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Effects of N -acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia

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ABSTRACT

Background: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).

Methods: Rats were randomized into five groups (n = 8 per group): (1) control group, (2) control + NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS + fluid resuscitation, and (5) LPS + fluid resuscitation + NAC (150 mg/kg/h). Fluid resuscitation was initiated at 120 min and maintained at fixed volume for 2 h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer’s solution (Volulyte) with or without supplementation with NAC (150 mg/kg/h). Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.

Results: Fluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p < 0.05). NAC supplementation dampened the accumulation of NGAL or L-FABP, hyaluronic acid, and nitric oxide in kidney tissue (p < 0.01).

Conclusion: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.

No MeSH data available.


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Percentage change of renal microvascular oxygen tension, oxygen delivery, and consumption from baseline to T3. In the renal cortex (CμpO2) (a), in the medulla (MμpO2) (b), renal oxygen delivery (DO2ren) (c), and renal oxygen consumption (VO2ren) (d). *p < 0.05, **p < 0.01, *p < 0.001 versus control; +p < 0.05 LPS versus LPS group
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Fig2: Percentage change of renal microvascular oxygen tension, oxygen delivery, and consumption from baseline to T3. In the renal cortex (CμpO2) (a), in the medulla (MμpO2) (b), renal oxygen delivery (DO2ren) (c), and renal oxygen consumption (VO2ren) (d). *p < 0.05, **p < 0.01, *p < 0.001 versus control; +p < 0.05 LPS versus LPS group

Mentions: The percentage variations in CμPO2, MμPO2, DO2ren, and VO2ren between baseline (T0) and the end of the experiment (T3) are shown in Fig. 2. Compared to the control groups, LPS infusion induced a significant decrease in CμPO2 (40.6 ± 8.8 mmHg versus 68.2 ± 4.1 mmHg in the control group at T3, p < 0.001) and MμPO2 (32.2 ± 7.9 mmHg versus 51.6 ± 3.2 mmHg in the control group, p < 0.001). Fluid resuscitation with HES-RA alone did not improve either CμPO2 or MμPO2. HES-RA combined with NAC significantly improved CμPO2 during sepsis (p < 0.01). LPS induced a significant decrease in DO2ren and VO2ren (8.3 ± 6.1 ml O2/min in the LPS group versus 67.2 ± 23.2 ml O2/min in the control group at T3 and 7.8 ± 6.5 ml O2/min in the LPS group versus 32.9 ± 10 ml O2/min in the control group at T3, p < 0.05, respectively). Fluid resuscitation with or without NAC significantly improved VO2ren compared to the LPS alone group (p < 0.05). Of note, the addition of NAC to the control group also increased VO2ren compared to the control group alone (p < 0.05). The hematocrit values are reported in Table 3. A significant decrease in hematocrit occurred after fluid resuscitation in both groups compared to the control and LPS alone groups (p < 0.001). The magnitude of hemodilution in both groups was in the same range.Fig. 2


Effects of N -acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia
Percentage change of renal microvascular oxygen tension, oxygen delivery, and consumption from baseline to T3. In the renal cortex (CμpO2) (a), in the medulla (MμpO2) (b), renal oxygen delivery (DO2ren) (c), and renal oxygen consumption (VO2ren) (d). *p < 0.05, **p < 0.01, *p < 0.001 versus control; +p < 0.05 LPS versus LPS group
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Fig2: Percentage change of renal microvascular oxygen tension, oxygen delivery, and consumption from baseline to T3. In the renal cortex (CμpO2) (a), in the medulla (MμpO2) (b), renal oxygen delivery (DO2ren) (c), and renal oxygen consumption (VO2ren) (d). *p < 0.05, **p < 0.01, *p < 0.001 versus control; +p < 0.05 LPS versus LPS group
Mentions: The percentage variations in CμPO2, MμPO2, DO2ren, and VO2ren between baseline (T0) and the end of the experiment (T3) are shown in Fig. 2. Compared to the control groups, LPS infusion induced a significant decrease in CμPO2 (40.6 ± 8.8 mmHg versus 68.2 ± 4.1 mmHg in the control group at T3, p < 0.001) and MμPO2 (32.2 ± 7.9 mmHg versus 51.6 ± 3.2 mmHg in the control group, p < 0.001). Fluid resuscitation with HES-RA alone did not improve either CμPO2 or MμPO2. HES-RA combined with NAC significantly improved CμPO2 during sepsis (p < 0.01). LPS induced a significant decrease in DO2ren and VO2ren (8.3 ± 6.1 ml O2/min in the LPS group versus 67.2 ± 23.2 ml O2/min in the control group at T3 and 7.8 ± 6.5 ml O2/min in the LPS group versus 32.9 ± 10 ml O2/min in the control group at T3, p < 0.05, respectively). Fluid resuscitation with or without NAC significantly improved VO2ren compared to the LPS alone group (p < 0.05). Of note, the addition of NAC to the control group also increased VO2ren compared to the control group alone (p < 0.05). The hematocrit values are reported in Table 3. A significant decrease in hematocrit occurred after fluid resuscitation in both groups compared to the control and LPS alone groups (p < 0.001). The magnitude of hemodilution in both groups was in the same range.Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Background: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).

Methods: Rats were randomized into five groups (n&thinsp;=&thinsp;8 per group): (1) control group, (2) control&thinsp;+&thinsp;NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS&thinsp;+&thinsp;fluid resuscitation, and (5) LPS&thinsp;+&thinsp;fluid resuscitation&thinsp;+&thinsp;NAC (150&nbsp;mg/kg/h). Fluid resuscitation was initiated at 120&nbsp;min and maintained at fixed volume for 2&nbsp;h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer&rsquo;s solution (Volulyte) with or without supplementation with NAC (150&nbsp;mg/kg/h). Oxygen tension in the renal cortex (C&mu;PO2), outer medulla (M&mu;PO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.

Results: Fluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p&thinsp;&lt;&thinsp;0.05). NAC supplementation dampened the accumulation of NGAL or L-FABP, hyaluronic acid, and nitric oxide in kidney tissue (p&thinsp;&lt;&thinsp;0.01).

Conclusion: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.

No MeSH data available.


Related in: MedlinePlus