prevencion de la IRA y proteccion de la Funcion renal en la Uci
Intensive Care Med (2010) 36:392–411DOI 10.1007/s00134-009-1678-y EXPERT PANELMichael JoannidisWilfred Druml Prevention of acute kidney injuryLui G. Forni and protection of renal functionA. B. Johan GroeneveldPatrick Honore in the intensive care unitHeleen M. Oudemans-van StraatenClaudio Ronco Expert opinion of the working group for nephrology, ESICMMarie R. C. SchetzArend Jan Woittiez A. B. J. Groeneveld expansion, diuretics, useReceived: 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 extracorporealESICM 2009 techniques. Method: A systematic P. HonoreThis 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 thesedoi:10.1007/s00134-009-1683-1. Neder-Over-Heembeek (Brussels), Belgium potential protective agents in adultElectronic supplementary material patients at risk for acute renal fail- H. M. Oudemans-van Straaten ure/kidney injury between 1966 andThe 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: majorto 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 replacementM. Joannidis ()) A. J. Woittiez therapy, length of stay, and mortal-Medical Intensive Care Unit, Division of Nephrology, ity. Studies are graded according toDepartment 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: firstname.lastname@example.org Groningen, The Netherlands Development, and EvaluationTel.: ?43-512-50424180 (GRADE) group system ConclusionsFax: ?43-512-50424202 and recommendations: Several Abstract Background: Acute measures are recommended, thoughW. Druml renal failure on the intensive care none carries grade 1A. We recom-Department of Internal Medicine III, unit is associated with signiﬁcantUniversity Hospital Vienna, Vienna, Austria mortality and morbidity. mend prompt resuscitation of the circulation with special attention to Objectives: To determine recom- providing adequate hydration whilstL. G. ForniWestern Sussex Hospitals Trust, mendations for the prevention of avoiding high-molecular-weightBrighton 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 bloodBrighton, UK tive maneuvers including volume
393pressure using vasopressors in media, and periprocedural hemoﬁl- Recommendations Á Position paper Ávasodilatory shock. We suggest tration in severe chronic renal Prevention Á Volume expansion Áusing vasopressors in vasodilatory insufﬁciency undergoing coronary Vasopressors Á Vasodilators Áhypotension, speciﬁc vasodilators intervention. Diuretics Á Hormones Á APC Áunder strict hemodynamic control, Renal replacement therapysodium bicarbonate for emergency Keywords Acute kidney injury Áprocedures administering contrast Systematic review ÁIntroduction 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 electronicof critical illness and, although previously considered as supplementary material (ESM), as are the endpointsa 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 provideassociated with an increase in both morbidity and mor- guidance for the clinician caring for a patient at risk oftality [1–11]. The major causes of AKI in the intensive AKI. The process of developing these recommendationscare 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 thedirect nephrotoxicity, although in most cases etiology is European Society of Intensive Care Medicine 2005 andmultifactorial [12–15]. Furthermore, epidemiological 2006, followed by electronic-based discussions. Thestudies involving patients undergoing cardiothoracic quality of the evidence was judged by predeﬁned Gradessurgery [16, 17] or contrast administration [18, 19] have of Recommendation, Assessment, Development, anddetermined additional risk factors including age, preex- Evaluation (GRADE) criteria, which has also beenisting hypertension, diabetes mellitus, heart failure, and employed in developing the latest Surviving Sepsisprolonged and complex surgery. It follows that mini- international guidelines . 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 andration 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 .(ESICM) with the principal aim of providing a critical According to the GRADE system the strength of theevaluation 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 . A strong recommendation (1) indicates that an inter-focused primarily on the role of volume expansion, vention’s desirable effects clearly outweigh undesirablediuretics, 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 balancewhich 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 . WeMethods regarded repeated large RCTs including C50 patients in each arm and meta-analyses showing low heterogeneity asA systematic search of the literature was performed using providing a high degree of evidence (A) and smaller RCTsthe following databases: Medline (1966 through 2009, or larger RCTs whose results could not be reproduced asApril), 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 of2009), and PubMed/PubMed Central to identify key greatest clinical importance. It should, however, bestudies, 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 asThe 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 anephrotoxic drugs and radiocontrast. Transplantation, single intervention or a combination.
