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Acute renal failure and sepsis: therapeutic approaches
1University Dept of Medicine, Royal Infirmary, Edinburgh, UK.
Abstract:
Previous studies of experimental sepsis suggested that excessive systemic vasodilatation might be the stimulus to renal hypofiltration and fluid retention in sepsis. Successful therapy for this syndrome requires agents that either act to improve systemic haemodynamics without adverse renal effects, or that act directly on the kidney without impairing circulatory homeostasis. The plasma kallikrein-kinin system is a potent vasodilator pathway, activated by endotoxin. We studied the effect of aprotinin (Trasylol), which inhibits plasma kallikrein, in an ovine model of surgically-induced intra-abdominal sepsis. Given either as an early or late intervention, aprotinin was associated with increased mean arterial pressure and systemic vascular resistance, improved glomerular filtration rate, and increased urinary sodium excretion. In further studies, treatment with the thromboxane synthetase inhibitor, U63,557A (Upjohn), either before or after the surgical induction of peritonitis, was associated with increased glomerular filtration rate and sodium excretion, without any effect on systemic haemodynamics. Logical use of specific antagonists, based on an understanding of the pathophysiology of the septic ARF syndrome, is a desirable strategy.
Insights
Aprotinin and U63,557A improved kidney function in experimental sepsis by targeting vasodilation and thromboxane pathways. These agents offer potential therapeutic strategies for septic acute renal failure without compromising systemic hemodynamics.
Area of Science:
- Nephrology
- Pharmacology
- Critical Care Medicine
Background:
- Sepsis-induced systemic vasodilation can lead to renal hypofiltration and fluid retention.
- Effective sepsis therapy requires agents that improve hemodynamics without renal compromise or vice versa.
- The plasma kallikrein-kinin system, activated by endotoxin, is a key vasodilator pathway in sepsis.
Purpose of the Study:
- To investigate the therapeutic potential of aprotinin (kallikrein inhibitor) and U63,557A (thromboxane synthetase inhibitor) in a sheep model of surgically induced intra-abdominal sepsis.
- To evaluate the effects of these agents on systemic hemodynamics and renal function.
Main Methods:
- Surgically induced ovine model of intra-abdominal sepsis.
- Administration of aprotinin as an early or late intervention.
- Administration of U63,557A before or after peritonitis induction.
- Monitoring of mean arterial pressure, systemic vascular resistance, glomerular filtration rate, and urinary sodium excretion.
Main Results:
- Aprotinin administration was associated with increased mean arterial pressure, systemic vascular resistance, glomerular filtration rate, and urinary sodium excretion.
- U63,557A treatment improved glomerular filtration rate and sodium excretion without altering systemic hemodynamics.
- Both agents demonstrated beneficial effects on renal function in the septic model.
Conclusions:
- Targeting specific pathways like plasma kallikrein-kinin and thromboxane synthesis offers a promising strategy for managing septic acute renal failure.
- Pharmacological interventions can improve renal function in sepsis without adverse effects on circulatory homeostasis.
- Understanding sepsis pathophysiology guides the rational use of specific antagonists for improved patient outcomes.