1. Intensive Care Med (2010) 36:392–411
DOI 10.1007/s00134-009-1678-y EXPERT PANEL
Michael Joannidis
Wilfred Druml
Prevention of acute kidney injury
Lui G. Forni and protection of renal function
A. B. Johan Groeneveld
Patrick Honore in the intensive care unit
Heleen M. Oudemans-van Straaten
Claudio Ronco Expert opinion of the working group for nephrology, ESICM
Marie R. C. Schetz
Arend Jan Woittiez
A. B. J. Groeneveld expansion, diuretics, use
Received: 30 November 2008 Department of Intensive Care,
Accepted: 13 August 2009 of inotropes, vasopressors/vasodi-
Published online: 17 November 2009 VU Medical Center, Amsterdam, lators, hormonal interventions,
Ó Copyright jointly hold by Springer and The Netherlands
nutrition, and extracorporeal
ESICM 2009 techniques. Method: A systematic
P. Honore
This article is discussed in the editorial Department of Intensive Care, Burn Center, search of the literature was per-
available at: Queen Astrid Military Hospital, formed for studies using these
doi:10.1007/s00134-009-1683-1. Neder-Over-Heembeek (Brussels), Belgium potential protective agents in adult
Electronic supplementary material patients at risk for acute renal fail-
H. M. Oudemans-van Straaten ure/kidney injury between 1966 and
The online version of this article
Department of Intensive Care Medicine,
(doi:10.1007/s00134-009-1678-y) contains 2009. The following clinical condi-
supplementary material, which is available Onze Lieve Vrouwe Gasthuis, tions were considered: major
to authorized users. Amsterdam, The Netherlands
surgery, critical illness, sepsis,
C. Ronco shock, and use of potentially neph-
Department of Nephrology Dialysis and rotoxic drugs and radiocontrast
Transplantation, San Bortolo Hospital, media. Where possible the following
Viale Rodolfi 37, Vicenza, Italy endpoints were extracted: creatinine
M. R. C. Schetz clearance, glomerular filtration rate,
Department of Intensive Care Medicine, increase in serum creatinine, urine
University Hospital, Catholic University output, and markers of tubular
Leuven, Leuven, Belgium injury. Clinical endpoints included
the need for renal replacement
M. Joannidis ()) A. J. Woittiez therapy, length of stay, and mortal-
Medical Intensive Care Unit, Division of Nephrology, ity. Studies are graded according to
Department of Internal Medicine I, Department of Medicine,
Medical University Innsbruck, University Medical Center the international Grades of Recom-
Anichstasse, 31, 6020 Innsbruck, Austria Groningen, University of Groningen, mendation, Assessment,
e-mail: michael.joannidis@i-med.ac.at Groningen, The Netherlands Development, and Evaluation
Tel.: ?43-512-50424180 (GRADE) group system Conclusions
Fax: ?43-512-50424202 and recommendations: Several
Abstract Background: Acute measures are recommended, though
W. Druml renal failure on the intensive care none carries grade 1A. We recom-
Department of Internal Medicine III, unit is associated with significant
University Hospital Vienna, Vienna, Austria mortality and morbidity.
mend prompt resuscitation of the
circulation with special attention to
Objectives: To determine recom- providing adequate hydration whilst
L. G. Forni
Western Sussex Hospitals Trust, mendations for the prevention of avoiding high-molecular-weight
Brighton and Sussex acute kidney injury (AKI), focusing hydroxy-ethyl starch (HES) prepa-
Medical School, University of Sussex, on the role of potential preventa- rations, maintaining adequate blood
Brighton, UK tive maneuvers including volume

2. 393
pressure using vasopressors in media, and periprocedural hemofil- Recommendations Á Position paper Á
vasodilatory shock. We suggest tration in severe chronic renal Prevention Á Volume expansion Á
using vasopressors in vasodilatory insufficiency undergoing coronary Vasopressors Á Vasodilators Á
hypotension, specific vasodilators intervention. Diuretics Á Hormones Á APC Á
under strict hemodynamic control, Renal replacement therapy
sodium bicarbonate for emergency Keywords Acute kidney injury Á
procedures administering contrast Systematic review Á
Introduction primary renal disease (e.g., vasculitis), and the hepatorenal
syndrome were not considered.
Acute kidney injury (AKI) often complicates the course Search terms and text words are available in electronic
of critical illness and, although previously considered as supplementary material (ESM), as are the endpoints
a marker rather than a cause of adverse outcomes, it is extracted.
now known to the extent possible to be independently These recommendations are intended to provide
associated with an increase in both morbidity and mor- guidance for the clinician caring for a patient at risk of
tality [1–11]. The major causes of AKI in the intensive AKI. The process of developing these recommendations
care unit (ICU) include renal hypoperfusion, sepsis/sys- included a modified Delphi process, three nominal con-
temic inflammatory response syndrome (SIRS), and sensus conferences during the annual meetings of the
direct nephrotoxicity, although in most cases etiology is European Society of Intensive Care Medicine 2005 and
multifactorial [12–15]. Furthermore, epidemiological 2006, followed by electronic-based discussions. The
studies involving patients undergoing cardiothoracic quality of the evidence was judged by predefined Grades
surgery [16, 17] or contrast administration [18, 19] have of Recommendation, Assessment, Development, and
determined additional risk factors including age, preex- Evaluation (GRADE) criteria, which has also been
isting hypertension, diabetes mellitus, heart failure, and employed in developing the latest Surviving Sepsis
prolonged and complex surgery. It follows that mini- international guidelines [20]. This allows the develop-
mizing renal injury should confer a benefit to patients. ment and grading of management recommendations
This review is the result of an international collabo- through rating the quality of available evidence and
ration of the Critical Care Nephrology Working Group of grading strength of recommendations in clinical practice,
the European Society of Intensive Care Medicine as described in more detail elsewhere [21].
