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Acute kidney injury in the intensive care unit: An update and primer for the intensivist

Dennen, Paula MD; Douglas, Ivor S. MD; Anderson, Robert MD

doi: 10.1097/CCM.0b013e3181bfb0b5
Concise Definitive Review

Objective: Acute kidney injury is common in critically ill patients and is associated with significant morbidity and mortality. Patients across the spectrum of critical illness have acute kidney injury. This requires clinicians from across disciplines to be familiar with recent advances in definitions, diagnosis, prevention, and management of acute kidney injury in the intensive care unit. The purpose of this concise review, therefore, is to address, for the non-nephrologist, clinically relevant topical questions regarding acute kidney injury in the intensive care unit.

Data Sources: The authors (nephrologists and intensivists) performed a directed review of PubMed to evaluate topics including the definition, diagnosis, prevention, and treatment of acute kidney injury in the intensive care unit. The goal of this review is to address topics important to the practicing intensivist.

Data Synthesis and Findings: Whenever available, preferential consideration was given to randomized controlled trials. In the absence of randomized trials, observational and retrospective studies and consensus opinions were included.

Conclusions: Acute kidney injury in the intensive care unit is a clinically relevant problem requiring awareness and expertise among physicians from a wide variety of fields. Although many questions remain controversial and without definitive answers, a periodic update of this rapidly evolving field provides a framework for understanding and managing acute kidney injury in the intensive care unit.

From Divisions of Nephrology and Critical Care Medicine (PD), Division of Pulmonary Sciences and Critical Care Medicine (ISD), and Department of Medicine (RA), Denver Health Medical Center and University of Colorado, Denver, CO.

Denver Health Medical Center and University of Colorado, Denver, CO, are Acute Respiratory Distress Syndreome network investigation sites (PD and ISD).

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail:

Acute kidney injury (AKI), previously termed acute renal failure, refers to a sudden decline in kidney function causing disturbances in fluid, electrolyte, and acid–base balance because of a loss in small solute clearance and decreased glomerular filtration rate (GFR). The nomenclature shift to AKI more accurately represents the spectrum of disease from subclinical injury to complete organ failure. This review focuses on key questions for the intensivist faced with AKI in the intensive care unit (ICU).

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Epidemiology of AKI in the ICU

AKI in the ICU is common, increasing in incidence (1–4), and is associated with a substantial increase in morbidity and mortality (5, 6). AKI occurs in approximately 7% of all hospitalized patients (7) and in up to 36% to 67% of critically ill patients depending on the definition used (6, 8–11). Based on >75,000 critically ill adults, more severe AKI occurs in 4% to 25% of all ICU admissions (6, 8, 9, 11). On average, 5% to 6% of ICU patients with AKI require renal replacement therapy (RRT) (6, 8–11).

Reported mortality in ICU patients with AKI varies considerably between studies depending on AKI definition and the patient population studied (e.g., sepsis, trauma, cardiothoracic surgery, or contrast nephropathy). In the majority of studies, mortality increases proportionately with increasing severity of AKI (6, 10–13). In patients with severe AKI requiring RRT, mortality is approximately 50% to 70% (9, 14–16). While AKI requiring RRT in the ICU is a well-recognized independent risk factor for in-hospital mortality (17), even small changes in serum creatinine (SCr) are associated with increased mortality (18–21). Notably, multiple studies of patients with AKI and sepsis (22–24), mechanical ventilation (25), major trauma (26, 27), cardiopulmonary bypass (17, 28–30), and burn injuries (31) have consistently demonstrated an increased risk of death despite adjustment for comorbidities and severity of illness.

Morbidity, a less appreciated consequence of AKI in the ICU, is associated with increased cost (18), increased length of stay (6, 14, 18, 26), and increased risk of chronic kidney disease (CKD), including end-stage kidney disease (9, 15, 16, 32–37). The true incidence of CKD after AKI is unknown because epidemiologic studies do not routinely or consistently report rates of renal recovery and those that do use variable definitions (38).

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Definition of AKI in the ICU

More than 35 definitions of AKI currently exist in the literature (39). The Acute Dialysis Quality Initiative convened in 2002 and proposed the RIFLE classification (risk, injury, failure, loss, end-stage kidney disease) specifically for AKI in critically ill patients (Table 1) (40). Using SCr and urine output, the RIFLE criteria define three grades of severity and two outcome classes. The most severe classification met by either criterion should be used. Of note, patients with primary kidney diseases such as glomerulonephritis were excluded from this definition.

Table 1

Table 1

More recently the Acute Kidney Injury Network (AKIN), an international multidisciplinary organization composed of nephrologists and intensivists, further modified the RIFLE criteria recognizing that even very small changes in SCr (≥0.3 mg/dL) adversely impact clinical outcome (6, 7, 10, 11, 19, 21, 41). According to AKIN, the most current consensus diagnostic criteria for AKI is “an abrupt (within 48 hrs) reduction in kidney function currently defined as an absolute increase in serum creatinine of more than or equal to 0.3 mg/dL (≥26.4 μmol/L), a percentage increase in serum creatinine of ≥50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of <0.5 mL/kg/hr for >6 hrs)” (42). Importantly, the AKIN definition and classification system incorporates creatinine, urine output, and time (Table 1). Both the RIFLE and AKIN criteria were developed to facilitate clinical investigation and comparison across study populations. Epidemiologic data comparing the RIFLE and AKIN criteria have demonstrated concordance in critically ill patients (43, 44).

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Diagnosis of AKI in the ICU

Traditional tools to diagnose AKI (SCr) and determine etiology of AKI (clinical history, physical examination, renal ultrasound, fractional excretion of sodium [FeNa], fractional excretion of urea, blood urea nitrogen [BUN], and urine microscopy) remain the cornerstone of diagnostic tools available to the clinician in the ICU. The use of SCr to estimate GFR is limited, however, by the lack of steady-state conditions in critically ill patients. Determinants of the SCr (rate of production, apparent volume of distribution, and rate of elimination) are variable in the ICU setting (6, 8–11, 45, 46). Medications (e.g., trimethoprim, cimetidine) impair creatinine secretion and therefore may cause increases in SCr without reflecting a true decrease in GFR. Finally, SCr lacks sensitivity and underestimates the degree of kidney dysfunction in a critically ill patient. Increases in SCr substantially lag behind a reduction in GFR (Fig. 1) and thus do not provide a useful real-time assessment of GFR.

Figure 1

Figure 1

AKI spans the continuum from prerenal azotemia to acute tubular necrosis, from functional to structural injury. Efforts to differentiate between these two entities have classically included FeNa and urine microscopy. Urine microscopy can be helpful in differential diagnosis (e.g., granular casts and renal tubular epithelial cells in acute tubular necrosis, cellular casts in glomerular injury, eosinophiluria in acute interstitial nephritis, or atheroembolic AKI). Of clinical note, nephrologist review of urine microscopy has been demonstrated to be superior to clinical laboratory interpretation (47). Using a proposed scoring system, microscopic examination of the urine sediment is a highly predictive method for differentiating prerenal azotemia from acute tubular necrosis (48). However, the presence of muddy brown casts and renal tubular epithelial cells are usually seen relatively late and thus are not sensitive for early detection of AKI (49, 50). FeNa is frequently useful for differentiating “prerenal” (diminished renal perfusion, FeNa <1%) from “intra-renal” (ischemia or nephrotoxins, FeNa >2%) (50, 51). Urine microscopy and FeNa can be valuable tools in determining the cause of AKI but have no current role in early detection or diagnosis of AKI. Furthermore, “prerenal” and “intra-renal” causes of AKI commonly coexist in the ICU patient.

Prerenal azotemia, in the absence of validated new diagnostic biomarkers, often remains a retrospective diagnosis, made only after response to a volume challenge. Whereas it is important to appropriately identify and treat prerenal azotemia, fluid administration is not without consequence in the critically ill patient. A complete assessment of the patient's overall volume status is pivotal before aggressive resuscitative efforts to enhance renal perfusion. This is of particular importance considering data demonstrating adverse effects of volume overload in critically ill patients (52, 53). Because of the limitations of traditional tools, novel candidate biomarkers of AKI (discussed separately) are being actively investigated.

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Common Causes of AKI in the ICU

The cause of AKI in the ICU is commonly “multi-factorial” and frequently develops from a combination of hypovolemia, sepsis, medications, and hemodynamic perturbations (Table 2). It is frequently not possible to isolate a single cause, thereby further complicating the search for effective interventions in this complex disease process. The pathophysiology of AKI varies according to the underlying etiology and is beyond the scope of this article.

Table 2

Table 2

Sepsis is the most common cause of AKI in a general ICU, accounting for up to 50% of cases (6, 8–11, 23, 45, 54). AKI is common after cardiac surgery, occurring in up to 42% of patients without pre-existing kidney disease, and is associated with increased morbidity and mortality with elevations in SCr as small as 0.3 mg/dL (19). Trauma associated AKI is multi-factorial (e.g., hemorrhagic shock, abdominal compartment syndrome, rhabdomyolysis) and occurs in up to 31% of adult trauma patients (55). The kidneys are early sensors of intra-abdominal hypertension and abdominal compartment pressures ≥12 mm Hg may be associated with AKI (56). A sustained intra-abdominal pressure >20 mm Hg in association with new organ dysfunction will be associated with AKI in >30% of cases (57, 58). Rhabdomyolysis accounts for 28% of trauma-associated AKI requiring dialysis (59).

Medications are a common cause of AKI and, according to Uchino et al (9), account for nearly 20% of all cases of AKI in the ICU. The mechanism of medication induced AKI is variable and includes acute interstitial nephritis, direct tubular toxicity (e.g., aminoglycosides), and hemodynamic perturbations (e.g., nonsteroidal anti-inflammatory agents, angiotensin-converting enzyme inhibitors). Acute interstitial nephritis is likely an under-recognized etiology of medication-associated AKI in the ICU because of the relative paucity of clinical findings and need for high index of suspicion. Table 3 lists common nephrotoxins encountered in the care of critically ill patients.

Table 3

Table 3

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Prevention and Management of AKI in the ICU

Primary prevention of AKI in the ICU is limited to those conditions in which the timing of injury is predictable, such as exposure to radiocontrast dye, cardiopulmonary bypass, large-volume paracentesis in a cirrhotic patient, or chemotherapy. In contrast to most cases of community-acquired AKI, nearly all cases of ICU-associated AKI result from more than a single insult (6, 8–11, 45, 50, 60, 61). In the critically ill patient, the first kidney insult is often not predictable. Therefore, prevention of AKI in the ICU often means prevention of a secondary insult in an “at-risk” patient. For example, in a retrospective study of >5000 ICU patients, 67% of patients had AKI develop, and 45% of AKI occurred after ICU admission (6). It is in these patients that there is a potential role for prevention.

