Acute tubular necrosis

Acute tubular necrosis (ATN) is a form of acute renal failure (ARF) that is common in hospitalized patients. In critical care units, it accounts for about 76% of cases of ARF. Despite the introduction of hemodialysis > 30 years ago, the mortality rates from ATN in hospitalized and ICU patients are about 37.1% and 78.6%, respectively. The purpose of this review is to discuss briefly the cause, diagnosis, and epidemiology of ARF, and to review in depth the clinical trials performed to date that have examined the influence of growth factors, hormones, antioxidants, diuretics, and dialysis. In particular, the role of the dialysis modality, dialyzer characteristics, and dosing strategies are discussed.

Key words: dialysis; nephrology; renal failure

Abbreviations: ANP = atrial natriuretic peptide; APACHE = acute physiology and chronic health evaluation; ARF = acute renal failure; ATN = acute tubular necrosis; CRRT = continuous renal replacement therapy; CVVH = continuous venovenous hemofiltration; DA = dopamine agonist; DF = hemodiafiltration; GFR = glomerular filtration rate; IGF = insulin-like growth factor; IHD = intermittent hemodialysis; MAP = mean arterial pressure; PD = peritoneal dialysis; PTX = pentoxifylline; RBF = renal blood flow; ROS = reactive oxygen species; RR = relative risk; RRT = renal replacement therapy; TNF = tumor necrosis factor

Learning Objectives: 1. Identify key clinical areas asociated with hospitalized and critically-ill patients with acute tubular necrosis (ATN) that best describes why this population is associated with significant mortality. 2. List the most current treatment methods for ATN that are based upon supportive measures. 3. Identify additional areas of research that are still needed in order to better define therapies that could alter the course of ATN.

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Acute renal failure is characterized by a sudden decline in the glomerular filtration rate (GFR), the accumulation of nitrogenous wastes, and inability of the kidney to regulate the electrolyte and water balance. (1) Commonly used definitions of acute renal failure (ARF) include an increase in serum creatinine of [greater than or equal to] 0.5 mg/dL over the baseline value, a reduction in the calculated creatinine clearance rate by 50%; or a decrease in renal function that results in a need for dialysis. (2,3) ARF can be oliguric (urinary output, < 400 mL/d) or nonoliguric (urinary output, [greater than or equal to] 400 mL/d).

The frequency of ARF among patients is 1% on hospital admission,4 2 to 5% during hospitalization, (5,6) and as high as 15% after cardiopulmonary bypass. (7) Ischemic or toxic acute tubular necrosis (ATN) is the predominant cause of ARF in hospitalized patients and in the ICU, accounting for 38% and 76% of cases of ARF, respectively. (8) Prerenal azotemia accounts for 70% of the community-acquired causes of ARF, (4) and for 40% of hospital-acquired causes. Sustained prerenal azotemia is the most common factor that predisposes patients to ischemic induced tubular necrosis. (8,9) Hospital-acquired ARF is often due to more than one insult. (8) Frequently encountered combinations of acute insults include exposure to aminoglycosides in the setting of sepsis, (2) the administration of radiocontrast agents in patients receiving angiotensin-converting enzyme inhibitors (10) or treatment with nonsteroidal antiinflammatory in the presence of congestive heart failure. (6) In the ICU, sepsis is the leading cause of ARF, occurring in approximately 19% of patients with moderate sepsis, 23% of patients with severe sepsis, and 51% of patients with septic shock when blood cultures findings are positive. (11-14)

The exact pathogenetic mechanisms and sequence of events resulting in renal dysfunction is sepsis are poorly understood. Systemic hypotension, the activation of vasoconstrictor hormones (including the renin-angiotensin-aldosterone system and endothelin), the induction of nitric acid synthase and nitric oxide (a potent vasodilator), the release of cytokines (such as tumor necrosis factor [TNF], interleukin-1, and chemokines), the enhanced synthesis of reactive oxygen species (ROS), and the activation of neutrophils by endotoxins all may contribute to renal injury. (14-16)

The terms acute renal failure and acute tubular necrosis are often mistakenly interchanged. ATN is a form of ARF that is caused by an ischemic or toxic injury to the tubular epithelial cells. The resulting cell death or detachment from the basement membrane causes tubular dysfunction. The urinalysis and urine chemistry levels reflect these processes, as discussed below, and can aid in distinguishing ATN from a variety of other conditions, including prerenal azotemia, urinary tract obstruction, vasculitis, glomerulonephritis, and acute interstitial nephritis, that also cause ARF. (7) Please note that the term ARF when used in the remainder of the article is, for the most part, specific to ATN as the underlying etiology.

DIAGNOSIS

Serum Markers

Creatinine and BUN: Clinical markers of impaired GFR must be carefully interpreted. Creatinine is a suboptimal indicator of renal function during ARF because plasma creatinine levels are influenced by many nonrenal events that regulate creatinine generation, the volume of distribution, and creatinine excretion. (17) As GFR decreases, the amount of tubular secretion becomes an increasingly important fraction of creatinine excretion, such that creatinine clearance overestimates GFR by 50 to 100% once the true GFR is < 15 mL/min. (17) Moran and Myers (18) (Fig 1) noted that a sudden fall in GFR to a constant low level causes a slow increase in plasma creatinine levels. The rate of rise depends on the new GFR but also on the rate of creatinine generation and the volume of the distribution of creatinine. While creatinine in the muscle is produced at a constant rate, the creatinine level in the blood can be elevated during catabolic states such as rhabdomyolysis. Aggressive fluid administration may dilute the serum creatinine level. Moreover, drugs such as cimetidine and trimethoprim, which inhibit the tubular secretion of creatinine, cause an increase in serum creatinine level in the absence of changes in GFR. (18)