(ESICM) with the principal aim of providing a critical According to the GRADE system the strength of the
evaluation of available evidence and to give recommen- recommendations is classified as either strong (1) or weak (2)
dations, where possible, for clinical practice. We have [22]. A strong recommendation (1) indicates that an inter-
focused primarily on the role of volume expansion, vention’s desirable effects clearly outweigh undesirable
diuretics, inotropes, vasopressors/vasodilators, hormonal effects such as risk, cost, and other burdens. Weak recom-
interventions, nutrition, and extracorporeal techniques, mendations (i.e., suggestions) (2) indicate that the balance
which are the major interventions routinely and easily between undesirable and desirable effects is less clear.
undertaken in intensive care practice. The degree (i.e., quality) of evidence for the recom-
mendations is classified from high (A) to low (C)
according to factors including study design, consistency of
the results, and directness of the evidence [22]. We
Methods regarded repeated large RCTs including C50 patients in
each arm and meta-analyses showing low heterogeneity as
A systematic search of the literature was performed using providing a high degree of evidence (A) and smaller RCTs
the following databases: Medline (1966 through 2009, or larger RCTs whose results could not be reproduced as
April), Embase (1980 through 2009, week 15), CINAHL providing lower-grade evidence (B). For clinical decision-
(1982 through 2009, April), Web of Science (1955 through making, the grade of recommendation is considered of
2009), and PubMed/PubMed Central to identify key greatest clinical importance. It should, however, be
studies, preferably randomized placebo-controlled trials emphasized that there may be circumstances in which a
(RCT) and meta-analyses, on AKI/acute renal failure recommendation cannot or should not be followed for an
(ARF) addressing the use of therapeutic strategies to individual patient. Furthermore, interventions are gener-
prevent renal dysfunction in adult critically ill patients. ally investigated separately, not in combination, and as
The following clinical conditions were considered: major such recommendations relate to the primary intervention.
surgery, critical illness, sepsis, shock, and use of potentially Local clinical guidelines will govern the use of either a
nephrotoxic drugs and radiocontrast. Transplantation, single intervention or a combination.

3. 394
Volume expansion isolation risks hyperoncotic impairment of glomerular
filtration [31, 32] as well as osmotic tubular damage,
Recommendations particularly in sepsis [33–35].
1. We recommend controlled fluid resuscitation in true Commonly employed colloids include human albumin
or suspected volume depletion (grade 1C). (HA), gelatins, dextranes, and HES. HA may appear
2. There is little evidence-based support for the prefer- attractive in hypooncotic hypovolemia but is costly [36–
ential use of crystalloids, human serum albumin, 38]. A large multicenter RCT comparing 4% albumin
gelatine-derived colloids or the lowest-molecular- with crystalloid failed to demonstrate any difference in
weight hydroxy-ethyl starches (HES) for renal protec- outcome parameters including renal function, but proved
tion as long as derangements of serum electrolytes are that albumin itself was safe [39]. Gelatines have an
prevented. average molecular weight of ca. 30 kDa, and the observed
3. We recommend avoiding 10% HES 250/0.5 (grade 1B) intravascular volume effect is shorter than that observed
as well as higher-molecular-weight preparations of HES with HA or HES. Advantages include the lack of dele-
and dextrans in sepsis (grade 2C). terious effects on renal function [40, 41] offset by the
4. We recommend prophylactic volume expansion by possibility of prion transmission, histamine release, and
isotonic crystalloids in patients at risk of contrast coagulation problems, particularly if large volumes are
nephropathy (grade 1B). We suggest using isotonic infused [42, 43]. Dextrans are single-chain polysaccha-
sodium bicarbonate solution, especially for emergency rides comparable to albumin in size (40–70 kDa) and with
procedures (grade 2B). a reasonably high volume effect, although anaphylaxis,
5. We suggest prophylactic volume expansion with coagulation disorders, and indeed AKI may occur at doses
crystalloids to prevent AKI by certain drugs (specified higher than 1.5 g/(kg day) [44–47]. HES are highly
below) (grade 2C). polymerized sugar molecules characterized by molecular
weight, grade of substitution, concentration, and C2/C6
ratio. Their volume effect is greater than that of albumin,
Rationale especially when larger-sized polymers are employed
which degrade through hydrolytic cleavage the products
Both relative and overt hypovolemia are significant risk of which undergo renal elimination. These degradation
factors for the development of AKI [23–26]. Conse- products may be reabsorbed and contribute to osmotic
quently, timely fluid administration is a preventive nephrosis and possibly medullary hypoxia [35, 48]. A
measure which should be effective both through restora- further problem with HES may be tissue deposition and
tion of circulating volume and minimizing drug-induced associated pruritus, which appears to be dose dependent
nephrotoxicity [27]. Where volume replacement is indi- [49–51]. These adverse effects may be less pronounced in
cated, this should be performed in a controlled fashion the more modern, rapidly degradable HES solutions such
directed by hemodynamic monitoring, as injudicious use as HES 130/0.4 [52–54].
