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Predictors of patient survival following living donor liver transplantation
Original Article / Transplantation
Predictors of patient survival following living donor liver transplantation Chuan Li, Tian-Fu Wen, Lu-Nan Yan, Bo Li, Jia-Ying Yang, Wen-Tao Wang, Ming-Qing Xu and Yong-Gang Wei Chengdu, China
BACKGROUND: Living donor liver transplantation (LDLT) is considered to be the alterative choice in light of the great shortage of cadaveric donors. However, the characteristics of the patients who will benefit from LDLT have not been well identified. The aim of this study was to define the pre- and intra-operative factors that may influence patient outcome.
KEY WORDS: living donor; liver transplantation; predictor; survival rate
METHODS: The data from 102 LDLT patients who had operations between 2002 and 2009 were collected and analyzed retrospectively. Data were analyzed using uni- and multi-variate analysis according to factors that are known to be associated with outcome in these patients.
Introduction
RESULTS: Overall, the accurate survival rate of recipients at 1, 3, and 5 years was 84%, 76%, and 70%, respectively. The independent risk factors, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male match (donor to recipient matching), were identified by Cox regression analysis. The pre-transplant model for end-stage liver disease score and a graft to recipient weight ratio of less than 0.8% were not predictive of outcome. The overall 1-, 3-, and 5-year survival of patients with one or no risk factors and two or more risk factors were 91%, 86%, and 83% and 67%, 56%, and 47%, respectively (P<0.0001). CONCLUSIONS: In our retrospective study, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male gender match were independent risk factors for LDLT recipient outcome. Two or more of these risk factors may contribute to poor outcome. (Hepatobiliary Pancreat Dis Int 2011; 10: 248-253)
Author Affiliations: Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, China (Li C, Wen TF, Yan LN, Li B, Yang JY, Wang WT, Xu MQ and Wei YG) Corresponding Author: Tian-Fu Wen, MD, Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, China (Tel: 8628-85422871, Fax: 86-28-85423269; Email: [email protected]) © 2011, Hepatobiliary Pancreat Dis Int. All rights reserved.
L
iver transplantation is widely accepted as the only curative therapy for patients with end-stage liver disease. It may cure cirrhosis, malignancies and severe liver dysfunction.[1] Excellent long-term survival rates for patients with both benign liver diseases and malignancies have been reported.[2, 3] However, these encouraging outcomes are greatly limited by the shortage of grafts, especially in Asian countries.[4] Since 1989, when Strong et al[5] performed the first successful liver transplantation from a living donor to her son who was diagnosed with biliary atresia, living donor liver transplantation (LDLT) has emerged as one of the effective alternatives to deceased donor liver transplantation (DDLT). However, right hepatectomy may impose a high surgical risk on the donor.[4] Determining which recipients will benefit from LDLT is a realistic problem that is of concern not only to transplant surgeons but also to the donor and recipient families. Studies in the literature have reported some risk factors that affect recipient and graft survival after liver transplantation.[6, 7] However, those risk factors are based on DDLT. Whether they pertain to LDLT has not been well established. The purpose of this study was to determine which pre- and intra-operative factors influence the outcome of LDLT.
