Efficacy and Safety of Terlipressin in the Treatment of Hepatorenal Syndrome: A Systematic Review
DOI:
https://doi.org/10.21116/ri.v81i1.1192Keywords:
Hepatorenal Syndrome, Terlipressin, Systematic ReviewAbstract
Hepatorenal syndrome (HRS) is a severe and potentially fatal complication of liver cirrhosis, characterized by acute kidney injury in patients with ascites, after excluding other causes of renal dysfunction. Its pathophysiology involves splanchnic vasodilation, decreased systemic vascular resistance, and compensatory activation of vasoconstrictor systems, such as the renin-angiotensin-aldosterone system and the sympathetic nervous system, resulting in marked renal vasoconstriction and progressive reduction of renal blood flow. Clinically, HRS is associated with high short-term mortality and represents a significant challenge in the management of patients with decompensated cirrhosis. Treatment requires a multifactorial approach, including optimization of volemia, salt restriction, albumin administration, and the use of vasoconstrictor agents, with emphasis on terlipressin, which acts selectively on splanchnic vasoconstriction, influencing renal perfusion. However, uncertainties remain regarding the optimal administration regimen, treatment duration, and drug safety. This study aims to evaluate, through a systematic review, the efficacy and safety of terlipressin in the treatment of HRS, considering different therapeutic strategies, doses, administration schedules, and relevant clinical outcomes, such as reversal of renal failure, mortality, need for liver transplantation, length of hospital stay, and adverse events. The results are expected to consolidate the available evidence, contribute to the update of HRS management protocols, and support future guideline revisions, providing evidence-based decision-making guidance for healthcare professionals.
References
ABDEL-RAZIK, A.; MOUSA, N.; ABDELSALAM, M.; ABDELWAHAB, A.; TAWFIK, M.; TAWFIK, A. M.; HASAN, A. S.; ELHELALY, R.; EL-WAKEEL, N.; ELDARS, W. Endothelin-1/Nitric Oxide Ratio as a Predictive Factor of Response to Therapy With Terlipressin and Albumin in Patients With Type-1 Hepatorenal Syndrome. Frontiers in Pharmacology, v. 11, p. 9, 31 jan. 2020. DOI: 10.3389/fphar.2020.00009.
AGRAWAL, J.; KUMAR, A.; SHARMA, P.; BANSAL, N.; SINGLA, V.; SHARMA, S.; ARORA, A. Delhi Model: A New Tool for Predicting Response to Terlipressin in Hepatorenal Syndrome–Acute Kidney Injury. Journal of Clinical and Experimental Hepatology, v. 14, n. 1, p. 101266, jan./fev. 2024. DOI: 10.1016/j.jceh.2023.08.002.
ARORA, V.; MAIWALL, R.; RAJAN, V.; JINDAL, A.; MURALIKRISHNA SHASTHRY, S.; KUMAR, G.; JAIN, P.; SARIN, S. K. Terlipressin Is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute on Chronic Liver Failure. Hepatology, v. 71, n. 2, p. 600–610, fev. 2020. DOI: 10.1002/hep.30208.
BRANDÃO NETO, R. A. et al. Medicina de emergência: abordagem prática. 17. ed. rev., atual. e ampl. Santana de Parnaíba, SP: Manole, 2023.
CAVALLIN, M.; KAMATH, P. S.; MERLI, M.; FASOLATO, S.; TONIUTTO, P.; SALERNO, F.; BERNARDI, M.; ROMANELLI, R. G.; COLLETTA, C.; SALINAS, F. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial. Hepatology (Baltimore, Md.), v. 62, n. 2, p. 567–57, 2015. DOI: 10.1002/hep.27709.
CAVALLIN, M.; PIANO, S.; ROMANO, A.; FASOLATO, S.; FRIGO, A. C.; BENETTI, G.; GOLA, E.; MORANDO, F.; STANCO, M.; ROSI, S. et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: a randomized controlled study. Hepatology (Baltimore, Md.), v. 63, n. 3, p. 983–992, 2016. DOI: 10.1002/hep.28396.
CULLARO, G.; ALLEGRETTI, A. S.; PATIDAR, K. R.; JAMIL, K.; VELEZ, J. C. Q. The relationship between mean arterial pressure and terlipressin in hepatorenal syndrome-acute kidney injury reversal: a post hoc analysis. Hepatology, 2025. DOI: 10.1097/HEP.0000000000001295.
GAMBINO, C.; PIANO, S.; STENICO, M.; TONON, M.; BROCCA, A.; CALVINO, V.; INCICCO, S.; ZENI, N.; GAGLIARDI, R.; COSMA, C. et al. Diagnostic and prognostic performance of urinary neutrophil gelatinase-associated lipocalin in patients with cirrhosis and acute kidney injury. Hepatology, v. 77, n. 5, p. 1630–1638, 2023. DOI: 10.1002/hep.32799.
