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 significant
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 benefits 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, fenoldo-
pam, and natriuretic peptides in both the prevention and treatment of AKI. Implications for current clinical practice
are outlined to guide clinical decisions in this field.
Semin Nephrol 31:523-534 2011 Elsevier Inc. All rights reserved.
Keywords: Acute kidney injury, diuretics, fenoldopam, natriuretic peptides

A cute kidney injury (AKI), previously known as

acute renal failure, is characterized by a sud-
den decline in glomerular filtration rate asso-
ciated with the retention of nitrogenous waste products
and disturbances in fluid, 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 replace-
ment therapy10,11 and the mortality rate in this popu-
lation that requires renal replacement therapy is ap-
proximately 50% to 70%.1,2,12 AKI also significantly
increases length of hospital stay and is associated with
a significant increase in the risk for chronic kidney
disease and end-stage renal disease.11,13 Recently,
studies also have identified that even small changes in
serum creatinine are associated with significant in-
creases 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 dis-
ease, 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, Bulfinch 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, particu-
larly for fluid 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], thia-
zide 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 med-
ullary tubular segments.22 In experimental settings,
loop diuretics also have been shown to improve renal
blood flow 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 manage-
ment of AKI have failed to show consistent benefits
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 man-
agement 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 significant diuretic

Seminars in Nephrology, Vol 31, No 6, November 2011, pp 523-534 523

524
and natriuretic properties that may be of significance
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 reabsorp-
tion of up to 40% of filtered load that normally occurs in
this nephron segment) and increases in medullary tonic-
ity leading to increased water reabsorption.26,29,30 Na-K-
2Cl transporter is a protein with 12 putative membrane-
spanning 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 non-
steroidal anti-inflammatory medications, which interfere
with prostaglandin synthesis.
In addition to blocking the Na-K-2Cl transporter, loop
diuretics have additional pharmacologic properties of
unclear clinical significance. Furosemide, but not bumet-
anide and torsemide, is a weak carbonic anhydrase in-
hibitor.33 Torsemide has been shown to have anti-aldo-
sterone effects in experimental studies.34
Pharmacokinetics
Loop diuretics are weak organic acids containing carbox-
ylic acid moieties. Loop diuretics are highly protein
bound (95%), and are therefore very minimally filtered
at the glomerulus.26,30 They reach the Na-K-2Cl trans-
porters 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 Hy-
poalbuminemia and the presence of other highly protein-
bound drugs such as warfarin significantly 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 distribu-
tion.30 However, there are significant 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
S.U. Nigwekar and S.S. Waikar
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 furo-
semide 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 insufficiency
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
insufficiency.40,41 However, similar to furosemide, deliv-
ery into the tubular fluid is impaired with renal dysfunc-
tion even for bumetanide and torsemide.
Because the ability of loop diuretic to function de-
pends on renal blood flow, reduction in blood flow as
seen in many cases with AKI slows the delivery of loop
diuretics into renal tubular fluid.33 In addition, accumu-
lated organic acids of renal failure or drugs used for other
conditions associated with AKI (such as cephalosporins
and ciprofloxacin in patients with sepsis) competitively
inhibit access of loop diuretics to the organic acid secre-
tory 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 re-
duce 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 effi-
cacy of loop diuretics even though remaining nephrons
respond satisfactorily when adequate doses of loop di-
uretics 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 (mea-
sured 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 relation-
ship 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 maxi-
mally effective dose of a loop diuretic agent is adminis-
tered, the only way to increase response is to administer
Diuretics in AKI
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 fail-
ure, the overall natriuretic response is limited by dimin-
ished filtered sodium. In addition, concomitant factors
such as heart failure, liver failure, volume depletion, and
nonsteroidal anti-inflammatory agents significantly 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 di-
uretic 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 tol-
erance from flooding of the distal nephron sites by the
solute not reabsorbed from the loop of Henle. This leads
to hypertrophy of collecting and connecting duct seg-
ments, 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, account-
ing for the synergistic response to the combination of a
thiazide and a loop diuretic.26,50-52 This phenomenon jus-
tifies 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 impor-
tant to keep in mind that such combination therapy can be
associated with significant adverse effects such as hypo-
tension 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 ex-
cluded before considering such combination therapy.52
Such combination therapy can be effective in patients
with pre-existing chronic kidney disease, although exces-
sive 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 efficacy and adverse events in different individu-
als.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 significantly different
with continuous intravenous infusion therapy compared
with bolus therapy and may account for increased effec-
525
tiveness of the diuretic agent when administered as a
continuous infusion in patients with impaired renal func-
tion.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 ther-
apy.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 sys-
tem of capillary flow that leads to partial pressures as low
as 15 mm Hg in the inner medulla. The mismatch be-
tween 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, experimen-
tal evidence has shown that loop diuretics increase oxy-
genation of renal tissue22,23 and prevent renal adenosine
5 triphosphate depletion,57 with reports of increases in