Methods Patients and clinical characteristics All adult patients (ı18 years; n=102) with benign liver diseases who had undergone their first LDLT between 2002 and 2009 at our center were considered for this study. Transplantations were approved by the Ethics
• Hepatobiliary Pancreat Dis Int，Vol 10，No 3 • June 15，2011 • www.hbpdint.com
Predictors of LDLT
Committee of West China Hospital, Sichuan University. We examined the characteristics of the donors, recipients, grafts and intraoperative factors, including age, gender, body mass index (BMI), gender disparity, ABO blood-type disparity, model for end-stage liver diseases (MELD) score, Child-Pugh score, preoperative renal dysfunction, graft-to-recipient weight ratio (GRWR), cold ischemia time (CIT), surgical duration, transfusion of red blood cells (RBCs) and platelets.[8] MELD scores were calculated according to the formula: MELD score=9.57× Ln creatinine (mg/dL)+11.2×(Ln INR)+3.78×Ln bilirubin (mg/dL)+6.43.[9] The decision for transfusions was based on clinical and hemodynamic criteria. RBCs were used to maintain hemoglobin levels above 7.0 g/dL.[7, 10] Platelet concentrates were administered if platelet counts decreased to 50×109/L.[7, 10] Preoperative renal dysfunction was defined as the level of serum creatinine greater than 1.5 mg/dL.[11] The cut-off point of BMI was 23, as suggested by the World Health Organisation.[12] The clinical characteristics of recipients and donors are shown in Table 1. The primary etiologies that Table 1. Clinical characteristics of recipients and donors Characteristics Etiology Hepatitis B Fulminant hepatic failure Hepatolithiasis Budd-Chiari syndrome Primary biliary cirrhosis Hepatic hydatid disease Alcohol cirrhosis Hepatitis C Autoimmune hepatitis Hepatic cyst Recipient Age (yr) Gender (male) BMI Donor Age (yr) Gender (male) BMI Child-Pugh grade A B C GRWR MELD score >25 RBCs transfusion >5 units Platelet transfusion Pretransplant renal dysfunction Pretransplant diabetes mellitus
n 66 17 4 4 3 2 2 2 1 1 41 (18-69) 86 22.38±2.93 37 (19-65) 59 22.85±2.05 32 50 20 0.91% (0.63%-1.27%) 32 54 9 14 5
necessitated transplantations included: hepatitis B (66 patients), fulminant hepatic failure (17), hepatolithiasis (4), Budd-Chiari syndrome (4), primary biliary cirrhosis (3), hepatic hydatid disease (2), alcoholic cirrhosis (2), hepatitis C (2), autoimmune hepatitis (1), and hepatic cyst (1). Five patients were diagnosed with diabetes mellitus before LDLT. Insulin injections were used to control blood sugar levels in one patient, whereas the other four were given oral diabetes medications. The median age of the recipients was 41 years (range 18-69 years) and the median age of the donors was 37 years (range 19-65 years). A higher proportion of both recipients and donors were male (84.31% and 57.84%, respectively). The mean of recipient and donor BMI was 22.38±2.93 and 22.85±2.05, respectively. In addition, 39.22% (n=40) of the donors had BMIs >23, and 49.02% (n=50) of the recipients had BMIs >23. Although the transplantations were carefully performed, 54 patients required transfusions of >5 units of allogenic RBCs. Due to preoperative hypersplenism and intra-operative bleeding, 9 recipients required platelet transfusions. Overall, 32 patients had high MELD scores (>25), and 32 had Child-Pugh A, 50 Child-Pugh B, and 20 ChildPugh C. Furthermore, 14 patients had preoperative renal dysfunction due to hepatorenal syndrome, and 3 underwent pre-transplant dialysis due to severe renal dysfunction. The GRWR ranged from 0.63% to 1.27% with a mean of 0.91%; 23 recipients received small grafts (GRWR <0.8%).
Donor selection and surgical procedure Donors were required to be healthy adult relatives with compatible ABO blood type and negative serum tests for HBV, HCV and human immunodeficiency virus. The donors were evaluated using computed tomography and volumetry to ensure that a right lobe without a middle hepatic vein that measured >40% of the estimated standard liver weight of the recipient and ƫ30% of the total liver volume of the donor could possibly be removed. If not, dual LDLT was suggested. The operation was performed through a right subcostal incision extended to the upper midline under general anesthesia. Abdominal exploration, liver biopsy and intraoperative cholangiograms were initially performed to assess the ratio of steatosis and the biliary anatomy of the donor. Thereafter, the first hepatic hilum was dissected, the right lobe of the liver was mobilized and the vena cava was dissected. Any short hepatic veins larger than 0.5 cm were preserved until harvesting for potential anastomosis in the recipient. The CUSA Excel device was used to divide the liver parenchyma without inflow occlusion. The falciform ligament was
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reconstructed, the stumps of the right hepatic and portal veins were closed by continuous non-absorbable sutures, and a drain was inserted into the right subphrenic cavity before closure.[13]
60 years were significantly associated with recipient survival (Table 2). Pre-transplant MELD scores were not correlated with post-transplant survival. There were also no significant differences in survival among the patients with Child-Pugh A, B or C. GRWR less than 0.8% did not have any predictive power. Post-transplant management and follow-up Multivariate analysis, using Cox regression, showed The post-transplant immunosuppression consisted of that preoperative renal dysfunction, RBC transfusions calcineurin inhibitors (CNI; tacrolimus or cyclosporine), greater than 5 units, and female to male gender match mycophenolate mofetil and steroids. Steroid pulse therapy was administered to patients with rejection. were independent risk factors for death (Table 3). The postoperative anti-HBV protocols consisted of Significant differences were found among recipients lamivudine combined with therapy with a low-dose of with zero, one only, two and three risk factors using intramuscular hepatitis B immune globulin. Hepatitis B immune globulin was administered to all recipients with HBV infection during and after the transplantation. [13-15] Table 2. Univariate analysis of factors associated with patients survival The recipients were followed up regularly until death or Characteristics Survived Died P value the termination of this study (May 2010). Recipient variables
Statistical analysis Categorical variables were compared with the chisquare test or Fisher's exact test, whereas the analysis of variance was performed for continuous variables. Cox regression was used to assess the variables that were significantly associated with negative outcomes of LDLT in univariate analysis. Post-transplant survival was estimated using the Kaplan-Meier method with the log-rank test. The diagnostic accuracy of the predictors was assessed using receiver operating curve (ROC) analysis. For all analyses, we used SPSS version 13.0, and considered a P value of <0.05 to be statistically significant.
