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ARTICLE
Early Postoperative Acute Kidney Injury Among Pediatric Liver Transplant Recipients

Objectives: Acute kidney injury after pediatric liver transplant is associated with increased morbidity and mortality. Here, we evaluated children with acute kidney injury early posttransplant using KDIGO criteria to determine incidence, risk factors, and clinical outcomes.

Materials and Methods: In this retrospective cohort study, medical records of all patients < 16 years old who underwent liver transplant from April 2007 to April 2017 were reviewed.

Results: Of 117 study patients, 69 (59%) were male and median age at transplant was 72 months (range, 12-120 mo). Forty children (34.2%) had postoperative acute kidney injury, with most having stage 1 disease (n = 21). Compared with children who had acute kidney injury versus those who did not, preoperative activated partial thromboplastin time (median 35.6 s [interquartile range, 32.4-42.8 s] vs 42.5 s [interquartile range, 35-49 s]; P = .007), intraoperative lactate levels at end of surgery (median 5.3 mmol/L [interquartile range, 3.3-8.6 mmol/L] vs 7.9 mmol/L [interquartile range, 4.3-11.2 mmol/L]; P = .044), and need for open abdomen (3% vs 15%; P = .024) were significantly higher. Logistic regression analysis revealed that preoperative high activated partial thromboplastin time (P = .02), intraoperative lactate levels at end of surgery (P = .02), and need for open abdomen (P = .03) were independent risk factors for acute kidney injury. Children who developed acute kidney injury had significantly longer intensive care unit stay (7.1 ± 8.5 vs 4.4 ± 5.4 days, P = .04) and mortality (12.8% vs 1.8%; P = .01).

Conclusions: Early postoperative acute kidney injury occurred in 34.2% of pediatric liver transplant recipients, with patients having increased mortality risk. High preoperative activated partial throm-boplastin time, high intraoperative end of surgery lactate levels, and need for open abdomen were shown to be associated with acute kidney injury after pediatric liver transplant.


Key words : Kidney Disease Improving Global Outcomes, Lactate, Partial thromboplastin time

Introduction

Liver transplant is the most effective treatment method for infants, children, and adults within all age groups for end-stage liver failure, primary and secondary liver tumors, and hepatic metabolic diseases. Since the first liver transplant, significant improvements have been observed in the post-operative care methods. In parallel with technological advances, developments in surgical techniques and immunosuppressive treatment protocols resulted in a 1-year survival rate of over 90%.1 In Turkey, liver transplant has been successfully implemented since 1988, with the first pediatric liver transplant conducted by Dr. Haberal and his team in 1990.2

Acute kidney injury (AKI) after liver transplant is a serious complication that is closely associated with increased morbidity and mortality. In the literature, the incidence of acute renal failure after liver transplant has been reported to range from 17% to 95%, and the causes are multifactorial.3 Acute kidney injury after pediatric liver transplant is also a serious complication associated with increased morbidity and mortality. There are few reports on the incidence, risk factors, and outcomes of Kidney Disease Improving Global Outcomes (KDIGO)-based AKI after pediatric liver transplant.

In this study, our aim was to evaluate children with AKI in the early postoperative period using KDIGO criteria and to compare patients with and without AKI to determine the incidence, risk factors, and clinical outcomes.

Materials and Methods

This study was approved by the Baskent University Institutional Review Board (project no: KA 18/123). For this study, we retrospectively analyzed medical records of pediatric patients who underwent liver transplant at Baskent University Hospital from April 2007 to April 2017. Patients over the age of 16 years, patients with chronic renal failure, and patients with missing data were excluded from the study. Collected data included demographic characteristics of children (age, sex, body weight, body mass index), systemic diseases, drugs, Pediatric End-Stage Liver Disease (PELD) score, Model of End-Stage Liver Disease (MELD) score, perioperative laboratory values and hemodynamic parameters, perioperative urine output, incidence of intraoperative massive hemorrhage (massive hemorrhage was defined4 as blood loss exceeding 150 mL/min), extubation time, length of intensive care unit (ICU)/hospital stay, and hospital mortality. Acute kidney injury was determined according to KDIGO 2012 criteria. Acute kidney injury according to KDIGO criteria is defined as an increase in serum creatinine by 0.3 mg/dL in 48 hours or increase of serum creatinine of 1.5 times or more versus baseline or urine output within 0.5 mL/kg/h in the first 6 hours.5

Incidence and stages of early postoperative AKI among the included pediatric liver transplant recipients were evaluated. Pediatric patients were then divided into 2 groups according to the presence of AKI to define risk factors and clinical outcomes.

