When to Initiate RRT in Patients with AKI - Does Timing Matter?


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Acute kidney injury is a serious illness which occurs commonly in the renal units and also in the ICU setting. It is an independent risk factor of increased mortality and morbidity, particularly when RRT is needed. The wide variation in utilization of RRT contributes to a lack of consensus among clinicians regarding the parameters which should guide the decision to initiate RRT.

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When to Initiate RRT in Patients with AKI - Does Timing Matter?

  1. 1. WhentoInitiateRRTinPatientswithAKI-DoesTimingMatter?
  2. 2. Review ArticleWhen to initiate RRT in patients with AKI e Does timingmatter?Saumya Gupta*Consultant Nephrologist, Apollo Gleneagles Hospital Limited, 58 Canal Circular Road, Kolkata, Indiaa r t i c l e i n f oArticle history:Received 5 December 2012Accepted 31 January 2013Available online 9 February 2013Keywords:Acute kidney injuryRenal replacement therapyTiminga b s t r a c tAcute kidney injury is a serious illness which occurs commonly in the renal units and alsoin the ICU setting. It is an independent risk factor of increased mortality and morbidity,particularly when RRT is needed. The wide variation in utilization of RRT contributes toa lack of consensus among clinicians regarding the parameters which should guide thedecision to initiate RRT. This problem is confounded by a paucity of high quality evidencein the current literature. This review examines the role of usual biochemical parameters aswell as conventional clinical indications for commencing RRT. It also discusses the po-tential role of biomarkers as predictors for the need of RRT in AKI. Initiating dialysis in AKIshould be based on dynamic clinical criteria and not only on specific biochemical values.Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.1. IntroductionAcute kidney injury (AKI) is a serious complication of criticalillness that is associated with substantial morbidity andmortality. Renal replacement therapy (RRT) has long beenused as supportive treatment of AKI, and has traditionallyfocused on averting the life threatening derangements asso-ciated with kidney failure (i.e. metabolic acidosis, hyper-kalemia, uraemia, and/or fluid overload) while allowing timefor organ recovery. In patients with AKI, RRT is regarded asa type of organ support aimed at achieving metabolic ho-meostasis and preventing fluid overload and new organ fail-ure. The benefits of RRT must be balanced by potential harm,including risks related to vascular access, infections andanticoagulation.1Whether or not to provide RRT, and when to start, are twoof the fundamental questions facing nephrologists andintensive-care practitioners in most cases of severe AKI. Inrecent publications, the timing of initiation of RRT was listedas one of the top priorities in research on AKI.2However, thisdimension has not been included as a factor in any of thelarge RCTs in this area. In current practice, the decision tostart RRT is based most often on clinical features of volumeoverload and biochemical features of solute imbalance. Ina recently published survey of nephrologists and intensivistsin Canada, serum potassium level and severity of pulmonaryoedema were the most commonly utilized factors for decid-ing when RRT should be started.3However, in the absence ofthese factors there is generally a tendency to avoid dialysis aslong as possible, a thought process that reflects the decisionsmade for patients with CKD Stage 5.4Clinicians tend to delayRRT when they suspect that patients may recover on theirown, and because of concern for the well-known risks asso-ciated with the RRT procedure. There is also some concernthat RRT may compromise recovery of renal function, andincrease the progression of CKD.5Whether these risks out-weigh the potential benefits of earlier initiation of RRT is stillunclear.* Flat No. 3G, Orbit Heights, 33 Gariahat Road South, Kolkata 700031, West Bengal, India. Tel.: þ91 9163262325.E-mail address: sgupta36@hotmail.com.Available online at www.sciencedirect.comjournal homepage: www.elsevier.com/locate/apmea p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 60976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.http://dx.doi.org/10.1016/j.apme.2013.01.016