glomerular filtration rate.58 Other salutary effects of loop
diuretics in animal models of AKI include improvement
in renal blood flow23,59,60 and prevention of tubular ob-
struction by increasing tubular flow and flushing tubular
debris.61,62 Recent data also have shown that low-dose
furosemide can reduce ischemia/reperfusion injury by
improving renal hemodynamics and attenuating isch-
emia-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 furo-
semide increases total renal blood flow.23,59,60,64 The ex-
act mechanism for the increase in renal blood flow re-
mains uncertain. Administration of furosemide is
associated with enhanced prostaglandin E2 release into
renal venous blood and urine,65 thereby increasing renal
blood flow. However, in experiments designed to study
the effects of prostaglandin-mediated renoprotection by
furosemide, indomethacin administration suppressed
prostaglandin E2 excretion as well as the furosemide-
induced increase in urinary prostaglandin excretion be-
fore 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. Significant contro-
versy also exists regarding whether loop diuretics truly
increase renal blood flow because experiments have re-
ported no change in renal blood flow,68 and some exper-
iments even have shown a reduction in renal blood
flow.69-72 In ischemic models of AKI, furosemide com-
pared with acetylcholine was shown to have a significant
526 S.U. Nigwekar and S.S. Waikar

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

Trials addressing
prevention of AKI
Solomon et al,78 Cardiac angiography 25 28 Saline 0.45% at 1 mL/kg/h Saline 0.45% at 1 mL/kg/h AKI AKI defined as increase
1994 for 12 h before and after for 12 h before and Need for dialysis in the baseline
angiography plus 80 mg after angiography serum creatinine
furosemide intravenously concentration of at
30 min before least 0.5 mg/dL
angiography within 48 h after the
injection of
radiocontrast agents
Trial also had a third
arm that received
saline 0.45% with
mannitol
Lassnigg et al,76 Cardiac surgery 41 40 Furosemide infusion 2.5 Saline 0.9% infusion since AKI AKI defined as increase
2000 mg/h since induction of induction of anesthesia Need for dialysis in the baseline
anesthesia until 48 h until 48 h after surgery Mortality serum creatinine
after surgery or or discharge from ICU concentration of at
discharge from ICU least 0.5 mg/dL
within 48 h
Trial also had a third
arm that received
dopamine infusion
Mahesh et al,86 2008 Cardiac surgery 21 21 Furosemide infusion at 4 Saline 0.9% infusion at 2 AKI AKI defined as 50%
mg/h since induction of mL/h since induction of Need for dialysis increase in serum
anesthesia until 12 h anesthesia until 12 h Mortality creatinine
after surgery after surgery 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 Cardiac angiography 46 46 Intervention solution Saline hydration protocol AKI AKI defined as a 0.5-
2009 consisted of saline 500 Need for dialysis mg/dL absolute or
mL 0.45%, 15 mmol of Mortality 25% relative
potassium chloride, increase in creatinine
25 g of mannitol, and level within 48 hours
100 mg of furosemide of the procedure
at 125 mL/h for 4 h In all study patients,
urine output was
replaced with half-
normal saline
milliliter per milliliter
each hour during
and for 12 hours
after angiography
Trials addressing
treatment of AKI
Cantarovich et al,82 AKI with urine 34 13 Group 1: furosemide 600 Conventional treatment Mortality
1971 output 400 mL/ mg/d until diuresis 2 (details not known)
d and no response L/d
to mannitol 60 g Group 2: geometric
within 24 h progression of
furosemide dose from
100 to 3,200 mg/d
Karayannopoulos,83 Established AKI 10 10 Furosemide 1 g initially Conventional treatment Need for dialysis Unclear how AKI was
1974 and increased to 3 g (details not known) defined
over a period of 7 d if
no response
Diuretics in AKI 527

Table 1. Continued
Number of Patients
Reported
Intervention Control Clinical
Study Setting Arm Arm Intervention Control Outcomes Notes

Kleinknecht et al,84 Oliguric AKI (no
1976 underlying CKD)
Hager et al,87 1996 Major abdominal,
chest or vascular
surgery patient
entering ICU with
moderate post-
surgery renal
impairment
Shilliday et al,79 AKI not caused by to 32 (Furosemide)
1997 prerenal or post- 30 (Torsemide)
renal causes
Cantarovich et al,81 AKI requiring dialysis 166
2004
van der Voort et al,85 Mechanically
2009 ventilated patients
coming off of
continuous veno-
veno
hemofiltration
Trials comparing
different doses of
loop diuretics
Brown et al,80 1981 AKI after trauma or
surgery (not
related to
obstruction or
volume depletion)
Kunt et al,88 2009 Cardiac surgery
33 33 Furosemide 3 mg/kg every Placebo (details not Need for dialysis Urine output in the
4 h to maintain urine known) Mortality intervention arm
output 20-100 mL/h and was replaced by
6 mg/kg/h if diuresis dextrose 5% with 6
remained 20 mL/h, g/L sodium chloride
1.5 mg/kg if diuresis and 1.5 g/L
between 100 and 150 potassium chloride
mL/h, and no
furosemide if diuresis
150 mL/h
62 59 Furosemide infusion at 1 Dextrose 5% infusion since Need for dialysis Enrolled patients in
mg/h since admission to admission to ICU to Mortality both groups had
ICU to discharge discharge moderate renal
impairment after
surgery before
initiation of the trial
medication
30 Furosemide or torsemide Placebo (details not Need for dialysis All patients also
at 3 mg/kg every 6 h known) Mortality received dopamine
(reduced to 2 mg/kg 2 g/kg/min and
then 1 mg/kg if the mannitol 20% 100
serum creatinine level mL/6 h
improved and stopped
when renal function
recovered) for 21 d or
until recovery or death
164 Furosemide 25 mg/kg/d Placebo (details not Renal recovery
infusion changed to 35 known) Mortality
mg/kg/d oral when
tolerated
36 35 Furosemide 0.5 mg/kg/h Placebo infusion (details Need for dialysis The criteria to restart
infusion continued until not known) Mortality hemofiltration were
the recovery of renal based on the
function or until a new institutional practice
hemofiltration session
was started
28 28 Furosemide 4 mg/min for Furosemide 4 mg/min for Need for dialysis
4 h followed by 2 mg/ 4h Mortality
min infusion or oral
furosemide 1 g to
maintain urine output
150-200 mL/h until
serum creatinine 3.39
mg/dL without dialysis
50 50 Furosemide intermittent Furosemide infusion at 20 AKI Both groups received
bolus at 1-3 mg/kg mg/h until 48 h after Need for dialysis dopamine infusion
every 4 h until 48 h surgery or discharge Mortality at 2-3 g/kg/min
after surgery or from ICU
discharge from ICU

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 influence on
renal blood flow. This has been thought to be owing to
improved osmolar clearance observed with furosemide
administration.73 Considering the variable influence on
renal blood flow, 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 flow.
