Risk factors for acute kidney injury after liver transplantation in intensive care unit: a retrospective cohort study

ABSTRACT BACKGROUND: Acute kidney injury (AKI) is a frequent complication during the postoperative period following liver transplantation. Occurrence of AKI in intensive care unit (ICU) patients is associated with increased mortality and higher costs. OBJECTIVE: To evaluate occurrences of moderate or severe AKI among patients admitted to the ICU after liver transplantation and investigate characteristics associated with this complication. DESIGN AND SETTING: Single-center retrospective cohort study in a public hospital, Belo Horizonte, Brazil. METHODS: Forty-nine patients admitted to the ICU between January 2015 and April 2017 were included. AKI was defined from a modified Kidney Disease Improving Global Outcomes (KDIGO) score (i.e. based exclusively on serum creatinine levels). RESULTS: Eighteen patients (36.7%) developed AKI KDIGO 2 or 3; mostly KDIGO 3 (16 out of the 18 patients). Lactate level within the first six hours after ICU admission (odds ratio, OR: 1.3; 95% confidence interval, CI: 1.021-1.717; P = 0.034) and blood transfusion requirement within the first week following transplantation (OR: 8.4; 95% CI: 1.687-41.824; P = 0.009) were independently associated with development of AKI. Patients with AKI KDIGO 2 or 3 underwent more renal replacement therapy (72.2% versus 3.2%; P < 0.01), had longer hospital stay (20 days versus 15 days; P = 0.001), higher in-hospital mortality (44.4% versus 6.5%; P < 0.01) and higher mortality rate after one year (44.4% versus 9.7%; P = 0.01). CONCLUSION: Need for blood transfusion during ICU stay and hyperlactatemia within the first six postoperative hours after liver transplantation are independently associated with moderate or severe AKI. Developing AKI is apparently associated with poor outcomes.


INTRODUCTION
Acute kidney injury (AKI) is a frequent complication during the postoperative period following liver transplantation, with consequent increases in hospital stay, deaths and costs. 1,2 Moreover, it is associated with an increased risk of developing chronic kidney disease, 1-3 acute graft failure, 1,3 sepsis and coagulopathy. 4 The incidence of AKI during the immediate postoperative period following liver transplantation ranges from 17% to 95% in different series, 1,5,6 and 8% to 17% of these patients require renal replacement therapy (RRT). 4 In Brazil, the reported incidence of AKI after liver transplantation has ranged from 32% to 72%, according to the definition criteria used; and the 30-day mortality in this group of patients has ranged from 12% to 25%, but may reach 50% among those requiring RRT. [7][8][9][10] Liver transplant recipients' survival has improved substantially over the last decades.
Nevertheless, occurrences of AKI in this population remain correlated with elevated mortality during the postoperative period. Additionally, even successful liver transplant patients seem to be at higher risk of chronic kidney disease, seen at the long-term follow-up, when they developed AKI during the first postoperative days. 11,12 The pathophysiology of AKI in these cases is multifactorial. 9,13 The most likely contributing factors include higher occurrence of hepatic ischemia-reperfusion injury (HIRI), 10,11 increased use of marginal or high-risk grafts and presence of receptors with a high Model of End-Stage Liver Disease (MELD) score. 12,14 Currently, Brazil is the country with the largest absolute number of liver transplantations in Latin America and the third globally, with more than 1,700 surgeries per year. 15

OBJECTIVE
Given this scenario, the aim of this study was to evaluate occurrences of moderate or severe AKI among patients undergoing liver transplantation at a reference center in Brazil and to investigate associated factors and consequences of this complication.

Study design and setting
A retrospective cohort study was conducted among adult patients

Clinical outcomes
We assessed occurrences of AKI during the first seven days of follow-up or up to the time of hospital discharge or death, whichever came first. We also investigated associations between AKI and some relevant patient outcomes, namely length of ICU and hospital stay, in-hospital mortality and mortality rate after one year.