of fluids carries its own inherent risk [26]. In the ICU
patient this may manifest in several ways, including
prolonged mechanical ventilation [28] or the development Clinical studies
of intra-abdominal hypertension, which itself is a risk
factor for AKI [29]. Unsurprisingly, no studies have specifically addressed the
Volume replacement may employ 5% glucose (i.e., effects of volume expansion in overt hypovolemia com-
free water), crystalloids (isotonic, half-isotonic), colloids, pared with no volume resuscitation given the intuitive
or more commonly in clinical practice, a combination benefits of volume replacement. A large prospective
thereof. Glucose solutions substitute free water and are observational trial of the CRYCO (CRYstalloids or
used to correct hyperosmolar states, although the main- COlloids?) study group found an increased risk of AKI in
stay for correction of extracellular volume depletion 1,013 ICU patients with shock receiving either hyperon-
remains isotonic crystalloids. However, the increased cotic artificial colloids or albumin as compared with
chloride load may result in hyperchloremic acidosis and crystalloids [55]. This is in contrast to the results of a
associated renal vasoconstriction as well as altered per- large RCT comparing isotonic sodium chloride to human
fusion of other organs such as the gut [30]. Crystalloids serum albumin in various clinical settings, where no dif-
expand plasma volume by approximately 25% of the ferences in renal function were demonstrated [39] (ESM
infused volume, whereas colloid infusion results in a Table S1). Given the lack of a marked beneficial effect
greater expansion of plasma volume. The degree of the use of albumin should be limited given its expense.
expansion is dependent on concentration, mean molecular Small studies performed in the perioperative setting
weight, and (for HES) the degree of molecular substitu- have compared a variety of fluid replacement regimes
tion. However, large-volume replacement with colloids in (mainly between various forms of HES, or HES versus

4. 395
gelatine or albumin) with no definitive conclusions [56– for at least 6 h post procedure [69, 71–73, 75]. Although
60]. Only one RCT reported better preserved early post- three recent RCTs indicated that hydration with saline
operative renal function with 6% HES 130/0.4 than with or sodium bicarbonate were equally effective [76–78],
4% gelatine following cardiac surgery [61]. when included in meta-analyses a benefit of sodium
In patients undergoing low-risk surgery with normal bicarbonate over normal saline could still be detected
renal function, a small RCT comparing lactated Ringers’ [74, 79–81] (ESM Table S2). In a recent RCT of cardiac
solution to three different forms of HES demonstrated no surgical patients at risk for AKI, intravenous sodium
adverse effects of either solution [62]. bicarbonate was associated with a lower incidence of
In severe sepsis the beneficial effects of timely vol- acute renal dysfunction [82]. Nevertheless, adequately
ume replacement on organ failure and mortality are well powered RCTs are still needed to determine whether
known and are a cornerstone of the Surviving Sepsis sodium bicarbonate will reduce clinically meaningful
campaign guidelines [20, 63]. A single-center RCT outcomes.
comparing 5% HA with gelatine in ICU patients showed Hypovolemia may also contribute significantly
no difference in renal function despite significant dif- towards drug-induced renal injury, although the available
ferences in serum albumin levels [64]. A study evidence supporting preventative hydration is observa-
comparing 6% HES 200/0.5 with gelatine in ICU tional with no consensus found as to the timing, optimal
patients with sepsis demonstrated slightly lower serum volume, and type of solution to be employed [12]. Pre-
creatinine levels in the group receiving gelatine, but no vention of nephrotoxicity through prophylactic volume
effect was observed on endpoints such as the need for expansion has been shown to be of benefit with ampho-
renal replacement therapy (RRT) or mortality [41] (ESM tericin B, antivirals including foscarnet, cidofovir, and
Table S1). However, a large German RCT in patients adefovir [83–85], as well as drugs causing crystal
with septic shock (the VISEP trial) showed a higher nephropathy such as indinavir, acyclovir, and sulfadiazine
incidence of AKI, requirement for RRT, and mortality in [86].
the group treated with 10% HES 200/0.5 compared with
Ringer’s lactate [65]. Adverse effects on renal function
may be restricted to higher-molecular-weight HES, as a
multivariate analysis in a large European multicenter Diuretics
observational study was unable to detect HES as an
independent risk factor, neither in 1,970 ICU patients Recommendations
requiring RRT nor in a subgroup of 822 patients with 1. We recommend that loop diuretics are not used to
severe sepsis [66]. prevent or ameliorate AKI (grade 1B).
Prophylactic volume expansion has been investigated
extensively in the setting of contrast-induced nephrop-
athy (CIN) [67–72]. The benefit of this measure has Rationale
been mainly shown for patients with inherent risk fac-
tors of CIN such as reduced glomerular filtration rate Oligo-anuria frequently is the first indicator of acute renal
(GFR) (50 ml/min/1.73 m2), heart failure or diabetes dysfunction. A multinational survey has demonstrated
characterized by various risk scores (e.g., Thakar score that 70% of intensivists used loop diuretics in a wide
[18] or Mehran score [19]). The first RCT comparing spectrum of AKI settings [87]. There may indeed be some
protection in CIN by half normal saline versus half theoretical attractions in using diuretics to ameliorate
normal saline plus diuretic therapy clearly demonstrated AKI, including prevention of tubular obstruction, reduc-
the superiority of volume expansion by half normal tion in medullary oxygen consumption, and increase in
saline at a rate of 1 ml/kg 12 h before and after angi- renal blood flow [88–90].
ography [67]. However, a larger RCT including 1,620
patients undergoing coronary angioplasty showed a
lower incidence of CIN when using normal saline
compared with half normal saline [68]. Given that Clinical studies
normal saline contains a high amount of chloride, the
protective effect of isotonic bicarbonate solutions (con- Few prospective randomized trials have addressed the
taining 150–154 mmol/l sodium) in patients with role of diuretics in the prevention of AKI. Most of the
impaired renal function receiving contrast agents has available studies have been done in the setting of contrast
been studied. This showed a significant reduction in the administration [67, 91, 92] and cardiac surgery [93, 94].
incidence of CIN [69–75], but not in the need of renal No protection against contrast nephropathy has been
replacement therapy or mortality. Most investigations observed with diuretics, and in cardiac surgery, higher
applied a hydration regimen starting at 3(–5) ml/(kg h) postoperative serum creatinine levels were found in
1 h before radiocontrast application, followed by 1 ml/(kg h) patients receiving furosemide [93, 94].