General principles of “secondary” AKI prevention include: (1) recognition of underlying risk factors that predispose patients to AKI (e.g., diabetes, chronic kidney disease, age, hypertension, cardiac or liver dysfunction); and (2) maintenance of renal perfusion, avoidance of hyperglycemia, and avoidance of nephrotoxins in these high-risk patients. Specific clinical situations in which there is evidence for preventive strategies (e.g., contrast exposure, hepatorenal syndrome [HRS]) are discussed.

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Preventing Contrast-Induced Nephropathy.

The primary strategies for contrast-induced nephropathy (CIN) prevention include hydration, N-acetylcysteine (NAC), and use of low-volume nonionic low-osmolar or iso-osmolar contrast. No strategy has been effective in completely preventing CIN. Risk factors for CIN include diabetes, CKD, hypotension, effective or true volume depletion (including cirrhosis and congestive heart failure), and concurrent use of nephrotoxic medications. Critically ill patients intuitively represent a patient population at high risk for CIN given frequent hemodynamic instability, multiple organ dysfunction, use of nephrotoxic medications, and multiple underlying comorbidities (e.g., diabetes, CKD). However, despite the large number of randomized controlled trials (RCT) published on prevention strategies for CIN, there has been only one RCT performed specifically in critically ill adults (111). The true incidence of and risk for CIN in critically ill patients is thus unknown.

Adequate volume expression is a well-established measure to decrease the risk of CIN, whereas the choice of fluid remains controversial. Trials comparing the use of sodium bicarbonate and sodium chloride for the prevention of CIN have yielded conflicting results. Five meta-analyses of sodium bicarbonate suggest a beneficial role of isotonic sodium bicarbonate over isotonic saline (112–116); however, there is considerable heterogeneity and some publication bias confounding these findings. The most recent RCT of bicarbonate vs. normal saline showed no difference in the primary outcome of ≥25% decrement in GFR within 4 days (117). Based on currently available evidence, there is a strong suggestion that sodium bicarbonate may be superior to isotonic saline to decrease the risk of CIN.

NAC is a free radical scavenger shown to decrease the risk of CIN compared to placebo (118). Since 2003, >10 meta-analyses published on the role of NAC in CIN have yielded conflicting results likely attributable, in part, to heterogeneity in patient populations. In a recent meta-analysis of 41 studies, NAC plus saline reduced the risk for CIN more effectively than saline alone (119). A previous meta-analysis in 2007 by Gonzales et al (120) did not support the efficacy of NAC to prevent or decrease the risk of CIN. Furthermore, there are conflicting data as to whether NAC, itself, may decrease SCr measurement without affecting GFR (121, 122).

Low-volume nonionic low-osmolar or iso-osmolar contrast preparations are clearly associated with a decrease in CIN when compared to high osmolar agents. The data regarding nonionic low-osmolar contrast media vs. iso-osmolar contrast media (currently only iodixanol) is controversial. Two meta-analyses report conflicting results (123, 124). McCullough et al (123) found that use of iso-osmolar contrast media resulted in a lower incidence of CIN when compared to low-osmolar contrast media. However, Heinrich et al (124), in the most recent meta-analysis, reported no significant difference between the two unless the low-osmolar contrast media was iohexol, suggesting that all low-osmolar contrast media preparations may not be the same.

Both small observational and prospective studies have shown an increase in the risk of CIN with peri-procedural use of angiotensin-converting enzyme inhibitors (125–127). However, a recent randomized prospective trial performed in stable outpatients did not show any difference in incidence of CIN between patients who did or did not discontinue angiotensin-converting enzyme inhibitors or angiotensin receptor blockers before contrast (128). Angiotensin-converting enzyme inhibitors have not been prospectively studied in the critically ill. Therefore, although there is currently insufficient evidence to support discontinuation of these medications in critically ill adults, further study is warranted given the widespread use of these agents in clinical practice.

Whereas the use of peri-procedural hemofiltration in patients undergoing percutaneous coronary intervention was shown, in two studies, to decrease the risk of AKI (5% vs. 50%; p = .0001) (129, 130), this has not been widely adopted into clinical practice. In a systematic review of extracorporeal therapies for prevention of CIN, analysis of the hemodialysis studies alone (including five RCT), there was no benefit of hemodialysis and, in fact, there was a trend favoring standard therapy compared to prophylactic hemodialysis (131). A subsequent RCT of prophylactic hemodialysis in 82 patients with advanced CKD (baseline SCr 4.9 mg/dL) demonstrated improved outcomes (shorter length of stay and lower rate of long-term dialysis dependence after hospital discharge) with prophylactic hemodialysis (132). A critical limitation of all of these studies is that the clinical end point SCr was directly impacted by the intervention itself (hemofiltration or hemodialysis).

Fenoldopam and theophylline are two additional agents that have been considered for their potential role in the prevention of CIN. None of the four RCT comparing fenoldopam to either saline alone (133, 134) or NAC (135, 136) demonstrated any beneficial effect in the prevention of CIN. The role of theophylline for CIN prevention is inconsistent across studies. Although two meta-analyses suggest that prophylactic theophylline may provide some benefit, the studies were performed in primarily low-risk patients, and clinically relevant outcomes were not consistently reported (137, 138). Therefore, we cannot currently recommend the use of theophylline for prevention of CIN in critically ill patients.

The majority of these studies were not performed in critically ill patients and therefore provide no definitive guidance as to how the risk of CIN in the critically ill should be ameliorated. Because of the absence of sufficient data in the patient population of interest, clinicians must extrapolate from the best available evidence from other patient populations. Therefore, our recommendations include: (1) avoid use of intravenous contrast in high-risk patients if alterative imaging techniques are available; (2) use preexposure volume expansion using either bicarbonate or isotonic saline; (3) although of questionable benefit, use of NAC is safe, inexpensive, and may decrease risk of AKI; (4) avoid concomitant use of nephrotoxic medications if possible; and (5) use low-volume low-osmolar or iso-osmolar contrast. Future studies are needed to determine the true role of these preventive measures in critically ill patients.

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Preventing AKI in Hepatic Dysfunction.

AKI is a common complication of critically ill patients with hepatic failure. Pentoxifylline decreases the incidence of AKI attributable to HRS in acute alcoholic hepatitis (139). Use of intravenous albumin in patients with cirrhosis and spontaneous bacterial peritonitis significantly reduces both the incidence of AKI (33% to 10%) and mortality (41% to 22%) (140). Albumin decreases the incidence of AKI after large-volume paracentesis (141), and when used in combination with splanchnic vasoconstricting agents (e.g., terlipressin) may decrease mortality in HRS (142, 143). However, definitive therapy for AKI as a consequence of HRS remains liver transplantation in appropriate candidates. Five randomized trials of vasoconstricting agents (terlipressin or noradrenalin) plus albumin in the treatment of HRS all demonstrated improved renal function in HRS (144–148). A mortality benefit was only demonstrated in responders to therapy (145). Terlipressin is not available in the US. In a retrospective study performed in the US, patients treated with vasopressin had significantly higher recovery rates and improved survival when compared to octreotide alone (149). Furthermore, findings from three small observational and retrospective studies demonstrate improved outcomes with midodrine and octreotide (HRS reversal and decreased mortality) (150–152). These findings justify a larger RCT to appropriately evaluate this treatment modality.

Management of AKI in the ICU revolves around optimizing hemodynamics and renal perfusion, correcting metabolic derangements, providing adequate nutrition, and mitigating progression of injury. These management considerations are discussed.

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Maintain Renal Perfusion.

Optimization of renal perfusion may require volume resuscitation, inotropic, or vasopressor support. Extrapolated primarily from animal studies (62, 63), the human kidney has a compromised ability to autoregulate (maintain constancy of renal blood flow and GFR over a wide range of renal perfusion pressures) in AKI. Therefore, as a priority, prevention or management of AKI should include maintenance of hemodynamic stability and avoidance of volume depletion. A mean arterial pressure of ≥65 mm Hg is a generally accepted target; however, the data are limited (64, 65) and do not include patients with established AKI (loss of autoregulation). The level at which renal blood flow becomes dependent on systemic arterial pressure varies significantly based on age, underlying illness (e.g., hypertension), and the acute illness or condition (AKI, sepsis, and cardiopulmonary bypass). After volume resuscitation, blood flow should be restored to within autoregulatory parameters. This frequently requires vasopressor or inotropic support in the setting of septic shock, the most common cause of AKI in the ICU. There are currently no RCT comparing vasopressor agents; therefore, there is no evidence that, from a renal protection standpoint, there is a vasopressor agent of choice to improve kidney outcomes.

Decreased renal blood flow (attributable to either hypotension or high renal vascular resistance, from an imbalance between renal vasoconstriction and vasodilation) is a common feature in many forms of AKI. Consequently, there has been considerable interest in renal vasodilators to maintain renal perfusion for prevention or treatment of AKI. Whereas dopamine infusion may cause a transient improvement in urine output (66), “renal” dose dopamine does not reduce the incidence of AKI, the need for RRT, or improve outcomes in AKI (66–71). Furthermore, “low-dose” dopamine may worsen renal perfusion in critically ill adults with AKI (72) and is associated with increased myocardial oxygen demand and an increased incidence of atrial fibrillation (73). There is additional concern for extrarenal adverse effects of dopamine, including negative immunomodulating effects (74). Thus, there is broad consensus that dopamine is potentially harmful and without evidence of clinical benefit for either prevention or treatment of AKI. Therefore, its continued use for putative “renal protection” should be avoided.

Fenoldopam is a selective dopamine-1 receptor agonist approved for the treatment of hypertensive crisis (75). Paradoxically, the lowest doses of fenoldopam (≤1 μg/kg per min) are purported to increase renal blood flow without systemic effects. Despite encouraging data from pilot studies, (76–78) a prospective placebo-controlled study of low-dose fenoldopam in sepsis failed to decrease mortality or need for RRT despite a smaller increase in SCr (79). Larger studies to validate the meta-analytic observation that fenoldopam both reduces the need for RRT (OR, 0.54; p = .007) and decreases mortality (OR, 0.64; p = .01) (80) are currently ongoing in cardiac surgery patients ( ID: NCT00557219).

