Prevention of Post-Cardiac Surgery Acute Kidney Injury by Proton Pump Inhibitor: A Prospective Randomized Controlled Trial
Phase: PHASE2
Conditions: Acute Kidney Injury
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prevention of Post-Cardiac Surgery Acute Kidney Injury by Proton Pump Inhibitor: 
A Prospective Randomized Controlled Trial 
 
NCT06154226 
 
Version Date: 04/02/2024 
 
 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
 
 
 
Protocol Title: 
 
Prevention of Post-Cardiac Surgery Acute Kidney Injury by Proton Pump Inhibitor: A 
Prospective Randomized Controlled Trial 
 
Principal Investigator: 
 
• 
Name: Yafen Liang, M.D. 
 
Co-Investigator (s): 
 
• 
Holger Eltzschig, M.D., Ph.D. – Contributor 
• 
Bindu Akkantti, M.D. – Co-Investigator 
• 
Charles Green, Ph.D. – Collaborator 
Study Coordinator: Connor Rollings 
 
Population: 
100 adult patients presenting for cardiac surgery with cardiopulmonary 
bypass at the Memorial Hermann Hospital TMC. 
 
Number of Sites: 
Single site / Memorial Hermann TMC 
 
Study Duration: 
1-2 years 
 
Subject Duration: 
30 days 
 
 
 
 
A. INTRODUCTION / BACKGROUND 
Each year more than 500,000 cardiac surgeries are performed in the USA alone. AKI is a 
common complication following cardiac surgery and is associated with poor patient outcome and 
increased health care cost.1,2 Therefore, there is an urgent need to identify medical interventions 
and treatments that prevent AKI or mitigate its severity when it occurs after cardiac surgery. 
One of the main causes of AKI following cardiac surgery involves renal 
hypoperfusion/ischemia and reperfusion injury.3,4 Hypoxia inducible factors (HIFs) are key 
transcription factors responsible for tissue adaptation to low oxygen, which orchestrate the 
expression of a wide variety of genes including a set of microRNAs.5,6 MicroRNAs are 
endogenous single-stranded noncoding miRNAs of nucleotides that participate in physiological 
and pathological functions via regulating post-transcription of target genes. During ischemic 
injury, hypoxia upregulates endothelial MicroRNAs that has a potential in renal protection 
through vascular integrity and regeneration. Additionally, microRNAs exerts protective effects 
via decreasing apoptosis and promoting tubular cell proliferation during ischemic AKI. 
DEPARTMENT OF ANESTHESIOLOGY CLINICAL PROTOCOL SUMMARY 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
Moreover, decreased serum levels of MicroRNAs are highly correlated with AKI severity in the 
intensive care unit (ICU) patients. 
Our preliminary study identified ATP4A as the downstream target gene of MicroRNAs in the 
kidney. ATP4A (catalytic α subunit of H+/K+ ATPase) is located in intercalated cells in the 
distal tubules and cortical collecting ducts, which regulates urine acidification through secretion 
of hydrogen and reabsorption of potassium from urine. Proton pump inhibitors (PPIs) block the 
ATP hydrolysis of the H+/K+ ATPase via binding its active site of ATP4A and further enhance 
this endogenous kidney protection pathway. Despite robust animal model data, randomized 
controlled trial aiming to test the effectiveness of PPI in post-cardiac surgery AKI prevention is 
lacking. If proven to be effective, our studies could be easily implemented in clinical practice 
and serve as an effective treatment for perioperative AKI. 
 
B. HYPOTHESIS 
 
We hypothesize that perioperative administration of PPI pantoprazole could reduce acute 
kidney injury following cardiac surgery. 
 
B. SPECIFIC AIMS 
 
Aim 1: To determine whether perioperative intravenous administration of pantoprazole (study 
group) will reduce urinary kidney injury biomarkers KIM-1 following cardiac surgery with 
cardiopulmonary bypass compared to famotidine (control group) (n=100 total; primary endpoint). 
 
Aim 2: To determine whether perioperative intravenous administration of pantoprazole will 
increase other urinary kidney injury biomarkers (NGAL, TIMP-2, and IGFBP-7), the incidence 
of postoperative AKI and major adverse kidney events (MAKE) at POD 30. 
 
