Diuretics in Acute Kidney Injury

Sagar U. Nigwekar, MD,* and Sushrut S. Waikar, MD, MPH

Summary: Acute kidney injury (AKI) is common in hospitalized patients and is associated with signicant morbidity and mortality. The incidence of AKI is increasing and despite clinical advances there has been little change in the outcomes associated with AKI. A variety of interventions, including loop diuretics, have been tested for the prevention and treatment of AKI; however, none to date have shown convincing benets in clinical studies, and the management of AKI remains largely supportive. In this article, we review the pharmacology and experimental and clinical evidence for loop diuretics in the management of AKI. In addition, we also review evidence for other agents with diuretic and/or natriuretic properties such as thiazide diuretics, mannitol, fenoldopam, and natriuretic peptides in both the prevention and treatment of AKI. Implications for current clinical practice are outlined to guide clinical decisions in this eld. Semin Nephrol 31:523-534 2011 Elsevier Inc. All rights reserved. Keywords: Acute kidney injury, diuretics, fenoldopam, natriuretic peptides

cute kidney injury (AKI), previously known as acute renal failure, is characterized by a sudden decline in glomerular ltration rate associated with the retention of nitrogenous waste products and disturbances in uid, electrolyte, and acid base balance. AKI is increasingly common,1,2 estimated to occur annually in more than 1 million hospitalized patients in the United States.3,4 The incidence of AKI varies across clinical settings. It is reported to occur in up to 5% to 7% of all hospitalized patients and in up to two thirds of critically ill patients.5-9 Approximately 5% to 6% of patients with AKI require renal replacement therapy10,11 and the mortality rate in this population that requires renal replacement therapy is approximately 50% to 70%.1,2,12 AKI also signicantly increases length of hospital stay and is associated with a signicant increase in the risk for chronic kidney disease and end-stage renal disease.11,13 Recently, studies also have identied that even small changes in serum creatinine are associated with signicant increases in mortality.13,14 Furthermore, AKI survivors are still at high risk for long-term adverse outcomes such as chronic kidney disease, end-stage renal disease, and premature death, even if the serum creatinine level returns to normal.15 Despite recent advances, the incidence of AKI has increased more than four-fold

*Division of Nephrology, Massachusetts General Hospital, Boston, MA and Scholars in Clinical Science Program, Harvard Medical School, Boston, MA. Renal Division, Brigham and Womens Hospital, Boston, MA. Address reprint requests to Sagar U. Nigwekar, MD, Massachusetts General Hospital, 55 Fruit St, Bulnch 127, Boston, MA 02114. E-mail: sagarnigs@gmail.com 0270-9295/ - see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2011.09.007

since 1988, with a yearly population incidence of more than 500 per 100,000 population and outcomes from AKI remain poor.1,16 Annually, AKI is estimated to incur $10 billion in excess health costs to the US health care system.3,13 Oliguria is a well-recognized and poor prognostic indicator in patients with AKI.10,17,18 The development of oliguria complicates clinical management, particularly for uid balance. It is therefore not surprising that diuretic agents are used frequently by clinicians to improve urine output or as an attempt to convert an oliguric state to a nonoliguric state. A number of diuretics with varying pharmacologic properties (loop diuretics [furosemide, bumetanide, torsemide], thiazide diuretics [metolazone, hydrochlorothiazide, often given in combination with loop diuretics], and osmotic diuretics such as mannitol) have been studied and are administered in the setting of AKI. Loop diuretics are the most potent of the diuretics and remain the most commonly used agents in the management of patients with AKI.19-21 Loop diuretics have been shown in animal models of AKI to reduce oxygen consumption and metabolic demands of injured renal tubular cells, thus limiting the ischemic damage of the outer medullary tubular segments.22 In experimental settings, loop diuretics also have been shown to improve renal blood ow by reducing renal vascular resistance and to attenuate ischemia/reperfusion-induced apoptosis and associated gene transcription in AKI.23,24 However, clinical trials evaluating loop diuretics in the management of AKI have failed to show consistent benets and hence controversy exists regarding use of these agents in the setting of AKI. In this review we focus primarily on loop diuretics and their pharmacology, experimental evidence, and results from clinical management of AKI. In addition, we cover other diuretic agents such as thiazides and mannitol. Finally, we also review other interventions such as fenoldopam and natriuretic peptides, which have signicant diuretic
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and natriuretic properties that may be of signicance in the prevention and/or treatment of AKI.