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Fluid Choice in AKI.

The primary physiologic intention of volume resuscitation is the restoration of circulating volume to prevent or mitigate organ injury. The kidneys normally receive up to 25% of the cardiac output and are exquisitely sensitive to hypoperfusion attributable to true or relative hypovolemia. For this reason, the question of whether a particular type of fluid influences development of AKI is of pivotal importance.

Whereas crystalloid solutions remain the preferred treatment in usual care, the debate over whether colloid solutions provide any additional benefit remains an area of active investigation (81–85). In a landmark trial evaluating the impact of fluid choice on clinical outcomes, the SAFE study investigators randomized nearly 7000 patients to volume resuscitation with saline or albumin. They demonstrated no difference in survival or need for RRT between the two groups (86). In post hoc subgroup analysis, resuscitation with albumin was associated with increased mortality in critically ill patients after traumatic brain injury (87). In contrast, there was a trend toward improved survival in septic shock patients receiving albumin (30.7% in albumin group vs. 35.3% in saline group; p = .09) (86). Based on currently available literature, there is no evidence of a mortality benefit supporting the preferential use of albumin over crystalloids in a heterogenous critically ill patient population (84).

Synthetic colloids (e.g., hydroxyethyl starches, dextrans) are still widely used despite multiple reported safety concerns with regard to renal outcomes (88–90). An increased risk of AKI with the use of hydroxyethyl starches has been demonstrated in multiple small studies, and most recently a systematic review of 12 randomized trials demonstrated an increased risk of AKI with the use of hydroxyethyl starches among patients with sepsis (91). In contrast, the largest individual retrospective analysis (SOAP study cohort, 92) explored the effects of hydroxyethyl starches on renal function and did not find the use of hydroxyethyl starches to be an independent risk factor for AKI or need for RRT (93). The dose and preparation varied between studies. The adverse event profile has been linked, in part, to the individual preparation, with the lowest molecular weight offering the best side effect profile.

The question of fluid management does not end with the choice of fluid; careful consideration of the amount of fluid administered is also important. Critical illness is a dynamic process requiring frequent assessment of and adjustment to fluid status. In a prospective RCT of patients with acute respiratory distress syndrome, a fluid conservative strategy decreased ventilator days and did not increase the need for RRT (53). Furthermore, an observational study of >3000 patients demonstrated an association between positive fluid balance and increased mortality in patients with AKI (52). However, the question remains whether this is simply a marker of severity of illness or true causation; this observation warrants further investigation.

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Avoid Hyperglycemia.

Although the beneficial effects of intensive insulin therapy on mortality in critically ill patients remains controversial (94–96), two large RCT demonstrated a decreased incidence of AKI and a decreased requirement for RRT with tight glucose control (95, 96). Furthermore, a more detailed secondary analysis strongly suggests that tight blood glucose control may be reno-protective in critically ill patients (97). Two smaller retrospective studies reported similar results (decreased incidence of AKI and decreased need for postoperative dialysis) in nondiabetic cardiac surgical patients (98) and in patients receiving total parenteral nutrition (99). However, in contrast, in the largest and most recent prospective RCT of intensive vs. conventional glucose control in >6000 critically ill patients, there was no difference in the number of patients requiring RRT (94). The overall incidence of AKI, however, was not reported in this study. It therefore remains unclear if there is a reno-protective role for tight glycemic control and, if present, whether any such effect is attributable to the avoidance of glucose toxicity or a beneficial effect of insulin. These findings warrant further study, especially in view of the fact that intensive glycemic control may be associated with a higher frequency of clinically relevant hypoglycemia.

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Avoid Nephrotoxins.

Nephrotoxic medications are a contributing factor in up to 25% of all severe AKI in critically ill patients (8, 9; Table 3 ). Identification of at-risk patients is pivotal. Aminoglycosides, although less commonly used for severe Gram-negative infections than previously, are associated with significant nephrotoxicity. Although once-daily dosing of aminoglycosides has been shown, in some studies, to decrease the incidence of AKI (100, 101), published meta-analyses support comparable efficacy and decreased cost but do not consistently demonstrate a significant reduction in nephrotoxicity (102–106). Extended interval dosing should not be used in patients with CKD. Standard amphotericin B has been associated with AKI in 25% to 30% of patients (107). The lipid formulation of amphotericin B is preferred because of reduced nephrotoxicity of 19% vs. 34% (108). Caspofungin, a newer antifungal agent, is associated with an even safer renal profile (109). The use of aprotinin, a serine protease inhibitor used to decrease blood loss during cardiac surgery, has been associated with increased risk of AKI and need for dialysis (110).

ICU patients frequently have fluctuating renal function and a variable volume of distribution. Standard estimates of renal function are poor in critically ill patients. Therefore, medications must be carefully dose adjusted because of varied pharmacokinetics in critically ill patients with and without underlying CKD.

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Diuretics in AKI.

Use of diuretics in the prevention or treatment of AKI has physiologic merit but its use is not supported by prospective clinical study. Diuretics can increase urine output but have not been found to have a consistent impact on mortality (153–157). Mehta et al (157) demonstrated that failure to respond to diuretics was associated with an increased risk of death and non-recovery of renal function. Subsequently, in a large, prospective, multinational study, Uchino et al (158) did not demonstrate an increased mortality, thus leaving unresolved the therapeutic role of diuretics in critically ill patients with renal dysfunction. Although oliguric AKI has been associated with worse outcomes than nonoliguric AKI (159), there is no evidence supporting efforts to convert nonoliguric AKI with diuretics. Diuretics have not been found to shorten the duration of AKI, reduce the need for RRT, or improve overall outcomes (160). Furthermore, a recently published RCT comparing the use of furosemide vs. placebo in the recovery phase of AKI requiring continuous renal replacement therapy (CRRT), furosemide was found to increase urine output and sodium excretion but did not improve renal recovery (161). In a multinational survey, nephrologists and intensivists reported clinical uncertainty about the use of diuretics in AKI, thus justifying the need for a definitive RCT (162).

Because diuretic use in AKI has not been shown to decrease mortality, there is no role for diuretics to convert oliguric AKI to nonoliguric AKI. However, regarding an increased appreciation for the potential detrimental downstream effects of volume overload, it may be reasonable to try diuretics for control of volume overload. The clinician should, however, be careful not to delay initiation of RRT for volume overload in the critically ill patient with AKI.

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Nutritional Considerations.

Malnutrition in hospitalized patients is associated with increased mortality (163). Assessment of the nutritional status of critically ill patients is limited by the unreliability of traditional markers of nutritional status in critical illness in general, and AKI in particular. Prealbumin is excreted mainly by the kidneys and hence may be falsely elevated in patients with AKI (164). Patients with AKI are hypercatabolic with a negative nitrogen balance (165), resulting from both increased protein catabolism and impaired protein synthesis.

The impact of CRRT on nutrition in the ICU is two-fold. Because protein catabolism is markedly increased in most patients requiring CRRT (165–167), the use of CRRT enhances the clinician's ability to provide adequate nutrition because of an improved ability to manage volume. Unfortunately, the recommended amount of protein in this population remains controversial and recommendations are based solely on expert opinion, because there are no data available from RCT. Although there are no studies demonstrating a benefit in outcomes (e.g., survival or dialysis-free days), consensus recommendations include nonprotein caloric intake of 20 to 30 kcal/kg body weight per day and a protein intake of 1.5 g/kg per day (168). However, several studies have demonstrated a less negative or even positive nitrogen balance in those patients receiving up to 2.5 g/kg per day while receiving CRRT without evidence of adverse effects (169–171). An increase in nonprotein calories in critically ill patients with AKI does not improve nitrogen balance (172).

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RRT for AKI in the ICU

Despite decades of clinical trials investigating potential pharmacologic interventions in AKI, current treatment options are primarily limited to RRT. Practice patterns vary widely regarding timing of initiation of RRT, dose delivered, and choice of modality as evidenced by international surveys (173–176). There is no current consensus on the indications for RRT for AKI. With a greater appreciation for and understanding of the role of the kidney in distant organ injury (177), it may be more appropriate to consider renal replacement therapy as renal supportive therapy (178). For the purposes of this review, we review the most up-to-date evidence available addressing timing, dosing, and modality of RRT.

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Timing of Renal Replacement.

There is little prospective data regarding the appropriate timing of initiation of RRT and that which are available are inconclusive. The “absolute” indications for initiation of dialysis (severe hyperkalemia, clinically apparent signs of uremia, severe acidemia, and volume overload, including pulmonary edema complicated by hypoxia or cardiogenic shock) are broadly accepted usual care standards. “Prophylactic” dialysis was introduced in the 1960s (179), and the first prospective study was published in 1975 comparing a BUN trigger of 70 mg/dL vs. nearly 150 mg/dL (180). Survival was 64% in the “early intervention” group as compared to 20% in the non-intensive or standard intervention group (p < .01). Conventional teaching based on this and other studies (181, 182) has been to initiate RRT before a BUN exceeds 100 mg/dL. Unfortunately, not only is the “ideal” BUN not established but also BUN per se is an imperfect reference value because it is widely influenced by nonrenal factors.

More recently, a review of the data from the PICARD study demonstrated an increased risk of death associated with initiation of RRT with a BUN >76 mg/dL in comparison to <76 mg/dL (183). An important limitation of this study is that patients who were conservatively managed (did not receive RRT) are “invisible” in this analysis, thereby limiting the validity of the findings regarding impact on mortality. In the only randomized study of timing of CRRT initiation (n = 106), there was no effect on mortality (184). “Early” dialysis was initiated after 6 hrs of oliguria. Of the 36 patients included in the “late” arm of this study, six patients did not receive RRT, of whom four survived, a fact that likely influenced the results of this study. Results from a large prospective multi-centered observational study of >1200 patients were internally inconsistent and dependent on the definition of “early” or “late” initiation of RRT (185). In this study, “late” initiation of RRT was associated with worse outcomes (higher crude mortality, longer duration of RRT, increased hospital length of stay, and greater dialysis dependence) when “late” was defined relative to date of ICU admission. However, there was no difference in crude mortality if the timing was defined by serum urea. Finally, there was a lower crude mortality if timing of RRT initiation was defined by SCr at initiation (higher SCr associated with a lower mortality) (185). Unfortunately, the question of timing remains unanswered and controversial (185, 186). There is clearly a need for a large RCT, with a clear definition of “early,” to help guide the clinician in determining the appropriate timing for initiation of RRT for AKI in the ICU.

