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Abstract
Objectives We examine the association between vitamin B12 level and risk for acute kidney injury (AKI) in patients undergoing living donor liver transplantation (LDLT).
Design Retrospective observational cohort study.
Setting University hospital, from January 2009 to December 2018.
Participants A total of 591 patients who underwent elective LDLT were analysed in this study. Those with a preoperative history of kidney dysfunction, vitamin B12 supplementation due to alcoholism, low vitamin B12 (<200 pg/mL) or missing laboratory data were excluded.
Primary and secondary outcome measures The population was classified into AKI and non-AKI groups according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, and associations between perioperative factors and AKI were analysed. After 1:1 propensity score (PS) matching, the association between high vitamin B12 (>900 pg/mL) and postoperative AKI was evaluated.
Results Preoperative vitamin B12 was higher in the AKI group. Potentially significant perioperative factors from univariate analyses were entered into multivariate analyses, including preoperative factors (vitamin B12, diabetes), intraoperative factors (hourly urine output) and donor graft fatty change in LDLT patients. PS matching analyses with adjustment using PS revealed that high serum vitamin B12 (>900 pg/mL) was associated with risk for AKI, and the risk was 2.8-fold higher in patients with high vitamin B12 than in those with normal vitamin B12. Higher vitamin B12 was also related to a higher AKI stage. In addition, inflammatory factors (C reactive protein, white blood cells and albumin) were associated with vitamin B12 level.
Conclusions Our study may improve the accuracy of predicting postoperative AKI by introducing preoperative vitamin B12 into risk assessments for patients undergoing LDLT.
- transplant surgery
- adult anaesthesia
- acute renal failure
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Strengths and limitations of this study
This is the first analysis of the association between high vitamin B12 and morbidity after liver transplantation.
One-to-one propensity score (PS) matching was performed to correct for confounder imbalance between the normal vitamin B12 group and high vitamin B12 group.
Our study could improve the accuracy of predicting postoperative acute kidney injury (AKI) by introducing preoperative vitamin B12 into risk assessments for patients undergoing living donor liver transplantation.
Further research is needed to identify the mechanism behind the relationship between vitamin B12 level and risk for AKI.
We analysed only liver transplants from living donors, and there are important differences between liver transplants from living donors and those from deceased donors.
Additional studies are required to validate the predictive role of vitamin B12 in liver transplantation from deceased donors.
Introduction
Living donor liver transplantation (LDLT) is an important treatment for patients with end-stage liver disease (ESLD), but postoperative complications may lead to mortality and morbidity. Many factors affect the development of acute kidney injury (AKI) after liver transplantation (LT) in patients with ESLD, including older donor age, male sex, model for end-stage liver disease (MELD) score, body mass index (BMI), chronic kidney disease (CKD) and diabetes mellitus (DM).1–4 Preoperative systemic inflammation is related to an increased risk for AKI after surgery. Systemic inflammatory markers such as C reactive protein (CRP) and albumin are associated with postoperative AKI in non-cardiac surgery.5 In addition, proinflammatory markers such as interleukin (IL)-6 are associated with AKI after LDLT.6 Many studies have reported that AKI negatively affects postoperative outcomes, resulting in a prolonged hospital stay, early graft dysfunction, infection and poor patient survival.7 8 Therefore, the risk for AKI should be evaluated before surgery, in particular in patients undergoing LDLT.
There are several definitions of AKI, including Risk, Injury, Failure, Loss and End-stage renal disease (RIFLE) as well as Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria.9 We determined AKI using the KDIGO definition based on a study by Tsai et al showing that the KDIGO definition provides better prognostic ability than the RIFLE or AKIN definitions.10
Vitamin B12 is an essential nutrient that is not created in the body and may be deficient in patients with malnutrition or medical conditions such as Wernicke-Korsakoff syndrome.11 12 Although there have been numerous studies on vitamin deficiency, including vitamin B12 deficiency, few studies have focused on patients with high vitamin B12 and the association between preoperative vitamin B12 and postoperative AKI in LDLT patients. However, the importance of high vitamin B12 in the clinical setting has recently emerged.13 14 High vitamin B12 is related to hepatic disease, haematological disorders such as leukaemia and polycythemia vera15 and renal impairment.11 16 There have also been reports of an association between high vitamin B12 and systemic inflammation, in particular CRP.17 18 In studies of intensive care unit (ICU) patients, elevated vitamin B12 was associated with mortality19 20 and length of hospital stay.14
We investigated the association between high serum vitamin B12 and the development of AKI after LDLT. Here, we propose a prognostic model to identify patients at high risk for AKI and compare postoperative outcomes between non-AKI and AKI groups.