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To date four randomized controlled trials have Clinical studies
examined the role of diuretics in established renal fail-
ure in the intensive care setting. No demonstrable Low-dose or ‘‘renal-dose’’ dopamine has been advocated
improvement in primary outcome parameters, such as in the past to prevent selective renal vasoconstriction in a
recovery of renal function or mortality, has been variety of conditions [107]. Although dopamine infusion
observed [35, 95–97]. Other studies have compared may improve renal perfusion in healthy volunteers, no
diuretics with dopamine or against placebo, again with improvement of renal perfusion nor preventive benefit
no perceived benefit [33, 98, 99]. Three meta-analyses with respect to renal dysfunction has been unequivocally
confirmed that the use of diuretics in established AKI demonstrated in the critically ill, where increased sym-
does not alter outcome but carries a significant risk of pathetic activity and local norepinephrine release may
side-effects such as hearing loss [100–102] (ESM contribute to renal vasoconstriction [108–110]. Dopamine
Table S3). Furthermore, in an international cohort study also has an inotropic effect, but observed increases in
an increase in the risk of death or an increase in diuresis or even a reduction in serum creatinine during
established renal failure was observed. These findings, dopamine infusion does not protect against AKI [107,
however, could not be confirmed in a second cohort 110, 111]. Several meta-analyses have concluded that
study [103, 104]. ‘‘renal-dose’’ dopamine is of no benefit in either pre-
venting or ameliorating AKI in the critically ill and may
even promote AKI [107, 109, 112].
The inotropic agents dobutamine and dopexamine
Vasopressors and inotropes have also been examined, but to date no prospective
controlled clinical trial has demonstrated a protective
Recommendations effect on renal function [113]. In contrast, the effect of
1. We recommend that mean arterial pressure (MAP) be dobutamine on renal function is variable, even when
maintained C60–65 mmHg (grade 1C), however, tar- favorably affecting cardiac output [111].
get pressure should be individualized where possible, Norepinephrine is known to be of use in the treatment
especially if knowledge of the premorbid blood pres- of vasodilatory shock after adequate fluid loading. In
sure is available. nonrandomized studies, administration of norepinephrine
2. In case of vasoplegic hypotension as a result of sepsis and resulting increases in arterial blood pressure have
or SIRS we recommend either norepinephrine or shown to increase diuresis and creatinine clearance [114].
dopamine (along with fluid resuscitation) as the first- Whether this is due to increased renal perfusion and thus
choice vasopressor agent to correct hypotension implies renal protection is unknown. A RCT on 252 adult
(grade 1C). patients comparing dopamine in septic shock with nor-
3. We recommend that low-dose dopamine not be used epinephrine as the initial vasopressor showed no
for protection against AKI (grade 1A). significant differences between groups with regard to
renal function or mortality. Though norepinephrine was
associated with significantly less sinus tachycardia and
Rationale arrhythmias (Patel GP et al., Shock, in press).
Vasopressin is gaining popularity in the treatment of
Preservation or improvement of renal perfusion can the- norepinephrine-refractory shock [115] increasing blood
oretically be achieved by fluid resuscitation, through renal pressure and enhancing diuresis in hypotensive oliguric
vasodilators, by systemic vasopressors that redirect blood patients but as yet has not been proven to enhance survival
flow to the kidney or by increasing cardiac output through nor to prevent or ameliorate AKI in the critically ill [116].
the use of inotropic drugs. Whereas a recent study indi-
cated that any MAP of C60 mmHg may be considered
adequate for patients with septic shock [105], additional
benefits with regards to renal function were not observed Vasodilators
when a target MAP of more than 85 mmHg was compared
to a target of 65 mmHg [106]. However, it must be borne Recommendations
in mind that this study may not be widely applicable to 1. We suggest using vasodilators for renal protection
the patients admitted to the intensive care unit with pre- when volume status is corrected and the patient is
existing comorbidities. Those at greatest risk of closely hemodynamically monitored with particular
developing AKI include those patients with vascular regard to the development of hypotension (grade 2C).
disease, hypertension, diabetes, increased age, and ele- When choosing a vasodilator, the clinical condition of
vated intra-abdominal pressure, for whom the target mean the patient, the availability of the drug, and the con-
arterial pressures may have to be individually tailored. comitant interventions should be considered.

6. 397
2. We suggest the prophylactic use of fenoldopam, if fenoldopam has been studied during surgery and follow-
available, in cardiovascular surgery patients at risk of ing administration of radiocontrast. A meta-analysis
AKI (grade 2B). We recommend that fenoldopam is including 1,059 patients undergoing cardiovascular sur-
not used for prophylaxis of contrast nephropathy gery found that fenoldopam consistently and significantly
(grade 1A). reduced the need for RRT and in-hospital mortality [125].
