Intravenous vs. Oral Hydration to Reduce the Risk of Post-Contrast Acute Kidney Injury After Intravenous Contrast-Enhanced Computed Tomography in Patients With Severe Chronic Kidney Disease (ENRICH)

Intravenous vs. Oral Hydration to Reduce the Risk of Post-Contrast Acute Kidney Injury After Intravenous Contrast-Enhanced Computed Tomography in Patients With Severe Chronic Kidney Disease

Intravenous vs. Oral Hydration to Reduce the Risk of Post-Contrast Acute Kidney Injury After Intravenous Contrast-Enhanced Computed Tomography in Patients With Severe Chronic Kidney Disease (ENRICH): A Randomized Controlled Trial

Department of Nephrology, Odense University Hospital, Department of Clinical Genetics, Odense University Hospital, The A.P. Moller Foundation, The Research Counsil of Odense University Hospital, Copenhagen University's Research Foundation for Medical Students, Helen and Ejnar Bjørnow's Foundation, Novo Nordisk A/S, Sophus Jacobsen and Astrid Jacobsen's Foundation, Open Patient data Explorative Network (OPEN)

The use of contrast media (CM) poses a risk of post-contrast acute kidney injury (PC-AKI), especially among patients chronic kidney disease (CKD). International guidelines recommend intravenous (IV) hydration with isotonic 0.9% NaCl for three-four hours pre-contrast and four-six hours post-contrast. Recent studies have proven that oral hydration or no hydration is non-inferior to IV hydration in patients with mild to moderate CKD (eGFR 30-60 mL/min/1.73 m2). However, no randomized controlled trials have evaluated alternative hydration methods against the guideline-recommended hydration protocol for the prevention of PC-AKI in high-risk patients with severe CKD (eGFR < 30 mL/min/1.73 m2). Thus, the main focus of this trial is to evaluate IV hydration vs. oral hydration for their efficacy to prevent of PC-AKI in patients with severe CKD, who are scheduled for an elective contrast-enhanced CT-scan (CECT) with IV contrast-administration. Our research hypotheses consist of the following: Oral hydration with bottled tap water is non-inferior to IV-hydration with isotonic 0.9% NaCl as renal prophylaxis to prevent PC-AKI in patients with severe CKD referred for an elective IV CECT. NGAL and cfDNA are early and precise plasma and urinary biomarkers of PC-AKI with excellent diagnostic and prognostic accuracy for PC-AKI, dialysis, renal adverse events, hospitalization, progression in CKD-symptoms, and all-cause mortality.

