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Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: A retrospective study
YJPSU-59290; No of Pages 5 Journal of Pediatric Surgery xxx (xxxx) xxx
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Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a retrospective study Yimao Zhang a, Bo Xiang a, Yang Wu a,b, Xiaolong Xie a, Junxiang Wang a, Shuguang Jin a,⁎ a b
West China of Hospital, Sichuan University, Department of Pediatric Surgery, No. 37 Guo Xue Xiang, Chengdu, Sichuan, China West China of Hospital, Sichuan University, Department of Pediatric Surgery, No.37 No. 37 Guo Xue Xiang, Chengdu, Sichuan, China
a r t i c l e
i n f o
Article history: Received 18 April 2019 Received in revised form 29 July 2019 Accepted 30 July 2019 Available online xxxx Key words: Pediatric liver transplantation Acute kidney injury Outcomes
a b s t r a c t Background: Acute kidney injury (AKI) may contribute to high mortality rates after liver transplantation. Few studies have investigated AKI in pediatric liver transplantation. This retrospective study was conducted to investigate the risk factors for and associated outcomes of AKI in pediatric liver transplant recipients. Methods: Eighty pediatric liver transplant patients were included. The occurrence of AKI was defined by the KDIGO Clinical Practice Guidelines for Acute Kidney Injury. A multivariate regression analysis model was used to investigate risk factors for AKI in the pediatric liver recipients. Results: The final multivariable regression model showed that biliary atresia (odds ratio [OR] = 0.097, p = 0.03), increased time of the anhepatic phase (OR = 0.871, p = 0.005) and lower postoperative jaundice clearance (OR = 13.936, p = 0.02) were independently associated with the development of AKI in pediatric patients. Additionally, cumulative 3-year patient (p = 0.15) and graft (p = 0.26) survival rates between the non-acute kidney injury (NAKI) and AKI groups were 95.2% vs 86.8% and 90.5% vs 84.2%, respectively. Conclusion: Pediatric liver transplant recipients with a presence of biliary atresia, increased time of anhepatic phase, and a lower postoperative jaundice clearance had an increased risk of AKI. The long-term outcomes of patients who developed AKI appears to be worse compared with those having NAKI. Type of Study: Prognosis study. Level of Evidence: Level III. Published by Elsevier Inc.
Liver transplantation is the most efficacious treatment for end-stage liver diseases [1]. Acute kidney injury (AKI) is a common complication of liver transplantation [2]; however, it has a wide range of reported incidence, occurring in 17%–95% of cases according to different studies [3–5]. Previous studies [3,6,7] have indicated that development of AKI in adult liver transplant patients may lead to end-stage renal disease and a higher mortality risk. However, pediatric liver recipients vary significantly from adults in age, primary etiology, physiological characteristics, reserve capacity of the kidney, and postoperative management. Furthermore, unlike in adults, end-stage liver diseases in children are primarily due to congenital or hereditary diseases [8]. Many studies investigating AKI in adults have been reported [1–11]. Currently, data on pediatric liver recipients are still rare. To address the current gap in the literature, this retrospective study was conducted to
Abbreviations: AKI, Acute kidney injury; NAKI, Non-acute kidney injury; RRT, Renal replacement treatment; KDIGO, Kidney Disease Improving Global Outcomes; PELD, Pediatric end-stage liver disease; CTP, Child-Pugh Score; PICU, Pediatric Intensive Care Unit. ⁎ Corresponding author. E-mail addresses: [email protected] (Y. Zhang), [email protected] (B. Xiang), [email protected] (Y. Wu), [email protected] (X. Xie), [email protected] (J. Wang), [email protected] (S. Jin).
investigate the risk factors for and associated outcomes of AKI in pediatric liver transplant recipients. 1. Material and methods This retrospective study was approved by the Ethics Committees of the West China Hospital of Sichuan University. From February 2012 to February 2019, 82 pediatric patients underwent liver transplantations in the West China Hospital of Sichuan University. Patients with chronic kidney disease, renal replacement treatment (RRT) in the preoperative period, those who died within first 7 days after transplantation, and those with a lack of clinical data were excluded. Therefore, one child who had undergone preoperative RRT and one child who died within the first 7 days after transplantation were excluded from this study. Thus, 80 patients were included in the study. In our single center, the median age of the patients was 34.2 months (5–158 months) with a mean weight of 13.3 kg (5–34 kg). A total of 41 patients (51.3%) were female. The median pediatric end-stage liver disease (PELD) score was 19 ± 9 (4–50) with an average Child-Pugh (CTP) score of 9.6 ± 2.2 (6–13). There were 65 cases of biliary atresia, 8 cases of decompensated cirrhosis, 2 cases of hepatoblastoma, 2 cases of hepatocellular carcinoma, 1 case of dysplasia of the bile duct, 1 case of biliary
https://doi.org/10.1016/j.jpedsurg.2019.07.019 0022-3468/Published by Elsevier Inc.