C. RESEARCH STRATEGY 
 
1) Significance/Rationale 
a. AKI is a common complication following cardiac surgery and is associated 
with increased postoperative morbidity, prolonged hospitalization, progression to 
chronic kidney disease, and increased short and long-term mortality. Although 
clinical definitions, biomarkers, and pathophysiology of AKI are intensively 
studied, clinical approaches to treat or prevent AKI are lacking. Based on animal 
studies, the opportunity to prevent AKI is an easier goal than the reversal of 
established AKI. In the perioperative setting most elective surgeries are carried out 
in patients without AKI. Therefore, prophylactic approaches to prevent AKI in 
patients undergoing surgeries would have a major impact. If the current proposal is 
successfully completed, PPIs such as pantoprazole could be given prophylactically 
throughout the perioperative period to prevent AKI. This could represent the first 
clinical approach for perioperative AKI prevention or treatment. 
 
2) Protocol 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
o Experimental Design/Flowchart 
 
Overview: The central hypothesis of this proposal is that perioperative 
administration of PPI pantoprazole could reduce acute kidney injury 
following cardiac surgery by enhancing the endogenous pathway for 
kidney protection. We propose a single-center, randomized, controlled, 
single-blinded trial to determine whether perioperative intravenous 
administration of pantoprazole will reduce urinary kidney injury 
biomarkers KIM-1 and other injury biomarkers, the incidence of AKI, and 
major adverse kidney events (MAKE) at POD 30 compared to famotidine 
after cardiac surgery with CPB. The specific aims of the study will be 
achieved by randomizing a cohort of 100 patients to receive pantoprazole 
(study) or famotidine (control) for 2 days perioperatively. 
 
Intervention: Patients will be randomized to receive pantoprazole (40 mg 
iv q12H) vs. famotidine (20 mg iv q12H) for 2 days perioperatively (first 
dose after anesthesia induction and before surgical incision, second dose at 
chest closure, then followed by 2 doses daily (Q12hr dosing) on POD 1 
and POD2 for a total of 4 doses over 2 days. There will be no other 
modifications in patient care. Both pantoprazole and famotidine are the 
standard medications used for GI prophylaxis at the current institution. 
 
Prospective in-Hospital Data Collection: Each patient will be followed 
daily until POD 30 or discharge (whichever is earlier). Primary 
hospitalization data including subjects’ demographics, co-morbidities, 
medications and other relevant preoperative clinical data as well as 
intraoperative information and postoperative outcomes and complications 
(specifically nosocomial pneumonia and C-Diff colitis) will be collected 
by trained research personnel using a detailed case report form. Data will 
be stored electronically and maintained in a secured computerized 
database. 
 
Blood and Urine Samples Collection: Laboratory tests will be collected 
according to institutional protocols and standard of care. For each patient 
urine samples will be collected at 5 time points: baseline after induction of 
anesthesia and prior to administration of first dose of study medication, at 
chest closure before the second dose of the study medication, 8 hours after 
ICU admission, and then 24, and 48 hours after ICU admission. Urine 
samples will be used to measure urine acidity and kidney injury 
biomarkers (KIM-1, NGAL, TIMP2 and IGFBP-7) for the 5 study points. 
Blood samples will be used to measure kidney function parameters (for 
the complete hospitalization period according to institutional practice). All 
the tests performed, and the time points are standard of care at current 
institution except for the urinary kidney injury biomarkers. The urinary 
samples for biomarker study will be stored in regular urine analysis 
container and then transported to the medical school 5.026, Dr. Eltzschig’s 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
laboratory. The sample will be stored for up to 2 days until they are 
analyzed. The container will be labeled with study ID, no patient identifier 
will be shown on the container. 
 
o Inclusion/Exclusion Criteria 
Inclusion - Adult patients (age 18-90) that are scheduled for elective 
cardiac surgery with CPB with moderate to high risk of developing AKI 
(Cleveland risk score equal or higher than 3, please see the appended table 
at end of the revised protocol) will be enrolled for the study. 
Exclusion - Patients who have preoperative eGFR<30 ml/min per 1.73 m2 
or dialysis dependence will be excluded from the study. In addition, 
emergency surgery, pregnancy or nursing patient, patients with interstitial 
nephritis, PPIs hypersensitivity, liver disease, or vitamin B12 deficiency 
will be also excluded. 
 
o Primary and Secondary End Points 
The primary outcome will be the area under the curve (AUC) of urinary 
kidney injury biomarker KIM-1 above baseline within 24 hours 
postoperatively. Secondary outcome will be the area under the curve 
(AUC) of other urinary kidney injury biomarkers (NGAL, TIMP-2, and 
IGFBP-7) above baseline within 24 hours postoperatively, and the 
composite result of the incidence of any-stage postoperative AKI within 7 
days of surgery (or until hospital discharge if earlier) and incidence of 
MAKE at 30 days. AKI will be defined using the 2012 Kidney Disease 
Improving Global Outcomes (KDIGO) criteria: SCr increase greater than 
50% from baseline or ≥ 0.3 mg/dL increase within 48 hours after surgery. 
The urine output criteria will not be used to determine AKI. MAKE is 
defined as the composite of death, dialysis, renal hospitalization or 
sustained kidney dysfunction (GFR decline of 25% or more from 
preoperative baseline) at 30 days after surgery. Additional clinical 
outcomes that will be collected include AKI severity in each group; 
maximal change in creatinine by POD 7 in each group; postoperative 
ventilation time, re-intubation, postoperative myocardial infarction, 
postoperative delirium, infection and ICU and hospital length of stay. 
 
