Short summary

The ENRICH-study is a randomized, analyzer-blinded, controlled, OPEN-labelled non-inferiority trial with two parallel arms, in which the patients are allocated to kidney prophylaxis with either oral hydration or IV-hydration prior to cardiac CT with IV-administration of contrast material. The primary outcome is to evaluate the incidence of contrast-induced acute kidney injury within the two arms.

Rationale

Radiological procedures utilizing intravascular iodinated contrast material (CM) are widely used for diagnostic purposes with approximately 26.000 cardiac computed tomography's (CT) being conducted in Denmark in 2019, and more than 75 million CM-procedures worldwide in 2021. The use of iodinated CM poses a risk of contrast-induced acute kidney injury (CI-AKI), and the risk is additively associated with comorbidities and health factors such as age, smoking, nephrotoxic drugs, cardiovascular disease (CVD), diabetes mellitus (DM), chronic kidney disease (CKD), periprocedural hemodynamic instability, anemia, and osmolality, infusion rate, and amount of CM. CKD is considered the most critical patient-related risk factor. The global prevalence of CKD was estimated to 8-16% in 2013, which could possibly indicate a yearly estimate of 6-12 million CM-procedures performed on high-risk patients with CKD. In hospitalized patients, CI-AKI is recognized as the 3rd most common cause of acute kidney injury (AKI). A study has also reported a 6,5 fold magnification of in-hospital mortality among inpatients with CI-AKI. Most of the CI-AKI literature is based on invasive angiocardiographic studies with intraarterial (IA) CM. These studies have reported of CI-AKI-rates of 19-20% , and a two-fold increase in CI-AKI related to the stage of CKD. On the contrary, a meta-analysis and systematic review found no significant difference in the incidence of CI-AKI between patients exposed to IV CM and unexposed patients with acute kidney injury (AKI). Thus, the incidence and severity of CI-AKI seem to dependent on the type of CM-procedure, patient setting, and the population's overall health status. However, the lack of high-quality scientific evidence has motivated an overall cautious attitude towards CM-procedures in patients with CKD.

The correlation between individual risk factors and CI-AKI stress the importance to identify patients at risk to undertake prophylactic procedures. The clinical risk is individually assessed from patient-related comorbidities and kidney function. CI-AKI is most commonly defined as a relative increase in serum creatinine (SCr) by >25% or an absolute increase in SCr of > 0,5 mg/dL 2-3 days after IV administration of CM, without any other plausible aetiology. SCr has limited sensitivity to detect the tubular injury caused by CM. Thus, tubular biomarkers and cell free-DNA (cfDNA) have been evaluated in CM-studies with various ad-ministration routes. Neutrophil gelatinase-associated lipocalin (NGAL) has demonstrated strong qualities as for the prognosis and diagnosing of CI-AKI among patients referred for elective CT with IV CM. cfDNA is a novel biomarker, of which elevated serum-levels have been associated with CI-AKI and mortality in end-stage renal disease in different patient settings. cfDNA has not been evaluated in CM-studies based on elective outpatients, but its diagnostic and prognostic qualities are promising. The immediate advantage is, that the plasma concentration of NGAL and cfDNA in-crease significantly 3-6 hours after CM-administration in the presence of kidney injury, whereas an increase of SCr consistent with CI-AKI first occurs 2-5 days after CM-administration. These findings could suggest that NGAL and cfDNA are early diagnostic and prognostic markers of CI-AKI and all-cause mortality.

The search for an optimal and patient-friendly hydration protocol as well as early and precise biomarkers for the diagnosing and prognosis of CI-AKI is ongoing. IV-hydration is the current cornerstone of CI-AKI prophylaxis in high-risk patients with CKD. ESUR-guidelines recommend IV-prophylaxis with isotonic NaCl 3-4 hours before CM-administration and 4-6 hours after CM-administration with various infusion rates. The hydration prophylaxis is demanding for the patient and the hospital in time and resources. Several studies have already demonstrated that oral hydration or no hydration at all prior to CM-administration is non-inferior to the current prophylaxis of IV-hydration. Oral hydration may be a safe strategy for preventing CI-AKI and is undeniably more cost- and time-effective. However, the clinical evidence of the studies is limited by their statistical power, lack of control groups, varying CM-procedures, and only moderate CKD in most of the patients. Randomized controlled trials (RCT) with patients at significant risk of CI-AKI due to severe CKD are therefore needed to verify oral hydration as a safe strategy in the prevention of CI-AKI.

Our study aims to evaluate if oral hydration with tap water prior to IV CM-procedures can be considered non-inferior to IV-hydration with isotonic NaCl in patients with eGFR<30 mL/min/1.73 m2. Furthermore, we seek to evaluate the predicative, diagnostic and prognostic value of NGAL and cfDNA for the occurrence of CI-AKI and all-cause mortality in outpatients referred for elective cardiac CT with IV CM.

Description of the cohort

The ENRICH-study enrols patients with an eGFR of <30 mL/min/1.73 m2 scheduled for elective IV contrast CT using 60-100 mL of CM. The study population consists of two cohorts of patients, who are referred for cardiac CT with IV CM in the work-up before either transcatheter aortic valve implantation (TAVI) or treatment of other CVDs, and kidney transplantation. The patients come from the Department of Cardiology and the Department of Nephrology at Odense University Hospital, respectively.

Data and biological material

From this study, SCr and eGFR from blood samples at baseline, day 0, day 2-3 and/or day 4-5, and day 30 will be available for all patients. If SCr continuously increases from the two measurement points after CM, measurements on day 7 and day 14-21 will also be conducted. Risk factors of CI-AKI will be collected at day 0. Blood samples for NGAL and cfDNA are collected before injection of CM and 3-4 hours after, from which the serum-levels will be determined ongoing in batch-analyses at OPEN lab and the Department of Clinical Immunology at Odense University Hospital.

Data concerning the patients' cardiac CT and the estimated calcification scores of the coronary arteries, aorta (ascendens, arcus aorta, descendens, suprarenal, infrarenal), renal arteries, and iliac arteries are available on day 0. Data concerning stenosis of the coronary arteries are also available on day 0. The prospective cohort is followed over a 30-day period for events of dialysis treatment, hospitalization due to heart failure or symptoms of overhydration, and all-cause mortality. The cardiac CT-data will be stored for further substudies and new studies of interest in the future along with the rest of the plasma from the NGAL- and cfDNA-analysis. All data will be typed and stored in our Research Electronic Data Capture (REDCap) Database.

Collaborating researchers and departments

Department of Nephrology, Odense Universitetshospital

• Professor, chief physician og PhD, Claus Bistrup

Department of Clinical Immunology, Odense Universitetshospital

• M.Sc., PhD, Marianne Antonius Jakobsen