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
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tract rhabdomyosarcoma, and 1 case of Wilson's disease. There were 51 patients who received living donor liver transplantation and 62 patients received split liver transplantation. All donor livers were made up of the left external lobe. The urine output per hour was recorded in the Pediatric Intensive Care Unit after transplantation. The diagnosis of postoperative AKI was defined by the KDIGO Clinical Practice Guidelines for Acute Kidney Injury [12]. Preoperative serum creatinine was used as the baseline. The following data were collected from each patient's medical records: age, sex, weight, etiology of liver disease, Child–Pugh classification, PLED scores, CTP scores, preoperative total bilirubin, the serum creatinine level within first 7 days, the anhepatic phase, total length of hospital stays, intraoperative blood loss, and postoperative jaundice clearance. Postoperative jaundice clearance was defined by a serum total bilirubin level of 1.2 mg/dL or lower [13,14]. Tacrolimus was used as the basic postoperative immunosuppressant. However, high levels of tacrolimus can also lead to an increased incidence of postoperative AKI due to its toxicity. Therefore, the initial dose of tacrolimus was 0.1–0.15 mg/kg per day in all patients. Additionally, blood concentrations were closely monitored and the dose of tacrolimus was adjusted immediately to prevent any damage to renal function. This careful monitoring of tacrolimus concentration can minimize its toxicity. Additionally, renal toxicity due to other medications can also increase the risk of AKI. Therefore, medical treatment using pharmaceuticals with low renal toxicity was implemented as long as possible during the perioperative period. For instance, the use of nephrotoxic antibiotics was avoided after transplantation. The percentage of fat emulsion was decreased in postoperative parenteral nutrition. According to the KDIGO Clinical Practice Guidelines for Acute Kidney Injury [12], the incidence of post-transplant AKI was 47.5% (38 patients), which included 10 cases with Stage 1, 22 cases with Stage 2, and 6 cases with Stage 3. SPSS 25.0 statistical software was used for all statistical analysis. Normally distributed measurement data were represented by x ± s, and the skewed measurement data were represented by M. Differences were evaluated using a Student's t test for continuous parametric data, the Wilcoxon test for continuous nonparametric data and the Pearson's chi-squared test for noncontinuous data. The Kaplan–Meier method was conducted to analyze the survival rate of patients and grafts. A multivariate logistic regression model was adopted for the analysis of multiple risk factors. p b 0.05 was considered statistically significant. 2. Results The characteristics of this study population are presented in Table 1. Analyses of the risk factors for postoperative AKI were conducted using
Table 2 Multivariate analysis of risk factors. Risk factors
Coefficients OR
95% CI of OR
p-Value
Patients with biliary atresia Anhepatic phase Intraoperative blood loss Postoperative jaundice clearance
−2.329 −0.138 −0.02 2.634
0.011–0.841 0.791–0.959 0.956–1.004 1.325–146.556
0.03 0.005 0.10 0.02
0.097 0.871 0.980 13.936
a univariable analysis (Table 1) and multivariable analysis (Table 2). The variation in the average level of serum creatinine is shown in Fig. 1. Patient and graft survival rates after transplant are shown in Figs. 2 and 3, respectively. In our univariable model, the significant risk factors of AKI in pediatric liver recipients were patients with biliary atresia, increased time of anhepatic phase, intraoperative blood loss, and postoperative jaundice clearance (the p-value for each parameter is stated in Table 1). In the final multivariable regression model, pediatric liver recipients with biliary atresia (odds ratio [OR] = 0.097, p = 0.03), an increased anhepatic phase (OR = 0.871, p = 0.005), and postoperative jaundice clearance (OR = 13.936, p = 0.02) had an independently associated risk of AKI occurrence. Although the differences were not statistically significant in the patient (p = 0.15) and graft (p = 0.26) survival curves, the overall cumulative 3-year patient (95.2% vs 86.8%) and graft (90.5% vs 84.2%) survival rates in NAKI groups were superior to those in the AKI groups. In our study, 32 patients (84.2%) returned to normal renal function without RRT. There were 5 patients (13.2%) who were oliguric early on in the first 3 days post-transplant who survived acute renal failure using hemodialysis. One patient (2.6%) died from multiple organ dysfunction syndrome. 3. Discussion In this retrospective study, which included 80 pediatric liver recipients in our single center, the incidence of AKI was 47.5%. Additionally, we found that patients with biliary atresia, increased anhepatic phase, and postoperative jaundice clearance had an increased risk of posttransplant AKI. In the process of reviewing the literature, only one research study [8] investigating the risk factors for AKI after pediatric liver transplantation was found. In this previous retrospective study, the incidence of AKI in pediatric liver recipients was 46.2%, which is similar to our results. Hamada et al. [8] also indicated that preoperative total bilirubin concentration and increased intraoperative blood loss were risk factors for AKI after pediatric liver transplantation. In our univariate
Table 1 Baseline characteristics of the study population and univariate comparison of AKI versus NAKI group. Variable
Age (m), mean Female Weight(kg), mean Patients with biliary atresia Living donor liver transplant Child-Pugh Classification
A B C
CTP scores, mean ± SD PELD scores, mean ± SD Preoperative serum creatinine (μmol/L), mean Preoperative estimated glomerular filtration rate (ml/min/1.73 m2), mean Preoperative total bilirubin (mg/dL), mean Anhepatic phase, (minutes), mean ± SD Intraoperative blood loss (ml/kg), mean Total hospital stays (d), mean Postoperative jaundice clearance
ALL
AKI
NAKI
(n = 80)
(n = 38)
(n = 42)
34.2 (5–158) 41 13.3 (5–36) 65 51 6 32 42 9.6 ± 2.2 19 ± 9 27.2 226.8 10.7 75.5 ± 10.5 62.3 41.7 66(82.5%)
31.3 (5–136) 18 31.1 (5–33) 42 23 4 17 17 9.54 ± 2.08 20 ± 8 34.1 236.4 10.8 82.0 ± 9.53 80.02 37.3(3–77) 25(65.9%)
36.8 (5–158) 23 37.1 (5.5–36) 23 28 2 15 25 9.7 ± 2.3 17 ± 10 24 218.3 10.6 69.7 ± 7.44 46.65 45.4(18–86) 37(88.1%)
p Values 0.60 0.58 0.64 0.02 0.17
0.80 0.40 0.17 0.06 0.71 0.01 0.03 0.18 0.01
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
The level of serum creatinine (umol/L)
Y. Zhang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
AKI 80 66.3
70
71.4
NAKI
66.8 55.2
60 50 40
34.1
30
24
31.2
40.5
35.1
32.6
20
22.2
10
28.3
28.1
19.7
0
Time
Fig. 1. The variation of average level of serum creatinine in two groups.