The same anesthetic technique was used in all patients. Anesthesia was induced with a combination of propofol (1.5-2.5 mg/kg) and fentanyl (3-5 μg/kg). Rocuronium was given to facilitate endotracheal intubation (0.5-1.2 mg/kg) and maintain paralysis during surgery (0.01-0.012 mg/kg/min). Anesthesia maintenance was achieved with a sevoflurane-air-oxygen mixture and an infusion of remifentanil (0.1-0.2 μg/kg/min). Routine monitoring included electrocardiography, pulse oximetry, capnography, nasopharyngeal temperature, invasive arterial blood pressure (radial pressure), and central venous pressure via the subclavian or internal jugular vein. After surgery, all patients were admitted to an ICU. The same surgical, anesthesia, and intensivist teams were assigned during the perioperative period of all liver transplant surgeries.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Chi-square test was used to compare categorical variables.

In terms of continuous variables, Mann-Whitney U test was applied to investigate differences in groups. In summary statistics, the median (minimum to maximum) was used for continuous variables, and frequency distributions and per-centages were used for categorical variables. Graphs were also generated using percentages and frequencies to summarize the results. P < .05 indicated statistical significance.

Results

During the 10-year study period, 121 liver transplant procedures were performed on patients who were potentially eligible for inclusion in our study. Of these, 4 patients who experienced pretransplant renal failure and placed on dialysis were excluded from the study. A total of 117 pediatric liver transplant recipients were analyzed. The median age at transplant was 72 months (range, 12-120 mo), and 69 (59%) were male. The demographic characteristics of patients included in the study are shown in Table 1. The most frequent diagnosis was biliary atresia (n = 26, 22%). Patient diagnosis, PELD and MELD scores, and presence of comorbidities are shown in Table 2. Table 3 provides the preoperative laboratory results. Early postoperative AKI was seen in 40 children (34.2%) of which 21 (18%) had stage 1, 12 (10.2%) had stage 2, and 7 (6%) had stage 3 disease.

The mean calculated MELD and PELD scores were similar in patients with and without AKI (Table 4). Compared with children who did not have AKI, preoperative activated partial thromboplastin time (aPTT) values (median of 35.6 s and interquartile range [IGR] of 32.4-42.8 s vs 42.5 s [IQR, 35.0-49.0 s]; P = .007) and intraoperative lactate levels at the end of surgery (median of 5.3 mmol/L [IQR, 3.3-8.6 mmol/L] vs 7.9 mmol/L [IQR, 4.3-11.2 mmol/L]; P = .044) were significantly higher in those who developed AKI (Table 5). Intraoperative blood and fluids administered during the intraoperative period were similar in both groups (Table 6). Compared with children who did not have AKI, need for open abdomen (3% vs 15%; P = .024) was significantly higher in those who had AKI (Table 7). Renal replacement therapy was initiated in 15% of children with AKI. Length of ICU stay was significantly longer in children who developed AKI (7.1 ± 8.5 vs 4.4 ± 5.4 days; P = .04). Duration of mechanical ventilation and length of hospital stay were similar between the groups. In-hospital mortality was significantly higher in children with AKI (12.8% vs 1.8%; P = .01) (Table 7).

Logistic regression analysis revealed that pre-operative high aPTT levels (odds ratio [OR] of 1.043; 95% confidence interval [CI], 1.006-1.082; P = .02), intraoperative end of surgery lactate levels (OR of 1.151; 95% CI, 1.021-1.297; P = .02), and need for open abdomen (OR of 0.162; 95% CI, 0.031-0.845; P = .03) were independent risk factors for AKI (Table 8).

Discussion

The incidence of early postoperative AKI was 34.2% in this retrospective study evaluating 117 pediatric liver transplant recipients. Preoperative elevated aPTT, increased intraoperative end of surgery lactate levels, and presence of open abdomen were defined as risk factors for early postoperative AKI. Renal replacement therapy was needed in 15% of the cases in which AKI developed, and the presence of AKI was associated with a prolonged ICU stay and increased hospital mortality.

