PATHOGENETIC FEATURES OF THE HEPATORENAL SYNDROME
DOI:
https://doi.org/10.32782/health-2024.1.6Keywords:
hepatorenal syndrome, liver cirrhosis, splanchnic vasodilatation, functional renal failureAbstract
The purpose of our study was to analyze the pathogenetic features of hepatorenal syndrome – a special form of functional renal failure in which the kidney is histologically unchanged, but renal blood flow is reduced. The pathophysiology of НRS is characterized by reduced systemic vascular resistance due to vasodilatation of the splanchnic artery, which occurs secondary to portal hypertension and is a key feature of progressive liver cirrhosis. Also, vasoconstriction of the renal blood circulation is a pathophysiological sign of НRS. Marked renal vasoconstriction in patients with HRS is likely the result of several factors and may include changes in systemic hemodynamics, activation of multiple vasoconstrictor factors, and inhibition of vasodilator factors that affect renal blood flow. Recent studies have shown that systemic inflammation may lead to increased release of inflammatory mediators and thus may play a role in the circulatory and renal dysfunction seen in НRS. Thus, it is now recognized that НRS involves not only circulatory dysfunction but also systemic inflammation. Systemic inflammatory response syndrome is observed in almost half of patients with НRS, regardless of the presence of infection. Bacterial translocation is the primary mechanism by which portal hypertension induces the circulatory dysfunction characteristic of НRS and is the primary mechanism involved in the pathogenesis of spontaneous bacterial peritonitis and other infections in cirrhotic patients. Therefore, signs that can develop even in the absence of circulatory dysfunction and, therefore, renal hypoperfusion, prove that the pathophysiology of НRS can deviate from the stable one traditionally accepted for more than 20 years.
References
European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010. № 53(3). Р. 397–417. doi:10.1016/j.jhep.2010.05.004
Allegretti A.S., Ortiz G., Wenger J., et al. Prognosis of acute kidney injury and hepatorenal syndrome in patients with cirrhosis: a prospective cohort study. Int J Nephrol. 2015. Р. 108139. doi:10.1155/2015/108139
Low G., Alexander G.J., Lomas D.J. Hepatorenal syndrome: aetiology, diagnosis, and treatment. Gastroenterology research and practice. 2015. Р. 207012. https://doi.org/10.1155/2015/207012
Ginès P., Schrier R.W. Renal failure in cirrhosis. The New England journal of medicine. 2009. № 361 (13). Р. 1279–1290. https://doi.org/10.1056/NEJMra0809139
Solà E., Ginès P. Renal and circulatory dysfunction in cirrhosis: Current management and future perspectives. J Hepatol. 201. № 53 (6). Р. 1135–1145.
Krag A., Bendtsen F., Henriksen J.H., Møller S. Low cardiac output redicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut. 2010. № 59 (1). Р. 105–110.
Sersté T., Melot C., Francoz C., et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology. 2010. № 52 (3). Р. 1017–1022.
Mandorfer M., Bota S., Schwabl P., et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014. № 146(7).
Acevedo J., Fernández J., Prado V., et al. Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short-term risk of severe sepsis, hepatorenal syndrome, and death. Hepatology. 2013. № 58 (5). Р. 1757–1765.
Theocharidou E., Krag A., Bendtsen F., Møller S., Burroughs A. K. Cardiac dysfunction in cirrhosis – does adrenal function play a role? A hypothesis. Liver Int. 2012. № 32 (9). Р. 1327–1332.
Weichselbaum L., Gustot T. The Organs in Acute-on-Chronic Liver Failure. Semin Liver Dis. 2016. № 36 (2). Р. 174–180.
Albillos A., Lario M., Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol. 2014. № 61. Р. 1385–1396.
Bernardi M., Moreau R., Angeli P., Schnabl B., Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol. 2015. № 63. Р. 1272–1284.
Ruiz-del-Arbol L., Monescillo A., Arocena C., et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology. 2005. № 42. Р. 439–447.
Bernardi M., Trevisani F., Gasbarrini A., Gasbarrini G. Hepatorenal disorders: role of the renin-angiotensinaldosterone system. Semin Liver Dis. 1994. № 14. Р. 23–34.
Henriksen J.H., Møller S., Ring-Larsen H., Christensen N.J. The sympathetic nervous system in liver disease. J Hepatol 1998. № 29. Р. 328–341.
Nazar A., Guevara M., Sitges M., et al. LEFT ventricular function assessed by echocardiography in cirrhosis: relationship to systemic hemodynamics and renal dysfunction. J Hepatol. 2013. № 58. Р. 51–57.
