Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Biomarker-­guided implementation of the KDIGO guidelines to reduce the occurrence of acute kidney injury in patients after cardiac surgery (PrevAKI-­ multicentre): protocol for a multicentre, observational study followed by randomised controlled feasibility trial Mira Küllmar,1 Christina Massoth,1 Marlies Ostermann,2 Sara Campos,2 Neus Grau Novellas,2 Gary Thomson,2 Michael Haffner,2 Christian Arndt,3 Hinnerk Wulf,4 Marc Irqsusi,5 Fabrizio Monaco,6 Ambra Di Prima,6 To cite: Küllmar M, Massoth C, Mercedes Garcia Alvarez,7 Stefano Italiano,7 Virginia Cegarra SanMartin,7 Ostermann M, et al. Biomarker-­ Gudrun Kunst,8 Shrijit Nair,8 Camilla L'Acqua,9 Eric A J Hoste,10 guided implementation of the KDIGO guidelines to reduce Wim Vandenberghe,10 Patrick M Honore,11 John Kellum,12 Lui Forni,13 the occurrence of acute kidney Philippe Grieshaber,14 Raphael Weiss,15 Joachim Gerss,16 Carola Wempe,1 injury in patients after cardiac Melanie Meersch,1 Alexander Zarbock ‍ ‍1 Protected by copyright. surgery (PrevAKI-­multicentre): protocol for a multicentre, observational study followed by randomised controlled feasibility trial. BMJ Open Abstract Strengths and limitations of this study 2020;10:e034201. doi:10.1136/ Introduction Acute kidney injury (AKI) is a frequent bmjopen-2019-034201 complication after cardiac surgery with adverse short-­ ►► This will be the first multinational trial using a term and long-­term outcomes. Although prevention of AKI ►► Prepublication history and biomarker-­guided approach to detect high-­risk pa- (PrevAKI) is strongly recommended, the optimal strategy is additional material for this tients for acute kidney injury (AKI). paper are available online. To uncertain. The Kidney Disease: Improving Global Outcomes ►► The strength of the prevention of AKI (PrevAKI) mul- view these files, please visit (KDIGO) guideline recommended a bundle of supportive ticentre project is the combination of a survey with the journal online (http://​dx.​doi.​ measures in high-­risk patients. In a single-­centre trial, a multicentre-­randomised controlled trial to explore org/​10.​1136/​bmjopen-​2019-​ we recently demonstrated that the strict implementation routine clinical practice and to investigate the feasi- 034201). of the KDIGO bundle significantly reduced the occurrence bility of the study protocol in multiple centres. of AKI after cardiac surgery. In this feasibility study, MK and CM contributed equally. ►► The PrevAKI multicentre trial is not powered to eval- we aim to evaluate whether the study protocol can be MM and AZ contributed equally. uate the preventive effect of the Kidney Disease: implemented in a multicentre setting in preparation for a Improving Global Outcomes bundles on the occur- MK and CM are joint first large multicentre trial. rence of AKI and therefore a definitive future trial will authors. Methods and analysis We plan to conduct a prospective, be needed. observational survey followed by a randomised controlled, Received 10 September 2019 multicentre, multinational clinical trial including 280 Revised 09 February 2020 patients undergoing cardiac surgery with cardiopulmonary Accepted 04 March 2020 Ethics and dissemination The PrevAKI multicentre bypass. The purpose of the observational survey is to explore the adherence to the KDIGO recommendations in study has been approved by the leading Research Ethics routine clinical practice. The second phase is a randomised Committee of the University of Münster and the respective © Author(s) (or their controlled trial. The objective is to investigate whether Research Ethics Committee at each participating site. The employer(s)) 2020. Re-­use the trial protocol is implementable in a large multicentre, results will be used to design a large, definitive trial. permitted under CC BY-­NC. No multinational setting. The primary endpoint of the Trial registration number NCT03244514. commercial re-­use. See rights interventional part is the compliance rate with the protocol. and permissions. Published by Secondary endpoints include the occurrence of any AKI BMJ. and moderate/severe AKI as defined by the KDIGO criteria Introduction For numbered affiliations see within 72 hours after surgery, renal recovery at day 90, Acute kidney injury (AKI) is a well-­recognised end of article. use of renal replacement therapy (RRT) and mortality at complication after cardiac surgery.1 Correspondence to days 30, 60 and 90, the combined endpoint major adverse Depending on the definition used, AKI occurs Dr Alexander Zarbock; kidney events consisting of persistent renal dysfunction, in up to 45% of cardiac surgery patients, ​zarbock@​uni-​muenster.