3. We suggest using theophylline to minimize risk of A second meta-analysis including 1,290 critically ill and
contrast nephropathy, especially in acute interventions surgical patients from 16 randomized studies reported that
(grade 2C) when hydration is not feasible. the use of fenoldopam reduced the incidence of acute
4. We suggest that natriuretic peptides are not used as renal injury, need for RRT, and hospital mortality [126].
protective agents against AKI in critically ill patients However, none of the larger RCTs showed that using
(grade 2B), while its use may be considered during fenoldopam for the prevention of contrast nephropathy
cardiovascular surgery (grade 2B). confers renal protection [127, 128] (studies summarized
in ESM Table S4).
Clonidine is a central and peripheral adrenergic-
Rationale receptor blocking agent with predominantly a2 blocking
effects which also reduces plasma renin levels. Two
Reduced tissue perfusion elicits neurohumoral activation RCTs, again involving cardiothoracic patients demon-
leading to increased sympathetic tone, endothelin pro- strated some beneficial effects of clonidine on renal
duction, and activation of the renin–angiotensin– function [129, 130]. However, the use of b-blockers as
aldosterone system which maintains systemic blood part of current practice is not mentioned in these studies
pressure often at the cost of both splanchnic and renal (ESM Table S5).
vasoconstriction. Glomerular perfusion and filtration Anaritide (ANP) is produced by cardiac atria in
pressure are maintained through afferent arteriolar vaso- response to atrial dilatation and induces afferent glomer-
dilatation and efferent vasoconstriction, but once these ular dilatation and efferent vasoconstriction as well as
compensatory mechanisms fail, a decline in glomerular increasing urinary sodium excretion, renal blood flow,
filtration ensues. This critical threshold for renal perfusion and GFR in early ischemic AKI with a dose-dependent
depends on the ability of compensatory intrarenal vaso- hypotensive effect [131]. Ularitide and nesiritide (brain
dilatation. It is increased, for example, with chronic natriuretic peptide, BNP) have similar effects. The first
hypertension and high venous pressure states and large RCT evaluating ANP in AKI found a reduction of
decreased by endogenous or exogenous vasodilators RRT in the oliguric subgroup only [132]. Disappointing
[117–121]. In circumstances of persistent renal vasocon- results were subsequently observed in RCTs of anaritide
striction, vasodilators might have a beneficial effect on and ularitide in patients with oliguric AKI [133–135]. In
kidney function. However, the use of vasodilators may contrast, a RCT in post cardiac surgery patients with heart
cause hypotension by counteracting compensatory vaso- failure and early renal dysfunction demonstrated that use
constriction, thus unmasking occult hypovolemia, and as of continuous low-dose anaritide significantly reduced the
such the correction of hypovolemia is crucial. need for RRT [136]. The effect of nesiritide was even
more pronounced in cardiac surgery patients with reduced
ejection fraction (NAPA trial), demonstrating shorter
Clinical studies hospital stay and reduced 180-day mortality [137]. The
observed differences might be explained by differences in
Fenoldopam is a pure dopamine A-1 receptor agonist. dose and duration of drug administration with a conse-
Three RCTs have evaluated the effects of continuous quent reduction in hypotension observed. Similarly,
infusion of fenoldopam on renal function in critically ill protective effects on renal function were observed with
patients with AKI and observed mixed results [122–124]. low-dose nesiritide in elective abdominal aneurysm repair
Two compared fenoldopam with placebo, and one with [138] and in cardiac bypass surgery [139]. Of note, a
dopamine. In one, fenoldopam was found to be beneficial recent meta-analysis comparing non-inotrope-based
with regard to the primary endpoints of dialysis-free treatment with nesiritide (h-BNP) therapy indicated that
survival at 21 days and need of RRT in the selected this may be associated with an increased risk of renal
subgroups of patients without ‘‘diabetes mellitus’’ or failure and death in a select population of patients with
‘‘after cardiac surgery’’ [124]. In another, fenoldopam acutely decompensated heart failure [140] (ESM
caused a significant decrease in mild AKI (defined as a Table S6).
rise in serum creatinine [150 lmol/L) and ICU stay, and Phosphodiesterase (PDE) inhibitors have both vasod-
a nonsignificant decrease in severe AKI (serum creatinine ilatory and inotropic effects and modulate the
[300 lmol/L) [123]. In the third, infusion of fenoldo- inflammatory response, rendering them interesting can-
pam, but not dopamine, over 4 days significantly reduced didates for the prevention of renal damage. Ten controlled
serum creatinine [122]. Prophylactic administration of trials evaluating the effect of theophylline on the

7. 398
prevention of contrast nephropathy showed varying effi- applying a local protocol which has proven efficacy in
cacy in attenuating increases in serum creatinine after minimizing rate of hypoglycemia.
administration of radiocontrast media [141–151]. The 2. We suggest not to use thyroxine (grade 2C), erythro-
results of three successive meta-analyses remained poietin (grade 2C), activated protein C (grade 2C) or
inconclusive [142, 147, 152]. However, a more recent steroids (grade 2C) routinely to prevent AKI.
trial has demonstrated a reduction in the incidence of
contrast nephropathy by preprocedural administration of
200 mg theophylline in critically ill patients [151]. Rationale
Anticipated adverse events such as arrhythmias were not
observed (ESM Table S7). The effects of blood glucose control with insulin on the
Pentoxifylline has been examined in low risk cardio- development or progression of nephropathy in patients
thoracic patients with no benefit [153] but other small with type I and type II diabetes is well documented [166].