Ruiz-del-Arbol L., Urman J., Fernández J., et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology. 2003. № 38. Р. 1210–1218.
Chan-Young Jung, Jai Won Chang. Hepatorenal syndrome: Current concepts and future perspectives. Clinical and Molecular Hepatology. 2023. № 29. Р. 891–908.
Barreto R., Fagundes C., Guevara M., et al. Type-1 hepatorenal syndrome associated with infections in cirrhosis: natural history, outcome of kidney function, and survival. Hepatology. 2014. № 59. Р. 1505–1513.
Elia C., Graupera I., Barreto R., et al. Severe acute kidney injury associated with non-steroidal antiinflammatory drugs in cirrhosis: A case-control study. J Hepatol. 2015. № 63. Р. 593–600.
Thabut D., Massard J., Gangloff A., et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology. 2007. № 46. Р. 1872–1882. doi:10.1002/ hep.21920
Wiest R., Lawson M., Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol. 2014. № 60. Р. 197–209.
Angeli P., Garcia-Tsao G., Nadim M.K., Parikh C.R. News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document. Journal of hepatology. 2019. № 71 (4). Р. 811–822. https://doi.org/10.1016/j.jhep.2019.07.002
Solé C., Solà E., Huelin P., et al. Characterization of inflammatory response in hepatorenal syndrome: Relationship with kidney outcome and survival. Liver Int. 2019. № 39. Р. 1246–1255. doi:10.1111/ liv.14037
Shah N., Mohamed F.E., Jover-Cobos M., et al. Increased renal expression and urinary excretion of TLR4 in acute kidney injury associated with cirrhosis. Liver Int. 2013. № 33. Р. 398–409. doi:10.1111/ liv.12047
Shah N., Dhar D., El Zahraa Mohammed F., et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression. J Hepatol. 2012. № 56. Р. 1047–1053. doi:10.1016/j.jhep.2011.11.024
Rivolta R., Maggi A., Cazzaniga M., et al. Reduction of renal cortical blood flow assessed by Doppler in cirrhotic patients with refractory ascites. Hepatology. 1998. № 28. Р. 1235–1240. doi:10.1002/ hep.510280510
Mindikoglu A.L., Dowling T.C., Wong-You-Cheong J.J., et al. A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements. Am J Nephrol. 2014. № 39. Р. 543–552.
Singh R.R., Walia R., Sachdeva N., Bhalla A., Singh A., Singh V. Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome). Dig Liver Dis. 2018. № 50. Р. 1232–1237. doi:10.1016/j. dld.2018.05.011
Piano S., Favaretto E., Tonon M., et al. Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure. Clin Gastroenterol Hepatol. 2020. № 18. Р. 1188–1196.e3. doi:10.1016/j.cgh.2019.09.035
Acevedo J., Fernández J., Prado V., et al. Relative adrenal insufficiency in decompensated cirrhosis: Relationship to shortterm risk of severe sepsis, hepatorenal syndrome, and death. Hepatology. 2013. № 58. Р. 1757–1765. doi:10.1002/hep.26535
Kim G., Huh J.H., Lee K.J., Kim M.Y., Shim K.Y., Baik S.K. Relative Adrenal Insufficiency in Patients with Cirrhosis: A Systematic Review and Meta-Analysis. Dig Dis Sci. 2017. № 62. Р. 1067–1079. doi:10.1007/s10620- 017-4471-80
Jang J.Y., Kim T.Y., Sohn J.H., et al. Relative adrenal insufficiency in chronic liver disease: its prevalence and effects on long-term mortality. Aliment Pharmacol Ther. 2014. № 40. Р. 819–826. doi:10.1111/apt.12891
Tsai M.H., Peng Y.S., Chen Y.C., et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology. 2006. № 43. Р. 673–681. doi:10.1002/hep.21101
Bornstein S.R. Predisposing factors for adrenal insufficiency. N. Engl. J. Med. 2009. № 360. Р. 2328–2339. doi:10.1056/NEJMra0804635
Bräsen J.H., Mederacke Y.S., Schmitz J., et al. Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts. Hepatology. 2019. № 69. Р. 2107–2019. doi:10.1002/ hep.30499
van Slambrouck C.M., Salem F., Meehan S.M., Chang A. Bile cast nephropathy is a common pathologic finding for kidney injury associated with severe liver dysfunction. Kidney Int. 2013. № 84. Р. 192–197. doi:10.1038/ki.2013.78.
Ficket P., Krones E., Pollheimer M.J., et al. Bile acids trigger cholemic nephropathy in common bile-ductligated mice. Hepatology. 2013. № 58. Р. 2056–2069.