analysis, increased blood loss (p = 0.03) was also related to the development of AKI. They also found that AKI may lead to prolonged hospital stays. However, the anhepatic phase was not included in their study. There was no statistical significance (p = 0.18) between AKI and the total length of hospital stay in our study. Hilmi et al. [6] reported in adult liver recipients that female, weight N100 kg, CTP scores, and pre-existing diabetes were risk factors for post-transplant AKI. Nevertheless, this model may not be suitable for pediatric recipients. Alexander et al. [15] reported that the duration of the anhepatic phase was an independent predictor of graft dysfunction. However, there was little evidence to fully explain the relationship between duration of the anhepatic phase and AKI. Prior studies have found that a prolonged anhepatic phase can cause renal congestion and renal function damage [16,17]. Additionally, it has been shown that during the anhepatic phase of liver transplantation, renal vein congestion significantly impacts hemodynamic parameters, which correlates with serum BK and ANGII levels [18]. Ultimately, decreased renal blood flow and glomerular filtration rates can further lead to renal function injury. Therefore, a shorter anhepatic phase may reduce the intraoperative renal function damage. In previous procedures, we opened the inferior vena cava after the suprahepatic inferior vena cava was
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anastomosed. Now, we simply blocked the blood flow of the hepatic vein and opened the inferior vena cava when the anastomosis of hepatic vein was completed. This greatly reduced blocking time of the inferior vena cava and alleviated renal congestion. After we made this improvement in the interruption method of inferior vena cava, the duration of anhepatic phase reduced from 81.6 ± 26.1 min to 66.8 ± 10.8 min. At the same time, the incidence of AKI decreased from 60% to 34.6% in our center. Biliary atresia has been reported as the most common cause of liver transplantation in pediatric recipients [19]. In addition, patients with biliary atresia are much younger than other patients [20]. The average age of patients with biliary atresia was only 12 months in this study. Prior studies have reported that renal function does not reach maturity until the age of two, and reserve function is poor [21]. Further, patients with biliary atresia are associated with decreased function in renal concentration and renal tubular reabsorption and excretion. Additionally, Salerno et al. [22] showed that patients with hepatorenal syndrome were more common in higher Model for End-Stage Liver Disease. Most patients with biliary atresia have significantly higher PELD scores and are also more likely to develop preoperative hepatorenal syndrome due to diminished renal blood flow. Both of which may cause injury and a subsequent decrease in renal function [23]. Elizabeth et al. [24] reported that 6% of children with hepatorenal syndrome ultimately required RRT. Jaundice clearance was initially used to predict the effect of the Kasai procedure [25–27]. In this study, postoperative jaundice clearance in the AKI group (65.9%) was notably lower than that in the NAKI group (88.1%). In the multivariable analysis, there was also a statistical difference (p = 0.02) between the development of AKI and postoperative jaundice clearance. A high postoperative bilirubin level can lead to various degrees of the hepatorenal syndrome. Renal blood flow and glomerular filtration rate can be decreased due to reduced effective circulation capacity. Further, bilirubin and bile salts in plasma can cause damage to renal function due to the presence of long-term hyperbilirubinemia. To the best of our knowledge, jaundice clearance was not reviewed in previous studies, which was related to AKI after liver transplantation in this study. Blood loss was once considered a risk factor for AKI in postoperative liver recipients. A massive blood loss causes reduced blood volume during the transplant, which directly exerts a substantial
Fig. 2. Patient survival after pediatric liver transplantation (p = 0.15).