​de RRT and mortality at day 90 and safety outcomes. and approximately 1%–2% of patients who Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. require renal replacement therapy (RRT).2–4 The under- Objectives and aims lying mechanisms of cardiac surgery-­associated AKI are Aim 1 (observational study) not fully understood, but ischaemia-­reperfusion injury, To evaluate adherence with the KDIGO guidelines inflammation and tubular epithelial cell dysfunction in routine clinical practice, we will test the following often contribute.5 hypothesis: Independent of the underlying aetiology, AKI is asso- ►► Hypothesis I: the CV surgery AKI bundle is not applied ciated with increased morbidity and mortality, especially to all high-­risk patients undergoing cardiac surgery. in patients undergoing cardiac surgery with cardiopul- monary bypass (CPB).6 7 Although most patients develop Aim 2 (interventional trial) mild AKI, mortality rates in these patients are five times To demonstrate that the implementation of the CV higher compared with patients without AKI.8 Moreover, surgery AKI bundle in cardiac surgery patients at high patients who survive an episode of severe AKI are at risk for AKI is feasible in a multicentre trial, we will test the following hypothesis: high risk of developing chronic kidney disease (CKD), ►► Hypothesis II: it is possible to implement the CV which is associated with a worse long-­ term outcome surgery AKI bundle in high-­risk patients undergoing and a tremendous economic burden for the health- cardiac surgery in the context of a multicentre study. care system.9 Therefore, prevention of AKI has a high priority.10 Despite numerous clinical trials using different Methods and analysis pharmacological treatments, the optimal strategy to Design and setting prevent AKI is unknown. This study is a prospective, observational survey followed The Kidney Disease: Improving Global Outcomes by a randomised-­controlled, parallel group multicentre (KDIGO) guideline from 2012 includes various recom- trial conducted in 12 centres across Europe including the mendations to prevent AKI in high-­ risk patients, UK (online supplementary eTable S1). The concept of including the discontinuation of all nephrotoxic agents the study was approved by all members of the steering when possible, optimisation of volume status and haemo- committee (online supplementary eTable S2). The dynamics, consideration of a functional haemodynamic protocol follows Consolidated Standards of Reporting Protected by copyright. monitoring, close monitoring of serum creatinine and Trials and the conduct of the study is in accordance with urine output, avoidance of hyperglycaemia and consider- the Declaration of Helsinki (version Fortaleza, 2013). ation of alternatives to radiocontrast agents.11 The flow chart is summarised in figure 1. Investigations have revealed that adherence with treat- ment bundles is often low in routine clinical practice.12 Patient and public involvement In addition, treatment bundles need to be applied before In Germany, Italy, Spain and Belgium, patients and public the condition of interest actually develops. For AKI, this were not involved in the research design of the study. means that the KDIGO recommendations should be In the UK, members of the Kidney Patient Association implemented in high-­risk patients before the onset of AKI. reviewed the protocol and were involved in designing the Novel biomarkers have been shown to identify patients at patient information sheets. Study results will be published high risk for AKI. Although a variety of biomarkers can open access. At request, patients or their representatives predict AKI after cardiac surgery,13 point-­of-­care devices will be informed about the results of the trial. to measure biomarkers at the bedside are only for neutro- Participants phil gelatinase-­associated lipocalin (NGAL), and tissue In the survey, we will include all adult patients under- inhibitor of metalloproteinases-2 and insulin-­like growth going cardiac surgery with CPB on two consecutive days factor-­binding protein7 ([TIMP-2]*[IGFBP7]). NGAL is in all participating centres. influenced by different comorbidities whereas [TIMP- In the interventional trial, patients need to meet all 2]*[IGFBP7] has a very high specificity and very good eligibility criteria to participate in the trial. All four inclu- predictive value. Therefore, we decided to use [TIMP- sion criteria need to be fulfilled prior to randomisation: 2]*[IGFBP7] to identify patients at increased risk for (1) patients undergoing cardiac surgery with CPB, (2) AKI.14–16 urinary [TIMP-2]*[IGFBP7]≥0.3 at 4 hours after CPB, (3) In a single-­centre trial, we previously demonstrated age between 18 and 90 years and (4) written informed that biomarker-­ guided implementation of the cardio- consent. Patients are excluded if