Incidence, Risk Factors and Consequences of Acute Kidney Injury in Patients Undergoing Esophageal Cancer Surgery: a Historical Cohort Study
Conditions: Acute Kidney Injury, Postoperative Complications
Sponsor: Azienda Ospedaliera di Padova

STUDY PROTOCOL
NCT number:
NCT04773080
TITLE:
Incidence, risk factors and consequences of acute kidney injury in patients
undergoing esophageal cancer surgery: a historical cohort
21/01/2021

TABLE OF CONTENTS
ABBREVIATIONS
3
INTRODUCTION
4
AIM OF THE STUDY                                                                                                                        5
STUDY DESIGN
5
METHODS                                                                                                                                          5
STUDY SETTING, POPULATION
5
PATIENT SELECTION CRITERIA
5
SAMPLE SIZE
6
PRIMARY ENDPOINTS
6
SECONDARY ENDPOINTS
6
STATISTICAL ANALYSIS
6
DATA COLLECTION
7
ASSESSMENT OF RENAL FUNCTION
7
ASSESSMENT OF COMPLICATIONS AND MORTALITY
8
ETHIC AND SCIENTIFIC DISSEMINATION POLICY
9
BUDGET OF THE STUDY
9
CASE REPORT FORMS                                                                                                                    9
BIBLIOGRAPHY
10
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ABBREVIATIONS
AKI acute kidney injury
SCr serum creatinine
AKD Acute kidney disease
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INTRODUCTION
Surgery alone, or in combination with neoadjuvant chemoradiation therapy, is still considered to be the
cornerstone treatment for locally advanced esophageal cancer 1. Esophagectomy serves as an exemplar
of major operative trauma, with well-known risk of pulmonary, cardiac, anastomotic, and septic
complications and the presence of postoperative complications after esophagectomies for cancer is
associated with a reduced long-term survival
2. There is a paucity in the literature regarding
postoperative renal outcomes after esophageal surgery, with a wide range of incidence.
McCulloch et al 2 reported in 2003 the results of the British ASCOT prospective database collecting
data from 955 patients (ASA score of 3-4 in 25%), of whom 229 underwent esophageal surgery. They
found an incidence of renal complications of 3.5%, but no definition of renal complication was present
in the study.
Lee et al 3 in 2014 investigated retrospectively 595 patients underwent esophageal surgery for cancer in
South Korea. AKI according AKIN criteria was found in 35.3% of the population with a mean age of
62 years and mainly ASA score 2 (91.8%). AKI was also associated with longer hospital stay.
Moore et al 4 compared in a retrospective analysis of 150 patients underwent complex or non-complex
esophageal reconstruction in 2016, reporting an incidence of renal insufficiency in 1.3% of the entire
population, without reference of any diagnostic criteria.
In 2017 Konda et al 5 performed a retrospective study on 897 patients with a mean age of 61 years and
mainly ASA 3 (83.6%) in USA, of whom 11.9% fulfilled the AKIN criteria for AKI.
Wang et al 6 showed in a Chinese retrospective case-control study published in 2017 a very low
incidence of AKI according RIFLE criteria (2.4%) in a population of 2094 patients with a median age
of 62 years and with ASA score of 2 in 84% of the patients.
The most recent study by Murphy et al 7 published in 2020 on 1135 patients with a mean age of 64
years underwent esophageal cancer surgery in three high-volume centers in Ireland showed an
incidence of AKI (defined by AKIN criteria) of 18.3%, associated with atrial fibrillation and longer
hospital stay.
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AIM OF THE STUDY
The aim of this study is to evaluate the incidence of postoperative AKI in patients undergoing elective
esophageal cancer surgery. Secondary, we will assess the progression of the acute injury and the
association with adverse pulmonary, cardiac, anastomotic, and septic events, as well as mortality. We
will also identify risk factors associated with AKI occurrence.
STUDY DESIGN
Retrospective study
METHODS
STUDY SETTING, POPULATION
All patients underwent elective esophagectomy at the Ospedale-Università di Padova
PATIENT SELECTION CRITERIA
INCLUSION CRITERIA
●
Elective esophagectomy
EXCLUSION CRITERIA
●
Age < 18 years;
●
End-stage renal disease
●
Missing data for AKI definition (serum creatinine or urine output)
●
Second surgery (for patients having multiple surgeries performed during a 30-day period, only
the first in each period was included)
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SAMPLE SIZE
Our sample size will be determined to help ensure stability around the point estimates in the final
multivariable model. To avoid overfitting our final outcome model, no more than 8 outcome events will
be required per covariate of interest. Thus, to fit a model with 8 covariates, we will require
approximately 64 outcome events. We will estimate the sample size after a pilot study on 100 patients.