Patients and methods
Patient and public involvement
Patients and/or the public were not involved in the design, conduct, reporting, or dissemination plans of this research.
Study population
Data from 591 adult patients (age >19 years) undergoing elective LDLT between January 2009 and December 2018 at Seoul St. Mary’s Hospital were retrospectively collected with the electronic medical record system. Exclusion criteria included a preoperative history of kidney dysfunction (eg, dialysis, chronic kidney disease (<60 mL/min/1.73 m2), hepatorenal syndrome), a history of vitamin B12 supplementation due to alcoholics, low vitamin B12 (<200 pg/mL) and missing laboratory data. Based on the exclusion criteria, 112 patients were excluded. In total, 479 adult patients were analysed, and 198 patients were matched after 1:1 propensity score (PS) matching.
Living donor liver transplantation
Surgery and anaesthesia were consistently provided by expert transplant surgeons and anesthesiologists, respectively. The surgical procedure and anaesthetic management were described in detail in our previous studies.21 Briefly, the piggyback surgical technique was performed using the right liver lobe with reconstruction of the middle hepatic vein. Vascular anastomoses of hepatic, portal vein and hepatic artery and bile duct anastomoses were performed, and hepatic vascular flow (such as portal venous flow and hepatic arterial resistive index) was checked with Doppler ultrasonography (Prosound SSD-5000; Hitachi Aloka Medical, Tokyo, Japan). Splenectomy, splenic artery ligation or portacaval shunting were performed as required.
Balanced anaesthesia was supplied with proper haemodynamic management (mean arterial pressure (MBP) ≥65 mm Hg and central venous pressure (CVP) ≤10 mm Hg) under multiple haemodynamic monitoring. Based on transfusion guidelines,22 packed red blood cells (PRBC) were transfused to reach a hematocrit ≥25%, and coagulation factors (fresh frozen plasma (FFP), single donor platelet and cryoprecipitate) were also transfused based on laboratory findings or thromboelastography.
Severe postreperfusion syndrome (PRS) was defined as follows: unstable vital signs (MBP ≥30% or hypotensive duration ≥5 min), fatal arrhythmia (asystole or ventricular tachycardia), use of rescue vasopressors (epinephrine or norepinephrine), continuing or reoccurring fibrinolysis or a requirement for antifibrinolytic drug treatment.23
An immunosuppression regimen (calcineurin inhibitor, mycophenolate mofetil and prednisolone) was administered according to our hospital’s LDLT protocol. The trough level of tacrolimus was preserved between 7 and 10 ng/mL for the first month after surgery and tapered to 5–7 ng/mL thereafter. We compared the serum calcineurin inhibitor level (table 1) between patients with and those without AKI, and there was no significant difference.
Comparison of preoperative and intraoperative recipient and donor factors between the non-AKI and AKI groups
Methylprednisolone was administered immediately before graft reperfusion and then gradually tapered. MMF was withdrawn at 3–6 months after surgery. Basiliximab was given prior to surgery and on postoperative day (POD) 4. Immunosuppressants were gradually adjusted and tapered after LDLT.
Patients with a malnutrition condition were under an oral supplement diet provided by experienced nutritionists.
Criteria for acute kidney injury
AKI was determined clinically by KDIGO classification as follows: stage 1, increase in serum creatinine (SCr) ≥0.3 mg/dL (in 48 hours) or 1.5–1.9 times baseline (in 7 days) or urine output <0.5 mL/kg/hour for 6–12 hours; stage 2, 2.0–2.9 times by baseline SCr or urine output <0.5 mL/kg/hour for ≥12 hours; stage 3, 3.0 or more times baseline SCr, increase in SCr ≥4.0 mg/dL, beginning of renal replacement therapy regardless of previous KDIGO stage or urine output <0.3 mL/kg/hour for ≥24 hours. Based on these definitions, AKI was classified as stage 1, stage 2 or stage 3. For the comparison of vitamin B12 by stage, we collapsed stages 2 and 3 into one group (stage 2–3). We divided the study population into non-AKI and AKI groups to evaluate the risk for AKI (see online supplemental additional file 1).