CLINICAL EVIDENCE FOR LOOP DIURETICS IN AKI
Observational Studies and Surveys
A body of experimental evidence suggests that loop
diuretics may have a beneficial role in the prevention or
treatment of AKI. This coupled with the intuitively ap-
pealing notion of converting oliguric to nonoliguric AKI
for fluid and electrolyte management has prompted cli-
528
nicians to use loop diuretics frequently in AKI.19-21 In-
deed, 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 al-
most 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 diuret-
ics 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 significantly 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 significantly 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 Kid-
ney (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 re-
ceived diuretic agents at the time of study enrollment,
and that furosemide was the most commonly used di-
uretic.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 multi-
variable analysis was not associated with increased mor-
tality.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 con-
tinuously for renoprotection in the perioperative period
of cardiothoracic surgery, and that 34 of 38 used furo-
semide bolus injections when urine output decreased to
less than 0.5 mL/kg/h.74 Results of a more recent multi-
national multicenter survey of nephrologists and inten-
sive care physicians using a self-reported questionnaire
confirmed that intravenous furosemide is the most com-
monly used diuretic.75 In this survey, participants en-
dorsed taking into account factors such as serum creati-
nine 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 replace-
ment therapy, or renal recovery.
S.U. Nigwekar and S.S. Waikar
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 radio-
contrast 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 evalu-
ated combination therapy with loop and thiazide diuretic
agents.
Overall, these studies have shown increases in urine
output with loop diuretic administration without signifi-
cant improvements on clinical outcomes such as mortal-
ity or renal recovery. All but two studies83,87 showed no
significant reduction in the requirement of renal replace-
ment therapy. Furthermore, these studies had major lim-
itations including small sample size, confounding with
co-interventions such as mannitol, and administration of
intervention late in the course of AKI when renal recov-
ery may be less likely. None of these trials individually
had adequate power to address the definite influence of
loop diuretics on clinical outcomes such as mortality or
need for renal replacement therapy.88
Multiple meta-analyses have been published to in-
crease cumulative sample size from these small stud-
ies43,88,89; 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% confidence 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
benefits in terms of number of dialysis sessions re-
quired, renal recovery, or length of hospital stay de-
spite an increase in urinary output and shorter duration
of renal replacement therapy. Furthermore, in one
meta-analysis, it was observed that high-dose furo-
semide (range, 1-3.4 g/d) was associated with a trend
toward increased risk of temporary deafness and tin-
nitus (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 radiocon-
trast nephropathy, furosemide administration was as-
sociated with an increased risk of contrast-induced
nephropathy (RR, 3.27; 95% CI, 1.48-7.26).
Sampath et al91 performed Bayesian evidence synthe-
sis to quantify the therapeutic efficacy of loop diuretics in
Diuretics in AKI
AKI. In this analysis, loop diuretics were not associated
with improved survival benefit; in fact, probability of
adverse mortality effect (RR1) was over 84%. In con-
trast to the findings 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 evi-
dence supporting benefits of loop diuretics in the man-
agement 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 prac-
tice patterns. Only an adequately powered, high-quality,
randomized, controlled trial can address this question satis-
factorily. Our search through clinicaltrials.gov identified a
phase II placebo-controlled, randomized, controlled study in
critically ill patients that will assess the influence of contin-
uous 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 reab-
sorption by inhibiting the electroneutral sodium-chloride
symporter in the upstream portion of the distal convo-
luted tubule.30,92 Similar to loop diuretics, they also have
inhibitory activity on carbonic anhydrase92; however, the
significance of this inhibition is not known. Thiazide
diuretics are typically thought to lose their effectiveness
as the glomerular filtration rate decreases to less than 30
to 40 mL/min in chronic kidney disease,92,93 and their
effectiveness in AKI is not well defined. In one study
involving patients with chronic kidney disease and ne-
phrotic syndrome, metolazone compared with other thi-
azide diuretics was reported to retain its diuretic effi-
cacy.94 No randomized controlled trials have evaluated
the role of thiazide diuretics in AKI specifically, 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.
MANNITOL
Mannitol, an osmotic diuretic, primarily acts at the prox-
imal 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
filtration rate when administered before an insult such as
ischemia.95 It may act as a free radical scavenger, pre-
serve mitochondrial function by reducing postischemic
swelling, and also has been shown to improve renal blood
529
flow by a variety of mechanisms including inhibition of
renin release, expansion of extracellular fluid volume,
and reduction in blood viscosity.96
However, as with other diuretic agents described ear-
lier, its role in the management of patients with AKI is
not defined. A randomized controlled trial of mannitol
failed to show any benefits compared with saline hydra-
tion in patients at risk for radiocontrast nephropathy.76
Although some experts suggest use of mannitol in pa-
tients 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 significant 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 beneficial evidence in
terms of clinical outcomes and potential for harm, pro-
phylactic 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
beneficial effects as a result of induction of higher tubular
flow 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 benefit re-
sulted 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 dopa-
mine-1receptor agonist that has been shown to induce
diuresis, natriuresis, and also improve renal blood flow in
experimental studies.106 Despite possible reductions in
systemic blood pressure, glomerular filtration rate and
renal blood flow 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 reabsorp-
tion in the proximal tubule and the cortical collecting
duct.108 Unfortunately, these experimental findings have
not translated consistently into clinical benefits because
results from randomized trials have been mixed with
some trials showing a reduction in the incidence of
AKI109-111 and others showing no benefit.112,113 Fenoldo-
pam trials generally have had a small sample size. Meta-
analyses performed by Landoni et al114,115 have suggested
530
that fenoldopam may reduce the need for renal replace-
ment 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 benefits of fenoldopam were driven by its renopro-
tective effect; however, given the limitations of the cur-
rently available clinical evidence, these effects need to be
confirmed in an adequately powered randomized con-
trolled study.
