Accelerated versus delayed initiation of renal-replacement strategies following cardiac surgery

Central MessageThe initiation of early renal-replacement therapy for acute kidney injury following cardiac surgery remains controversial, with data supporting both accelerated and delayed strategies.See Commentaries on pages 198 and 200. The initiation of early renal-replacement therapy for acute kidney injury following cardiac surgery remains controversial, with data supporting both accelerated and delayed strategies. See Commentaries on pages 198 and 200. Feature Editor Note—Cardiac surgery–associated acute kidney injury (AKI) is common and has significant prognostic implications, including the substantial long-term effects of persistent renal failure and a clear impact in mortality. Moreover, fluid overload is a frequent consequence of perioperative resuscitation in the early stages of recovery after cardiac surgery, specifically after complex procedures with massive fluid shifts. An important component of the approach to manage severe AKI is the use of renal-replacement therapy (RRT). Timing of initiation of RRT for AKI with or without volume overload is a controversial dilemma that we encounter frequently in perioperative cardiothoracic care. Broadly speaking, there is no difference in mortality when evaluating accelerated or early RRT initiation versus delayed or only starting RRT when absolutely indicated in critically ill patients, and data in cardiac surgery are conflicting at best. There may be benefit from early RRT in subsets of cardiac surgical patients, but also there appears to be a significant number of patients who recover renal function in whom initiation of RRT could be detrimental or counterproductive. In this invited expert opinion paper, Dr Merritt-Genore and colleagues review this controversial and timely topic. The authors start by acknowledging the different definitions of AKI and the fact that currently there are no clear tools to determine whether AKI is likely to be transient or persistent at time of diagnosis, data that would help determine when would be best to have a careful watchful approach versus early RRT. The authors go on to review the data for the timing of RRT in critically ill patients in general, followed by segments specific to cardiac surgery and special patient populations, such as those with left ventricular assist devices, heart transplant recipients, and those receiving extracorporeal membrane oxygenation complicated with AKI. The debate is not settled. It is clear that having more tools to determine the probability for persistent AKI would help solve the controversy to ideally provide RRT at the right time to the right patient. Juan N. Pulido, MD Acute kidney injury (AKI) is known to increase length of hospital stay, morbidity, and mortality following cardiac surgery. Multiple definitions exist for the designation and classification of AKI. For instance, the Society of Thoracic Surgeons establishes acute renal failure as a 2-fold rise in serum creatinine (SCr), or SCr >4.0 mg/dL (with a minimum rise of 0.5 mg/dL), or new hemodialysis.1O’Brien S.M. Shahian D.M. Filardo G. Ferraris V.A. Haan C.K. Rich J.B. et al.The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2—isolated valve surgery.Ann Thorac Surg. 2009; 88: S23-S42Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar The definition of AKI from Kidney Disease: Improving Global Outcomes, in contrast, includes an increase in SCr by >0.3 mg/dL within 48 hours or an increase within 7 days’ time of baseline SCr by >1.5 times or urine output <0.5 mL/kg/h for 6 hours, and further characterizes the stage of AKI to more granular levels. While the criteria to define AKI vary,2Dudar I. Loboda O. Savchuk V. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: summary of recommendation statements and practice points translated into Ukrainian.Ukrainian J Nephrol Dial. 2020; 68: 59-66Crossref Google Scholar the incidence of kidney injury remains high in cardiac surgery, with between 4% and 35% of patients experiencing some form of AKI3Bastin A.J. Ostermann M. Slack A.J. Diller G.