Trial design: This study is a pragmatic investigator-iniated, single-centre, open-labelled, parallel-group non-inferiority randomized controlled trial with two parallel arms. Patients will randomly be allocated to preventive treatment with IV hydration or oral hydration. Participants and study setting: The ENRICH-trial is conducted at Odense University Hospital (OUH), which is a tertiary health-care centre. The referral area covers the region of Southern Denmark, which corresponds to 1.25 million citizens in 22 municipalities of both urban and rural environment. The trial enrols high-risk patients with an eGFR < 30 mL/min/1.73 m2 scheduled for IV CECT using approximately 50-150 mL of CM (GE Healthcare, Omnipaque 500 mL, osmolality 350 mg I/mL). The study population will consist of patients, who are referred for an elective IV CECT in the work-up for treatment of CVD (e.g., transaortic valve-implantation, ablation, endocarditis etc.) or suspected CVD (e.g., angina etc.), suspected cancer, thoracic/abdominal/urogenital diseases, or cardiovascular work-up before kidney transplantation. Patients referred for an acute or subacute IV CECT with competing etiologies for PC-AKI (e.g., sepsis, acute tubular necrosis, cardiogenic shock etc.) will not be considered eligible for inclusion. Randomization: The randomized allocation to preventive treatment with either IV-hydration or oral hydration will be performed in REDCap, which is computer-based tool provided by our collaborator, Open Patient data Explorative Network (OPEN). The randomization sequence list is generated and implemented in the computer-based randomization tool by our data manager and will remain unknown throughout the study period. The randomization will be performed as 2-4-2 block randomization with stratification for DM-status, CKD-stage (eGFR < 15 mL/min/1.73 m2 or 15-29 mL/min/1.73 m2), and the basis of referral for IV CECT (kidney transplantation or other diseases). Participants are then followed for a 30-day period with standard blood testing for kidney function at two-five days after IV CECT and a 30-day follow-up for the key secondary outcomes. Definition of PC-AKI: PC-AKI is defined in accordance with the KDIGO-guidelines, which is a relative increase in serum creatinine (SCr) > 50% from baseline or an absolute increase of SCr > 0.3 mg/dL from baseline. Course of action: High-risk patients with severe CKD (eGFR < 30 mL/min/1.73 m2) and a scheduled IV CECT will be considered for eligibility. Eligible patients will be screened according to the study's inclusion/exclusion criteria. Eligibility is assessed from the patient's electronic health record (EHR), which contains data regarding health status and recent test results for evaluation of renal function. Eligible patients will be presented to the guideline-recommendations for preventive treatment with IV hydration along with blood sampling for evaluation of their renal function < seven days prior to the IV CECT at the time of the scheduling of their IV CECT, according to normal routine at Odense University Hospital. Furthermore, the patients will be presented with a short introduction to this study. If the patient is interested, he/she will be contacted by the lead investigators, after which a verbal consent to participate in the study is obtained (approximately seven to 14 days prior to the scheduled IV CECT). After the verbal consent is given, the guideline-required evaluation of renal function < seven days prior to their IV CECT will be planned along with an additional blood sample to evaluate the renal function one-three days prior to their IV CECT. Furthermore, blood samples to evaluate renal function will be planned at two-three days, four-five days, and 30 days after IV CECT along with follow-up consultations four-five days and 30 days after IV CECT. A thorough presentation of the study-information will be given by one of the lead investigators at baseline, while the patient has been informed about the possibility of bringing an assessor of their choice. The information will be delivered in a quiet room, which is solely used to deliver patient information. The lead investigators will make sure that the presentation is given within a reasonable timeframe prior to their scheduled IV CECT. During the presentation of the study the patient will be informed of the purpose of the study and the written patient information will be sent via e-mail or physically handed to the patient if desired. Patients will be given as much time as wanted to decide if they wish to participate in the study after the oral information has been given. Patients will be offered the possibility to call or physically meet with one of the lead investigators in case of additional questions before signing the informed consent. Subjects can leave the study at any time for any reason if they wish to do so without any clinical consequences. Signed informed consent will be provided prior to any research procedures. A subject is considered enrolled in the study once the subject is randomized. Patient data from EHR will be obtained according to the REDCap-database and the study endpoints after the verbal consent is delivered. Participant retention, follow-up, and withdrawal: Once a patient is enrolled and randomized, the research group will make every reasonable effort to follow the patient for the entire study period. If the patient fails to attend their appointment for blood sampling to evaluate renal function, the patient will be contacted by telephone, and a new appointment for blood sampling is scheduled within the next 24 hours. The patient will only be excluded from the study after randomization if the patient does not receive the preventive treatment according to the randomization or if the IV CECT is cancelled after randomization and preventive treatment. The rate of loss-to-follow-up for the primary and secondary outcomes are expected to be < 10%. Variables: Standard blood parameters to evaluate renal function will be obtained < 90 days, < seven days, one-three days, and at baseline prior to the scheduled IV CECT. Furthermore, an urine sample for albumine/creatinine ratio (mg/g) will be obtained at baseline before CM exposure. The standard blood parameters will also be obtained two-three days and/or four-five days, and 25-40 days after the scheduled IV CECT. Additional blood sampling to evaluate renal function will be performed at seven days and/or 14-21 days after IV CECT if the patient has increasing SCr four-five days after IV CECT consistent with PC-AKI. The standard blood parameters for patients referred for IV CECT consist of the following: Hemoglobin (mM), erythrocytes (count/L), SCr (μmol/L), eGFR (mL/min/1.73 m2), albumine (μmol/L), sodium (mM), and potassium (mM). The prospective cohort is followed over a 30-day period for events of dialysis treatment, renal adverse events, hospitalization due to hydration- or contrast-related sequelae (i.e., symptomatic heart failure, arrythmias, renal insufficiency, hyponatremia or hypernatremia), and all-cause mortality. Progression in CKD-symptoms will be obtained from registration of uremic symptoms through a medical interview at baseline and ≤ 30 days after IV CECT. A trained interviewer will identify any clinical signs of progression in CKD within the 30-day follow-up. Progression in CKD is defined as progression in uremic symptoms, which consist of the following: - Weight loss, loss of appetite, cramps, nausea, vomiting, pruritus, bruising, fatigue, peripheral edema, impaired consciousness, and changes in sense of taste. The medical history, medicine use, and echocardiography will be obtained at baseline before initiation of the hydration protocol. The patient will then tend to their IV CECT. Blood- and urine samples for biomarkers of PC-AKI will be collected before IV CECT and three-four hours after IV CECT. The admission time is defined as the timespan between the start and the completion of the preventive treatment, which is registered as 'date-month-year-hours-minutes'. Dates and reasons for hospital admission < 90 days before IV CECT will also be registered along with additional contrast exposure within the 30-day follow-up period after the scheduled IV CECT. The following parameters will also be obtained for the subgroup of participants, who are referred for a cardiac IV CECT: Estimated coronary artery calcification score (CAC-score). Stenosis > 50% of the left main coronary artery (LM). The grade of stenosis will be analyzed if present in the coronary arteries; LM, left anterior descending artery (LAD), left circumflex artery (LCx), and right coronary artery (RCA). Aortic valve calcification (AVC) and mitral annulus calcification (MAC). Calcification (Agatson-score) of the aorta (aorta ascendens, arcus aorta, and aorta descendens), the suprarenal and infrarenal aorta, and the renal arteries. The diameter of aorta (aorta ascendens, arcus aorta, aorta descendens) and iliac arteries. The size of the left atrium (cm2). Safety: An interim analysis will be performed after inclusion of 127 patients to evaluate the primary outcomes and the key secondary outcomes. The steering committee will consider terminating the study preliminary if the analyses conclude a significant difference in the incidence of the primary and/or the key secondary outcomes between the two groups.