NATRIURETIC PEPTIDES
Multiple experimental and human studies have shown
that natriuretic peptides such as atrial natriuretic peptide,
brain natriuretic peptide, and urodilatin have significant
diuretic and natriuretic properties.116 These properties
may help in reducing tubular obstruction and their addi-
tional actions of vasodilatation and angiotensin inhibition
have been shown to improve glomerular filtration in
animal models.117 Multiple clinical trials have investi-
gated the use of natriuretic peptides in both the preven-
tion 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 natri-
uretic peptides in the treatment of established AKI was
performed by Allgren et al.118 This multicenter, random-
ized, double-blind, placebo-controlled, clinical trial in-
volved 504 critically ill patients with acute tubular ne-
crosis. The patients received a 24-hour intravenous
infusion of either anaritide or placebo. The rate of dial-
ysis-free survival was not significantly different between
the two groups: 47% in the placebo group and 43% in the
anaritide group (P .35), although a prespecified sub-
group analysis pointed toward benefit in those with oli-
guria. 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 meta-
analyses, the majority of the trials have been small and
methodologically flawed.124,125 In addition, trials investi-
gating natriuretic peptides in the treatment of AKI typi-
cally enrolled patients with advanced AKI and thus ef-
fects 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 ben-
efits of these agents. Indeed, as shown in a meta-analyses
by Nigwekar et al,123,124 low-dose natriuretic peptide
preparations may be beneficial in terms of reducing AKI
and need for renal replacement therapy when adminis-
tered to prevent AKI, especially in the cardiovascular
surgery setting. Low-dose preparations were not associ-
ated with hypotension or arrhythmias. However, given
the limitations of these meta-analyses, these results need
to be confirmed in future randomized controlled trials
with adequate power and high methodologic quality.
S.U. Nigwekar and S.S. Waikar
IMPLICATIONS FOR CLINICAL PRACTICE
Loop Diuretics
The use of loop diuretics is Food and Drug Administra-
tion approved for the indications of edema associated
with congestive heart failure, cirrhosis, and renal failure,
including nephrotic syndrome, and in adults with hyper-
tension. The striking disconnect between the widespread
popularity of off-label use of loop diuretics to prevent or
treat AKI and the overall lack of benefit in trials con-
ducted to date suggests that loop diuretics may be over-
used clinically, with possible adverse effects. We suggest
that loop diuretics not be used routinely for the specific
purpose of preventing AKI. Loop diuretics probably do
not improve outcomes in patients with established AKI,
although the induction of urine flow for volume manage-
ment in the oliguric patient without resorting to dialytic
therapy undoubtedly is appealing. Given the accumulat-
ing evidence of harm with volume overload in critically
ill patients,126,127 diuretics may be important adjuncts to
judicious volume-management strategies. However, di-
uretic 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 abnor-
malities, 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 po-
tential 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. Thia-
zide diuretics may augment the efficacy of loop diuretics
but do not have a specific therapeutic or prevention role
in AKI. Fenoldopam and the natriuretic peptides may
offer clinical benefit in settings such as post-cardiac
surgery AKI; however, their renoprotective effects need
further evaluation before considering their routine clini-
cal application.
REFERENCES
1. Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM.
Declining mortality in patients with acute renal failure, 1988 to
2002. J Am Soc Nephrol. 2006;17:1143-50.
2. Xue JL, Daniels F, Star RA, Kimmel PL, Eggers PW, Molitoris
BA, et al. Incidence and mortality of acute renal failure in
Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol. 2006;
17:1135-42.
Diuretics in AKI
3. Palevsky PM. Epidemiology of acute renal failure: the tip of the
iceberg. Clin J Am Soc Nephrol. 2006;1:6-7.
4. Waikar SS, Winkelmayer WC. Chronic on acute renal failure:
long-term implications of severe acute kidney injury. JAMA.
2009;302:1227-9.
5. Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC,
De Bacquer D, 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.
6. Bagshaw SM, George C, Dinu I, Bellomo R. A multi-centre eval-
uation of the RIFLE criteria for early acute kidney injury in criti-
cally ill patients. Nephrol Dial Transplant. 2008;23:1203-10.
7. Ostermann M, Chang RW. Acute kidney injury in the intensive
care unit according to RIFLE. Crit Care Med. 2007;35:1837-43.
8. Uchino S, Kellum JA, Bellomo R, et al, on behalf of the
Beginning and Ending Supportive Therapy for the Kidney
(BEST Kidney) Investigators. Acute renal failure in critically ill
patients: a multinational, multicenter study. JAMA. 2005;294:
813-8.
9. Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C. An
assessment of the RIFLE criteria for acute renal failure in
hospitalized patients. Crit Care Med. 2006;34:1913-7.
10. Guerin C, Girard R, Selli JM, Perdrix JP, Ayzac L. Initial versus
delayed acute renal failure in the intensive care unit: a multi-
center prospective epidemiological study. Rhone-Alpes Area
Study Group on Acute Renal Failure. Am J Respir Crit Care
Med. 2000;161:872-9.
11. Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH,
Mucenski M, et al. Prognosis for longterm survival and renal
recovery in critically ill patients with severe acute renal failure:
a population-based study. Crit Care. 2005;9:R700-9.
12. Mehta RL, Pascual MT, Soroko S, Savage BR, Himmelfarb J,
Ikizler TA, et al. Spectrum of acute renal failure in the intensive
care unit: the PICARD experience. Kidney Int. 2004;66:1613-21.
13. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW.
Acute kidney injury, mortality, length of stay, and costs in
hospitalized patients. J Am Soc Nephrol. 2005;16:3365-70.
14. Lassnigg A, Schmid ER, Hiesmayr M, Falk C, Druml W, Bauer
P, et al. Impact of minimal increases in serum creatinine on
outcome in patients after cardiothoracic surgery: do we have to
revise current definitions of acute renal failure? Crit Care Med.
2008;36:1129-37.
15. Coca SG. Long-term outcomes of acute kidney injury. Curr Opin
Nephrol Hypertens. 2010;19:266-72.
16. Hsu CY, McCulloch CE, Fan D, Ordonez JD, Chertow GM, Go
AS. Community-based incidence of acute renal failure. Kidney
Int. 2007;72:208-12.
17. Bagshaw SM, Bellomo R, Kellum JA. Oliguria, volume over-
load, and loop diuretics. Crit Care Med. 2008;36 Suppl:S172-8.