The onset of AKI after liver transplant is a relatively frequent complication. The incidence of AKI after adult liver transplant can range from 17% to 95%, although recent studies have reported a range of 39% to 56%.3,6,7 Studies on the deve-lopment of AKI in pediatric liver transplant recipients are so far scarce. In a retrospective study from Hamada and associates8 that evaluated the development of AKI after pediatric liver transplant, incidence of AKI was 46.2%, among which 21.8%, 20.5%, and 3.8% were reported to be grade 1, grade 2, and grade 3, respectively. Our finding of 34.2% incidence was comparable, with 18%, 10.2%, and 6% having grade 1, grade 2, and grade 3 disease, respectively.

Comorbidities (diabetes mellitus and chronic renal failure) in adult patients are reported to in-crease the incidence of AKI after liver transplant.9-11 Compared with results in adult patients, our lower incidence of AKI can be attributed to the fact that no accompanying chronic diseases were present in our patients. Our lower incidence of AKI versus that reported by Hamada and associates8 could be attributed to the fact that baseline creatinine levels and urine outputs were within normal ranges in all patients included in our study.

In the present study, we found that elevated aPTT was associated with development of AKI; however, no significant differences were found regarding amount of replacement of intraoperative blood or blood products. That said, the requirement of blood or blood products was higher in patients with AKI than in those without AKI, and this was considered to be clinically significant. We believe that use of more blood and blood products in the group with higher preoperative aPTT levels may have been related to the development of AKI. In previous studies, intraoperative use of blood products has been blamed as a risk factor for the development of AKI after liver transplant,12-14 which was supported by findings in our study.

Intraoperative increases in lactate levels were also found to be associated with the development of AKI in the present study. The production of lactate, as a by-product of carbohydrate and nonessential amino acid metabolism, occurs in various parts of the body, including skin, erythrocytes, central nervous system, and muscles; however, 60% and 30%, respectively, are excreted by liver and kidneys.15,16 Elevated lactate levels have been associated with increased mortality, morbidity, and a prolonged ICU stay.17 In a study from Jipa and colleagues,18 in which the effects of increased arterial lactate during liver transplant on postoperative outcome were evaluated, elevated lactate levels at the end of a surgical operation were reported to be associated with increased mortality, prolonged ICU duration, and liver and kidney dysfunction. In parallel to the findings in the literature, we also found that increased end-surgical lactate levels were associated with the development of AKI.

In our study, we noted that the presence of an open abdomen represented a risk factor for the development of AKI. Open abdomen has been reported to be associated with prolonged durations of mechanical ventilation, fluid loss, delays in early mobilization, increased infection rates, and an increased usage of antibiotics, although new methods have been developed to try and lower the rate of complications after open abdomen surgery.19-22 We suggest that the development of AKI in patients with open abdomen in the present study may be associated with fluid loss and antibiotic usage due to repetitive operations and increased intra-abdominal infection secondary to peritoneal cavity contamination.

The frequency of postoperative antibiotic usage was significantly higher in children who had AKI in the present study (75% vs 51%; P = .017). The use of antibiotics may be due to early postoperative sepsis, which is known to cause AKI.23 Finally, although we observed significant differences in preoperative sodium levels between children with and without AKI, this was clinically insignificant as the values were within normal limits.

The limitations of this study included its retrospective nature, the fact that not all patient data could be reached, and the few studies in the literature on the development of AKI in pediatric liver transplant recipients. Accordingly, prospective studies with larger patient series are required.

In conclusion, the incidence of early postoperative AKI was 34.2% in the present study of 117 pediatric liver transplant recipients. Preoperative elevated aPTT and intraoperative higher lactate levels and the presence of open abdomen were determined as risk factors for the development of AKI. Regarding clinical outcomes, 15% of children required renal replacement therapy among those who developed AKI and had prolonged ICU stay and increased hospital mortality.


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DOI : 10.6002/ect.2018.0214


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From the 1Anesthesiology and ICM Department and the 2Transplantation Department, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have no conflicts of interest to declare. This study was supported by the Baskent University Research Fund.
Corresponding author: Helin Sahinturk, Baskent University, Faculty of Medicine, Department of Anesthesiology and ICM, Fevzi Cakmak Caddesi 10, Sokak No:45 Bahcelievler, 06490 Ankara, Turkey
Phone: +90 312 2126868/4817
E-mail: helinsahinturk@yahoo.com