Key words : Acute kidney injury, Early allograft dysfunction, Length of hospital stay, Nosocomial infection, Somatostatin analog

Introduction

Liver transplant (LT) is currently the standard of care for advanced liver disease.^1,2 This effective treatment also has several inherent complications that may affect long-term outcomes of patients.

Renal insufficiency is one of the most common and life-threatening complications following LT.^3,4 After LT, the prevalence of renal failure has been reported to vary between 25% and 75%.^5,6 Development of acute kidney injury (AKI) after LT can result in increased length of hospital stay and higher mortality and morbidity rates.7

Acute kidney injury after LT has several risk factors, including surgery-related events (blood loss, hypotension), nephrotoxic drugs, hepatorenal syndrome, infection, and sepsis.^3,4 An inducible mechanism of post-LT AKI is mediated by splanchnic vasodilatation as a result of liver cirrhosis, in which hypovolemia develops, and vasoactive mechanisms initiate compensatory activation of vasoconstrictor catecholamine, resulting in deterioration of kidney function.⁸

Early allograft dysfunction (EAD) is another complication of LT, and it may result in increased rates of mortality and morbidity.⁹ Early allograft dysfunction usually affects grafts that show marginal function early after LT. Patients with EAD have a longer intensive care unit (ICU) admission and hospital stay.¹⁰ In the literature, EAD is defined as a bilirubin level higher than 10 mg/dL on day 7, an international normalized ratio higher than 1.6 on day 7, and alanine aminotransferase or aspartate aminotransferase levels higher than 2000 IU/mL within the first 7 days after transplant.¹¹

Several supportive measures are used to prevent AKI and EAD after LT, but there is no standard medical interventions that can decrease the prevalence of these events.

Octreotide is a somatostatin analog and an effective therapy for variceal bleeding and hepatorenal syndrome in patients with cirrhosis.¹² Octreotide induces potent splanchnic vasoconstriction, which may be mediated in part by inhibition of glucagon release.¹³ Furthermore, octreotide can reduce ischemia-reperfusion injury by decreasing portal pressure. It is also a well-known adjuvant therapy for hepatorenal syndrome. Octreotide is widely available and well tolerated. According to some studies, octreotide seems to have organ-protective effects. In animal models of hepatic ischemia-reperfusion injury, use of octreotide resulted in a possible protective effect. Octreotide administration resulted in diminished levels of endotoxin and proinflammatory cytokines (tumor necrosis factor-α and interleukin 1β) and inhibition of hepatocellular apoptosis¹⁴ as well as enhanced autophagy.¹⁵

We hypothesized that establishing renal perfusion through octreotide’s visceral vasoconstrictor effect and its anti-inflammatory effect can be effective in preventing AKI and EAD and the consequent adverse outcomes of these 2 major complications in LT recipients.

Given the shortage of published literature on this topic, this study was designed to evaluate the efficacy of octreotide infusion in preventing renal failure, EAD, and other early postoperative complications in LT recipients in a randomized double-blind trial in the Shiraz transplant center (Shiraz, Iran).

Materials and Methods

This randomized, double-blind placebo-controlled trial was conducted to evaluate the effects of octreotide on early posttransplant outcomes in LT recipients.

Ethical considerations
This study was approved by the Ethics Committee of Shiraz University of Medical Sciences (ethics committee reference number IR.SUMS.MED.REC. 1400.252 ID). The purpose of the study was explained to the patients, and written informed consent was obtained from each participant.

Study setting and participants
The randomized controlled trial was conducted by the gastroenterology and hepatology departments of Shiraz University of Medical Sciences in Abu-Ali Sina Hospital, the referral organ transplant center.16 Eligible patients were adults aged 18 to 60 years and included 21 male (42%) and 29 female (58%) patients. Mean age was 46.64 and 51.04 years for the octreotide treatment group and the control group (without octreotide treatment), respectively. Eligible patients were candidates for deceased donor orthotopic LT; candidates were properly informed while on the transplant wait list and gave their consent to participate in the study. Women of childbearing potential were required to have a negative pregnancy test.

The following criteria resulted in exclusion of patients from this study: pregnant women, nursing mothers, systolic blood pressure ≥150 mm Hg and/or diastolic blood pressure ≥90 mm Hg, patients who were treated with a transjugular intrahepatic portosystemic shunt or surgical portosystemic shunts in the past, candidates for simultaneous liver and kidney transplants, cardiac or respiratory failure, positivity for HIV, obstructive uropathy and urinary retention, ischemic heart disease, cerebrovascular accident or peripheral vascular disease, narrow-angle glaucoma, thyrotoxicosis, history of hemodialysis before LT, and pretransplant creatinine above 2.5 mg/dL.

