Lipopolysaccharide or endotoxin, the major cell wall component of gram-negative bacteria, plays a pivotal role in the pathogenesis of sepsis. It is able to activate the host defense system through the interaction with Toll-like receptor 4, thus triggering pro-inflammatory mechanisms. When the production of inflammatory mediators becomes uncontrolled and excessive, septic shock develops with multiple organ dysfunction, such as myocardial and renal impairment, which are hallmarks of cardiorenal syndrome type 5. In this review, we will analyze the role of endotoxin in the pathogenesis of sepsis, its effects on cardiac and renal interactions in the setting of cardiorenal syndrome type 5 and the possible use of extracorporeal therapies in this clinical condition.

1.
Ianaro A, Tersigni M, D'Acquisto F: New insight in LPS antagonist. Mini Rev Med Chem 2009;9:306-317.
2.
Romaschin AD, Klein DJ, Marshall JC: Bench-to-bedside review: clinical experience with the endotoxin activity assay. Crit Care 2012;16:248.
3.
Tavener SA, et al: Immune cell Toll-like receptor 4 is required for cardiac myocyte impairment during endotoxemia. Circ Res 2004;95:700-707.
4.
Wang X, Quinn PJ: Lipopolysaccharide: biosynthetic pathway and structure modification. Prog Lipid Res 2010;49:97-107.
5.
Hoshino K, et al: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999;162:3749-3752.
6.
Qureshi ST, et al: Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 1999;189:615-625.
7.
Schromm AB, et al: Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J Exp Med 2001;194:79-88.
8.
Nagai Y, et al: Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 2002;3:667-672.
9.
Shimazu, R, et al: MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 1999;189:1777-1782.
10.
Tavener SA, Kubes P: Is there a role for cardiomyocyte toll-like receptor 4 in endotoxemia? Trends Cardiovasc Med 2005;15:153-157.
11.
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997;388:394-397.
12.
Reilly JM, et al: A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest 1989;95:1072-1080.
13.
Lefer AM: Mechanisms of cardiodepression in endotoxin shock. Circ Shock Suppl 1979;1:1-8.
14.
Jo SK, et al: Inflammatory cytokines and lipopolysaccharide induce Fas-mediated apoptosis in renal tubular cells. Nephron 2002;91:406-415.
15.
Cantaluppi V, et al: Protective effect of resin adsorption on septic plasma-induced tubular injury. Crit Care 2010;14:R4.
16.
Guo R, et al: Acute renal failure in endotoxemia is dependent on caspase activation. J Am Soc Nephrol 2004;15:3093-3102.
17.
Ronco C, et al: Cardiorenal syndrome. J Am Coll Cardiol 2008;52:1527-1539.
18.
Soni SS, et al: Cardio-renal syndrome type 5: epidemiology, pathophysiology, and treatment. Semin Nephrol 2012;32:49-56.
19.
Mehta RL, et al: Cardiorenal syndrome type 5: clinical presentation, pathophysiology and management strategies from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 2013;182:174-194.
20.
McCullough PA, et al: Pathophysiology of the cardiorenal syndromes: executive summary from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 2013;182:82-98.
21.
Srisawat N, Hoste EE, Kellum JA: Modern classification of acute kidney injury. Blood Purif 2010;29:300-307.
22.
Chelazzi C, Villa G, De Gaudio AR: Cardiorenal syndromes and sepsis. Int J Nephrol 2011;2011:652967.
23.
Tavernier B, et al: Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J 2001;15:294-296.
24.
Vieillard-Baron A, Cecconi M: Understanding cardiac failure in sepsis. Intensive Care Med 2014;40:1560-1563.
25.
Khan RZ, Badr KF: Endotoxin and renal function: perspectives to the understanding of septic acute renal failure and toxic shock. Nephrol Dial Transplant 1999;14:814-818.
26.
Brenner M, et al: Detection of renal blood flow abnormalities in septic and critically ill patients using a newly designed indwelling thermodilution renal vein catheter. Chest 1990;98:170-179.
27.
Lucas CE, et al: Altered renal homeostasis with acute sepsis. Clinical significance. Arch Surg 1973;106:444-449.
28.
Rector F, et al: Sepsis: a mechanism for vasodilatation in the kidney. Ann Surg 1973;178:222-226.
29.
Wan L, et al: Pathophysiology of septic acute kidney injury: what do we really know? Crit Care Med 2008;36(4 suppl):S198-S203.