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
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Fig. 3. Graft survival after pediatric liver transplantation (p = 0.26).
impact on renal flow. Therefore, prerenal acute kidney injury would occur due to renal vasoconstriction and decreased glomerular filtration rate. In the univariate analysis of the current study, there was statistical significance (p = 0.03) between blood loss in the AKI and NAKI groups. However, no statistical significance was found in the multivariate analysis (p = 0.10). Although the difference did not reach statistical significance in patient or graft survival rates among the two groups in the current study, many studies [3,6,7] in adults have reported that postoperative AKI may decrease the survival rates in either the patient or graft. In a single-center study involving 424 adult liver transplantations, Hilmi et al. [6] found that the development of AKI within 72 h of transplantation impacted short-term and long-term graft survival. In addition, Barri et al. [3] found that postoperative AKI was related to decreased survival rates in patients and grafts among 1050 adult liver transplantations. Therefore, more studies are required to investigate the correlation between AKI and short-term or long-term outcomes in pediatric liver recipients. Previous studies [28,29,30] found patients who were diagnosed with AKI after liver transplantation universally had a higher percentage of RRT. Although RRT has been an effective therapy for severe AKI cases after liver transplantation [24], Papadopoulos et al. [31] found that adult patients who required postoperative RRT after liver transplantation had a higher associated mortality rate. This may be due to a larger number of transfusions. In our center, most patients (84.2%) with AKI returned to normal renal function without RRT. Some studies have shown that preventive blood purification treatment can be considered to rapidly remove excessive waste material and water, relieve symptoms, promote early recovery of kidney function, and improve postoperative survival rates in infants before associated complications can occur [32–34]. There were several limitations in the current study. First, this was a single-center study, which may reduce the generalizability of our results. Additionally, the sample size was small because of the low number of pediatric liver transplantations compared with adult transplantations. Finally, the associated risk factors investigated in our study were limited. Therefore, further studies are still needed. Despite these limitations, previous studies investigating postoperative AKI in pediatric liver transplantations remain scarce, and hence, our study is highly impactful. This study improves the understanding of the risk factors for posttransplant AKI in pediatric liver recipients.
4. Conclusion Pediatric liver transplant recipients with a presence of biliary atresia, increased time of anhepatic phase, and a lower postoperative jaundice clearance had an increased risk of AKI. The long-term outcomes of patients who developed AKI appears to be worse compared with those having NAKI. Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board and Ethical Committee at the West China Hospital of Sichuan University in China with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent for publication Written informed consent was obtained from patient's parents to publish this study. This material is original research. It has not been previously published and has not been submitted for publication elsewhere while under consideration. Competing interests The authors declare that they have no competing interests. Funding This study was supported by Natural Science Foundation of China (NSFC:81571473). Acknowledgements Not applicable. References [1] Kjaergard LL, Liu J, Als-Nielsen B, et al. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure. JAMA 2003;289:217–22.
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
Y. Zhang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx [2] Klaus F, et al. Acute kidney injury after liver transplantation: incidence and mortality. Transplant Proc 2014;46(6):1819–21. [3] Barri YM, et al. Acute kidney injury following liver transplantation: definition and outcome. Liver Transpl 2009;15(5):475–83. [4] Lima EQ, Zanetta DM, Castro I, et al. Risk factors for development of acute renal failure after liver transplantation. Ren Fail 2003;25:553–60. [5] Fraley DS, Burr R, Bernardini J, et al. Impact of acute renal failure on mortality in endstage liver disease with or without transplantation. Kidney Int 1998;54:518–24. [6] Hilmi IA, et al. Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes. Br J Anaesth 2015; 114(6):919–26. [7] Ferreira AC, et al. Impact of RIFLE classification in liver transplantation. Clin Transplant 2010;24(3):394–400. [8] Hamada M, et al. Acute kidney injury after pediatric liver transplantation: Incidence, risk factors, and association with outcome. J Anesth 2017;31(5):758–63. [9] Gainza FJ, Valdivieso A, Quintanilla N, et al. Evaluation of acute renal failure in liver transplantation perioperative period: incidence and impact. Transplant Proc2002; 34: 250–1 [10] Gonwa TA, McBride MA, Anderson K, et al. Continued influence of perioperative renal function on outcome of orthotopic liver transplant in US: where will the MELD lead US? Am J Transplant 2006;6:2651–9. [11] Bilbao I, Charco R, Balsells J, et al. Risk factors for acute renal failure requiring dialysis after liver transplantation. Clin Transplant 1998;12:123–9. [12] Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron 2012; 120(4):c179–84. [13] Wang Z, et al. Five-year native liver survival analysis in biliary atresia from a single large Chinese center: the death/liver transplantation hazard change and the importance of rapid early clearance of jaundice. J Pediatric Surgery 2018;54(8):1680–5. [14] Nakajima H, et al. Does time taken to achieve jaundice-clearance influence survival of the native liver in post-Kasai biliary atresia? World J Pediatric 2018;14(2):191–6. [15] IJtsma AJC, et al. The clinical relevance of the anhepatic phase during liver transplantation. Liver Transpl 2009;15(9):1050–5. [16] Li SR, Shen N, Yi HM, et al. Changes of systemic and pulmonary hemodynamics and plasma levels of inducible nitric oxide synthase and endothelin-1 in patients with hepatopulmonary syndrome, 29; 2009; 2030–2. [17] Li Z. Hemodynamics and vasoactive substance levels during renal congestion that occurs in the anhepatic phase of liver transplantation. World J Gastroenterol 2015; 21(18):5482. [18] Li Z. Hemodynamics and vasoactive substance levels during renal congestion that occurs in the anhepatic phase of liver transplantation. World J Gastroenterol 2015; 21(18):5482.