Intravenous, Contrast material, Computed Tomography, Cardiac CT, Prophylaxis, Oral Hydration, IV-hydration

The IV-hydration with isotonic 0.9% NaCl will be initiated three hours prior to the IV CECT and completed four hours after IV CECT (infusion rate of 1-3 mL/kg/hour). Patients are prescribed a fixed volume of 1000 mL, which is equally distributed before and after IV CECT (500 mL before and 500 mL after). Patients with heart failure (LVEF ≤ 40%) are prescribed a reduced volume of 500 mL, which is also equally distributed before and after IV CECT (250 mL before and 250 mL after).

The oral hydration regimen will be initiated one-two hours prior to IV CECT and completed within four hours after IV CECT. Patients are prescribed a fixed volume of 1000 mL, which is distributed equally before and after IV CECT (500 mL before and 500 mL after). Patients with heart failure (LVEF ≤ 40%) are prescribed a reduced volume of 500 mL, which is equally distributed before and after IV CECT (250 mL before and 250 mL after).

The incidence of patients with incident need for dialysis treatment, which is registered from the EHR and/or telephone consultation

The incidence of renal adverse events defined as a relative increase in SCr > 15% and/or a decrease in eGFR > 15% and/or progression in CKD-stage from CKD-stage IV to CKD-stage Va

The incidence of patients hospitalized due to symptomatic heart failure, which is registered from the EHR and/or telephone consultation

Hospitalization due to suspected hydration- or contrast-related sequelae (e.g., arrythmias, renal insufficiency, hyponatremia or hypernatremia), which is registered from the EHR and/or telephone consultation

Progression in CKD-symptoms within 30 days after IV CECT defined as an increase in number of uremic symptoms compared to number of uremic at baseline within the two arms (see definition of "uremic symptoms" under "Variables" in the detailed description of the trial)