Data collection
Data were extracted from the electronic medical records of AKI was defined as a 1.5-fold increase in baseline serum creatinine (SCr) level during the first seven days or an increase in SCr ≥ 0.3 mg/dl within 48 hours following liver transplantation.
We used a modified AKI KDIGO score (without diuresis measurement) to classify the stage of AKI as KDIGO 1, 2 or 3. 20

Statistical analysis
Categorical variables were expressed as absolute and relative frequencies and were compared using the chi-square test or Fisher's exact test, as indicated. Continuous nonparametric variables were expressed as medians and interquartile ranges (Q1-Q3) and were compared using the Mann-Whitney test.
Patients with AKI were stratified into the subgroups 1, 2 and 3, in accordance with their AKI KDIGO score. Thus, they were classified into two groups: non-AKI and AKI KDIGO 1 (absent or mild) or AKI KDIGO 2/3 (moderate to severe), for further com- York, United States), was used for data analysis.

RESULTS
Out of a total of 57 patients who underwent liver transplantation during the study period, 49 were included in the final analyses ( Figure 1).
The main baseline characteristics of the patients included are shown in Table 1 Table 2).

AKI and patient outcomes
The in-hospital mortality rate was 22.4% (   Knowledge of postoperative risk factors associated with AKI in liver transplantation patients is scarce: this has mostly been studied in the pre and intraoperative periods. 23,27,[28][29][30] It is currently believed that bleeding that leads to transfusion requirements during the surgical procedure is associated with AKI, especially a need for red blood cells and cryoprecipitate. 6,22,30 In our study, the need for blood transfusion at any time during the ICU stay was associated with an odds ratio eight times higher for the development of AKI KDIGO 2 or 3.
Erdost et al. evaluated the three surgical periods among liver transplantation patients and found that only in the intraoperative period was blood transfusion associated with AKI development. 30 Zongyi et al. also evaluated the three surgical periods and identified that transfusion of red blood cells and fresh frozen plasma in the intraoperative period was associated with postoperative AKI development in liver transplantation patients. 29 These authors did not find that the need for transfusion in the postoperative period was a risk factor associated with development of AKI, but they noted that there was an association between postoperative intraperitoneal hemorrhage and AKI. 29 We hypothesize that the need for blood transfusion is an indirect marker of the severity of patients' condition, such that it is more frequent among patients with postoperative complications and among those who need surgical reintervention.
We showed that higher serum lactate levels within the first six hours after ICU admission were independently associated with   Table 3).

DISCUSSION
In this study, occurrence of AKI KDIGO 2 or 3 during the postoperative period following liver transplantation was common (36.7%) and was independently associated with a requirement for blood transfusion during the ICU stay and with higher levels of lactate during the first six hours after ICU admission.
Additionally, our exploratory data suggested that patients who developed AKI at these stages had worse outcomes, such as longer ICU and hospital stay and higher short and long-term mortality rates.
Previous studies have suggested that pre-transplantation renal impairment, measured through creatinine levels, plays an essential role in the development of postoperative AKI. [21][22][23] It is well known that in cirrhotic patients, serum creatinine levels can be falsely low due to malnutrition, reduced muscle mass or decreased creatinine biosynthesis. 24 In order to better identify occurrences of AKI, we These are somewhat expected findings, since AKI probably serves as a marker for other types of organ dysfunction and for clinical severity in general.
This study had limitations that need to be considered. Firstly, because of the retrospective design, we were unable to assess diuresis in our definition of AKI, quantify vasopressor use or analyze the use of each vasopressor separately. Also, we did not evaluate early calcineurin therapy in the postoperative period following liver transplantation (e.g. tacrolimus serum levels). Secondly, this was a single-center study, with inclusion of a small number of patients, thus limiting the power of our statistical inferences. Thirdly, we were unable to characterize the severity of illness of the patients included using a severity score (e.g. Acute Physiology and Chronic Health Evaluation II [APACHE II] or Simplified Acute Physiology Score 3 [SAPS 3]), which precluded any adjustment of our associative analyses for this relevant parameter.

CONCLUSION
This study showed that the need for blood transfusion during ICU stay and hyperlactatemia at ICU admission are independently associated with development of AKI KDIGO stages 2 or 3.
Furthermore, our findings suggest that AKI patients require RRT more often, have a longer hospital stay and might have higher short and long-term mortality. Prospective studies are needed in order to better identify early factors associated with acute renal function loss during the immediate postoperative period following liver transplantation, thereby enabling more assertive and prompter interventions that might result in better clinical outcomes.