394Volume 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 appear2. 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 . Gelatines have an prevented. average molecular weight of ca. 30 kDa, and the observed3. 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 the4. 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 productsBoth relative and overt hypovolemia are signiﬁcant risk of which undergo renal elimination. These degradationfactors for the development of AKI [23–26]. Conse- products may be reabsorbed and contribute to osmoticquently, timely ﬂuid administration is a preventive nephrosis and possibly medullary hypoxia [35, 48]. Ameasure which should be effective both through restora- further problem with HES may be tissue deposition andtion of circulating volume and minimizing drug-induced associated pruritus, which appears to be dose dependentnephrotoxicity . Where volume replacement is indi- [49–51]. These adverse effects may be less pronounced incated, this should be performed in a controlled fashion the more modern, rapidly degradable HES solutions suchdirected by hemodynamic monitoring, as injudicious use as HES 130/0.4 [52–54].of ﬂuids carries its own inherent risk . In the ICUpatient this may manifest in several ways, includingprolonged mechanical ventilation  or the development Clinical studiesof intra-abdominal hypertension, which itself is a riskfactor for AKI . 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 intuitiveor more commonly in clinical practice, a combination beneﬁts of volume replacement. A large prospectivethereof. Glucose solutions substitute free water and are observational trial of the CRYCO (CRYstalloids orused to correct hyperosmolar states, although the main- COlloids?) study group found an increased risk of AKI instay 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 withchloride load may result in hyperchloremic acidosis and crystalloids . This is in contrast to the results of aassociated renal vasoconstriction as well as altered per- large RCT comparing isotonic sodium chloride to humanfusion of other organs such as the gut . Crystalloids serum albumin in various clinical settings, where no dif-expand plasma volume by approximately 25% of the ferences in renal function were demonstrated  (ESMinfused volume, whereas colloid infusion results in a Table S1). Given the lack of a marked beneﬁcial effectgreater 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 settingweight, and (for HES) the degree of molecular substitu- have compared a variety of ﬂuid replacement regimestion. However, large-volume replacement with colloids in (mainly between various forms of HES, or HES versus
395gelatine or albumin) with no deﬁnitive conclusions [56– for at least 6 h post procedure [69, 71–73, 75]. Although60]. Only one RCT reported better preserved early post- three recent RCTs indicated that hydration with salineoperative renal function with 6% HES 130/0.4 than with or sodium bicarbonate were equally effective [76–78],4% gelatine following cardiac surgery . when included in meta-analyses a beneﬁt of sodium In patients undergoing low-risk surgery with normal bicarbonate over normal saline could still be detectedrenal function, a small RCT comparing lactated Ringers’ [74, 79–81] (ESM Table S2). In a recent RCT of cardiacsolution to three different forms of HES demonstrated no surgical patients at risk for AKI, intravenous sodiumadverse effects of either solution . bicarbonate was associated with a lower incidence of In severe sepsis the beneﬁcial effects of timely vol- acute renal dysfunction . Nevertheless, adequatelyume replacement on organ failure and mortality are well powered RCTs are still needed to determine whetherknown and are a cornerstone of the Surviving Sepsis sodium bicarbonate will reduce clinically meaningfulcampaign guidelines [20, 63]. A single-center RCT outcomes.comparing 5% HA with gelatine in ICU patients showed Hypovolemia may also contribute signiﬁcantlyno difference in renal function despite signiﬁcant dif- towards drug-induced renal injury, although the availableferences in serum albumin levels . 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, optimalpatients with sepsis demonstrated slightly lower serum volume, and type of solution to be employed . Pre-creatinine levels in the group receiving gelatine, but no vention of nephrotoxicity through prophylactic volumeeffect 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  (ESM tericin B, antivirals including foscarnet, cidofovir, andTable S1). However, a large German RCT in patients adefovir [83–85], as well as drugs causing crystalwith septic shock (the VISEP trial) showed a higher nephropathy such as indinavir, acyclovir, and sulfadiazineincidence of AKI, requirement for RRT, and mortality in .the group treated with 10% HES 200/0.5 compared withRinger’s lactate . Adverse effects on renal functionmay be restricted to higher-molecular-weight HES, as amultivariate analysis in a large European multicenter