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[19] Sundaram SS, et al. Biliary atresia: indications and timing of liver transplantation and optimization of pretransplant care. Liver Transpl 2017;23(1):96–109. [20] Berg UB, Németh A. Well preserved renal function in children with untreated chronic liver disease. J Pediatr Gastroenterol Nutr 2018;66(4):575–80. [21] Schwartz GJ, Work DF. Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 2009;4(11):1832. [22] Salerno F, et al. Diagnosis, treatment and survival of patients with hepatorenal syndrome: a survey on daily medical practice. J Hepatol 2011;55(6):1241–8. [23] Solà E, Ginès P. Renal and circulatory dysfunction in cirrhosis: current management and future perspectives. J Hepatol 2010;53(6):1135. [24] Elizabeth PC, et al. Renal replacement therapy in infants and children with hepatorenal syndrome awaiting liver transplantation: a case-control study. Liver Transpl 2014;20(12):1468–74. [25] Nakamura H, et al. Reappraising the portoenterostomy procedure according to sound physiologic/anatomic principles enhances postoperative jaundice clearance in biliary atresia. Pediatric Surg Int 2012;28(2):205–9. [26] Selvalingam S, et al. Jaundice clearance and cholangitis in the first year following portoenterostomy for biliary atresia. Med J Malaysia 2002;57(1):92–6. [27] Superina R, et al. The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg 2011;254(4):577–85. [28] Faenza S, et al. Acute renal failure requiring renal replacement therapy after Orthotopic liver transplantation. Transplant Proc 2006;38(4):1141–2. [29] Contreras G, Garces G, Quartin AA, et al. An epidemiologic study of early renal replacement therapy after orthotopic liver transplantation. J Am Soc Nephrol 2002; 13:228. [30] Tinti F, et al. RIFLE criteria and hepatic function in the assessment of acute renal failure in liver transplantation. Transplant Proc 2010;42(4):1233–6. [31] Papadopoulos S, et al. Causes and incidence of renal replacement therapy application in Orthotopic liver transplantation patients: our experience. Transplant Proc 2014; 46(9):3228–31. [32] Villa G, et al. Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications. Crit Care 2016;20(1):283. [33] Thorat A, Jeng LB. Management of renal dysfunction in patients with liver cirrhosis: role of pretransplantation hemodialysis and outcomes after liver transplantation. Semin Vasc Surg 2016;29(4):227–35. [34] Pertica N, et al. Safety and efficacy of citrate anticoagulation for continuous renal replacement therapy for acute kidney injury after liver transplantation: a single-center experience. Transplant Proc 2017;49(4):674–6.
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a retrospective study Yimao Zhang a, Bo Xiang a, Yang Wu a,b, Xiaolong Xie a, Junxiang Wang a, Shuguang Jin a,⁎ a b
West China of Hospital, Sichuan University, Department of Pediatric Surgery, No. 37 Guo Xue Xiang, Chengdu, Sichuan, China West China of Hospital, Sichuan University, Department of Pediatric Surgery, No.37 No. 37 Guo Xue Xiang, Chengdu, Sichuan, China
a r t i c l e
i n f o
Article history: Received 18 April 2019 Received in revised form 29 July 2019 Accepted 30 July 2019 Available online xxxx Key words: Pediatric liver transplantation Acute kidney injury Outcomes
a b s t r a c t Background: Acute kidney injury (AKI) may contribute to high mortality rates after liver transplantation. Few studies have investigated AKI in pediatric liver transplantation. This retrospective study was conducted to investigate the risk factors for and associated outcomes of AKI in pediatric liver transplant recipients. Methods: Eighty pediatric liver transplant patients were included. The occurrence of AKI was defined by the KDIGO Clinical Practice Guidelines for Acute Kidney Injury. A multivariate regression analysis model was used to investigate risk factors for AKI in the pediatric liver recipients. Results: The final multivariable regression model showed that biliary atresia (odds ratio [OR] = 0.097, p = 0.03), increased time of the anhepatic phase (OR = 0.871, p = 0.005) and lower postoperative jaundice clearance (OR = 13.936, p = 0.02) were independently associated with the development of AKI in pediatric patients. Additionally, cumulative 3-year patient (p = 0.15) and graft (p = 0.26) survival rates between the non-acute kidney injury (NAKI) and AKI groups were 95.2% vs 86.8% and 90.5% vs 84.2%, respectively. Conclusion: Pediatric liver transplant recipients with a presence of biliary atresia, increased time of anhepatic phase, and a lower postoperative jaundice clearance had an increased risk of AKI. The long-term outcomes of patients who developed AKI appears to be worse compared with those having NAKI. Type of Study: Prognosis study. Level of Evidence: Level III. Published by Elsevier Inc.
