Mary K. Stamatakis
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Assess a patient’s kidney function based on clinical presentation, laboratory results, and urinary indices.
2. Identify pharmacotherapeutic outcomes and endpoints of therapy in a patient with acute kidney injury (AKI).
3. Apply knowledge of the pathophysiology of AKI to the development of a treatment plan.
4. Design a diuretic regimen with consideration to the pharmacokinetic and pharmacodynamic characteristics of the drug.
5. Select pharmacotherapy to treat complications associated with AKI.
6. Develop strategies to minimize the occurrence of AKI.
7. Monitor and evaluate the safety and efficacy of the therapeutic plan.
KEY CONCEPTS
Equations to estimate creatinine clearance (CrCl) which incorporate a single creatinine concentration (e.g., Cockcroft-Gault) may underestimate or overestimate kidney function depending on whether acute kidney injury (AKI) is worsening or resolving.
There is no evidence that drug therapy hastens patient recovery in AKI, decreases length of hospitalization, or improves survival.
Loop diuretics are the diuretics of choice for the management of volume overload in AKI.
There is no indication for the use of low-dose dopamine in the treatment of AKI.
Identifying patients at high risk for development of AKI and implementing preventive methods to decrease its occurrence or severity is critical.
Acute kidney injury (AKI) is a potentially life-threatening clinical syndrome that occurs primarily in hospitalized patients and frequently complicates the course of the critically ill. It is characterized by a rapid decrease in glomerular filtration rate (GFR) and the resultant accumulation of nitrogenous waste products (e.g., creatinine and urea nitrogen), with or without a decrease in urine output. The term acute renal failure (ARF) has traditionally been used to describe this syndrome. However, AKI has emerged as a name that more completely encompasses the entire spectrum of acute injury to the kidney, from mild changes in kidney function to end-stage kidney disease, requiring renal replacement therapy (RRT). Furthermore, the definition of ARF has been inconsistent in the literature and a recent survey showed more than 35 definitions for ARF used in the literature.1 Efforts to standardize the definition of ARF in recent years has lead to a change in terminology to AKI as well as a consensus definition and severity staging for AKI.2 The acronym RIFLE has been coined to represent the classification scheme of AKI and places patients into categories, dependent on their change in serum creatinine or GFR from baseline and/or decrease in urine output.3 The categories of kidney dysfunction include patients at risk (R); those with kidney injury (I); and those with kidney failure (F). Two additional categories of clinical outcomes include sustained loss (L), which requires RRT for at least 4 weeks; and end stage (E), which necessitates RRT for at least 3 months. These two outcome classes are defined by the duration of loss of kidney function. The complete schematic for the RIFLE classification and the diagnostic criteria are further depicted in Figure 25–1. For example, a patient with a urine output of less than 0.5 mL/kg/h for less than 6 hours would be in the risk (R) category, while a patient with the same decrease in urine output but for 12 hours would be in the injury (I) category. For the purposes of this chapter, the term AKI is used to be consistent with the recent consensus statement.
FIGURE 25–1. Alogrithm for classification of acute kidney injury. The classification system includes separate criteria for creatinine and urine output. A patient can fulfill the criteria through changes in serum creatinine or changes in urine output, or both. The criteria that lead to the worst possible classification should be used. Note that the F component of RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease) is present even if the increase in SCr is under threefold as long as the new SCr is greater than 4.0 mg/dL (350 μmol/L) in the setting of an acute increase of at least 0.5 mg/dL (44 μmol/L). The designation RIFLE-FC should be used in this case to denote “acute-on-chronic” disease. Similarly, when the RIFLE-F classification is achieved by urine output criteria, a designation of RIFLE-FO should be used to denote oliguria. The shape of the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specificity). In contrast, at the bottom of the figure the criteria are strict and therefore specific, but some patients will be missed. (AKI, acute kidney injury; GFR, glomerular filtration rate; SCr, serum creatinine concentration; UO, urine output.) (From Ref. 2.)
EPIDEMIOLOGY AND ETIOLOGY
Between 5% and 25% of all hospitalized patients develop AKI.4 A greater prevalence of AKI is found in critically ill patients.5 Despite improvements in the medical care of individuals with AKI, mortality generally exceeds 50%.6
PATHOPHYSIOLOGY
There are typically three categories of AKI: prerenal, intrinsic, and postrenal AKI. The pathophysiologic mechanisms differ for each of the categories.