Results
Age >60 yr 4 Female 15 BMI >23 35 MELD score 25 Child-Pugh grade A 26 B 40 C 17 Donor variables Age >50 yr 12 Female 31 BMI >23 43 Recipient-donor match Sex disparity 36 Female-male 27 ABO disparity 18 Diagnosis Renal dysfunction 8 Diabetes mellitus 5 Etiology 83 Graft variable GRWR <0.8% 19 Surgical parameters CIT (min) 107.27±40.90 RBCs transfusion 39 Platelet transfusion 8 Surgical duration 589.23±113.48
4 1 5 7
0.038 0.293 0.202 0.569 0.889
6 10 3 1 12 7
0.453 0.040 0.239
12 12 5
0.119 0.013 0.762
6 0.012 Survival analysis 0 0.581 The median post-transplant follow-up was 27.32 months 19 0.367 (range 0.03-101.7 months). During the study period, a total of 19 patients died. The causes of death were 4 0.863 infection (n=8), multiple organ failure (6), renal failure (2), rejection (1), graft failure (1), or cerebrovascular 107.00±31.08 0.979 accident (1). Among patients with pre-transplant renal 15 0.012 dysfunction, 6 recipients died of various causes, 7 1 0.544 recovered, and 1 survived with slight renal dysfunction 614.57±65.43 0.351 (without the need for dialysis). Overall, the 1-, 3-, and 5-year survival rates for the recipients were 84%, 76%, and 70%, respectively. Table 3. Independent risk factors in the Cox regression for overall
survival
Risk factors for survival After the clinical features were analyzed by univariate analysis, we found that preoperative renal dysfunction, RBCs transfusions greater than 5 units, female to male gender match, and recipients older than
Characteristics
β
SE
Wald P
Exp(β)
Renal dysfunction 1.123 0.500 5.038 0.025 3.074 RBCs >5 units 1.161 0.568 4.171 0.041 3.192 Female-male 1.003 0.478 4.394 0.036 2.726
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95% CI Lower Upper 1.153 8.194 1.048 9.725 1.067 6.963
Predictors of LDLT
Fig. A: Cumulative survival curves for patients with zero, one, two or three risk factors that were confirmed by multivariate analysis (P<0.0001); B: Cumulative survival curves of patients with 0-1 risk factor and 2-3 risk factors that were confirmed by multivariate analysis (P<0.0001); C: ROC curve for the predictive risk factors that were confirmed by multivariate analysis.