Incidence of PC-AKI based on the criteria from the previously used and most cited definition of PC-AKI

The incidence of PC-AKI within the population and the two arms defined as a relative increase in SCr > 25% from baseline or an absolute increase > 0.5 mg/dL

The difference in PC-AKI diagnosed two-three days after IV CECT and four-five days after IV CECT within the population and the two arms

Number of participants with normalization of PC-AKI within study population and the two arms defined as a decline in SCr below the criteria for PC-AKI

Mean changes in SCr from baseline at different timepoints within the study population and the two arms

SCr is measured on the following time-points (days from baseline): -89 to -seven days, -six to -four days, -three to -one days, 0 days (baseline), +two to three days, +four to five days, and +25 to +40 days

Mean changes in eGFR from baseline at different timepoints within the study population and the two arms

eGFR is measured on the following time-points (days from baseline): -89 to -seven days, -six to -four days, -three to -one days, 0 days (baseline), +two to three days, +four to five days, and +25 to +40 days

Mean changes in standard blood parameters within the two arms. Standard blood parameters are the following: Hemoglobin (mM), erythrocytes (count/L), SCr (micromole/L), eGFR (mL/min/1.73 m2), albumine (micromole/L), sodium (mM), and potassium (mM)

Standard blood parameters will be obtained after IV CECT at +two to three days and/or +four to five days, and +25 to +40 days from baseline

Mean values of plasma and urinary NGAL (μg/mg) and cell-free DNA (ng/mg) at baseline and 4 hours after IV CECT

In-hospital: Before initiation of the hydration protocol and the IV CECT (baseline) and 4 hours after IV CECT

Mean changes in plasma and urinary NGAL (μg/mg) and cell-free DNA (ng/mg) from baseline (0 hours) to four hours after IV CECT

In-hospital: Before initiation of the hydration protocol and the IV CECT (baseline) and 4 hours after IV CECT

Sensitivities, specificities, negative predictive values, positive predictive values, negative likelihood-ratios, and positive likelihood-ratios of plasma and urinary NGAL (μg/mg) and cell-free DNA (ng/mg) based on the most optimal cut-off point for each biomarker based on Receiver Operating Characteristics-Curves (ROC-curves) and their corresponding Area Under Curve (AUC). The most optimal cut-off is defined as the closest point on the ROC-curves, at which the sensitivity = specificity = 1.0

In-hospital: Before initiation of the hydration protocol and the IV CECT (baseline) and 4 hours after IV CECT

Assesment of the most optimal cut-off point for each biomarker based on Receiver Operating Characteristics-Curves (ROC-curves) and their corresponding Area Under Curve (AUC). The most optimal cut-off is defined as the closest point on the ROC-curves, at which the sensitivity = specificity = 1.0

In-hospital: Before initiation of the hydration protocol and the IV CECT (baseline) and 4 hours after IV CECT

The correlation between SCr and plasma and urinary NGAL (μg/mg) and cell-free DNA (ng/mg) will be illustrated in Scatter Plots.

In-hospital: Before initiation of the hydration protocol and the IV CECT (baseline) and 4 hours after IV CECT

The use of resources (presented in DKK, EUR, and USD) for IV-hydration and oral hydration within the two arms are calculated from the following parameters: The cost of occupying a hospital bed per hour (nursing, staff salaries etc.), IV-drip, and hydration bags with saline or bottled tap water.

The two hydration methods are compared for the amount of time (hours and minutes) from initiation to completion hydration protocols.

The size of the right and left kidney will be measured and indexed to the body-size of the patient and analyzed as a risk factor for the occurence of PC-AKI

Inclusion Criteria: eGFR < 30 mL/min/1.73 m2 Scheduled for elective IV CECT Age ≥ 18 Signed informed consent Exclusion Criteria: Allergy to Iodine Pregnancy Active dialysis treatment Acute infectious or inflammatory disease Acute pre- and/or post-renal kidney failure Unable to understand study information

Individual participant data (IPD) will be available in an anonymous format in accordance with the legislations from GDPR upon reasonable request. Rules for external researchers to apply for and access data will be laid out towards the end of the study.

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