Prerenal AKI
Prerenal AKI is characterized by reduced blood delivery to the kidney. A common cause is intravascular volume depletion due to conditions such as hemorrhage, dehydration, or GI fluid losses. Prompt correction of volume depletion can restore kidney function to normal because no structural damage to the kidney has occurred. Conditions of reduced cardiac output (e.g., congestive heart failure [CHF] or myocardial infarction) and hypotension can also reduce renal blood flow, resulting in decreased glomerular perfusion and prerenal AKI. With a mild to moderate decrease in renal blood flow, intraglomerular pressure is maintained by dilation of afferent arterioles (arteries supplying blood to the glomerulus), constriction of efferent arterioles (arteries removing blood from the glomerulus), and redistribution of renal blood flow to the oxygen-sensitive renal medulla.7 Drugs may cause a functional AKI when these adaptive mechanisms are compromised. Nonsteroidal anti-inflammatory drugs (NSAIDs) impair prostaglandin-mediated dilation of afferent arterioles. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit angiotensin II–mediated efferent arteriole vasoconstriction. Cyclosporine and tacrolimus, particularly in high doses, are potent renal vasoconstrictors. All of these agents can reduce intraglomerular pressure, with a resultant decrease in GFR. Prompt discontinuation of the offending drug can often return kidney function to normal. Other causes of prerenal AKI are renovascular obstruction (e.g., renal artery stenosis), hyperviscosity syndromes (e.g., multiple myeloma), or systemic vasoconstriction (e.g., hepatorenal syndrome). Prerenal AKI occurs in approximately 10% to 25% of patients diagnosed with AKI.8
Intrinsic AKI
Intrinsic renal failure is caused by diseases that can affect the integrity of the tubules, glomerulus, interstitium, or blood vessels. Damage is within the kidney; changes in kidney structure can be seen on microscopy.9 Acute tubular necrosis (ATN) is a term that is often used synonymously with intrinsic renal failure, but relates more specifically to a pathophysiologic condition that results from toxic (e.g., aminoglycosides, contrast agents, or amphotericin B) or ischemic insult to the kidney only. ATN results in necrosis of the proximal tubule epithelium and basement membrane, decreased glomerular capillary permeability, and backleak of glomerular filtrate into the venous circulation.10Maintenance of ATN is mediated by intrarenal vasoconstriction.10 The most common cause of intrinsic renal failure is due to ATN and it accounts for approximately 50% of all cases of AKI.8 Glomerular, interstitial, and blood vessel diseases may also lead to intrinsic AKI, but occur with a much lower incidence. Examples include glomerulonephritis, systemic lupus erythematosus, interstitial nephritis, and vasculitis. In addition, prerenal AKI can progress to intrinsic AKI if the underlying condition is not promptly corrected.9
Postrenal AKI
Postrenal AKI is due to obstruction of urinary outflow. Causes include benign prostatic hypertrophy, pelvic tumors, and precipitation of renal calculi.9 Rapid resolution of postrenal AKI without structural damage to the kidney can occur if the underlying obstruction is corrected. Postrenal AKI accounts for less than 10% of cases of AKI.8
ASSESSMENT OF KIDNEY FUNCTION
The most common measure of overall kidney function is GFR. It is defined as the volume of plasma filtered across the glomerulus per unit time and correlates well with the filtration, secretion, reabsorption, endocrine, and metabolic functions of the kidney. In addition to aiding in the diagnosis and assessment of the severity of AKI, an accurate estimate of GFR can assist in proper dosing of drugs that undergo renal elimination. In an individual with normal kidney function, GFR ranges from approximately 90 to 120 mL/min. Because GFR is difficult to measure directly, it is routinely estimated by determining the renal clearance of a substance that is filtered at the glomerulus and which does not undergo significant tubular reabsorption or secretion. Creatinine is an endogenous substance that is a normal byproduct of muscle metabolism. Ninety percent of creatinine is eliminated by glomerular filtration; tubular secretion is responsible for the remaining 10%.
Direct measurement of creatinine clearance (CrCl) requires collection of urine over an extended time interval (usually 24 hours) with measurement of urine volume, urine creatinine concentration, and serum creatinine concentration (SCr) (Table 25–1). Because kidney function can fluctuate significantly during AKI, this method may underestimate or overestimate kidney function depending on whether AKI is worsening or resolving.
Numerous equations have been developed for a quick bedside estimate of CrCl or GFR. They incorporate patient-specific variables such as SCr, body weight, age, and gender. One of the most widely used equations is the Cockcroft-Gault equation (Table 25–1).11 It is generally considered acceptable in individuals whose renal function is relatively constant, as defined as a daily change in serum creatinine of less than 10% to 15% within 24 hours. Because only a single SCr is factored into equations such as Cockcroft-Gault, the calculated CrCl may underestimate or overestimate kidney function depending on whether AKI is worsening or resolving.
In instances where kidney function is fluctuating, several equations have been developed to assess unstable kidney function.12–14 These equations estimate CrCl by considering the change in serum creatinine over a specified time period. While they are more mathematically difficult to calculate, they take into consideration a change in serum creatinine compared to an equation that only includes a single creatinine concentration. It should be noted that these methods have not been validated, and drug dosage adjustments based on CrCl estimates from these formulas in patients with AKI have not been evaluated. CrCl estimates in AKI must be viewed as best estimates under variable conditions, and ongoing patient monitoring is necessary to avoid drug toxicity. The Jelliffe equation for changing renal function is listed in Table 25–1.
Estimating CrCl is only one part of evaluating a patient’s overall kidney function. Other factors, such as symptomatology, laboratory test results, urinary indices, and results of diagnostic procedures will aid in the diagnosis and assessment of the severity of disease. By monitoring SCr on a routine basis, it can be estimated whether kidney function is improving or worsening. Kidney function can also be evaluated based on urine output. Oliguria and anuriaare defined as urine outputs of less than 400 mL and 50 mL over 24 hours, respectively. Patients with reduced urine output often have an increased mortality and may represent a more severe form of AKI. Nonoliguric AKI is defined as a urine output of greater than 400 mL per day. It may still represent severe AKI but may be associated with better patient outcomes.15
TREATMENT
Desired Outcomes
A primary goal of therapy is ameliorating any identifiable underlying causes of AKI such as hypovolemia, nephrotoxic drug administration, or ureter obstruction. Prerenal and postrenal AKI can be reversed if the underlying problem is promptly identified and corrected, while treatment of intrinsic renal failure is more supportive in nature. There is no evidence that drug therapy hastens patient recovery in AKI, decreases length of hospitalization, or improves survival.16 Therefore, options are limited to supportive therapy, such as fluid, electrolyte, and nutritional support, RRT, and treatment of nonrenal complications such as sepsis and GI bleeding while regeneration of the renal epithelium occurs. In addition, prevention of adverse drug reactions by discontinuing nephrotoxic drugs or adjustment of drug dosages based on the patient’s renal function is desired.