PHARMACOLOGY OF LOOP DIURETICS

Mechanism of Action Furosemide is one of the most frequently prescribed drugs in the United States.25 The principal mechanism of action involves the blockade of the Na-K-2Cl transporter on the luminal side of the thick ascending limb of the loop of Henle.25-30 Expression of this transporter leads to sodium retention (accounting for high sodium reabsorption of up to 40% of ltered load that normally occurs in this nephron segment) and increases in medullary tonicity leading to increased water reabsorption.26,29,30 Na-K2Cl transporter is a protein with 12 putative membranespanning domains; loop diuretics bind to domains 11 and 12, whereas domains 2, 4, and 7 are involved in the transport of Na, K, and/or Cl.31,32 The expression of the Na-K-2Cl transporter is regulated via cyclic adenosine monophosphate pathways with vasopressin amplifying its expression and prostanoid prostaglandin E2 reducing its expression.26 These expression dynamics may partly explain the differences in pharmacodynamic properties of loop diuretics in conditions such as heart failure, which interfere with vasopressin pathways, and nonsteroidal anti-inammatory medications, which interfere with prostaglandin synthesis. In addition to blocking the Na-K-2Cl transporter, loop diuretics have additional pharmacologic properties of unclear clinical signicance. Furosemide, but not bumetanide and torsemide, is a weak carbonic anhydrase inhibitor.33 Torsemide has been shown to have anti-aldosterone effects in experimental studies.34 Pharmacokinetics Loop diuretics are weak organic acids containing carboxylic acid moieties. Loop diuretics are highly protein bound (95%), and are therefore very minimally ltered at the glomerulus.26,30 They reach the Na-K-2Cl transporters by active secretion from the blood into the urine by the organic acid transporters located in the proximal tubule.35 Approximately 50% of a dose of furosemide is secreted in the urine in an unchanged form and the remainder is metabolized in the kidney itself.36 Hypoalbuminemia and the presence of other highly proteinbound drugs such as warfarin signicantly reduce the tubular secretion of loop diuretics and increase their metabolic clearance, leading to a reduction in diuretic effect.37,38 All the loop diuretics have similar onset time, peak action time, duration of action, and volume of distribution.30 However, there are signicant differences in other pharmacokinetic properties such as elimination half-life and bioavailability. Elimination half-life is 1 hour for bumetanide, 1.5 to 2 hours for furosemide, and 3 to 4 hours for torsemide.25 The average bioavailability of oral

furosemide is 50%; however, it is highly variable, ranging from 10% to 100%.25 This variability needs to be taken into account while switching from intravenous to oral furosemide in clinical settings such as AKI. In comparison, absorption of oral bumetanide and oral torsemide ranges from 80% to 100%, and hence their oral dose is equivalent to the intravenous dose. The elimination half-life of furosemide is prolonged (from 1.5-2 to 2.8 h) in patients with renal insufciency because both urinary excretion and renal metabolism are reduced.36,39 In comparison, bumetanide and torsemide are metabolized predominantly in the liver and hence their half-lives are not prolonged in patients with renal insufciency.40,41 However, similar to furosemide, delivery into the tubular uid is impaired with renal dysfunction even for bumetanide and torsemide. Because the ability of loop diuretic to function depends on renal blood ow, reduction in blood ow as seen in many cases with AKI slows the delivery of loop diuretics into renal tubular uid.33 In addition, accumulated organic acids of renal failure or drugs used for other conditions associated with AKI (such as cephalosporins and ciprooxacin in patients with sepsis) competitively inhibit access of loop diuretics to the organic acid secretory pump at the proximal tubule and thus further alter the expected diuretic response.42,43 Metabolic acidosis associated with renal failure depolarizes the membrane potential of proximal tubular cells and may further reduce secretion of organic acids such as loop diuretics.44,45 Therefore, the dose of loop diuretics needed to achieve an effective diuretic response is typically several-fold higher in patients with AKI. The diuretic response to furosemide is compromised in patients with increasing severity of AKI.46 In advanced chronic kidney disease, reduction in total nephron mass also may contribute to reduced efcacy of loop diuretics even though remaining nephrons respond satisfactorily when adequate doses of loop diuretics are administered.45 Pharmacodynamics Because loop diuretics exert their response by acting on the luminal side of the nephron, their diuretic response correlates more with urinary than plasma concentration.47 The relationship between the natriuretic response (measured by fractional excretion of sodium) and the amount of diuretic reaching the site of action is sigmoid shaped.30,33 This relationship is important clinically in establishing a threshold below which there will be no diuretic action and also a ceiling dose above which no additional diuretic action will take place.33 This relationship holds for all the loop diuretics and the maximal effect (excretion of 200-250 mmol of sodium in 3-4 L of urine over a period of 3 to 4 h in healthy individuals) is the same for all loop diuretics.30,47 Thus, once a maximally effective dose of a loop diuretic agent is administered, the only way to increase response is to administer