[FIGURE 1 OMITTED]

Levels of BUN depend on the exogenous urea load (intake), endogenous urea production (catabolic rate), and tubular reabsorption. In reduced effective renal perfusion states, enhanced reabsorption of urea from the medullary collecting duct may lead to an elevation of the BUN level that is disproportionate to the increase in serum creatinine level (ratio, > 10:1 or 15:1). (19)

Urinary Electrolytes and Sediment

In the setting of impaired renal perfusion, low urine sodium concentration, and fractional excretion of sodium, elevated urine osmolality and elevated urine/plasma creatinine ratio indicate preserved tubular function and an appropriate renal response to the prerenal azotemic state. With the onset of ATN, tubule dysfunction leads to an increase in urinary sodium concentration and the fractional excretion of sodium, and to impairment in urinary concentrating capacity, which is characterized by a decrease in urine osmolality and urine/plasma creatinine ratio. (19)

Advanced chronic kidney disease and recent diuretic use may alter the ability of these urinary measures. Furthermore, ATN in the setting of rhabdomyolysis and myoglobinuria, hemolysis, sepsis, cirrhosis, heart failure, and radiocontrast nephropathy may be associated with a low urinary sodium concentration (eg, < 10 mEq/L) and fractional excretion of sodium (eg, < 1%). (20-23)

As mentioned before, recognition of the characteristic urinary sediment of ATN, including renal tubular epithelial cells, epithelial cell casts, and muddy brown granular casts, helps to make the diagnosis. However, since there is no "gold standard," the diagnostic approach must rely on a synthesis of data from the patient's history, physical examination, and laboratory studies. (24)

In general, a renal biopsy in not necessary in the evaluation and therapy of patients with ATN. However, when the history, clinical features, and findings of laboratory and radiologic investigations suggest a diagnosis of primary renal disease other than ischemic or toxin-related ARF, a kidney biopsy may establish the diagnosis and guide therapy. (1) There have been studies (25,26) that have assessed the value of the renal biopsy in patients with atypical features of ARF that suggested pathologic conditions other than ATN. One prospective study by Richards et al (27) of 266 patients showed that the results of the biopsy altered management in 22 of 31 patients (71%) with ARF, in 24 of 28 patients (86%) with nephrotic range proteinuria, in 58 of 128 patients (45%) with chronic renal failure, in 9 of 28 patients (32%) with hematuria and proteinuria, in 3 of 25 patients (12%) with non-nephrotic range proteinuria alone, and in 1 of 36 patients (3%) with hematuria alone. Management was altered in 42% of cases overall.

MORTALITY

Simple ARF in the presence of no underlying illness has about a 7 to 23% mortality rate, whereas the mortality rate of ARF in an ICU setting is 50 to 80%. (1,8,28-30) Various risk factors for increased mortality in patients with ATN have been identified, including male sex, advanced age, comorbid illness, malignancy, oliguria, sepsis, mechanical ventilation, multiorgan failure, and severity-of-illness score. (30,31) Other factors such as acute myocardial infarction, acute stroke or seizure, chronic immunosuppression, and metabolic acidosis also have been associated with the relative risk (RR) of death after progressive ARF due to ATN. (32)

OUTCOMES

Several models have been created to predict outcomes and mortality in critically ill patients with ARF. A predictive model with high specificity would be ideal to identify patients with extremely high mortality, in whom a less invasive approach might be taken, without denying therapy to those who might benefit. (30)

Traditional models of predicting death in critically ill patients, such as the original acute physiology and chronic health evaluation (APACHE), (33) the original simplified acute physiology score, (34) the original mortality prediction model, (35) APACHE II score, (36) APACHE III score, (37) simplified acute physiology score II, (38) and mortality prediction model II score (39) were developed to plot the course of critical illness and to help clinical decision making. These scoring systems are powerful research tools that can be used to quantify disease severity, estimate mortality, and allow comparisons among patients. However, these scoring systems do not have sufficient statistical power to study most disease subsets in critical care and may be inaccurate if used as such. (40,41) Therefore, specific severity-of-illness scores to predict outcome for patients with ARF in the ICU have been developed. (42,43) Models designed by Liano and colleagues (42) and by the Cleveland Clinic (29,32,44) have been prospectively validated. The model of Llano et al (42) revealed coma, assisted respiration, hypotension, oliguria, and jaundice as having independent influence on mortality. The Cleveland Clinic model was based on ARF patients in the ICU who required dialysis. It was important to evaluate these patients as a separate group since their physiologic and clinical needs change once they are exposed to dialysis. (43) Significant factors affecting mortality were male gender, respiratory failure requiring intubation, hematologic dysfunction (ie, platelet count, < 50,000 cells/[micro]L; WBC count; < 2,500 cells/[micro]L; or bleeding diathesis), bilirubin level of > 2.0 mg/dL, the absence of surgery, serum creatinine level on the first dialysis day, and an increased BUN level from the time of hospital admission (Table 1).

It is now established that ATN independently and significantly affects patient survival. Levy and colleagues (45) performed a cohort analysis study of > 16,000 patients undergoing radiocontrast procedures. They identified 174 patients who developed contrast nephropathy (defined as an increase in serum creatinine of at least 25% to 2 mg/dL), and matched them to patients of similar age and baseline creatinine level who underwent similar contrast procedures without developing ARF. This small 25% change in serum creatinine level may reflect a reduction of as much as 50% in GFR. (46) Of the 174 patients with ARF, 21 required dialysis. The mortality rate in patients without renal failure was 7% compared with 32% in the index patients. After adjusting for differences in comorbidity, renal failure was associated with an odds ratio of 5.5 for mortality. Thus, the high mortality rate seen in patients with ARF is not explained by the underlying comorbid conditions alone. ARF should not be regarded as a benign condition of a serious illness. Instead, changes in creatinine level, however small, should be taken seriously and should trigger subsequent steps to determine the cause and specific treatment of the renal failure.