any of the following vascular (CV) surgery AKI bundle (derived from the criteria is present: pre-­existing AKI (≥stage 1), need for KDIGO bundle) significantly decreased the occurrence cardiac assist devices (extracorporeal membrane oxygen- of AKI in high-­risk patients undergoing cardiac surgery ation, left ventricular assist device, right ventricular (55.1% intervention vs 71.7% control group; p=0.004).17 assist device, intra-­aortic balloon pump), pregnancy or In preparation for a definitive adequately powered future breast feeding, known glomerulonephritis/interstitial randomised controlled trial (RCT), we designed the nephritis/vasculitis, CKD with an estimated glomerular prevention of acute kidney injury (PrevAKI) multicentre filtration rate <20 mL/min/1.73 m2, chronic dialysis feasibility study to test the protocol in a multicentre dependency, prior kidney transplant within the last 12 setting. months and participation in another interventional trial 2 Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 Open access BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Protected by copyright. Figure 1 Trial workflow. Patients will be screened in all participating sites for eligibility on a daily basis. Prior to enrolment, it is assured that none of the exclusion criteria are present and informed consent process is performed. Four hours after cardiopulmonary bypass (CPB), urine samples for the measurement of tissue inhibitor of metalloproteinases-2 and insulin-­like growth factor-­binding protein 7 [TIMP-2]*[IGFBP7] will be collected. In case [TIMP-2]*[IGFBP7] is ≥0.3, patients are at high risk and randomisation can be performed. Patients in the intervention group will receive a functional haemodynamic monitoring (according to the routine of each centre) immediately after randomisation and haemodynamic situation will be optimised according to a haemodynamic algorithm (figure 2). Laboratory test will be analysed and variables relevant for the assessment of renal and haemodynamic situation and safety will be recorded. Follow-­up will be performed after 30, 60 and 90 days. ACEi, ACE inhibitors; AKI, acute kidney injury; ARBs, angiotensin receptor blockers; eGFR, estimated glomerular filtration rate; HES, hydroxyethyl starch; KDIGO, Kidney Disease: Improving Global Outcomes; RRT, renal replacement therapy; SCr, serum creatinine. Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 3 Open access BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. within the last 3 months. In addition, patients with any consent has been obtained. The treatment protocol will kind of relationship with the investigator or employed by be applied immediately after randomisation. the sponsor/investigator and patients held in an institu- Blinding of the intervention is not possible. Study inter- tion by legal or official order will not be included in the vention will be performed by clinical staff involved in trial. anaesthesia and perioperative care. Endpoint assessment will be performed by a blinded researcher not involved Consent process in providing anaesthesia and perioperative care. Patients For the survey, written informed consent will be obtained will remain blinded to allocation. according to the country-­ specific requirement of the research ethics committee. Treatment For the interventional trial, a member of the research In the survey, there will be no study-­related treatment team will inform the patient about the nature of the trial, procedures. Every patient will be treated according to the its aims, potential benefits as well as possible risks (online standards at the individual centre. supplementary material 1). Participants will be asked to In the interventional trial, 4 hours after CPB, urinary give written consent to participate in the study prior to [TIMP-2]*[IGFBP7] will be measured to identify patients surgery. The consent form will be countersigned by a at high risk for AKI. Patients with a value ≥0.3 (ng/ member of the research team. The original document mL)2/1000 will be randomised to one of the two treat- will be stored in a secure place and the patient will receive ment arms. a copy. If the patient is unable to provide written consent, Control group: patients will receive standard of care as a legally authorised representative will be consulted. If an per centre. authorised representative is not immediately available, Intervention group: the CV surgery AKI bundle will be the research team will follow the agreed recommenda- strictly implemented. tions of their local research ethics committee or country-­ At different time points, blood and urine samples from specific institutional review boards. recruited patients will be collected to analyse different All data will be kept confidential and will be