studies examined populations at higher risk and demon- In animal models, insulin-like growth factor 1 (IGF-1) has
strated beneficial effects on both preservation of renal been shown to accelerate recovery from ischemic and
function and clinical outcomes [154, 155]. cisplatin-induced AKI [167–169], through either renal
Enoximone is a selective phosphodiesterase III hemodynamic actions or through a direct metabolic,
inhibitor with both vasodilatory and anti-inflammatory mitogenic, and antiapoptotic effect on injured tubular
properties. Two small studies in cardiac surgery have cells. Thyroid hormone has also been seen to accelerate
evaluated the effect of enoximone, with one study com- renal recovery in various animal models of AKI [170,
bining enoximone with the b-blocker esmolol [156, 157]. 171]. There is increasing experimental evidence from
Both demonstrated a reduction in post-bypass inflamma- ischemia/reperfusion models that erythropoietin (EPO)
tion and renal protective effects, although the studies were reduces apoptotic cell death and induces tubular prolif-
not designed to show effects on clinical outcomes. eration [172–175]. A retrospective clinical study also
A new phosphodiesterase inhibitor with myocardial showed a slowing of the progression of chronic renal
calcium sensitizer activity, levosimendan, has recently failure in predialysis patients [176]. However, erythro-
been approved for the treatment of congestive cardiac poietin in high doses may induce renal vasoconstriction,
failure. A small RCT in 80 patients with acute decom- systemic hypertension, increase the risk of thrombosis,
pensated heart failure demonstrated short-term and increase tumor burden, limiting clinical applicability
improvement of renal function as measured by eGFR [177]. New derivatives of EPO that are devoid of hema-
which could not be achieved by dobutamine alone [158]. topoietic activity may be safer [178].
The compensatory release of the vasodilator prosta- Activated protein C (APC) has pleiotropic actions
glandin PGE1 contributes to the maintenance of renal including anticoagulation, profibrinolysis, anti-inflamma-
perfusion through dilatation of both the afferent arteriole tion, and antiapoptosis activity, and may therefore be an
and medullary vessels in renal hypoperfusion. Three ideal candidate to prevent ischemia/reperfusion-induced
clinical studies showed a mild protective effect of vaso- organ failure. Indeed, animal models of ischemia/reper-
dilator prostaglandins (PGE1/PGI2) [159–161]. fusion and sepsis have documented beneficial effects on
Angiotensin blockade may have renal protective kidney function [179–182].
effects in the acute setting; for example, angiotensin
blockade augments renal cortical microvascular PO2
[162] and restores endothelial dysfunction [163]. Two Clinical studies
studies evaluating the effect of short-term intravenous
enalaprilat in a cardiac surgical population with poor A large prospective randomized controlled trial in 1,548
cardiac function demonstrated improved cardiac and renal surgical ICU patients compared tight blood glucose
function [164, 165]. control with insulin (blood glucose 80–110 mg/dL)
versus standard care (insulin therapy when blood glu-
cose [200 mg/dL resulting in mean blood glucose of
150–160 mg/dL) and showed not only an improved sur-
Hormonal manipulation and activated protein C vival rate but also a 41% reduction in AKI requiring RRT.
Additionally, tight glucose control also reduced by
Recommendations 27% the number of patients with peak plasma creatinine
1. We recommend against the routine use of tight gly- [2.5 mg/dL [183]. A similar study was undertaken in the
cemic control in the general ICU population medical ICU of the same hospital where tight blood
(grade 1A). We suggest ‘‘normal for age’’ glycemic glucose control again improved survival of prolonged
control with intravenous (IV) insulin therapy to pre- ICU stay but had no effect on the need for RRT.
vent AKI in surgical ICU patients (grade 2C), on However, there was a 34% reduction in newly acquired
condition that it can be done adequately and safely renal injury, defined as a doubling of serum creatinine

8. 399
compared with the admission level [184]. A combined baseline. In patients with normal renal function at base-
analysis of the two clinical trials, using modified Rifle line there was also no effect on the development of renal
criteria, showed a more pronounced renal protection when impairment [198].
normoglycemia was achieved. The absence of a reduction No RCT has evaluated the effect of erythropoietin in
in the need for RRT in medical patients could be AKI. A RCT trial on EPO in critically ill patients showed
explained by the higher illness severity with more renal no difference in the incidence of AKI (mentioned as an
dysfunction on admission, precluding an impact of this adverse event, not as an outcome parameter) [199]. A
mainly protective intervention [185]. Two large sequen- retrospective cohort study in 187 critically ill patients
tial cohort studies, one in a medical-surgical ICU [186] requiring RRT used a propensity-adjusted analysis and
and the other in the setting of cardiac surgery [187], also found an improvement in renal recovery in patients
revealed a significant reduction in observed renal dys- administered EPO [198].
function after the implementation of tight glycemic
control. Finally, a recent meta-analysis indicated that
survival benefit by applying tight glycemic control, if any,
may be restricted only to patients in surgical ICUs [188]. Metabolic interventions
More recent randomized trials in septic [65] and
general [189, 190] ICU patients and a meta-analysis [191] Recommendations
do not confirm the renoprotective effect of intensive 1. We suggest that all patients at risk of AKI have ade-
insulin therapy as evaluated by the need for RRT only. quate nutritional support, preferably through the
A major obstacle to the broad implementation of tight enteral route (grade 2C).
glycemic control is the increased risk of hypoglycemia. If 2. We suggest that N-acetylcysteine is not used as
the clinician decides to adopt tight glycemic control then prophylaxis against contrast induced nephropathy or
steps should be taken to ensure that fluctuations in glucose other forms AKI in critically ill patients because of
levels are minimized and standardized and that reliable conflicting results, possible adverse reactions, and
tools to measure blood glucose are employed [192]. An better alternatives (grade 2B).
important concern is the fact that the NICE-Sugar trial 3. We recommend against the routine use of selenium to
found a higher mortality in patients treated with tight protect against renal injury (grade 1B).
glycemic control compared with an intermediate level,
which was found independent from hypoglycemia [190].