sepsis,[21] length of stay in the intensive care unit,[22] the need for preoperative and postoperative dialysis,[21] financial burden,[23] hospital death, and postoperative survival[21, 24-27] have been well defined by many investigators. In our study, 14 patients were diagnosed with pre-transplant renal dysfunction. Unfortunately, six died from various causes. Among the six patients, five died during the perioperative period. This result is consistent with that reported previously. Furthermore, it was suggested that preoperative renal dysfunction also predicts a worse outcome in the long-term postoperative period.[24] Our study confirmed that RBC transfusions of greater than 5 units have a negative impact on the outcome of LDLT. Many risks are involved in allogeneic Discussion blood transfusions, such as transfusion-related acute lung injury, bacterial sepsis and immunosuppressive A number of studies have confirmed that MELD scores [10] A study[28] confirmed that massive blood effects. and Child-Pugh category may be good indicators for prediction of the outcome of liver transplantation.[4, 6, 16, 17] product transfusions are not only associated with longer However, our data showed that recipient mortality was hospital stays but also are associated with reduced closely associated with preoperative renal dysfunction, survival. However, in our study many patients received RBC transfusion and female to male gender match. RBCs transfusions of greater than 5 units. We speculate These results were not surprising; in our previous that this may be due to massive hemorrhage of the study,[18] we confirmed that high pre-transplant MELD upper gastrointestinal tract in many of the patients scores do not negatively impact short-term survival before transplantation. Moreover, many patients in our after liver transplantation. Although patients with high study had chronic anemia associated with digestive tract pre-transplant MELD scores are in extremely poor hemorrhage, hypersplenism and malnutrition. A number of clinical and animal studies focusing on condition, they also experience a similar incidence of post-transplant complications, and the biochemical gender disparity, especially female to male gender match parameters recover quickly after LDLT.[18] Jacob et al[19, 20] in solid organ transplantation showed that this may be suggested that the outcomes after liver transplantation associated with a negative outcome in the kidney, heart, may depend on unpredictable events that occur during lung, and liver transplantation. This was also revealed [29-33] Studies have confirmed that estrogens the perioperative period rather than on the severity of in our study. may impair the secretion of bile, resulting in disorders the underlying liver disease. Pre-transplant renal dysfunction was an independent of biliary secretion.[34] Moreover, Wittnich et al[35] found risk factor in our study. The correlations between increased acidosis in female livers during ischemia recipient serum creatinine and early post-transplant due to a rapid and greater degree of tissue lactate the Kaplan-Meier method with the log-rank test (Fig. A, P<0.0001). When the number of risk factors was analyzed and confirmed by multivariate analysis with an ROC, the best cut-off value for the number of risk factors was determined to be 2 (Fig. C). The corresponding area under the ROC was 0.704. We also compared the survival curve between patients with fewer than two risk factors and those with two or three of the risk factors. The overall 1-, 3-, and 5-year survival rates of patients with one or less and two or more risk factors were 91%, 86%, and 83% and 67%, 56%, and 47%, respectively. There were significant differences in these rates (Fig. B, P<0.0001).
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and H+ accumulation. Except for metabolic factors, graft size was suggested as a potential explanation for this phenomenon by Gu et al.[36] They hypothesized that the complex inflammatory responses caused by perfusion contribute to the less favourable outcomes in male rat recipients with small-for-size female liver grafts.[36] However, our study confirmed that GRWR <0.8% did not show any prognostic power. Contrary to these studies, Lehner et al[37] suggested that genderincompatible liver transplantation may not achieve a poor outcome. Our data have shown that male recipients of female livers have a worse survival rate that is independent of recipient age and other clinical characteristics. However, currently, the mechanism underlying this is still unclear. Our study suggested that patients with one or none of the identified risk factors achieved a much better survival than those with two or three risk factors. Pretransplant renal dysfunction is sometimes difficult to treat successfully unless the liver function has recovered. Therefore, intra-operative transfusions and gender matching may be the key to improving the outcome of recipients. Although blood transfusions often cannot be avoided during surgery, studies have struggled to minimize the intra-operative blood requirements.[10, 28] Advances in surgical and anesthetic management of patients undergoing LDLT will decrease both intraoperative blood loss and the requirement for blood products.[10] Increased understanding of the risk factors of massive blood loss is another effective method. Ramos et al[28] suggested that preoperative hemoglobin level is an independent risk factor in the prediction of the need for RBCs transfusions. Moreover, Ramos et al[28] also emphasized that the normalisation of preoperative hemoglobin level reduces the intraoperative transfusion requirement. Nonetheless, strategies to reduce intraoperative blood use should be developed. In addition, female to male gender matching should be avoided when there is more than one qualified donor. There are several limitations to our study. It was a retrospective, single-center study, with a limited number of patients, especially those of advanced age. Moreover, the censored rate of this investigation was slightly high because the follow-up duration was too short for the number of individuals. We believe a larger series and a multicentre study design would minimize these limitations. In conclusion, our preliminary study showed that preoperative renal dysfunction, intraoperative RBC transfusions of more than 5 units, and female to male gender match were independent risk factors for recipient survival. Patients with two or more of these risk factors would achieve worse outcomes.
