Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05471583 |
| Other study ID # |
KCH19-107 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 16, 2021 |
| Est. completion date |
June 30, 2023 |
Study information
| Verified date |
July 2022 |
| Source |
King's College London |
| Contact |
Jennifer Joslin, MA(Oxon) MBBS |
| Phone |
07970766125 |
| Email |
jennifer.joslin[@]kcl.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Abstract Significance: Cardiac surgery-associated acute kidney injury (CSA-AKI) is common and
has serious immediate and long-term sequelae. Better early prediction of those at highest
risk and greater understanding of underlying pathological processes are needed to prevent or
minimise damage.
Hypotheses
- Dynamic changes in systemic endothelial glycocalyx (Glx) and microcirculatory parameters
during coronary artery bypass graft (CABG) surgery are predictive of CSA-AKI.
- Mechanisms for Glx degradation during CABG surgery are akin to those during sepsis Aims
- Investigate Glx and microcirculatory health throughout CABG surgery and recovery and
their association with CSA-AKI.
- Explore association between inflammation and Glx degradation during CABG surgery.
Methodology
1. Prospective cohort study: serial sampling and microcirculatory perfusion imaging of 70
patients undergoing CABG surgery with evaluation of CSA-AKI predictors, including plasma
Syndecan-1.
2. Examination of inflammation and cardiometabolic proteome and association with vascular
changes
3. In vitro mechanistic assessment of Glx degradation and relative timing of organelle
exocytosis in cultured endothelial cells in response to patient serum, targeting
identified candidate mediators.
Impact: Enhancing CSA-AKI risk stratification with new mechanistic biomarkers will enable
individualised management of at-risk patients, and pathophysiological insights will create
possible therapeutic targets, thus reducing morbidity, mortality and cost of CSA-AKI.
Description:
Study design: Prospective cohort study.
The investigators will recruit 70 elective patients undergoing CABG surgery with and without
cardiopulmonary bypass (CPB), with blood and urine sampling and assessment of
microcirculatory perfusion by IDF in pre- peri- and post-operative periods, with informed
written consent. The investigators have completed a feasibility study with successful
recruitment and data collection at all time points and the current protocol and patient
material have been reviewed by a patient representative.
Blood and urine samples will be analysed to consider markers of endothelial glycocalyx
degradation (including syndecan-1 (SDC1)), endothelial activation (including thrombomodulin
(TM)), and markers of renal tubular stress (NephroCheck).
Sublingual microcirculatory perfusion assessed by IDF imaging is painless and low risk and
participant acceptability has been confirmed during the feasibility study. The process
involves using a small handheld probe to gently press on the underside of the tongue and
takes 3-10 minutes. Four video clips of 10s will be taken from each participant from
different sites within the sublingual area. Videos will be exported as pseudonymised files
for analysis. Image collection and analysis will be performed in accordance with
international consensus recommendations, using a CytoCam video-microscope (Braedius Medical
B.V., Huizen, The Netherlands). Images will be analysed using a dedicated software tool
(Automated Vascular Analysis V.3.02, Microvision Medical, The Netherlands). Data generated
will include flow and density-based measures of the microcirculation, including Perfused
Vessel Density (PVD) and Microcirculatory Flow Index (MFI).
Peri-operative sampling and imaging will occur at predefined surgical time-points, in keeping
with previous studies and informed by the feasibility study. Time-points were selected in
anticipation of the most informative results, including point of peak "reperfusion" after
final surgical anastomosis, and to minimise participant inconvenience (existing arterial line
and urinary catheter tubing will be used) and to avoid surgical disruption and delays (IDF is
quicker during anaesthesia and previous studies have shown negligible change between baseline
and assessment immediately after anaesthesia prior to surgery).
Confounding factors: Factors affecting development of AKI include medical history (chronic
kidney disease, hypertension, diabetes), surgical factors (operation, CPB and aortic cross
clamp duration, use of blood products), free haemoglobin (fHb) and macrovascular parameters
(blood pressure, lactate, cardiac output, haematocrit) will be recorded and statistical
analyses adjustment performed.
Follow up: Until seven days post-op or discharge from hospital, whichever is soonest.
Proposed sample size: 70 (single centre study)
Power calculations: The cohort study is powered to determine the primary outcome: peak plasma
SDC1 concentration between those who do and do not develop CSA-AKI. The investigators'
retrospective analysis found post-CABG CSA-AKI incidence in their hospital to be 19%. The
most appropriate published study offering test statistics to guide the power calculation is
one of AKI in a cohort of patients with acute decompensated heart failure. The difference in
mean SDC1 between those with and without AKI (effect size) was calculated from presented data
as 153.2±123.8ng/ml. Assuming a power value of 80% and significance level of 5%, a
calculation using the T statistic yields a sample of 36: 7 with CSA-AKI and 29 without. The
investigators have further repeated the calculations using unpublished data from patients
with traumatic haemorrhagic shock, where the difference in mean SDC1 between those with and
without AKI was 175.2±185.5ng/ml. With the same assumptions as previously, the calculation
yields a sample of 61: 12 with CSA-AKI and 49 without. The investigators will use the more
conservative of these calculations, allow for a 10% dropout rate, and aim to recruit 70
patients.
Loss to follow-up: As all sampling and data collection will take place over a very short
period there should be no loss to follow-up, as in the feasibility study. If participants
withdraw consent then no further samples or images will be collected.
Bias: Participants will be recruited by consecutive convenience sampling. There is unlikely
to be any differences between those approached and not approached, and selection bias is
unlikely to apply. Information bias is also unlikely as all measurements and data to be
collected is objective. The investigators will protect against assessment bias when analyzing
results by pseudonymisation of samples and IDF videos. Confounding factors will be accounted
for during analysis, as above.
Statistical analysis: Patients will be divided into two groups based on CSA-AKI presence or
absence. The difference between peak SDC1 between groups will be assessed using T-tests.
Multiple logistic regression with AKI as the outcome and peak SDC1 as independent predictor
will be used to consider confounding parameters, including fHb. P-values <0.05 will be
considered statistically significant. Analysis will be repeated for difference between peak
SDC1 and baseline for each participant, to take into account possible pre-existing
glycocalyceal injury. Correlation between SDC1 and TM and PVD / MFI will be calculated, using
either continuous variables or categorical groups as appropriate. To determine the predictive
value of SDC1 and microcirculatory variables in CSA-AKI receiver operating characteristic
(ROC) curves will be constructed for each variable by plotting sensitivity versus
(1-specificity) for a series of threshold values and calculating the area under the curve
(AUC) for each. These will be compared to those for NephroCheck score, Cleveland Clinic
Score, fHb, lactate, and macrovascular parameters.
Data access: Data collected during this study will only be accessible to the study team, and
to the Sponsor for regulatory purposes.
Data and sample storage: All data will be stored in accordance with Caldicott Principles.