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Choosing a Renal Replacement Dose.

Six prospective RCT have been published addressing the question of dose of RRT in critically ill adults (37, 184, 187–190; Table 4). Three of these studies suggest that a higher dose of dialysis translates into improved outcomes, specifically decreased mortality (37, 187, 188). Ronco et al (187) published the first RCT in 2000 addressing this question. These investigators compared 20, 35, and 45 mL/kg/hr dosing strategies. There was a high mortality in all groups but a statistically lower mortality in the two groups with higher dose of ultrafiltration (35 and 45 mL/kg/hr) without any difference in complication rates between groups (187). In 2002, Schiffl et al (37) found daily dialysis to be superior to alternate day dialysis in a prospective randomized study. There were significantly fewer hypotensive episodes in the daily dialysis group (5% vs. 25%). In an intention-to-treat analysis, mortality was 28% for daily dialysis and 46% for alternate-day dialysis (p = .01) (37). An important limitation of this study is that the delivered dose was significantly less than the prescribed dose; therefore, the daily dialysis group received only “adequate” therapy as judged by contemporary standards. It may be said, therefore, that it was a comparison between adequate and inadequate dialysis. In 2006, Saudan et al demonstrated that continuous veno-venous hemodiafiltration (CVVHDF); addition of dialysate (1–1.5 L/hr) to continuous veno-venous hemofiltration (1–2.5 L/hr); improved 28- and 90-day survival compared with hemofiltration alone in 206 critically ill adults; 39% vs. 59%; p = .03 and 34% vs. 59%; p = .0005, respectively, suggesting that small solute clearance is important (188).

Table 4

Table 4

In contrast, three prospective RCT have demonstrated no difference in mortality (184, 189, 190; Table 4). Bouman et al (184), in 2002, showed no difference in 28-day mortality when comparing early high-volume hemofiltration, early low-volume hemofiltration vs. late low-volume hemofiltration with the median dose (mL/kg/hr) of 48, 20, and 19, respectively. More recently, Tolwani et al (189) compared two different doses, 20 mL/kg/hr and 35 mL/kg/hr, of pre-filter CVVHDF and found no difference in 30-day mortality (44% vs. 51%, p = .32). Of note, the delivered dose in these two groups were 17 mL/kg/hr and 29 mL/kg/hr, respectively (189). The largest and only multi-centered trial designed to address the question of dose of RRT in critically ill adults is the acute tubular necrosis study published in 2008 (190). This was a two-arm study comparing intensive to standard RRT. The intensive therapy group underwent daily dialysis, CVVHDF, or sustained low-efficiency dialysis (SLED) at a dose of 35 mL/kg/hr, whereas the standard therapy group had alternate day dialysis (three times per wk), CVVHDF, or SLED at 20 mL/kg/hr. Notably, patients were able to move from intermittent to continuous modalities based on hemodynamic stability but they stayed within their assigned intensive or standard treatment therapy groups. There was no difference in the primary outcome, death from any cause (190). The RENAL study, comparing CVVHDF 25 mL/kg/hr to 40 mL/kg/hr, has completed enrollment but results have not yet been published.

An important factor in considering the results of the currently available data are the difference between study populations, use of solely convective or combination convective and diffusive modalities, and the potential gap between prescribed and delivered doses. Findings from these negative trials should not be interpreted to mean that dose is not important. On the contrary, it is likely that dose is important and, above a minimal dose, further escalation may not provide additional benefit. Based on currently available data, it is our recommendation that to ensure an actual delivered dose of 20 mL/kg/hr for continuous modalities one must prescribe a higher dose (e.g., 25 mL/kg/hr) to account for filter clotting, time off the machine for interventions, or radiographic studies, etc. For intermittent RRT, one should target a Kt/V of 1.2 to 1.4 per treatment for alternate day (three times per wk) hemodialysis. Furthermore, in addition to an appropriate target dose, there must be close attention given to the actual delivered dose. In summary, one dose does not fit all; RRT dose must be weight-adjusted.

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Choosing a Renal Replacement Modality.

Continuous RRT modalities more closely approximate normal physiology with slow correction of metabolic derangements and removal of fluid. Therefore, CRRT is commonly thought to be better-tolerated in the critically ill and hemodynamically unstable patient. The question of superiority remains given the absence of clear evidence that these apparent physiologic advantages translate into a decrease in ICU or hospital mortality (191–196).

Since 2000 there have been seven prospective RCT designed to address the important clinical question regarding optimal RRT modality (192, 193, 195, 197–200); of these, only three were multi-centered studies (193, 198, 200). Of note, many of these trials, although published after 2000, enrolled patients in the 1990s. In six of the trials, mortality was the primary outcome. There have been several meta-analyses and systematic reviews comparing outcomes of intermittent vs. continuous renal replacement modalities with conflicting results (191, 201–204). A recent meta-analysis (nine randomized trials) comparing intermittent to continuous renal replacement therapy (intermittent RRT vs. CRRT) in AKI demonstrated no difference in mortality or renal recovery (defined as independence from RRT) (202). Of note, mortality was the primary outcome in eight of the nine included trials. Mortality, however, may not be the only clinically significant outcome. Two studies have shown that CRRT is associated with better long-term kidney recovery when compared to intermittent RRT (205, 206). In contrast, four RCT that included renal recovery as a primary outcome showed no difference in need for chronic RRT (193, 195, 198, 200). In the absence of definitive data in support of a particular modality (191, 201), the choice of RRT modality is currently influenced by multiple factors, including individual site availability, expertise, resources, cost, and likely clinician bias.

Hybrid therapies include SLED and extended daily dialysis. These modalities utilize standard intermittent hemodialysis machines but provide a slower solute and fluid removal similar to CRRT technologies. Although there have been no prospective randomized trials evaluating outcomes, hybrid therapies have been shown to be safe and effective alternatives to treating AKI in critically ill patients (207, 208).

The question of optimal modality has not yet been definitively answered. It is important to note that although the data strongly suggest that there is no difference in outcome between intermittent and continuous modalities, several key patient populations have been excluded. Namely, hemodynamically unstable patients, brain-injured patients, and those with fulminant hepatic failure were excluded and are widely believed to require continuous modalities. Furthermore, a critical limitation of all of the studies is the absence of a standardized dose (both within and between modalities) (202). RRT, like other medical treatments, must be considered in terms of dose adequacy to appropriately draw conclusions regarding clinical outcomes. Large randomized trials may be necessary to identify other potential subsets of patients who might benefit from continuous modalities.

Anticoagulation is frequently required to prevent clotting in extracorporeal circuits. There are no large RCT available to guide the choice of anticoagulation: heparin (unfractionated or low-molecular-weight heparin) or citrate-based protocols. Bleeding complications remain the primary concern with anticoagulation. Three small RCT, however, have demonstrated both similar or prolonged filter life and less bleeding and transfusion with citrate protocols when compared to use of heparins (209–211). In a recent larger, randomized, non-blinded trial comparing citrate to nadroparin, circuit survival was similar in both groups, but the citrate group had a lower mortality rate (212). Currently available data support the use of citrate for anticoagulation; however, this requires local expertise.

In summary, whereas RRT remains the cornerstone of treatment of AKI in the ICU, many key questions remain controversial. This is a rapidly evolving field and requires early consultation for appropriate expertise in the management of RRT for the critically ill patient with AKI.

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On the Horizon

The identification of novel candidate biomarkers of early AKI provides hope for the success of future clinical early intervention trials. Advances in treatment of AKI have been limited by the inability to diagnose AKI early. Previously failed interventions may portend different outcomes if implemented earlier in the course of AKI. Novel pharmacologic agents on the horizon include erythropoietic agents and natriuretic peptides. Novel interventions include the use of stem cell therapy, renal tubule assist device, and high-flux hemofiltration for sepsis.

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Candidate Biomarkers.

Biomarkers of AKI in the ICU have three primary potential roles: early detection of AKI, differential diagnosis (e.g., hepatorenal syndrome vs. acute tubular necrosis), and prognosis (e.g., need for RRT or mortality). The ideal biomarker for AKI would be sensitive, specific, inexpensive, available noninvasively as a point-of-care test, and provide a real-time assessment of GFR. A panel of biomarkers or kidney function tests may be needed to address the complexity and heterogeneity of AKI in the ICU (213). Early identification of AKI with rapid and reproducible biomarkers is a critical first step toward improving outcomes in AKI.

According to several studies in critically ill patients, serum cystatin C is better than SCr for early detection of AKI (214, 215) and as a more sensitive marker of small changes in GFR (216–218). However, in one smaller study there was no correlation between cystatin C and SCr (219). In a recent study, urinary cystatin C but not plasma cystatin C was superior to conventional plasma markers in the early identification of AKI after cardiac surgery (220). Whereas rapid automated assays for cystatin C are currently available, more information on the use of cystatin C in the ICU setting and in specific patient populations (e.g., post-cardiothoracic surgery, sepsis, and trauma) is necessary before implementation in clinical practice.

Several studies support neutrophil gelatinase-associated lipocalin (221–227), kidney injury molecule-1 (228, 229), and interleukin (IL)-18 (222, 230, 231) as promising candidate biomarkers for the early detection of AKI. Point-of-care tests for urinary IL-18 and neutrophil gelatinase-associated lipocalin will likely be available for clinical use soon (213, 231–234). Urinary excretion of enzymes (alkaline phosphatase, gamma glutamyl transaminase, N-acetyl-beta-d-glucosamine) (235), transporters (sodium-hydrogen exchanger isoform 3) (236), cytokines (IL-6, IL-8, and IL-18), and protein-like substances (fetuin A) (237) are presumably “shed” into the urine with AKI; therefore, they may have a role in the early identification of AKI (232, 233).

In addition to emerging biomarkers, promising real-time imaging for use in early detection of AKI is on the horizon (238, 239). Ongoing discovery using urinary proteomic analyses or analysis of genetic polymorphisms may identify susceptibility to AKI (240–244). Overall, biomarkers in AKI, although rapidly evolving, are a field still in its relative infancy. Their role in the diagnosis and management of AKI in the ICU, although promising, remains unproven. Furthermore, judging novel biomarkers against an imperfect “gold-standard” biomarker (SCr) may have its limitations.

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Erythropoietic Agents.