  3. 3. In ICU patients, AKI is often observed at an early stagebefore traditional measures of renal function are deranged.Many specialists regard AKI as a systemic disease, rather thana single organ failure in isolation characterised by a systemicinflammatory response with distant organ injury.6The causeof the acute kidney injury (AKI) requiring RRT is also relevant.Without an underlying cause, clinicians do not have muchinformation other than an observed disturbance in conven-tionally measured biochemical parameters of kidney functioncombined with oliguria or anuria. The outcome from AKI ina young patient secondary to a crush syndrome is very dif-ferent from that of an elderly diabetic developing AKI fol-lowing systemic infection from an ischaemic limb. It may bethat the aetiology of the underlying condition is also of greatimportance with regard to timing of treatment. This high-lights the differences between ‘single organ AKI’ and ‘multi-organ AKI’ in that timing of RRT on a renal unit may differsignificantly from ICU patients in terms of both dose deliveredand duration of treatment.7The timing of initiation of RRT remains a topic of discus-sion for some years in both groups of patients suffering fromchronic kidney disease8and AKI9respectively. A recentlypublished systematic review and meta-analysis concludedthat earlier initiation of RRT in critically ill AKI patients mayhave a beneficial effect on survival but that, in the absence ofnew evidence from suitably designed randomized trials,a definitive treatment recommendation cannot be made.92. Where do we stand now regarding currentevidence?Studies looking at the timing of initiation of RRT need toaddress the criteria used for commencing therapy; but this ishampered by the lack of any universally accepted criteria forinitiation. They have evaluated various arbitrary cut-offs forserum creatinine, serum urea or urine output, fluid balance,time from admission or duration of AKI and often differ-entiated between ‘early’ and ‘late’ RRT (Table 1).10e26In the current literature, there are 2 RCTs,17,192prospective cohort studies,10,1413 retrospective cohortstudies11e13,15,16,18,20e26and 3 meta-analyses/systematic re-views.9,27,28Significant heterogeneity still remains regardingthe potential parameters which are monitored by clinicians todecide that the time has come to commence RRT. Most clinicaltrials used serum creatinine, serum urea and/or urine outputto define timing of RRT but the exact cut-offs were variablebetween studies.2.1. Serum creatinineFive studies contained data on the role of serum creatinine asa trigger for RRT (Table 1).10,11,22e24The results are conflicting.Shiao et al11retrospectively analysed the data of 98 patientswith AKI post-abdominal surgery and showed that patientswho were started on CVVH at RIFLE stage Risk (i.e. after rise inserum creatinine by 150e200%) had a significantly lowerhospital mortality than patients who started RRT with eitherRIFLE-Injury or RIFLE-Failure (i.e. after serum creatinine riseby >200%). In contrast, Chou et al12showed no difference inhospital mortality in 370 AKI patients between the group whostarted RRT with RIFLE-Risk or even before they fulfilled theRIFLE criteria and patients in whom AKI had progressed toRIFLE-Injury or RIFLE-Failure when RRT was started. Twolarger studies concluded that mortality was significantlyhigher in patients who had a serum creatinine < 309 mmol/Lwhen RRT was started compared to those with higher crea-tinine values.10,232.2. Serum ureaDifferent levels of serum urea were used as triggers for RRT ineight studies.10,13e17,23,26Liu et al14reported a significantlylower mortality in 122 patients who had a serum ure-a < 27.1 mmol/L at the time of initiation of RRT compared to121 patients with a higher value. When adjusted for age, he-patic failure, sepsis, thrombocytopaenia and serum crea-tinine, the relative risk of death with a higher urea level at thetime of RRT was 1.85 [95% confidence interval (CI) 1.2e3.2].Improved mortality was also reported in retrospective studieswhen RRT was instituted