Study design
In this single-center, randomized, double-blind, and placebo-controlled trial, we randomly assigned patients to receive either octreotide or placebo. The trial is registered with the Iranian Registry of Clinical Trial (trial registration number: IRCT20190619043942N1).

Outcome measures
The primary outcome was renal function based on the Kidney Disease: Improving Global Outcome (KDIGO) criteria, which has high sensitivity for diagnosis of AKI in LT recipients.¹⁷ We assessed AKI within the first 7 days after LT. This time frame was selected to exclude factors affecting kidney function chronically, such as immunosuppressive therapy. We did not use estimated glomerular filtration rate measures because the study aimed to evaluate AKI. In addition, measurement of estimated glomerular filtration rate has been shown to be of lower accuracy in patients with liver disease.¹⁸

Acute kidney injury was categorized into 3 stages based on its severity. Stage I is defined by the sudden decrease (within 48 h) of renal function, defined as an increase in absolute serum creatinine of at least
0.3 mg/dL or by a percentage increase of ≥50% (1.5 to 1.9× baseline) or by a decrease in urine output (documented oliguria <0.5 mL/kg/h for 6-12 h). Stage II is defined by an increase of ≥2 to 2.9 times serum creatinine over baseline or decrease in urine output <0.5 mL/kg/h for ≥12 hours. Stage III is defined by an increase of ≥3 times serum creatinine over baseline or serum creatinine level ?4 mg/dL or decrease in urine output <0.3 mL/kg/h for more than 24 hours or anuria for more than 12 hours or need for initiation of renal replacement therapy. The last laboratory test of serum creatinine was considered as the baseline level.

Secondary outcomes were the length of ICU and hospital stays, nosocomial infection rate, and EAD rate (defined as bilirubin level higher than 10 mg/dL on day 7, international normalized ratio above 1.6 on day 7, and alanine aminotransferase or aspartate aminotransferase levels ?2000 IU/mL within the first 7 days posttransplant).

Sample size calculation
For this study, 50 LT recipients aged 18 to 60 years were selected. There is limited evidence on the influence of octreotide infusion on early post-LT 0.35 mg/dL and 1.2 mg/dL for the octreotide treatment and control groups, respectively. The power of the study was set at 80% with 0.05% type I error. Using the sample size calculator software (https://clincalc.com/stats/samplesize.aspx), we calculated a sample size of 21 patients for each group (42 patients in total). However, we increased the sample size to 25 patients for each group (50 patients in total).

Randomization
We randomized the included patients into 2 groups at a ratio of 1:1 using random allocation software. The randomization codes remained concealed until all patients had completed their follow-up and the database had been verified and closed. No emergency case required breaking the blind on randomization.

Using the random allocation software, we randomly divided the 50 eligible participants into 2 separate groups, with sealed number assigned to each patient to indicate which group. Both patients and investigators involved in the research were blinded (masked) with regard to group placement.

Intervention
After LT and immediately after entrance to the ICU, patients were given either octreotide infusion or placebo. The octreotide and placebo (normal saline) were in 1-mL vials, which were identical in appearance. A nurse, who did participate in the study, prepared the vials at the ICU. The 1-mL vials with the A label contained 50 μg octreotide, and the 1-mL vials with the B label contained 1 mL of normal saline. The patients and investigators involved in assessment of results were not aware of the contents of vials A and B.

In the octreotide group, octreotide was started with 50 μg/h infusion. In the control group, normal saline infusion was started. The infusion of the drug was continued for 3 days.

Statistical analyses
This study analyzed the factors associated with infection and rejection using multivariate logistic regression. We used the Mann-Whitney U test and the Fisher exact test to assess the hypothesis of no differences across groups (octreotide treatment and control). Significance level was set at P = .05.

Results

Enrolled patients
Among 79 patients who underwent deceased donor orthotopic LT from September 2020 to November 2020, 50 patients fulfilled the study inclusion requirements. There were 25 patients randomly allocated into the control group and 25 patients randomly allocated into the octreotide treatment group (Figure 1).

Study findings
Group comparisons of patients in the control and octreotide treatment groups are presented in Table 1. The baseline characteristics of patients are outlined in Table 2. Mean ages of patients were 46.64 years in the octreotide group and 51.04 in the control group. Table 3 represents the causes of end-stage liver disease in the study participants.

The Fisher exact test indicated differences in infection and EAD between the control group and the octreotide group. The results of the Mann-Whitney U-test showed differences for AKI and length of ICU admission across the control and octreotide groups. The mean rank of AKI in the control group (29) was significantly higher than that in the octreotide group (22).

