
==== Front
Cureus
Cureus
2168-8184
Cureus
2168-8184
Cureus Palo Alto (CA)

10.7759/cureus.66581
Gastroenterology
Internal Medicine
Nephrology
Efficacy and Safety of Terlipressin Infusion in Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI): A Retrospective Observational Study
Muacevic Alexander
Adler John R
Gowda Manoj 1
Dilipbhai Dave Manan 1
Jalihal Umesh 1
Kumar Madduri Pavan 1
Gowda S Bharath 1
Jain Anil 1
Ganjoo Naveen 2
1 Medical Gastroenterology and Hepatology, Sapthagiri Institute of Medical Sciences and Research Centre, Bengaluru, IND
2 Hepatology, Aster RV Hospital, Bengaluru, IND
Manoj Gowda manoj.gowda1@gmail.com
10 8 2024
8 2024
16 8 e6658110 8 2024
Copyright © 2024, Gowda et al.
2024
Gowda et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article is available from https://www.cureus.com/articles/270598-efficacy-and-safety-of-terlipressin-infusion-in-hepatorenal-syndrome-acute-kidney-injury-hrs-aki-a-retrospective-observational-study
Background

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is an event that occurs in chronic liver disease (CLD) and is associated with high morbidity and mortality. Terlipressin, a vasopressin analog, is used for the treatment of portal hypertension-related gastrointestinal (GI) bleeding and is found to be effective in the management of HRS-AKI. Continuous infusion of terlipressin maintains a high mean arterial pressure while reducing adverse events. It is better tolerated and equally effective at lower doses than intravenous boluses in patients with HRS-AKI.

Aim of the study

This study aimed to evaluate the safety and efficacy of terlipressin infusion at the rate of 4 mg/day in the treatment of HRS-AKI.

Methods

This retrospective study included patients who had HRS-AKI according to the modified International Club of Ascites (ICA) definition. Patients were started on a continuous intravenous infusion. The included patients received terlipressin 1 mg stat followed by a 4 mg infusion over 24 hours, and the infusion was continued until specific response criteria were met or for a maximum of seven days.

Results

In total, 136 patients were included in this study. The mean age of the study group was 45 years, the mean Child-Turcotte-Pugh (CTP) score was 11, the mean model for end-stage liver disease (MELD) score was 30, and the mean serum creatinine was 2.46 mg/dl. A response to treatment in the form of reduction of serum creatinine was observed in 94 (69.1%) patients, 30 (22%) patients showed no response, and worsening of creatinine was seen in 12 (8.8%) patients. The mean duration of hospital stay was 7.6 days, the mean serum creatinine was 1.17 mg/dl at the end of treatment, and the mean CTP and MELD scores in treatment responders were nine and 27, respectively. A total of 29 (21.3%) of 136 patients had adverse events during the terlipressin infusion therapy. 

Conclusion

Terlipressin infusion has sustained effects on splanchnic hemodynamics with fewer and less severe adverse events than intravenous bolus doses. Terlipressin infusion at a dose of 4 mg/day appeared to be well tolerated, with similar outcomes to that of 2 mg/day with a significantly lower albumin dose. These findings emphasize the importance of optimizing treatment protocols, particularly those favoring infusion methods, to enhance efficacy and minimize adverse effects.

hrs-aki
hepatorenal syndrome-acute kidney injury
hepatorenal syndrome
chronic liver disease (cld)
acute kidney injury
albumin
terlipressin infusion
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pmcIntroduction

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a sequence of events occurring in the setting of chronic liver disease (CLD), which is associated with splanchnic vascular dilatation, leading to significant renal arterial vasoconstriction and progressive renal failure [1]. There are no histological changes in the kidneys in the initial phase, and prompt management of portal hypertension normalizes renal function [2,3]. The annual frequency of HRS-AKI in cirrhotic patients with ascites is 8%-40% [4]. Upon the establishment of HRS-AKI, both morbidity and mortality remain high, which has led to a focus on the prevention, early diagnosis, and therapy of renal dysfunction in patients with cirrhosis.

