The Role of Circulating Cell-Free Hemoglobin in Sepsis-Associated Acute Kidney Injury

Abstract

Sepsis is a heterogeneous clinical syndrome that is complicated commonly by acute kidney injury (sepsis-AKI). Currently, no approved pharmacologic therapies exist to either prevent sepsis-AKI or to treat sepsis-AKI once it occurs. A growing body of evidence supports a connection between red blood cell biology and sepsis-AKI. Increased levels of circulating cell-free hemoglobin (CFH) released from red blood cells during hemolysis are common during sepsis and can contribute to sepsis-AKI through several mechanisms including tubular obstruction, nitric oxide depletion, oxidative injury, and proinflammatory signaling. A number of potential pharmacologic therapies targeting CFH in sepsis have been identified including haptoglobin, hemopexin, and acetaminophen, and early phase clinical trials have suggested that acetaminophen may have beneficial effects on lipid peroxidation and kidney function in patients with sepsis. Bedside measurement of CFH levels may facilitate predictive enrichment for future clinical trials of CFH-targeted therapeutics. However, rapid and reliable bedside tests for plasma CFH will be required for such trials to move forward.

Keywords: Sepsis; acetaminophen; acute kidney injury; biomarkers; cell-free hemoglobin; hemolysis.