The clinician should, however, be aware of important Rationale
differences between the Leuven and the NICE-Sugar trial
[192] (ESM Table S8). Metabolic factors are crucial for maintaining cellular
The use of IGF-1 has not been exposed to as much integrity and organ function, and nutrition is a basic
scrutiny. A multicenter RCT in 72 patients with AKI requirement in the care of any critically ill patients.
failed to show an effect of IGF-1 on renal recovery [193]. Starvation accelerates protein breakdown and impairs
A small RCT of IGF-1 administered postoperatively in 54 protein synthesis in the kidney, whereas refeeding might
patients undergoing vascular surgery versus placebo did exert the opposite effects and promote renal regeneration.
reveal a lower proportion of patients developing renal For example, in animal experiments increased protein
dysfunction (fall in GFR compared with baseline), but no intake has been shown to reduce tubular injury [200, 201].
difference in need for dialysis or creatinine at discharge Arginine (possibly by producing nitric oxide) helps to
was observed [194]. preserve renal perfusion and tubular function in both
The role of thyroxine has been examined in one RCT nephrotoxic and ischemic models of AKI. However,
in 59 patients with AKI. No effect of thyroxine on any amino acids infused before or during ischemia may also
measure of AKI severity compared with placebo was enhance tubular damage and accelerate loss of renal
found [195]. function [202]. In part, this ‘‘amino acid paradox’’ is
With regard to the use of corticosteroids for renal related to the increase in metabolic work for transport
protection one small RCT (n = 20) has been performed processes which may aggravate ischemic injury. How-
on patients undergoing on-pump cardiothoracic surgery. ever, amino acids per se do not exert intrinsic nephrotoxic
This failed to demonstrate any effect of dexamethasone effects.
on the transient renal impairment observed in the post- One aspect of nutrition is the adequate supply of
operative period [196]. nutritional cofactors and antioxidant. The role of reactive
Treatment with APC reduces mortality of patients oxygen species (ROS) under both normal and pathologi-
with severe sepsis [197]. A post hoc analysis of secondary cal conditions has undergone much scrutiny with the
endpoints of this trial, however, failed to show an effect NAD(P)H oxidase system believed to be pivotal in their
on the resolution of renal failure (measured with the formation and instrumental in the development of certain
SOFA score criteria) in patients with renal dysfunction at pathophysiological conditions in the kidney [203–206].

9. 400
Under certain specific circumstances a role for antioxidant benefit when combined with hydration, with multivariate
supplementation may be proposed, with potential candi- analysis confirming age, volume of contrast, diabetes, and
dates being the modified form of cysteine, N-acetylcysteine peripheral vascular disease as significant factors for CIN
(NAC), the antioxidant vitamins [vitamin E (a-tocopherol) development [232]. However, no benefit was observed in
and vitamin C (ascorbic acid)], as well as selenium and studies using NAC in vascular patients [233, 234] nor in
other novel antioxidants. diabetic patients when compared with hydration alone
[235]. Several recent studies have employed the use of
NAC with other agents such as bicarbonate [236, 237],
Clinical studies hydration, and theophylline, with mixed results [70, 151,
237–240].
Protein(s) and amino acids, including glutamine, augment Several RCTs examining the role of NAC to prevent
renal perfusion and improve renal function, a fact which renal dysfunction in other high-risk groups did not dem-
was termed ‘‘renal reserve capacity’’ [207]. However, this onstrate a beneficial effect of NAC regarding renal
potential beneficial effect has received little attention in dysfunction or need for renal support [241–245] (ESM
terms of prevention and therapy of AKI to date. Intrave- Table S9), although one study in 177 patients found a
nous amino acids appear to improve renal plasma flow mortality benefit for the patients treated with NAC [246].
and glomerular filtration rate in cirrhotic patients with It must be considered, though, that especially IV NAC
functional renal failure [208]. One study has reported on a may be harmful, leading to allergic reactions [247] or
positive effect of enteral versus parenteral nutrition on thedecreased cardiac output or survival in patients with
resolution of AKI [209]. septic shock [248, 249].
Most studies on antioxidants have centered on NAC, A recent single-center trial showed a protective effect
which besides being an antioxidant, also has a vasodila- of oral ascorbic acid on the development of contrast
tory effect [210]. NAC undergoes rapid first-pass nephropathy [250]. Here too, the rate of nephropathy in
metabolism through deacylation and as a result its bio- the control group was high and no patients required renal
availability is low even following IV administration. support. Two further studies investigating protection
There is no evidence that administration of NAC increa- against contrast nephropathy could not prove protective
ses glutathione concentrations in the kidney [211, 212]. effects of ascorbic acid [72, 251].
