External Validation Study of a Laboratory-based Perioperative Prediction Model for Acute Kidney Injury After Cardiac Surgery.
Conditions: Cardiac Surgery Associated - Acute Kidney Injury, CKD (Chronic Kidney Disease) Stage 5D, Acute Kidney Injury, Acute Kidney Disease
Sponsor: Universidad de Oviedo

External validation study of a 
laboratory-based perioperative 
prediction model for acute kidney 
injury after cardiac surgery. 
 
 
 
 
 
 
Protocol version:  October 2023 
Sponsor: Department of Anaesthesiology and Critical Care. University Clinic of Navarra. 
Department of Anaesthesiology and Critical Care. Hospital Universitario Central de Asturias. 
 
 
 
 

1.General Information ___________________________________________________ 4 
1.1 Title __________________________________________________________________ 4 
1.2 Protocol version ________________________________________________________ 4 
1.3 Sponsor of the study _____________________________________________________ 4 
1.4 Coordinating researcher __________________________________________________ 4 
1.5 Methodology of the study ________________________________________________ 4 
1.6 Coordination and monitoring of the study ___________________________________ 4 
1.7 Steering Committee _____________________________________________________ 5 
1.8 Scientific Committee _____________________________________________________ 5 
1.8 Clinical Research Ethics Committee _________________________________________ 5 
1.9 Participating Centres _____________________________________________________ 5 
2. Background and current status of the issue ________________________________ 6 
3. Hypothesis __________________________________________________________ 7 
4. Objectives ___________________________________________________________ 7 
4.1 Main __________________________________________________________________ 7 
4.2 Secondary _____________________________________________________________ 7 
5. Methodology ________________________________________________________ 8 
5.1 Design ________________________________________________________________ 8 
5.2 Study population ________________________________________________________ 8 
5.3 Ethical aspects __________________________________________________________ 8 
5.4 Inclusion criteria ________________________________________________________ 8 
5.5 Exclusion criteria ________________________________________________________ 8 
5.6 Study variables _________________________________________________________ 8 
5.7 
Sample size estimation ______________________________________________ 13 
5.8 
Data collection _____________________________________________________ 14 

5.9 
Analysis of results __________________________________________________ 14 
5.10 
Limitations of the study ______________________________________________ 14 
5.11 
Timeline __________________________________________________________ 14 
6.  Ethical aspects ______________________________________________________ 15 
7.  Dissemination of research results and substudies __________________________ 16 
8.  Data management and ownership______________________________________ 16 
9.  Privacy and use of clinical information __________________________________ 17 
10. 
Legal and organisational aspects ___________________________________ 17 
10.1 
Trial funding _______________________________________________________ 17 
10.2 
Compensation _____________________________________________________ 17 
11. Bibliography _______________________________________________________ 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1.General Information
1.1 Title: External Validation Study of a Laboratory-Based Perioperative 
Prediction Model for Acute  Kidney Injury after Cardiac Surgery 
1.2 Protocol version
3.0 
1.3 Sponsor of the study 
1.4 Coordinating researcher 
1.5 Methodology of the study 
1.6 Coordination and monitoring of the study 

1.8 Scientific Committee 
1.8 Clinical Research Ethics Committee
The Clinical Research Ethics Committee of the Principality of  Asturias approved version 
1.0: CEImPA Code 2023.111 
1.9 Participating Centres 
All anaesthesia services and intensive care units of all European hospitals with cardiac 
surgery services will be invited to participate, most of them belonging to the 
Spanish group of renal dysfunction in cardiac surgery (GEDRCC2).  

