Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response to an infectious insult. Together with a systemic inflammation triggered by surgery this often leads to widespread tissue injury and multiple organ dysfunction. In particular, the development of acute kidney injury (AKI) is one of the most frequent complications, which increases the complexity and cost of care, and is an independent risk factor for mortality. The pathophysiology of AKI is very complex and not fully understood. Recently published studies have shown multiple factors that trigger or contribute to AKI, however, their dynamics and interdependence in vivo is still enigmatic.
In addition to/or in lieu of ischemia, DAMPs (damage-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns) are released, initiating the inflammatory response, including humoral and cellular immune activation. Disturbances of the microvascular flow, oxidative stress, metabolic/bioenergetic and cell-cycle alterations, and impaired cellular differentiation processes can further corroborate AKI progression. In addition, renal tubular dysfunction with activation of the tubuloglomerular feedback mechanism appears to be a crucial contributor to sepsis-induced AKI. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here, macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease.
Glutamine is an α-amino acid that is commonly used for parenteral nutrition substitution in critically ill patients. Kidney tubular epithelial and immune cells are the main consumers of glutamine in the body. Recently, it has been suggested that glutamine substitution may influence kidney function during inflammatory disorders, e.g. in a murine model of sepsis-induced AKI in mice where administration of glutamine resulted in a reduced inflammatory response together with an attenuated kidney damage.
This project is designed to elucidate the effect of glutamine on the development of AKI in mice and to understand the mechanism by which glutamine affects disease progression. The final goal is to take these findings into the clinical setting to develop strategies to prevent or blunt the development of AKI following cardiac surgery. Our translational approach will employ whole-body imaging of neutrophil dynamics and glutamine consumption in correlation to kidney function, in sepsis models by SPECT and PET in vivo; to decipher cellular and metabolic changes in response to glutamine with the long-term aim to translate findings into sepsis patients. Besides a potentially new clinical intervention based on glutamine administration to prevent and/or ameliorate the development of AKI this project is designed to also provide novel diagnostic biomarkers for diagnosis, therapy monitoring and prognosis of AKI.