Diureticsobservational study was unable to detect HES as anindependent risk factor, neither in 1,970 ICU patients Recommendationsrequiring RRT nor in a subgroup of 822 patients with 1. We recommend that loop diuretics are not used tosevere sepsis . prevent or ameliorate AKI (grade 1B). Prophylactic volume expansion has been investigatedextensively in the setting of contrast-induced nephrop-athy (CIN) [67–72]. The beneﬁt of this measure has Rationalebeen 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 demonstratedcharacterized by various risk scores (e.g., Thakar score that 70% of intensivists used loop diuretics in a wide or Mehran score ). The ﬁrst RCT comparing spectrum of AKI settings . There may indeed be someprotection in CIN by half normal saline versus half theoretical attractions in using diuretics to amelioratenormal 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 insaline at a rate of 1 ml/kg 12 h before and after angi- renal blood ﬂow [88–90].ography . However, a larger RCT including 1,620patients undergoing coronary angioplasty showed alower incidence of CIN when using normal salinecompared with half normal saline . Given that Clinical studiesnormal saline contains a high amount of chloride, theprotective effect of isotonic bicarbonate solutions (con- Few prospective randomized trials have addressed thetaining 150–154 mmol/l sodium) in patients with role of diuretics in the prevention of AKI. Most of theimpaired renal function receiving contrast agents has available studies have been done in the setting of contrastbeen 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 beenreplacement therapy or mortality. Most investigations observed with diuretics, and in cardiac surgery, higherapplied a hydration regimen starting at 3(–5) ml/(kg h) postoperative serum creatinine levels were found in1 h before radiocontrast application, followed by 1 ml/(kg h) patients receiving furosemide [93, 94].
396 To date four randomized controlled trials have Clinical studiesexamined the role of diuretics in established renal fail-ure in the intensive care setting. No demonstrable Low-dose or ‘‘renal-dose’’ dopamine has been advocatedimprovement in primary outcome parameters, such as in the past to prevent selective renal vasoconstriction in arecovery of renal function or mortality, has been variety of conditions . Although dopamine infusionobserved [35, 95–97]. Other studies have compared may improve renal perfusion in healthy volunteers, nodiuretics with dopamine or against placebo, again with improvement of renal perfusion nor preventive beneﬁtno perceived beneﬁt [33, 98, 99]. Three meta-analyses with respect to renal dysfunction has been unequivocallyconﬁrmed 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 mayside-effects such as hearing loss [100–102] (ESM contribute to renal vasoconstriction [108–110]. DopamineTable S3). Furthermore, in an international cohort study also has an inotropic effect, but observed increases inan increase in the risk of death or an increase in diuresis or even a reduction in serum creatinine duringestablished 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 thatstudy [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 dopexamineVasopressors and inotropes have also been examined, but to date no prospective controlled clinical trial has demonstrated a protectiveRecommendations effect on renal function . In contrast, the effect of1. 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 . 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 norepinephrine2. 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 . 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 andRationale arrhythmias (Patel GP et al., Shock, in press). Vasopressin is gaining popularity in the treatment ofPreservation or improvement of renal perfusion can the- norepinephrine-refractory shock  increasing bloodoretically be achieved by ﬂuid resuscitation, through renal pressure and enhancing diuresis in hypotensive oliguricvasodilators, by systemic vasopressors that redirect blood patients but as yet has not been proven to enhance survivalﬂow to the kidney or by increasing cardiac output through nor to prevent or ameliorate AKI in the critically ill .the use of inotropic drugs. Whereas a recent study indi-cated that any MAP of C60 mmHg may be consideredadequate for patients with septic shock , additionalbeneﬁts with regards to renal function were not observed Vasodilatorswhen a target MAP of more than 85 mmHg was comparedto a target of 65 mmHg . However, it must be borne Recommendationsin mind that this study may not be widely applicable to 1. We suggest using vasodilators for renal protectionthe patients admitted to the intensive care unit with pre- when volume status is corrected and the patient isexisting comorbidities. Those at greatest risk of closely hemodynamically monitored with particulardeveloping 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 ofvated 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.