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diuretics that block other segments of a nephron such as thiazide diuretics. Although the pharmacodynamic properties of loop diuretics per se are preserved in patients with renal failure, the overall natriuretic response is limited by diminished ltered sodium. In addition, concomitant factors such as heart failure, liver failure, volume depletion, and nonsteroidal anti-inammatory agents signicantly alter the pharmacodynamic properties of loop diuretics. In conditions such as heart failure and liver failure there is a reduction in diuretic response to loop diuretics26,48 that is not improved by increasing the doses of loop diuretic beyond the maximally effective dose; however, the diuretic response can be improved by administering modest doses more frequently or by administering a continuous infusion.26 Also, patients with heart failure who are on chronic loop diuretic therapy develop loop diuretic tolerance from ooding of the distal nephron sites by the solute not reabsorbed from the loop of Henle. This leads to hypertrophy of collecting and connecting duct segments, resulting in an increase in the reabsorption of sodium at distal sites and a reduction in total diuresis.26,49 Thiazide diuretics may augment the diuretic response of loop diuretic by blocking reabsorption distally, accounting for the synergistic response to the combination of a thiazide and a loop diuretic.26,50-52 This phenomenon justies using a loop and thiazide diuretic combination in patients who do not respond adequately to maximally effective doses of a loop diuretic. However, it is important to keep in mind that such combination therapy can be associated with signicant adverse effects such as hypotension and hypokalemia and is only expected to work in patients with loop diuretic resistance caused by distal tubule hypertrophy from chronic loop diuretic exposure; hence, other causes of diuretic resistance should be excluded before considering such combination therapy.52 Such combination therapy can be effective in patients with pre-existing chronic kidney disease, although excessive volume depletion may lead to prerenal azotemia.52 It is apparent from the earlier discussion that the response to loop diuretics is a function of the relationship between the pharmacokinetic and pharmacodynamic properties. These properties can be altered by a variety of mechanisms in patients with AKI. Multiple factors need to be taken into account before deciding on an effective dose of a loop diuretic agent. Investigations also are underway to identify genetic polymorphisms in proteins involved in pharmacokinetics and pharmacodynamics of loop diuretics that may further explain differences in their efcacy and adverse events in different individuals.53 Another factor pertinent to critically ill patients with AKI that plays an important role in loop diuretic response is the time course of the delivery of a loop diuretic to its site of action. This time course is signicantly different with continuous intravenous infusion therapy compared with bolus therapy and may account for increased effec-

tiveness of the diuretic agent when administered as a continuous infusion in patients with impaired renal function.54,55 The mechanism for the enhanced diuretic action of continuous furosemide infusion may be related to its prolonged inhibition of Na-K-Cl2 co-transporters and a speculation that continuous submaximal diuresis with continuous intravenous infusion over time produces a greater cumulative response compared with bolus therapy.56