2. Background and current status of the issue
Acute Kidney Injury (AKI) is a major complication of cardiac surgery and its most severe 
forms are associated with significant morbidity and mortality[1][2] . 
Identification of patients at risk may facilitate early use of management protocoolos 
recommended by KDIGO (Kidney Disease: Improving Global Outcomes), such as 
haemodynamic and volume optimisation, monitoring of renal function and 
discontinuation or reduction of nephrotoxic drugs[3][4] . The rate associated with cardiac 
surgery varies according to its different historical definitions, from 0.3% to 29.7%[5][6] . 
Cases requiring renal replacement therapy (RRT) occur between 1 .2%-3.0% in the 
studied cardiac surgery cohorts and their presence is a n independent predictor of 
mortality. 
Because AKI still lacks effective treatments in addition to support and elimination of the 
cause, early and specific diagnosis is an unmet but critical need f o r successful and 
personalised patient management. [8][9][10] 
Creatinine, urea and urine output have been and are the main ways to diagnose and treat 
renal failure. Other types of biomarkers that seem to be related to risk of postoperative 
AKI are currently under study. Although more research is needed, they may eventually 
become predictive diagnostic tools. Several studies have indicated that the urinary level 
of NGAL[11][12] excreted intraoperatively and after surgery is effective in predicting AKI 
in both adult and paediatric populations. Similar results have been obtained with other 
urinary biomarkers, such as the cell cycle arrest biomarkers TIMP-2 and IGFBP7)[11] 
KIM-1, NAG, IL-18 and L-FAP[12] . The major limitation of these biomarkers is that they 
are not easily accessible in all hospitals and clinical settings. Recently Demirjian et al[13] 
developed a predictive model in which they observed that perioperative change in serum 
creatinine and postoperative blood urea nitrogen, serum sodium, potassium, bicarbonate 
and albumin from the first metabolic panel after cardiac surgery show good predictive 
value for moderate to severe AKI within 72 hours and 14 days after the surgical procedure. 

3. Hypothesis 
 
The score developed by Demirjian et al has a good predictive ability for moderate 
to severe AKI after cardiac surgery in the European population. 
4. Objectives 
 
4.1 Main 
- Confirm the usefulness and externally validate the scale. 
- Compare this scale with other models of AKI prediction after cardiac    surgery: 
Thakar, Mehta, ISR, Callejas, Leicester, CRATE. 
4.2 Secondary 
- Identify new risk factors for Acute Kidney Injury (AKI)  
- Understanding the incidence of AKI after cardiac surgery in Europe 
- Validating a model for predicting discharge dialysis after cardiac surgery 
- Investigate the performance of these models in specific surgeries: coronary 
surgery without cardiopulmonary bypass  and heart transplantation. 
- Assess the performance of other scales and compare them. 
- Determine the prevalence and risk factors for Acute Kidney Disease (AKD) 
(renal injury beyond 7 days, up to 90 days). 
- Determine the prevalence and risk factors for new Chronic Kidney Disease 
(CKD) (follow-up for 120 days or 4 months). 
- Determine the prevalence and risk factors for CKD progression, defined by a 
one-stage progression in patients with pre-existing CKD. Follow-up for 120 days 
(4 months). 
 

5. Methodology 
 
5.1 Design: descriptive, observational, prospective, multicentre, prospective 
study. 
5.2 Study population: patients undergoing cardiac surgery. 
5.3 Ethical aspects: the study has been approved for assessment by the Ethical 
Committee for Research with Medicines of the Principality of Asturias. 
5.4 Inclusion criteria: All patients over 18 years of age undergoing cardiac 
surgery. 
5.5 Exclusion criteria 
- Exitus in the first 48h postoperative period 
- Patient undergoing renal replacement therapy or preoperative dialysis 
- Minor" cardiac surgery ( sternal dehiscence, MCP removal or implantation, pericardial 
window) 
 
5.6 Study variables 
 
  Hospital 
Age  
Sex 
Male  
Female 
Race 
Asian 

Black  
Multiracial  
White  
Weight (kg)  
Height(cm)  
BMI 
 
 
Comorbidities 
Hypertension 
Insulin-dependent diabetes  
Non-insulin-dependent diabetes  
Congestive heart failure  
Coronary artery disease  
Tripple Vessel coronary artery disease 
Chronic obstructive pulmonary disease 
Poor mobility (musculoskeletal, neurological)  
Chronic kidney disease 
Peripheral vascular disease 
Atrial fibrillation  
Liver disease 
NYHA (New York Heart Association Functional Classification)  
Left ventricular ejection fraction (LVEF) %   
Pulmonary systolic pressure (mmHg)  