-P. Finney S.J. Evans T.W. Acute kidney injury after cardiac surgery according to Risk/Injury/Failure/Loss/End-stage, Acute Kidney Injury Network, and Kidney Disease: Improving Global Outcomes classifications.J Crit Care. 2013; 28: 389-396Crossref PubMed Scopus (113) Google Scholar, 4Ramos K.A. Dias C.B. Acute kidney injury after cardiac surgery in patients without chronic kidney disease.Braz J Cardiovasc Surg. 2018; 33: 454-461Crossref Scopus (7) Google Scholar, 5Hu J. Chen R. Liu S. Yu X. Zou J. Ding X. Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: a systematic review and meta-analysis.J Cardiothorac Vasc Anesth. 2016; 30: 82-89Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar and between 2% and 20% of patients requiring renal-replacement therapy (RRT) in the postoperative period. In this population, RRT is independently associated with an up to 8-fold increase in mortality.4Ramos K.A. Dias C.B. Acute kidney injury after cardiac surgery in patients without chronic kidney disease.Braz J Cardiovasc Surg. 2018; 33: 454-461Crossref Scopus (7) Google Scholar The causes of AKI after cardiac surgery are many. In addition to known preoperative risk factors (pre-existing renal dysfunction, recent contrast, diabetes, advanced age), perioperative myocardial injury and fluctuations in cardiac output may lead to increased sympathetic activity, increased production of vasopressin, and activation of the renin–angiotensin–aldosterone system. Added to this are the effects of the cardiopulmonary bypass circuit on arterial resistance and subsequent volume retention postoperatively. All of this may create a vicious cycle of repeated kidney injury with renal sodium and water retention and extracellular fluid expansion. Perioperative fluid overload is associated with worse outcomes and is a primary risk factor for multiorgan failure, including acute renal failure,6Stein A. de Souza L.V. Belettini C.R. Menegazzo W.R. Viégas J.R. Costa Pereira E.M. et al.Fluid overload and changes in serum creatinine after cardiac surgery: predictors of mortality and longer intensive care stay. A prospective cohort study.Crit Care. 2012; 16: R99Crossref PubMed Scopus (64) Google Scholar yet the timing and intensity of RRT in the postoperative cardiac patient remains controversial, with many factors playing into the decision for initiation, such as acidosis, urine output, and fluid balance, and the overall clinical picture (Figure 1). In addition, there are few data to guide the clinician's determination as to whether the AKI is transient and retains capacity for early recovery or whether the injury will progress to azotemia and volume overload, perhaps despite a lower SCr. In this Expert Review, we will examine and summarize contemporary studies focusing on accelerated versus delayed strategies for RRT following cardiac surgery. As the bulk of high-quality studies come from critically ill populations (and not specifically cardiac surgery patients), we will examine the data separately and discuss what can be generalized to individual populations. Contemporary studies examining the impact of the timing of RRT have tended to focus on critically ill patients, which may or may not include cardiac surgical patients specifically. The studies have generally concentrated on survival benefit and recovery of renal function as primary outcomes. A large 2020 meta-analysis including 10 randomized controlled trials (RCTs) and 2143 critically ill patients with severe AKI found that in the absence of urgent indicators for RRT, there was no survival benefit to early RRT initiation. Somewhat surprisingly, this study also showed that up to 42% of patients in the late RRT group had recovery of renal function and never went on to require dialysis.7Gaudry S. Hajage D. Benichou N. Chaïbi K. Barbar S. Zarbock A. et al.Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.Lancet. 