at a serum urea < 21 mmol/L,26<29 mmol/L13or <35.7 mmol/L,15suggesting that RRT atlower serum urea levels is better than late RRT. In contrast,two larger studies did not find a correlation between serumurea at the time of RRT and outcome.10,232.3. Urine outputData on the role of specific urine volumes as triggers forRRT were included in eight studies12,16e19,23e25often com-bined with serum urea or creatinine criteria. The majority ofstudies showed better outcomes; when oliguria was used asthe trigger for RRT instead of serum creatinine or ureavalues.12,16,18,24,25However, the definitions for oliguria variedfrom urine output < 100 ml/h in 8 h16,24to <400 ml/24 h23and<30 ml/h for 6 h.172.4. Fluid overloadThere is increasing evidence that fluid overload in patientswith AKI is associated with poor outcome.21,29Bouchard et al29showed that ICU mortality was significantly higher in patientswhose body weight on the first day of RRT was 1e20% abovethat on ICU admission compared to patients without weightgain during this period. There was a direct correlation be-tween the degree of fluid gain and ICU mortality. Similar re-sults were reported by Payen et al21who performeda subgroup analysis of the multicentre ‘Sepsis Occurrence inAcutely Ill Patients (SOAP) study’. Two hundred and thirteenpatients were treated with RRT within 2 days of ICU admissioncompared to 65 patients who had RRT after 2 days in ICU.Although patients in the early RRT group had higher severityof illness scores, their ICU and 60-day mortality was lower. Apotential explanation for this difference was the higher cu-mulative fluid balance and greater need for mechanical ven-tilation in the late RRT group. Consequently, it may beappropriate to consider starting RRT in patients with AKI priorto fluid accumulation of 10% of body weight.30a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 642
  4. 4. Table 1 e Parameters at the time of RRT and subsequent outcome.Study RRT mode Patient population Parameters at the time of RRT Outcome (early vs lateRRT)Early LateBagshaw et al10prospectivestudyCRRT; IHD 1238 mixed ICU patients Serum Cr 3.5 mg/dl serumurea 136 mg/dlSerum Cr 3.5 mg/dl serumurea 136 mg/dlHospital mortality 71 vs 53.4%P 0.0001 P ¼ 0.48Shiao et al11retrospectivestudyCVVH; IH 98 patients post-abdominalsurgeryAKI as per RIFLE classification;no AKI or RIFLE-RiskAKI as per RIFLE classificationRIFLE Injury or FailureHospital mortality 43 vs 75%P ¼ 0.002Chou et al12retrospective CVVH; SLED;SLED-f; IHD370 patients with AKI andsepsisRIFLE-0 or RIFLE-Risk RIFLE-Injury or RIFLE-Failure Hospital mortality 70.8 vs69.7% P 0.05Wu et al13retrospective study CRRT; IHD 80 patients with AKI and acuteliver failureSerum urea 160 mg/dl Serum urea 160 mg/dl ICU mortality 57 vs 85%P ¼ 0.02Liu et al14prospective study CRRT; IHD 243 mixed ICU patients Serum urea 152 mg/dl Serum urea 152 mg/dl Hospital mortality RR 1.85with higher urea (95% CI 1.2e3.2)Carl et al15retrospective study CRRT 147 patients with AKI andsepsisSerum urea 200 mg/dl Serum urea 200 mg/dl 28 day mortality 52.3 vs 68%P 0.05Elahi et al16retrospectivestudyCRRT 64 patients post-cardiacsurgeryUrine output 100 ml in 8 h Serum urea 168 mg/dl serumCr 2.82 mg/dl or K 6 mmol/LHospital mortality 22 vs 43%P 0.05Bouman et al17RCT CRRT 106 patients with AKIcirculatory and respiratoryfailureUrine output 30 ml/h for 6 hand Cr Cl 20 ml/minSerum urea 224 mg/dl orK 6.5 mmol/L or severepulmonary oedema28 day mortality 29 vs 25%P ¼ 0.08Manche et al18retrospectivestudyIHD 71 patients with AKI post-cardiac surgeryUrine output 0.5 ml/kgdespite fluid challenge andsingle dose of diureticAKI which failed to respond toall supportive medicalmeasuresICU mortality 25 vs 87%P ¼ 0.00001Sugahara et al19RCT CRRT 28 patients post-cardiacsurgeryUrine output 30 ml/h for 3 h Urine output 20 ml/h for 2 h 14 day mortality 14 vs 86%P 0.01Piccinni et al20retrospectivestudyCRRT 80 patients with AKI, ALI andseptic shockWithin 12 h of admission toICU‘Classic’ indications for RRT ICU mortality 30 vs 60%P ¼ 0.003 28 day mortality 72.5vs 45%, P ¼ 0.005Payen et al21retrospectivestudyRRT 278 patients with sepsis andAKIPeriod from admission to ICUto RRT 2 daysPeriod from admission to ICUto