Exacerbates kidney injury in mice subjected to sepsis: critical impact of used heparin


American Journal of BioMedicine  Volume 2, Issue 11, pages1175-1187 November 2014

Peter Weighardt; Niels Hayashi; Gordon Medzhitov; Sean Newcomb


Sepsis is the leading cause of death in critically ill patients, and the incidence of sepsis is increasing causes multiorgan failure, including acute kidney injury (AKI) and patients with both sepsis and AKI have an especially high mortality rate.  Several different pathophysiological mechanisms have been proposed for sepsis-induced AKI: vasodilation-induced glomerular hypoperfusion, dysregulated circulation within the peritubular capillary network, inflammatory reactions by systemic cytokine storm or local cytokine production, and tubular dysfunction induced by oxidative stress animal sepsis models have been developed using LPS infusion. Renal dysfunction evaluated by serum creatinine and BUN was found in acute non-survivors (<24 hours) and decreased urine output in subacute non-survivors (24–96 hours). The study show that increased AKI in animal with blood collected heparin (P=0.002) compared to citrate, furthermore; sham mice that received heparin did not develop AKI.  

Keywords: Sepsis; Acute kidney injury (AKI); Heparin; Cytokine; LPS

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1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR., et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med 2001;29:1303–1310. [PubMed]

2. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit. Care Med 2007;35:1244–1250. [PubMed]

3. Bagshaw SM, Laupland KB, Doig CJ, et al. Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit. Care 2005;9:R700–R709. [PubMed]

4. Silvester W, Bellomo R, Cole L. Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit. Care Med. 2001;29:1910–1915. [PubMed]

5.Riedemann NC, Guo RF, Ward PA. The enigma of sepsis. J. Clin. Invest 2003;112:460–467. [PubMed]

6. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N. Engl. J. Med 2003;348:138–150. [PubMed]

7.Remick DG, Newcomb DE, Bolgos GL, Call DR. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 2000;13:110–116. [PubMed]

8. Cunningham PN, Wang Y, Guo R, He G, Quigg RJ. Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J. Immunol 2004;172:2629–2635. [PubMed]

9. McMasters KM, Peyton JC, Hadjiminas DJ, Cheadle WG. Endotoxin and tumour necrosis factor do not cause mortality from caecal ligation and puncture. Cytokine. 1994;6:530–536. [PubMed]

10. Leemans JC, Stokman G, Claessen N, et al. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J. Clin. Invest 2005;115:2894–2903. [PubMed]

11. TThurau K, Boylan JW. Acute renal success. The unexpected logic of oliguria in acute renal failure. Am. J. Med 1976;61:308–315. [PubMed]

12. Wu L, Tiwari MM, Messer KJ, 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. [PubMed]

13. Xiao H, Siddiqui J, Remick DG. Mechanisms of mortality in early and late sepsis. Infect. Immun 2006;74:5227–5235. [PubMed]

14. James MT, Laupland KB, Tonelli M, et al. Risk of bloodstream infection in patients with chronic kidney disease not treated with dialysis. Arch. Intern. Med 2008;168:2333–2339. [PubMed]

15. Naqvi SB, Collins AJ. Infectious complications in chronic kidney disease. Adv. Chronic Kidney Dis.2006;13:199–204. [PubMed]

16. Guidet B, Aegerter P, Gauzit R., et al. Incidence and impact of organ dysfunctions associated with sepsis. Chest 2005;127:942–951. [PubMed]

17. Liptak P, Ivanyi B. Primer: histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat. Clin. Pract. Nephrol 2006;2:398–404. [PubMed]

18. Dear JW, Kobayashi H, Jo SK, et al. Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice. Kidney Int. 2005;67:2159–2167. [PubMed]

19. Muenzer JT, Davis CG, Dunne BS, Unsinger J, Dunne WM, Hotchkiss RS. Pneumonia after cecal ligation and puncture: a clinically relevant “two-hit” model of sepsis. Shock 2006;26:565–570. [PubMed]

20. Yang S, Hauptman JG. The efficacy of heparin and antithrombin III in fluid-resuscitated cecal ligation and puncture. Shock. 1994;2:433–437. [PubMed]

21. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348:1546–1554. [Abstract/FREE Full Text]

22. Hoshino KO, 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. [Abstract/FREE Full Text]

23. Annane D,Bellissant E,Cavaillon JM. Septic shock. Lancet 2005;365:63–78. [PubMed]

24. Gallay P,Heumann D, Le Roy D, Barras C, Glauser MP. Lipopolysaccharide-binding protein as a major plasma protein responsible for endotoxemic shock. Proc Natl Acad Sci USA 1993;90:9935–9938. [Abstract/FREE Full Text]

25. Le Roy D, et al. Critical role of lipopolysaccharide-binding protein and CD14 in immune responses against gram-negative bacteria. J Immunol 2001; 167:2759–2765. [Abstract/FREE Full Text]

26. Mullarkey M, et al. Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4–directed endotoxin antagonist. J Pharmacol Exp Ther 2003;304:1093–1102. [Abstract/FREE Full Text]

27. Roger T, David J, Glauser MP, Calandra T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 2001; 414:920–924. [PubMed]

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