EXPERIMENTAL EVIDENCE FOR LOOP DIURETICS IN AKI

The bulk of the kidneys metabolic activity is devoted to sodium reabsorption. The medullary thick ascending limb therefore has high oxygen demand, but also has limited oxygen supply owing to the countercurrent system of capillary ow that leads to partial pressures as low as 15 mm Hg in the inner medulla. The mismatch between oxygen supply and demand make the medullary thick ascending limb particularly prone to hypoxic injury, and it stands to reason that reducing oxygen consumption by interfering with active sodium transport may be an appealing therapeutic target in AKI. Indeed, experimental evidence has shown that loop diuretics increase oxygenation of renal tissue22,23 and prevent renal adenosine 5 triphosphate depletion,57 with reports of increases in glomerular ltration rate.58 Other salutary effects of loop diuretics in animal models of AKI include improvement in renal blood ow23,59,60 and prevention of tubular obstruction by increasing tubular ow and ushing tubular debris.61,62 Recent data also have shown that low-dose furosemide can reduce ischemia/reperfusion injury by improving renal hemodynamics and attenuating ischemia-related changes in angiogenic gene transcription.63 Low-dose furosemide infusion also has been shown to attenuate ischemia/reperfusion-induced apoptosis.24 A number of animal studies have shown that furosemide increases total renal blood ow.23,59,60,64 The exact mechanism for the increase in renal blood ow remains uncertain. Administration of furosemide is associated with enhanced prostaglandin E2 release into renal venous blood and urine,65 thereby increasing renal blood ow. However, in experiments designed to study the effects of prostaglandin-mediated renoprotection by furosemide, indomethacin administration suppressed prostaglandin E2 excretion as well as the furosemideinduced increase in urinary prostaglandin excretion before and after ischemia but did not modify the protective effect of the diuretic.66,67 This implies that mechanisms other than the intrarenal prostaglandin system need to be considered to explain the potential renoprotective effects of loop diuretics in ischemic AKI. Signicant controversy also exists regarding whether loop diuretics truly increase renal blood ow because experiments have reported no change in renal blood ow,68 and some experiments even have shown a reduction in renal blood ow.69-72 In ischemic models of AKI, furosemide compared with acetylcholine was shown to have a signicant

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Table 1. Randomized Controlled Trials Addressing Loop Diuretics in the Management of AKI
Number of Patients Intervention Arm Control Arm Reported Clinical Outcomes

Study

Setting

Intervention

Control

Notes

Trials addressing prevention of AKI Cardiac angiography Solomon et al,78 1994

25

28

Saline 0.45% at 1 mL/kg/h for 12 h before and after angiography plus 80 mg furosemide intravenously 30 min before angiography

Saline 0.45% at 1 mL/kg/h for 12 h before and after angiography

AKI Need for dialysis

Lassnigg et al,76 2000

Cardiac surgery

41

40

Furosemide infusion 2.5 mg/h since induction of anesthesia until 48 h after surgery or discharge from ICU

Saline 0.9% infusion since induction of anesthesia until 48 h after surgery or discharge from ICU

AKI Need for dialysis Mortality

Mahesh et al,86 2008 Cardiac surgery

21

21

Furosemide infusion at 4 mg/h since induction of anesthesia until 12 h after surgery

Saline 0.9% infusion at 2 mL/h since induction of anesthesia until 12 h after surgery

AKI Need for dialysis Mortality

AKI dened as increase in the baseline serum creatinine concentration of at least 0.5 mg/dL within 48 h after the injection of radiocontrast agents Trial also had a third arm that received saline 0.45% with mannitol AKI dened as increase in the baseline serum creatinine concentration of at least 0.5 mg/dL within 48 h Trial also had a third arm that received dopamine infusion AKI dened as 50% increase in serum creatinine postoperatively, or 1.4 mg/dL, or requirement for dialysis, or all of these Patients were at risk for post-surgery AKI with 1 of the following criteria: serum Cr 1.4 mg/ dL, EF 50%, DM, combined CABG and valve surgery, redo cardiac surgery

Majumdar et al,89 2009

Cardiac angiography

46

46

Intervention solution consisted of saline 500 mL 0.45%, 15 mmol of potassium chloride, 25 g of mannitol, and 100 mg of furosemide at 125 mL/h for 4 h

Saline hydration protocol

AKI Need for dialysis Mortality

AKI dened as a 0.5mg/dL absolute or 25% relative increase in creatinine level within 48 hours of the procedure In all study patients, urine output was replaced with halfnormal saline milliliter per milliliter each hour during and for 12 hours after angiography

Trials addressing treatment of AKI Cantarovich et al,82 1971

AKI with urine output 400 mL/ d and no response to mannitol 60 g within 24 h

34

13

Karayannopoulos,83 1974

Established AKI

10

10

Group 1: furosemide 600 mg/d until diuresis 2 L/d Group 2: geometric progression of furosemide dose from 100 to 3,200 mg/d Furosemide 1 g initially and increased to 3 g over a period of 7 d if no response

Conventional treatment (details not known)

Mortality

Conventional treatment (details not known)

Need for dialysis Unclear how AKI was dened

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Table 1. Continued
Number of Patients Intervention Arm 33 Control Arm 33 Reported Clinical Outcomes Need for dialysis Mortality

Study Kleinknecht et al,84 1976

Setting Oliguric AKI (no underlying CKD)

Intervention

Control

Notes Urine output in the intervention arm was replaced by dextrose 5% with 6 g/L sodium chloride and 1.5 g/L potassium chloride