RRT 2 days60 day mortality 44.8 vs 64.6%P 0.01Ji et al22retrospective study CVVHD 58 patients with AKI post-cardiac surgeryUrine output 0.5 ml/kg/h for12 hUrine output 0.5 ml/kg/h for12 hHospital mortality 8.8 vs 37.5%P ¼ 0.02Ostermann et al23retrospective studyCRRT; IHD 1847 mixed ICU patients Serum Cr 3.5 mg/dl serumpH 7.2Serum Cr 3.5 mg/dl serumpH 7.2ICU mortality 59 vs 48%P 0.0001 74 vs 48% P 0.0001Demirkilic et al24retrospectivestudyCRRT 61 patients with AKI post-cardiac surgeryUrine output 100 ml within8 h post surgerySerum Cr 5.0 mg/dl or K 5.5 ICU mortality 18 vs 48%P ¼ 0.014 hospital mortality23.5 vs 56% P ¼ 0.016Iyem et al25retrospectivestudyCVVH 185 patients with AKI post-cardiac surgeryUrine output 0.5 ml/kg/hand a 50% increase in pre opurea and creatinine48 h after urineoutput 0.5 ml/kg/hr anda 50% increase in pre op ureaand creatinineHospital mortality 5.2 vs 6.6%P 0.05Gettings et al26retrospectivestudyCRRT 100 trauma patients Serum urea 120 mg/dl Serum urea 120 mg/dl Hospital mortality 61 vs 80%P ¼ 0.041CRRT, continuous renal replacement therapy; IHD, intermittent haemodialysis; RR, relative risk; ALI, acute lung injury; RIFLE, Risk Injury Failure Loss of renal function End stage renal disease; SLED,slow extended dialysis; SLEDf, slow extended dialysis with haemofiltration; CVVHD, continuous veno-venous haemodialysis.apollomedicine10(2013)41e4643
  5. 5. 2.5. HyperkalemiaUntreated hyperkalemia is universally fatal. 1 RCT17and 2 ret-rospective studies16,24have used serum potassium as a markerregarding the timing to initiate RRT. It is interesting to note thatthe cut-off in each of these studies were different, namely6.5 mmol/L,176 mmol/L16and 5.5 mmol/L24respectively.2.6. Metabolic acidosisA retrospective study conducted by Ostermann et al23foundthat ICU mortality was significantly high (48% vs 74%,P 0.0001) in the late group as defined by serum pH Non-renal factorsA large retrospective analysis of 1847 ICU patients treated withRRT for AKI highlighted that the most important independentrisk factors for ICU mortality were need for mechanical ven-tilation, associated organ failure, pre-existing chronic healthproblems, acidosis, oliguria and age.23Patients who were oli-guric (urine output 400 ml/24 h) and acidotic with serumpH 7.2 at the time of RRT had an ICU mortality of 79.1%.Serum urea and creatinine were not found to be independ-ently associated with outcome. The results of this study sug-gest that the decision to start RRT should depend less onspecific serum creatinine or urea values but more on degree ofacidosis, urine output and associated organ failure.3. DiscussionThe idea that earlier initiation of treatment should be bene-ficial stems from our belief that sometimes complex in-terventions may change the course of a serious diseaseprocess. Recently published KDIGO guidelines regarding thisquestion mention to initiate RRT emergently when lifethreatening changes in fluid, electrolyte and acid-base bal-ance exist. It also mentions that consideration needs to begiven to the broader clinical context, modifiable conditionswith relation to RRT and trends of biochemical parametersrather than their thresholds alone.4In the common clinical scenario of AKI and sepsis, manyclinicians believe that initiating RRT early in sepsis can removecirculating levels of inflammatory cytotoxins and may there-fore have a beneficial effect on the pathophysiologic mecha-nisms. Unfortunately, the validity of this hypothesis has neverbeen proven, and existing evidence rather points to the con-trary.31In patients with septic AKI, RRT should not be seen asa curative therapy, but rather as a supportive intervention,preventing the patient from dying due to hyperkalemia or fluidoverload during the time period when AKI was present.Whatever criteria are used to define ‘early’ vs ‘late’ RRT, itis clear that what may be ‘early’ for one patient could be ‘late’for another patient depending on the patient’s comorbidityand clinical course.30Since the course of patients with AKI canbe very variable, it is essential that clinicians assess thesepatients regularly to ensure that RRT is started at the ‘right’time. As mentioned before, there are only 2 RCT’s17,19in theliterature, which