PREVENTION OF ATN

Implementing an intervention before the toxic or ischemic event insult affords the best opportunity for preventing or attenuating the course of ATN. (24) Investigators have targeted prevention efforts at agents or events that are known to cause renal damage, such as radiocontrast material and certain antibiotics, to reduce the risk of renal dysfunction (Table 2). (47-72)

MANAGEMENT OF ATN

Nondialytic

Supportive Care: In the absence of therapies with proven beneficial effects for the treatment of ATN, appropriate supportive care is mandated. The avoidance of further nephrotoxic insults, such as nonsteroidal antiinflammatory drugs, nephrotoxic antibiotics, and radiocontrast media is very important. Also, adequate maintenance of hemodynamics and renal perfusion is the cornerstone of care. (24) Solez and colleagues (73) showed that patients with ATN are highly susceptible to recurrent ischemic damage by demonstrating fresh necrotic tubules in biopsy specimens of their kidneys. Thus, either mild or severe decreases in BP due to volume depletion, dialysis, sepsis, cardiac dysfunction, anesthesia, or antihypertensive medications can further decrease renal perfusion and can lead to recurrent ischemic injury. (24) In the normal mammalian kidney, the loss of autoregulation of renal blood flow (RBF) generally occurs at a mean arterial pressure (MAP) of 75 to 80 mm Hg. (74) In experimental ATN models, (75-77) it has been shown that impaired autoregulation of GFR and RBF occurs throughout all ranges of MAP and that renal perfusion is linearly dependent on MAP even in the normal range of BP. Furthermore, paradoxical renal vasoconstriction occurs at low MAP. Animal models (78) have shown increments in RBF when MAP was increased with norepinephrine from 52 to 65 mm Hg, but not further. LeDoux et al (79) have reported that increasing MAP from 65 to 85 mm Hg did not alter urine output. However, this was a small study involving only 10 patients, 2 of whom were anurie while receiving continuous venovenous hemofiltration (CVVH). Although it has been recommended that MAP should not be increased > 65 to 70 mm Hg, (80) maintaining a MAP of 65 mm Hg may be inadequate for renal resuscitation in elderly patients, or in patients with known hypertension or diabetes. (81) A prospective randomized controlled trial is needed to clarify whether the augmentation of perfusion pressure can achieve improvement in renal function or even prevent the occurrence of renal dysfunction.

Ensuring adequate volume status must underlie any treatment strategy as renal perfusion is dependent on an adequate intravascular volume state. (81) The clinical assessment of volume status in a critically ill patient is, however, often difficult. Overzealous fluid administration in an attempt to improve hemodynamics in a septic patient with leaky pulmonary vasculature can precipitate noncardiogenic pulmonary edema. (18) Studies (82-85) have also shown that increasing cardiac output and oxygen delivery through the administration of large volumes of fluid and inotropic agents, and aggressive RBC transfusion may increase mortality. The estimation of volume status in vasodilated septic patients can be achieved by careful daily measurements of body weight and urine output.

Vasoactive Agents: Dopamine has selective renal vasodilatory properties that cause natriuresis and increased urine output. (86,87) Dopamine, at a dose of 0.5 to 2.0 [micro]g/kg/min, activates dopamine-1 receptors, which induce renal vasodilation and increased RBF. (88) Selective use of this "renal dose" of dopamine has not been shown to be of value in patients with ARF.(89-92) Bellomo and colleagues9a reported on 328 critically ill patients with ARF who were randomly assigned to continuous infusion of placebo or low-dose dopamine (2 [micro]g/kg/min). Peak serum creatinine concentration, requirement for dialysis, length of hospital stay, and mortality rate did not differ between groups. Also, the prophylactic use of low-dose dopamine in patients undergoing coronary artery bypass surgery has not been shown to be effective in preventing the development of renal impairment in these patients. (94-97) The use of dopamine also has been associated (98) with serious cardiac, vascular, and metabolic complications in critically ill patients and therefore should be used with caution. Other than dopamine, the literature provides little guidance on the effects of other vasoactive agents on the kidney; therefore, there is a great need for large randomized controlled trials to clarify this issue. (99)

Fenoldopam: Fenoldopam is a selective dopamine agonist (DA) for receptor 1 that causes DA-1 receptor-mediated vasodilation and does not stimulate DA-2 or adrenergic [alpha] or [beta] receptors. (81) Fenoldopam reduced renal vascular resistance, and increased RBF, the fractional excretion of sodium, and free water clearance in studies in healthy volunteers and hypertensive patients. (100) The results of a few studies in animal models (101,l02) are consistent with the notion that DA-1 may be useful in preventing or treating ARF. Human studies have been encouraging in the treatment (103) and prevention (104,l05) of contrast-induced nephropathy and when used perioperatively in patients undergoing cardiovascular surgery. (106,107) One study (108) showed that when fenoldopam was used prophylactically in patients undergoing aortic surgery, its use was associated with improvement in renal function, and reductions in dialysis requirements, length of hospital stay, and mortality. Again, these studies were small, and therefore it is difficult to define the role of fenoldopam in clinical situations without a large-scale randomized controlled trial.