The endothelium plays a central role in the initiation and maintenance phases of AKI. Animal models demonstrate a renal-protective effect of erythropoietin on endotoxin-related kidney injury (245). Decreased severity of AKI is proposed to occur through tubular regeneration from the direct effects of erythropoietin on tubular epithelial cells (246). These findings support the ongoing trials exploring the role of erythropoietic agents in the prevention or early intervention for AKI using early biomarkers (personal communication and NCT00476619).

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Atrial Natriuretic Peptide.

Recombinant human atrial natriuretic peptide decreased the need for dialysis (21% vs. 47%) and improved dialysis-free survival at 21 days (57% vs. 28%) in a RCT of 61 complicated post-cardiopulmonary bypass patients without preexisting CKD (247). Previously, however, in two multi-centered, prospective, randomized trials in patients with acute tubular necrosis (248) or late oliguric AKI (249), atrial natriuretic peptide had no effect on need for dialysis or overall mortality. Further trials are needed before the use of atrial natriuretic peptide can be recommended for routine clinical use in cardiac surgery patients.

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Renal Tubule Assist Device.

Results from a recent RCT of the renal tubule assist device, in which the renal tubule assist device added to conventional CRRT was compared to CRRT alone, are promising with respect to both safety and efficacy. There was a non-statistically significant decrease in mortality at 28 days and a statistically significant difference at 180 days (secondary outcome) (250).

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Hemofiltration for Sepsis.

Payen et al (251) recently published the findings from the largest RCT of hemofiltration for severe sepsis and septic shock. At interim analysis, standard CVVH was found to be deleterious, with increased organ failures in the CVVH group compared to standard therapy. The study was stopped at interim analysis and consequently enrollment was insufficient to detect a difference in mortality with sufficient power. These findings contrast with those of Honore et al (252) in 2000, suggesting a beneficial role for hemofiltration in refractory septic shock. An important difference between these two studies was the delivered dose. In the first study, the dose, on average, was approximately 2 L/hr, whereas in the second study the dose was, on average, 8.7 L/hr for 4 hrs.

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Stem Cells and the Kidney.

Progenitor cell therapies represent an exciting future opportunity for treatment of AKI in the critically ill. Phase 1 trials of mesenchymal stem cells for treatment of patients at high risk for cardiac surgery-associated AKI are underway. A phase 2 RCT will be conducted if safety is demonstrated in phase 1 ( ID: NCT00733876).

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Many unanswered questions remain with respect to early identification, prevention, optimal timing, dose, and modality of RRT for AKI in the ICU. With respect to AKI in the ICU, the fundamental principal that guides all medical therapy—do no harm—is especially pertinent. AKI in the ICU most commonly results from multiple insults. Therefore, appropriate and early identification of patients at risk for AKI provides an opportunity to prevent subsequent renal insults and ultimately impact overall ICU morbidity and mortality. Strategies to prevent AKI in these patients are of pivotal importance. Key components of optimal prevention and management of the critically ill patient with AKI include maintenance of renal perfusion and avoidance of nephrotoxins. Whereas management of AKI remains limited primarily to supportive care, there are many potential therapies and interventions on the horizon.

Although it is widely accepted that early intervention therapies have been limited by the lack of tools for early detection, there are several promising candidate biomarkers in the pipeline. Furthermore, through the establishment of AKIN, an international and interdisciplinary collaborative network with the overarching objective to address AKI in the ICU, there has been tremendous progress in establishing a uniform definition (AKIN criteria) that is valuable for classification, clinical research study design, and prognosis.

A greater appreciation for the role of AKI in the ICU as an active contributor to morbidity and mortality is essential to furthering our knowledge and understanding of the influence of AKI in the critically ill patient. Early detection will facilitate early intervention. Early intervention designed to target the deleterious systemic effects of AKI will likely improve overall morbidity and mortality. For now, recognition of risk factors, excellent supportive care, and avoidance of clinical conditions known to cause or worsen AKI remain the cornerstone of management of AKI in the ICU.