Liver transplantation is the most efficacious treatment for end-stage liver diseases [1]. Acute kidney injury (AKI) is a common complication of liver transplantation [2]; however, it has a wide range of reported incidence, occurring in 17%–95% of cases according to different studies [3–5]. Previous studies [3,6,7] have indicated that development of AKI in adult liver transplant patients may lead to end-stage renal disease and a higher mortality risk. However, pediatric liver recipients vary significantly from adults in age, primary etiology, physiological characteristics, reserve capacity of the kidney, and postoperative management. Furthermore, unlike in adults, end-stage liver diseases in children are primarily due to congenital or hereditary diseases [8]. Many studies investigating AKI in adults have been reported [1–11]. Currently, data on pediatric liver recipients are still rare. To address the current gap in the literature, this retrospective study was conducted to
Abbreviations: AKI, Acute kidney injury; NAKI, Non-acute kidney injury; RRT, Renal replacement treatment; KDIGO, Kidney Disease Improving Global Outcomes; PELD, Pediatric end-stage liver disease; CTP, Child-Pugh Score; PICU, Pediatric Intensive Care Unit. ⁎ Corresponding author. E-mail addresses: [email protected] (Y. Zhang), [email protected] (B. Xiang), [email protected] (Y. Wu), [email protected] (X. Xie), [email protected] (J. Wang), [email protected] (S. Jin).
investigate the risk factors for and associated outcomes of AKI in pediatric liver transplant recipients. 1. Material and methods This retrospective study was approved by the Ethics Committees of the West China Hospital of Sichuan University. From February 2012 to February 2019, 82 pediatric patients underwent liver transplantations in the West China Hospital of Sichuan University. Patients with chronic kidney disease, renal replacement treatment (RRT) in the preoperative period, those who died within first 7 days after transplantation, and those with a lack of clinical data were excluded. Therefore, one child who had undergone preoperative RRT and one child who died within the first 7 days after transplantation were excluded from this study. Thus, 80 patients were included in the study. In our single center, the median age of the patients was 34.2 months (5–158 months) with a mean weight of 13.3 kg (5–34 kg). A total of 41 patients (51.3%) were female. The median pediatric end-stage liver disease (PELD) score was 19 ± 9 (4–50) with an average Child-Pugh (CTP) score of 9.6 ± 2.2 (6–13). There were 65 cases of biliary atresia, 8 cases of decompensated cirrhosis, 2 cases of hepatoblastoma, 2 cases of hepatocellular carcinoma, 1 case of dysplasia of the bile duct, 1 case of biliary
https://doi.org/10.1016/j.jpedsurg.2019.07.019 0022-3468/Published by Elsevier Inc.
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
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tract rhabdomyosarcoma, and 1 case of Wilson's disease. There were 51 patients who received living donor liver transplantation and 62 patients received split liver transplantation. All donor livers were made up of the left external lobe. The urine output per hour was recorded in the Pediatric Intensive Care Unit after transplantation. The diagnosis of postoperative AKI was defined by the KDIGO Clinical Practice Guidelines for Acute Kidney Injury [12]. Preoperative serum creatinine was used as the baseline. The following data were collected from each patient's medical records: age, sex, weight, etiology of liver disease, Child–Pugh classification, PLED scores, CTP scores, preoperative total bilirubin, the serum creatinine level within first 7 days, the anhepatic phase, total length of hospital stays, intraoperative blood loss, and postoperative jaundice clearance. Postoperative jaundice clearance was defined by a serum total bilirubin level of 1.2 mg/dL or lower [13,14]. Tacrolimus was used as the basic postoperative immunosuppressant. However, high levels of tacrolimus can also lead to an increased incidence of postoperative AKI due to its toxicity. Therefore, the initial dose of tacrolimus was 0.1–0.15 mg/kg per day in all patients. Additionally, blood concentrations were closely monitored and the dose of tacrolimus was adjusted immediately to prevent any damage to renal function. This careful monitoring of tacrolimus concentration can minimize its toxicity. Additionally, renal toxicity due to other medications can also increase the risk of AKI. Therefore, medical treatment using pharmaceuticals with low renal toxicity was implemented as long as possible during the perioperative period. For instance, the use of nephrotoxic antibiotics was avoided after transplantation. The percentage of fat emulsion was decreased in postoperative parenteral nutrition. According to the KDIGO Clinical Practice