Single article

DOI: 10.47026/2413-4864-2020-3-7-19

Karzakova L.M., Ivanova A.L., Kudryashov S.I., Sokolova E.V., Lutkova T.S.

Immune Mechanisms for the Development of Hepatorenal Syndrome in Liver Cirrhosis

Keywords: hepato-renal syndrome, cirrhosis of the liver, innate immunity, cytokines

Hepatorenal syndrome is a life-threatening complication of liver cirrhosis. 90% of patients with liver cirrhosis die within 2 months since the onset of hepatorenal syndrome development. For many years the hypothesis of the hemodynamic mechanism of hepatorenal syndrome development was accepted as the only true one, according to this hypothesis compensatory systemic vasodilation in response to portal hypertension causes renal ischemia and the development of functional specific acute kidney damage, the so-called “hepatorenal syndrome – acute kidney damage”. In recent years some works were published that substantiate the role of a systemic inflammatory reaction in the development of hepatorenal syndrome; this inflammatory reaction being associated with activation of innate immunity cells in response to a bacterial infection, including that to the microflora of the intestine which is adjacent to the liver. Data has been obtained which indicated that Toll-like receptors (TLRs), in particular TLR4 and TLR9 are involved in the development of hepatorenal syndrome.


  1. Bulatova I.A., Shhjokotova A.P., Dolgih O.V., Paducheva S.V. Citokinovyi status u bol’nykh tsirrozami pecheni raznoi etiologii [Cytokine status in patients with cirrhosis of the liver of different etiology]. Sovremennye problemy nauki i obrazovaniya, 2016, no. 3. Available at: (Accessed 13.08.2020).
  2. Toneeva M.A., Kulikov V.E. Vzaimosvyaz’ mezhdu kolichestvennymi parametrami pecheni i urovnyami tsitokinov u pacientov s cirrozami pecheni virusnoi etiologii [Relationship between quantitative parameters of the liver and cytokine levels in patients with cirrhosis of the liver of viral etiology]. Ul’trazvukovaja i funkcional’naja diagnostika, 2015, no. 5S, p. 173a.
  3. Albillos A., Lario M., Álvarez-Mon M. Cirrhosis-associated immune dysfunction: Distinctive features and clinical relevance. J Hepatol., 2014, vol. 61, pp. 1385–1396.
  4. Angeli P., Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol., 2008, vol. 48, Suppl 1, pp. S93–S103.
  5. Antoniades C.G., Khamri W., Abeles R.D., Taams L.S., Triantafyllou E., Possamai L.A. et al. Secretory leukocyte protease inhibitor: A pivotal mediator of anti-inflammatory responses in acetaminophen-induced acute liver failure. Hepatology, 2014, vol. 59, pp. 1564–1576.
  6. Bajaj J.S., Heuman D.M., Hylemon P.B., Sanyal A.J., White M.B., Monteith P. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. Hepatol., 2014, vol. 60, pp. 940–947.
  7. Bauer T.M., Steinbruckner B., Brinkmann F.E., Ditzen A.K., Schwacha H., Aponte J.J. et al. Small intestinal bacterial overgrowth in patients with cirrhosis: Prevalence and relation with spontaneous bacterial peritonitis. J. Gasteroenterol., 2001, vol. 96, pp. 2962–2967.
  8. Bruewer M., Luegering A., Kucharzik T., Parkos C.A., Madara J.L., Hopkins A.M., Nusrat A. Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. Immunol., 2003, vol. 171, pp. 6164–6172.