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1. Bagshaw SM, George C, Bellomo R: Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care 2007; 11:R68
2. Collins AJ, Foley R, Herzog C, et al: Excerpts from the United States Renal Data System 2007 annual data report. Am J Kidney Dis 2008; 51:S1–S320
3. Waikar SS, Wald R, Chertow GM, et al: Validity of International Classification of Diseases, Ninth Revision, Clinical Modification Codes for Acute Renal Failure. J Am Soc Nephrol 2006; 17:1688–1694
4. Xue JL, Daniels F, Star RA, et al: Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 2006; 17:1135–1142
5. Chertow GM, Soroko SH, Paganini EP, et al: Mortality after acute renal failure: Models for prognostic stratification and risk adjustment. Kidney international 2006; 70:1120–1126
6. Hoste EA, Clermont G, Kersten A, et al: RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: A cohort analysis. Crit Care 2006; 10:R73
7. Nash K, Hafeez A, Hou S: Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39:930–936
8. Mehta RL, Pascual MT, Soroko S, et al: Spectrum of acute renal failure in the intensive care unit: The PICARD experience. Kidney international 2004; 66:1613–1621
9. Uchino S, Kellum JA, Bellomo R, et al: Acute renal failure in critically ill patients: A multinational, multicenter study. Jama 2005; 294:813–818
10. Uchino S, Bellomo R, Goldsmith D, et al: An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Critical care medicine 2006; 34:1913–1917
11. Ostermann M, Chang RW: Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med 2007; 35:1837–1843; quiz 1852
12. Lin CY, Chen YC, Tsai FC, et al: RIFLE classification is predictive of short-term prognosis in critically ill patients with acute renal failure supported by extracorporeal membrane oxygenation. Nephrol Dial Transplant 2006; 21:2867–2873
13. Lopes JA, Jorge S, Resina C, et al: Prognostic utility of RIFLE for acute renal failure in patients with sepsis. Crit Care 2007; 11:408
14. Metnitz PG, Krenn CG, Steltzer H, et al: Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 2002; 30:2051–2058
15. Liano F, Felipe C, Tenorio MT, et al: Long-term outcome of acute tubular necrosis: A contribution to its natural history. KidneyInt 2007; 71:679–686
16. Bagshaw SM, Laupland KB, Doig CJ, et al: Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: A population-based study. Crit Care 2005; 9:R700–R709
17. Chertow GM, Levy EM, Hammermeister KE, et al: Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998; 104:343–348
18. Chertow GM, Burdick E, Honour M, et al: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005; 16:3365–3370
19. Lassnigg A, Schmidlin D, Mouhieddine M, et al: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 2004; 15:1597–1605
20. Waikar SS, Liu KD, Chertow GM: The incidence and prognostic significance of acute kidney injury. Curr Opin Nephrol Hypertens 2007; 16:227–236
21. Coca SG, Peixoto AJ, Garg AX, et al: The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. Am J Kidney Dis 2007; 50:712–720
22. Yegenaga I, Hoste E, Van Biesen W, et al: Clinical characteristics of patients developing ARF due to sepsis/systemic inflammatory response syndrome: Results of a prospective study. Am J Kidney Dis 2004; 43:817–824
23. Bagshaw SM, Uchino S, Bellomo R, et al: Septic acute kidney injury in critically ill patients: Clinical characteristics and outcomes. Clin J Am Soc Nephrol 2007; 2:431–439
24. Bernieh B, Al Hakim M, Boobes Y, et al: Outcome and predictive factors of acute renal failure in the intensive care unit. Transplant Proc 2004; 36:1784–1787
25. Vincent JL, de Mendonca A, Cantraine F, et al: Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: Results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 1998; 26:1793–1800
26. Harbrecht BG, Rosengart MR, Zenati MS, et al: Defining the contribution of renal dysfunction to outcome after traumatic injury. Am Surg 2007; 73:836–840
27. Radovic M, Ostric V, Djukanovic L: Validity of prediction scores in acute renal failure due to polytrauma. Ren Fail 1996; 18:615–620
28. Kuitunen A, Vento A, Suojaranta-Ylinen R, et al: Acute renal failure after cardiac surgery: evaluation of the RIFLE classification. Ann Thorac Surg 2006; 81:542–546
29. Thakar CV, Worley S, Arrigain S, et al: Influence of renal dysfunction on mortality after cardiac surgery: Modifying effect of preoperative renal function. Kidney international 2005; 67:1112–1119
30. Bove T, Calabro MG, Landoni G, et al: The incidence and risk of acute renal failure after cardiac surgery. J Cardiothorac Vasc Anesth 2004; 18:442–445
31. Holm C, Horbrand F, von Donnersmarck GH, et al: Acute renal failure in severely burned patients. Burns 1999; 25:171–178
32. Morgera S, Kraft AK, Siebert G, et al: Long-term outcomes in acute renal failure patients treated with continuous renal replacement therapies. Am J Kidney Dis 2002; 40:275–279
33. Prescott GJ, Metcalfe W, Baharani J, et al: A prospective national study of acute renal failure treated with RRT: Incidence, aetiology and outcomes. Nephrol Dial Transplant 2007; 22:2513–2519
34. Leacche M, Rawn JD, Mihaljevic T, et al: Outcomes in patients with normal serum creatinine and with artificial renal support for acute renal failure developing after coronary artery bypass grafting. Am J Cardiol 2004; 93:353–356
35. Korkeila M, Ruokonen E, Takala J: Costs of care, long-term prognosis and quality of life in patients requiring renal replacement therapy during intensive care. Intensive Care Med 2000; 26:1824–1831
36. Basile DP: Novel approaches in the investigation of acute kidney injury. J Am Soc Nephrol 2007; 18:7–9
37. Schiffl H, Lang SM, Fischer R: Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002; 346:305–310
38. Macedo E, Bouchard J, Mehta RL: Renal recovery following acute kidney injury. Curr Opin Crit Care 2008; 14:660–665
39. Mehta RL, Chertow GM: Acute renal failure definitions and classification: Time for change? J Am Soc Nephrol 2003; 14:2178–2187
40. Bellomo R, Ronco C, Kellum JA, et al: Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8:R204–R212
41. Dasta JF, Kane-Gill SL, Durtschi AJ, et al: Costs and outcomes of acute kidney injury (AKI) following cardiac surgery. Nephrol Dial Transplant 2008
42. Mehta RL, Kellum JA, Shah SV, et al: Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11:R31
43. Bagshaw SM, George C, Bellomo R: A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008; 23:1569–1574
44. Lopes JA, Fernandes P, Jorge S, et al: Acute kidney injury in intensive care unit patients: A comparison between the RIFLE and the Acute Kidney Injury Network classifications. Crit Care 2008; 12:R110
45. Guerin C, Girard R, Selli JM, et al: Initial versus delayed acute renal failure in the intensive care unit. A multicenter prospective epidemiological study. Rhone-Alpes Area Study Group on Acute Renal Failure. Am J Respir Crit Care Med 2000; 161:872–879
46. Moran SM, Myers BD: Course of acute renal failure studied by a model of creatinine kinetics. Kidney international 1985; 27:928–937
47. Tsai JJ, Yeun JY, Kumar VA, et al: Comparison and interpretation of urinalysis performed by a nephrologist versus a hospital-based clinical laboratory. Am J Kidney Dis 2005; 46:820–829
48. Perazella MA, Coca SG, Kanbay M, et al: Diagnostic value of urine microscopy for differential diagnosis of acute kidney injury in hospitalized patients. Clin J Am Soc Nephrol 2008; 3:1615–1619
49. da Silva Magro MC, de Fatima Fernandes Vattimo M: Does urinalysis predict acute renal failure after heart surgery? Ren Fail 2004; 26:385–392
50. Lee VWS, Harris DCH, Anderson RJ, et al: Acute Renal Failure. In: Diseases of the Kidney & Urinary Tract. 8th ed. Schrier RW (Ed). Philadelphia, Wolters Kluwer Health/Lippincott Williams & Wilkins, 2007
51. Miller TR, Anderson RJ, Linas SL, et al: Urinary diagnostic indices in acute renal failure: a prospective study. Ann Intern Med 1978; 89:47–50
52. Payen D, de Pont AC, Sakr Y, et al: A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008; 12:R74
53. Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:2564–2575
54. Ali T, Khan I, Simpson W, et al: Incidence and outcomes in acute kidney injury: A comprehensive population-based study. J Am Soc Nephrol 2007; 18:1292–1298
55. Vivino G, Antonelli M, Moro ML, et al: Risk factors for acute renal failure in trauma patients. Intensive Care Med 1998; 24:808–814
56. De laet I, Malbrain ML, Jadoul JL, et al: Renal implications of increased intra-abdominal pressure: are the kidneys the canary for abdominal hypertension? Acta Clin Belg Suppl 2007:119–130
57. Sugrue M, Jones F, Deane SA, et al: Intra-abdominal hypertension is an independent cause of postoperative renal impairment. Arch Surg 1999; 134:1082–1085
58. Cheatham ML, Malbrain ML, Kirkpatrick A, et al: Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. II. Recommendations. Intensive Care Med 2007; 33:951–962
59. Sharp LS, Rozycki GS, Feliciano DV: Rhabdomyolysis and secondary renal failure in critically ill surgical patients. Am J Surg 2004; 188:801–806
60. Obialo CI, Okonofua EC, Tayade AS, et al: Epidemiology of de novo acute renal failure in hospitalized African Americans: Comparing community-acquired vs hospital-acquired disease. Arch Intern Med 2000; 160:1309–1313
61. Wang Y, Cui Z, Fan M: Hospital-acquired and community-acquired acute renal failure in hospitalized Chinese: A ten-year review. Ren Fail 2007; 29:163–168
62. Kelleher SP, Robinette JB, Conger JD: Sympathetic nervous system in the loss of autoregulation in acute renal failure. Am J Physiol 1984; 246:F379–F386
63. Schlichtig R, Kramer DJ, Boston JR, et al: Renal O2 consumption during progressive hemorrhage. J Appl Physiol 1991; 70:1957–1962
64. Bourgoin A, Leone M, Delmas A, et al: Increasing mean arterial pressure in patients with septic shock: Effects on oxygen variables and renal function. Crit Care Med 2005; 33:780–786
65. LeDoux D, Astiz ME, Carpati CM, et al: Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 2000; 28:2729–2732
66. Friedrich JO, Adhikari N, Herridge MS, et al: Meta-analysis: Low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005; 142:510–524
67. Kellum JA, M Decker J: Use of dopamine in acute renal failure: A meta-analysis. Crit Care Med 2001; 29:1526–1531
68. Marik PE: Low-dose dopamine: A systematic review. Intensive Care Med 2002; 28:877–883
69. Holmes CL, Walley KR: Bad medicine: Low-dose dopamine in the ICU. Chest 2003; 123:1266–1275
70. Dunning J, Khasati N, Barnard J: Low dose (renal dose) dopamine in the critically ill patient. Interact Cardiovasc Thorac Surg 2004; 3:114–117
71. Bellomo R, Chapman M, Finfer S, et al: Low-dose dopamine in patients with early renal dysfunction: A placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000; 356:2139–2143
72. Lauschke A, Teichgraber UK, Frei U, et al: ‘Low-dose' dopamine worsens renal perfusion in patients with acute renal failure. Kidney Int 2006; 69:1669–1674
73. Argalious M, Motta P, Khandwala F, et al: “Renal dose” dopamine is associated with the risk of new-onset atrial fibrillation after cardiac surgery. Crit Care Med 2005; 33:1327–1332
74. Devins SS, Miller A, Herndon BL, et al: Effects of dopamine on T-lymphocyte proliferative responses and serum prolactin concentrations in critically ill patients. Crit Care Med 1992; 20:1644–1649
75. Murphy MB, Murray C, Shorten GD: Fenoldopam: A selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med 2001; 345:1548–1557
76. Samuels J, Finkel K, Gubert M, et al: Effect of fenoldopam mesylate in critically ill patients at risk for acute renal failure is dose dependent. Ren Fail 2005; 27:101–105
77. Brienza N, Malcangi V, Dalfino L, et al: A comparison between fenoldopam and low-dose dopamine in early renal dysfunction of critically ill patients. Crit Care Med 2006; 34:707–714
78. Tumlin JA, Finkel KW, Murray PT, et al: Fenoldopam mesylate in early acute tubular necrosis: A randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis 2005; 46:26–34
79. Morelli A, Ricci Z, Bellomo R, et al: Prophylactic fenoldopam for renal protection in sepsis: A randomized, double-blind, placebo-controlled pilot trial. Crit Care Med 2005; 33:2451–2456
80. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al: Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007; 49:56–68
81. Schierhout G, Roberts I: Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: A systematic review of randomised trials. BMJ 1998; 316:961–964
82. Alderson P, Schierhout G, Roberts I, et al: Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2000:CD000567
83. Alderson P, Bunn F, Lefebvre C, et al: Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev 2002:CD001208
84. Alderson P, Bunn F, Lefebvre C, et al: Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev 2004:CD001208