Furosemide and Mannitol: Furosemide is a loop diuretic and a vasodilator; it may decrease the metabolic work of the thick ascending limb. (109) Furosemide, if administered early in the course of ischemic ARF can convert the patient from an oliguric state to a nonoliguric state. Although nonoliguric ARF is generally associated with a lower mortality rate, there is little evidence that conversion from an oliguric to a nonoliguric state decreased the mortality rate. (110-112) A prospective, randomized, placebo-controlled, double-blind study (113) examining the effect of loop diuretics on renal recovery, dialysis, and death in patients with ARF found no effect. Observational data have suggested that diuretic use in critically ill patients with ARF is associated with increased mortality using multivariate analysis and propensity scores. (114) More recently, a prospective, multicenter epidemiologic study by Uchino et al (115) examined the impact of diuretics on critically ill patients with ARF and found that their use was not associated with higher mortality. Therefore, it is reasonable to administer a single trial of furosemide in escalating doses, and if the patients does not respond, the drug should not be readministered, as large doses of furosemide are ototoxic and the large infusion volume can cause pulmonary edema. (116)

Mannitol is a diuretic that has been shown in animal models (117,118) to help protect the kidney against ischemic injury with the rationale that its effects on preventing cell swelling and causing increasing tubular flow might decrease intratubular obstruction and mitigate renal dysfunction. Studies in humans (99,119) failed to demonstrate the effectiveness of mannitol in the prevention or treatment of ischemic or toxic ARF. However, mannitol has been shown to be beneficial when added to organ preservation solutions during renal transplantation (120) and also may protect against ARF that is caused by crush injury involving myoglobinuria, if administered extremely early in the course of treatment. (121)

Atrial Natriuretic Peptide: The natriuretic effect of an extract of mammalian atrial myocytes was discovered in the early 1980s. Subsequently, this substance has been characterized as a polypeptide called atrial natriuretic peptide (ANP). (122) The primary stimulus to ANP synthesis and release is the distension of the atria. (123) In the kidney, ANP inhibits sodium and water reabsorption in the collecting duct, vasodilates the afferent arteriole, and vasoconstricts the efferent arteriole, thus increasing GFR without affecting RBF. (124-126) In animals, ANP use can attenuate the severity of renal failure and potentiate the recovery of renal function even when administered after an ischemic insult. (127) In humans, a study of 53 patients with established ATN, who were randomly assigned to receive ANP or placebo, the intrarenal and IV administration of ANP improved creatinine clearance and decreased the need for dialysis. (128) However, subsequent larger randomized controlled trials (129,130) failed to demonstrate this, with no statistically significant decrease in the need for dialysis or mortality with ANP use in patients with ARF.

Growth Factors: ARF is a reversible organ failure caused by structural injury to renal vascular and epithelial cells. Renal regeneration starts immediately after an acute renal insult. (131,132) Several growth factors like epidermal growth factor, transforming growth factor-[alpha], insulin-like growth factor (IGF) 1, and hepatocyte growth factor have been shown to be important in repair processes in the kidney, (133-135) Receptors for these growth factors have been found in the renal epithelial cells, medullary interstitial cells, and glomeruli. They result in repair by promoting the proliferation of renal tubular cells. (136-138) In animal models with ischemic insults to the kidneys, the exogenous administration of epidermal growth factor (139,140) and IGF-1 (141) has been shown to result in more rapid recovery of renal function. In a clinical study (142) examining the role of IGF-1 in the course of ARF, in which the study population consisted of patients undergoing surgical procedures that required renal ischemic time (ie, renal vascularization or cross-clamping of the aorta above the renal arteries), it was shown that IGF-1 prevented the decrease in creatinine clearance associated with the procedure (as opposed to placebo). In a large randomized, double-blind, placebo-controlled trial (143) in the ICUs of 20 teaching hospitals involving 72 patients, it was shown that IGF-1 does not accelerate the recovery of renal function in ARF patients with substantial co-morbidities. Similarly, there is no role for thyroxine in modifying the course and outcome of ARF; in fact, it could have a negative effect on outcome through prolonged suppression of thyroid stimulating hormone. (144) Therefore, based on the current data, there is no role for the use of growth factors in the treatment of ARF.

Free Radical Scavengers and Antioxidants: One of the main pathogenic components of the injury sustained during ARF is oxygen free radical generation. (145,146) Renal ischemia/reperfusion injury initiates a complex and interrelated sequence of events resulting in injury and the eventual death of renal cells. (1,147) The initial lack of blood flow and oxygen delivery results in tubular cell damage, which is followed by reperfusion, which, although essential for the survival of the ischemic tissue, itself causes additional injury by the generation of ROS. (148,149) The mechanisms by which ROS cause renal injury include its effects on intracellular calcium handling in smooth muscle cells leading to vascular reactivity (150); the induction of vasoconstrictive species such as endothelin, (151) isoprostanes, (152) and thromboxane (153); the impairment of basement membrane function (154); a reduction in the bioavailability of nitric oxide leading to renal vasoconstriction (155); and the induction of apoptosis. (156,157)

Antioxidants perform as free radical scavengers by binding metal ions, degrading peroxidases to nonradical compounds, preventing chain reactions by scavenging initiating radicals, and breaking down chain reactions. Well-known biological antioxidants include superoxide dismutase, glutathione peroxidase, catalase, vitamin E, ghitathione, ascorbic acid, and zinc. (158) There have been multiple animal studies looking at the whether antioxidants protect against reperfusion injury in the kidney. These have yielded mixed results, with some studies showing a protective effect (159-162) and others showing no benefit. (163,164) We know that oxygen radical production occurs within the first few minutes of postischemic reperfusion (146) and, if given prior to reperfusion in animals, reduces renal dysfunction. (162) In most clinical instances, this is not possible. However, in a specific setting such as in early resuscitative efforts in patients experiencing hypotension/shock, antioxidant therapy might reasonably protect against postischemic injury. (158) To our knowledge, there have been no large clinical trials looking at the effects of these agents in patients with ATN.