Hager et al,87 1996

Major abdominal, chest or vascular surgery patient entering ICU with moderate postsurgery renal impairment

62

59

Furosemide 3 mg/kg every Placebo (details not 4 h to maintain urine known) output 20-100 mL/h and 6 mg/kg/h if diuresis remained 20 mL/h, 1.5 mg/kg if diuresis between 100 and 150 mL/h, and no furosemide if diuresis 150 mL/h Furosemide infusion at 1 Dextrose 5% infusion since mg/h since admission to admission to ICU to ICU to discharge discharge

Need for dialysis Mortality

Enrolled patients in both groups had moderate renal impairment after surgery before initiation of the trial medication All patients also received dopamine 2 g/kg/min and mannitol 20% 100 mL/6 h

Shilliday et al,79 1997

AKI not caused by to 32 (Furosemide) prerenal or post30 (Torsemide) renal causes

30

Furosemide or torsemide at 3 mg/kg every 6 h (reduced to 2 mg/kg then 1 mg/kg if the serum creatinine level improved and stopped when renal function recovered) for 21 d or until recovery or death Furosemide 25 mg/kg/d infusion changed to 35 mg/kg/d oral when tolerated Furosemide 0.5 mg/kg/h infusion continued until the recovery of renal function or until a new hemoltration session was started

Placebo (details not known)

Need for dialysis Mortality

Cantarovich et al,81 2004

AKI requiring dialysis

166

164

Placebo (details not known)

Renal recovery Mortality

van der Voort et al,85 Mechanically 2009 ventilated patients coming off of continuous venoveno hemoltration Trials comparing different doses of loop diuretics AKI after trauma or Brown et al,80 1981 surgery (not related to obstruction or volume depletion)

36

35

Placebo infusion (details not known)

Need for dialysis Mortality

The criteria to restart hemoltration were based on the institutional practice

28

28

Kunt et al,88 2009

Cardiac surgery

50

50

Furosemide 4 mg/min for 4 h followed by 2 mg/ min infusion or oral furosemide 1 g to maintain urine output 150-200 mL/h until serum creatinine 3.39 mg/dL without dialysis Furosemide intermittent bolus at 1-3 mg/kg every 4 h until 48 h after surgery or discharge from ICU

Furosemide 4 mg/min for 4h

Need for dialysis Mortality

Furosemide infusion at 20 mg/h until 48 h after surgery or discharge from ICU

AKI Need for dialysis Mortality

Both groups received dopamine infusion at 2-3 g/kg/min

Abbreviations: AKI, acute kidney injury; CABG, coronary artery bypass graft; CKD, chronic kidney disease; CR, creatinine; DM, diabetes mellitus; EF, ejection fraction; ICU, intensive care unit.

renoprotective effect independent of the inuence on renal blood ow. This has been thought to be owing to improved osmolar clearance observed with furosemide administration.73 Considering the variable inuence on renal blood ow, it is reasonable to conclude that the pattern of renal vascular responses to loop diuretics is complex and probably has notable differences between effects on the cortical and medullary blood ow.

CLINICAL EVIDENCE FOR LOOP DIURETICS IN AKI

Observational Studies and Surveys A body of experimental evidence suggests that loop diuretics may have a benecial role in the prevention or treatment of AKI. This coupled with the intuitively appealing notion of converting oliguric to nonoliguric AKI for uid and electrolyte management has prompted cli-