The diagnostic criteria for HRS-AKI proposed by the International Club of Ascites (ICA) were modified in 2019, and urine output was added to the existing criteria [5]. Treatment of HRS-AKI consists of discontinuation of nephrotoxic agents, antibiotics for infection, and volume expansion by intravenous albumin and vasopressor therapy. Terlipressin, a vasopressin analog used for the treatment of portal hypertension-related gastrointestinal (GI) bleeding, is found to be effective in the management of HRS-AKI. The distribution half-life of terlipressin is eight minutes, and the peak concentration occurs around 10 minutes after intravenous bolus administration. Endothelial peptidases cleave terlipressin, causing lysine vasopressin to be released gradually over four to six hours [6-8].

The recommended dose of terlipressin is 1 mg intravenously every four hours, to begin with, and increases up to 2 mg every four hours if the baseline serum creatinine level does not improve by 25% on day three of therapy. The effect of terlipressin on splanchnic hemodynamics, such as portal pressure, wears off three to four hours after intravenous administration in individuals with cirrhosis. Terlipressin reached its peak concentration 10 min after intravenous bolus administration. However, the current intravenous terlipressin bolus protocol suggests a four- to six-hour interval between bolus doses. Theoretically, the drug can improve arterial splanchnic hemodynamics but should not be able to maintain a stable state for 24 hours [9]. Continuous infusion of terlipressin has been found to maintain a high mean arterial pressure while reducing adverse events; however, it is important to note that it may still be associated with severe adverse effects in patients with a high model for end-stage liver disease (MELD) score [10]. This study aims to establish the efficacy, safety, and adverse effects of continuous terlipressin infusion in the treatment of HRS-AKI.

Materials and methods

In this retrospective study, patients with HRS who received terlipressin as an infusion between September 2022 and March 2024 were identified. Using the hospital database, a total of 165 patients were identified who were admitted to the Sapthagiri Institute of Medical Sciences and Research Centre, Bangalore, India, between September 2022 and March 2024 with decompensated CLD, portal hypertension, and HRS and received terlipressin infusion to reduce portal pressure and improve renal perfusion.

After obtaining clearance from the Sapthagiri Institute of Medical Sciences and Research Centre's institutional ethics committee (approval number: 09/SS-08/2024-25), the data were analyzed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY) and the SAS statistical package, version 9.4 (SAS Inc., Cary, NC).

Out of 165 cases, 29 were found to be ineligible with the inclusion criteria and were excluded from the study. Of these 29 patients, two were aged >70 years, two were diagnosed with hepatocellular carcinoma, two had chronic kidney disease, seven had diabetes, two had severe hypertension, nine had sepsis, and five had hyponatremia <120 mEq/l.

Patients who met the HRS-AKI criteria, according to the modified ICA definition, were included. Diuretic medications were withheld, and an albumin infusion (20 g/day) was administered for plasma expansion. Patient demographics, clinical information, laboratory results, vital signs, and prognostic scores were collected from available data. Physical examination, electrocardiogram, chest radiography, and standard laboratory tests conducted during the therapy were compared. The included patients received terlipressin 1 mg stat followed by a 4 mg infusion over 24 hours and continued until specific response criteria were met or for a maximum of seven days.

Inclusion criteria

Inclusion criteria and exclusion criteria are defined in Table 1 and Table 2, respectively.

Table 1 Inclusion criteria

GI: gastrointestinal; AKI: acute kidney injury; ICA: International Club of Ascites; HRS: hepatorenal syndrome

Inclusion criteria	
Age >18 years	
Cirrhosis demonstrated by clinical, biochemical, imaging, or liver biopsy, with additional information from an upper GI endoscopy	
Diagnosis of AKI according to the ICA criteria; diagnosis of Type 1 HRS according to the ICA criteria	

Table 2 Exclusion criteria

Exclusion criteria	
Septic shock	
Evidence of recent use of nephrotoxic agents, absence of intrinsic renal disease	
Hepatocellular carcinoma	
Cardiac, respiratory failure, or serious extrahepatic illness	
Contraindications to terlipressin	
Hyponatremia <120 mEq/l	

Response to therapy

Response to therapy has been divided into complete and incomplete responses as shown in Table 3. 

