhibitors. J Intern Med 2003;253:643–652.
22. Sharfuddin AA, Weisbord SD, Palevsky PM, Molitoris BA. Acute kidney injury. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 9th ed. Philadelphia: WB Saunders, 2011:1044–1100.
23. Kelly CJ, Neilson EG. Tubulointerstitial diseases. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 9th ed. Philadelphia: WB Saunders, 2011:1332–1355.
24. Frokiaer J, Zeidel ML. Urinary tract obstruction. In: Brenner BM, ed. Brenner and Rector’s The Kidney, 9th ed. Philadelphia: WB Saunders, 2011:1382–1410.
25. Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 2007;13:638–644.
26. Baumann TJ, Staddon JE, Horst HM, Bivins BA. Minimum urine collection periods for accurate determination of creatinine clearance in critically ill patients. Clin Pharm 1987;6:393–398.
27. Slocum JL, Heung M, Pennathur S. Marking renal injury: Can we move beyond serum creatinine? Transl Res 2012;159:277–289.
28. Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int 2004;66:1115–1122.
29. Inker LA, Okparavero A. Cystatin C as a marker of glomerular filtration rate: Prospects and limitations. Curr Opin Nephrol Hypertens 2011;20:631–639.
30. Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004;65:1416–1421.
31. Manetti L, Pardini E, Genovesi M, et al. Thyroid function differently affects serum cystatin C and creatinine concentrations. J Endocrinol Invest 2005;28:346–349.
32. Devarajan P. Neutrophil gelatinase-associated lipocalin: A promising biomarker for human acute kidney injury. Biomark Med 2010;4:265–280.
33. Haase M, Bellomo R, Devarajan P, et al. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: A systematic review and meta-analysis. Am J Kidney Dis 2009;54:1012–1024.
34. Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: A prospective study. Clin J Am Soc Nephrol 2008;3:665–673.
35. Bagshaw SM, Bennett M, Haase M, et al. Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med 2010;36:452–461.
36. Parikh CR, Jani A, Melnikov VY, et al. Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 2004;43:405–414.
37. Parikh CR, Mishra J, Thiessen-Philbrook H, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006;70:199–203.
38. Ho E, Fard A, Maisel A. Evolving use of biomarkers for kidney injury in acute care settings. Curr Opin Crit Care 2010;16:399–407.
39. van Timmeren MM, van den Heuvel MC, Bailly V, et al. Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol 2007;212:209–217.
40. Liangos O, Tighiouart H, Perianayagam MC, et al. Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 2009;14:423–431.
41. Vaidya VS, Ford GM, Waikar SS, et al. A rapid urine test for early detection of kidney injury. Kidney Int 2009;76:108–114.
42. Wiedermann CJ, Dunzendorfer S, Gaioni LU, et al. Hyperoncotic colloids and acute kidney injury: A meta-analysis of randomized trials. Crit Care 2010;14:R191.
43. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2012;6:CD000567.
44. McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008;28:1419–1428.
45. Weisbord SD, Palevsky PM. Prevention of contrast-induced nephropathy with volume expansion. Clin J Am Soc Nephrol 2008;3:273–280.
46. Caulfield JL, Singh SP, Wishnok JS, et al. Bicarbonate inhibits N-nitrosation in oxygenated nitric oxide solutions. J Biol Chem 1996;271:25859–25863.
47. Briguori C, Airoldi F, D’Andrea D, et al. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): A randomized comparison of 3 preventive strategies. Circulation 2007;115:1211–1217.
48. Klima T, Christ A, Marana I, et al. Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: A randomized controlled trial. Eur Heart J 2012;33:2071–2079.
49. Cruz DN, Goh CY, Marenzi G, et al. Renal replacement therapies for prevention of radiocontrast-induced nephropathy: A systematic review. Am J Med 2012;125:66–78.e3.
50. Marenzi G, Lauri G, Campodonico J, et al. Comparison of two hemofiltration protocols for prevention of contrast-induced nephropathy in high-risk patients. Am J Med 2006;119:155–162.
51. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006;333:420.
52. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: Low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005;142:280–224.
53. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: A meta-analysis of randomized clinical trials. Am J Kidney Dis 2007;49:56–68.
54. Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK. Atrial natriuretic peptide for preventing and treating acute kidney injury. Cochrane Database Syst Rev 2009;(4):CD006028.
55. Lingegowda V, Van QC, Shimada M, et al. Long-term outcome of patients treated with prophylactic nesiritide for the prevention of acute kidney injury following cardiovascular surgery. Clin Cardiol 2010;33:217–221.
56. Cetin M, Devrim E, Serin Kilicoglu S, et al. Ionic high-osmolar contrast medium causes oxidant stress in kidney tissue: Partial protective role of ascorbic acid. Ren Fail 2008;30:567–572.
57. Boscheri A, Weinbrenner C, Botzek B, et al. Failure of ascorbic acid to prevent contrast-media induced nephropathy in patients with renal dysfunction. Clin Nephrol 2007;68:279–286.
58. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acid prevents contrast-mediated nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 2004;110:2837–2842.
59. Zhou L, Chen H. Prevention of contrast-induced nephropathy with ascorbic acid. Intern Med 2012;28:531–535.
60. Amini M, Salarifar M, Amirbaigloo A, et al. N-Acetylcysteine does not prevent contrast-induced nephropathy after cardiac catheterization in patients with diabetes mellitus and chronic kidney disease: A randomized clinical trial. Trials 2009;10:45.
61. Jo SH, Koo BK, Park JS, et al. N-Acetylcysteine versus ascorbic acid for preventing contrast-induced nephropathy in patients with renal insufficiency undergoing coronary angiography NASPI study—A prospective randomized controlled trial. Am Heart J 2009;157:576–583.