have tried to address this issue. Boumanet al17randomized 106 severely ill patients into three groups;35 patients were treated with early high volume hemofiltra-tion, 35 patients with early low volume hemofiltration and 36patients with late low volume hemofiltration. Median ultra-filtrate rate was 48.2 ml/kg/h, 20.1 ml/kg/h and 19 ml/kg/hrespectively in the 3 groups. There was no statistically sig-nificant difference in survival rates among the 3 groups(P ¼ 0.8). Median duration of renal failure in hospital survivorsalso did not reach statistical significance (P ¼ 0.25) in the 3groups. Another RCT by Sugahara et al19conducted in 28 post-cardiac surgery patients showed significant improvement in14 day mortality (P 0.01) in the early group.Three meta-analyses9,27,28concluded that earlier initiationof RRT in critically ill AKI patients might be associated witha survival benefit though the studies were heterogenous, ofvariable quality with a paucity of RCTs. Of studies reportingsecondary outcomes in the meta-analysis by Karvellas et al,9majority reported greater renal recovery, decreased durationof RRT and decreased ICU length of stay in the early RRT group.Currentlythere islittledata to accurately distinguish inadvancebetween the injured kidney that will need dialytic support andtheonethatwill recoverspontaneously.Studies inthe literaturemost commonly used serum creatinine, serum urea and urineoutput as the parameters to trigger RRT with varying cut-offvalues. However, their value is limited due to the fact thatthey are not always renal specific. In the early stages of AKI, GFRcan decrease significantly without any major shift in serumcreatinine measurements.32Serum urea concentrations mayalso vary as a result of changes in urea production and tubularreabsorption without changes in GFR.33The usefulness of urinecriteria for the definition of AKI has also been discussedwidely.34Proponents argue that a fall in urine output oftenprecedes renal dysfunction in patients before changes in serumcreatinine. In contrast, critics argue that urine output is affectedby volume status, intrinsic levels of anti-diuretic hormone,presence of obstruction and use of diuretics. Despite this, thereis increasing evidence that urine output of 500e600 ml/24 hshould be viewed as an ominous sign and trigger an evaluationof the indications for RRT. Furthermore, oliguria is closely cor-related with fluid accumulation. Recent data suggest that fluidoverload of 10% of body weight is an independent risk factorfor mortality in AKI.29Consequently, it may be appropriate toconsider starting RRT prior to fluid accumulation reachinga threshold of 10% of body weight.The current literature shows that individual stages of AKIare not adequate in identifying the optimal time for RRTeither. The RIFLE and AKIN classifications are scoring systemswhich were developed to grade prognosis of AKI.35,36Althoughthey correlate with mortality, they were never intended topredict the need for RRT. Two retrospective studies11,12con-ducted amongst patients after abdominal surgery and pa-tients with AKI and sepsis in a surgical ICU utilized the RIFLEcriteria while separating the groups who underwent ‘early’ or‘late’ RRT. Unfortunately they showed conflicting results.Shiao et al11showed that the hospital mortality was sig-nificantly lower (43% vs 75%, P ¼ 0.002) in the group whocommenced RRT ‘early’ when in the RIFLE-Risk stage. Theother study by Chou et al12showed that there was no signifi-cant difference in the hospital mortality (70.8% vs 69.7%,P 0.05) between the ‘early’ and ‘late’ groups.a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 644