Table 3 Response to therapy

AKI: acute kidney injury

Response to therapy	
Complete response	Defined as a decrease in serum creatinine to <1.5 mg/dl from the baseline value at admission	
Partial response	Defined as a fall in the AKI stage of at least one with serum creatinine >0.3 mg/dl above the baseline value [11]	

Objectives

The objectives of the study are defined in Table 4.

Table 4 Objectives of the study

Objectives	
Primary endpoint	Assessment of response to therapy	
Secondary endpoints	Safety of therapy measured by the frequency of drug-related adverse events	

Results

Using the hospital database, a total of 165 patients who were admitted to the Sapthagiri Institute of Medical Sciences and Research Centre between September 2022 and March 2024 with decompensated CLD, portal hypertension, and hepatorenal syndrome and received terlipressin infusion to reduce portal pressure and improve renal perfusion were identified.

A total of 136 patients who fulfilled the inclusion criteria were included in this study. The mean age of the patients in the study group was 45 years. Of the 136 patients, 115 (84.4%) were male and 21 (15.4%) were female, as shown in Figure 1. Eighty-seven (64%) patients had alcohol-related CLD, 45 (33%) had nonalcoholic steatohepatitis (NASH)-related CLD, three (2.2%) had hepatitis B-related CLD, and one (0.7%) had hepatitis C-related CLD, as shown in Figure 2. The mean Child-Turcotte-Pugh (CTP) score was found to be 11, the mean MELD score was found to be 30, and the mean serum creatinine at admission was 2.46 mg/dl in the study group. The mean values of the liver function test at admission are as follows: the mean total bilirubin was 6.8 mg/dl, the mean aspartate aminotransferase (AST) was 218 IU/l, the mean alanine transaminase (ALT) was 182 IU/l, the mean serum protein was 6.2 g/dl, the mean albumin was 2.77 g/dl, and the mean serum sodium was 130 mEq/l, as shown in Table 5.

Figure 1 Distribution of patients according to gender

Figure 2 Distribution of patients according to their etiology

CLD: chronic liver disease; MAFLD: metabolic dysfunction–associated fatty liver disease

Table 5 Baseline parameters of patients with hepatorenal syndrome–acute kidney injury

Blood investigation	Patient values	
Hemoglobin (g/dl)	9.2	
Total leucocyte count (× 103/l)	8.8	
Platelet count (× 109/l)	92	
Total bilirubin (mg/dl)	6.8	
Direct bilirubin (mg/dl)	4.5	
Aspartate aminotransferase (IU/l)	218	
Alanine transaminase (IU/l)	182	
Alkaline phosphatase (IU/l)	137	
Gamma-glutamyl transferase (IU/l)	80	
Albumin (g/dl)	2.77	
Protein (g/dl)	6.2	
International normalized ratio	2	
Serum creatinine (mg/dl)	2.46	
Blood urea nitrogen (mg/dl)	87	
Child–Turcotte–Pugh score	11	
Model for end-stage liver disease score	30	
Serum sodium (mEq/l)	130	
Serum potassium (mEq/l)	4.8	

Response to treatment with terlipressin infusion in the form of reduction of serum creatinine was observed in 94 (69.1%) patients; serum creatinine in 30 (22%) patients remained the same as the admission level, whereas worsening of creatinine was seen in 12 (8.8%) patients. Details of the treatment response are shown in Figure 3. The mean duration of hospital stay was 7.6 days, the mean end-of-treatment serum creatinine was 1.17 mg/dl, the mean cumulative dose of albumin was 100 g, the maximum daily dose of terlipressin was 4 mg, and the mean CTP and MELD scores in treatment responders were nine and 27, respectively, as shown in Table 6. Of the 12 patients who had worsening creatinine levels, 11 had an alcohol-related CLD with a mean MELD score of 36, and one patient had a NASH-related CLD with a MELD score of 33.