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nicians to use loop diuretics frequently in AKI.19-21 Indeed, in the Project to Improve Care in cute Renal Disease (PICARD) study, a large cohort study of severe AKI in critically ill patients, diuretics were used in almost 60% of the patients at the time of consultation with a nephrologist, and an additional 12% were prescribed diuretics after nephrology consultation.19 This study also showed that loop diuretics are given with thiazide diuretics in approximately one third of patients. The median doses of furosemide, bumetanide, and metolazone were 80 (10%-90% range, 20-320), 10 (10%-90% range, 2-29), and 10 (10%-90% range, 5-20) mg/d, respectively. Diuretic use was associated signicantly with older age, presumed nephrotoxic AKI origin, a lower blood urea nitrogen level, acute respiratory failure, and a history of congestive heart failure. A propensity scoreadjusted analysis in this population showed that diuretic use was associated signicantly with in-hospital mortality and nonrecovery of renal function,19 although the extent of confounding by indication still remains unclear. Similar to the PICARD study, investigators from the Beginning and Ending Supportive Therapy for the Kidney (BEST) study reported that 70% of critically ill patients with AKI in this multicenter, multination (54 centers, 23 countries) cohort of 1,713 patients had received diuretic agents at the time of study enrollment, and that furosemide was the most commonly used diuretic.20 However, unlike the PICARD study, this study reported that combination diuretic therapy was seldom used (98 of 1,713 patients) and diuretic use in a multivariable analysis was not associated with increased mortality.20 A survey of the members of the European Workgroup of Cardiothoracic Intensivists conducted almost a decade ago showed that 11 of 38 centers used furosemide continuously for renoprotection in the perioperative period of cardiothoracic surgery, and that 34 of 38 used furosemide bolus injections when urine output decreased to less than 0.5 mL/kg/h.74 Results of a more recent multinational multicenter survey of nephrologists and intensive care physicians using a self-reported questionnaire conrmed that intravenous furosemide is the most commonly used diuretic.75 In this survey, participants endorsed taking into account factors such as serum creatinine level, urine output, blood pressure, central venous pressure, and risk of toxicity while deciding on a dose of diuretic. Diuretic use was considered most commonly in patients with pulmonary edema and also was common with other conditions such as rhabdomyolysis, major surgery, cardiogenic shock, and sepsis. The majority of responders targeted a diuresis of 0.5 to 1.0 mL/kg/h. Interestingly, despite the widespread use of diuretics, the majority of responders did not believe that diuretics could improve clinical outcomes such as mortality, need for renal replacement therapy, duration of renal replacement therapy, or renal recovery.

Randomized Controlled Trials Several randomized controlled trials have evaluated the role of loop diuretics in the prevention of AKI74,76-78 or management of established AKI79-87 (Table 1). Targeted patient populations have included patients undergoing cardiovascular surgery74,77,87 and those at risk for radiocontrast nephropathy.76,78 As outlined in Table 1, the dose of diuretic agents varied considerably across these studies: furosemide infusion rates from 1 to 20 mg/h, bolus dose of 1 to 3 mg/kg in the prevention studies, and daily furosemide of 600 to 3,400 mg in the treatment cohort. Most of the trials have studied the effects of furosemide and one trial studied the effects of torsemide on clinical outcomes.79 None of the studies have evaluated combination therapy with loop and thiazide diuretic agents. Overall, these studies have shown increases in urine output with loop diuretic administration without signicant improvements on clinical outcomes such as mortality or renal recovery. All but two studies83,87 showed no signicant reduction in the requirement of renal replacement therapy. Furthermore, these studies had major limitations including small sample size, confounding with co-interventions such as mannitol, and administration of intervention late in the course of AKI when renal recovery may be less likely. None of these trials individually had adequate power to address the denite inuence of loop diuretics on clinical outcomes such as mortality or need for renal replacement therapy.88 Multiple meta-analyses have been published to increase cumulative sample size from these small studies43,88,89; the most recent meta-analysis by Ho et al43 showed that furosemide, when used as a preventive or therapeutic drug in AKI, did not reduce the risk of requiring renal replacement therapy (relative risk [RR], 1.02; 95% condence interval [CI], 0.90-1.16; P .73) or hospital mortality (RR, 1.12; 95% CI, 0.93-1.34; P .23). Other meta-analyses88,89 also have failed to show benets in terms of number of dialysis sessions required, renal recovery, or length of hospital stay despite an increase in urinary output and shorter duration of renal replacement therapy. Furthermore, in one meta-analysis, it was observed that high-dose furosemide (range, 1-3.4 g/d) was associated with a trend toward increased risk of temporary deafness and tinnitus (RR, 3.97; 95% CI, 1.00-15.78; P .05).89 However, even despite pooling data from multiple studies, these meta-analyses did not have adequate power to address outcomes such as mortality or the need for renal replacement therapy.43 In an analysis of randomized controlled trials performed by Kelly et al90 evaluating interventions in the prevention of radiocontrast nephropathy, furosemide administration was associated with an increased risk of contrast-induced nephropathy (RR, 3.27; 95% CI, 1.48-7.26). Sampath et al91 performed Bayesian evidence synthesis to quantify the therapeutic efcacy of loop diuretics in