2020; 395: 1506-1515Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar A second recent large meta-analysis of 18 RCTs confirmed similar findings and reinforced the idea that a delayed strategy may obviate the need for RRT in critically ill populations.8Zhang L. Chen D. Tang X. Li P. Zhang Y. Tao Y. Timing of initiation of renal replacement therapy in acute kidney injury: an updated meta-analysis of randomized controlled trials.Ren Fail. 2020; 42: 77-88Crossref PubMed Scopus (6) Google Scholar The recently published STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) multinational RCT randomized nearly 3000 critically ill patients (including 230 cardiac surgery patients) into early RRT or standard management of AKI, in which RRT was discouraged unless standard criteria for initiation were met.9STARRT-AKI Investigators Canadian Critical Care Trials Group Australian and New Zealand Intensive Care Society Clinical Trials Group United Kingdom Critical Care Research Group Canadian Nephrology Trials Network Irish Critical Care Trials Group et al.Timing of initiation of renal-replacement therapy in acute kidney injury.N Engl J Med. 2020; 383: 240-251Crossref PubMed Scopus (91) Google Scholar The primary end point of death at 90 days was similar between groups (43.9% vs 43.7%, P = .92). Prolonged RRT was observed at greater rates in 90-day survivors in the accelerated strategy group (10.4% vs 6%; relative risk, 1.74; 95% confidence interval [CI], 1.24-2.43). While the STARRT-AKI trial did include 230 patients who underwent cardiac surgery (accelerated [n = 112]; standard [n = 118]), there has not yet been a subgroup analysis of the cardiac surgery group. Significant heterogeneity in the population may limit the applicability of the results; thus, it is difficult to discern outcomes differences in cardiac surgery patients specifically based on the results of the STAART AKI trial. Selected studies have also examined the effect of fluid balance in critically ill populations regarding the timing of RRT initiation. In a large retrospective study of 18,084 critically ill patients with AKI from various etiologies,10Balakumar V. Murugan R. Sileanu F.E. Palevsky P. Clermont G. Kellum J.A. Both positive and negative fluid balance may be associated with reduced long-term survival in the critically ill.Crit Care Med. 2017; 45: e749-e757Crossref PubMed Scopus (60) Google Scholar positive fluid balance was associated with increased short- and long-term mortality (adjusted hazard ratio, 1.3-1.92) compared with even fluid balance. Negative fluid balance did show increased mortality risk using Gray's statistical model but not using logistic regression analysis. Interestingly, recovery of renal function was similar between all groups. A contrasting prospective study of 618 critically ill patients demonstrated fluid overload (>10% body weight) at the time of RRT initiation was associated with odds ratio of death of 2.07, and that patients with fluid overload at the time of peak creatinine were less likely to recovery kidney function long-term.11Bouchard J. Soroko S.B. Chertow G.M. Himmelfarb J. Ikizler T.A. Paganini E.P. et al.Program to Improve Care in Acute Renal Disease (PICARD) Study Group Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.Kidney Int. 2009; 76: 422-427Abstract Full Text Full Text PDF PubMed Scopus (686) Google Scholar There are fewer studies that specifically focus on the timing of RRT in cardiac surgery patients, and conclusions are somewhat conflicting. For instance, a 2016 retrospective study by Yang and colleagues12Yang X.-M. Tu G.-W. Gao J. Wang C.-S. Zhu D.-M. Shen B. et al.A comparison of preemptive versus standard renal replacement therapy for acute kidney injury after cardiac surgery.J Surg Res. 2016; 204: 205-212Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar included intraoperative and postoperative factors in the selection of patients for pre-emptive and standard RRT and found that a pre-emptive strategy had reduced rates of mortality. These findings were related to reducing fluid overload with early RRT compared with the standard treatment group. A 2014 meta-analysis of 841 cardiac surgery patients also reported a lower mortality in patients who received earlier RRT as compared with standard therapy (odds ratio [OR], 0.29; 95% CI, 0.16-0.52, P < .0001), and suggested a trend toward shorter length of stay in the intensive care unit (ICU). This meta-analysis included studies dating back as far as 1950, however, and a large degree of heterogeneity was observed, making generalization difficult.13Liu Y. Davari-Farid S. Arora P. Porhomayon J. Nader N.D. Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury after cardiac surgery: a systematic review and meta-analysis.J Cardiothorac Vasc Anesth. 