Unstable angina 
Recent miocardial infarction (90 days) 
Smoker YES/NO/Ex-smoker 
Receives iSGLT2 (dapagliflozin, canaglifozin, empagliflozin...)  
Receives GLP1 agonists (liraglutide, semaglutide, dulaglutide...)  
Receives calcium antagonists (verapamil, nifedipine, amlodipine...) 
Preoperative values 
Serum creatinine (mg/dL) 
FGe by Cockroft-Gault mL/min/1.73 m² 
FGe by EPI CKD ml/min 
eGFR by MDRD ml/min/ 
Serum Albumin (mg/dL) 
Serum Urea (mg/dL) or Serum BUN (mg/dL) 
Serum sodium (mmol/L) 
Serum potassium (mmol/L) 
Serum bicarbonate (mmol/L) 
Haemoglobin (mg/dL) 
Platelets 
Bilirubin (mg/dL) 
Surgery 
On-pump CABG  
Off-pump CABG  
Valvular 
Aortic 
Combined (coronary+valvular)  
Other, multiple procedures (>2)  
Heart transplant 
Previous heart surgery 

YES/NO 
Euroscore II  
Classification Surgery 
Emergent  
Urgent  
Elective 
Salvage (pre-operative cardiopulmonary resuscitation) 
Catheter to surgery 
Within 24 h 
>24 h this admission 
>24 h previous admission 
No catheter prior to surgery 
Pre-operative critical status (IABP, mechanical ventilation, VT, CRP, amines, renal 
failure) 
YES/NO 
Endocarditis at the time of surgery 
YES/NO 
Preoperative cardiogenic shock 
YES/NO 
 
Use of IABP prior to surgery 
YES/NO 
Intraoperative variables 
CPB (cardiopulmonary bypass) time min  
Aorta cross-clamp time (min)  
Vasopressors YES/NO  
Inotropes YES/NO 
Red blood cell transfusion YES/NO 

Number of red cell concentrates transfused  
Platelet transfusion YES/NO 
Fresh Frozen Plasma Transfusion YES/NO  
Intraoperative diuresis (ml) 
Nadir hemoglobin (lowest intraoperative in mg/dL) 
Antibiotic (Gentamicin, Vancomycin, Cefazolin...) 
Immediate postoperative values 
Time from end of surgery to first analytical panel (hours)  
Serum creatinine (mg/dL) 
Serum albumin (mg/dL)  
Urea (mg/dL) or BUN (mg/dL) 
Serum sodium (mmol/L)  
Serum potassium (mmol/L)  
Serum chlorine (mmol/L)  
Serum bicarbonate (mmol/L)  
Lactate (mmol/L) 
Urgent re-intervention first 24h 
YES/NO  
Length of hospital stay (days) 
 Discharge status 
Discharge 
Éxitus 
Need for  dialysis at discharge 
YES/NO 
 
 
Postoperative renal failure 

Creatinine at ICU  admission   
  
  
  
  
Creatinine at  24h   
  
  
  
  
  
Creatinine at 48h  
Creatinine at 72h  
Peak creatine 4th to 7th day     
  
  
  
  
Peak creatine 7th to 14th day   
  
  
  
 
 
  
Last  creatinine at hospital discharge 
Does the patient develops Stage 1 AKI in the first 14 days? 
*Stage 1 AKI: (↑) Creatinine 1.5-1.9 times baseline or  ≥0.3 mg/dL increase 
 If yes, which day? 
 
Does the patient develops Stage 2 AKI in the first 14 days? 
*Stage 2 AKI: (↑) Creatinine 2-2.9 times baseline   
 
 
 
 
If yes, which day? 
Does the patient develops severe AKI in the first 14 days? 
* Stage 3 AKI : (↑) Creatinine  ≥3 times baseline or  ≥ 4 mg/dLincrease or dialysis. 
If yes, which day? 
Does the patient requires renal replacement therapy within the 
first 14 days?  
 