Supplemental material
Measurement of serum vitamin B12
As a part of preoperative patient assessment, laboratory variables, including vitamin B12, were measured for all patients scheduled for LDLT. All laboratory variables were measured with venous or arterial blood samples (Clot Activator Tube; BD Vacutainer, Becton, Dickinson, Franklin, New Jersey, USA) collected the day before surgery and processed on an automated chemistry analyser (Hitachi 7600; Hitachi, Tokyo, Japan). If multiple tests were performed on a single day, the results of the test closest to the time of surgery were used in the study.
Perioperative recipient and donor graft factors
Preoperative recipient factors included age, sex, BMI, aetiology for LDLT, comorbidity (eg, diabetes mellitus or hypertension), MELD score, hepatic decompensation (eg, encephalopathy (West-Haven grade I or II),24 varix and ascites), transthoracic echocardiography (ejection fraction and diastolic dysfunction)25 and laboratory variables (white blood cell (WBC) count, albumin, platelet count, sodium, potassium, calcium, glucose, creatinine ammonia). Intraoperative recipient factors included surgical duration, PRS,26 average vital signs (MBP, heart rate (HR) and CVP), mean lactate, amount of blood product transfused (PRBC, FFP, platelet concentrate), hourly fluid infusion and urine output. Donor graft factors included age, sex, graft recipient weight ratio, graft ischaemic time and donor graft fatty change.
Postoperative outcomes included total length of hospital and ICU stay, infection (eg, pneumonia or sepsis), early allograft dysfunction (EAD) and overall patient mortality.
Clinical postoperative outcomes
Clinical postoperative outcomes included duration of ICU stay and hospital stay, incidence of infection, EAD and overall mortality. EAD was defined as the presence of one or more of the following: total bilirubin ≥10 mg/dL or international normalised ratio ≥1.6 on postoperative day 7 and aspartate transaminase or alanine transaminase ≥2000 IU/mL during the first week.27
Statistical analyses
We compared perioperative recipient and donor graft factors between the non-AKI and AKI groups using the Mann-Whitney U test and the χ2 test or Fisher’s exact test, as appropriate. The association between the perioperative factors and AKI was analysed with univariate and multivariate logistic regression. Potentially significant factors (p<0.1) in the univariate analyses were entered into forward and backward multivariate logistic analyses. When multiple perioperative variables were intercorrelated, the most clinically relevant factors were retained in the analyses. The predictive accuracy of the models was evaluated with the area under the receiver operating characteristic curve (AUROC). In addition, 1:1 PS matching was used to correct the imbalance in confounders between the normal vitamin B12 group and high vitamin B12 group. After matching, we compared perioperative recipient and donor graft factors using the Mann-Whitney U test and the χ2 test or Fisher’s exact test, as appropriate. The association between high vitamin B12 (>900 pg/mL) and postoperative AKI was evaluated with multivariate logistic regression analyses with PS adjustment, and ORs with 95% CIs were calculated. Continuous data are presented as medians and IQRs, and categorical data are presented as frequencies and proportions. Correlations between inflammatory factors and vitamin B12 level were evaluated with Spearman’s method.
In all analyses, p<0.05 was taken to indicate statistical significance. Statistical analyses were performed with SPSS for Windows (V.24; IBM, Chicago, Illinois, USA), R V.2.10.1 (R Foundation for Statistical Computing, Vienna, Austria) and MedCalc for Windows (V.11.0; MedCalc, Ostend, Belgium).
Results
Baseline characteristics of the study population
The population of the study was largely male (69.1%), and the median (IQR) age and BMI were 53 (48–59) years and 24.3 (22.2–26.8) kg/m2. The aetiology for LDLT was as follows: hepatitis B (58%), alcoholic hepatitis (20%), hepatitis C (7.7%), autoimmune hepatitis (2.3%), hepatitis A (1.9%), drug and toxic hepatitis (1.5%) and cryptogenic hepatitis (8.6%). The median (IQR) MELD score and ejection fraction were 149–24 and 64.5 (62–67). The prevalence of hypertension, diabetes, encephalopathy, varix and ascites was 19.6% (n=94), 26.1% (n=125), 6.7% (n=32), 25.9% (n=124) and 48.9% (n=234), respectively.