Table 25–1 Equations for Estimation of CrCl
Pharmacologic Therapy
Loop Diuretics
There is significant controversy over the role of loop diuretics in the treatment of AKI. Theoretical benefits in hastening recovery of renal function include decreased metabolic oxygen requirements of the kidney, increased resistance to ischemia, increased urine flow rates that reduce intraluminal obstruction and filtrate backleak, and renal vasodilation.8 Theoretically, these effects could lead to increased urine output, decreased need for dialysis, improved renal recovery, and ultimately, increased survival. However, there are conflicting reports in the literature over the efficacy of loop diuretics. Most studies demonstrate an improvement in urine output, but with no effect on survival or need for dialysis. There are some reports that loop diuretics may worsen kidney function.17 This may be due in part to excessive preload reduction that results in renal vasoconstriction. Thus, loop diuretics are limited to instances of volume overload and edema, and are not intended to hasten renal recovery or improve survival.
Clinical Presentation and Diagnosis of AKI
While some clinical and laboratory findings assist in the general diagnosis of AKI, others are used to differentiate among prerenal, intrinsic, and postrenal AKI. For example, patients with prerenal AKI typically demonstrate enhanced sodium reabsorption, which is reflected by a low urine sodium concentration and a low fractional excretion of sodium. Urine is typically more concentrated with prerenal AKI and there is a higher urine osmolality and urine:plasma creatinine ratio compared to intrinsic and postrenal AKI.
Signs and Symptoms of Uremia
• Peripheral edema
• Weight gain
• Nausea/vomiting/diarrhea/anorexia
• Mental status changes
• Fatigue
• Shortness of breath
• Pruritus
• Volume depletion (prerenal AKI)
• Weight loss (prerenal AKI)
• Anuria alternating with polyuria (postrenal AKI)
• Colicky abdominal pain radiating from flank to groin (postrenal AKI)
Physical Examination Findings
• Hypertension
• Jugular venous distention (JVD)
• Pulmonary edema
• Rales
• Asterixis
• Pericardial or pleural friction rub
• Hypotension/orthostatic hypotension (prerenal AKI)
• Rash (acute interstitial nephritis)
• Bladder distention (postrenal bladder outlet obstruction)
• Prostatic enlargement (postrenal AKI)
Laboratory Tests
• Elevated SCr (normal range approximately 0.6-1.2 mg/dL [53 to 106 μmol/L])
• Elevated BUN concentration (normal range approximately 8 to 25 mg/dL [2.9-8.9 mmol/L])
• Decreased CrCl (normal 90–120 mL/min)
• BUN: creatinine ratio (elevated in prerenal AKI) Greater than 20:1 for traditional units (prerenal AKI) Less than 20:1 for traditional units (intrinsic or postrenal AKI)
• Hyperkalemia
• Metabolic acidosis
Urinalysis
• Sediment
• Scant or bland (prerenal or postrenal AKI)
• Brown, muddy granular casts (highly indicative of ATN)
• Proteinuria (glomerulonephritis or allergic interstitial nephritis)
• Eosinophiluria (acute interstitial nephritis)
• Hematuria/red blood cell casts (glomerular disease or bleeding in urinary tract)
• WBCs or casts (acute interstitial nephritis or severe pyelonephritis)
FENa is a measure of the percentage of sodium excreted by the kidney. A FENa of less than 1% may indicate prerenal AKI as it represents the response of the kidney to decreased renal perfusion by decreasing sodium excretion. Loop diuretics such as furosemide enhance sodium excretion and increase FENa, confounding the interpretation of the test.
Common Diagnostic Procedures
• Urinary catheterization (insertion of a catheter into a patient’s bladder; an increase in urine output may occur with postrenal obstruction)
• Renal ultrasound (uses sound waves to assess size, position, and abnormalities of the kidney; dilatation of the urinary tract can be seen with postrenal AKI)
• Renal angiography (administration of IV contrast dye to assess the vasculature of the kidney)
• Retrograde pyelography (injection of contrast dye into the ureters to assess the kidney and collection system)
• Kidney biopsy (collection of a tissue sample of the kidney for the purpose of microscopic evaluation; may aid in the diagnosis of glomerular and interstitial diseases)
Patient Encounter, Part 1
A 73-year-old man with a history of diabetes mellitus, chronic kidney disease, gout, osteoarthritis, and hypertension is hospitalized with pyelonephritis and possible urosepsis. He recently completed a 14-day course of antibiotics and was ready for discharge when his morning labs showed an increase in BUN (42 mg/dL or 15 mmol/L) and SCr (2.9 mg/dL). His serum creatinine 24 hours earlier was 2.4 mg/dL (212 μmol/L). Upon examination, he was found to have 2+ pitting edema, weight gain, nausea, elevated blood pressure, and rales on chest auscultation.
What signs and symptoms does the patient have that may indicate AKI?
What risk factors does he have for the development of AKI?
What additional information do you need to fully assess this patient?