Funding: None. Ethical approval: Not needed. Contributors: LC and WTF proposed the study and wrote the first draft. LC analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. WTF is the guarantor. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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Hepatobiliary Pancreat Dis Int，Vol 10，No 3 • June 15，2011 • www.hbpdint.com •
Predictors of patient survival following living donor liver transplantation Chuan Li, Tian-Fu Wen, Lu-Nan Yan, Bo Li, Jia-Ying Yang, Wen-Tao Wang, Ming-Qing Xu and Yong-Gang Wei Chengdu, China
BACKGROUND: Living donor liver transplantation (LDLT) is considered to be the alterative choice in light of the great shortage of cadaveric donors. However, the characteristics of the patients who will benefit from LDLT have not been well identified. The aim of this study was to define the pre- and intra-operative factors that may influence patient outcome.
KEY WORDS: living donor; liver transplantation; predictor; survival rate
METHODS: The data from 102 LDLT patients who had operations between 2002 and 2009 were collected and analyzed retrospectively. Data were analyzed using uni- and multi-variate analysis according to factors that are known to be associated with outcome in these patients.
Introduction
RESULTS: Overall, the accurate survival rate of recipients at 1, 3, and 5 years was 84%, 76%, and 70%, respectively. The independent risk factors, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male match (donor to recipient matching), were identified by Cox regression analysis. The pre-transplant model for end-stage liver disease score and a graft to recipient weight ratio of less than 0.8% were not predictive of outcome. The overall 1-, 3-, and 5-year survival of patients with one or no risk factors and two or more risk factors were 91%, 86%, and 83% and 67%, 56%, and 47%, respectively (P<0.0001). CONCLUSIONS: In our retrospective study, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male gender match were independent risk factors for LDLT recipient outcome. Two or more of these risk factors may contribute to poor outcome. (Hepatobiliary Pancreat Dis Int 2011; 10: 248-253)
Author Affiliations: Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, China (Li C, Wen TF, Yan LN, Li B, Yang JY, Wang WT, Xu MQ and Wei YG) Corresponding Author: Tian-Fu Wen, MD, Division of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, China (Tel: 8628-85422871, Fax: 86-28-85423269; Email: [email protected]) © 2011, Hepatobiliary Pancreat Dis Int. All rights reserved.
L
iver transplantation is widely accepted as the only curative therapy for patients with end-stage liver disease. It may cure cirrhosis, malignancies and severe liver dysfunction.[1] Excellent long-term survival rates for patients with both benign liver diseases and malignancies have been reported.[2, 3] However, these encouraging outcomes are greatly limited by the shortage of grafts, especially in Asian countries.[4] Since 1989, when Strong et al[5] performed the first successful liver transplantation from a living donor to her son who was diagnosed with biliary atresia, living donor liver transplantation (LDLT) has emerged as one of the effective alternatives to deceased donor liver transplantation (DDLT). However, right hepatectomy may impose a high surgical risk on the donor.[4] Determining which recipients will benefit from LDLT is a realistic problem that is of concern not only to transplant surgeons but also to the donor and recipient families. Studies in the literature have reported some risk factors that affect recipient and graft survival after liver transplantation.[6, 7] However, those risk factors are based on DDLT. Whether they pertain to LDLT has not been well established. The purpose of this study was to determine which pre- and intra-operative factors influence the outcome of LDLT.