Figure 3 Treatment response of the patients

Table 6 Details of the treatment responders

Details of treatment responders: mean values	n = 94	
Duration of hospital stay (days)	7.6	
End of treatment serum creatinine (mg/dl)	1.17	
Cumulative dose of albumin (gm)	100	
Maximum daily dose of terlipressin (mg)	4	
Child–Turcotte–Pugh score	9	
Model for end-stage liver disease score	27	

Twenty-nine (21.3%) of 136 patients had adverse events during terlipressin infusion therapy. Seven (5.1%) patients had circulatory overload, 10 (7.4%) had diarrhea, 11 (8%) had abdominal pain, and one (0.7%) had arrhythmia, as shown in Figure 4. Patients with diarrhea and abdominal pain were managed with a reduction in the infusion rate for a few hours. Once the symptoms subsided, they were again started at an infusion rate of 4 mg/24 hours. Initially, the infusion was stopped for patients developing circulatory overload, albumin was optimized, and the patients were restarted on infusion of terlipressin at 2 mg/24 hours, eventually reaching 4 mg/24 hours. Infusion was completely discontinued in the patients who developed arrhythmia. There was a mean reduction in serum sodium by 1.2 mEq/l; none of the patients developed severe hyponatremia requiring termination of terlipressin infusion.

Figure 4 Adverse events noted among the patients

Discussion

This study provides insights into the demographic and etiological patterns of CLD in its cohort by comparing its findings with those of several other studies. In our study, the mean age of the participants was 45 years, with a significant preponderance of male patients (84.5% men and 15.4% women). The primary cause of CLD was alcohol-related, accounting for 64% of cases. Other etiologies included metabolic dysfunction-related fatty liver disease (33%), hepatitis B (2.2%), and hepatitis C (0.7%).

In our study, the mean CTP and MELD scores were 11 and 30, respectively. Studies with similar MELD and CTP scores, which included terlipressin administration for HRS-AKI, were analyzed and compared with our study. Cavallin et al. found that the mean CTP scores were 10.79 in the infusion group and 10.78 in the bolus group, with MELD scores of 29.2 and 29.8, respectively [12]. These scores are very similar to those of our study, suggesting a similar severity of liver dysfunction among the patients. In a study by Wong et al., the mean CTP score was 10 and the mean MELD score was 32.7 [13]. In a study by Gupta et al., the mean CTP score was slightly higher in the infusion group (12) than in the bolus group (10.45), while the mean MELD scores were 30.2 and 27.08, respectively [14]. Across all studies, the CTP and MELD scores reflected a high severity of liver disease.

In our study, the mean serum creatinine level was 2.46 mg/dl; in a study by Gupta et al. [14], the mean serum creatinine levels were 2.4 mg/dl in the infusion group and 2.1 mg/dl in the bolus group. These values are similar to our findings, indicating similar renal impairment. In addition, Cavallin et al. [12] reported that the mean serum creatinine levels were higher, at 3.4 mg/dl in the infusion group and 3.1 mg/dl in the bolus group, suggesting more severe renal dysfunction in their cohort compared to our study. Wong et al. reported the highest mean serum creatinine level of 3.5 mg/dl. Our study's mean creatinine level suggests significant but less severe renal dysfunction compared with the studies by Cavallin et al. [12] and Wong et al. [13], which reported levels >3 mg/dl.

