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.

Figure 1.

Renoprotective effects of acetaminophen in rats with rhabdomyolysis. (A) Gross examination of a representative kidney from a normal rat (Left), a rat with rhabdomyolysis (Center), and a rat with rhabdomyolysis treated with acetaminophen (APAP) (Right). Effect of treatment with APAP on reactive oxygen species (B) and on kidney function (C) in normal rats (controls), in normal rats treated with APAP (control + ApAP), in rats with rhabdomyolysis (Rhabdo), and in rats with rhabdomyolysis treated with APAP (Rhabdo + ApAP). (B) Urinary excretion of F₂-isoprostanes. **, P < 0.0001 for Rhabdo vs. controls; *, P < 0.005 for Rhabdo + APAP vs. controls. (C) Plasma creatinine levels. **, P < 0.0001 for Rhabdo vs. controls; *, P = 0.0002 for Rhabdo + APAP vs. controls. For both figures, the brackets indicate that APAP significantly reduced urinary F₂-isoprostanes and plasma creatinine compared with Rhabdo alone. (n ≥ 6 in each group). Abbreviations: ApAP – Acetaminophen. F₂-IsoPs − F₂-isoprostanes. Reproduced with permission.

Figure 2.

Creatinine measurements over study period in the Acetaminophen for the Reduction of Oxidative injury in Severe Sepsis (ACROSS) Trial. In patients never receiving any type of renal replacement therapy during or after the study (n = 36), creatinine levels were similar at baseline (study day 0) and were significantly reduced in the acetaminophen group on study day 3, the day following study completion (day 4), through the remainder of hospitalization, and at discharge or death. P values represent between-group comparisons at each time point. Circles and squares represent medians of placebo and acetaminophen groups, respectively. Whiskers represent interquartile ranges (between 25th and 75th percentiles). Table under figure represents number of patients (n) at each time point. Reproduced with permission.

Figure 3.

Effect of acetaminophen on serum creatinine in randomized trial of severe falciparum malaria. Points represent mean percent change in creatinine from baseline at 12, 24, 36, 60, 48, and 72 hours in the entire cohort (A) and in patients stratified by level of intravascular hemolysis (B and C). Plasma cell-free hemoglobin (CFH) ≥45000 ng/mL (B); plasma CFH <45000 ng/mL (C). Frequencies in rows below figures represent number of patients (n) at each time point. P value represents overall treatment effect. Abbreviations: Cr, creatinine; CFH, cell-free hemoglobin. Reproduced under the terms of the Creative Commons CC BY license from reference, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.