Investigations Into Sepsis-associated Acute Kidney Injury

Study Overview
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Brief Summary
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In this study the investigators would like to study systemic and regional disturbances in patients with sepsis-associated acute kidney injury and in healthy controls undergoing laparoscopic abdominal surgery. Specifically study metabolic, hemodynamic and oxygen transport variables.

Detailed Description
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Acute kidney injury (AKI) in patients with sepsis has a very poor prognosis with up to 60% mortality. The pathobiology remains to be fully understood. Creatine and phosphocreatine, products of arginine metabolism through L-arginine:glycine amidinotransferase (AGAT) and its sister enzyme guanidinoacetate N-methyl-transferase (GAMT), provide an energy-buffering system that is essential for intracellular adenosine triphosphate (ATP) supply. We hypothesized that sepsis associated AKI may be caused by failure of this energy-buffering system. In series of pilot studies, we explored metabolic and bioenergetic patterns in patients and animals with high risk of developing AKI. These data suggest that sepsis associated AKI may be caused by failure of this alternative renal energy source. In the current application we propose a clinical investigation of renal metabolism and renal bioenergetics in patients with high and low risk of developing sepsis associated AKI. The primary objective is to directly investigate renal AGAT activity through the arginyl metabolites homoarginine, guanidino acetate, and creatine. Secondary objectives are to study renal and systemic hemodynamics, renal oxygenation, glomerular filtration rate (GFR), renal tubular function, and mitochondrial respiration.

Official Title
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Investigations Into the Mechanisms for Bioenergetic Failure in Sepsis-associated Acute Kidney Injury

Conditions
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Acute Kidney Injury

Intervention / Treatment
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* Drug: Para Aminohippurate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria sepsis group: Sepsis diagnosed or suspected Normal premorbid serum creatinine measured or anticipated (if data are not available) Normovolemia as indicated by a pulse pressure variation less than 12% Comparator group Previously healthy individuals scheduled for laparoscopic colon cancer resection Normal creatinine levels within 3 months before admittance to hospital. Patients admitted to the intensive care unit with sepsis diagnosed or suspected Previously healthy patients listed for elective colon cancer surgery Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sepsis patients<br>Patients admitted to the intensive care unit with sepsis diagnosed or suspected | Drug: Para Aminohippurate<br>* Measurements of renal plasma flow and glomerular filtration rate<br>* Other names: iohexol;|
| Surgical patients<br>Previously healthy patients who are operated for colon cancer with laparoscopic technique. | Drug: Para Aminohippurate<br>* Measurements of renal plasma flow and glomerular filtration rate<br>* Other names: iohexol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics | Systemic and regional hemodynamics | Repeated measures at 10am, 12am, 2pm, 4pm,6pm, and 8pm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic alterations | Renal arginine metabolism | Repeated measures at 10am, 12am, 2pm, 4pm,6pm, and 8pm |