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


CONCLUSIONS
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.
Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. b.ergin@amc.uva.nl.|Department of Intensive Care, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. b.ergin@amc.uva.nl.
Bulent
B
Ergin
Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|University of Lorraine, Vandoeuvre-Lès-Nancy, France.
Philippe
http://orcid.org/0000-0002-4664-1861
P
Guerci
Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Lara
L
Zafrani
Divisional Medical & Clinical Affairs Generics & Standard Solutions, Volume Therapy, Fresenius Kabi Deutschland GmbH, Berlin, Germany.
Frank
F
Nocken
Department of Biology, Faculty of Science, University of Istanbul, Istanbul, Turkey.
Asli
A
Kandil
Department of Biology, Faculty of Science, University of Istanbul, Istanbul, Turkey.
Ebru
E
Gurel-Gurevin
Department of Biology, Faculty of Science, University of Istanbul, Istanbul, Turkey.
Cihan
C
Demirci-Tansel
Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.|Department of Intensive Care, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Can
C
Ince
Acute kidney injury; Inflammation; Kidney oxygenation; N-acetylcysteine; Sepsis
Crit Care. 2014 Aug 06;18(4):460
25185110
Am J Physiol Renal Physiol. 2008 Mar;294(3):F676-81
18184739
Crit Care. 2005;9 Suppl 4:S13-9
16168069
Shock. 2012 Aug;38(2):137-45
22683725
Mol Med. 2008 Jul-Aug;14 (7-8):502-16
18488066
J Biomed Sci. 2004 Mar-Apr;11(2):152-62
14966365
Intensive Care Med. 2010 Aug;36(8):1286-98
20443110
Am J Physiol Lung Cell Mol Physiol. 2012 Apr 1;302(7):L640-50
22268121
Crit Care Med. 2000 Dec;28(12 ):3799-807
11153617
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18351-2
24187149
Am J Hypertens. 2003 Jul;16(7):577-84
12850392
Crit Care Med. 2009 Apr;37(4):1423-32
19318827
Resuscitation. 2012 Jun;83(6):767-73
22142654
J Appl Physiol (1985). 2006 Apr;100(4):1301-10
16357065
Crit Care Med. 1994 Nov;22(11):1738-46
7956276
Crit Care Med. 2007 Sep;35(9 Suppl):S584-90
17713413
Crit Care. 2014 Oct 13;18(5):538
25497357
Intensive Care Med. 2000 Mar;26(3):267-74
10823382
Crit Care Med. 2007 Jan;35(1):118-26
17095947
Inflammation. 2011 Dec;34(6):539-50
20882329
Kidney Int. 2015 Aug;88(2):213-5
26230196
Shock. 2016 Mar;45(3):259-70
26871664
Crit Care Med. 2004 Feb;32(2):342-9
14758146
Eur Respir J. 1997 Sep;10 (9):1962-6
9311486
Am J Physiol. 1994 May;266(5 Pt 2):H1746-54
8203575
Crit Care Med. 2008 Aug;36(8):2328-34
18664787
Eur Surg Res. 1995;27(5):292-300
7589000
Crit Care Med. 1996 Aug;24(8):1302-10
8706483
Life Sci. 2006 Oct 19;79(21):2010-6
16860347
Shock. 2003 Apr;19(4):366-72
12688549
Cell Mol Life Sci. 2003 Jan;60(1):6-20
12613655
Intensive Care Med. 2011 Sep;37(9):1534-42
21695476
N Engl J Med. 2011 Feb 17;364(7):656-65
21323543
Semin Nephrol. 2015 Jan;35(1):75-84
25795501
Kidney Int. 2003 Feb;63(2):634-41
12631128
Trop Biomed. 2011 Apr;28(1):7-15
21602763
Resuscitation. 2013 Jan;84(1):121-7
22664745
J Surg Res. 2011 May 15;167(2):e307-13
19959187
Cochrane Database Syst Rev. 2012 Sep 12;(9):CD006616
22972094
J Nephrol. 2003 Jan-Feb;16(1):75-80
12653105
Am J Respir Crit Care Med. 2000 Jun;161(6):1907-11
10852765
Crit Care. 2014 Nov 14;18(6):602
25394836
Am J Physiol Renal Physiol. 2015 May 1;308(9):F956-66
25673809
J Invest Surg. 2006 May-Jun;19(3):175-84
16809227
Nephrol Dial Transplant. 2015 Feb;30(2):169-77
24848133
Crit Care Med. 1999 Jun;27(6):1100-4
10397212
Crit Care Med. 1989 Jun;17(6):547-50
2721213
Crit Care Med. 2007 Aug;35(8):1869-75
17568325
N Engl J Med. 2013 Aug 29;369(9):840-51
23984731
Crit Care. 2014 Jan 06;18(1):R5
24393404
Med Chem. 2007 Jan;3(1):29-34
17266621