Patient Encounter, Part 2: The Medical History, Physical Examination, and Laboratory Tests
PMH: Type 1 diabetes mellitus since the age of 32; chronic kidney disease (BUN and serum creatinine were 30 mg/dL [10.7 mmol/L] and 2.5 mg/dL [221 μmol/L], respectively, on admission); hypertension; gout; osteoarthritis
FH: Father with a history of type 2 diabetes mellitus, hypertension, and stage 5 chronic kidney disease; he died from a myocardial infarction at age 68; mother with a history of hypertension; she died from injuries sustained in a motor vehicle accident at the age of 52
SH: Retired coal miner; no smoking, occasional alcohol use
Hospital Meds: Gentamicin 120 mg IV piggyback every 12 hours (dose discontinued after 3 days); gentamicin 120 mg IV piggyback every 24 hours (days 4 through 14, discontinued this morning); ampicillin 2 g IV piggyback every 8 hours (14-day course, discontinued this morning); sliding scale insulin; allopurinol 100 mg orally daily; ranitidine 150 mg orally every 12 hours; atenolol 50 mg orally daily; naproxen 275 mg orally every 12 hours; enalapril 2.5 mg orally daily
Home Meds: NPH insulin 20 units in the morning and 10 units in the evening; regular insulin 10 units in the morning and 10 units in the evening; allopurinol 100 mg orally daily; naproxen 275 mg orally every 12 hours; atenolol 50 mg orally daily
ROS: (-) fever or chills, (+) N, (-) V/D
PE:
VS: BP 154/95 mm Hg, pulse 80 bpm, RR 26/min, temperature 37.7°C, current wt 79 kg (admission wt 75 kg), ht 5’10” (178 cm)
Chest: Basilar crackles, inspiratory wheezes
CV: S1 S2 normal, no S3
MS/Exts: 2+ pedal edema
Urinalysis: Color, yellow; character, hazy; glucose (-); ketones (-); specific gravity 1.020; pH 5.0; (+) protein; coarse granular casts, 5 to 10/low-powered field; WBC count, 5 to 10/high-powered field; RBC count, 2 to 5/high-powered field; no bacteria; nitrite (-); blood small; osmolality 325 mOsm; urinary sodium 77 mEq/L (77 mmol/L); urinary creatinine 63 mg/dL (5,569 μmol/L)
Day 3 Labs:
Gentamicin Concentrations:
• 3.4 mcg/mL (7.12 μmol/L) = trough concentration drawn immediately prior to the next dose
• 6.4 mcg/mL (13.38 μmol/L) = peak concentration drawn 1 hour after the end of the infusion
• Urine (+) Enterococcus spp.
Given this additional information, what is your assessment of the patient’s condition?
Identify your treatment goals for the patient.
Loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) are all equally effective when given in equivalent doses. Therefore, selection is based on the side-effect profile, cost, and pharmacokinetics of the agents. The incidence of ototoxicity is significantly higher with ethacrynic acid compared to the other loop diuretics; therefore, its use is limited to patients who are allergic to the sulfa component in the other loop diuretics.18 While ototoxicity is a well-established side effect of furosemide, its incidence may be greater when administered by the IV route at a rate exceeding 4 mg/min. Torsemide has not been reported to cause ototoxicity.
There are several pharmacokinetic differences between loop diuretics. Fifty percent of a dose of furosemide is excreted unchanged by the kidney with the remainder undergoing glucuronide conjugation in the kidney.19 In contrast, liver metabolism accounts for 50% and 80% of the elimination of bumetanide and torsemide, respectively.19 Thus, patients with AKI may have a prolonged half-life of furosemide. The bioavailability of both torsemide and bumetanide is higher than for furosemide. The IV: oral ratio for bumetanide and torsemide is 1:1, bioavailability of oral furosemide is approximately 50%, with a reported range of 10% to 100%.20
Furosemide and bumetanide are both available in generic formulations and are generally less expensive than torsemide.
The pharmacodynamic characteristics of loop diuretics are similar when equivalent doses are administered. Because loop diuretics exert their effect from the luminal side of the nephron, urinary excretion correlates with diuretic response. Substances that interfere with the organic acid pathway, such as endogenous organic acids which accumulate in renal disease, competitively inhibit secretion of loop diuretics. Therefore, large doses of loop diuretics may be required to ensure that adequate drug reaches the nephron lumen. In addition, loop diuretics have a ceiling effect where maximal natriuresis occurs.19,21 Thus, very large doses of furosemide (e.g., 1 g) are generally not considered necessary and may unnecessarily increase the risk of ototoxicity.
Several adaptive mechanisms by the kidney limit effectiveness of loop diuretic therapy. Postdiuretic sodium retention occurs as the concentration of diuretic in the loop of Henle decreases. This effect can be minimized by decreasing the dosage interval (i.e., dosing more frequently) or by administering a continuous infusion.22 In patients with a CrCl of 25 mL/min or higher, furosemide at a dose of 10 mg/h would be a reasonable starting dose.19 A starting dose of 20 mg/h would be reasonable in patients with a CrCl of less than 25 mL/min.19 With a continuous infusion, a loading dose is recommended. Continuous infusion loop diuretics may be easier to titrate than bolus dosing, requires less nursing administration time, and may lead to fewer adverse reactions.
Prolonged administration of loop diuretics can lead to a second type of diuretic resistance. Enhanced delivery of sodium to the distal tubule can result in hypertrophy of distal convoluted cells.19 Subsequently, increased sodium chloride absorption occurs in the distal tubule which diminishes the effect of the loop diuretic on sodium excretion. Addition of a distal convoluted tubule diuretic, such as metolazone or hydrochlorothiazide, to a loop diuretic can result in a synergistic increase in urine output. There are no data to support the efficacy of one distal convoluted tubule diuretic over another. The common practice of administering the distal convoluted tubule diuretic 30 to 60 minutes prior to the loop diuretic has not been studied, although this practice may first inhibit sodium reabsorption at the distal convoluted tubule before it is inundated with sodium from the loop of Henle.