stored in biomarkers. All other therapies will be directed by the patient’s clinical team. All medications will be dose Protected by copyright. pseudonymised form. The patient has the right to with- draw from the study at any time without providing a reason adjusted according to renal function in accordance with and without their medical treatment being affected. standard dosing guidelines. Observation CV surgery AKI bundle In the observational part, all adult patients undergoing The CV surgery AKI bundle includes the following cardiac surgery in the participating centres will be measures: ►► Discontinuation of all nephrotoxic agents if possible. included. Data regarding routine management will be ►► Haemodynamic monitoring and optimisation collected, especially the adherence with the different elements of the KDIGO bundle (online supplementary according to a predefined haemodynamic algorithm material 2). This includes (1) discontinuation of all neph- (figure 2). ►► Close monitoring of serum creatinine (twice a day), rotoxic agents, (2) optimisation of volume status and haemodynamics (target mean arterial pressure (MAP) fluid balance (twice a day) and urine output (every ≥65 mm Hg (not fulfilled if MAP is <65 mm Hg and no hour as long as the patient has a Foley catheter; if the treatment is initiated to achieve this goal), (3) functional patient does not have a Foley catheter, the urine is collected for a certain time period and divided by the haemodynamic monitoring (including echocardiog- number of hours to calculate hourly urine volume). raphy, pulse contour cardiac output or pulmonary artery ►► Avoidance of hyperglycaemia (defined as >150 mg/ catheter), (4) close monitoring of serum creatinine dL for more than 3 hours) by close monitoring for the every 12 hours and urine output hourly, (5) avoidance first 72 hours after surgery. of hyperglycaemia (blood glucose levels ≤150 mg/dL or ►► Consideration of alternatives to radio contrast agents. ≤8.3 mmol/L) and (6) avoidance of radiocontrast agents. ►► Discontinuation of ACE inhibitors and angiotensin II receptor blockers for the first 48 hours after surgery. Randomisation and blinding ►► Avoidance of hydroxyethyl starch, gelatin and In the interventional trial, randomisation will be chloride-­rich solutions. performed centrally using a web-­ based randomisation system provided by the European Society of Intensive Outcomes Care Medicine. Randomisation lists will be stratified by In the survey, we will explore whether the different centre, and generated using block randomisation with elements of the KDIGO bundle are already incorporated randomly varying block sizes. Randomisation assignment into routine clinical practice in the different centres. The (in a 1:1 ratio to the two treatment arms) will be given primary endpoint of this observation is the binary indi- only to those patients who fulfil the inclusion criteria and cator whether the CV surgery AKI bundle is completely have none of the exclusion criteria, and where informed fulfilled at all times or not. 4 Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 Open access BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Figure 2 Haemodynamic algorithm of the intervention group. Patients of the intervention group will receive a functional haemodynamic monitoring and an optimisation according to a haemodynamic algorithm consisting of three steps which need to be checked every 3 hours: step 1—performance of the passive leg raising test. If the cardiac output (CO) increases by >10%, then volume has to be supplemented (crystalloids 500–1000 mL according to the treating intensivist). If CO is ≤10%, step 2— measurement of the cardiac index (CI). If the CI is <2.5 L/min/m2, then dobutamine or epinephrine (according to the treating intensivist) needs to be applied. If CI is >2.5 L/min/m2, then step 3—measurement of mean arterial pressure (MAP). If the MAP is <65 mm Hg, then norepinephrine needs to be adjusted. If MAP is >65 mm Hg, then the goal is achieved. This is checked every 3 hours up to 12 hours after randomisation. PLRT, passive leg raising test. Secondary outcomes will include Sample size Protected by copyright. ►► adherence to the different components of the KDIGO For the survey, no power analysis is required. The number bundle. of patients is based on surgical volumes in the two consec- The primary outcome of the interventional trial is the utive days prior to the interventional trial and is expected compliance rate defined as proportion of patients who to be about n=100. are treated according to the trial protocol (CV surgery In the interventional trial, 1000 patients will be assessed AKI bundle fulfilled at all time). Adherence to the trial for eligibility, and 280 patients will be enrolled into the trial