  9. Busk T.M., Bendtsen F., Møller S. Hepatorenal syndrome in cirrhosis: diagnostic, pathophysiological, and therapeutic aspects. Expert Rev. Gastroenterol. Hepatol., 2016, vol. 10, no. 10, pp. 1153–1161.
  10. Chancharoenthana W., Leelahavanichkul A. Acute kidney injury spectrum in patients with chronic liver disease: Where do we stand?. World J. Gastroenterol., 2019, 25, no. 28, pp. 3684–3703.
  11. Chen Y., Yang F., Lu H., Wang B., Chen Y., Lei D. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology, 2011, vol. 54, pp. 562–572.
  12. Chiva M., Guarner C., Peralta C., Llovet T., Gomez G., Soriano G. et al. Intestinal mucosal oxidative damage and bacterial translocation in cirrhotic rats. J. Gastroenterol. Hepatol., 2003, vol. 15, pp. 145–150.
  13. Clària J., Stauber R.E., Coenraad M.J., Moreau R., Jalan R., Pavesi M. et al. Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. Hepatology, 2016, vol. 64, pp. 1249–1264.
  14. Colino J., Duke L., Snapper C. M. Autologous albumin enhances the humoral immune response to capsular polysaccharide covalently coattached to bacteria-sized latex beads. European Journal of Immunology, 2014, vol. 44, 5, pp. 1433–1443.
  15. Dagher L., Moore K. The hepatorenal syndrome. Gut., 2001, vol. 49, 5, pp. 729–737.
  16. Etienne-Mesmin L., Vijay-Kumar M., Gewirtz A.T., Chassaing B. Hepatocyte Toll-Like Receptor 5 Promotes Bacterial Clearance and Protects Mice Against High-Fat Diet-Induced Liver Disease. Cell Mol. Gastroenterol. ,2016, vol. 2, pp. 584–604.
  17. Fernandez J., Navasa M., Gomez J., Colmenero J., Vila J., Arroyo V. et al. Bacterial Infections in cirrhosis: Epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology, 2002, vol. 35, pp. 140–148.
  18. Francoz C., Glotz D., Moreau R., Durand F. The evaluation of renal function and disease in patients with cirrhosis.  Hepatol., 2010, vol. 52, no. 4, pp. 605–613.
  19. Francoz C., Nadim M.K., Durand F. Kidney biomarkers in cirrhosis. Hepatol., 2016, vol. 65, no. 4, pp. 809–824.
  20. Gäbele E., Mühlbauer M., Dorn C., Weiss T.S., Froh M., Schnabl B. et al. Role of TLR9 in hepatic stellate cells and experimental liver fibrosis.  Biophys. Res. Commun., 2008, vol. 376, no. 2, pp. 271–276.
  21. Ginès A., Salmerón J.M., Ginès P., Arroyo, Jiménez W., Rivera F., Rodéset J. al. Oral misoprostol or intravenous prostaglandin E2 do not improve renal function in patients with cirrhosis and ascites with hyponatremia or renal failure. J. Hepatol., 1993, vol. 17, no. 2, pp. 220–226.
  22. Hartmann P., Haimerl M., Mazagova M., Brenner D.A., Schnabl B. Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice. Gastroenterology, 2012, vol. 143, 5, pp. 1330–1340.e1.
  23. Hernaez R., Solà E., Moreau R., Ginès P. Acute-on-chronic liver failure: an update. Gut., 2017, vol. 66, 3, pp. 541–553.
  24. Heymann F., Tacke F. Immunology in the liver-from homeostasis to disease. Rev. Gastroenterol. Hepatol., 2016, vol. 13, pp. 88–110.
  25. Lange C.M. Systemic inflammation in hepatorenal syndrome – A target for novel treatment strategies?. Liver Int., 2019, vol. 39, 7, pp. 1199–1201.
  26. Liu D., Cao S., Zhou Y., Xiong Y. Recent advances in endotoxin tolerance. Cell Biochem, 2019, vol. 120, pp. 56–70.
  27. Lutz H. U., Binder C. J., Kaveri S. Naturally occurring auto-antibodies in homeostasis and disease. Trends in Immunology, 2009, vol. 30, 1, pp. 43–51.