Guidelines for Acute Kidney Injury [12], the incidence of post-transplant AKI was 47.5% (38 patients), which included 10 cases with Stage 1, 22 cases with Stage 2, and 6 cases with Stage 3. SPSS 25.0 statistical software was used for all statistical analysis. Normally distributed measurement data were represented by x ± s, and the skewed measurement data were represented by M. Differences were evaluated using a Student's t test for continuous parametric data, the Wilcoxon test for continuous nonparametric data and the Pearson's chi-squared test for noncontinuous data. The Kaplan–Meier method was conducted to analyze the survival rate of patients and grafts. A multivariate logistic regression model was adopted for the analysis of multiple risk factors. p b 0.05 was considered statistically significant. 2. Results The characteristics of this study population are presented in Table 1. Analyses of the risk factors for postoperative AKI were conducted using
Table 2 Multivariate analysis of risk factors. Risk factors
Coefficients OR
95% CI of OR
p-Value
Patients with biliary atresia Anhepatic phase Intraoperative blood loss Postoperative jaundice clearance
−2.329 −0.138 −0.02 2.634
0.011–0.841 0.791–0.959 0.956–1.004 1.325–146.556
0.03 0.005 0.10 0.02
0.097 0.871 0.980 13.936
a univariable analysis (Table 1) and multivariable analysis (Table 2). The variation in the average level of serum creatinine is shown in Fig. 1. Patient and graft survival rates after transplant are shown in Figs. 2 and 3, respectively. In our univariable model, the significant risk factors of AKI in pediatric liver recipients were patients with biliary atresia, increased time of anhepatic phase, intraoperative blood loss, and postoperative jaundice clearance (the p-value for each parameter is stated in Table 1). In the final multivariable regression model, pediatric liver recipients with biliary atresia (odds ratio [OR] = 0.097, p = 0.03), an increased anhepatic phase (OR = 0.871, p = 0.005), and postoperative jaundice clearance (OR = 13.936, p = 0.02) had an independently associated risk of AKI occurrence. Although the differences were not statistically significant in the patient (p = 0.15) and graft (p = 0.26) survival curves, the overall cumulative 3-year patient (95.2% vs 86.8%) and graft (90.5% vs 84.2%) survival rates in NAKI groups were superior to those in the AKI groups. In our study, 32 patients (84.2%) returned to normal renal function without RRT. There were 5 patients (13.2%) who were oliguric early on in the first 3 days post-transplant who survived acute renal failure using hemodialysis. One patient (2.6%) died from multiple organ dysfunction syndrome. 3. Discussion In this retrospective study, which included 80 pediatric liver recipients in our single center, the incidence of AKI was 47.5%. Additionally, we found that patients with biliary atresia, increased anhepatic phase, and postoperative jaundice clearance had an increased risk of posttransplant AKI. In the process of reviewing the literature, only one research study [8] investigating the risk factors for AKI after pediatric liver transplantation was found. In this previous retrospective study, the incidence of AKI in pediatric liver recipients was 46.2%, which is similar to our results. Hamada et al. [8] also indicated that preoperative total bilirubin concentration and increased intraoperative blood loss were risk factors for AKI after pediatric liver transplantation. In our univariate
Table 1 Baseline characteristics of the study population and univariate comparison of AKI versus NAKI group. Variable
Age (m), mean Female Weight(kg), mean Patients with biliary atresia Living donor liver transplant Child-Pugh Classification
A B C
CTP scores, mean ± SD PELD scores, mean ± SD Preoperative serum creatinine (μmol/L), mean Preoperative estimated glomerular filtration rate (ml/min/1.73 m2), mean Preoperative total bilirubin (mg/dL), mean Anhepatic phase, (minutes), mean ± SD Intraoperative blood loss (ml/kg), mean Total hospital stays (d), mean Postoperative jaundice clearance
ALL
AKI
NAKI
(n = 80)
(n = 38)
(n = 42)
34.2 (5–158) 41 13.3 (5–36) 65 51 6 32 42 9.6 ± 2.2 19 ± 9 27.2 226.8 10.7 75.5 ± 10.5 62.3 41.7 66(82.5%)
31.3 (5–136) 18 31.1 (5–33) 42 23 4 17 17 9.54 ± 2.08 20 ± 8 34.1 236.4 10.8 82.0 ± 9.53 80.02 37.3(3–77) 25(65.9%)
36.8 (5–158) 23 37.1 (5.5–36) 23 28 2 15 25 9.7 ± 2.3 17 ± 10 24 218.3 10.6 69.7 ± 7.44 46.65 45.4(18–86) 37(88.1%)
p Values 0.60 0.58 0.64 0.02 0.17
0.80 0.40 0.17 0.06 0.71 0.01 0.03 0.18 0.01
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
The level of serum creatinine (umol/L)
Y. Zhang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
AKI 80 66.3
70
71.4
NAKI
66.8 55.2
60 50 40
34.1
30
24
31.2
40.5
35.1
32.6
20
22.2
10
28.3
28.1
19.7
0
Time
Fig. 1. The variation of average level of serum creatinine in two groups.