HEIDEMANN, J.; BARTELS, C.; BERSSENBRÜGGE, C.; SCHMIDT, H.; MEISTER, T. Hepatorenal Syndrome: Outcome of Response to Therapy and Predictors of Survival. Gastroenterology Research and Practice, 2015. DOI: 10.1155/2015/457613.
HORVATITS, T.; HÜBENER, P.; TOUMA, M.; HORVATITS, K.; FISCHER, L.; LOHSE, A. W.; STERNECK, M. Improvement of renal function prior to liver transplantation is not associated with better long-term renal outcome or survival. Annals of Hepatology, v. 26, 2021. DOI: 10.1016/j.aohep.2021.100559.
JAMIL, K.; PAPPAS, S. C.; DEVARAKONDA, K. R. In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V1 and V2. Journal of Experimental Pharmacology, v. 10, p. 1–7, 2017. DOI: 10.2147/JEP.S146034.
JAMIL, K.; PAPPAS, S. C.; WONG, F.; SANYAL, A. J. Verified hepatorenal syndrome reversal as a robust multi-component primary end point: the CONFIRM study trial design. Open Access Journal of Clinical Trials, v. 11, p. 67–73, 2019. DOI: 10.2147/OAJCT.S224974.
JINDAL, A.; BHADORIA, A. S.; MAIWALL, R.; SARIN, S. K. Evaluation of acute kidney injury and its response to terlipressin in patients with acute-on-chronic liver failure. Liver International, v. 36, n. 1, p. 59–67, 2016. DOI: 10.1111/liv.12895.
KALAMBOKIS, G. N.; TSIAKAS, I.; CHRISTAKI, M.; KOUSTOUSI, C.; CHRISTOU, L.; BALTAYIANNIS, G.; CHRISTODOULOU, D. Systemic hemodynamic response to terlipressin predicts development of hepatorenal syndrome and survival in advanced cirrhosis. European Journal of Gastroenterology & Hepatology, v. 30, n. 6, p. 659–667, 2018. DOI: 10.1097/MEG.0000000000001088.
KARVELLAS, C. J.; SUBRAMANIAN, R.; OLSON, J. C.; JAMIL, K. Role of Terlipressin in Patients With Hepatorenal Syndrome-Acute Kidney Injury Admitted to the ICU: A Substudy of the CONFIRM Trial. Critical Care Explorations, v. 5, n. 4, p. e0890, 2023. DOI: 10.1097/CCE.0000000000000890.
KRISHNA, R.; RAJ, J.; DEV, D.; PRASAD, S. C.; REGHU, R.; V, S. O. A study on clinical outcomes of combination of terlipressin and albumin in Hepatorenal Syndrome. Scandinavian Journal of Gastroenterology, v. 55, n. 7, p. 860–864, 2020. DOI: 10.1080/00365521.2020.1786851.
LOSCALEZO, J. et al. Medicina interna de Harrison: [recurso eletrônico]. 21. ed. Tradução de André Garcia Islabão et al.; revisão técnica de Antônio de Barros Lopes et al. Porto Alegre: AMGH, 2024.
MA, A. T.; SOLÉ, C.; JUANOLA, A.; ESCUDÉ, L.; NAPOLEONE, L.; AVITABILE, E.; PÉREZ-GUASCH, M.; CAROL, M.; POMPILI, E.; GRATACÓS-GINÉS, J. et al. Prospective validation of the EASL management algorithm for acute kidney injury in cirrhosis. Journal of Hepatology, v. 81, n. 3, p. 441–450, set. 2024. DOI: 10.1016/j.jhep.2024.03.006.
MOORE, K.; JAMIL, K.; VERLEGER, K.; LUO, L.; KEBEDE, N.; HEISEN, M.; CORMAN, S.; LEONARDI, R.; BAKKER, R.; MAÏ, C.; SHAMSEDDINE, N.; HUANG, X.; ALLEGRETTI, A. S. Real-world treatment patterns and outcomes using terlipressin in 203 patients with the hepatorenal syndrome. Alimentary Pharmacology & Therapeutics, v. 52, n. 2, p. 351–358, 2020. DOI: 10.1111/apt.15836.
MUJTABA, M. A.; GAMILLA-CRUDO, A. K.; MERWAT, S. N.; HUSSAIN, S. A.; KUEHT, M.; KARIM, A.; KHATTAK, M. W.; ROONEY, P. J.; JAMIL, K. Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older. Annals of Hepatology, v. 28, n. 5, p. 101126, 2023. DOI: 10.1016/j.aohep.2023.101126.