Comparison of preoperative and intraoperative factors between the non-AKI and AKI groups
Preoperative BMI, DM, MELD, ascites and vitamin B12 were higher in the AKI group than in the non-AKI group. Preoperative albumin and platelet count were higher in the non-AKI group than in the AKI group (table 1). Intraoperative mean HR, amount of blood product transfused and graft ischaemic time were higher in the AKI group than in the non-AKI group. Intraoperative mean blood pressure and hourly urine output were higher in the non-AKI group than in the AKI group. The prevalence of patients with exposure to nephrotoxic drugs such as non-steroidal anti-inflammatory drugs, aminoglycosides, ACE inhibitors, angiotensin II receptor blockers and diuretics was similar in the AKI and non-AKI groups (p=0.367).
Associations between preoperative and intraoperative factors and postoperative development of AKI
According to results of the univariate logistic regression (table 2), preoperative factors (BMI, DM, MELD, ascites, haemoglobin, WBC count, platelet count, vitamin B12) and intraoperative factors (mean HR, PRC, FFP, hourly urine output, graft ischaemic time, donor graft fatty change) were potentially significant.
Associations between preoperative and intraoperative recipient and donor factors and postoperative development of AKI
Multivariate logistic regression (table 2) revealed that vitamin B12 (continuous data) was significantly associated with AKI as well as the incidence of diabetes mellitus, hourly urine output and donor graft fatty change (area under the curve (AUC): 0.718, 95% CI: 0.669 to 0.767, sensitivity: 68.7%, specificity: 66.5%, p<0.001 in the predictive model). The probability of patients with high vitamin B12 (>900 pg/dL) developing AKI was about threefold higher than that of patients with normal vitamin B12 (200–900 pg/dL; OR: 2.955, 95% CI: 1.669 to 5.232, p<0.001; online supplemental additional file 2). Multivariate logistic regression analysis without vitamin B12 (see online supplemental additional file 3) showed an area under the ROC curve of 0.695 (figure 1).
Supplemental material
Supplemental material
Comparison of area under the curve (AUC)-receiver operating characteristic (ROC) of multiple logistic regressions models with or without inclusion of vitamin B12.
Comparison of preoperative and intraoperative recipient and donor graft factors before and after PS matching
There were significant differences between the groups in preoperative factors (ascites, haemoglobin, WBC count, platelet count, sodium), intraoperative factors (PRC, FFP, hourly urine output) and donor graft parameters (sex; table 3). After PS matching, there were no significant differences between the groups.
Comparison of preoperative and intraoperative recipient and donor graft factors before and after PS matching
Proportions of PS-matched patients with normal kidney function, mild AKI and moderate-to-severe AKI according to vitamin B12 level
The overall incidence of AKI was higher in patients with high vitamin B12 levels than in those with normal vitamin B12 levels. The severity of kidney injury, according to the KDIGO stage, was more aggravated in the high vitamin B12 group than in the normal vitamin B12 group (table 4 and online supplemental additional file 4).
Supplemental material
Comparison of proportions in PS-matched patients by normal kidney function, mild AKI and moderate-to-severe AKI according to vitamin B12 level
Comparison of vitamin B12 level by AKI stage in PS-matched patients
Patients with a higher AKI stage exhibited higher median and IQR values of vitamin B12 (figure 2). Median (IQR) vitamin B12 levels were 841.3 (671.3–1282.1), 1373.5 (741.5–1954.3) and 1566.8 (724.9–3525.8) for stages 0, 1 and 2–3, respectively.
Comparison of serum vitamin B12 by acute kidney injury (AKI) stage in patients undergoing living donor liver transplantation (LDLT). The box plots show the median (line in the middle of the box), IQR (box) and 5th and 95th percentiles (whiskers). *P<0.05 compared with normal kidney function.
Correlation between high vitamin B12 and postoperative AKI in PS-matched patients
High vitamin B12 was associated with the development of AKI in the entire study population and in PS-matched patients (table 5). After PS adjustment, high vitamin B12 remained an independent factor related to AKI (p=0.008).