A usual starting dose of IV furosemide for the treatment of AKI is 40 mg (Fig. 25–2). Reasonable starting doses for bumetanide and torsemide are 1 mg and 20 mg, respectively.19 Efficacy of diuretic administration can be determined by comparison of a patient’s hourly fluid balance. Other methods to minimize volume overload, such as fluid restriction and concentration of IV medications, should be initiated as needed. If urine output does not increase to about 1 mL/kg/h, the dosage can be increased to a maximum of 160 to 200 mg of furosemide or its equivalent (Fig. 25–2).20 Dosing frequency is based on the patient’s response, the ability to restrict sodium intake, and the duration of action of the diuretic. Other methods to improve diuresis can be initiated sequentially, such as: (a) shortening the dosage interval, (b) adding hydrochlorothiazide or metolazone, and (c) switching to a continuous infusion loop diuretic. A loading dose should be administered prior to both initiating a continuous infusion and increasing the infusion rate. When high doses of loop diuretics are administered, especially in combination with distal convoluted tubule diuretics, the hemodynamic and fluid status of the patient should be monitored every shift, and the electrolyte status of the patient should be monitored at least daily to prevent profound diuresis and electrolyte abnormalities, such as hypokalemia. Patients will not benefit from switching from one loop diuretic to another because of the similarity in mechanisms of action.
Other Diuretics
Thiazide diuretics, when used as single agents, are generally not effective for fluid removal. Mannitol is also not recommended for the treatment of volume overload associated with AKI. Mannitol is removed by the body by glomerular filtration. In patients with renal dysfunction, mannitol excretion is decreased, resulting in expanded blood volume and hyperosmolality. Potassium-sparing diuretics, which inhibit sodium reabsorption in the distal nephron and collecting duct, are not sufficiently effective in removing fluid. In addition, they increase the risk of hyperkalemia in patients already at risk. Thus, loop diuretics are the diuretics of choice for the management of volume overload in AKI.
Dopamine
Low-dose dopamine (LDD), in doses ranging from 0.5 to 3 mcg/kg/min, predominantly stimulates dopamine-1 receptors, leading to renal vascular vasodilation and increased renal blood flow. While this effect has been substantiated in healthy, euvolemic individuals with normal kidney function, a lack of efficacy data exists in patients with AKI. The most comprehensive study evaluating efficacy of LDD, the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group study, did not find that LDD alters peak SCr, need for RRT, duration of stay in the intensive care unit, or survival to discharge compared to placebo.23 A recent meta-analysis was performed on all published human trials that used LDD in the prevention or treatment of AKI.24 A total of 61 studies were identified that randomized more than 3,300 patients to LDD or placebo. Results reveal no significant difference between the treatment and control groups for mortality, requirement for RRT, or adverse effects.
FIGURE 25–2. Algorithm for treatment of extracellular fluid expansion. (CrCl, creatinine clearance; ECF, extracellular fluid; HCTZ, hydrochlorothiazide; po, oral.)
LDD is not without adverse reactions and most studies have failed to evaluate its potential toxicities. Adverse reactions that may be associated with LDD include: tachycardia, arrhythmias, myocardial ischemia, depressed respiratory drive, gut ischemia, and impaired resistance to infection. Furthermore, significant overlap in receptor activation occurs. Therefore, doses considered to activate only dopamine receptors may increase cardiac output and blood pressure through dopamine’s effect on β- or α-adrenergic receptors.
Based on the results of the ANZICS trial, the lack of conclusive evidence in many earlier studies, and several meta-analyses, there is no indication for the use of LDD in the treatment of AKI.
Fenoldopam
Fenoldopam is a selective dopamine-1 receptor agonist that is approved for short-term management of severe hypertension. Because it does not stimulate dopamine-2, α-adrenergic, and β-adrenergic receptors, fenoldopam causes vasodilation in the renal vasculature with potentially fewer nonrenal effects than dopamine. In normotensive individuals with normal kidney function, IV fenoldopam increases renal blood flow without lowering systemic blood pressure.25 While preliminary studies in animal models of AKI are encouraging, few studies are available assessing its effectiveness in the treatment of AKI. A prospective randomized study comparing fenoldopam to placebo in early ATN did not find a difference in need for dialysis or mortality26. A second prospective, randomized study in septic patients did find less of an increase in SCr in the fenoldopam group compared to placebo, but no difference in survival or need for RRT.27 Large, prospective trials are needed before fenoldopam can be recommended. Other agents that are under evaluation for the treatment of AKI include atrial natriuretic peptide, urodilatin, and nesiritide.
Nonpharmacologic Treatment
Renal Replacement Therapy
RRT using dialysis may be necessary in patients with established AKI to treat volume overload that is unresponsive to diuretics, to minimize the accumulation of nitrogenous waste products, and to correct electrolyte and acid-base abnormalities while renal function recovers. Five to thirty percent of patients with AKI treated with dialysis will not have recovery of their renal function and will need to remain on long-term dialysis.28 This may be due in part to underlying illnesses, as AKI is often seen in the setting of multiorgan failure. There are two types of dialysis modalities commonly used in AKI: intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT). IHD is a higher-efficiency form of dialysis which is provided for several hours a day at a variable frequency (usually daily or three to five times per week) at a higher blood flow rate. CRRT is a pump-driven form of dialysis which provides slow fluid and solute removal on a continuous, 24-hour basis. The primary advantage of CRRT is hemodynamic stability and better volume control, particularly in patients who are unable to tolerate rapid fluid removal. The primary disadvantages associated with CRRT are continuous nursing requirements, continuous anticoagulation, frequent clotting of the dialyzer, patient immobility, and increased cost. There is no conclusive evidence that one type of dialysis is preferred to another in terms of mortality and recovery of renal function.29 Thus, selection of CRRT over IHD is often governed by the critical illness of the patient and by the comfort level of the institution with one particular type of dialysis.