In our study, the overall response rate was 69.1%, with 43.4% of patients achieving a complete response and 25.7% achieving a partial response. The mean CTP score among the responders was nine, and the mean MELD score was 27. In a study by Gupta et al. [14], the response rate was higher in the infusion group (76%) than in the bolus group (68.75%). The mean CTP score was 11.2, and the mean MELD score was 27.8 among responders in the infusion group. These scores indicate slightly more severe liver disease than in our study, yet with a comparable response rate. In the study by Cavallin et al. [12], the response rate in the infusion group was 76.5% (with 55.8% achieving complete response and 20.59% partial response). In the bolus group, the response rate was 64.9% (45.95% complete response and 18.9% partial response). These lower MELD scores compared with those in our study suggest that their patients may have had slightly less severe liver disease. In a study by Wong et al. [13], the response rate was notably lower (39.2%). Although specific CTP and MELD scores for responders were not provided, the overall lower response rate could indicate a more challenging patient population or differences in treatment efficacy. In the study by Gupta et al. [14], the better response could be attributed to the higher dosage of albumin administered (1 gm/kg/day, with a maximum of 100 g/day) compared with our study, where patients were given 20 g of albumin per day. The purpose of using a lower dose of albumin was to evaluate the effect of a higher dose of terlipressin infusion initiated at admission instead of waiting for an albumin response at the end of 48 hours, where the deleterious effect of progressive renal impairment could cause an increase in morbidity and mortality. The difference in response rates between the infusion and bolus groups reported by Gupta et al. [14] and Cavalin et al. [12] indicates that the method of administration could influence treatment outcomes, and infusion seems to provide a better response rate. Early initiation of a terlipressin infusion at a dose of 4 mg/day along with a lower dose of albumin showed beneficial effects similar to those of a higher albumin dose (100 g/day).

In our study, the overall adverse event rate was 21.3%, with the most common events being abdominal pain (8%) and diarrhea (7.4%); of these, infusion had to be completely stopped in only one (0.73%) patient who developed arrhythmia. In a study by Gupta et al. [14], the infusion group had no adverse events, whereas the bolus group showed an adverse event rate of 31.2%, with diarrhea being the most common. This higher rate compared with that in our study suggests that the bolus method may be less tolerated. In the study by Cavallin et al. [12], the adverse event rate was 35.29%, with 20.59% of the patients experiencing severe events in the infusion group. The most common adverse event was angina pectoris, indicating significant cardiovascular risk. The adverse event rate was much higher (62.16%), with 42.24% experiencing severe events in the bolus group, the most common being circulatory overload. These findings suggest that the bolus method not only increases the overall adverse event rate but also the severity of events, highlighting the significant risks associated with this administration method. Wong et al. [13] reported a very high adverse event rate of 88%, but only 12% of them were severe. The most common adverse events were respiratory failure (10%) and abdominal pain (5%). This high rate of adverse events, albeit mostly non-severe, suggests the need for close monitoring and reconsideration of the treatment approach. Our study's adverse event rate was relatively low, particularly when compared with the much higher rates observed by Cavallin et al. [12] and Wong et al. [13]. The stark contrast in adverse event rates between infusion and bolus groups in the studies by Gupta et al. [14] and Cavallin et al. [12] underscore the importance of administration methods. Infusion seems to result in fewer and less severe adverse events than bolus administration.

Terlipressin infusion at a dose of 4 mg/day appears to have similar tolerability with a slight increase in adverse effects, with probable better outcomes compared with a lower infusion dosage of 2 mg/day, and may also decrease the cumulative dosage of terlipressin and albumin required in resource-limited settings.

Limitations

Our retrospective observational study lacked randomization and a comparator arm for bolus terlipressin administration. Albumin was administered at a fixed dosage of 20 g/day, as per the standard recommendation. The maximum dosage of terlipressin used in our study was 4 mg/day with a 1 mg bolus on day one, which is less than the maximal optimization dosage of 12 mg/day. There is limited data for comparison of terlipressin infusion at different doses.