and randomised (based on our previous findings). protocol is achieved if all elements of the bundle are This sample size is determined as follows: followed. In addition, we will calculate the adherence Patients will be randomised in a 1:1 ratio to one of the with the different individual components of the bundle. two treatment arms (intervention vs control). Randomisa- Secondary outcomes include: tion serves to estimate the incidence of AKI as a secondary ►► Occurrence of AKI within the first 72 hours after outcome to generate preinformation in preparation for cardiac surgery (AKI as defined by the KDIGO an upcoming confirmatory trial. criteria). The primary endpoint of the interventional trial is the ►► Moderate and severe AKI within 72 hours (according compliance rate, that is, the proportion of patients treated to the KDIGO criteria). according to the trial protocol (intervention group: CV ►► Free days through day 28 of vasoactive medications surgery AKI bundle fulfilled at all time; control group: and mechanical ventilation. documented standard of care according to current clin- ►► Renal recovery (defined as serum creatinine <0.5 mg/ ical practice). In order to estimate the compliance rate, dL higher than baseline) at days 30, 60 and 90. the two treatment groups will be pooled together. In the ►► All-­cause mortality at days 30, 60 and 90. primary analysis, the compliance rate across all study ►► Length of stay in intensive care unit and hospital. patients will be estimated along with a two-­sided 95% CI. As the compliance rate cannot be quantified in advance, ►► Use of RRT at days 30, 60 and 90. we pursue a worst-­case approach and assume a compli- ►► Major adverse kidney events (MAKE90 consisting ance rate of 50%. In this case, the CI has maximal width. of mortality, dialysis dependency persistent renal Based on this assumption, with a sample size of n=280 dysfunction at day 90). patients, the calculated 95% CI according to Clopper-­ ►► Determination of different biomarkers (eg, TIMP2, Pearson (Fleiss 2003) ranges from 44% to 56%. There- IGFBP7, NGAL, kidney injury molecule-1, chitinase, fore, in case of any observed compliance rate apart from hyaluronic acid). the worst-­case scenario, the 95% CI is never wider than ►► Complications related to the implementation of the 56%−44%=12%. This corresponds to an estimation of the KDIGO guidelines documented (eg, arrhythmias). compliance rate with a precision of ±6%. Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 5 Open access BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. Statistical analysis The Standard Protocol Items: Recommendations forIn- The study is designed to examine the feasibility of the terventional Trials checklist is included in the online trial protocol in a multicentre setting (as previously supplementary material. described). In the observational study, we will evaluate whether the different elements of the KDIGO guidelines are already Discussion implemented in routine clinical practice. The primary The PrevAKI-­multicentre study is a prospective, observa- endpoint of the observational study is the binary indicator tional survey followed by randomised controlled, multi- whether the CV surgery AKI bundle is completely fulfilled centre and multinational, clinical trial with the primary at all times or not. Descriptive data analyses will include the goal to investigate the feasibility of the study protocol in calculation of means, SD and absolute and relative frequen- a multicentre and multinational setting. In the absence cies. No formal statistical hypothesis will be tested. of any preventive pharmacological options, the KDIGO In the interventional trial, beyond descriptive analyses, guidelines recommend a bundle of supportive measures inferential statistical analyses will be performed. In the in patients at high risk for AKI.11 Whether these recom- primary statistical analysis, the two treatment groups will mendations truly reduce the occurrence of AKI remains be pooled together and the compliance rate across all to be confirmed. In the first single-­centre randomised recruited study patients will be estimated along with a two-­ controlled PrevAKI trial, we could demonstrate that the sided 95% CI according to Clopper-­Pearson (Fleiss 2003). new renal biomarkers [TIMP-2]*[IGFBP7] identified Randomisation serves to estimate the incidence of AKI patients at high risk for the development of AKI and separately in two treatment groups as secondary outcome, that the CV surgery AKI bundle significantly reduced in order to generate preinformation in preparation for the occurrence of AKI by 15%.17 A further single-­centre an upcoming confirmatory trial. Randomisation will be trial demonstrated similar results in patients undergoing checked