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AKI. In this analysis, loop diuretics were not associated with improved survival benet; in fact, probability of adverse mortality effect (RR1) was over 84%. In contrast to the ndings on mortality, the study did show a reduction in the duration of oliguria and a trend toward reduction in the need for renal replacement therapy with diuretic use compared with placebo. As described earlier, at present there is no clear evidence supporting benets of loop diuretics in the management of AKI and some investigators have suggested possible worsening of outcomes such as mortality with their use.19 In high doses, loop diuretic use may be associated with adverse effects of ototoxicity. Despite these clinical data, widespread use of loop diuretics in the management of AKI is a common practice indicating an obvious disconnect between the current evidence and practice patterns. Only an adequately powered, high-quality, randomized, controlled trial can address this question satisfactorily. Our search through clinicaltrials.gov identied a phase II placebo-controlled, randomized, controlled study in critically ill patients that will assess the inuence of continuous furosemide infusion on the progression from early AKI to advanced AKI. This trial by Bagshaw et al (NCT00978354) will not be powered for a mortality end point.

THIAZIDE DIURETICS
Thiazide diuretics act by interfering with sodium reabsorption by inhibiting the electroneutral sodium-chloride symporter in the upstream portion of the distal convoluted tubule.30,92 Similar to loop diuretics, they also have inhibitory activity on carbonic anhydrase92; however, the signicance of this inhibition is not known. Thiazide diuretics are typically thought to lose their effectiveness as the glomerular ltration rate decreases to less than 30 to 40 mL/min in chronic kidney disease,92,93 and their effectiveness in AKI is not well dened. In one study involving patients with chronic kidney disease and nephrotic syndrome, metolazone compared with other thiazide diuretics was reported to retain its diuretic efcacy.94 No randomized controlled trials have evaluated the role of thiazide diuretics in AKI specically, although they are used in combination frequently to augment the maximal diuretic effect of high-ceiling loop diuretics, especially in the setting of advanced congestive heart failure.

ow by a variety of mechanisms including inhibition of renin release, expansion of extracellular uid volume, and reduction in blood viscosity.96 However, as with other diuretic agents described earlier, its role in the management of patients with AKI is not dened. A randomized controlled trial of mannitol failed to show any benets compared with saline hydration in patients at risk for radiocontrast nephropathy.76 Although some experts suggest use of mannitol in patients with rhabdomyolysis, most data come from animal studies and no randomized controlled trial supports its use in this setting.97 In a retrospective analysis of patients admitted to the intensive care unit with rhabdomyolysis, mannitol administration has not been associated with improved outcomes such as incidence of AKI, need for renal replacement therapy, or mortality.98,99 Furthermore, there are signicant adverse effects of mannitol including volume depletion and hypernatremia produced by strong osmotic diuretic effects.96 Hyponatremia, hyperkalemia, and metabolic acidosis also have been reported when hypertonic mannitol is retained.96 Cumulative doses of mannitol and high plasma concentrations are associated with AKI.100,101 Despite the lack of benecial evidence in terms of clinical outcomes and potential for harm, prophylactic mannitol use is common in certain high-risk situations such as cardiac surgery, vascular surgery, and biliary surgery.96,102 This is performed mainly to increase urine output in these settings, and theoretically may have benecial effects as a result of induction of higher tubular ow rates and preventing tubular obstruction commonly seen in acute tubular necrosis. In the setting of renal transplantation, mannitol along with volume expansion has been shown to reduce the incidence of post-surgery AKI103; however, it is unclear whether this benet resulted from action of mannitol or whether it simply emphasizes the importance of volume resuscitation in the perioperative period.103-105

FENOLDOPAM
Fenoldopam is a selective peripheral and renal dopamine-1receptor agonist that has been shown to induce diuresis, natriuresis, and also improve renal blood ow in experimental studies.106 Despite possible reductions in systemic blood pressure, glomerular ltration rate and renal blood ow are maintained or increased during fenoldopam treatment107 and these effects are preserved even in patients with renal impairment.107 The diuresis and natriuresis can occur even without vasodilatation because fenoldopam directly reduces sodium reabsorption in the proximal tubule and the cortical collecting duct.108 Unfortunately, these experimental ndings have not translated consistently into clinical benets because results from randomized trials have been mixed with some trials showing a reduction in the incidence of AKI109-111 and others showing no benet.112,113 Fenoldopam trials generally have had a small sample size. Metaanalyses performed by Landoni et al114,115 have suggested

MANNITOL
Mannitol, an osmotic diuretic, primarily acts at the proximal tubule and loop of Henle by extracting water from intracellular compartments. It has been shown in animal models of AKI to attenuate the reduction in glomerular ltration rate when administered before an insult such as ischemia.95 It may act as a free radical scavenger, preserve mitochondrial function by reducing postischemic swelling, and also has been shown to improve renal blood

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that fenoldopam may reduce the need for renal replacement and mortality in critically ill patients with AKI as well as in patients undergoing cardiovascular surgery who are at risk for AKI. Although nonrenal pleiotropic effects of fenoldopam cannot be ruled out, it is likely that most benets of fenoldopam were driven by its renoprotective effect; however, given the limitations of the currently available clinical evidence, these effects need to be conrmed in an adequately powered randomized controlled study.