3972. 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 .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 acute4. We suggest that natriuretic peptides are not used as renal injury, need for RRT, and hospital mortality . 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. TwoReduced 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 renalduction, and activation of the renin–angiotensin– function [129, 130]. However, the use of b-blockers asaldosterone system which maintains systemic blood part of current practice is not mentioned in these studiespressure often at the cost of both splanchnic and renal (ESM Table S5).vasoconstriction. Glomerular perfusion and ﬁltration Anaritide (ANP) is produced by cardiac atria inpressure 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 ascompensatory 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-dependentdepends on the ability of compensatory intrarenal vaso- hypotensive effect . Ularitide and nesiritide (braindilatation. It is increased, for example, with chronic natriuretic peptide, BNP) have similar effects. The ﬁrsthypertension and high venous pressure states and large RCT evaluating ANP in AKI found a reduction ofdecreased by endogenous or exogenous vasodilators RRT in the oliguric subgroup only . Disappointing[117–121]. In circumstances of persistent renal vasocon- results were subsequently observed in RCTs of anaritidestriction, vasodilators might have a beneﬁcial effect on and ularitide in patients with oliguric AKI [133–135]. Inkidney function. However, the use of vasodilators may contrast, a RCT in post cardiac surgery patients with heartcause hypotension by counteracting compensatory vaso- failure and early renal dysfunction demonstrated that useconstriction, thus unmasking occult hypovolemia, and as of continuous low-dose anaritide signiﬁcantly reduced thesuch the correction of hypovolemia is crucial. need for RRT . The effect of nesiritide was even more pronounced in cardiac surgery patients with reduced ejection fraction (NAPA trial), demonstrating shorterClinical studies hospital stay and reduced 180-day mortality . The observed differences might be explained by differences inFenoldopam 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 withpatients with AKI and observed mixed results [122–124]. low-dose nesiritide in elective abdominal aneurysm repairTwo compared fenoldopam with placebo, and one with  and in cardiac bypass surgery . Of note, adopamine. In one, fenoldopam was found to be beneﬁcial recent meta-analysis comparing non-inotrope-basedwith regard to the primary endpoints of dialysis-free treatment with nesiritide (h-BNP) therapy indicated thatsurvival at 21 days and need of RRT in the selected this may be associated with an increased risk of renalsubgroups of patients without ‘‘diabetes mellitus’’ or failure and death in a select population of patients with‘‘after cardiac surgery’’ . In another, fenoldopam acutely decompensated heart failure  (ESMcaused 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) . 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 controlledserum creatinine . Prophylactic administration of trials evaluating the effect of theophylline on the
398prevention of contrast nephropathy showed varying efﬁ- applying a local protocol which has proven efﬁcacy incacy 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) orinconclusive [142, 147, 152]. However, a more recent steroids (grade 2C) routinely to prevent AKI.trial has demonstrated a reduction in the incidence ofcontrast nephropathy by preprocedural administration of200 mg theophylline in critically ill patients . RationaleAnticipated adverse events such as arrhythmias were notobserved (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 patientsthoracic patients with no beneﬁt  but other small with type I and type II diabetes is well documented .studies examined populations at higher risk and demon- In animal models, insulin-like growth factor 1 (IGF-1) hasstrated beneﬁcial effects on both preservation of renal been shown to accelerate recovery from ischemic andfunction 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 tubularproperties. Two small studies in cardiac surgery have cells. Thyroid hormone has also been seen to accelerateevaluated 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 fromBoth 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 renalcalcium sensitizer activity, levosimendan, has recently failure in predialysis patients . 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 applicabilityimprovement of renal function as measured by eGFR . New derivatives of EPO that are devoid of hema-which could not be achieved by dobutamine alone . topoietic activity may be safer . The compensatory release of the vasodilator prosta- Activated protein C (APC) has pleiotropic actionsglandin 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 anand medullary vessels in renal hypoperfusion. Three ideal candidate to prevent ischemia/reperfusion-inducedclinical 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, angiotensinblockade augments renal cortical microvascular PO2 and restores endothelial dysfunction . Two Clinical studiesstudies evaluating the effect of short-term intravenousenalaprilat in a cardiac surgical population with poor A large prospective randomized controlled trial in 1,548cardiac function demonstrated improved cardiac and renal surgical ICU patients compared tight blood glucosefunction [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 byRecommendations 27% the number of patients with peak plasma creatinine1. We recommend against the routine use of tight gly- [2.5 mg/dL . 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
