Reduction of Occurence of Acute Kidney Injury (AKI) Through Administration of Glutamine

Study Overview
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Brief Summary
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The aim of this study is to evaluate whether the application of glutamine versus control in patients with high risk for AKI identified by biomarkers can reduce kidney damage after cardiac surgery.

Detailed Description
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Cardiac surgery is characterized by an increased production of free radicals as a consequence of surgical trauma, ischemia-reperfusion injury, inflammatory response syndrome in response to the use of the extracorporeal circulation. This results in an increased production and release of free radicals which may lead to an exhaustion of antioxidants and organ failure since the lungs, kidneys, liver and gastrointestinal tract are particularly susceptible to reactive oxidant species. Glutamine is considered as a conditionally indispensable amino acid in catabolic states of critically ill patients. It belongs, together with other mediators, to the host defense as major intracellular direct free radical scavengers. Its depletion has been demonstrated to be an independent predictor of mortality in a group of ICU (intensive care unit) patients. Clinical studies showed a positive outcome effect. In animal models, glutamine reduces the occurrence of AKI after ischemia-reperfusion injury. This could be demonstrated through reduced functional markers as well as reduced renal biomarker levels. Preliminary data suggest that glutamine has pleiotropic effects since it has effects on the immune system (reduced expression of cytokines) as well as on tubular epithelial cells (unpublished animal data from our laboratory). Thus, a randomized-controlled trial to analyze the effects of glutamine supplementation in high risk patients identified by renal biomarkers undergoing cardiac surgery with cardiopulmonary bypass (CPB) on the effects of kidney damage is urgently needed.

Official Title
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Biomarker-guided Implementation of Glutamine to Reduce the Occurence of AKI After Cardiac Surgery

Conditions
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Cardiac Surgery, Acute Kidney Injury

Intervention / Treatment
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* Drug: L-Alanyl/L-Glutamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients undergoing cardiac surgery with CPB Urinary [TIMP-2]*[IGFBP7] >= 0.3 4h after CPB Written informed consent Exclusion Criteria: Preexisting AKI (stage 1 and higher) Patients with cardiac assist devices Pregnant women, nursing women and women of childbearing potential Known (Glomerulo-) Nephritis, interstitial nephritis or vasculitis Chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) < 30 ml/min Dialysis dependent CKD Prior kidney transplant within the last to 12 months Hypersensitivity to the active substance, or to any of the excipients of the study medication Hepatic insufficiency Severe metabolic acidosis (pH < 7.2) Participation in another intervention trial in the past 3 months Persons with any kind of dependency on the investigator or employed by the institution responsible or investigator Persons held in an institution by legal or official order

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glutamine group<br>Intravenous infusion of 0.5 g/kg body weight (2.5 ml/kg body weight) L-alanyl-Lglutamine over 12 h after randomization | Drug: L-Alanyl/L-Glutamine<br>* Immediately after randomization (not longer than 30 min after fulfilling eligibility criteria), patients will receive intravenous infusions with the investigational drug<br>|
| Placebo Comparator: Control group<br>Intravenous infusion of 2.5 ml/kg body weight sodium chloride 0.9 % over 12 h after randomization | Drug: Placebo<br>* Immediately after randomization (not longer than 30 min after fulfilling eligibility criteria), patients will receive intravenous infusions with the placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kidney damage after cardiac surgery identified by measuring biomarkers ([TIMP-2]*[IGFBP7] | The presence of tissue inhibitor of metalloproteinases (TIMP-2) and insulin-like grwoth-factor binding protein 7 (IGFBP7) in the urine will be measured. | 12 hours after cardiac surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurence of acute kidney injury according to the KDIGO (Kidney Disease: Improving Global Outcomes) criteria |  | 72 hours after end of cardiac surgery | 
| Severity of acute kidney injury (number of patients with KDIGO stage 1, KDIGO stage 2 or KDIGO stage 3) | Definition and classification of acute injury according to the KDIGO (Kidney Disease Improving Global Outcomes) clinical practice guidelines on acute kidney injury | 72 hours after end of cardiac surgery | 
| Creatinine Clearance |  | one day after cardiac surgery | 
| Free-days of vasoactive medications and mechanical ventilation |  | 28 days after cardiac surgery | 
| Renal recovery | Renal recovery is defined as serum creatinine levels < 0.5 mg/dL higher than baseline serum creatinine | 30 days after cardiac surgery | 
| Renal recovery | Renal recovery is defined as serum creatinine levels < 0.5 mg/dL higher than baseline serum creatinine | 60 days after cardiac surgery | 
| Renal recovery | Renal recovery is defined as serum creatinine levels < 0.5 mg/dL higher than baseline serum creatinine | 90 days after cardiac surgery | 
| Mortality |  | 30 days after cardiac surgery | 
| Mortality |  | 60 days after cardiac surgery | 
| Mortality |  | 90 days after cardiac surgery | 
| ICU and Hospital stay |  | up to 90 days after cardiac surgery (until discharge) | 
| Number of patients with renal replacement therapy |  | up to 90 days after cardiac surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac surgery, glutamine