by suitable two-­sided statistical tests (χ2, or Fish- major abdominal surgeries receiving a bundled interven- er’s exact test for categorical data, Students’ t-­test or Mann-­ tion.18 However, these were single-­centre trials and single-­ Whitney U tests for continuous data). If normality of the centre trials often show positive results. A large RCT is data is not given, non-­parametric methods will be used. Protected by copyright. needed to confirm these findings. In preparation, it is Secondary endpoints will be analysed in the intention necessary to explore first how many patients are already to treat collective using Fisher’s exact tests or χ2 tests for treated according to the KDIGO recommendations and categorical data, and Student’s t-­tests or Mann-­Whitney U second whether the implementation of the CV surgery tests for continuous data. In a secondary analysis, we will AKI bundle is feasible in a multicentre, multinational investigate whether there is a difference in the incidence setting. The results will inform the researchers whether of AKI as defined by serum creatinine, urine output and changes to the protocol are required before proceeding the composite of the two between the treatment groups. with a large trial to reduce the occurrence of AKI after Prognostic risk factors for AKI will be identified using a cardiac surgery. multivariable logistic regression analysis, accounting for confounding factors. In particular, based on a full model with potentially relevant covariates (eg, sex, age, previous Trial status heart surgery, preoperative creatinine), the final model Recruitment started in November 2017. We estimate to will be established applying a stepwise variable selection complete the study in January 2020. procedure. Author affiliations 1 Anesthesiology, Intensive Care and Pain Medicine, Universitatsklinikum Munster, Ethics and dissemination Munster, Nordrhein-­Westfalen, Germany The PrevAKI-­ multicentre study has been approved by 2 Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, the leading Research Ethics Committee of the Univer- London, UK 3 Department of Anesthesiology and Operative Intensive Care, University Hospital sity of Münster (2017-291 f-­ S) and the corresponding Marburg, Marburg, UK Research Ethics Committee at each participating site 4 Anesthesiology & Intensive Care Medicine, Philipps-­Universitat Marburg (online supplementary eTable S3). Trial oversight will Fachbereich Medizin, Marburg, Germany be performed by an independent Data Safety and Moni- 5 Department of Cardiothoracic Surgery, Philipps-­Universitat Marburg Fachbereich toring Board. The task is to oversee the safety of the Medizin, Marburg, Germany 6 trial subjects and to monitor integrity and validity of the Intensive Care and Anesthesia Unit, Scientific Institute San Raffaele, Milano, Italy 7 Department of Anesthesiology, Hospital de la Santa Creu i Sant Pau, Barcelona, conduct of the clinical trial. Catalunya, Spain The results will be presented at national as well as 8 Department of Anesthesia, Critical Care and Pain, King's College London, London, international conferences. The final manuscript will be UK 9 published in a peer-­reviewed journal and results will be Department of Anesthesia and Critical Care, Centro Cardiologico Monzino IRCCS, Milano, Lombardia, Italy used to design a large multicentre trial with the primary 10 ICU, Universiteit Gent, Gent, Belgium objective to investigate whether the implementation of 11 Department of Intensive Care, CHU Brugmann, Brussels, Belgium the CV surgery AKI bundle reduces the occurrence of 12 Center for Critical Care Nephrology, Department of Critical Care Medicine, AKI in high-­risk patients undergoing cardiac surgery. University of Pittsburgh, Pittsburgh, Pennsylvania, USA 6 Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 Open access BMJ Open: first published as 10.1136/bmjopen-2019-034201 on 6 April 2020. Downloaded from http://bmjopen.bmj.com/ on October 26, 2023 at Univesity Autonomous of Barcelona. 13 Department of Intensive Care Medicine, Royal Surrey County Hospital NHS Trust, conference of the ADQI (acute disease quality initiative) group. J Am Guildford, UK Heart Assoc 2018;7. doi:10.1161/JAHA.118.008834. [Epub ahead of 14 Department of Cardiac Surgery, Justus Liebig Universität Giessen Fachbereich print: 01 Jun 2018]. 2 Chertow GM, Lazarus JM, Christiansen CL, et al. Preoperative renal Medizin, Giessen, Hessen, Germany 15 risk stratification. Circulation 1997;95:878–84. Department of Anaesthesiology, University Hospital Münster, Münster, Germany 3 Hobson CE, Yavas S, Segal MS, et al. Acute kidney injury is 16 Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-­Universität associated with increased long-­term mortality after cardiothoracic Münster, Münster, Germany surgery. Circulation 2009;119:2444–53. 