o What is routine clinical care for the conditions being studied? 
Both pantoprazole and famotidine are the standard medications used for 
GI prophylaxis at the current institution. The patient will receive either 
medication for GI prophylaxis after cardiac surgery. 
 
o Safety and Adverse Events: 
Due to the simple study design and essentially just following the standard 
of care at the current institution, we do not expect major issues with 
patient enrollment or study protocol execution. Any adverse events such 
as c.diffile colitis, nosocomial pneumonia will be reported. 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
The Data Monitoring and Safety Board (DMSB) will consist of members 
from departmental research committee, a cardiac anesthesiologist, a 
cardiac surgeon and an intensivist. They will review the safety of the study 
protocol every 6 months to ensure safe execution of the research protocol. 
 
o Are study risks accurately described (if any)? 
Due to the simple study design and essentially just following the standard 
of care at the current institution, we do not expect major issues with 
patient enrollment or study protocol execution. 
 
3) Statistical Plan 
 
o Sample size and statistical analysis (see attachment) 
 
o This is a pilot feasibility study. We will use the preliminary data 
achieved with this study proposal for further larger-scale trials and 
external funding applications. Therefore, no sample size calculation will 
be needed. 
 
Ethics: Written informed consent will be obtained. Patients will be approached at the preoperative 
holding area or on the ward and offered participation in the trial. The person who obtains research 
consent should not be directly related with patient’s care. Benefits and risks of participating the 
study will be explained to the patient in detail, all questions shall be answered. 
o Subject Selection and Withdrawal 
Patients will be approached at the preoperative holding area or on the ward 
and offered participation in the trial. Once informed consent is obtained, 
patients will be enrolled and randomized to pantoprazole or famotidine by 
trained research coordinators using a computerized randomization 
software and provided with pantoprazole or famotidine based on their 
randomization. Enrolled patients cannot participate in other studies 
investigating post-cardiac surgery AKI. Patients have the right to 
withdraw from the study at any point. 
 
Data handling and record keeping 
 
− Patient’s data will be accessed through Care 4 electronic medical record system at MH TMC. 
All reasonable efforts will be made to keep each patient’s protected health information (PHI) 
private and confidential. There will be limited access to medical records and de- 
identification of all records. Potential human subjects for the study will be identified through 
MHTMC operating room tracker. 
− The patient data will be linked to study ID. The linkage is stored in a centered password 
protected UTHealth computer, only study key personnel has access to the linkage data. The 
data collection form and consent form will be stored in a secured office for 3 years. 
− Data will be stored in secured areas on password protected UTHealth PCs conforming to the 
latest UTHealth IS security policies. Computer databases will be maintained on password 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
protected UTHealth PCs. All study staff have completed employee education regarding 
patient confidentiality and have completed Human Subjects protection education (CITI 
course) as specified by the UTHealth IRB. Research Records will be retained for a period of 
3 years after the submission of the final report and close-out procedures on the research 
project for which the Research Records were prepared. The retention of the original Research 
Records shall be the responsibility of the Principal Investigator. 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
References: 
1. 
O'Neal JB, Shaw AD, Billings FTt. Acute kidney injury following cardiac surgery: 
current understanding and future directions. Crit Care. 2016;20(1):187. 
2. 
Wang Y, Bellomo R. Cardiac surgery-associated acute kidney injury: risk factors, 
pathophysiology and treatment. Nat Rev Nephrol. 2017;13(11):697-711. 
3. 
Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011;364(7):656- 
665. 
4. 
Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat 
Med. 2011;17(11):1391-1401. 
5. 
Eltzschig HK, Bratton DL, Colgan SP. Targeting hypoxia signalling for the treatment of 
ischaemic and inflammatory diseases. Nat Rev Drug Discov. 2014;13(11):852-869. 
6. 
Eckle T, Hartmann K, Bonney S, et al. Adora2b-elicited Per2 stabilization promotes a 
HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat Med. 
2012;18(5):774-782. 

IRB NUMBER: HSC-MS-22-0502 
IRB APPROVAL DATE: 04/02/2024 
 
 
 
Table 1: Cleveland Risk Score for acute kidney injury.