18. Uchino S. Outcome prediction for patients with acute kidney
injury. Nephron Clin Pract. 2008;109:c217-23.
19. Mehta RL, Pascual MT, Soroko S, Chertow GM; PICARD
Study Group. Diuretics, mortality, and nonrecovery of renal
function in acute renal failure. JAMA. 2002;288:2547-53.
20. Uchino S, Doig GS, Bellomo R, Morimatsu H, Morgera S,
Schetz M, et al. Diuretics and mortality in acute renal failure.
Crit Care Med. 2004;32:1669-77.
21. Van Biesen W, Yegenaga I, Vanholder R, Verbeke F, Hoste E,
Colardyn F, et al. Relationship between fluid status and its
management on acute renal failure (ARF) in intensive care unit
(ICU) patients with sepsis: a prospective analysis. J Nephrol.
2005;18:54-60.
22. Heyman SN, Rosen S, Epstein FH, Spokes K, Brezis ML. Loop
diuretics reduce hypoxic damage to proximal tubules of the
isolated perfused rat kidney. Kidney Int. 1994;45:981-5.
23. Nuutinen LS, Tuononen S. The effect of furosemide on renal
blood flow and renal tissue oxygen tension in dogs. Ann Chir
Gynaecol. 1976;65:272-6.
24. Aravindan N, Aravindan S, Riedel BJ, Weng HR, Shaw AD.
531
Furosemide prevents apoptosis and associated gene expression
in a rat model of surgical ischemic acute renal failure. Ren Fail.
2007;29:399-407.
25. Wargo KA, Banta WM. A comprehensive review of the loop
diuretics: should furosemide be first line? Ann Pharmacother.
2009;43:1836-47.
26. Shankar SS, Brater DC. Loop diuretics: from the Na-K-2Cl
transporter to clinical use. Am J Physiol Renal Physiol. 2003;
284:F11-21.
27. Burg MB. Tubular chloride transport and the mode of action of
some diuretics. Kidney Int. 1976;9:189-97.
28. Haas M, Forbush B III. Na,K,Cl-cotransport system: character-
ization by bumetanide binding and photolabelling. Kidney Int
Suppl. 1987;23:S134-43.
29. Rose BD. Diuretics. Kidney Int. 1991;39:336-52.
30. Brater DC. Diuretic therapy. N Engl J Med. 1998;339:387-95.
31. Obermuller, N, Kunchaparty S, Ellison DH, Bachmann S. Ex-
pression of the Na-K-2Cl cotransporter by macula densa and
thick ascending limb cells of rat and rabbit nephron. J Clin
Invest. 1996;98:635-40.
32. Haas M, Forbush B III. The Na-K-Cl cotransporter of secretory
epithelia. Annu Rev Physiol. 2000;62:515-34.
33. Wang DJ, Gottlieb SS. Diuretics: still the mainstay of treatment.
Crit Care Med. 2008;36 Suppl:S89-94.
34. Uchida T, Yamanaga K, Nishikawa M, Ohtaki Y, Kido H,
Watanabe M. Anti-aldosteronergic effect of torasemide. Eur
J Pharmacol. 1991;205:145-50.
35. Odlind B, Beermann B. Renal tubular secretion and effects of
furosemide. Clin Pharmacol Ther. 1980;27:784-90.
36. Beerman B. Aspects on pharmacokinetics of some diuretics.
Acta Pharmacol Toxicol. 1984;54:17-32.
37. Inoue M, Okajima K, Itoh K, Ando Y, Watanabe N, Yasaka T,
et al. Mechanism of furosemide resistance in analbuminemic rats
and hypoalbuminemic patients. Kidney Int. 1987;32:198-203.
38. Pichette V, Geadah D, du Souich P. Role of plasma protein
binding on renal metabolism and dynamics of furosemide in the
rabbit. Drug Metab Dispos. 1999;27:81-5.
39. Cutler RE, Forrey AW, Christopher TG, Kimpel BM. Pharma-
cokinetics of furosemide in normal subjects and functionally
anephric patients. Clin Pharmacol Ther. 1974;15:588-96.
40. Holazo AA, Colburn WA, Gustafson JH, Young RL, Parsonnet
M. Pharmacokinetics of bumetanide following intravenous, in-
tramuscular, and oral administrations to normal subjects.
J Pharm Sci. 1984;73:1108-13.
41. Brater DC, Leinfelder J, Anderson SA. Clinical pharmacology of
torsemide, a new loop diuretic. Clin Pharmacol Ther. 1987;42:
187-92.
42. Brater DC. Resistance to diuretics: emphasis on a pharmacolog-
ical perspective. Drugs. 1981;22:477-94.
43. Ho KM, Power BM. Benefits and risks of furosemide in acute
kidney injury. Anaesthesia. 2010;65:283-93.
44. Cemerikic D, Wilcox CS, Giebisch G. Intracellular potential and
K activity in rat kidney proximal tubular cells in acidosis and
K depletion. J Membr Biol. 1982;69:159-65.
45. Wilcox CS. New insights into diuretic use in patients with
chronic renal disease. J Am Soc Nephrol. 2002;13:798-805.
46. Ho KM, Walters S, Faulke D, Liang J. Clinical predictors of
acute renal replacement therapy in critically ill patients with
acute renal impairment. Crit Care Resusc. 2003;5:97-102.
47. Brater DC. Clinical pharmacology of loop diuretics in health and
disease. Eur Heart J. 1992;13 Suppl G:10-4.
48. Brater DC, Chennavasin P, Seiwell R. Furosemide in patients
with heart failure: shift in dose-response curves. Clin Pharmacol
Ther. 1980;28:182-6.
49. Ellison DH, Velazquez H, Wright FS. Adaptation of the distal
convoluted tubule of the rat. Structural and functional effects of
dietary salt intake and chronic diuretic infusion. J Clin Invest.
1989;3:113-26.
50. Ellison DH, Velazquez H, Wright FS. Adaptation of the distal
532
convoluted tubule of the rat. Structural and functional effects of
dietary salt intake and chronic diuretic infusion. J Clin Invest.