85. Choi PT, Yip G, Quinonez LG, et al: Crystalloids vs. colloids in fluid resuscitation: A systematic review. Critical care medicine 1999; 27:200–210
86. Finfer S, Bellomo R, Boyce N, et al: A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350:2247–2256
87. Myburgh J, Cooper DJ, Finfer S, et al: Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007; 357:874–884
88. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre randomised study. Lancet 2001; 357:911–916
89. Brunkhorst FM, Engel C, Bloos F, et al: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125–139
90. Cittanova ML, Leblanc I, Legendre C, et al: Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet 1996; 348:1620–1622
91. Wiedermann CJ: Systematic review of randomized clinical trials on the use of hydroxyethyl starch for fluid management in sepsis. BMC Emerg Med 2008; 8:1
92. Vincent JL, Sakr Y, Sprung CL, et al: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34:344–353
93. Sakr Y, Payen D, Reinhart K, et al: Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98:216–224
94. Finfer S, Chittock DR, Su SY, et al: Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283–1297
95. Van den Berghe G, Wilmer A, Hermans G, et al: Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449–461
96. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345:1359–1367
97. Schetz M, Vanhorebeek I, Wouters PJ, et al: Tight blood glucose control is renoprotective in critically ill patients. J Am Soc Nephrol 2008; 19:571–578
98. Lecomte P, Van Vlem B, Coddens J, et al: Tight perioperative glucose control is associated with a reduction in renal impairment and renal failure in non-diabetic cardiac surgical patients. Crit Care 2008; 12:R154
99. Cheung NW, Napier B, Zaccaria C, et al: Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Diabetes Care 2005; 28:2367–2371
100. Rybak MJ, Abate BJ, Kang SL, et al: Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999; 43:1549–1555
101. Prins JM, Buller HR, Kuijper EJ, et al: Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341:335–339
102. Hatala R, Dinh T, Cook DJ: Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996; 124:717–725
103. Barza M, Ioannidis JP, Cappelleri JC, et al: Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312:338–345
104. Munckhof WJ, Grayson ML, Turnidge JD: A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996; 37:645–663
105. Galloe AM, Graudal N, Christensen HR, et al: Aminoglycosides: Single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol 1995; 48:39–43
106. Ferriols-Lisart R, Alos-Alminana M: Effectiveness and safety of once-daily aminoglycosides: A meta-analysis. Am J Health Syst Pharm 1996; 53:1141–1150
107. Harbarth S, Pestotnik SL, Lloyd JF, et al: The epidemiology of nephrotoxicity associated with conventional amphotericin B therapy. Am J Med 2001; 111:528–534
108. Walsh TJ, Finberg RW, Arndt C, et al: Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med 1999; 340:764–771
109. Wingard JR, Wood CA, Sullivan E, et al: Caspofungin versus amphotericin B for candidemia: A pharmacoeconomic analysis. Clin Ther 2005; 27:960–969
110. Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354:353–365
111. Huber W, Eckel F, Hennig M, et al: Prophylaxis of contrast material-induced nephropathy in patients in intensive care: Acetylcysteine, theophylline, or both? A randomized study. Radiology 2006; 239:793–804
112. Joannidis M, Schmid M, Wiedermann CJ: Prevention of contrast media-induced nephropathy by isotonic sodium bicarbonate: A meta-analysis. Wien Klin Wochenschr 2008; 120:742–748
113. Ho KM, Morgan DJ: Use of isotonic sodium bicarbonate to prevent radiocontrast nephropathy in patients with mild pre-existing renal impairment: A meta-analysis. Anaesth Intensive Care 2008; 36:646–653
114. Hogan SE, L'Allier P, Chetcuti S, et al: Current role of sodium bicarbonate-based preprocedural hydration for the prevention of contrast-induced acute kidney injury: A meta-analysis. Am Heart J 2008; 156:414–421
115. Meier P, Ko DT, Tamura A, et al: Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: A meta-analysis. BMC Med 2009; 7:23
116. Navaneethan SD, Singh S, Appasamy S, et al: Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: A systematic review and meta-analysis. Am J Kidney Dis 2009; 53:617–627
117. Brar SS, Shen AY, Jorgensen MB, et al: Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: A randomized trial. JAMA 2008; 300:1038–1046
118. Tepel M, van der Giet M, Schwarzfeld C, et al: Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343:180–184
119. Kelly AM, Dwamena B, Cronin P, et al: Meta-analysis: Effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med 2008; 148:284–294
120. Gonzales DA, Norsworthy KJ, Kern SJ, et al: A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: Unsupervised clustering to resolve heterogeneity. BMC Med 2007; 5:32
121. Hoffmann U, Fischereder M, Kruger B, et al: The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 2004; 15:407–410
122. Haase M, Haase-Fielitz A, Ratnaike S, et al: N-Acetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant 2008
123. McCullough PA, Bertrand ME, Brinker JA, et al: A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol 2006; 48:692–699
124. Heinrich MC, Haberle L, Muller V, et al: Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: Meta-analysis of randomized controlled trials. Radiology 2009; 250:68–86
125. Holscher B, Heitmeyer C, Fobker M, et al: Predictors for contrast media-induced nephropathy and long-term survival: prospectively assessed data from the randomized controlled Dialysis-Versus-Diuresis (DVD) trial. Can J Cardiol 2008; 24:845–850
126. Cirit M, Toprak O, Yesil M, et al: Angiotensin-converting enzyme inhibitors as a risk factor for contrast-induced nephropathy. Nephron Clin Pract 2006; 104:c20–c27
127. Onuigbo MA, Onuigbo NT: Does renin-angiotensin aldosterone system blockade exacerbate contrast-induced nephropathy in patients with chronic kidney disease? A prospective 50-month Mayo Clinic study. Ren Fail 2008; 30:67–72
128. Rosenstock JL, Bruno R, Kim JK, et al: The effect of withdrawal of ACE inhibitors or angiotensin receptor blockers prior to coronary angiography on the incidence of contrast-induced nephropathy. Int Urol Nephrol 2008; 40:749–755
129. Marenzi G, Marana I, Lauri G, et al: The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med 2003; 349:1333–1340
130. Marenzi G, Lauri G, Campodonico J, et al: Comparison of two hemofiltration protocols for prevention of contrast-induced nephropathy in high-risk patients. Am J Med 2006; 119:155–162
131. Cruz DN, Perazella MA, Bellomo R, et al: Extracorporeal blood purification therapies for prevention of radiocontrast-induced nephropathy: A systematic review. Am J Kidney Dis 2006; 48:361–371
132. Lee PT, Chou KJ, Liu CP, et al: Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am Coll Cardiol 2007; 50:1015–1020
133. Tumlin JA, Wang A, Murray PT, et al: Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: A pilot trial in the prevention of contrast nephropathy. Am Heart J 2002; 143:894–903
134. Stone GW, McCullough PA, Tumlin JA, et al: Fenoldopam mesylate for the prevention of contrast-induced nephropathy: A randomized controlled trial. JAMA 2003; 290:2284–2291
135. Allaqaband S, Tumuluri R, Malik AM, et al: Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 2002; 57:279–283
136. Briguori C, Colombo A, Airoldi F, et al: N-Acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2004; 44:762–765
137. Bagshaw SM, Ghali WA: Theophylline for prevention of contrast-induced nephropathy: A systematic review and meta-analysis. Arch Intern Med 2005; 165:1087–1093
138. Ix JH, McCulloch CE, Chertow GM: Theophylline for the prevention of radiocontrast nephropathy: A meta-analysis. Nephrol Dial Transplant 2004; 19:2747–2753
139. Akriviadis E, Botla R, Briggs W, et al: Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: A double-blind, placebo-controlled trial. Gastroenterology 2000; 119:1637–1648
140. Sort P, Navasa M, Arroyo V, et al: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999; 341:403–409
141. Gines P, Tito L, Arroyo V, et al: Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988; 94:1493–1502
142. Gluud LL, Kjaer MS, Christensen E: Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev 2006:CD005162
143. Ortega R, Gines P, Uriz J, et al: Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective, nonrandomized study. Hepatology 2002; 36:941–948
144. Solanki P, Chawla A, Garg R, et al: Beneficial effects of terlipressin in hepatorenal syndrome: A prospective, randomized placebo-controlled clinical trial. J Gastroenterol Hepatol 2003; 18:152–156
145. Sanyal AJ, Boyer T, Garcia-Tsao G, et al: A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology 2008; 134:1360–1368
146. Martin-Llahi M, Pepin MN, Guevara M, et al: Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: A randomized study. Gastroenterology 2008; 134:1352–1359
147. Alessandria C, Ottobrelli A, Debernardi-Venon W, et al: Noradrenalin vs terlipressin in patients with hepatorenal syndrome: A prospective, randomized, unblinded, pilot study. J Hepatol 2007; 47:499–505
148. Sharma P, Kumar A, Shrama BC, et al. An open label, pilot, randomized controlled trial of noradrenaline versus terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response. Am J Gastroenterol 2008; 103:1689–1697
149. Kiser TH, Fish DN, Obritsch MD, et al: Vasopressin, not octreotide, may be beneficial in the treatment of hepatorenal syndrome: A retrospective study. Nephrol Dial Transplant 2005; 20:1813–1820
150. Angeli P, Volpin R, Gerunda G, et al: Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 1999; 29:1690–1697
151. Esrailian E, Pantangco ER, Kyulo NL, et al: Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci 2007; 52:742–748
152. Skagen C, Einstein M, Lucey MR, et al: Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol 2009; 43:680–685
153. Cantarovich F, Rangoonwala B, Lorenz H, et al: High-dose furosemide for established ARF: A prospective, randomized, double-blind, placebo-controlled, multicenter trial. Am J Kidney Dis 2004; 44:402–409
154. Sampath S, Moran JL, Graham PL, et al: The efficacy of loop diuretics in acute renal failure: Assessment using Bayesian evidence synthesis techniques. Crit Care Med 2007; 35:2516–2524
155. Ho KM, Sheridan DJ: Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006; 333:420
156. Bagshaw SM, Delaney A, Haase M, et al: Loop diuretics in the management of acute renal failure: A systematic review and meta-analysis. Crit Care Resusc 2007; 9:60–68
157. Mehta RL, Pascual MT, Soroko S, et al: Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002; 288:2547–2553
158. Uchino S, Doig GS, Bellomo R, et al: Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32:1669–1677
159. Chertow GM, Lazarus JM, Paganini EP, et al: Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group. J Am Soc Nephrol 1998; 9:692–698
160. Venkataram R, Kellum JA: The role of diuretic agents in the management of acute renal failure. Contrib Nephrol 2001:158–170
161. van der Voort PH, Boerma EC, Koopmans M, et al: Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: A double blind randomized controlled trial. Critical care medicine 2009; 37:533–538
162. Bagshaw SM, Delaney A, Jones D, et al: Diuretics in the management of acute kidney injury: A multinational survey. Contrib Nephrol 2007; 156:236–249
163. McWhirter JP, Pennington CR: Incidence and recognition of malnutrition in hospital. BMJ 1994; 308:945–948
164. Goldstein-Fuchs D: Assessment of nutritional status in renal diseases. In: Handbook of Nutrition and Kidney. Mitch WE, Klahr S (Eds). Philadelphia: Lippincott Williams & Wilkins, 2002, pp. 42–92
165. Druml W: Nutritional management of acute renal failure. J Ren Nutr 2005; 15:63–70
166. Frankenfield DC, Reynolds HN: Nutritional effect of continuous hemodiafiltration. Nutrition 1995; 11:388–393
167. Wooley JA, Btaiche IF, Good KL: Metabolic and nutritional aspects of acute renal failure in critically ill patients requiring continuous renal replacement therapy. Nutr Clin Pract 2005; 20:176–191
168. Cano N, Fiaccadori E, Tesinsky P, et al: ESPEN Guidelines on Enteral Nutrition: Adult renal failure. Clin Nutr 2006; 25:295–310
169. Macias WL, Alaka KJ, Murphy MH, et al: Impact of the nutritional regimen on protein catabolism and nitrogen balance in patients with acute renal failure. JPEN J Parenter Enteral Nutr 1996; 20:56–62
170. Bellomo R, Tan HK, Bhonagiri S, et al: High protein intake during continuous hemodiafiltration: Impact on amino acids and nitrogen balance. Int J Artif Organs 2002; 25:261–268
