Abstract
Background: We investigated the association of damage-associated molecular pattern (DAMP) removal with mortality in sepsis patients undergoing continuous veno–venous hemofiltration (CVVH).Methods: Circulating levels of DAMPs [mitochondrial DNA (mtDNA); nuclear DNA (nDNA); heat shock protein 70 (HSP70); and high mobility group box 1 (HMGB1)] and cytokines were measured at baseline, 6 and 12 h after initiation of CVVH. Urinary DNA levels were analyzed at baseline and end of CVVH. The expression of human leukocyte antigen (HLA)-DR was assayed at 0, 3, and 7 days after initiation of CVVH. Moreover, the effects of HSP70 and HMGB1 clearance on survival were analyzed.Results: We evaluated 43 patients with acute kidney injury (AKI) (33 sepsis patients). Twenty-two sepsis patients (67%) and three non-sepsis patients (30%) expired (P = 0.046). Significant reductions in the levels of circulating interleukin-6 (P = 0.046) and tumor necrosis factor-α (P = 0.008) were found in the sepsis group. The levels of mtDNA were increased (ND2, P = 0.035; D-loop, P = 0.003), whereas that of HSP70 was reduced (P = 0.000) in all patients during the first 12 h. The levels of DAMPs in the plasma were markedly increased after blood passage from the inlet through the dialyzer in survivor sepsis patients. The clearance rates of HSP70 and HMGB1 were good predictors of mortality [area under the curve (AUC) = 0.937, P = 0.000; AUC = 0.90, P = 0.001, respectively]. The level of HLA-DR was increased in response to higher HSP70 clearance (P = 0.006). Survival was significantly worse in groups with higher clearance rates of HSP70 and HMGB1 than the cut-off value (log-rank test: P = 0.000 for both). Higher HSP70 clearance was a significant independent predictor of mortality (odds ratio = 1.025, 95% confidence interval [CI]: 1.012–1.039, P = 0.000). The urinary nDNA (β-globin) level before CVVH was an independent risk factor for the duration of CVVH in patients with sepsis (sRE = 0.460, 95% CI: 1.720–8.857, P = 0.005).Conclusion: CVVH removes inflammatory factors, reduces urinary DAMPs, and removes plasma DAMPs. However, survival decreases in response to higher HSP70 clearance.
Highlights
Sepsis is a life-threatening disease caused by a dysregulated host response to infection [1]
We investigated the association of damage-associated molecular pattern (DAMP) removal with mortality in sepsis patients undergoing continuous veno–venous hemofiltration (CVVH)
Our results indicated that extensive removal of DAMPs during CVVH was associated with poor prognosis, which may neutralize the beneficial effect of this treatment
Summary
Sepsis is a life-threatening disease caused by a dysregulated host response to infection [1]. The high mortality associated with septic AKI may be at least partly explained by an incomplete understanding of its pathophysiology and a delay in diagnosis. The levels of pro-inflammatory mediators in the serum are increased in patients with AKI, regardless of its cause [4, 5]. Proand anti-inflammatory mediators, as well as damage-associated molecular patterns (DAMPs), play important roles in regulating the immunological response that mediates the severity and complications of sepsis [6, 7]. DAMPs, known as alarmins, are constitutively available endogenous molecules released in response to tissue damage and involved in the activation of the immune system. We investigated the association of damage-associated molecular pattern (DAMP) removal with mortality in sepsis patients undergoing continuous veno–venous hemofiltration (CVVH)
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