1989;83:113-26.
51. Sica DA, Gehr TW. Diuretic combinations in refractory oedema
states: pharmacokinetic-pharmacodynamic relationships. Clin
Pharmacokinet. 1996;30:229-49.
52. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop
diuretics with thiazide-type diuretics in heart failure. J Am Coll
Cardiol. 2010;56:1527-34.
53. Vormfelde SV, Burckhardt G, Zirk A, Wojnowski L, Brock-
mller J. Pharmacogenomics of diuretic drugs: data on rare
monogenic disorders and on polymorphisms and requirements
for further research. Pharmacogenomics. 2003;4:701-34.
54. Sanjay S, Annigeri RA, Seshadri R, Rao BS, Prakash KC, Mani
MK. The comparison of the diuretic and natriuretic efficacy of
continuous and bolus intravenous furosemide in patients with
chronic kidney disease. Nephrology (Carlton). 2008;13:247-50.
55. Ostermann M, Alvarez G, Sharpe MD, Martin CM. Frusemide
administration in critically ill patients by continuous compared
to bolus therapy. Nephron Clin Pract. 2007;107:c70-6.
56. Rudy DW, Voelker JR, Greene PK, Esparza FA, Brater DC.
Loop diuretics for chronic renal insufficiency: a continuous
infusion is more efficacious than bolus therapy. Ann Intern Med.
1991;115:360-6.
57. Burke TJ, Malhotra D, Shapiro JI. Effects of enhanced oxygen
release from hemoglobin by RSR13 in an acute renal failure
model. Kidney Int. 2001;60:1407-14.
58. Schetz M. Diuretics in acute renal failure? Contrib Nephrol.
2004;144:166-81.
59. Ludens JH, Heitz DC, Brody MJ, Williamson HE. Differential
effect of furosemide on renal and limb blood flows in the
conscious dog. J Pharmacol Exp Ther. 1970;171:300-6.
60. Chrysant SG, Baxter PR, Amonette RL. The mechanism for the
renal hemodynamic and tubular action of furosemide. Arch Int
Pharmacodyn Ther. 1981;249:289-96.
61. Katayama S, Attallah AA, Stahl RA, Bloch DL, Lee JB. Mech-
anism of furosemide-induced natriuresis by direct stimulation of
renal prostaglandin E2. Am J Physiol. 1984;247:F555-61.
62. Bayati A, Nygren K, Kllskog O, Wolgast M. The effect of loop
diuretics on the long-term outcome of post-ischaemic acute renal
failure in the rat. Acta Physiol Scand. 1990;139:271-9.
63. Aravindan N, Shaw A. Effect of furosemide infusion on renal
hemodynamics and angiogenesis gene expression in acute renal
ischemia/reperfusion. Ren Fail. 2006;28:25-35.
64. Bailie MD, Davis LE, Loutzenhiser R. Intrarenal secretion of
renin in the dog: effect of furosemide. Am J Physiol. 1973;224:
425-30.
65. Kramer HJ, Schrmann J, Wassermann C, Dsing R. Prosta- 85. van der Voort PH, Boerma EC, Koopmans M, Zandberg M, de
glandin-independent protection by furosemide from oliguric
ischemic renal failure in conscious rats. Kidney Int. 1980;17:
455-64.
66. Data JL, Rane A, Gerkens J, Wilkinson GR, Nies AS, Branch
RA. The influence of indomethacin on the pharmacokinetics,
diuretic response and hemodynamics of furosemide in the dog.
J Pharmacol Exp Ther. 1978;206:431-8.
67. Dunn MJ, Zambraski EJ. Renal effects of drugs that inhibit
prostaglandin synthesis. Kidney Int. 1980;18:609-22.
68. Shimizu T, Nakamura M. Renal effect of atrial natriuretic poly-
peptide: comparison with standard saluretics. Eur J Pharmacol.
1986;127:249-59.
69. Yoshida M, Suzuki-Kusaba M, Satoh S. Participation of the
prostaglandin system in furosemide-induced changes of renal
function in anesthetized rats. Ren Physiol. 1987;10:25-32.
70. Christensen S, Petersen JS. Effects of furosemide on renal hae-
modynamics and proximal tubular sodium reabsorption in con-
scious rats. Br J Pharmacol. 1988;95:353-60.
71. Tenstad O, Williamson HE. Effect of furosemide on local and
zonal glomerular filtration rate in the rat kidney. Acta Physiol
Scand. 1995;155:99-107.
S.U. Nigwekar and S.S. Waikar
72. Bak M, Shalmi M, Petersen JS, Poulsen LB, Christensen S.
Effects of angiotensin-converting enzyme inhibition on renal
adaptations to acute furosemide administration in conscious rats.
J Pharmacol Exp Ther. 1993;266:33-40.
73. De Torrente A, Miller PD, Cronin RE, Paulsin PE, Erickson AL,
Schrier RW. Effects of furosemide and acetylcholine in norepi-
nephrine-induced acute renal failure. Am J Physiol. 1978;235:
F131-6.
74. Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hies-
mayr M. Lack of renoprotective effects of dopamine and furo-
semide during cardiac surgery. J Am Soc Nephrol. 2000;11:97-104.
75. Bagshaw SM, Delaney A, Jones D, Ronco C, Bellomo R. Di-
uretics in the management of acute kidney injury: a multina-
tional survey. Contrib Nephrol. 2007;156:236-49.
76. Solomon R, Werner C, Mann D, DElia J, Silva P. Effects of
saline, mannitol, and furosemide to prevent acute decreases in
renal function induced by radiocontrast agents. N Engl J Med.
1994;331:1416-20.
77. Mahesh B, Yim B, Robson D, Pillai R, Ratnatunga C, Pigott D.
Does furosemide prevent renal dysfunction in high-risk cardiac
surgical patients? Results of a double blinded prospective ran-
domised trial. Eur J Cardiothorac Surg. 2008;33:370-6.