Pentoxifylline

Pentoxifylline (PTX) is a nonspecific phosphodiesterase inhibitor that has been shown to modulate arachidonic acid metabolism, to promote prostaglandin [I.sub.2] release, to inhibit the production of various cytokines such as TNF, and additionally to influence the behavior of monocytes, neutrophils, platelets, and endothelial cells in patients with sepsis. (165-169) In animal models, PTX has been shown to prevent progressive renal damage associated with septic shock, (170) likely by protecting the renal microcirculation. (165) It may also exert a protective effect on tubular function in patients with ischemic/reperfusion injury, (171) as well as have a protective benefit in nephrotoxicity induced by cisplatin, (172) myoglobinuria, (173) and cyclosporine. (174) A prospective randomized blinded study (175) in critically ill patients undergoing CVVH revealed that continuous IV administration of PTX was successful in blunting the increase in soluble adhesion molecules, which serve as ligands for neutrophils to mount the systemic inflammatory response syndrome. However, whether this effect confers a clinical improvement on the outcome of patients with sepsis or ARF has yet to be determined. PTX has also been studied*r6 in the prevention of renal insufficiency in elderly patients undergoing cardiac surgery, with positive results. However, further clinical trials are needed to identify the role of PTX in the prevention of or treatment of ARF.

Nutrition: Preexisting or hospital-acquired malnutrition is an important factor contributing to high mortality in patients with ARF (Table 3). (46,177,178) ARF not only affects water, electrolyte, and acid base metabolism, but induces specific alterations in protein and amino acid levels, carbohydrate levels, and lipid metabolism. (179) The metabolic alterations in ARF patients are determined not only by the short-term loss of renal function, but also by the underlying disease process (ie, sepsis, trauma, or multiple organ failure), and by the type and intensity of RRT. (177,178,180)

The hallmark of metabolic alterations in ARF patients is the activation of protein catabolism with the excessive release of amino acids from skeletal muscle and sustained negative nitrogen balance. (181,182) The hepatic extraction of amino acids from the circulation, gluconeogenesis, and ureagenesis are all increased. Several additional catabolic factors are operative in ARF such as the secretion of catabolic hormones, hyperparathyroidism, the suppression of and decreased sensitivities to growth factors, and the release of inflammatory mediators, all of which mediate protein breakdown. (183) However, the dominant mechanism is the stimulation of hepatic gluconeogenesis from amino acids, which can be decreased but not halted by exogenous substrate supply. (181,184)

Frequently, ARF is associated with hyperglycemia caused by insulin resistance. (177) When the plasma insulin concentration is elevated, the maximal insulin-stimulating glucose uptake by skeletal muscle is decreased by 50%. ARF is also associated with accelerated hepatic gluconeogenesis, mainly from the conversion of amino acids released during protein catabolism, which cannot be suppressed by exogenous glucose infusions. (184)

The triglyceride content of plasma lipoproteins, especially of very low-density lipoproteins and low-density lipoproteins, is increased in ARF patients, whereas levels of total cholesterol and, in particular, high-density lipoprotein cholesterol are decreased. (185) The major cause of lipid abnormalities in ARF patients is the impairment of lipolysis.

Renal replacement therapies (RRTs), especially extracorporeal therapies (ie, hemodialysis and continuous RRTs [CRRTs]) have significant metabolic and nutritional consequences. Protein catabolism is increased via substrate losses, the activation of protein breakdown from the release of leukocyte-derived proteases, and the release of cytokines such as TNF-[gamma] and interleukins stimulated by blood membrane interaction during dialysis. The membranes used in hemofiltration are more porous and small proteins, and also are filtered. Moreover, many water-soluble substances such as vitamins and carnitine are lost during extracorporeal therapies. (177,178,180,183) Multivitamins and trace elements are therefore included in most enteral and parenteral formulas. However, there have been no randomized controlled trials looking at whether the administration of these vitamins results in fewer complications or mortality in the ARF setting. There is evidence that the addition of n-3 fatty acids (ie, fish oil) improves protein metabolism in animal studies. (186,187) In surgical critically ill patients, the administration of n-3 polyunsaturated fatty acids has been associated with significant reductions in infection rate, number of ventilator days, and length of hospital stay, but not in overall mortality. (188,189)

Energy expenditure remains unchanged and nearly normal in patients with uncomplicated ARF such as monofactorial ARF. In contrast, V[O.sub.2] and resting energy expenditure increases by 30% and even more when sepsis or systemic inflammatory response syndrome is associated with ARF. (177) Patients with ARF should receive 25 to 30 kcal/kg body weight per day. Even in hypermetabolic conditions, such as sepsis or multiple organ failure, energy expenditure rarely is > 130% of the calculated basic energy expenditure, and energy intake should not exceed 30 kcal/kg body weight per day. (183) Overfeeding critically ill patients is serious and can lead to metabolic complications such as hypertonic hydration and metabolic acidosis. (190)