Methods Patients and clinical characteristics All adult patients (ı18 years; n=102) with benign liver diseases who had undergone their first LDLT between 2002 and 2009 at our center were considered for this study. Transplantations were approved by the Ethics
• Hepatobiliary Pancreat Dis Int，Vol 10，No 3 • June 15，2011 • www.hbpdint.com
Predictors of LDLT
Committee of West China Hospital, Sichuan University. We examined the characteristics of the donors, recipients, grafts and intraoperative factors, including age, gender, body mass index (BMI), gender disparity, ABO blood-type disparity, model for end-stage liver diseases (MELD) score, Child-Pugh score, preoperative renal dysfunction, graft-to-recipient weight ratio (GRWR), cold ischemia time (CIT), surgical duration, transfusion of red blood cells (RBCs) and platelets.[8] MELD scores were calculated according to the formula: MELD score=9.57× Ln creatinine (mg/dL)+11.2×(Ln INR)+3.78×Ln bilirubin (mg/dL)+6.43.[9] The decision for transfusions was based on clinical and hemodynamic criteria. RBCs were used to maintain hemoglobin levels above 7.0 g/dL.[7, 10] Platelet concentrates were administered if platelet counts decreased to 50×109/L.[7, 10] Preoperative renal dysfunction was defined as the level of serum creatinine greater than 1.5 mg/dL.[11] The cut-off point of BMI was 23, as suggested by the World Health Organisation.[12] The clinical characteristics of recipients and donors are shown in Table 1. The primary etiologies that Table 1. Clinical characteristics of recipients and donors Characteristics Etiology Hepatitis B Fulminant hepatic failure Hepatolithiasis Budd-Chiari syndrome Primary biliary cirrhosis Hepatic hydatid disease Alcohol cirrhosis Hepatitis C Autoimmune hepatitis Hepatic cyst Recipient Age (yr) Gender (male) BMI Donor Age (yr) Gender (male) BMI Child-Pugh grade A B C GRWR MELD score >25 RBCs transfusion >5 units Platelet transfusion Pretransplant renal dysfunction Pretransplant diabetes mellitus
n 66 17 4 4 3 2 2 2 1 1 41 (18-69) 86 22.38±2.93 37 (19-65) 59 22.85±2.05 32 50 20 0.91% (0.63%-1.27%) 32 54 9 14 5
necessitated transplantations included: hepatitis B (66 patients), fulminant hepatic failure (17), hepatolithiasis (4), Budd-Chiari syndrome (4), primary biliary cirrhosis (3), hepatic hydatid disease (2), alcoholic cirrhosis (2), hepatitis C (2), autoimmune hepatitis (1), and hepatic cyst (1). Five patients were diagnosed with diabetes mellitus before LDLT. Insulin injections were used to control blood sugar levels in one patient, whereas the other four were given oral diabetes medications. The median age of the recipients was 41 years (range 18-69 years) and the median age of the donors was 37 years (range 19-65 years). A higher proportion of both recipients and donors were male (84.31% and 57.84%, respectively). The mean of recipient and donor BMI was 22.38±2.93 and 22.85±2.05, respectively. In addition, 39.22% (n=40) of the donors had BMIs >23, and 49.02% (n=50) of the recipients had BMIs >23. Although the transplantations were carefully performed, 54 patients required transfusions of >5 units of allogenic RBCs. Due to preoperative hypersplenism and intra-operative bleeding, 9 recipients required platelet transfusions. Overall, 32 patients had high MELD scores (>25), and 32 had Child-Pugh A, 50 Child-Pugh B, and 20 ChildPugh C. Furthermore, 14 patients had preoperative renal dysfunction due to hepatorenal syndrome, and 3 underwent pre-transplant dialysis due to severe renal dysfunction. The GRWR ranged from 0.63% to 1.27% with a mean of 0.91%; 23 recipients received small grafts (GRWR <0.8%).
Donor selection and surgical procedure Donors were required to be healthy adult relatives with compatible ABO blood type and negative serum tests for HBV, HCV and human immunodeficiency virus. The donors were evaluated using computed tomography and volumetry to ensure that a right lobe without a middle hepatic vein that measured >40% of the estimated standard liver weight of the recipient and ƫ30% of the total liver volume of the donor could possibly be removed. If not, dual LDLT was suggested. The operation was performed through a right subcostal incision extended to the upper midline under general anesthesia. Abdominal exploration, liver biopsy and intraoperative cholangiograms were initially performed to assess the ratio of steatosis and the biliary anatomy of the donor. Thereafter, the first hepatic hilum was dissected, the right lobe of the liver was mobilized and the vena cava was dissected. Any short hepatic veins larger than 0.5 cm were preserved until harvesting for potential anastomosis in the recipient. The CUSA Excel device was used to divide the liver parenchyma without inflow occlusion. The falciform ligament was
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reconstructed, the stumps of the right hepatic and portal veins were closed by continuous non-absorbable sutures, and a drain was inserted into the right subphrenic cavity before closure.[13]
60 years were significantly associated with recipient survival (Table 2). Pre-transplant MELD scores were not correlated with post-transplant survival. There were also no significant differences in survival among the patients with Child-Pugh A, B or C. GRWR less than 0.8% did not have any predictive power. Post-transplant management and follow-up Multivariate analysis, using Cox regression, showed The post-transplant immunosuppression consisted of that preoperative renal dysfunction, RBC transfusions calcineurin inhibitors (CNI; tacrolimus or cyclosporine), greater than 5 units, and female to male gender match mycophenolate mofetil and steroids. Steroid pulse therapy was administered to patients with rejection. were independent risk factors for death (Table 3). The postoperative anti-HBV protocols consisted of Significant differences were found among recipients lamivudine combined with therapy with a low-dose of with zero, one only, two and three risk factors using intramuscular hepatitis B immune globulin. Hepatitis B immune globulin was administered to all recipients with HBV infection during and after the transplantation. [13-15] Table 2. Univariate analysis of factors associated with patients survival The recipients were followed up regularly until death or Characteristics Survived Died P value the termination of this study (May 2010). Recipient variables
Statistical analysis Categorical variables were compared with the chisquare test or Fisher's exact test, whereas the analysis of variance was performed for continuous variables. Cox regression was used to assess the variables that were significantly associated with negative outcomes of LDLT in univariate analysis. Post-transplant survival was estimated using the Kaplan-Meier method with the log-rank test. The diagnostic accuracy of the predictors was assessed using receiver operating curve (ROC) analysis. For all analyses, we used SPSS version 13.0, and considered a P value of <0.05 to be statistically significant.