 
 
 
 
 
 
If yes, which day? 
5.7 Sample size estimation: Taking into account an incidence of moderate 
severe AKI in Spain of 9% according to previous studies and using the 

Wilcoxon test, 1045 patients are needed to detect a difference of 0.1 in aROC 
with a power of 80% and an alpha error of 0.05. Assuming a 10% loss to 
follow-up, 1150 patients would be needed. 
5.8 Data collection: a data collection notebook will be used to carry out the 
study. The researcher will include in it the sample of patients, without any 
data that would allow their identification.  
5.9 Analysis of results: the results will be analysed using the statistical 
package IBM-SPSS 20.0 for Mac OS and RStudio version 1.1.463. The basic 
statistics of centralisation and dispersion will be used to describe the results. 
For comparison of means, t-tests for independent data or Mann-Whitney U-
tests will be used in those cases where the conditions for their application are 
violated. Chi-square tests shall be used for comparison of proportions. 
Bonferroni correction shall be applied for multiple contrasts. To study the 
predictive ability, 2 measures will be studied, the discrimination ability by 
means of the area under the ROC curve and the calibration by means of the 
Hoshmer Lemeshow  Test. The areas under the ROC curve will be compared 
using the Mann-Whitney U test. 
 
5.10 Limitations of the study 
Those due to the prospective study design and those arising from the impossibility of 
reviewing the patients included in the database. 
 
5.11 Timeline 
- 
Completion of the project protocol and application to the ethics 
committee: February-March 2023 
- 
Completion of the database: from obtaining the ethics committee to 
completing the sample size: 

6-12 months 
- 
Statistical analysis: 2 months 
- 
Project drafting: 6-12 months 
- 
 
6.  Ethical aspects 
 
This study will follow the ethical principles set out in the Declaration of Helsinki, the 
Council of Europe Convention on Human Rights and Biomedicine and the Unesco 
Universal Declaration on the Human Genome and Human Rights. In addition, it will 
comply with the requirements of Spanish legislation in relation to biomedical research, 
personal data protection and bioethics. To ensure its approval, it will be submitted to the 
Research Ethics Committee (EC) and only patients who have signed an informed consent 
form will be included. Confidentiality and data security will be maintained in the 
following areas 
The research manager will be responsible for maintaining the records at each site and 
determining the publication policy. 
 
 
 

7.  Dissemination of research results and substudies 
 
The Scientific Committee will appoint an Editorial Committee to prepare the 
scientific report(s) of this research, which will be disseminated in due course. A 
number of secondary analyses are expected to be carried out, the conduct of which 
will be prioritised by the investigators and they will be encouraged to carry them 
out. Participation in these analyses will be based on the contribution to the study 
in their respective fields. The Steering Committee, before granting any 
application, will consider both the scientific validity and the possible impact on 
the anonymity of the participating centres. If required, the terms of collaboration 
will be established in advance by written agreement. The approval of the final 
version of all manuscripts, prior to submission, rests with the Scientific 
Committee. In case of disagreement within the Steering Committee, the Head of 
Research will make the final decision. 
 
8.  Data management and ownership 
 
The study sponsor will act as the data custodian. In accordance with the principles 
of data preservation and data sharing, the Steering Committee, following 
publication of the overall database, will consider all reasonable requests for 
secondary analyses. The quality and validity of any proposed analysis shall be the 
main criteria to be taken into account when deciding on such requests. Only 
summary data will be publicly disclosed and it will be ensured that all data at 
international, national, institutional and patient level will be strictly anonymised. 
Patient data provided by participating hospitals are the sole property of their 
respective institutions. Once each local coordinator has confirmed the 
completeness and accuracy of the data provided by their hospital, the data will be 
transferred to a general database. The complete dataset of the participants will be 
coded for patients, hospitals and communities, and will be made freely available 
to the public for two years from the publication of the main scientific report. Prior 

to this deadline, the Scientific Committee will not be obliged to release the data 
to any collaborator or third party if it considers that this does not align with the 
broader objectives of the project. All identifiable data collected, processed and 
stored for project purposes will be kept confidential at all times and will comply 
with Good Clinical Practice for Research (GCP) guidelines and the General Data 
Protection Regulation (GDPR) EU Regulation 2016/679. 
9.  Privacy and use of clinical information 
 