2014; 28: 557-563Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Another large contemporary meta-analysis14Zou H. Hong Q. Xu G. Early versus late initiation of renal replacement therapy impacts mortality in patients with acute kidney injury post cardiac surgery: a meta-analysis.Crit Care. 2017; 21: 150Crossref PubMed Scopus (30) Google Scholar included 1479 cardiac surgery patients in 15 different studies and concluded that AKI treated with early RRT had decreased 28-day mortality (OR, 0.36; 95% CI, 0.23-0.57) and shortened ICU and hospital length of stay. A subgroup analysis was performed comparing the outcomes of cohort studies with the 5 RCTs. While the cohort studies supported the benefit of early RRT, the RCT analysis did not show a statistically significant decrease in mortality (OR, 0.41; 95% CI, 0.14-1.24). There was also an earlier meta-analysis15Seabra V.F. Balk E.M. Liangos O. Sosa M.A. Cendoroglo M. Jaber B.L. Timing of renal replacement therapy initiation in acute renal failure: a meta-analysis.Am J Kidney Dis. 2008; 52: 272-284Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar in 2008 that performed a subgroup analysis of RCTs and came to a similar conclusion that there was no survival benefit with earlier RRT initiation (RR, 0.64; 95% CI, 0.64-1.05; P = .08). How do we reconcile this difference and apply these data to our own patients? Dropout bias frequently seen in cohort studies can negatively impact studies looking at an intervention in regards to timing, because patients likely have a better prognosis if their disease process improves before initiation of the intervention. This is illustrated in the largest RCT on cardiac surgical patients to date, where more than one third of patients in the delayed RRT arm survived without ever needing RRT.16Combes A. Bréchot N. Amour J. Cozic N. Lebreton G. Guidon C. et al.Early high-volume hemofiltration versus standard care for post–cardiac surgery shock. The HEROICS study.Am J Respir Crit Care Med. 2015; 192: 1179-1190Crossref PubMed Scopus (68) Google Scholar In 2015, Crescenzi and colleagues17Crescenzi G. Torracca L. Pierri M.D. Rosica C. Munch C. Capestro F. “Early” and “late” timing for renal replacement therapy in acute kidney injury after cardiac surgery: a prospective, interventional, controlled, single-centre trial.Interact Cardiovasc Thorac Surg. 2015; 20: 616-621Crossref PubMed Scopus (15) Google Scholar attempted to avoid the dropout bias by prospectively enrolling 1658 cardiac surgery patient at the time of ICU admission, before any signs of postoperative renal insult. A total of 56 patients (3.6%) required RRT after cardiac surgery within this study. Patients in the “late” group (oliguria for >12 hours) required significantly less RRT than in the early group (oliguria for >6 hours), highlighting again the possibility that patients may recover renal function before requiring RRT. There was no significant difference in mortality or length of stay in the ICU or hospital between groups. Importantly, the authors looked at the “late” group and determined that patients who did not start RRT would have received RRT had been in the as the of their would have overall mortality was similar between a survival benefit was observed for a of patients with renal in the “late” RRT group. This may a benefit in for patients cardiac surgery with preoperative renal dysfunction, but more is in this of these trials use different such as urine output, and for initiation of RRT. the definition of versus “late” initiation of RRT significantly between with some trials using time from decreased urine output versus time after acute renal failure was of these not many complex factors to be and specifically in the cardiac postoperative these factors AKI but are not indicators for RRT. In patients cardiac surgery, volume are common in postoperative recovery and are by use of renal function is volume retention may lead to effects in a left or right and some have for earlier initiation of RRT to these The of AKI in postoperative heart transplant patients is also a with up to of patients requiring RRT, and an with greater hospital and mortality in these C. P. P. A. M.A. K. et kidney injury in patients cardiac a Google Scholar Shen and B. Xu J. Wang Y. Y. et of early renal replacement therapy for the treatment of acute kidney injury after heart a Cardiothorac Vasc Anesth. 