With either type of dialysis, studies suggest that recovery of renal function is decreased in AKI patients who undergo dialysis compared with those not requiring dialysis. Decreased recovery of renal function may be due to hemodialysis-induced hypotension causing additional ischemic injury to the kidney. Also, exposure of a patient’s blood to bioincompatible dialysis membranes (cuprophane or cellulose acetate) results in complement and leukocyte activation which can lead to neutrophil infiltration into the kidney and release of vasoconstrictive substances that can prolong renal dysfunction.30 Synthetic membranes composed of substances such as polysulfone, polyacrylonitrile, and polymethylmethacrylate are considered to be more biocompatible and would be less likely to activate complement. Synthetic membranes are generally more expensive than cellulose-based membranes. Several recent metaanalyses found no difference in mortality between biocompatible and bioincompatible membranes. Whether biocompatible membranes lead to better patient outcomes continues to be debated.
Supportive Therapy
Supportive therapy in AKI includes adequate nutrition, correction of electrolyte and acid-base abnormalities (particularly hyperkalemia and metabolic acidosis), fluid management, and correction of any hematologic abnormalities. Because AKI is often associated with multiorgan failure, treatment includes the medical management of infections, cardiovascular and GI conditions, and respiratory failure. Finally, all drugs should be reviewed, and dosage adjustments made based on an estimate of the patient’s GFR.
Patient Encounter, Part 3: Creating a Care Plan
Based on the information presented, create a care plan for this patient’s AKI. Your plan should include: (a) a statement of the drug-related need and/or problems, (b) the goals of therapy, (c) a detailed patient-specific therapeutic plan, and (d) a plan for follow-up to determine whether the goals have been achieved and adverse effects avoided.
PREVENTION OF ACUTE RENAL FAILURE
Avoidance
The best preventive measure for AKI, especially in individuals at high risk, is to avoid medications that are known to precipitate AKI. Nephrotoxicity is a significant side effect of aminoglycosides, ACE inhibitors, angiotensin receptor antagonists, amphotericin B, NSAIDs, cyclosporine, tacrolimus, and radiographic contrast agents.8 Unfortunately, an effective, non-nephrotoxic alternative may not always be appropriate for a given patient and the risks and benefits of selecting a drug with nephrotoxic potential must be considered. For example, serious gram-negative infections may require double antibiotic coverage, and based on culture and sensitivity reports, aminoglycoside therapy may be necessary. In cases such as this, other measures to reduce the risk of AKI should be instituted. Thus, identifying patients at high risk for development of AKI and implementing preventive methods to decrease its occurrence or severity is critical.
Drug-Induced ARF
Aminoglycosides
Aminoglycosides (gentamicin, tobramycin, and amikacin) can cause nonoliguric intrinsic AKI. Injury is due to binding of aminoglycosides to proximal tubular cells in the renal cortex, and subsequent cellular uptake and cell death.31In clinical practice, all aminoglycosides are considered equally nephrotoxic, and similar precautions should be used for all of the agents. High cumulative drug exposure increases the incidence of aminoglycoside-induced AKI. Additional risk factors include a prolonged course of aminoglycoside therapy (typically longer than 7–10 days), pre-existing chronic kidney disease, and increased age.32 Alternative antibiotics should be considered in individuals with AKI or those who are at a high risk for developing AKI, although resistance of some strains of gram-negative organisms to other antibiotics may necessitate their use.
Methods to minimize drug exposure with conventional (multiple doses per day) dosing include maintaining trough concentrations less than 2 mcg/mL for gentamicin and tobramycin (less than 10 mcg/mL for amikacin), minimizing length of therapy, and avoiding repeated courses of aminoglycosides. Concurrent exposure to other nephrotoxic medications and dehydration may also worsen AKI. There is conflicting evidence as to whether the combination of vancomycin and an aminoglycoside has a higher incidence of AKI than aminoglycoside therapy alone. Aminoglycoside-induced AKI is usually reversible upon drug discontinuation; however, dialysis may be needed in some individuals while kidney function improves.
Another method to minimize toxicity is with extended-interval dosing (e.g., once daily). The goal of extended-interval dosing is to provide greater efficacy against the microorganism with a lower incidence of nephrotoxicity. Aminoglycosides demonstrate concentration-dependent killing and a prolonged postantibiotic effect. The mechanism by which extended-interval aminoglycoside dosing may reduce the incidence of nephrotoxicity is by providing high, transient concentrations of drug which saturate proximal tubule uptake sites. Once saturated, the remaining aminoglycoside molecules pass through the proximal tubule and are excreted in the urine.33 Thus, less drug is available for cellular uptake during a 24-hour period. A consistent finding in studies is that extended-interval aminoglycoside dosing is as effective as conventional dosing and is not more nephrotoxic, and in some studies is less nephrotoxic than conventional dosing. Aminoglycosides can also cause hearing loss and/or vestibular toxicity, although the incidence of ototoxicity appears to be similar with extended-dosing and conventional dosing. Prolonged exposure to the drug, repeated courses of therapy, and concurrent use of other ototoxic drugs increase toxicity. Extended-interval dosing is not recommended in patients with pre-existing kidney disease, conditions where high concentrations are not needed (e.g., urinary tract infections), hyperdynamic patients that may demonstrate increased drug clearance (e.g., burn patients), and others where you would suspect altered pharmacokinetics or increased risk of ototoxicity.
