Prevention of Post-Cardiac Surgery Acute Kidney Injury by Proton Pump Inhibitor

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether perioperative intravenous administration of pantoprazole will improve kidney function parameters following cardiac surgery with cardiopulmonary bypass compared to famotidine and to determine whether perioperative intravenous administration of pantoprazole will decrease the incidence of postoperative Acte Kidney Injury (AKI) and major adverse kidney events (MAKE).

Detailed Description
-----------------
Each year more than 500,000 cardiac surgeries are performed in the United States of America (USA) alone. Acute kidney injury ( AK) I is a common complication following cardiac surgery and is associated with poor patient outcomes and increased healthcare costs. 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. 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 micro-ribonucleic acid (microRNAs). 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 the potential in renal protection through vascular integrity and regeneration. Additionally, microRNAs exert protective effects via decreasing apoptosis and promoting tubular cell proliferation during ischemic AKI. 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. Adenosine triphosphate (ATP)4A (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.

Official Title
-----------------
Prevention of Post-Cardiac Surgery Acute Kidney Injury by Proton Pump Inhibitor: A Prospective Randomized Controlled Trial

Conditions
-----------------
Acute Kidney Injury

Intervention / Treatment
-----------------
* Drug: Pantoprazole
* Drug: Famotidine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Scheduled for elective cardiac surgery with cardio pulmonary bypass (CPB) with a high risk of developing AKI (Cleveland risk score higher than 6, please see the appended table at end of the revised protocol) Exclusion Criteria: Preoperative eGFR<30 ml/min per 1.73 m2 Dialysis dependence Emergency surgery Interstitial nephritis Pregnancy Nursing Patients Proton pump inhibitors (PPIs) hypersensitivity Liver disease Vitamin B12 deficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pantoprazole group<br>Pantoprazole (40 mg iv every 12 hours/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 postoperative (POD) 1 for a total of 4 doses over 2 days. There will be no other modifications in patient care. | Drug: Pantoprazole<br>* Subjects will receive pantoprazole (40 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 post operative day 1 (POD 1) for a total of 4 doses over 2 days.<br>|
| Active Comparator: Famotidine Group<br>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 for a total of 4 doses over 2 days. There will be no other modifications in patient care. | Drug: Famotidine<br>* Subjects will receive 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 for a total of 4 doses over 2 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The area under the curve (AUC) of urinary kidney injury biomarkers Kidney Injury Molecule-1 (KIM-1) above baseline within 24 hours postoperatively |  | Baseline, post operative day 7 (POD 7)(or hospital discharge if earlier) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with incidence of any-stage postoperative AKI | AKI will be defined using the 2012 Kidney Disease Improving Global Outcomes (KDIGO) criteria: serum creatinine (SCr) increase greater than 50% from baseline or ≥ 0.3 mg/dL increase within 48 hours after surgery. | Post Operative Day 7 (or hospital discharge if earlier). | 
| Number of subjects with incidence of MAKE | MAKE is defined as the composite of death, dialysis, renal hospitalization or sustained kidney dysfunction (glomerular filtration rate/GFR decline of 25% or more from preoperative baseline) | 30 days after surgery | 
| The area under the curve (AUC) of Urinary Kidney Injury Biomarkers (Neutrophil gelatinase-associated lipocalin/NGAL, tissue inhibitor of metalloproteinases/TIMP-2, and insulin-like growth factor/IGFBP-7) |  | 24 hours postoperatively | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cardiac surgery