Few studies have attempted to define amino acid or protein requirements in ARF patients. Macias et al (191) prospectively evaluated the impact of the nutritional regimen on protein catabolism and nitrogen balance in 40 patients with ARF whose conditions were managed by CVVH. The protein catabolic rate in these hypercatabolic patients accounted for 1.4 g/kg body weight per day, and a protein intake of about 1.5 to 1.8 g/kg body weight per day was required to maintain a positive nitrogen balance. This level of intake coupled with a caloric intake of about 30 kcal/kg/d has been suggested to be optimal in reducing protein catabolism. In noncatabolic patients during the polyuric phase of ARF, a lesser protein intake of 1.0 to 1.3 g/kg body weight per day has been suggested to be adequate. (192) Higher protein intakes of about 2.5g/kg/d have been shown to improve nitrogen balance in critically ill patients receiving CRRT, (193) although it offers no survival advantage. Furthermore, this high intake is safe and has been shown not to result in overt uremia. Therefore, it must be stressed that a low protein intake is unnecessary, and protein intake should not be restricted in ARF patients to limit the need for dialysis. In terms of the type of amino acids used, solutions or diets including both essential and nonessential amino acids in standard proportions are recommended. (180)

Besides protein, glucose should be used as the main energy substrate, with an intake of < 5 g/kg body weight per day used as an acceptable amount, because higher intake levels are not used for energy but will promote lipogenesis with fatty infiltration of the liver and excessive carbon dioxide production. Because of the presence of insulin resistance in ARF patients, the energy requirements often cannot be met by glucose alone; therefore a proportion of energy should be supplied by fat with a recommended amount of about 1 g/kg body weight per day (Table 3). (177,180)

Enteral nutrition should be the primary type of nutritional support for patients with ARF, administered either by food or specific enteral formulas that have been adapted to the metabolic alterations caused by uremia. Enteral nutrition has been shown (194) to be a safe and effective nutritional technique to deliver artificial nutrition in ARF patients. Furthermore, it has been suggested that the catabolic response can be minimized with enteral nutrition instead of parenteral nutrition. (195,196) In experimental ARF, (197) enteral nutrition can augment renal plasma flow and improve renal function. When patients cannot be fed enterally, total parenteral nutrition should be used cautiously. It is costly, results in higher rates of infection, and may be associated with several metabolic complications, including hyperglycemia/hypoglycemia, hyperlipidemia, hypercapnia, refeeeding syndrome, acid-base disturbances, liver complications, metabolic bone disease, gut atrophy, and immune suppression. (198-200)

Nephrology Consultation: Early consultation with a nephrologist improves the outcome of patients with ARF. Mehta et a1 (201) showed that a nephrology consultation was delayed in 28% of ICU patients with ARF. The delay in consultation was associated with higher mortality, longer ICU length of stay, and an increased number of systems failing at the time of consultation. The delay in nephrology consultation was likely to occur if the degree of ARF was underestimated because of low creatinine level (ie, 4.5 mg/dL) or modest urine output (ie, > 400 mL/d). The lower creatinine level was often a consequence of a volume overload, which diluted the plasma creatinine concentration, or severe malnutrition, which decreased creatinine generation. (17)

RRT

Dialysis is required in about 85% of patients with oliguric ARF and in 30% of patients with nonoliguric ARF. (46) The contribution of RRTs to clinical outcomes in patients with ARF remains unresolved, due in part to the underlying disease severity, which remains a very important determinant of outcome, especially now that ARF is commonly seen in the setting of multiorgan failure. (32) Several factors that are operative during RRT for ARF may impact clinical outcomes. These include dialysis modality, dialyzer membrane characteristics, and dosing strategies.

Dialysis Modality: Physicians caring for patients must select a continuous or intermittent method of dialysis. Among these, the most commonly used methods of dialysis in clinical practice are intermittent hemodialysis (IHD) and CVVH/hemodiafiltration (DF). (202) Mehta and colleagues (203) randomized 166 patients with ARF to receive either CRRT or IHD and found a higher mortality among patients receiving CRRT (66% vs 48%, respectively; p < 0.02). The groups, however, were not well-matched, and the CRRT had more men, higher APACHE II and III scores, and higher rates of liver failure. After adjustment for these factors, ICU or hospital mortality did not differ between groups; however, complete renal recovery was more likely in the CRRT group, and hospital length of stay was shorter. An analysis of nine published studies (204) comparing CRRT to IHD in patients with ARF in whom APACHE II scores were used to grade severity of illness showed no significant difference in clinical outcomes between the two groups. Kellum et al (205) published a metaanalysis of 13 clinical trials, totaling 1,400 patients, including three randomized controlled trials that were published in abstract format. The authors found no mortality difference between CRRT and IHD (RR, 0.93; 95% confidence interval, 0.79 to 1.09; p = 0.29). However, after adjusting for severity of illness and study quality, mortality was found to be lower in the CRRT group (RR, 0.72; 95% confidence interval, 0.60 to 0.87; p < 0.01). More recently, a well-designed study (206) looked at 80 critically ill patients with ARF requiring dialysis and were randomized to treatment with CVVHD and IHD. The authors used the Cleveland Clinic severity score. (29) The mean score in both groups was about 12. There was no differences in survival or renal recovery between groups.

Continuous therapies are being used more often in academic centers (204) as they allow the treatment of hypotensive patients, and manage the control of fluid, electrolytes, and solute, particularly when large-volume total parenteral nutrition is used. (207) However, since CRRT is not readily available in all hospitals and requires qualified ICU support staff, the use of extended daily dialysis for 6 to 8 h/d, 6 days a week, has been shown to be a safe, effective alternative to CRRT that offers comparable hemodynamic stability and small solute control. (208)

Peritoneal dialysis (PD) is infrequently used for the treatment of critically ill patients with ARF. It is a popular method for the treatment of ARF in developing countries as it is less costly and obviates the need for anticoagulation. (209) One prospective randomized controlled trial (210) comparing CVVH with PD in 71 critically ill patients with ARF found a significantly higher mortality rate in the PD group (47%) compared with the CVVH group (15%). This excess mortality rate persisted after adjustment for other comorbid conditions. Acid-base and solute status corrected faster in the CVVH group, although acetate was used as a buffer in the PD group compared with the use of lactate in the CVVH group. (210)