IMPLICATIONS FOR CLINICAL PRACTICE

Loop Diuretics The use of loop diuretics is Food and Drug Administration approved for the indications of edema associated with congestive heart failure, cirrhosis, and renal failure, including nephrotic syndrome, and in adults with hypertension. The striking disconnect between the widespread popularity of off-label use of loop diuretics to prevent or treat AKI and the overall lack of benet in trials conducted to date suggests that loop diuretics may be overused clinically, with possible adverse effects. We suggest that loop diuretics not be used routinely for the specic purpose of preventing AKI. Loop diuretics probably do not improve outcomes in patients with established AKI, although the induction of urine ow for volume management in the oliguric patient without resorting to dialytic therapy undoubtedly is appealing. Given the accumulating evidence of harm with volume overload in critically ill patients,126,127 diuretics may be important adjuncts to judicious volume-management strategies. However, diuretic use should not delay the timely institution of dialytic therapy when appropriate.128 Adverse effects of loop diuretics, including volume contraction leading to prerenal azotemia, stimulation of the adrenergic and renin-angiotensin-aldosterone system, electrolyte abnormalities, and metabolic alkalosis need to be considered and monitored carefully. Other nonrenal effects such as ototoxicity, impairment of mucociliary function of the respiratory tract in patients on mechanical ventilation,129 and immunosuppressive/cytotoxic effects on peripheral blood mononuclear cells130 actually may negate any potential renoprotective effects. Mannitol, Thiazide Diuretics, Natriuretic Peptides, and Fenoldopam Mannitol is Food and Drug Administration approved for the prevention and treatment of oliguric AKI. Mannitol is used commonly for AKI prevention and treatment in the perioperative period, after kidney transplantation, and in rhabdomyolysis, but has not been studied extensively to provide strong evidence-based recommendations. Thiazide diuretics may augment the efcacy of loop diuretics but do not have a specic therapeutic or prevention role in AKI. Fenoldopam and the natriuretic peptides may offer clinical benet in settings such as post-cardiac surgery AKI; however, their renoprotective effects need further evaluation before considering their routine clinical application.

NATRIURETIC PEPTIDES
Multiple experimental and human studies have shown that natriuretic peptides such as atrial natriuretic peptide, brain natriuretic peptide, and urodilatin have signicant diuretic and natriuretic properties.116 These properties may help in reducing tubular obstruction and their additional actions of vasodilatation and angiotensin inhibition have been shown to improve glomerular ltration in animal models.117 Multiple clinical trials have investigated the use of natriuretic peptides in both the prevention and treatment of AKI.118-122 However, these trials have failed to show any convincing improvement in clinical outcomes. The largest study to date to evaluate the role of natriuretic peptides in the treatment of established AKI was performed by Allgren et al.118 This multicenter, randomized, double-blind, placebo-controlled, clinical trial involved 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide or placebo. The rate of dialysis-free survival was not signicantly different between the two groups: 47% in the placebo group and 43% in the anaritide group (P .35), although a prespecied subgroup analysis pointed toward benet in those with oliguria. Additional studies in oliguric AKI have failed to show improvement in hard outcomes such as need for renal replacement therapy.123 As noted in recent metaanalyses, the majority of the trials have been small and methodologically awed.124,125 In addition, trials investigating natriuretic peptides in the treatment of AKI typically enrolled patients with advanced AKI and thus effects on milder AKI are not known. Also, the dose of preparations used in some of these trials was quite high and this high dose could have led to adverse effects of hypotension and arrhythmias, negating the potential benets of these agents. Indeed, as shown in a meta-analyses by Nigwekar et al,123,124 low-dose natriuretic peptide preparations may be benecial in terms of reducing AKI and need for renal replacement therapy when administered to prevent AKI, especially in the cardiovascular surgery setting. Low-dose preparations were not associated with hypotension or arrhythmias. However, given the limitations of these meta-analyses, these results need to be conrmed in future randomized controlled trials with adequate power and high methodologic quality.

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