Conclusions

Terlipressin remains the most studied and widely used pharmacotherapy for the treatment of HRS-AKI. Our study provides a detailed analysis of the demographic, clinical, and safety profiles of patients with CLD undergoing treatment for HRS-AKI in a tertiary care hospital in South India. Terlipressin infusion has sustained effects on splanchnic hemodynamics with fewer severe adverse events. These findings emphasize the importance of optimizing treatment protocols: early initiation of terlipressin infusion at a higher dose (4 mg/day) with optimized albumin usage could decrease morbidity and mortality associated with HRS-AKI and minimize the adverse effects associated with terlipressin.

Disclosures

Author Contributions

Human subjects: Consent was obtained or waived by all participants in this study. Sapthagiri Institute of Medical Sciences and Research Centre's institutional ethics committee issued approval (SIMS & RC / EC- 09/SS-08/2024-25). The study is being guided by Dr Umesh Jalihal and Dr Manoj Gowda, from the Department of Medical Gastroenterology & Hepatology.

Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Concept and design:  Manoj Gowda, Dave Manan Dilipbhai, Bharath Gowda S, Anil Jain, Naveen Ganjoo

Acquisition, analysis, or interpretation of data:  Manoj Gowda, Dave Manan Dilipbhai, Umesh Jalihal, Madduri Pavan Kumar, Bharath Gowda S, Anil Jain, Naveen Ganjoo

Drafting of the manuscript:  Manoj Gowda, Dave Manan Dilipbhai, Madduri Pavan Kumar, Bharath Gowda S, Anil Jain, Naveen Ganjoo

Critical review of the manuscript for important intellectual content:  Manoj Gowda, Umesh Jalihal, Madduri Pavan Kumar, Bharath Gowda S, Anil Jain

Supervision:  Umesh Jalihal, Naveen Ganjoo
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References

1 Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis J Hepatol Angeli P Merkel C 0 103 48 Suppl 1 2008
2 Outcomes for hepatorenal syndrome and acute kidney injury in patients undergoing liver transplantation: a single-center experience Transplant Proc Shusterman B Mchedishvili G Rosner MH 1496 1500 39 2007 17580171
3 The liver and the kidney: mutual clearance or mixed intoxication Contrib Nephrol Arroyo V 17 23 156 2007 17464111
4 Pathogenesis and treatment of hepatorenal syndrome Semin Liver Dis Arroyo V Fernandez J Ginès P 81 95 28 2008 18293279
5 News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document J Hepatol Angeli P Garcia-Tsao G Nadim MK Parikh CR 811 822 71 2019 31302175
6 Terlipressin: vasopressin analog and novel drug for septic shock Ann Pharmacother Pesaturo AB Jennings HR Voils SA 2170 2177 40 2006 17148649
7 Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers Drugs Exp Clin Res Nilsson G Lindblom P Ohlin M Berling R Vernersson E 307 314 16 1990 https://pubmed.ncbi.nlm.nih.gov/2086166/ 2086166
8 Terlipressin for the treatment of hepatorenal syndrome Gastroenterol Hepatol (N Y) 773 774 3 2007 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104157/ 21960785
9 Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1 Gastroenterology Boyer TD Sanyal AJ Wong F 1579 1589 150 2016 26896734
10 Terlipressin has stood the test of time: clinical overview in 2020 and future perspectives Liver Int Kulkarni AV Arab JP Premkumar M 2888 2905 40 2020 33065772
11 Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites Gut Angeli P Gines P Wong F 531 537 64 2015 25631669
12 Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: a randomized controlled study Hepatology Cavallin M Piano S Romano A 983 992 63 2016 26659927
13 Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome N Engl J Med Wong F Pappas SC Curry MP 818 828 384 2021 33657294
14 Comparison of intravenous terlipressin infusion versus bolus in patients with acute-on-chronic liver failure-acute kidney injury - an open label RCT Clin Exp Hepatol Gupta T Goel A Ranga N Goyal SK 351 358 9 2023 38774204