analysis, increased blood loss (p = 0.03) was also related to the development of AKI. They also found that AKI may lead to prolonged hospital stays. However, the anhepatic phase was not included in their study. There was no statistical significance (p = 0.18) between AKI and the total length of hospital stay in our study. Hilmi et al. [6] reported in adult liver recipients that female, weight N100 kg, CTP scores, and pre-existing diabetes were risk factors for post-transplant AKI. Nevertheless, this model may not be suitable for pediatric recipients. Alexander et al. [15] reported that the duration of the anhepatic phase was an independent predictor of graft dysfunction. However, there was little evidence to fully explain the relationship between duration of the anhepatic phase and AKI. Prior studies have found that a prolonged anhepatic phase can cause renal congestion and renal function damage [16,17]. Additionally, it has been shown that during the anhepatic phase of liver transplantation, renal vein congestion significantly impacts hemodynamic parameters, which correlates with serum BK and ANGII levels [18]. Ultimately, decreased renal blood flow and glomerular filtration rates can further lead to renal function injury. Therefore, a shorter anhepatic phase may reduce the intraoperative renal function damage. In previous procedures, we opened the inferior vena cava after the suprahepatic inferior vena cava was
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anastomosed. Now, we simply blocked the blood flow of the hepatic vein and opened the inferior vena cava when the anastomosis of hepatic vein was completed. This greatly reduced blocking time of the inferior vena cava and alleviated renal congestion. After we made this improvement in the interruption method of inferior vena cava, the duration of anhepatic phase reduced from 81.6 ± 26.1 min to 66.8 ± 10.8 min. At the same time, the incidence of AKI decreased from 60% to 34.6% in our center. Biliary atresia has been reported as the most common cause of liver transplantation in pediatric recipients [19]. In addition, patients with biliary atresia are much younger than other patients [20]. The average age of patients with biliary atresia was only 12 months in this study. Prior studies have reported that renal function does not reach maturity until the age of two, and reserve function is poor [21]. Further, patients with biliary atresia are associated with decreased function in renal concentration and renal tubular reabsorption and excretion. Additionally, Salerno et al. [22] showed that patients with hepatorenal syndrome were more common in higher Model for End-Stage Liver Disease. Most patients with biliary atresia have significantly higher PELD scores and are also more likely to develop preoperative hepatorenal syndrome due to diminished renal blood flow. Both of which may cause injury and a subsequent decrease in renal function [23]. Elizabeth et al. [24] reported that 6% of children with hepatorenal syndrome ultimately required RRT. Jaundice clearance was initially used to predict the effect of the Kasai procedure [25–27]. In this study, postoperative jaundice clearance in the AKI group (65.9%) was notably lower than that in the NAKI group (88.1%). In the multivariable analysis, there was also a statistical difference (p = 0.02) between the development of AKI and postoperative jaundice clearance. A high postoperative bilirubin level can lead to various degrees of the hepatorenal syndrome. Renal blood flow and glomerular filtration rate can be decreased due to reduced effective circulation capacity. Further, bilirubin and bile salts in plasma can cause damage to renal function due to the presence of long-term hyperbilirubinemia. To the best of our knowledge, jaundice clearance was not reviewed in previous studies, which was related to AKI after liver transplantation in this study. Blood loss was once considered a risk factor for AKI in postoperative liver recipients. A massive blood loss causes reduced blood volume during the transplant, which directly exerts a substantial
Fig. 2. Patient survival after pediatric liver transplantation (p = 0.15).
Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019
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Y. Zhang et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
Fig. 3. Graft survival after pediatric liver transplantation (p = 0.26).
impact on renal flow. Therefore, prerenal acute kidney injury would occur due to renal vasoconstriction and decreased glomerular filtration rate. In the univariate analysis of the current study, there was statistical significance (p = 0.03) between blood loss in the AKI and NAKI groups. However, no statistical significance was found in the multivariate analysis (p = 0.10). Although the difference did not reach statistical significance in patient or graft survival rates among the two groups in the current study, many studies [3,6,7] in adults have reported that postoperative AKI may decrease the survival rates in either the patient or graft. In a single-center study involving 424 adult liver transplantations, Hilmi et al. [6] found that the development of AKI within 72 h of transplantation impacted short-term and long-term graft survival. In addition, Barri et al. [3] found that postoperative AKI was related to decreased survival rates in patients and grafts among 1050 adult liver transplantations. Therefore, more studies are required to investigate the correlation between AKI and short-term or long-term outcomes in pediatric liver recipients. Previous studies [28,29,30] found patients who were diagnosed with AKI after liver transplantation universally had a higher percentage of RRT. Although RRT has been an effective therapy for severe AKI cases after liver transplantation [24], Papadopoulos et al. [31] found that adult patients who required postoperative RRT after liver transplantation had a higher associated mortality rate. This may be due to a larger number of transfusions. In our center, most patients (84.2%) with AKI returned to normal renal function without RRT. Some studies have shown that preventive blood purification treatment can be considered to rapidly remove excessive waste material and water, relieve symptoms, promote early recovery of kidney function, and improve postoperative survival rates in infants before associated complications can occur [32–34]. There were several limitations in the current study. First, this was a single-center study, which may reduce the generalizability of our results. Additionally, the sample size was small because of the low number of pediatric liver transplantations compared with adult transplantations. Finally, the associated risk factors investigated in our study were limited. Therefore, further studies are still needed. Despite these limitations, previous studies investigating postoperative AKI in pediatric liver transplantations remain scarce, and hence, our study is highly impactful. This study improves the understanding of the risk factors for posttransplant AKI in pediatric liver recipients.
4. Conclusion Pediatric liver transplant recipients with a presence of biliary atresia, increased time of anhepatic phase, and a lower postoperative jaundice clearance had an increased risk of AKI. The long-term outcomes of patients who developed AKI appears to be worse compared with those having NAKI. Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board and Ethical Committee at the West China Hospital of Sichuan University in China with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent for publication Written informed consent was obtained from patient's parents to publish this study. This material is original research. It has not been previously published and has not been submitted for publication elsewhere while under consideration. Competing interests The authors declare that they have no competing interests. Funding This study was supported by Natural Science Foundation of China (NSFC:81571473). Acknowledgements Not applicable. References [1] Kjaergard LL, Liu J, Als-Nielsen B, et al. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure. JAMA 2003;289:217–22.
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Please cite this article as: Y. Zhang, B. Xiang, Y. Wu, et al., Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a ..., Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2019.07.019