62. Ho KM, Morgan DJ. Meta-analysis of N-acetylcysteine to prevent acute renal failure after major surgery. Am J Kidney Dis 2009;53:33–40.
63. Mehta RL. Glycemic control and critical illness: Is the kidney involved? J Am Soc Nephrol 2007;18:2623–2627.
64. Vanhorebeek I, Gunst J, Ellger B, et al. Hyperglycemic kidney damage in an animal model of prolonged critical illness. Kidney Int 2009;76(5):512–520.
65. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283–1297.
66. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449–461.
67. Griesdale DE, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: A meta-analysis including NICE-SUGAR study data. CMAJ 2009;180:821–827.
68. Kelly AM, Dwamena B, Cronin P, et al. Meta-analysis: Effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med 2008;148:284–294.
69. Bagshaw SM, Ghali WA. Theophylline for prevention of contrast-induced nephropathy: A systematic review and meta-analysis. Arch Intern Med 2005;165:1087–1093.
70. Johnson DW, Pat B, Vesey DA, et al. Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int 2006;69:1806–1813.
71. Endre ZH, Walker RJ, Pickering JW, et al. Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 2010;77:1020–1030.
72. Joslin J, Ostermann M. Care of the critically ill emergency department patient with acute kidney injury. Emerg Med Int 2012;2012:760623.
73. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: Systematic review and meta-analysis. J Card Fail 2007;13:599–608.
74. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296–327.
75. Vincent JL. Relevance of albumin in modern critical care medicine. Best Pract Res Clin Anaesthesiol 2009;23:183–191.
76. Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int 2009;76:422–427.
77. Ding F, Humes HD. The bioartificial kidney and bioengineered membranes in acute kidney injury. Nephron Exp Nephrol 2008;109:e118–e122.
78. Hoste EA, Dhondt A. Clinical review: Use of renal replacement therapies in special groups of ICU patients. Crit Care 2012;16:201.
79. Fieghen HE, Friedrich JO, Burns KE, et al. The hemodynamic tolerability and feasibility of sustained low efficiency dialysis in the management of critically ill patients with acute kidney injury. BMC Nephrol 2010;11:32.
80. Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002;346:305–310.
81. Rabindranath K, Adams J, Macleod AM, Muirhead N. Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev 2007;(3):CD003773.
82. Bellomo R, Cass A, Cole L, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 2009;361:1627–1638.
83. Casey ET, Gupta BP, Erwin PJ, et al. The dose of continuous renal replacement therapy for acute renal failure: A systematic review and meta-analysis. Ren Fail 2010;32:555–561.
84. Oudemans-van Straaten HM, Wester JP, de Pont AC, Schetz MR. Anticoagulation strategies in continuous renal replacement therapy: Can the choice be evidence based? Intensive Care Med 2006;32:188–202.
85. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 2009;29:562–577.
86. Kumar VA, Craig M, Depner TA, Yeun JY. Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis 2000;36:294–300.
87. Dager WE. Filtering out important considerations for developing drug-dosing regimens in extended daily dialysis. Crit Care Med 2006;34:240–241.
88. Churchwell MD, Mueller BA. Drug dosing during continuous renal replacement therapy. Semin Dial 2009;22:185–188.
89. Joy MS, Matzke GR, Frye RF, Palevsky PM. Determinants of vancomycin clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Am J Kidney Dis 1998;31:1019–1027.
90. Lau AH, Kronfol NO. Determinants of drug removal by continuous hemofiltration. Int J Artif Organs 1994;17:373–378.
91. Matzke GR, Frye RF, Joy MS, Palevsky PM. Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Antimicrob Agents Chemother 2000;44:1639–1644.
92. Wade GN, Schneider JE, Friedman MI. Insulin-induced anestrus in Syrian hamsters. Am J Physiol 1991;260:R148–R152.
93. Karajala V, Mansour W, Kellum JA. Diuretics in acute kidney injury. Minerva Anestesiol 2009;75:251–257.
94. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diuretics with thiazide-type diuretics in heart failure. J Am Coll Cardiol 2010;56:1527–1534.
95. Vilay AM, Churchwell MD, Mueller BA. Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury. Crit Care 2008;12:235.
96. Dager WE, King JH. Aminoglycosides in intermittent hemodialysis: Pharmacokinetics with individual dosing. Ann Pharmacother 2006;40:9–14.
97. Kane-Gill SL, Feng Y, Bobek MB, et al. Administration of enoxaparin by continuous infusion in a naturalistic setting: Analysis of renal function and safety. J Clin Pharm Ther 2005;30:207–213.
98. Heinemeyer G, Link J, Weber W, et al. Clearance of ceftriaxone in critical care patients with acute renal failure. Intensive Care Med 1990;16:448–453.
99. Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacokinetics in acute renal failure: Preservation of nonrenal clearance. Clin Pharmacol Ther 1991;50:688–694.
100. Mueller BA, Scarim SK, Macias WL. Comparison of imipenem pharmacokinetics in patients with acute or chronic renal failure treated with continuous hemofiltration. Am J Kidney Dis 1993;21:172–179.
101. Yagi N, Leblanc M, Sakai K, et al. Cooling effect of continuous renal replacement therapy in critically ill patients. Am J Kidney Dis 1998;32:1023–1030.
102. Rickard CM, Couchman BA, Hughes M, McGrail MR. Preventing hypothermia during continuous veno-venous haemodiafiltration: A randomized controlled trial. J Adv Nurs 2004;47:393–400.