Associations between high vitamin B12 and postoperative AKI in the entire study population and in PS-matched patients
Analysis using alternative cut-offs for high vitamin B12
Patients were divided into low and high vitamin B12 level groups using 1300 pg/mL as an alternative cut-off value for AKI development (AUC: 0.659, 95% CI: 0.519 to 0.623, sensitivity: 71.3%, specificity: 51.14%, p<0.001). After PS matching with adjustment for the PS (table 6), a high serum vitamin B12 level (>1300 pg/mL) was also associated with a risk for AKI, and the risk was 3.2-fold higher in patients with high vitamin B12 levels than in those with normal vitamin B12 levels.
Association of high vitamin B12 levels with postoperative AKI development, using 1300 pg/mL as the cut-off value, in the entire and PS-matched patients
Correlations between vitamin B12 level and inflammatory markers in PS-matched patients
Vitamin B12 level was significantly associated with inflammatory markers, including CRP, WBC and albumin, in PS-matched patients (p<0.001, p=0.005 and p=0.002, respectively).
Comparison of postoperative outcomes
Among all patients, postoperative AKI was associated with mortality, EAD and infection (p=0.005, p=0.001 and p=0.029, respectively). In addition, AKI was associated with length of ICU stay and hospital stay (p=0.001 and p=0.002, respectively).
Among PS-matched patients, there were no significant differences in complications, including ICU stay, hospital stay, infection, graft rejection, EAD or mortality (table 7).
Comparison of postoperative outcomes between the normal vitamin B12 group and high vitamin B12 group in PS-matched patients
Discussion
The main findings of our study are that preoperative factors (diabetes, vitamin B12), intraoperative factors (hourly urine output) and donor factors (donor graft fatty change percentage) are associated with postoperative AKI in LDLT patients. Among PS-matched patients, high serum vitamin B12 (>900 pg/mL) with adjustment using PS was associated with risk for AKI, and the risk was 2.8-fold higher in patients with high vitamin B12 than in those with normal vitamin B12. The level of vitamin B12 and the proportion of patients with high vitamin B12 increased significantly according to the severity of AKI.
AKI is a common postoperative complication, and the incidence of AKI after LT ranges from 17% to 90%.12 28 Its pathogenesis may include inflammation, hypotension and perioperative nephrotoxin usage.29–31 Aggravation of the systemic inflammatory response is an important contributor to the development of AKI.32 CRP may also act as a pathogenic mediator in the development of AKI.33 Tang et al indicated that CRP promotes AKI by impairing G1/S-dependent tubular epithelial cell regeneration.33 Sergio et al found that tubular epithelial cells interact with circulating inflammatory mediators, such as tumour necrosis factor alpha and IL-6, which are related to AKI.34 Han et al showed that leukocytosis, a clinical sign of inflammation, is associated with the risk for AKI in critically ill patients.35 Postoperative AKI is an important risk factor associated with morbidity and mortality after LDLT.36–38 Therefore, it is important to predict the development of postoperative AKI in patients undergoing major surgery, in particular LDLT. In our study, the AKI group had a higher incidence of EAD and infection, longer ICU and hospital stays, and worse overall patient survival than the non-AKI group.
Vitamin B12 is a water-soluble vitamin that plays an important role in maintaining cell function, blood cell formation and homocysteine metabolism.11 Serum vitamin B12 is usually maintained within the range of 200–900 pg/mL.16 39 40 Although vitamin B12 deficiency is a well-known pathological condition that can cause haematological and neurological disorders or coronary artery disease,41 high vitamin B12 (>900 pg/mL) is also associated with systemic inflammatory response syndrome and impaired hepatic and/or renal function.15 41 In critically ill or elderly patients, high vitamin B12 is significantly related to increased morbidity and mortality.19 20 41–43 Because it is stored mainly in the liver, vitamin B12 increases with the severity of hepatic injury.15 44 In patients with cirrhosis, high vitamin B12 is associated with mortality. In patients with acute-on-chronic liver failure, high vitamin B12 is correlated with the severity of hepatic disease and with mortality.45 Serum vitamin B12 increases with Child-Pugh score in patients with viral hepatitis and is an independent predictor of patient survival.46
High vitamin B12 is related to impaired kidney function due to impaired clearance of transcobalamin, the transporter of vitamin B12.11 13 15 16 In addition, because vitamin B12 uptake by mononuclear cells decreases in patients with end-stage renal disease, high vitamin B12 is found in such patients.11 47 Although the role of vitamin B12 in AKI is unclear, elevated vitamin B12 is significantly associated with the severity of inflammation and may serve as a blood marker for AKI. This result is supported by previous studies showing an association between elevated vitamin B12 levels and systemic inflammation. A study by Corcoran et al indicated that elevated vitamin B12 is correlated with higher levels of CRP in ICU patients.17 Similarly, Philippe et al found that elevated vitamin B12 is related to CRP in patients with cancer.18 Vitamin B12 toxicity may also be related to renal injury. In a multicentre study by House et al, high doses of B vitamins containing vitamin B12 (1 mg/day) decreased GFR in patients with diabetic nephropathy.48 In that study, serum B vitamins were very high in the B vitamin group. The authors suggested that the accumulation of folate and vitamin B12 due to reduced renal function can result in vitamin toxicity. One study examined the use of folic acid and B vitamins to decrease homocysteine levels in vascular disease (HOPE-2) and found that high-dose B vitamin supplements did not affect renal dysfunction.49 However, mean serum vitamin B12 was within the normal range in the supplement group. In our study, mean serum vitamin B12 in the AKI group was >2000 pg/mL, which suggests an association between vitamin B12 toxicity and the development of renal injury.