PRIMARY ENDPOINTS
●
To evaluate the incidence of postoperative AKI according to KDIGO criteria within 48
hours after surgery
SECONDARY ENDPOINTS
●
Distinction between transient and persistent AKI
●
Occurrence of recovery or progression at 7 days, 30 days and 3 months
●
Association between AKI and pulmonary complications, major adverse cardiovascular events,
anastomotic or septic complications, or death.
●
Identify risk factors associated with AKI occurrence.
STATISTICAL ANALYSIS
The statistical analysis will be conducted with the help of Spss software.
Continuous variables are presented through descriptive statistics, including mean, median, variance,
minimum and maximum value. Categorical variables are described by the absolute frequencies and
percentages.
Data will be examined by T-test or one-way ANOVA (normally distributed variable), Mann-Whitney U
test, Kruskal-Wallis one way analysis test (not normally distributed variables), Pearson or Mc Nemar’s
chi-square test (categorical variables) will be used to evaluate the difference across non-AKI group
versus AKI group according to KDIGO criteria or each type of AKI. Two-sided p-values of less than
0,05 were accepted as statistically significant.
Logistic regression analysis will used to build a model of covariates associated with development of
AKI and risk of AKI. Likelihood ratio (LR) test statistic, Hosmer-Lemeshow (HL) statistic will used
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for assessing goodness of fit (GOF) in the regression models. A discriminatory performance [DP]
assessment of the binary logistic model will be performed by classification/diagnostic table, ROC and
area under the curve (AUC).
DATA COLLECTION
A team properly instructed will collect patient’s data, which will be filled in a CRF (Case Report
Form). An electronic copy of CRF will be retained in Microsoft Excel format.
All collected data will be identified and stored in such a way as to protect patient confidentiality. The
staff involved in the collection and management of data will not use or disseminate such information
for purposes other than those provided for the realization of the study.
All data will be collected and processed in a completely anonymous way, in compliance with the
guarantee terms of privacy and as approved by Comitato Etico per la Sperimentazione Clinica della
Provincia di Padova.
Assessment of renal function
“Acute kidney injury” (AKI) is defined as an increase in serum creatinine (SCr) by ≥0.3 mg/dL within
48 h the baseline value (as determined by all available SCr values from hospital and outpatient medical
records within the previous 90 days) or urine output <0.5 mL/kg/h for 6 h 8. For those who do not have
available baseline SCr levels, expand the screening criteria to an increase or decrease in SCr by 0.3
mg/dl during hospital stay. Second, these suspected AKI were reviewed on a case-by-case basis to
confirm the diagnosis. Positive fluid balance and hemodilution are considered in the diagnosis and
staging of AKI using the following formula 9:
Adjusted SCr level = SCr × correction factor
where the correction factor = (weight (kg) upon hospital admission × 0.6 + Σ (daily cumulative fluid
balance (L)))/hospital admission weight × 0.6
The
estimated
glomerular
filtration
rate
is
determined
using
SCr
10.
Chronic
Kidney
Disease-Epidemiology Collaboration equations.
Persistent acute kidney injury (AKI) is defined by the continuance of AKI by serum creatinine or urine
output criteria (according KDIGO criteria) beyond 48 h from AKI onset 11. Complete reversal of AKI
by KDIGO criteria within 48 h of AKI onset is defined transient AKI 11. 
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Acute kidney disease (AKD) is defined as a condition wherein criteria for AKI stage 1 or greater
persists ≥7 days after surgery.
Assessment of complications and mortality
Postoperative pulmonary complications were identified and categorized based on European
Perioperative Clinical Outcome (EPCO) definitions from the ESA-ESICM joint taskforce on
perioperative outcome measures 12. These include respiratory infection, respiratory failure, pleural
effusion, atelectasis, pneumothorax, bronchospasm, aspiration pneumonitis.
Major adverse cardiac and cerebrovascular events (MACCE) was a composite outcome of non-fatal
cardiac arrest, acute myocardial infarction, congestive heart failure, new cardiac arrhythmia, angina,
ischemic stroke 12.
Sepsis was defined according Sepsis-3 definition13.
We performed separate analyses of complications apparently related to surgical technique (for instance,
anastomotic leakage, fistula, abscess, hemorrhage) and medical complications, i.e. pulmonary,
cardiovascular (acute myocardial infarction, atrial fibrillation, cardiogenic shock) and septic.
All complications were evaluated 30 days after surgery.