We observed significantly lower rates of AKI, EAD, and nosocomial infection in the octreotide group compared with the control group (P < .05). Moreover, we observed significant differences between the 2 groups with regard to length of hospital stay and ICU admission (P < .05) (Table 1).

The results of multivariate logistic regression based on the odds ratio (OR) for infection and EAD are shown in Table 4 and Table 5, respectively. Female patients had a higher likelihood of infection (OR = 23.19) than male patients. Patients in the octreotide group were less likely to have an infection (OR = 0.027) than patients in the control group. The likelihood of EAD in the octreotide group was significantly lower than in the control group (OR = 0.14). We found that ICU admission was associated with a higher probability of EAD (OR = 1.34). In contrast, an increase in intubation time was associated with a decrease in the pro-bability of EAD (OR = 0.93). Results are showed in Table 4 and Table 5.

Discussion

In this randomized controlled trial, we examined the effects of octreotide administration on early post-LT complications. In addition, we compared total ICU admission, length of hospital stays, and nosocomial infection rates in the 2 groups (control group and octreotide treatment group). Our results showed that octreotide infusion led to a significant decrease in the occurrence of AKI and EAD. In addition, the nosocomial infection rate decreased significantly in patients who received octreotide infusion. The total lengths of ICU (7.4 vs 10.16 days; P = .042) and hospital stays (12.25 vs 16.4 days; P = .023) were remarkably reduced in patients who received octreotide infusion in the post-LT period. We also demonstrated that LT recipients who received posttransplant octreotide infusion had a lower AKI rate than those who did not receive octreotide.

Although a higher AKI rate has been reported in LT recipients,^7,19-22 the clinical benefit of octreotide infusion for preventing AKI is still a matter of debate. Octreotide was shown to be effective in treatment of hepatorenal syndrome²³ and variceal bleeding²⁴ in patients with cirrhosis. However, it remains uncertain whether octreotide has a role in prevention of AKI in LT recipients.²⁵ Octreotide was proven to be an effective drug for reducing portal pressure26 and increasing mean arterial pressure.²⁷ So far, clinical trial results have not shown that octreotide affects renal hemodynamics and renal tubular function in patients with cirrhosis.²⁸ In a study from Sahmeddini and colleagues, infusion of octreotide in combination with norepinephrine led to higher urine output and mean arterial pressure compared with the control group, with no significant effects on creatinine as a marker of renal function.²⁵ In their study, Pomier-Layrargues and colleagues reported that octreotide requires at least 48 hours before an effect on renal function parameters is shown.²⁹ In the study from Sahmeddini and colleagues, the absolute amount of creatinine in their 2 groups was evaluated; however, in our study, we evaluated the incidence of acute renal failure based on standard criteria. This issue and the duration of octreotide infusion may explain the discrepancy between the results of our study and the previous study. Our findings could open a new horizon for further investigations in this field.

Hepatic ischemia-reperfusion injury is one of the most important causes of patient morbidity after LT30; severe inflammatory responses can occur after ischemia-reperfusion injury.³¹ Several studies have reported on the organ-protective effects of octreotide.^32-34 Sun and colleagues showed that octreotide reduced renal inflammation apoptosis and protected against AKI after hepatic ischemia-reperfusion injury.³⁵ The group also noted that octreotide induced autophagy in the kidney after hepatic ischemia-reperfusion injury, supporting the protective effects of octreotide.³⁵

In a case report from Eberhardt, octreotide monot-herapy did not affect renal hemodynamic maintenance and splanchnic vasculature³⁶ in treatment of hepatorenal syndrome, it seems that anti-inflammatory effects and enhancing autophagy were more effective in preventing AKI in the study patient. On the other hand, in our study, the rate of EAD in the octreotide treatment group was significantly lower than in the control group. In an animal study, the investigators demonstrated that octreotide could ameliorate liver ischemia-reperfusion injury, possibly via the induction of HO-1-mediated autophagy, which may define a novel mechanism of octreotide in the control of acute liver injury and support the potential utility of octreotide to prevent and treat liver dysfunction after ischemia-reperfusion injury.¹⁵

In our study, nosocomial infection rates were reduced in patients who received octreotide after LT. This may be related to the anti-inflammatory effect of octreotide or the reduction in major postoperative complications (AKI, EAD), which shortened the patient’s total length of hospital stay and ICU admission.

To the best of our knowledge, this is the first placebo-controlled clinical trial showing that octreotide can be effective in decreasing AKI and EAD and subsequently lowering the nosocomial infection rate and length of hospital stay. Our study was limited by its single-center design. Studies with larger sample sizes and longer follow-up periods could further assess the potential effects of octreotide on LT recipients.

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