399compared with the admission level . 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 renalcriteria, showed a more pronounced renal protection when impairment .normoglycemia was achieved. The absence of a reduction No RCT has evaluated the effect of erythropoietin inin the need for RRT in medical patients could be AKI. A RCT trial on EPO in critically ill patients showedexplained by the higher illness severity with more renal no difference in the incidence of AKI (mentioned as andysfunction on admission, precluding an impact of this adverse event, not as an outcome parameter) . Amainly protective intervention . Two large sequen- retrospective cohort study in 187 critically ill patientstial cohort studies, one in a medical-surgical ICU  requiring RRT used a propensity-adjusted analysis andand the other in the setting of cardiac surgery , also found an improvement in renal recovery in patientsrevealed a signiﬁcant reduction in observed renal dys- administered EPO .function after the implementation of tight glycemiccontrol. Finally, a recent meta-analysis indicated thatsurvival beneﬁt by applying tight glycemic control, if any,may be restricted only to patients in surgical ICUs . Metabolic interventions More recent randomized trials in septic  andgeneral [189, 190] ICU patients and a meta-analysis  Recommendationsdo 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 asthe clinician decides to adopt tight glycemic control then prophylaxis against contrast induced nephropathy orsteps should be taken to ensure that ﬂuctuations in glucose other forms AKI in critically ill patients because oflevels are minimized and standardized and that reliable conﬂicting results, possible adverse reactions, andtools to measure blood glucose are employed . An better alternatives (grade 2B).important concern is the fact that the NICE-Sugar trial 3. We recommend against the routine use of selenium tofound 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 .The clinician should, however, be aware of important Rationaledifferences between the Leuven and the NICE-Sugar trial (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 basicscrutiny. 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 . Starvation accelerates protein breakdown and impairsA small RCT of IGF-1 administered postoperatively in 54 protein synthesis in the kidney, whereas refeeding mightpatients 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 proteindysfunction (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 towas observed . 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 alsomeasure of AKI severity compared with placebo was enhance tubular damage and accelerate loss of renalfound . function . In part, this ‘‘amino acid paradox’’ is With regard to the use of corticosteroids for renal related to the increase in metabolic work for transportprotection 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 nephrotoxicThis 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 ofoperative period . 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 . A post hoc analysis of secondary cal conditions has undergone much scrutiny with theendpoints of this trial, however, failed to show an effect NAD(P)H oxidase system believed to be pivotal in theiron the resolution of renal failure (measured with the formation and instrumental in the development of certainSOFA score criteria) in patients with renal dysfunction at pathophysiological conditions in the kidney [203–206].
400Under certain speciﬁc circumstances a role for antioxidant beneﬁt when combined with hydration, with multivariatesupplementation may be proposed, with potential candi- analysis conﬁrming age, volume of contrast, diabetes, anddates 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 . However, no beneﬁt was observed inand vitamin C (ascorbic acid)], as well as selenium and studies using NAC in vascular patients [233, 234] nor inother novel antioxidants. diabetic patients when compared with hydration alone . 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 preventrenal perfusion and improve renal function, a fact which renal dysfunction in other high-risk groups did not dem-was termed ‘‘renal reserve capacity’’ . However, this onstrate a beneﬁcial effect of NAC regarding renalpotential beneﬁcial effect has received little attention in dysfunction or need for renal support [241–245] (ESMterms of prevention and therapy of AKI to date. Intrave- Table S9), although one study in 177 patients found anous amino acids appear to improve renal plasma ﬂow mortality beneﬁt for the patients treated with NAC .and glomerular ﬁltration rate in cirrhotic patients with It must be considered, though, that especially IV NACfunctional renal failure . One study has reported on a may be harmful, leading to allergic reactions  orpositive effect of enteral versus parenteral nutrition on thedecreased cardiac output or survival in patients withresolution of AKI . septic shock [248, 249]. Most studies on antioxidants have centered on NAC, A recent single-center trial showed a protective effectwhich besides being an antioxidant, also has a vasodila- of oral ascorbic acid on the development of contrasttory effect . NAC undergoes rapid ﬁrst-pass nephropathy . Here too, the rate of nephropathy inmetabolism through deacylation