30.
Langenberg C, et al: Renal blood flow in sepsis. Crit Care 2005;9:R363-R374.
31.
Molitoris BA: Renal blood flow in sepsis: a complex issue. Crit Care 2005;9:327-328.
32.
Cohen RI, et al: Renal effects of nitric oxide in endotoxemia. Am J Respir Crit Care Med 2001;164:1890-1895.
33.
Dellepiane S, Marengo M, Cantaluppi V: Detrimental cross-talk between sepsis and acute kidney injury: new pathogenic mechanisms, early biomarkers and targeted therapies. Crit Care 2016;20:61.
34.
Wolfs TG, et al: In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol 2002;168:1286-1293.
35.
El-Achkar TM, et al: Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am J Physiol Renal Physiol 2006;290:F1034-F1043.
36.
El-Achkar TM, Hosein M, Dagher PC: Pathways of renal injury in systemic gram-negative sepsis. Eur J Clin Invest 2008;38(suppl 2):39-44.
37.
Mariano F, et al: Circulating plasma factors induce tubular and glomerular alterations in septic burns patients. Crit Care 2008;12:R42.
38.
Cunningham PN, et al: Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J Immunol 2004;172:2629-2635.
39.
El-Achkar TM, et al: Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am J Physiol Renal Physiol 2008;295:F534-F544.
40.
Wu L, et al: Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice. Am J Physiol Renal Physiol 2007;292:F261-F268.
41.
Jacobs R, et al: Septic acute kidney injury: the culprit is inflammatory apoptosis rather than ischemic necrosis. Blood Purif 2011;32:262-265.
42.
Lerolle N, et al: Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med 2010;36:471-478.
43.
Jo SK, et al: α-Melanocyte stimulating hormone (MSH) decreases cyclosporine a induced apoptosis in cultured human proximal tubular cells. J Korean Med Sci 2001;16:603-609.
44.
Brocca A, et al: Cardiorenal syndrome type 5: in vitro cytotoxicity effects on renal tubular cells and inflammatory profile. Anal Cell Pathol (Amst) 2015;2015:469461.
45.
Virzi GM, et al: Cardiorenal syndrome type 5 in sepsis: role of endotoxin in cell death pathways and inflammation. Kidney Blood Press Res 2016;41:1008-1015.
46.
Cruz DN, et al: Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA 2009;301:2445-2452.
47.
Cruz DN, et al: Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Crit Care 2007;11:R47.
48.
Celes MR, Prado CM, Rossi MA: Sepsis: going to the heart of the matter. Pathobiology 2013;80:70-86.
49.
Stengl M, et al: Reduced L-type calcium current in ventricular myocytes from pigs with hyperdynamic septic shock. Crit Care Med 2010;38:579-587.
50.
Good DW, George T, Watts BA 3rd: Toll-like receptor 2 mediates inhibition of HCO(3)(-) absorption by bacterial lipoprotein in medullary thick ascending limb. Am J Physiol Renal Physiol 2010;299:F536-F544.
51.
Hsiao HW, et al: The decline of autophagy contributes to proximal tubular dysfunction during sepsis. Shock 2012;37:289-296.
52.
Danner RL, et al: Endotoxemia in human septic shock. 1991. Chest 2009;136(5 suppl):e30.
53.
Brandtzaeg P, Mollnes TE, Kierulf P: Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 1989;160:58-65.
54.
Opal SM, et al: Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013;309:1154-1162.
55.
Shoji H, et al: Extracorporeal endotoxin removal by polymyxin B immobilized fiber cartridge: designing and antiendotoxin efficacy in the clinical application. Ther Apher 1998;2:3-12.
56.
Li J, et al: Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis 2006;6:589-601.
57.
Morrison DC, Jacobs DM: Binding of polymyxin B to the lipid A portion of bacterial lipopolysaccharides. Immunochemistry 1976;13:813-818.
58.
Cutuli SL, et al: Polymyxin-B hemoperfusion in septic patients: analysis of a multicenter registry. Ann Intensive Care 2016;6:77.
59.
Klein DJ, et al: The EUPHRATES trial (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock): study protocol for a randomized controlled trial. Trials 2014;15:218.
60.
Riedemann NC, Guo RF, Ward PA: The enigma of sepsis. J Clin Invest 2003;112:460-467.
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