4 Koyner JL, Bennett MR, Worcester EM, et al. Urinary cystatin C as an Acknowledgements The authors would like to thank all the participating centres early biomarker of acute kidney injury following adult cardiothoracic and corresponding staff member involved in this trial. surgery. Kidney Int 2008;74:1059–69. 5 Rosner MH, Okusa MD. Acute kidney injury associated with cardiac Contributors MK, CM, RW, SC, NGN, GT, MH, CA, HW, MI, FM, ADP, MGA, SI, VCS, surgery. Clin J Am Soc Nephrol 2006;1:19–32. GK, SN, CL, WV, PMH, PG, RW performed the study and drafted the manuscript. 6 Wijeysundera DN, Karkouti K, Dupuis J-­Y, et al. Derivation and MO and EAJH helped designing the trial, performed the study and drafted the validation of a simplified predictive index for renal replacement manuscript. JK, LF and JG helped designing the trial and drafted the manuscript. therapy after cardiac surgery. JAMA 2007;297:1801–9. CW helped designing the trial, performed study coordination and drafted the 7 Ostermann ME, Taube D, Morgan CJ, et al. Acute renal failure manuscript. MM and AZ conceived the study, designed the trial and drafted the following cardiopulmonary bypass: a changing picture. Intensive manuscript. All authors read and approved the final manuscript. MM and AZ share Care Med 2000;26:565–71. 8 Kellum JA, Bellomo R, Ronco C. Kidney attack. JAMA last authorship. 2012;307:2265–6. Funding The trial is supported by the European Society of Intensive Care Medicine. 9 Basile DP, Bonventre JV, Mehta R, et al. Progression after AKI: understanding maladaptive repair processes to predict and identify Disclaimer The content of this paper is solely the responsibility of the authors and therapeutic treatments. J Am Soc Nephrol 2016;27:687–97. does not necessarily represent the official views of the funding agency. 10 Kellum JA, Angus DC. Patients are dying of acute renal failure. Crit Competing interests MM, JK and AZ have received lecture fees from Astute Care Med 2002;30:2156–7. Medical, Fresenius and Baxter, unrelated to the current study. JK and AZ have 11 Kellum J ALN, Aspelin P, Barsoum RS, et al. KDIGO clinical received grant support from Astute Medical, unrelated to the current study. MO practice guideline for Acte kidney injury 2012. Kidney Int Suppl 2012;2:1–138. has received lecture fees from Biomerieux, Fresenius Medical and Baxter. CA 12 Leone M, Ragonnet B, Alonso S, et al. Variable compliance with has received lecture fees from Baxter. LF has received research funding from clinical practice guidelines identified in a 1-­day audit at 66 French Baxter and Ortho Clinical Diagnostics, consultancy fees from Medibeacon/La Jolla adult intensive care units. Crit Care Med 2012;40:3189–95. Pharmaceuticals and honoraria from Biomerieux/Astute. 13 Parikh CR, Coca SG, Thiessen-­Philbrook H, et al. Postoperative Patient consent for publication Not required. biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. J Am Soc Nephrol 2011;22:1748–57. Protected by copyright. Provenance and peer review Not commissioned; externally peer reviewed. 14 Kashani K, Al-­Khafaji A, Ardiles T, et al. Discovery and validation of Open access This is an open access article distributed in accordance with the cell cycle arrest biomarkers in human acute kidney injury. Crit Care Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 2013;17:R25. 15 Meersch M, Schmidt C, Van Aken H, et al. Urinary TIMP-2 and permits others to distribute, remix, adapt, build upon this work non-­commercially, IGFBP7 as early biomarkers of acute kidney injury and renal recovery and license their derivative works on different terms, provided the original work is following cardiac surgery. PLoS One 2014;9:e93460. properly cited, appropriate credit is given, any changes made indicated, and the use 16 Engelman DT, Ben Ali W, Williams JB, et al. Guidelines for is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. perioperative care in cardiac surgery: enhanced recovery after surgery Society recommendations. JAMA Surg 2019. doi:10.1001/ ORCID iD jamasurg.2019.1153. [Epub ahead of print: 04 May 2019]. Alexander Zarbock http://​orcid.​org/​0000-​0002-​2124-​1714 17 Meersch M, Schmidt C, Hoffmeier A, et al. Prevention of cardiac surgery-­associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med 2017;43:1551–61. References 18 Göcze I, Jauch D, Götz M, et al. Biomarker-­Guided intervention 1 Nadim MK, Forni LG, Bihorac A, et al. Cardiac and vascular Surgery-­ to prevent acute kidney injury after major surgery: the prospective Associated acute kidney injury: the 20th international consensus randomized BigpAK study. Ann Surg 2018;267:1013–20. Küllmar M, et al. BMJ Open 2020;10:e034201. doi:10.1136/bmjopen-2019-034201 7