The processing, communication and transfer of data will be carried out in a c c o r d a n c 
e with the provisions of Regulation (EU) 2016/679 of the European Parliament and of the 
Council of 27 April 2016  on the protection of individuals with regard to data processing. 
and the free movement of data, and the Ley Org nica 3/2018, de 5 de diciembre, de 
Protecci n de Datos Personales y garant a de los derechos digitales. 
10. Legal and organisational aspects. 
10.1 Trial funding The study is not currently funded. 
10.2 Compensation Neither trial sites, investigators nor patients w i l l receive 
financial compensation. 
11. Bibliography 
 
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requiring dialysis after open heart surgery: early prognostic indicators. Am 
Heart J. 1987;113(5):1138-1143. doi: 10.1016/0002-8703(87)90925-2 
2. Chertow GM,Levy EM,Hammermeister KE, Grover F, Daley J. Independent 
association between acute renal failure and mortality following cardiac surgery. 
Am J Med. 1998;104(4):343-348. doi:10. 1016/S0002-9343(98)00058-8 

3. Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US commentary on the 2012 
KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis. 
2013;61(5):649-672. doi:10.1053/j.ajkd.2013.02.349. 
4. Zarbock, Alexander, et al. "Prevention of Cardiac Surgery-Associated Acute 
Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients 
Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled 
Trial". Anesthesia & Analgesia, vol. 133, no. 2, August 2021, pp. 292-302. 
5. Hoste EA, Cruz DN, Davenport A, et al. The epidemiology of cardiac surgery-
associated acute kidney injury. Int J Artif Organs.2008;31:158-165. Medline. 
6. Lassnigg A, Schmidlin D, Mouhieddine M, et al. Minimal changes of serum 
creatinine predict prognosis in patients after cardiothoracic surgery: a 
prospective cohort study. J Am Soc Nephrol. 2004;15:1597-1605. Medline. 
doi:10.1097/01. 
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7. Mehta RH, Grab JD, O'Brien SM, et al. Bedside tool for predicting the risk of 
postoperative dialysis in patients undergoing cardiac surgery. Circulation. 
2006;114:2208-2216. Medline. doi:10.1161/CIRCULATIONAHA.106.635573 
8. Ronco, C.; Bellomo, R.; Kellum, J.A. Acute kidney injury. Lancet 2019, 394, 
1949-1964. [CrossRef]. 
9. Kashani, K.; Cheungpasitporn, W.; Ronco, C. Biomarkers of acute kidney 
injury: The pathway from discovery to clinical adoption.Clin. Chem. Lab. Med. 
(CCLM) 2017, 55, 1074-1089. [CrossRef] [PubMed]. 
10. 
Soni, S.S.; Ronco, C.; Katz, N.; Cruz, D.N. Early diagnosis of acute kidney 
injury: The promise of novel biomarkers. Blood Purif. 2009, 28, 165-174. 
[CrossRef] [PubMed]. 
11. 
Zhou,F.;Luo,Q.;Wang,L.;Han,L.Diagnosticvalueofneutrophilgelatinase-
associatedlipocalinforearlydiagnosisofcardiac surgery-associated acute kidney 
injury: A meta-analysis. Eur. J. Cardio-Thorac. Surg. 2015, 49, 746-755. 
[CrossRef]. 
12. 
Vandenberghe,W.;DeLoor,J.;Hoste,E.Diagnosisofcardiacsurgery-associated 
acutekidney injury from functional to damage biomarkers. Curr. Opin. 
Anaesthesiol. 2017, 30, 66-75. [CrossRef]. 
13. 
Demirjian S, Bashour CA, Shaw A, et al. Predictive Accuracy of a 
Perioperative Laboratory Test-Based Prediction Model for Moderate to Severe 
Acute Kidney Injury After Cardiac Surgery. JAMA. 2022;327(10):956-964. 
doi:10.1001/jama.2022.1751