  6. 6. The recent literature has seen an expansion in studiesexamining potential ‘biomarkers’ for the early detection ofAKI. Candidate molecules include neutrophil gelatinaseassociated lipocalin (NGAL), kidney injury molecule (KIM)-1and cystatin C, and the list continues to grow, although thequest for the renal ‘troponin’ has been hampered by a desirefor one biomarker to be seen as superior over others. A meta-analysis including 1948 patients from nine studies confirmedthat urinary or plasma NGAL indeed predicted the need forRRT.37Cystatin C has been shown to predict AKI, but its su-periority over serum creatinine has not been observed uni-versally in conducted studies.38Currently available data areinsufficient to conclude that timing of RRT should be based onthese new biomarkers but results of future clinical trials areawaited.4. ConclusionThere is no doubt that RRT should be initiated in the casewhere life threatening conditions such as refractoryhyperkalemia, severe acidosis and fluid overload is evident.There is also a broad consensus among clinicians that RRTshould be started, if possible, before frank uraemic symptomsdevelop. Ostermann et al33recently proposed an algorithm(Fig. 1) for initiation of RRT, incorporating the AKIN criteriaand also including the non-renal indications. The message isthat the criteria for initiating RRT should be individualizedbased on the existing dynamic parameters rather than abso-lute values with the aim to support organ function and pre-vent complications.The question whether RRT in AKI should be started ‘early’or ‘late’ remains unanswered with the current available evi-dence. May be we cannot answer this question now because itmay be the wrong question; as dialysis is a supportive ratherthan a curative therapy. Future research in this very impor-tant field is desperately needed and should include a combi-nation of clinical and emerging biomarkers. What we need, isto look forward to doing away with comparisons of ‘early’ vs‘late’ dialysis and focus on improving outcomes with timelyinterventions of renal support tailored to individual patientneed.Fig. 1 e Algorithm to guide decision regarding the timing of initiating RRT. MAP [ mean arterial blood pressure. Diagnosisof AKI based on the AKIN classification.35a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 6 45
  7. 7. Conflicts of interestThe author has none to declare.r e f e r e n c e s1. Oudemans-van Straaten HM. Primum non nocere, safety ofcontinuous renal replacement therapy. Curr Opin Crit Care.2007;13:635e637.2. Kellum JA, Mehta RL, Levin A, et al. Development of a clinicalresearch agenda for acute kidney injury using aninternational, interdisciplinary, three-step modified Delphiprocess. Clin J Am Soc Nephrol. 2008;3:887e894.3. Clark E, Wald R, Walsh M, Bagshaw SM. Timing of initiation ofrenal replacement therapy for acute kidney injury: a survey ofnephrologists and intensivists in Canada. Nephrol DialTransplant. 2012;27(7):2761e2767.4. KDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012;2:89e115.5. Palevsky PM, Baldwin I, Davenport A, et al. Renal replacementtherapy and the kidney: minimizing the impact of renalreplacement therapy on recovery of acute renal failure. CurrOpin Crit Care. 2005;11:548e554.6. Druml W. Acute renal failure is not a “cute” renal failure!.Intensive Care Med. 2004;30:1886e1890.7. Joannidis M, Forni LG. Clinical review: timing of renalreplacement therapy. Crit Care. 2011;15:223.8. Lameire N, Van BW. The initiation of renal replacementtherapy e just-in-time delivery. N Engl J Med.2010;363:678e680.9. Karvellas CJ, Farhat MR, Saijad I, et al. A comparison of earlyversus late initiation of renal replacement therapy incritically ill patients with RRT for AKI: a systematic reviewand meta-analysis. Crit Care. 2011;15:R72.10. Bagshaw SM, Uchino S, Bellomo R, et al. Timing of renalreplacement therapy and clinical outcomes in critically illpatients with severe acute kidney injury. J Crit Care.2009;24:129e140.11. Shiao CC, Wu VC, Li WY, et al. Late initiation of renalreplacement therapy is associated with worse outcomes inacute kidney injury after major abdominal surgery. Crit Care.2009;13:R171.12. Chou YH, Huang TM, Wu VC, et al. Impact of timing of renalreplacement therapy initiation on outcome of septic acutekidney injury. Crit Care. 2011;15:R134.13. Wu VC, Ko WJ, Chang HW, et al. Early renal replacementtherapy in patients with postoperative acute liver failureassociated with acute renal failure: effect on postoperativeoutcomes. J Am Coll Surg. 2007;205:266e276.14. Liu KD, Himmelfarb J, Paganini E, et al. Timing of initiation ofdialysis in critically ill patients with acute kidney injury. Clin JAm Soc Nephrol. 