NGUYEN-TAT, M.; JÄGER, J.; REY, J. W.; NAGEL, M.; LABENZ, C.; WÖRNS, M. A.; GALLE, P. R.; MARQUARDT, J. U. Terlipressin and albumin combination treatment in patients with hepatorenal syndrome type 2. United European Gastroenterology Journal, v. 7, n. 4, p. 529–537, 2019. DOI: 10.1177/2050640619825719.
PIANO, S.; GAMBINO, C.; VETTORE, E.; CALVINO, V.; TONON, M.; BOCCAGNI, P.; GRINGERI, E.; GERMANI, G.; BURRA, P.; CILLO, U.; ANGELI, P. Response to Terlipressin and Albumin Is Associated With Improved Liver Transplant Outcomes in Patients With Hepatorenal Syndrome. Hepatology, v. 73, n. 5, p. 1909–1919, 2021. DOI: 10.1002/hep.31529.
PIANO, S.; SCHMIDT, H. H.; ARIZA, X.; AMOROS, A.; ROMANO, A.; HÜSING-KABAR, A.; SOLÀ, E.; GERBES, A.; BERNARDI, M.; ALESSANDRIA, C. et al. Association Between Grade of Acute on Chronic Liver Failure and Response to Terlipressin and Albumin in Patients With Hepatorenal Syndrome. Clinical Gastroenterology and Hepatology, v. 16, n. 11, p. 1792–1800.e3, 2018. DOI: 10.1016/j.cgh.2018.01.035.
REY, R. M.; DELGADO, A. F.; DE ZUBIRIA, A.; PINTO, R.; DE LA HOZ-VALLE, J. A.; PÉREZ-RIVEROS, E. D.; ARDILA, G.; SIERRA-ARANGO, F. Prevalence and short-term outcome of hepatorenal syndrome: A 9-year experience in a high-complexity hospital in Colombia. PLoS One, v. 15, n. 10, p. e0239834, 2020. DOI: 10.1371/journal.pone.0239834.
SAIF, R. U.; DAR, H. A.; SOFI, S. M.; ANDRABI, M. S.; JAVID, G.; ZARGAR, S. A. Noradrenaline versus terlipressin in the management of type 1 hepatorenal syndrome: A randomized controlled study. Indian Journal of Gastroenterology, v. 37, n. 5, p. 424–429, 2018. DOI: 10.1007/s12664-018-0876-3.
SRIVASTAVA, S.; SHALIMAR; VISHNUBHATLA, S.; PRAKASH, S.; SHARMA, H.; THAKUR, B.; ACHARYA, S. K. Randomized Controlled Trial Comparing the Efficacy of Terlipressin and Albumin with a Combination of Concurrent Dopamine, Furosemide, and Albumin in Hepatorenal Syndrome. Journal of Clinical and Experimental Hepatology, v. 5, n. 4, p. 276–285, 2015. DOI: 10.1016/j.jceh.2015.08.003.
VÉLEZ, J. C. Q.; WONG, F.; REDDY, K. R.; SANYAL, A. J.; VARGAS, H. E.; CURRY, M. P.; GONZALEZ, S. A.; PAPPAS, S. C.; JAMIL, K. The Effect of Terlipressin on Renal Replacement Therapy in Patients with Hepatorenal Syndrome. Kidney360, v. 4, n. 8, p. 1030–1038, 2023. DOI: 10.34067/KID.0000000000000132.
WONG, F.; BOYER, T. D.; SANYAL, A. J.; PAPPAS, S. C.; ESCALANTE, S.; JAMIL, K. Reduction in acute kidney injury stage predicts survival in patients with type-1 hepatorenal syndrome. Nephrology Dialysis Transplantation, v. 35, n. 9, p. 1554–1561, 2020. DOI: 10.1093/ndt/gfz048.
WONG, F.; PAPPAS, S. C.; BOYER, T. D.; SANYAL, A. J.; BAJAJ, J. S.; ESCALANTE, S.; JAMIL, K. Terlipressin Improves Renal Function and Reverses Hepatorenal Syndrome in Patients With Systemic Inflammatory Response Syndrome. Clinical Gastroenterology and Hepatology, v. 15, n. 2, p. 266–272.e1, 2017. DOI: 10.1016/j.cgh.2016.07.016.
WONG, F.; PAPPAS, S. C.; CURRY, M. P.; REDDY, K. R.; RUBIN, R. A.; PORAYKO, M. K.; GONZALEZ, S. A.; MUMTAZ, K.; LIM, N.; SIMONETTO, D. A. et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. The New England Journal of Medicine, v. 384.