171. Scheinkestel CD, Kar L, Marshall K, et al: Prospective randomized trial to assess caloric and protein needs of critically Ill, anuric, ventilated patients requiring continuous renal replacement therapy. Nutrition 2003; 19:909–916
172. Fiaccadori E, Maggiore U, Rotelli C, et al: Effects of different energy intakes on nitrogen balance in patients with acute renal failure: A pilot study. Nephrol Dial Transplant 2005; 20:1976–1980
173. Ricci Z, Picardo S, Ronco C: Results from international questionnaires. Contrib Nephrol 2007; 156:297–303
174. Ricci Z, Ronco C, D'Amico G, et al: Practice patterns in the management of acute renal failure in the critically ill patient: An international survey. Nephrol Dial Transplant 2006; 21:690–696
175. Ronco C, Ricci Z, Bellomo R: Current worldwide practice of dialysis dose prescription in acute renal failure. Current opinion in critical care 2006; 12:551–556
176. RENAL Study Investigators: Renal replacement therapy for acute kidney injury in Australian and New Zealand intensive care units: a practice survey. Crit Care Resusc 2008; 10:225–230
177. Hoke TS, Douglas IS, Klein CL, et al: Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 2007; 18:155–164
178. Mehta RL: Indications for dialysis in the ICU: Renal replacement vs. renal support. Blood Purif 2001; 19:227–232
179. Teschan PE, Baxter CR, O'Brien TF, et al: Prophylactic hemodialysis in the treatment of acute renal failure. Ann Intern Med 1960; 53:992–1016
180. Conger JD: A controlled evaluation of prophylactic dialysis in post-traumatic acute renal failure. J Trauma 1975; 15:1056–1063
181. Gillum DM, Dixon BS, Yanover MJ, et al: The role of intensive dialysis in acute renal failure. Clin Nephrol 1986; 25:249–255
182. Gettings LG, Reynolds HN, Scalea T: Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med 1999; 25:805–813
183. Liu KD, Himmelfarb J, Paganini E, et al: Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2006; 1:915–919
184. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, et al: Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med 2002; 30:2205–2211
185. Bagshaw SM, Uchino S, Bellomo R, et al: Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care 2009; 24:129–140
186. Bouman CS, Oudemans-van Straaten HM: Timing of renal replacement therapy in critically ill patients with acute kidney injury. Curr Opin Crit Care 2007; 13:656–661
187. Ronco C, Bellomo R, Homel P, et al: Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 2000; 356:26–30
188. Saudan P, Niederberger M, De Seigneux S, et al: Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int 2006; 70:1312–1317
189. Tolwani AJ, Campbell RC, Stofan BS, et al: Standard versus high-dose CVVHDF for ICU-related acute renal failure. J Am Soc Nephrol 2008; 19:1233–1238
190. Palevsky PM, Zhang JH, O'Connor TZ, et al: Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med 2008; 359:7–20
191. Tonelli M, Manns B, Feller-Kopman D: Acute renal failure in the intensive care unit: A systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis 2002; 40:875–885
192. Uehlinger DE, Jakob SM, Ferrari P, et al: Comparison of continuous and intermittent renal replacement therapy for acute renal failure. Nephrol Dial Transplant 2005; 20:1630–1637
193. Vinsonneau C, Camus C, Combes A, et al: Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: A multicentre randomised trial. Lancet 2006; 368:379–385
194. Bagshaw SM, Bellomo R: Fluid resuscitation and the septic kidney. Curr Opin Crit Care 2006; 12:527–530
195. Augustine JJ, Sandy D, Seifert TH, et al: A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004; 44:1000–1007
196. Rabindranath K, Adams J, Macleod AM, et al: Intermittent versus continuous renal replacement therapy for acute renal failure in adults. Cochrane Database Syst Rev 2007:CD003773
197. John S, Griesbach D, Baumgartel M, et al: Effects of continuous haemofiltration vs intermittent haemodialysis on systemic haemodynamics and splanchnic regional perfusion in septic shock patients: A prospective, randomized clinical trial. Nephrol Dial Transplant 2001; 16:320–327
198. Mehta RL, McDonald B, Gabbai FB, et al: A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001; 60:1154–1163
199. Gasparovic V, Filipovic-Grcic I, Merkler M, et al: Continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD)–what is the procedure of choice in critically ill patients? Ren Fail 2003; 25:855–862
200. Lins RL, Elseviers MM, Van der Niepen P, et al: Intermittent versus continuous renal replacement therapy for acute kidney injury patients admitted to the intensive care unit: Results of a randomized clinical trial. Nephrol Dial Transplant 2009; 24:512–518
201. Kellum JA, Angus DC, Johnson JP, et al: Continuous versus intermittent renal replacement therapy: A meta-analysis. Intensive Care Med 2002; 28:29–37
202. Bagshaw SM, Berthiaume LR, Delaney A, et al: Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: A meta-analysis. Critical care medicine 2008; 36:610–617
203. Ghahramani N, Shadrou S, Hollenbeak C: A systematic review of continuous renal replacement therapy and intermittent haemodialysis in management of patients with acute renal failure. Nephrology (Carlton) 2008; 13:570–578
204. Pannu N, Klarenbach S, Wiebe N, et al: Renal replacement therapy in patients with acute renal failure: A systematic review. JAMA 2008; 299:793–805
205. Uchino S, Bellomo R, Kellum JA, et al: Patient and kidney survival by dialysis modality in critically ill patients with acute kidney injury. Int J Artif Organs 2007; 30:281–292
206. Bell M, Granath F, Schon S, et al: Continuous renal replacement therapy is associated with less chronic renal failure than intermittent haemodialysis after acute renal failure. Intensive Care Med 2007; 33:773–780
207. Kumar VA, Yeun JY, Depner TA, et al: Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal failure: A two-year single center report. Int J Artif Organs 2004; 27:371–379
208. Kielstein JT, Kretschmer U, Ernst T, et al: Efficacy and cardiovascular tolerability of extended dialysis in critically ill patients: A randomized controlled study. Am J Kidney Dis 2004; 43:342–349
209. Monchi M, Berghmans D, Ledoux D, et al: Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: A prospective randomized study. Intensive Care Med 2004; 30:260–265
210. Kutsogiannis DJ, Gibney RT, Stollery D, et al: Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int 2005; 67:2361–2367
211. Betjes MG, van Oosterom D, van Agteren M, et al: Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: Similar hemofilter survival but significantly less bleeding. J Nephrol 2007; 20:602–608
212. Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al: Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37:545–552
213. Dennen P, Parikh CR: Biomarkers of acute kidney injury: Can we replace serum creatinine? Clin Nephrol 2007; 68:269–278
214. Ahlstrom A, Tallgren M, Peltonen S, et al: Evolution and predictive power of serum cystatin C in acute renal failure. Clin Nephrol 2004; 62:344–350
215. Herget-Rosenthal S, Marggraf G, Husing J, et al: Early detection of acute renal failure by serum cystatin C. Kidney international 2004; 66:1115–1122
216. Le Bricon T, Leblanc I, Benlakehal M, et al: Evaluation of renal function in intensive care: plasma cystatin C vs. creatinine and derived glomerular filtration rate estimates. Clin Chem Lab Med 2005; 43:953–957
217. Delanaye P, Lambermont B, Chapelle JP, et al: Plasmatic cystatin C for the estimation of glomerular filtration rate in intensive care units. Intensive Care Med 2004; 30:980–983
218. Villa P, Jimenez M, Soriano MC, et al: Serum cystatin C concentration as a marker of acute renal dysfunction in critically ill patients. Crit Care 2005; 9:R139–R143
219. Mazul-Sunko B, Zarkovic N, Vrkic N, et al: Proatrial natriuretic peptide (1–98), but not cystatin C, is predictive for occurrence of acute renal insufficiency in critically ill septic patients. Nephron Clin Pract 2004; 97:c103–c107
220. Koyner JL, Bennett MR, Worcester EM, et al: Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery. Kidney Int 2008; 74:1059–1069
221. Mishra J, Dent C, Tarabishi R, et al: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365:1231–1238
222. Parikh CR, Mishra J, Thiessen-Philbrook H, et al: Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006; 70:199–203
223. Wagener G, Jan M, Kim M, et al: Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006; 105:485–491
224. Mishra J, Ma Q, Kelly C, et al: Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol 2006; 21:856–863
225. Parikh CR, Jani A, Mishra J, et al: Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation. Am J Transplant 2006; 6:1639–1645
226. Zappitelli M, Washburn KK, Arikan AA, et al: Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: A prospective cohort study. Crit Care 2007; 11:R84
227. Nickolas TL, O'Rourke MJ, Yang J, et al: Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 2008; 148:810–819
228. Han WK, Bailly V, Abichandani R, et al: Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int 2002; 62:237–244
229. Han WK, Waikar SS, Johnson A, et al: Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 2008; 73:863–869
230. Parikh CR, Jani A, Melnikov VY, et al: Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 2004; 43:405–414
231. Parikh CR, Abraham E, Ancukiewicz M, et al: Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005; 16:3046–3052
232. Trof RJ, Di Maggio F, Leemreis J, et al: Biomarkers of acute renal injury and renal failure. Shock 2006; 26:245–253
233. Waikar SS, Bonventre JV: Biomarkers for the diagnosis of acute kidney injury. Curr Opin Nephrol Hypertens 2007; 16:557–564
234. Bonventre JV: Diagnosis of acute kidney injury: from classic parameters to new biomarkers. Contrib Nephrol 2007; 156:213–219
235. Westhuyzen J, Endre ZH, Reece G, et al: Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant 2003; 18:543–551
236. du Cheyron D, Daubin C, Poggioli J, et al: Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF. Am J Kidney Dis 2003; 42:497–506
237. Zhou H, Pisitkun T, Aponte A, et al: Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. Kidney Int 2006; 70:1847–1857
238. Yu W, Sandoval RM, Molitoris BA: Rapid determination of renal filtration function using an optical ratiometric imaging approach. Am J Physiol Renal Physiol 2007; 292:F1873–R1880
239. Rabito CA, Panico F, Rubin R, et al: Noninvasive, real-time monitoring of renal function during critical care. J Am Soc Nephrol 1994; 4:1421–1428
240. Treszl A, Kaposi A, Hajdu J, et al: The extent to which genotype information may add to the prediction of disturbed perinatal adaptation: none, minor, or major? Pediatr Res 2007; 62:610–614
241. Haase-Fielitz A, Haase M, Bellomo R, et al: Genetic polymorphisms in sepsis- and cardiopulmonary bypass-associated acute kidney injury. Contrib Nephrol 2007; 156:75–91
242. Jaber BL, Pereira BJ, Bonventre JV, et al: Polymorphism of host response genes: Implications in the pathogenesis and treatment of acute renal failure. Kidney Int 2005; 67:14–33
243. Liangos O, Balakrishnan VS, Pereira BJ, et al: Cytokine single nucleotide polymorphism. Role in acute renal failure. Contrib Nephrol 2004; 144:63–75
244. Nguyen MT, Ross GF, Dent CL, et al: Early prediction of acute renal injury using urinary proteomics. Am J Nephrol 2005; 25:318–326
245. Mitra A, Bansal S, Wang W, et al: Erythropoietin ameliorates renal dysfunction during endotoxaemia. Nephrol Dial Transplant 2007; 22:2349–2353
246. Sharples EJ, Yaqoob MM: Erythropoietin in experimental acute renal failure. Nephron Exp Nephrol 2006; 104:e83–e88
247. Sward K, Valsson F, Odencrants P, et al: Recombinant human atrial natriuretic peptide in ischemic acute renal failure: A randomized placebo-controlled trial. Crit Care Med 2004; 32:1310–1315
248. Allgren RL, Marbury TC, Rahman SN, et al: Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 1997; 336:828–834
249. Lewis J, Salem MM, Chertow GM, et al: Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 2000; 36:767–774
250. Tumlin J, Wali R, Williams W, et al: Efficacy and safety of renal tubule cell therapy for acute renal failure. J Am Soc Nephrol 2008; 19:1034–1040
251. Payen D, Mateo J, Cavaillon JM, et al: Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: A randomized controlled trial. Crit Care Med 2009; 37:803–810
252. Honore PM, Jamez J, Wauthier M, et al: Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med 2000; 28:3581–3587

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Critical Care Medicine
Hypovolemia is not a common cause of acute kidney injury
Leibowitz, A
Critical Care Medicine, 38(6): 1505.
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acute kidney injury; intensive care unit

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