2006;1:915e919.15. Carl DE, Grossman C, Behnke M, et al. Effect of timing ofdialysis on mortality in critically ill, septic patients with acuterenal failure. Hemodial Int. 2010;14:11e17.16. Elahi MM, Lim MY, Joseph RN, et al. Early hemofiltrationimproves survival in post-cardiotomy patients with acuterenal failure. Eur J Cardiothorac Surg. 2004;26:1027e1031.17. Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, et al.Effects of early high-volume continuous veno-venoushemofiltration on survival and recovery of renal function inintensive care patients with acute renal failure:a prospective, randomized trial. Crit Care Med.2002;30:2205e2211.18. Manche A, Casha A, Rychter J, et al. Early dialysis in acutekidney injury after cardiac surgery. Interact Cardiovasc ThoracSurg. 2008;7:829e832.19. Sugahara S, Suzuki H. Early start on continuous hemodialysistherapy improves survival rate in patients with acute renalfailure following coronary bypass surgery. Hemodial Int.2004;8:320e325.20. Piccinni P, Dan M, Barbacini S, et al. Early isovolaemichaemofiltration in oliguric patients with septic shock.Intensive Care Med. 2006;32:80e86.21. Payen D, de Pont AC, Sakr Y, et al. A positive fluid balance isassociated with a worse outcome in patients with acute renalfailure. Crit Care. 2008;12:R74.22. Ji Q, Mei Y, Wang X, et al. Timing of continuous veno-venoushemodialysis in the treatment of acute renal failure followingcardiac surgery. Heart Vessels. 2011;26:183e189.23. Ostermann M, Chang RWS. Correlation between parametersat initiation of renal replacement therapy and outcome inpatients with acute kidney injury. Crit Care. 2009;13:R175.24. Demirkilic U, Kuralay E, Yenicesu M, et al. Timing ofreplacement therapy for acute renal failure after cardiacsurgery. J Cardiovasc Surg. 2004;19:17e20.25. Iyem H, Tavli M, Akcicek F, et al. Importance of early dialysisfor acute renal failure after an open-heart surgery. HemodialInt. 2009;13:55e61.26. Gettings LG, Reynolds HN, Scalea T. Outcome inposttraumatic acute renal failure when continuous renalreplacement therapy is applied early versus late. IntensiveCare Med. 1999;25:805e813.27. Pannu N, Klarenbach S, Wiebe N, et al. Renal replacementtherapy in patients with acute renal failure: a systematicreview. J Am Med Assoc. 2008;299:793e805.28. Seabra VF, Balk EM, Liangos O, et al. Timing of renalreplacement therapy in acute renal failure: a meta-analysis.Am J Kidney Dis. 2008;52:272e284.29. Bouchard J, Soroko SB, Chertow GM, et al. Fluid accumulation,survival and recovery of kidney function in critically illpatients with acute kidney injury. Kidney Int. 2009;76:422e427.30. Macedo E, Mehta R. When should renal replacement therapybe initiated for acute kidney injury? Semin Dial.2011;24:132e137.31. De Vriese AS, Colardyn FA, Philippe JJ, et al. Cytokine removalduring continuous hemofiltration in septic patients. J Am SocNephrol. 1999;10:846e853.32. Lameire N, Hoste E. Reflections on the definition,classification, and diagnostic evaluation of acute renalfailure. Curr Opin Crit Care. 2004;10:468e475.33. Ostermann M, Dickie H, Barrett NA. Renal replacementtherapy in critically ill patients with acute kidney injury ewhen to start. Nephrol Dial Transplant. 2012;27:2242e2248.34. Yerram P, Karuparthi PR, Misra M. Fluid overload and acutekidney injury. Hemodial Int. 2010;14:348e354.35. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney InjuryNetwork (AKIN): report of an initiative to improve outcomesin acute kidney injury. Crit Care. 2007;11:R31.36. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure edefinition, outcome measures, animal models, fluid therapyand information technology needs: the Second InternationalConsensus Conference of the Acute Dialysis Quality Initiative(ADQI) Group. Crit Care. 2004;8:R204eR212.37. Haase M, Bellomo R, Devarajan P, et al. Accuracy ofneutrophil gelatinase-associated lipocalin (NGAL) indiagnosis and prognosis in acute kidney injury: a systematicreview and meta-analysis. Am J Kidney Dis. 2009;54:1012e1024.38. Cruz DN, De Geus HR, Bagshaw SM. Biomarker strategies topredict need for renal replacement therapy in acute kidneyinjury. Semin Dial. 2011;24:124e131.a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 4 1 e4 646
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