Results
Age >60 yr 4 Female 15 BMI >23 35 MELD score 25 Child-Pugh grade A 26 B 40 C 17 Donor variables Age >50 yr 12 Female 31 BMI >23 43 Recipient-donor match Sex disparity 36 Female-male 27 ABO disparity 18 Diagnosis Renal dysfunction 8 Diabetes mellitus 5 Etiology 83 Graft variable GRWR <0.8% 19 Surgical parameters CIT (min) 107.27±40.90 RBCs transfusion 39 Platelet transfusion 8 Surgical duration 589.23±113.48
4 1 5 7
0.038 0.293 0.202 0.569 0.889
6 10 3 1 12 7
0.453 0.040 0.239
12 12 5
0.119 0.013 0.762
6 0.012 Survival analysis 0 0.581 The median post-transplant follow-up was 27.32 months 19 0.367 (range 0.03-101.7 months). During the study period, a total of 19 patients died. The causes of death were 4 0.863 infection (n=8), multiple organ failure (6), renal failure (2), rejection (1), graft failure (1), or cerebrovascular 107.00±31.08 0.979 accident (1). Among patients with pre-transplant renal 15 0.012 dysfunction, 6 recipients died of various causes, 7 1 0.544 recovered, and 1 survived with slight renal dysfunction 614.57±65.43 0.351 (without the need for dialysis). Overall, the 1-, 3-, and 5-year survival rates for the recipients were 84%, 76%, and 70%, respectively. Table 3. Independent risk factors in the Cox regression for overall
survival
Risk factors for survival After the clinical features were analyzed by univariate analysis, we found that preoperative renal dysfunction, RBCs transfusions greater than 5 units, female to male gender match, and recipients older than
Characteristics
β
SE
Wald P
Exp(β)
Renal dysfunction 1.123 0.500 5.038 0.025 3.074 RBCs >5 units 1.161 0.568 4.171 0.041 3.192 Female-male 1.003 0.478 4.394 0.036 2.726
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95% CI Lower Upper 1.153 8.194 1.048 9.725 1.067 6.963
Predictors of LDLT
Fig. A: Cumulative survival curves for patients with zero, one, two or three risk factors that were confirmed by multivariate analysis (P<0.0001); B: Cumulative survival curves of patients with 0-1 risk factor and 2-3 risk factors that were confirmed by multivariate analysis (P<0.0001); C: ROC curve for the predictive risk factors that were confirmed by multivariate analysis.