78. Majumdar SR, Kjellstrand CM, Tymchak WJ, Hervas-Malo M,
Taylor DA, Teo KK. Forced euvolemic diuresis with mannitol
and furosemide for prevention of contrast-induced nephropathy
in patients with CKD undergoing coronary angiography: a ran-
domized controlled trial. Am J Kidney Dis. 2009;54:602-9.
79. Shilliday IR, Quinn KJ, Allison ME. Loop diuretics in the
management of acute renal failure: a prospective, double-blind,
placebo-controlled, randomized study. Nephrol Dial Transplant.
1997;12:2592-6.
80. Brown CB, Ogg CS, Cameron JS. High dose frusemide in acute
renal failure: a controlled trial. Clin Nephrol. 1981;15:90-6.
81. Cantarovich F, Rangoonwala B, Lorenz H, Verho M, Esnault
VL. High-dose furosemide in acute renal failure study group.
High-dose furosemide for established ARF: a prospective, ran-
domized, double-blind, placebo-controlled, multicenter trial.
Am J Kidney Dis. 2004;44:402-9.
82. Cantarovich F, Fernandez JC, Locatelli A, Perez Loredo J.
Furosemide in high doses in the treatment of acute renal failure.
Postgrad Med J. 1971;47 Suppl:13-7.
83. Karayannopoulos S. High-dose frusemide in renal failure. Br
Med J. 1974;2:278-9.
84. Kleinknecht D, Ganeval D, Gonzalez-Duque LA, Fermanian J.
Furosemide in acute oliguric renal failure. A controlled trial.
Nephron. 1976;17:51-8.
Ruiter J, Gerritsen RT, et al. Furosemide does not improve renal
recovery after hemofiltration for acute renal failure in critically
ill patients: a double blind randomized controlled trial. Crit Care
Med. 2009;37:533-8.
86. Hager B, Betschart M, Krapf R. Effect of postoperative intrave-
nous loop diuretic on renal function after major surgery. Schweiz
Med Wochenschr. 1996;126:666-73.
87. Kunt AT, Akgn S, Atalan N, Bitir N, Arsan S. Furosemide
infusion prevents the requirement of renal replacement therapy
after cardiac surgery. Anadolu Kardiyol Derg. 2009;9:499-504.
88. Bagshaw SM, Delaney A, Haase M, Ghali WA, Bellomo R.
Loop diuretics in the management of acute renal failure: a
systematic review and meta-analysis. Crit Care Resusc. 2007;9:
60-8.
89. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or
treat acute renal failure. BMJ. 2006;333:420.
90. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC.
Meta-analysis: effectiveness of drugs for preventing contrast-
induced nephropathy. Ann Intern Med. 2008;148:284-94.
91. Sampath S, Moran JL, Graham PL, Rockliff S, Bersten AD,
Abrams KR. The efficacy of loop diuretics in acute renal failure:
Diuretics in AKI
assessment using Bayesian evidence synthesis techniques. Crit
Care Med. 2007;35:2516-24.
92. Ernst ME, Moser M. Use of diuretics in patients with hyperten-
sion. N Engl J Med. 2009;361:2153-64.
93. Dussol B, Moussi-Frances J, Morange S, Somma-Delpero C,
Mundler O, Berland Y. A randomized trial of furosemide vs
hydrochlorothiazide in patients with chronic renal failure and
hypertension. Nephrol Dial Transplant. 2005;20:349-53.
94. Paton RR, Kane RE. Long-term diuretic therapy with metola-
zone of renal failure and the nephrotic syndrome. J Clin Phar-
macol. 1977;17:243-51.
95. Brunton P, Lazo J, Parker K, editors. Goodmans and Gillmans
the pharmacological basis of therapeutics 11th ed. Milan:
McGraw Hill Publishing; 2005.
96. Lameire N, Vanholder R. Pathophysiologic features and preven-
tion of human and experimental acute tubular necrosis. J Am Soc
Nephrol. 2001;12 Suppl 17:S20-32.
97. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney
injury. N Engl J Med. 2009;361:62-72.
98. Homsi E, Barreiro MF, Orlando JM, Higa EM. Prophylaxis of
acute renal failure in patients with rhabdomyolysis. Ren Fail.
1997;19:283-8.
99. Brown CV, Rhee P, Chan L, Evans K, Demetriades D, Velma-
hos GC. Preventing renal failure in patients with rhabdomyoly-
sis: do bicarbonate and mannitol make a difference? J Trauma.
2004;56:1191-6.
100. Fang L, You H, Chen B, Xu Z, Gao L, Liu J, et al. Mannitol is
an independent risk factor of acute kidney injury after cerebral
trauma: a case-control study. Ren Fail. 2010;32:673-9.
101. Dorman HR, Sondheimer JH, Chadnapaphomhai P. Mannitol-
induced acute renal failure. Medicine (Baltimore). 1990;69:
153-9.
102. Smith MN, Best D, Sheppard SV, Smith DC. The effect of
mannitol on renal function after cardiopulmonary bypass in
patients with established renal dysfunction. Anaesthesia. 2008;
63:701-4.
103. Tiggeler RGW, Berden JHM, Hotsma AJ, Koene RAP. Preven-
tion of acute tubular necrosis in cadaveric kidney transplantation
by the combined use of mannitol and moderate hydration. Ann
Surg. 1985;201:246-51.
104. Weimar W, Geerlings W, Bijnen AB, Obertop H, van Urk H,
Lameijer LD, et al. A controlled study on the effect of mannitol
on immediate renal function after cadaver donor kidney trans-
plantation. Transplantation. 1983;35:99-101.
105. Van Valenberg PLJ, Hoitsma AJ, Tiggeler RGWL. Mannitol as
an indispensable constituent of an intraoperative hydration pro-
tocol for the prevention of acute renal failure. Transplantation.
1987;19:4140-2.
106. Lokhandwala MF. Preclinical and clinical studies on the cardio-
vascular and renal effects of fenoldopam: a DA-1 receptor
agonist. Drug Dev Res. 1987;10:123-34.