2020; Full Text Full Text PDF Scopus Google Scholar a retrospective study of patients 10 time to determine timing for initiation of RRT in cardiac transplant patients with AKI postoperatively. Patients with earlier RRT had significantly lower mortality vs P = shorter ICU and hospital of stay, and lower overall to some of the recovery of renal function was more common in the accelerated RRT group than for the delayed cohort in this study. a 2020 retrospective study by Liu and H. D. J. A. et al.Early versus standard renal replacement therapy after left ventricular assist Surg. 2020; Scopus Google Scholar Kidney Disease: Improving Global Outcomes for AKI to determine the need for RRT in patients with a left ventricular assist In this an strategy was associated with a trend toward shorter ICU and hospital length of stay, as as lower need for RRT, with similar mortality between groups. is in the of and left ventricular assist devices, including high-quality prospective studies to examine the timing of RRT to in patients with an acute or right There has also been the that RRT may help the prognosis of critically ill patients by in addition to volume RCTs have examined RRT and in critically ill patients with is with many of such as and in patient populations and of of study have the applicability of and the results somewhat R. for renal replacement 2018; Scopus Google G. Y. J. P. Y. Li X. there a for in critically severe Fail. 2020; 42: PubMed Scopus Google Scholar RCT examining cardiac surgery patients with severe and renal RRT to and but found no significant differences in the RRT versus standard groups for mortality or renal A. Bréchot N. Amour J. Cozic N. Lebreton G. Guidon C. et al.Early high-volume hemofiltration versus standard care for post–cardiac surgery shock. The HEROICS study.Am J Respir Crit Care Med. 2015; 192: 1179-1190Crossref PubMed Scopus (68) Google Scholar These of have been recently in the of the disease and data are at this it has been that renal in patients supported on extracorporeal membrane oxygenation A large recent meta-analysis that included adult patients on demonstrated an increased risk of death (RR, 95% CI, P < for patients who required new RRT on S. K. G. K. use of renal replacement therapy extracorporeal membrane oxygenation a systematic review and meta-analysis.J Res. Scholar Fluid balance has been as a of mortality in patients receiving C.R. S.B. B. et patients treated with renal replacement therapy extracorporeal membrane a retrospective 2020; Scopus (7) Google Scholar there has been a trend toward survival in patients receiving the further is in this to define for initiation of RRT and to decrease renal in this complex It is clear the long-term effect of AKI after cardiac surgery is While the use of RRT can of renal function and help in the postoperative mortality is greater in patients who AKI after cardiac surgery of whether RRT is patients who do not recover to their baseline renal function may have the long-term mortality risk than those who do C. R. N. of acute kidney injury after cardiac surgery: a systematic review and meta-analysis.J Cardiothorac Vasc Anesth. 2016; 30: Full Text Full Text PDF PubMed Scopus Google Scholar from RCTs in care populations a delayed strategy may renal recovery and a high of of long-term RRT S. Hajage D. Benichou N. Chaïbi K. Barbar S. Zarbock A. et al.Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.Lancet. 2020; 395: 1506-1515Abstract Full Text Full Text PDF PubMed Scopus (44) Google L. Chen D. Tang X. Li P. Zhang Y. Tao Y. Timing of initiation of renal replacement therapy in acute kidney injury: an updated meta-analysis of randomized controlled trials.Ren Fail. 2020; 42: 77-88Crossref PubMed Scopus (6) Google J. Soroko S.B. Chertow G.M. Himmelfarb J. Ikizler T.A. Paganini E.P. et al.Program to Improve Care in Acute Renal Disease (PICARD) Study Group Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury.Kidney Int. 2009; 76: 422-427Abstract Full Text Full Text PDF PubMed Scopus (686) Google A. Bréchot N. Amour J. Cozic N. Lebreton G. Guidon C. et al.Early high-volume hemofiltration versus standard care for post–cardiac surgery shock. The HEROICS study.Am J Respir Crit Care Med. 2015; 192: 1179-1190Crossref PubMed Scopus (68) Google Scholar without an increased risk of mortality.

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