Mortality in hospital after resection of esophageal cancer was defined as any death during the
admission when the operation was performed. This was more reliably quantified than 30-day mortality.
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ETHIC AND SCIENTIFIC DISSEMINATION POLICY
Patient Information/Informed Consent
As a retrospective analysis, we would base normative n. 9/2014 (“in merito al trattamento dei dati
personali effettuato per scopi di ricerca scientifica dell’11 dicembre 2014”).
After completion of the study, the data will be reported at scientific meetings and/or submitted and
published in a scientific journal, regardless of the outcome. In these cases, a publication committee will
be responsible for these activities and will work with the investigators to determine how the manuscript
is written and edited, the number and order of authors, the publication to which it will be submitted,
and other related issues.
BUDGET OF THE STUDY
The present study is NO PROFIT.
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CASE REPORT FORM
Retrospective study on AKI incidence after esophageal cancer surgery
PATIENT ID
Inclusion criteria:
●
elective esophageal cancer patients
Exclusion criteria:
●
Age < 18 years.
●
ongoing KRT or ESRD.
●
Missing data for AKI criteria (serum creatinine and urine output).
●
Second surgery.
PREOPERATIVE EVALUATION:
Gender
□ M
□ F
Age
__________
Birthday
__________
Weight __________kg
Height __________m
Surgery date___________
COMORBIDITIES:
□ COPD 🡪Gold class ___
□ Interstitial Lung Disease
□ pulmonary hypertension
□ asthma
□ active smokers
□ dyspnea
□ stroke/TIA
□ coronary artery disease
□ DM
□ hypertension with medication
□ active solid organ neoplasm
□ hematologic neoplasm
□ disseminated cancer
□ alcohol use disorder
□ dementia
□ congestive heart failure in 30 days prior to surgery
□ dialysis
□ ascites within 30 days prior to surgery
□ systemic sepsis within 48 hours prior to surgery
□ ventilator dependent
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ASA class ____
Functional status: Karnofsky_________
ECOG_____________
Weight loss within the last 3 months ______
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PREOPERATIVE MEDICATION:
□ Statins
□ ACE-inhibitors
□ Sartans
□ beta-blockers
□ PPI
□ steroid use in chronic
□ NSAIDs
□ insulin
□ CT
□ RT
□ ___________________________________________________________________________
PREOPERATIVE LABORATORY TESTS
Hb ______
MCV_________
Alb _________
sCr ________
eGFR_________
urea __________
BNP________
Trop_________
CARDIOVASCULAR TESTS
□ AF at EKG
□ FE <45%
□ carotid stenosis
RESPIRATORY TESTS
FEV1____
FVC_________
DLCO__________
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INTRAOP DATA
Type of surgery:
□ thoracoscopy □ thoracotomy
□ vls
□ lpt
□ cervico
Type of anesthesia:
□ inhaled
□ TIVA
□ epidural+inhaled
□ epidural+TIVA
□ Lidocaine ____mg
□ Magnesium________mg
□ Dexamethasone _________mg
□ Ranitidine________mg
□ PPI _________________mg
NMB: □ rocuronium
□ cisatracurium
NMB reversal: □ neostigmine
□ sugammadex
Duration of anesthesia: ____________h
Type of ventilation: □ OLV
□ TLV
max FiO2__________
min SpO2________
Hemodynamics:
□  IABP
min SBP________mmHg
fluids:
□ crystalloids__________ml
□ colloids_________ml
□ blood_________ml
blood loss_________ml
end_surgery Hb_______
end_surgery lactate_________
□ use of vasopressors
□ max dose______
□ use of inotropes
□ max dose_______
□ arrhythmia during surgery
□ use of antiarrhythmics
Diuresis: total ________ml
□  use of diuretics: ____________ dose___________
End-surgery medication:
□ NSAIDs
□  Extubation at the end of surgery
□ PACU
□ ICU
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POSTOP :
6h
12h
24h
48h
72h
4d
5d
6d
7d
ICU
dischar
ge
H
dischar
ge
30d
1y
sCr
eGFR
urea
Tropon
in
BNP
Hb
NGAL
diuresi
s
Fluids
in
drainag
es
diureti
cs
vasopr
essors
inotrop
es
*NA if not present in the medical records
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Outcomes:
□ need for RRT: _______days
□ MACCE within 30 days: □ AMI
□ congestive heart failure
□ non-fatal cardiac arrest
□ new cardiac arrhythmia
□ angina
□ stroke
□ pulmonary complications within 30 days:
□ respiratory infection at ____day (i.e. patients has received
antibiotics for a suspected respiratory infection + one of the following: new or changed sputum, new or