Membrane Type: Dialysis membranes are classified as cellulose-derived or non-cellulose-derived. The non-cellulose-derived membranes are synthetic polymers and are generally more biocompatible but more expensive. (202) The free hydroxyl groups on the cellulosic dialysis membrane activate the alternate pathway of complement, leading to neutrophil activation and subsequent sequestration in the pulmonary circulation and infiltration into other organs. The side group modifications on substituted cellulose membranes and the high adsorptive capacity of synthetic membranes generally lead to a decrease in the intensity of blood-membrane interactions. (211,212)

Biocompatible vs Bioincompatible Membranes: There have been multiple prospective randomized controlled trims that have compared the impact of dialysis membrane compatibility on clinical outcomes in ARF, with some showing improved outcome with the use of biocompatible membranes (213,214) and others showing no significant differences. (215-219) Among these trials, the largest number of patients studied was 160. A metaanalysis (220) of these trials (n = 722) found no difference in mortality between the biocompatible and bioincompatible membrane groups (45% vs 46%, respectively). Given the profound morbidity of patients with ARF, if a survival advantage attributable to biocompatible membranes exists, it is at best small. (202)

High-Flux Membranes: The term high-flux membrane refers to a membrane with a high ultrafiltration coefficient. These membranes allow greater "solute drag" during fluid removal, resulting in higher clearance of middle molecules. (221,222) Middle molecules have a molecular mass of 300 to 12,000 d, examples of which are B2 microglobulin, complement fragments (C3a and C5a), indoles, prostaglandins, and leukotrienes. Small molecules (molecular mass, < 300 d) include urea, creatinine, and phosphorus. (223) Since middle-molecular-weight toxins may be operative in patients with sepsis and ARF, one may argue that high-flux membranes may be more beneficial. Ponikvar et al (224) prospectively randomized 72 patients to a low-flux or high-flux dialyzer but found no differences in survival, recovery of renal function, or duration of dialysis.

Initiation and Dose

Initiation: Common indications for acute dialysis include volume overload, hyperkalemia, metabolic acidosis, and symptoms and signs of uremia. There is however, no consensus among nephrologists as to when to begin dialysis or how frequently to perform dialysis. (1) Retrospective studies have shown that dialysis used to keep BUN concentrations at < 150% improves survival. (225,226) Conger (227) performed a paired study during the Vietnam War on soldiers who developed ATN and found that sufficient dialysis to keep creatinine levels at < 10 mg/dL (880 [micro]mol/L) and BUN levels at < 100 mg/dL (35.5 mmol/L) caused an 80% mortality rate, while intensive dialysis to keep creatinine levels at < 5 mg/dL (440 [micro]mol/L) and BUN levels at < 70 mg/dL (25 mmol/L) was associated with a 36% mortality rate. Unfortunately, because of the small size of the trial, the difference was not statistically significant. In a prospective trial by Gillum et al (228) that included a better randomized design, 34 civilians with ATN were randomized to receive intensive dialysis (ie, predialysis serum creatinine level, < 5 mg/dL [< 440 [micro]mol/L]; predialysis serum BUN level, < 60 mg/dL [< 21.5 mmol/L]) or to conventional dialysis (predialysis creatinine level, < 9 mg/dL [< 800 [micro]mol/L]; BUN level, < 100 mg/dL [< 35.5 mmol/ L]). Intensive dialysis resulted in a decrease of hemorrhagic events. Mortality and the course of ATN did not significantly differ among the groups. A more recent study involving 69 patients who required CVVH due to ARF after cardiac surgery was performed by Demirkilic et al. (229) CVVH-DF was performed in the patients in group 1 (27 patients) when creatinine level exceeded 5 mg/dL or the potassium level exceeded 5.5 mEq/L, irrespective of urine output, and in group 2 (34 patients) when urine output was < 100 mL within a consecutive 8-h period, with no response to the administration of 50 mg of furosemide with the supplementary criterion that urine sodium levels should be > 40 mEq/L before the administration of furosemide. The ICU mortality rate was 48.1% for group 1 and 17.6% for group 2 (p = 0.014). The overall hospital mortality rate was 55.5% for group 1 and 23.5% for group 2 (p = 0.016). The mean ([+ or -] SD) elapsed time between surgery and the initiation of CVVH-DF was 2.56 [+ or -] 1.67 days in group 1 and 0.88 [+ or -] 0.33 days in group 2 (p = 0.0001). The mean ICU stay for group 1 was 12 [+ or -] 3.44 days, and for group 2 it was 7.85 [+ or -] 1.26 days (p = 0.0001). Therefore, the recognition of ARF and the early start of therapy with CVVH-DF are important.