107. Mathur VS, Swan SK, Lambrecht LJ, Anjum S, Fellmann J,
McGuire D, et al. The effects of fenoldopam, a selective
dopamine receptor agonist, on systemic and renal hemody-
namics in normotensive subjects. Crit Care Med. 1999;27:
1832-7.
108. Satoh T, Cohen HT, Katz AI. Intracellular signaling in the
regulation of renal sodium, potassium-ATPase. I. Role of
cyclic AMP and phospholipase A2. J Clin Invest. 1992;89:
1496-500.
109. Caimmi PP, Pagani L, Micalizzi E, Fiume C, Guani S, Bernardi
M, et al. Fenoldopam for renal protection in patients undergoing
cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2003;17:
491-4.
110. Brienza N, Malcangi V, Dalfino L, Trerotoli P, Guagliardi C,
Bortone D, et al. A comparison between fenoldopam and low-
dose dopamine in early renal dysfunction of critically ill patients.
Crit Care Med. 2006;34:707-14.
111. Morelli A, Ricci Z, Bellomo R, Ronco C, Rocco M, Conti G, et
533
al. Prophylactic fenoldopam for renal protection in sepsis: a
randomized, double-blind, placebo-controlled pilot trial. Crit
Care Med. 2005;33:2451-6.
112. Bove T, Landoni G, Calabr MG, Aletti G, Marino G, Cer-
chierini E, et al. Renoprotective action of fenoldopam in
high-risk patients undergoing cardiac surgery: a prospective,
double-blind, randomized clinical trial. Circulation. 2005;
111:3230-5.
113. Tumlin JA, Finkel KW, Murray PT, Samuels J, Cotsonis G,
Shaw AD. Fenoldopam mesylate in early acute tubular necrosis:
a randomized, double-blind, placebo-controlled clinical trial.
Am J Kidney Dis. 2005;46:26-34.
114. Landoni G, Biondi-Zoccai GG, Marino G, Bove T, Fochi O, Maj
G, et al. Fenoldopam reduces the need for renal replacement
therapy and in-hospital death in cardiovascular surgery: a meta-
analysis. J Cardiothorac Vasc Anesth. 2008;22:27-33.
115. Landoni G, Biondi-Zoccai GG, Tumlin JA, Bove T, De Luca
M, Calabr MG, 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.
116. Vesely DL. Natriuretic peptides and acute renal failure. Am J
Physiol Renal Fluid Electrolyte Physiol. 2003;285:167-77.
117. Conger JD, Falk SA, Hammond WS. Atrial natriuretic peptide
and dopamine in established acute renal failure in the rat. Kidney
Int. 1991;40:21-8.
118. Allgren RL, Marbury TC, Rahman SN, Weisberg LS, Fenves
AZ, Lafayette RA, et al. Anaritide in acute tubular necrosis.
Auriculin Anaritide Acute Renal Failure Study Group. N Engl
J Med. 1997;336:828-34.
119. Hayashi Y, Ohtani M, Sawa Y, Hiraishi T, Akedo H, Kobayashi
Y, et al. Synthetic human alpha-atrial natriuretic peptide im-
proves the management of postoperative hypertension and renal
dysfunction after the repair of abdominal aortic aneurysm. J Car-
diovasc Pharmacol. 2003;42:636-41.
120. Kurnik BR, Allgren RL, Genter FC, Solomon RJ, Bates ER,
Weisberg LS. Prospective study of atrial natriuretic peptide for
the prevention of radiocontrast-induced nephropathy. Am J Kid-
ney Dis. 1998;3:674-80.
121. Lewis J, Salem MM, Chertow GM, Weisberg LS, McGrew F,
Marbury TC, et al. Atrial natriuretic factor in oliguric acute renal
failure. Anaritide Acute Renal Failure Study Group. Am J Kid-
ney Dis. 2000;36:767-74.
122. Sezai A, Shiono M, Orime Y, Hata H, Hata M, Negishi N, et al.
Low-dose continuous infusion of human atrial natriuretic pep-
tide during and after cardiac surgery. Ann Thorac Surg. 2000;
69:732-8.
123. Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK. Atrial
natriuretic peptide for preventing and treating acute kidney in-
jury. Cochrane Database Syst Rev. 2009;4:CD006028.
124. Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK. Atrial
natriuretic peptide for management of acute kidney injury: a
systematic review and meta-analysis. Clin J Am Soc Nephrol.
2009;4:261-72.
125. Nigwekar SU, Hix JK. The role of natriuretic peptide adminis-
tration in cardiovascular surgery-associated renal dysfunction: a
systematic review and meta-analysis of randomized controlled
trials. J Cardiothorac Vasc Anesth. 2009;23:151-60.
126. Simmons RS, Berdine GG, Seidenfeld JJ, Prihoda TJ, Harris
GD, Smith JD, et al. Fluid balance and the adult respiratory
distress syndrome. Am Rev Respir Dis. 1987;135:924-9.
127. Uchino S, Bellomo R, Morimatsu H, et al, for PAC/PiCCO
Use and Likelihood of Success Evaluation [PULSE] Study
Group. Pulmonary artery catheter versus pulse contour anal-
ysis: a prospective epidemiological study. Crit Care. 2006;
10:R174.
534
128. Seabra VF, Balk EM, Liangos O, Sosa MA, Cendoroglo M, Jaber
BL. Timing of renal replacement therapy initiation in acute renal
failure: a meta-analysis. Am J Kidney Dis. 2008;52:272-84.
129. Kondo CS, Macchionne M, Nakagawa NK, de Carvalho CR,
King M, Saldiva PH, et al. Effects of intravenous furosemide on
S.U. Nigwekar and S.S. Waikar
mucociliary transport and rheological properties of patients
under mechanical ventilation. Crit Care. 2002;6:81-7.
130. Yuengsrigul A, Chin TW, Nussbaum E. Immunosuppressive and
cytotoxic effects of furosemide on human peripheral blood mono-
nuclear cells. Ann Allergy Asthma Immunol. 1999;83:559-66.