sepsis,[21] length of stay in the intensive care unit,[22] the need for preoperative and postoperative dialysis,[21] financial burden,[23] hospital death, and postoperative survival[21, 24-27] have been well defined by many investigators. In our study, 14 patients were diagnosed with pre-transplant renal dysfunction. Unfortunately, six died from various causes. Among the six patients, five died during the perioperative period. This result is consistent with that reported previously. Furthermore, it was suggested that preoperative renal dysfunction also predicts a worse outcome in the long-term postoperative period.[24] Our study confirmed that RBC transfusions of greater than 5 units have a negative impact on the outcome of LDLT. Many risks are involved in allogeneic Discussion blood transfusions, such as transfusion-related acute lung injury, bacterial sepsis and immunosuppressive A number of studies have confirmed that MELD scores [10] A study[28] confirmed that massive blood effects. and Child-Pugh category may be good indicators for prediction of the outcome of liver transplantation.[4, 6, 16, 17] product transfusions are not only associated with longer However, our data showed that recipient mortality was hospital stays but also are associated with reduced closely associated with preoperative renal dysfunction, survival. However, in our study many patients received RBC transfusion and female to male gender match. RBCs transfusions of greater than 5 units. We speculate These results were not surprising; in our previous that this may be due to massive hemorrhage of the study,[18] we confirmed that high pre-transplant MELD upper gastrointestinal tract in many of the patients scores do not negatively impact short-term survival before transplantation. Moreover, many patients in our after liver transplantation. Although patients with high study had chronic anemia associated with digestive tract pre-transplant MELD scores are in extremely poor hemorrhage, hypersplenism and malnutrition. A number of clinical and animal studies focusing on condition, they also experience a similar incidence of post-transplant complications, and the biochemical gender disparity, especially female to male gender match parameters recover quickly after LDLT.[18] Jacob et al[19, 20] in solid organ transplantation showed that this may be suggested that the outcomes after liver transplantation associated with a negative outcome in the kidney, heart, may depend on unpredictable events that occur during lung, and liver transplantation. This was also revealed [29-33] Studies have confirmed that estrogens the perioperative period rather than on the severity of in our study. may impair the secretion of bile, resulting in disorders the underlying liver disease. Pre-transplant renal dysfunction was an independent of biliary secretion.[34] Moreover, Wittnich et al[35] found risk factor in our study. The correlations between increased acidosis in female livers during ischemia recipient serum creatinine and early post-transplant due to a rapid and greater degree of tissue lactate the Kaplan-Meier method with the log-rank test (Fig. A, P<0.0001). When the number of risk factors was analyzed and confirmed by multivariate analysis with an ROC, the best cut-off value for the number of risk factors was determined to be 2 (Fig. C). The corresponding area under the ROC was 0.704. We also compared the survival curve between patients with fewer than two risk factors and those with two or three of the risk factors. The overall 1-, 3-, and 5-year survival rates of patients with one or less and two or more risk factors were 91%, 86%, and 83% and 67%, 56%, and 47%, respectively. There were significant differences in these rates (Fig. B, P<0.0001).
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and H+ accumulation. Except for metabolic factors, graft size was suggested as a potential explanation for this phenomenon by Gu et al.[36] They hypothesized that the complex inflammatory responses caused by perfusion contribute to the less favourable outcomes in male rat recipients with small-for-size female liver grafts.[36] However, our study confirmed that GRWR <0.8% did not show any prognostic power. Contrary to these studies, Lehner et al[37] suggested that genderincompatible liver transplantation may not achieve a poor outcome. Our data have shown that male recipients of female livers have a worse survival rate that is independent of recipient age and other clinical characteristics. However, currently, the mechanism underlying this is still unclear. Our study suggested that patients with one or none of the identified risk factors achieved a much better survival than those with two or three risk factors. Pretransplant renal dysfunction is sometimes difficult to treat successfully unless the liver function has recovered. Therefore, intra-operative transfusions and gender matching may be the key to improving the outcome of recipients. Although blood transfusions often cannot be avoided during surgery, studies have struggled to minimize the intra-operative blood requirements.[10, 28] Advances in surgical and anesthetic management of patients undergoing LDLT will decrease both intraoperative blood loss and the requirement for blood products.[10] Increased understanding of the risk factors of massive blood loss is another effective method. Ramos et al[28] suggested that preoperative hemoglobin level is an independent risk factor in the prediction of the need for RBCs transfusions. Moreover, Ramos et al[28] also emphasized that the normalisation of preoperative hemoglobin level reduces the intraoperative transfusion requirement. Nonetheless, strategies to reduce intraoperative blood use should be developed. In addition, female to male gender matching should be avoided when there is more than one qualified donor. There are several limitations to our study. It was a retrospective, single-center study, with a limited number of patients, especially those of advanced age. Moreover, the censored rate of this investigation was slightly high because the follow-up duration was too short for the number of individuals. We believe a larger series and a multicentre study design would minimize these limitations. In conclusion, our preliminary study showed that preoperative renal dysfunction, intraoperative RBC transfusions of more than 5 units, and female to male gender match were independent risk factors for recipient survival. Patients with two or more of these risk factors would achieve worse outcomes.
Funding: None. Ethical approval: Not needed. Contributors: LC and WTF proposed the study and wrote the first draft. LC analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. WTF is the guarantor. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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