Dose: Several studies have attempted to link urea removal to clinical outcomes in patients with ARF. Halstenberg et al (29) retrospectively assessed the outcomes of 842 critically ill patients with ARF who required IHD. Using the Cleveland Clinic Foundation mortality score in the ARF model, (43) they found that among patients with intermediate scores, a urea reduction ratio of 58% was associated with a significant reduction in mortality. However, patients with very low and very high scores had survival rates of 78% and 0%, respectively, regardless of the dialysis dose. These findings suggest the presence of an interaction between severity of illness and the delivered dose of dialysis; not necessarily cause and effect. (130) More recently, Schiffl et al (230) reported the results of a trial of 172 critically ill patients with ARF who were randomized to receive either daily or alternate-day dialysis using biocompatible high-flux dialyzers. The two groups were well-matched in age, severity of ARF, APACHE II scores, and prescribed dialysis techniques. The overall mortality rate was significantly improved in the daily dialysis group compared to the alternate-day group (28% vs 47%, respectively; p = 0.01). When analyzed in terms of the delivered dialysis dose ([Kt/V], where K denoted the dialyzer urea clearance, t was the duration of dialysis, and V was the volume of distribution, which approximates total body water (231)), the weekly Kt/V was higher for patients undergoing daily dialysis compared with alternate-day dialysis (5.8 vs 3, respectively). Daily dialysis was associated with a significantly shorter time to the recovery of renal function (9 vs 16 days, respectively; p = 0.001). This is the first study to show that the amount of dialysis is an independent determinant of mortality in critically ill patients with ARF. Previous studies (232,233) in patients with ARF have shown that the actual delivered dose of dialysis is lower than the prescribed dose. Similarly, the relationship between a higher dialysis dose and improved mortality was shown in critically ill patients receiving CVVH in a prior study, (234) which will be described in the next section. There are ongoing larger prospective multicenter trials to validate these findings. For now, daily IHD is preferable to alternate-day dialysis in critically ill patients with ARF as it is allows the strict control of uremia and fluid volume.

Ultrafiltration Rate: There have been two studies (160,161) that have been carried out to examine whether CRRT dosing strategies offer a survival advantage in patients with ARF. Storck and colleagues (235) compared continuous arteriovenous hemofiltration to high-volume CVVH (defined by > 15 L of ultrafiltration per day) in 116 patients with postoperative ARF, and they observed better survival in the CVVH group (29% vs 13%, respectively; p < 0.05). In this study, the targeted ultrafiltration rate corresponded to about 10 mL/kg/d assuming a weight of 70 kg for patients. The authors (235) ascribed this survival advantage to better removal of middle molecules. Ronco et al (234) performed a prospective randomized controlled trial to determine the optimal dosing strategy in CVVH. A total of 425 critically ill patients with ARF were randomly assigned to CVVH at an ultrafiltration rate of 20, 35, or 45 mL/kg/h. Adjusted analysis demonstrated lower survival rates among patients assigned to the rate of 20 mL/kg/h, compared with 35 mL/kg/h and 45 mL/kg/h (41% vs 57% vs 58%, respectively; p < 0.05). Therefore, ultrafiltration rates should be prescribed based on body weight and should be at least 35 mL/kg/h. It remains unknown as to whether higher ultrafiltration rates of > 50 mL/kg/h would further reduce mortality.

Prophylactic Dialysis: Postoperative patients are at an increased risk of ATN because preoperative fluid depletion, anesthesia, and intraoperative losses can lead to fluid depletion and reductions in GFR (up to 30 to 45%), urine volume, and sodium excretion. (236-240) Surgical procedures with the highest risk of ATN are abdominal aortic aneurysm surgery, (238) cardiac surgery, (239,240) and surgery to correct obstructive jaundice. (241) The overall incidence of postoperative ARF and the need for dialysis was about 7.7% and 1.4%, respectively, in patients undergoing myocardial revascularization. (240) Several methods have been tried to reduce the incidence of postoperative ATN. Perioperative prophylactic hemodialysis in patients with chronic kidney disease (serum creatinine level, > 2.5 mg/dL) who were undergoing on-pump coronary artery bypass graft surgery have been shown to decrease both operative mortality and morbidity. Durmaz et al (242) studied 44 patients with serum creatinine levels of > 2.5 mg/dL who did not require dialysis and randomly divided them into two groups. In group 1 (21 patients), perioperative prophylactic hemodialysis prior to cardiopulmonary bypass was performed, and group 2 (23 patients) was taken as a control group in which hemodialysis was performed only if postoperative ARF was diagnosed. The hospital mortality rate was 9.8% (one patient) in the dialysis group, and 30.4% (eight patients) in the control group (p = 0.048). Postoperative ARF requiring hemodialysis was seen in one patient (4.8%) in the dialysis group and in eight patients (34.8%) in the control group (p = 0.023). Thirty-three postoperative complications were observed in the control group for an early morbidity rate of 52.2% (12 patients), and 13 complications occurred in 8 patients in the dialysis group (38.1%). The average length of ICU stay and postoperative hospital stay were shorter in the dialysis group than in the control group (p = 0.005 and p = 0.023, respectively).

CONCLUSION

The management of ARF is still a medical challenge to clinicians. The current treatment of ARF is supportive, involving judicious fluid management and nutritional supplementation. Continuous dialysis modalities are better tolerated in sicker ICU patients, especially those with septic shock. Well-designed multicenter clinical trials to test methods for altering the course of ATN, decreasing the need for dialysis and improving survival, are very much needed to strengthen evidence-based conclusions. Phase 2 clinical studies are underway for the development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in conjunction with a renal tubule assist device containing human renal proximal tubule cells to provide the many reabsorptive, metabolic, synthetic, and endocrine functions that occur in the kidney and cannot be duplicated by RRT alone. This could potentially change the natural history of patients with ARF. (243-245)

The following authors have indicated to the ACCP that no significant relationships exist with any company/organization whose products or services may be discussed in this article submission: Namita Gill, MD; Richard A. Fatica, MD; and Joseph V. Nally, MD.

Manuscript received February 16, 2005; revision accepted March 15, 2005.

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Namita Gill, MD; Joseph V. Nally, Jr, MD; and Richard A. Fatica, MD

* From the Departments of General Internal Medicine (Dr. Gill) and Nephrology and Hypertension (Drs. Nally and Fatica), Cleveland Clinic Foundation, Cleveland, OH.

Correspondence to: Namita Gill, MD, Cleveland Clinic Foundation, General Internal Medicine, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: gilln1@ccf.org

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