  28. Macdonald S., Andreola F., Bachtiger P., Amoros A., Pavesi M., Mookerjee R. et al. Cell death markers in patients with cirrhosis and acute decompensation. Hepatology, 2018, vol. 67, pp. 989–1002.
  29. Mandal A.K., Lansing M., Fahmy A. Acute tubular necrosis in hepatorenal syndrome: an electron microscopy study.  J. Kidney Dis., 1982, vol. 2, no. 3, pp. 363–374.
  30. McGovern B.H., Golan Y., Lopez M., Pratt D., Lawton A., Moore G. et al. The impact of cirrhosis on CD4+ T cell counts in HIV-seronegative patients. Clinical Infectious Diseases, 2007, vol. 44, 3, pp. 431–437.
  31. Mogensen T.H. Pathogen recognition and inflammatory signaling in innate immune defenses.  Microbiol. Rev., 2009, vol. 22, no. 2, pp. 240–273.
  32. Qin N., Yang F., Li A., Prifti E., Chen Y., Shao L. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature, 2014, vol. 513, 7516, pp. 59–64.
  33. Ramachandran A., Prabhu R., Thomas S., Reddy J.B., Pulimood A., Balasubramanian K.A. Intestinal mucosal alterations in experimental cirrhosis in the rat: Role of oxygen free radicals. 2002, vol. 35, pp. 622–629.
  34. Rivera-Huizar S., Rincón-Sánchez A.R., Covarrubias-Pinedo A., Islas-Carbajal M.C., Gabriel-Ortíz G., Pedraza-Chaverrí J. et al. Renal dysfunction as a consequence of acute liver damage by bile duct ligation in cirrhotic rats.  Toxicol. Pathol., 2006, vol. 58, no. 2-3, pp. 185–195.
  35. Roh Y.S., Zhang B., Loomba R., Seki E. TLR2 and TLR9 contribute to alcohol-mediated liver injury through induction of CXCL1 and neutrophil infiltration.  J. Physiol. Gastrointest. Liver Physiol., 2015, vol. 309, no. 1, pp. 30–41.
  36. Rolando N., Wade J., Davalos M., Wendon J., Philpott-Howard J., Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology, 2000, vol. 32, pp. 734–739.
  37. Runyon B.A., AASLD Practice Guidelines Committee. Management of Adult Patients with Ascites Due to Cirrhosis: Update 2012. Hepatology, 2013, vol. 57, pp. 2087–2107.
  38. Schirren, C.A., Jung, M.C., Zachoval R., Diepolder H., Hoffmann R., Riethmüller G., Pape R. Analysis of T cell activation pathways in patients with liver cirrhosis, impaired delayed hypersensitivity and other T cell-dependent functions. Clinical and Experimental Immunology, 1997, vol. 108, no. 1, pp. 144–150.
  39. Shah N., Dhar D., El Zahraa Mohammed F., Habtesion A., Davies N.A., Jover-Cobos M. et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.  Hepatol., 2012, vol. 56, no. 5, pp. 1047–1053.
  40. Shah N., Mohamed F.E., Jover-Cobos M., Macnaughtan J., Davies N., Moreau R. et al. Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis. Liver Int., 2013, vol. 33, 3, pp. 398–409.
  41. Singal A. K., Salameh H., Kamath P. S. Prevalence and in-hospital mortality trends of infections among patients with cirrhosis: a nationwide study of hospitalized patients in the United States. Pharmacol. Ther., 2014, vol. 40, pp. 105–112.
  42. Solé C., Solà E., Huelin P., Carol M., Moreira R., Cereijo U. et al. Characterization of inflammatory response in hepatorenal syndrome: Relationship with kidney outcome and survival. Liver Int., 2019, vol. 39, 7, pp. 1246–1255.
  43. Sriskandan S., Altmann D.M. The immunology of sepsis. Pathol. 2008, vol. 214, pp. 211–223.
  44. Takeda K., Akira S. TLR signaling pathways.  Immunol., 2004, vol. 16, no. 1, pp. 3–9.