In the current study, diabetes was a preoperative risk factor for the development of postoperative AKI. Although the mechanism behind the development of AKI in diabetic kidney remains unknown, some reports indicate that diabetic kidneys lack proper recovery of renal perfusion after ischaemia. In those studies, higher apoptosis of proximal tubular cells and delayed reperfusion in cortex were suggested as possible causes of renal ischaemia reperfusion injury in diabetic kidneys.50 51
Decreased hourly urine output during surgery was independently associated with postoperative AKI in the current study. Decreased urine output usually indicates hypotension or hypovolemia, which are related to decreased perfusion to the afferent arteriole of the glomerulus.52 Mizota et al reported that intraoperative oliguria was significantly associated with increased risk for postoperative AKI in patients undergoing major abdominal surgery.53
Graft steatosis is a risk factor for postoperative morbidity and mortality. Marsman et al reported that the use of liver grafts containing up to 30% fat is associated with lower patient and graft survival.54 Steatosis of liver graft is also associated with EAD and AKI.8 Multivariate analyses in the present study showed that donor graft fat content was associated with the development of AKI after liver transplantation. In addition, more EAD occurred in the AKI group than in the non-AKI group.
Our study has several limitations. First, although confounder imbalance was corrected between the normal vitamin B12 group and high vitamin B12 group after PS matching, hidden biases due to the retrospective study design may have been present. Second, the mechanism underlying the association between high serum vitamin B12 and postoperative AKI is still unknown. Although vitamin B12 is associated with systemic inflammation, further studies are required to identify the specific pathways of the effects of vitamin B12 on renal injury. Further research on vitamin B12 toxicity in the kidney is also needed. Third, there are important differences between liver transplants from living donors and those from deceased donors. In previous studies, liver grafts from deceased donors were more than twice as strongly associated with postoperative AKI than grafts from living donors.55 Therefore, the association between vitamin B12 and AKI may differ according to the graft donor. Additional studies are required to validate the predictive role of vitamin B12 in LT from living donors and from deceased donors.
Conclusion
AKI, a common postoperative complication in patients undergoing liver transplantation, is associated with patient morbidity and mortality. Thus, the risk for AKI should be evaluated before liver transplantation. Our results may increase the accuracy of risk stratification of postoperative AKI by introducing vitamin B12 as a risk factor for patients undergoing LDLT. Predictive models of AKI that include preoperative vitamin B12 and other perioperative factors (eg, diabetes, intraoperative hourly urine output, graft steatosis) will help predict AKI and enable early management of patients.
Acknowledgments
The authors would like to thank Eunju Choi, Hyeji An and Hyunsook Yoo (Anesthesia Nursing Unit, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea) for their support and dedication.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors JP and MSC were responsible for the study concept and design. JP wrote the manuscript. JP, JHC, HJC, SHH, CSP, JHC and MSC participated in the collection and interpretation of the data. All authors approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The institutional review board of Seoul St. Mary’s Hospital Ethics Committee approved this study for LDLT recipients (KC19RESI0214), and it was performed according to the principles of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective design.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.