Amphotericin B
Amphotericin B–induced AKI occurs in as many as 49% to 65% of patients treated with the conventional desoxycholate formulation.34 Nephrotoxicity is due to renal arterial vasoconstriction and distal renal tubule cell damage. Risk factors include high daily dosage, large cumulative dose, preexisting kidney dysfunction, dehydration, and concomitant use of other nephrotoxic drugs.34 Three lipid-based formulations of amphotericin B have been developed in an attempt to improve efficacy and limit toxicity, particularly nephrotoxicity: amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B. The range of nephrotoxicity reported is 15% to 25% for these formulations. The mechanism for decreased nephrotoxicity has not been completely elucidated, but it is thought to be due to preferential delivery of amphotericin B to the site of infection, with less of an affinity for the kidney.35 Lipid-based formulations are recommended in individuals with risk factors for development of AKI. Administration of IV normal saline may also attenuate nephrotoxicity associated with amphotericin B.
Whether there are significant differences in nephrotoxicity between the three lipid-based formulations remains unclear. A recent review of the literature from 1997 through 2007 summarized the studies to date comparing lipid-based formulations.35 Only amphotericin B lipid complex and liposomal amphotericin B have been compared, mainly in observational studies. Nine studies showed a similar incidence of AKI between amphotericin B lipid complex and liposomal amphotericin B. However, in one prospective, randomized study, the incidence of nephrotoxicity was lower with liposomal amphotericin B dosed at 5 mg/kg/day (14.8%) compared to amphotericin B lipid complex dosed at 5 mg/kg/day (42%) in febrile, neutropenic patients.36 Large, prospective studies comparing the incidence of nephrotoxicity between these agents are needed to ascertain differences in nephrotoxicity.
Radiocontrast Agents
Intravascular radiographic contrast agents are administered during radiologic studies and carry with them the well-documented risk of AKI. Patients at risk for developing AKI include patients with chronic kidney disease, diabetic nephropathy, dehydration, and higher doses of contrast dye.37 Contrast agents are water-soluble, triiodinated, benzoic acid salts that cause an osmotic diuresis due to their osmolality, which exceeds that of plasma. The mechanism of nephrotoxicity is not fully understood; however, direct tubular toxicity, renal ischemia, and tubular obstruction have been implicated.38 Diatrizoate and iothalamate are ionic contrast agents. Iohexol, iopamidol, ioversol, and iopromide represent nonionic agents. The incidence of nephrotoxicity with ionic and nonionic agents is similar in patients at low risk for developing AKI; however, in high-risk patients, nephrotoxicity is significantly greater when ionic contrast agents are used. In diabetic patients with chronic kidney disease and an SCr of greater than 1.5 mg/dL (133 μmol/L), nephrotoxicity occurred in 33.3% and 47.7% of patients receiving nonionic and ionic contrast agents, respectively.39 The cost of nonionic agents is approximately 10-fold higher, which may limit their routine use in all patients undergoing radiographic studies.
Therapeutic measures that have been used to decrease the incidence of contrast-induced nephropathy include extracellular volume expansion, minimization of the amount of contrast administered, and treatment with oral acetylcysteine. Theophylline, fenoldopam, loop diuretics, mannitol, dopamine, and calcium antagonists have no effect or may worsen AKI.
The most effective therapeutic maneuver to decrease the incidence of contrast-induced nephropathy is extracellular volume expansion.40 Several recent studies have compared the efficacy of isotonic sodium chloride (0.9%) to half normal saline (0.45%) or to oral hydration.41,42 Isotonic fluid is superior to hypotonic fluid in prevention of nephropathy. A common regimen is IV isotonic sodium chloride (1 mL/kg of body weight/hour) administered for 12 hours before and 12 hours after the procedure. Fluid should be administered cautiously to patients with CHF, left ventricular dysfunction, and significant renal dysfunction. Recent evidence suggests that hydration, plus sodium bicarbonate to alkalize renal tubule fluid, may reduce free radical formation and lead to less oxidant damage, although studies have been conflicting.43,44 Most studies investigating sodium bicarbonate hydration administered therapy at a rate of 3 mL/kg/h (154 mEq/L) for one before the procedure, and 1 mL/kg/h during and 6-hour postcontrast. A large, randomized clinical trial that provides definitive conclusions is needed.
Minimizing the quantity of contrast media administered may be beneficial in preventing nephropathy. Some studies, but not all, have directly associated dose of contrast media and nephrotoxicity. Avoidance of contrast dye with alternative diagnostic procedures should be considered in high-risk patients, but may not always be feasible. In addition, avoidance of multiple contrast studies in a short time period will allow renal function to return to normal between procedures.
