Traumatic Hemorrhagic shock and rhabdomyolysis: prevention of acute kidney injury – TAKIN
Severe trauma remains a major public health problem either in civilian society or in military settings since it involves young patients with a negative impact in terms of mortality and morbidity. Hemorrhagic shock is still the first leading cause of death in severe trauma patients because of uncontrolled hemorrhage at the initial phase but also because of organ dysfunction due to prolonged hemorrhage-induced hypoperfusion at a later stage. Rhabdomyolysis, which is frequently associated to hemorrhage in trauma patients, is caused by traumatic tissue attrition and can lead to organ dysfunction, in particular acute kidney injury.
During hemorrhage, the drop in transglomerular pressure associated to a decrease in tubular perfusion (tubular hypoxia) causes renal insult, which may lead to acute kidney injury (loss in renal function). On the other hand, rhabdomyolysis has detrimental consequences on different renal components: intrarenal vasoconstriction, direct tubular injuries induced by oxidative stress, tubular lumen obstruction and renal inflammation.
Most recent studies report acute kidney injury incidences as high as 50% in severe trauma patients. In two series of severe trauma patients (one French military series and one civilian series from "Ile de France" area), the project initiators report that hemorrhage and rhabdomyolysis severity are the two main factors contributing to acute kidney injury after trauma. Myoglobin is to this day the main factor mediating renal toxicity in rhabdomyolysis. Experimental studies conducted on renal isolated vessels have recently shown that myoglobin exacerbates vasoconstriction properties of molecules (angiotensin) that are massively secreted during hemorrhage. This suggests a deleterious synergy between hemorrhage and rhabdomyolysis on renal function. There is currently no specific treatment targeting myoglobin action during hemorrhage. Indeed, rhabdomyolysis resuscitation is only based on fluid administration to increase diuresis in order to lower myoglobin aggregation in renal tubules.
We propose to identify early factors mediating rhabdomyolysis induced renal injury during hemorrhage and to explore whether their eviction (by adsorption) may prevent acute kidney injury.
This work will study interaction between hemorrhage and rhabdomyolysis in a model of hemorrhagic shock in pigs during which renal oxygenation and perfusion are accurately measured at cortical and medullar level. We chose a linear approach with 3 experimental series:
1/ The first series of experiments aim at characterizing the double agression hemorrhage/rhabdomyolysis on renal function. This will allow us to describe the time course of renal agression to propose afterwards a therapeutic at the optimal time.
2/ The second series aim at demonstrating that myoglobin is the major molecule mediating kidney injury in rhabdomyolysis in the context of hemorrhagic shock. It will ensure that myoglobin (and its effects) is an interesting target to prevent acute kidney injury after severe trauma.
3/ The third series aim at studying the effects of early myoglobin adsorption on renal perfusion, oxygenation and function. Ultimately, we aim at establishing that hemoadsorption is a therapeutic of interest to prevent organ failure (renal failure) after trauma.
Monsieur Jacques Duranteau (Biomarqueurs et maladies cardioneurovasculaires)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
CCML - UMR-S 999 Hypertension artérielle, pulmonaire : physiopathologie et innovation thérapeutique
BioCANVAS - INSERM PXI Biomarqueurs et maladies cardioneurovasculaires
Help of the ANR 300,000 euros
Beginning and duration of the scientific project: December 2018 - 36 Months