NAC has mainly been studied in the setting of contrast There have been several studies on antioxidant sup-
nephropathy following the initial publication by Tepel plementation in the ICU, although few large studies have
et al. [213] which provided the catalyst for the subsequent been conducted. The use of an antioxidant cocktail in
proliferation of similar studies [127, 213–222]. This patients undergoing elective aortic aneurysm repair
subject continues to generate much research and has led resulted in an increased creatinine clearance on the sec-
to several meta-analysis [152, 223–228] (ESM Table S9). ond postoperative day but the incidence of renal failure
Most report a risk reduction, although study heterogeneity was very low [252].
and positive reporting bias somewhat hinders definitive A a small RCT in 42 patients showed that selenium
recommendations [229]. However, studies demonstrating supplementation decreased the requirement for RRT from
a positive effect have a higher incidence of CIN in the 43% to 14% [253]. These findings, however, could not be
control arms, reflecting differences in risk profile, the reproduced in a larger RCT using selenium in 249
route of NAC administration, the dose, the timing (with patients with sepsis (SIC study) [254, 255]. More recent
earlier dosing perhaps being more efficacious), and the studies in the critically ill demonstrated that, although
total contrast load given. Importantly, some investigators selenium supplementation increased both selenium and
suggest that the reduction in serum creatinine with NAC glutathione peroxidase levels, there was no effect on the
may be a direct effect of the drug on the creatinine requirement for RRT [256].
measurement and does not reflect a decrease of GFR,
although subsequent work has not replicated these find-
ings when serum creatinine is measured via the Jaffe
method [230, 231]. An issue of concern is also the fact Extracorporeal therapies
that the endpoint used in all the studies is a change
in creatinine and not clinically relevant endpoints such as Recommendations
a need for RRT, length of stay or death. This is corrob- 1. We suggest periprocedural continuous veno-venous
orated by a recent study where contrast-induced AKI was hemofiltration (CVVH) in an ICU environment to limit
not independently associated with death and had no effect contrast nephropathy after coronary interventions in
on other clinical events [6, 219]. In patients stratified as high-risk patients with advanced chronic renal insuf-
high or low risk based on GFR, NAC conferred some ficiency (grade 2C).

10. 401
Rationale cases of ethylene glycol intoxication as well as rasburi-
case following adequate volume expansion in order to
Extracorporeal therapies may protect the kidney by prevent tumor lysis syndrome before consideration of
removal of substance(s) such as contrast, particularly in extracorporeal therapy. Similarly, the use of extracorpo-
patients with chronic renal insufficiency, because of the real techniques to remove myoglobin will require
higher contrast load delivered to the remaining nephrons. membranes with a high cutoff [266], possibly used in
The relative amount of contrast removal by hemofiltration series for a minimal duration of 6 h, which is not readily
depends on the pore size of the filter [257], on hemofil- available [267–273]. Four studies have evaluated leuk-
tration dose, and on residual renal function. Control of odepletion during cardiopulmonary bypass [274–277],
homeostasis or maintenance of fluid balance may be with three suggesting a beneficial effect on renal function
equally important. [274–276].
Clinical studies
Conclusions and summary
Several studies have employed renal replacement tech-
niques in an attempt to limit contrast nephropathy. One of the major problems with any review discussing
Amongst those, three studies utilized periprocedural AKI is the fact that definitions used in many publications
hemodialysis, with variable benefit [258–261]. Prophy- vary largely. As a consequence comparing studies is
lactic CVVH was evaluated in a total of 114 patients at fraught with difficulties and calls for uniformly applicable
high risk of contrast nephropathy undergoing coronary indicators of severity of renal dysfunction, such as dura-
intervention. The intervention group had a significantly tion and degree of oliguria as well as dependence on renal
reduced mortality as well as a reduced need for continued replacement techniques. Fortunately, initiatives in this
renal support, particularly in those with baseline creatinine direction have recently been taken and should aid further
[300 lmol/l [262]. The same author performed a sec- study [5, 278].
ond RCT in 92 patients, which demonstrated that only In order to prevent AKI, prompt resuscitation of the
combined pre- and postprocedural CVVH, and not post- circulation with fluids, inotropes, vasoconstrictors and/or
procedural CVVH alone, had any renoprotective effect vasodilators is the primary aim and is recommended.
[263]. It should be emphasized that the patients receiving Volume expansion is recommended for the prevention of
CRRT were treated in ICU and those receiving hydration AKI in states of true and suspected hypovolemia, but
alone were not, which raises the question of whether the uncontrolled volume expansion and the use of high-
hemofiltration procedure itself or the preprocedural opti- molecular-weight HES preparations and dextrans should
mization in the ICU environment led to a better outcome. be avoided. Following volume resuscitation hypotensive
Other mechanisms such as pre- and periprocedural patients should be given a vasoconstrictor which should
hydration during CVVH, correction of acidosis or control be titrated individually, with a mean target blood pres-
of fluid balance might be relevant [264, 265]. sure of 60–65 mmHg being adequate in most
Renal replacement techniques have also been used to individuals. Vasodilators are recommended if optimiza-
ameliorate myoglobin-induced tubular damage in rhab- tion of cardiac output or reduction in hypertension is
domyolysis or to remove oxalate following ethylene required, and some dilators may be considered to pre-
glycol ingestion. Finally, prophylactic use of extracor- vent deterioration of renal function under strict
poreal treatments in oncology patients at high risk of hemodynamic control. Together with these measures a
tumor lysis syndrome has been reported. This available review of all medications, with the cessation of those
literature is limited to case reports and small case series known to be nephrotoxic (e.g., amphotericin B, amino-
and no recommendation can be drawn. However, it should glycosides), is mandatory.
be emphasized that fomepizole should be used as a first-
line treatment before attempting extracorporeal therapy in
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