Because production of reactive oxygen species has been implicated in the pathophysiology of contrast-induced AKI, prophylactic administration of the antioxidant acetylcysteine has been investigated. An oral dose of 600 mg twice daily the day before and the day of the procedure decreased the incidence of AKI in one small study, although patient outcomes such as mortality and length of hospitalization were not evaluated.45 Since then, at least 25 additional studies evaluating the efficacy of oral acetylcysteine have been conducted, with mixed results. In addition, a series of metaanalyses have also analyzed the results of the studies with varying conclusions. The studies were varied in terms of study population, sample size, definition of contrast nephropathy, type of contrast agent used, hydration, and formulation of acetylcysteine administered, thus making collective interpretation of the results difficult. It is routinely used in many hospitals due to its low cost and safe side effect profile at low oral doses, although data are not conclusive that it prevents development of AKI, particularly on patient outcomes such as mortality, need for dialysis, and length of hospitalization. It is noted that acetylcysteine is not considered a replacement for adequate hydration, which remains the standard of care for prevention of contrast nephropathy.
Fenoldopam does not decrease the incidence of contrast nephropathy.46 Due to its hypotensive effect, it may worsen kidney function.
Cyclosporine and Tacrolimus
Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for AKI is renal vascular vasoconstriction.47 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.47 Cyclosporine and tacrolimus are extensively metabolized by the liver through the cytochrome P450 3A4 pathway and drugs that inhibit their metabolism (e.g., erythromycin, clarithromycin, fluconazole, ketoconazole, verapamil, diltiazem, and nicardipine) can precipitate AKI. Because AKI is dose dependent, careful monitoring of cyclosporine or tacrolimus trough concentrations can minimize its occurrence; however, AKI can develop with normal or low blood concentrations. In addition, there is some evidence that calcium channel blockers have a renoprotective effect through dilation of the afferent arterioles and are often used preferentially as antihypertensive agents in kidney transplant recipients.
It is often difficult to differentiate AKI from acute rejection in the kidney transplant recipient, as both conditions may present with similar symptoms and physical examination findings. However, fever and graft tenderness are more likely to occur with rejection while neurotoxicity is more likely to occur with cyclosporine or tacrolimus toxicity. Kidney biopsy is often needed to confirm the diagnosis of rejection.
ACE Inhibitors and ARBs
In instances of decreased renal blood flow, production of angiotensin II increases, resulting in efferent arteriole vasoconstriction and maintenance of glomerular capillary pressure and GFR (Fig. 25–3). In patients initiated on ACE inhibitors or ARBs, angiotensin II synthesis decreases, thereby dilating efferent arterioles and decreasing glomerular capillary pressure and GFR. Risk factors for developing AKI are pre-existing renal dysfunction, severe atherosclerotic renal artery stenosis, volume depletion, and severe CHF.48 AKI often develops within days, with a rapid rise in blood urea nitrogen (BUN) and SCr. Discontinuation of the drug usually results in return of renal function to baseline, although a small decrease in kidney function may be acceptable in patients with severe CHF who would benefit from the hemodynamic effect of ACE inhibitors or ARBs.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs (e.g., inbuprofen, naproxen, sulindac) can likewise cause prerenal AKI through inhibition of prostaglandin-mediated renal vasodilation. Risk factors are similar to those of ACE inhibitors and ARBs. Additional risk factors include hepatic disease with ascites, systemic lupus erythematosus, and advanced age. The onset is often within days of initiating therapy and patients typically present with oliguria. It is usually reversible with drug discontinuation. Agents that preferentially inhibit cyclooxygenase-2 pose a similar risk as traditional, nonselective NSAIDs.49
Other Drugs
Other drugs that are commonly implicated in causing AKI include acyclovir, adefovir, carboplatin, cidofovir, cisplatin, foscarnet, ganciclovir, indinavir, methotrexate, pentamidine, ritonavir, sulfinpyrazone, and tenofovir.50
OUTCOME EVALUATION
Goals of therapy are to maintain a state of euvolemia with good urine output (at least 1 mL/kg/h), to return serum creatinine to baseline, and to correct electrolyte and acid-base abnormalities. In addition, appropriate drug dosages based on kidney function and avoidance of nephrotoxic drugs are goals of therapy. Assess vital signs, weight, fluid intake, urine output, BUN, creatinine, and electrolytes daily in the unstable patient.
FIGURE 25–3. Normal glomerular autoregulation serves to maintain intra-glomerular capillary hydrostatic pressure, glomerular filtration rate, and ultimately, urine output. This is accomplished by modulation of afferent and efferent arterioles. Afferent and efferent arteriolar vasoconstrictions are primarily mediated by angiotensin II, whereas afferent vasodilation is primarily mediated by prostaglandins. (PGE2, prostaglandin E2.)
Patient Care and Monitoring
1. Assess kidney function by evaluating a patient’s signs and symptoms, laboratory test results, and urinary indices. Calculate a patient’s CrCl to evaluate the severity of kidney disease.
2. Obtain a thorough and accurate drug history, including the use of nonprescription drugs such as NSAIDs.
3. Evaluate a patient’s current drug regimen to:
• Determine if drug therapy may be contributing to AKI. Consider not only drugs that can directly cause AKI (e.g., aminoglycosides, amphotericin B, NSAIDs, cyclosporine, tacrolimus, ACE inhibitors, and ARBs), but also drugs that can predispose a patient to nephrotoxicity or prerenal AKI (i.e., diuretics and antihypertensive agents).
• Determine if any drugs need to be discontinued, or alternate drugs selected, to prevent worsening of renal function.
• Adjust drug dosages based on the patient’s CrCl or evidence of adverse drug reactions or interactions.
4. Develop a plan to provide symptomatic care of complications associated with AKI, such as diuretic therapy to treat volume overload. Monitor the patient’s weight, urine output, electrolytes (such as potassium), and blood pressure to assess efficacy of the diuretic regimen.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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