and as a result its bio- the control group was high and no patients required renalavailability is low even following IV administration. support. Two further studies investigating protectionThere is no evidence that administration of NAC increa- against contrast nephropathy could not prove protectiveses 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 haveet al.  which provided the catalyst for the subsequent been conducted. The use of an antioxidant cocktail inproliferation of similar studies [127, 213–222]. This patients undergoing elective aortic aneurysm repairsubject 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 failureMost report a risk reduction, although study heterogeneity was very low .and positive reporting bias somewhat hinders deﬁnitive A a small RCT in 42 patients showed that seleniumrecommendations . However, studies demonstrating supplementation decreased the requirement for RRT froma positive effect have a higher incidence of CIN in the 43% to 14% . These ﬁndings, however, could not becontrol arms, reﬂecting differences in risk proﬁle, the reproduced in a larger RCT using selenium in 249route of NAC administration, the dose, the timing (with patients with sepsis (SIC study) [254, 255]. More recentearlier dosing perhaps being more efﬁcacious), and the studies in the critically ill demonstrated that, althoughtotal contrast load given. Importantly, some investigators selenium supplementation increased both selenium andsuggest that the reduction in serum creatinine with NAC glutathione peroxidase levels, there was no effect on themay be a direct effect of the drug on the creatinine requirement for RRT .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 Jaffemethod [230, 231]. An issue of concern is also the fact Extracorporeal therapiesthat the endpoint used in all the studies is a changein creatinine and not clinically relevant endpoints such as Recommendationsa need for RRT, length of stay or death. This is corrob- 1. We suggest periprocedural continuous veno-venousorated by a recent study where contrast-induced AKI was hemoﬁltration (CVVH) in an ICU environment to limitnot independently associated with death and had no effect contrast nephropathy after coronary interventions inon 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).
401Rationale cases of ethylene glycol intoxication as well as rasburi- case following adequate volume expansion in order toExtracorporeal therapies may protect the kidney by prevent tumor lysis syndrome before consideration ofremoval 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 requirehigher contrast load delivered to the remaining nephrons. membranes with a high cutoff , possibly used inThe relative amount of contrast removal by hemoﬁltration series for a minimal duration of 6 h, which is not readilydepends on the pore size of the ﬁlter , 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 functionequally important. [274–276].Clinical studies Conclusions and summarySeveral studies have employed renal replacement tech-niques in an attempt to limit contrast nephropathy. One of the major problems with any review discussingAmongst those, three studies utilized periprocedural AKI is the fact that deﬁnitions used in many publicationshemodialysis, with variable beneﬁt [258–261]. Prophy- vary largely. As a consequence comparing studies islactic CVVH was evaluated in a total of 114 patients at fraught with difﬁculties and calls for uniformly applicablehigh 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 renalreduced mortality as well as a reduced need for continued replacement techniques. Fortunately, initiatives in thisrenal support, particularly in those with baseline creatinine direction have recently been taken and should aid further[300 lmol/l . 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 thecombined pre- and postprocedural CVVH, and not post- circulation with ﬂuids, inotropes, vasoconstrictors and/orprocedural CVVH alone, had any renoprotective effect vasodilators is the primary aim and is recommended.. It should be emphasized that the patients receiving Volume expansion is recommended for the prevention ofCRRT were treated in ICU and those receiving hydration AKI in states of true and suspected hypovolemia, butalone 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 shouldmization in the ICU environment led to a better outcome. be avoided. Following volume resuscitation hypotensiveOther mechanisms such as pre- and periprocedural patients should be given a vasoconstrictor which shouldhydration 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 isdomyolysis 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 strictporeal treatments in oncology patients at high risk of hemodynamic control. Together with these measures atumor lysis syndrome has been reported. This available review of all medications, with the cessation of thoseliterature 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 inReferences 1. Chertow GM, Levy EM, 2. Groeneveld AB, Tran DD, van der MJ, 3. Levy EM, Viscoli CM, Horwitz RI Hammermeister KE, Grover F, Daley Nauta JJ, Thijs LG (1991) Acute renal (1996) The effect of acute renal failure J (1998) Independent association failure in the medical intensive care unit: on mortality. A cohort analysis. JAMA between acute renal failure and predisposing, complicating factors and 275:1489–1494 mortality following cardiac surgery. outcome. Nephron 59:602–610 Am J Med 104:343–348
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