changed opacities, fever, wbc >12000)
□ respiratory failure at ____day (PaO2 < 60 mmHg at room air,
a P/F < 300 mmHg or SpO2 <90% requiring oxygen therapy)
□ pleural effusion at _____day
□ atelectasis at _______day
□ pneumothorax at ____day
□ bronchospasm at ____day (bronchodilators treatment for
new expiratory wheezing)
□ aspiration pneumonitis at ____day
□ length of CMV ___h
□ need for NIV in _______h
□ surgical complications within 30 days: □ fistula
□ hemorrhage
□abscess
Clavien-Dingo grading of complications:
□ I: any deviation from the normal postoperative course without the need for pharmacological treatment or
surgical, endoscopic, or radiological interventions. Permitted therapeutic interventions include: drugs such
anti-emetics, antipyretics, analgesics, diuretics, electrolytes and physiotherapy. Also included wound infections
opened at the bedside
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□ II: drugs other than grade I
□ III: requiring surgical, endoscopic, or radiological interventions
□ IIIa: not under general anesthesia
□ IIIb: under general anesthesia
□ IV: life-threatening complication (including CNS complications) requiring critical care
□ IVa: single-organ dysfunction (including KRT)
□ IV b: multi-organ dysfunction
□ V: death of a patient
Day of ICU discharge: _________
□ Alive
□  Dead
Day of H discharge: _________
□ Alive
□  Dead
□ Death at 30 days after surgery
□ readmission  _____________ (date)
□ second surgery
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BIBLIOGRAPHY
1
van Hagen P, Hulshof MC, van Lanschot JJ, et al.: Preoperative chemoradiotherapy for
esophageal or junctional cancer. The New England journal of medicine. 366:2074-2084, 2012.
2
McCulloch P, Ward J, Tekkis PP, et al.: Mortality and morbidity in gastrooesophageal cancer
surgery: initial results of ASCOT multicentre prospective cohort study. BMJ. 327:1192-1197,
2003
3
Lee EH, Kim HR, Baek SH, et al. Risk factors of postoperative acute kidney injury in patients
undergoing esophageal cancer surgery. J Cardiothorac Vasc Anesth. 2014;28(4):936-942
4
Moore JM, Hooker CM, Molena D, et al.: Complex Esophageal Reconstruction Procedures
Have Acceptable Outcomes Compared With Routine Esophagectomy. Ann Thorac Surg. 2016.
5
Konda P, Ai D, Guerra CE, et al. Identification of Risk Factors Associated With Postoperative
Acute Kidney Injury After Esophagectomy for Esophageal Cancer. J Cardiothorac Vasc Anesth.
2017;31(2):474-481. doi:10.1053/j.jvca.2016.07.030
6
Wang W, Wang T, Feng X, Sun L. Incidence and risk factors of acute kidney injury after
esophageal cancer surgery: A nested case-control study. Int J Surg. 2017;39:11-15
7
Murphy CF, Dunne T, Elliott JA, et al. Acute Kidney Injury After Esophageal Cancer Surgery:
Incidence, Risk Factors, and Impact on Oncologic Outcomes [published online ahead of print,
2020 Jul 24]. Ann Surg. 2020;10.1097/SLA.0000000000004146
8
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group.
KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012: 1–138
9
Macedo E, Bouchard J, Soroko SH, et al. Fluid accumulation, recognition and staging of acute
kidney injury in critically-ill patients. Crit Care 2010; 14: R82
10 Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate.
Ann Intern Med 2009; 150: 604–612
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11 Chawla, L., Bellomo, R., Bihorac, A. et al. Acute kidney disease and renal recovery: consensus
report
of
the
Acute
Disease
Quality
Initiative
(ADQI)
16
Workgroup. Nat
Rev
Nephrol 13, 241–257 (2017)
12 Jammer I, Wickboldt N, Sander M, Smith A, Schultz MJ, Pelosi P, Leva B, Rhodes A, Hoeft A,
Walder B, Chew MS, Pearse RM; European Society of Anaesthesiology (ESA) and the
European Society of Intensive Care Medicine (ESICM); European Society of Anaesthesiology;
European Society of Intensive Care Medicine. Standards for definitions and use of outcome
measures for clinical effectiveness research in perioperative medicine: European Perioperative
Clinical Outcome (EPCO) definitions: a statement from the ESA-ESICM joint taskforce on
perioperative outcome measures. Eur J Anaesthesiol. 2015 Feb;32(2):88-105.
13 Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions
for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–810
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