  45. Teltschik Z., Wiest R., Beisner J., Nuding S., Hofmann C., Schoelmerich J. et al. Intestinal bacterial translocation in cirrhotic rats is related to compromised Paneth cell antimicrobial host defence. Hepatology, 2012, vol. 55, pp. 1154–1163.
  46. Triantafyllou E., Woollard K.J., McPhail M.J.W., Antoniades C.G., Possamai L.A. The Role of Monocytes and Macrophages in Acute and Acute-on-Chronic Liver Failure. Front Immunol., 2018, vol. 9, p. 2948.
  47. Weist R., Garcia-Tsao G. Bacterial Translocation (BT) in cirrhosis. Hepatology, 2005, vol. 41, pp. 422–433.
  48. Wiest R., Krag A., Gerbes A. Spontaneous bacterial peritonitis: Recent guidelines and beyond. , 2012, vol. 61, pp. 297–310.
  49. Wilde B., Katsounas A. Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis. Mediators Inflamm., 2019, 2019, p. 7537649.
  50. Wong F. Diagnosing and treating renal disease in cirrhotic patients. Minerva Gastroenterol. Dietol., 2016, vol. 62, 3, pp. 253–266.
  51. Wong F. Recent advances in our understanding of hepatorenal syndrome.  Rev. Gastroentero.l Hepatol., 2012, vol. 9, no. 7, pp. 382–391.
  52. Woolbright B.L., Jaeschke H. The impact of sterile inflammation in acute liver injury. Clin. Transl. Res., 2017, vol. 3, pp. 170–188.
  53. Yakut M., Özkan H.F., Karakaya M., Erdal H. Diagnostic and Prognostic Role of Serum Interleukin-6 in Malignant Transformation of Liver Cirrhosis. Euroasian J. Hepatogastroenterol., 2018, vol. 8, 1, pp. 23–30.
  54. Yan A.W., Fouts D.E., Brandl J., Starkel P., Torralba M., Schott E. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology, 2011, vol. 53, pp. 96–105.
  55. Youssef Al-Okbi S., Abdou Mohamed D., El-Sayed Hamed T., Bayoumi Abd El Khalek A., Elsayed Mohammed S. Role of Probiotic Mixture with and Without Green Tea Extract in Prevention of Hepatorenal Syndrome in Rat Model.  J. Biol. Sci., 2019, vol. 22, no. 1, pp. 21–27.
  56. Zhangdi H.J., Su S.B., Wang F., Carol M., Moreira R., Cereijo U. et al. Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J. Gastroenterol., 2019, vol. 25, 33, pp. 4835–4849.
  57. Zimmermann H.W., Seidler S., Gassler N., Nattermann J., Luedde T., Trautwein C., Tacke F. Interleukin-8 is activated in patients with chronic liver diseases and associated with hepatic macrophage accumulation in human liver fibrosis. PLoS One, 2011, vol. 6, 6, p.e21381.

About authors

Karzakova Luiza M.
Doctor of Medical Sciences, Professor, Head of Internal Diseases Department, Chuvash State University, Russia, Cheboksary (; ORCID:
Ivanova Antonina L.
Post-Graduate Student of Internal Diseases Department, Chuvash State University, Russia, Cheboksary (; ORCID:
Kudryashov Sergei I.
Candidate of Medical Sciences, Assistant Lecturer of Internal Diseases Department, Chuvash State University, Russia, Cheboksary (; ORCID:
Sokolova Evgeniya V.
Candidate of Medical Sciences, Associate Professor of the Department of Immunology, N.I. Pirogov Russian National Research Medical University, Russia, Moscow (; )
Lutkova Tatyana S.
Candidate of Medical Sciences, Associate Professor of Internal Diseases Department, Chuvash State University, Russia, Cheboksary (; ORCID:

Article link

Karzakova L.M., Ivanova A.L., Kudryashov S.I., Sokolova E.V., Lutkova T.S. Immune Mechanisms for the Development of Hepatorenal Syndrome in Liver Cirrhosis [Electronic resource] // Acta medica Eurasica. – 2020. – №3. P. 7-19. – URL: DOI: 10.47026/2413-4864-2020-3-7-19.