- Email: [email protected]
Risk Factors for Portal Vein Stenosis in Living-Donor Liver Transplantation
Risk Factors for Portal Vein Stenosis in Living-Donor Liver Transplantation S. Miyagi, N. Kawagishi, K. Maida, W. Nakanishi, Y. Hara, C. Nakanishi, I. Takeda, K. Satoh, N. Ohuchi, and S. Satomi ABSTRACT Background. In living-donor liver transplantation (LDLT), the recipient’s portal vein is short. Furthermore, portal vein thrombosis and stenosis can be lethal complications. We had begun the systemic administration of gabexate mesilate, a strong serine protease inhibitor, which has cytoprotective effects of endothelial cells. It is often effective on disseminated intravascular coagulation. The purpose of this study was to examine the effects of gabexate mesilate and to reveal risk factors for portal vein stenosis in LDLT. Methods. From 1991 to 2012, we performed 153 LDLTs. For the present cohort study, patients were divided into 2 groups. In group I, we treated with gabexate mesilate mildly (0e20 mg/kg/d; n ¼ 29). In group II, we treated with gabexate mesilate at full dose (40 mg/ kg/d; n ¼ 124). We investigated the survival rates of both groups and performed univariate and multivariate analyses to identify the independent risk factors for portal vein stenosis. Results. The survival rate of group II was significantly better than that of group I (P < .05). On univariate analysis, the risk factors identified to be associated with a P value of <.20 were old age (P ¼ .0385), heavy body weight (P ¼ .1840), tall height (P ¼ .1122), small lumen diameter of portal vein (P ¼ .1379), high volume of blood loss (P ¼ .0589), small amount of gabexate mesilate infusion (P ¼ .0103), and large graft weight (P ¼ .1326). On multiple logistic regression analysis we identified old age (P ¼ .0073) and small amount of gabexate mesilate infusion (P ¼ .0339) to be the independent risk factors for portal vein stenosis. Conclusions. On multivariate analysis, we found that gabexate mesilate infusion contributed to the reduction of portal vein stenosis.
I
N LIVING-DONOR liver transplantation (LDLT), the recipient’s portal vein is short and located deep in the abdominal cavity. Compared with that with a cadaveric donor, LDLT is difficult owing to the short vessels, severe intimal damage, and limited usable vessel grafts. Furthermore, portal vein thrombosis and stenosis can be lethal complications. To reduce portal vein stenosis, we began systemic administration of gabexate mesilate, a strong serine protease inhibitor [1e6]. This serine protease inhibitor has cytoprotective effects on endothelial cells and has been effective for the treatment of disseminated intravascular coagulation (DIC) compared with heparin [3e6]. The purpose of the present study was to examine the effects of gabexate mesilate and to reveal the risk factors for portal vein stenosis in LDLT. ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 689e691 (2014)
MATERIALS AND METHODS Informed consents were obtained from the donors and recipients. All of the procedures were reviewed and approved by the Ethical
From the Division of Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Supported by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan and Ministry of Welfare of Japan and a grant from Tohoku University Graduate School of Medicine. Address reprint requests to S. Miyagi, MD, Division of Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.042 689
690
MIYAGI, KAWAGISHI, MAIDA ET AL
Committee of Tohoku University School of Medicine and therefore performed in accordance with the ethical standards of the Declaration of Helsinki. From July 1991 to December 2012, we performed 153 LDLTs. For the present cohort study, patients were divided into 2 groups. Group I was treated with gabexate mesilate mildly (0e20 mg/kg/d; n ¼ 29). Group II was treated with gabexate mesilate at full dose (40 mg/kg/d for 7 days; n ¼ 124). Group I were mainly pediatric cases (left lobe graft only), and group II were mainly adult cases (left:right ¼ 61:63; Table 1). We examined portal vein stenosis with the use of ultrasonography every 8 hours for 14 days after transplantation [7]. On the 3rd week, we reduced the frequency of the ultrasonographic examinations to once per day until 21 days and eventually discontinued it as a routine diagnostic procedure. We investigated frequencies of the occurrence of portal vein stenosis and the survival rates of both groups. Furthermore, we investigated the cases retrospectively and performed univariate and multivariate analyses to identify the independent risk factors for portal vein stenosis.
Statistics All calculations were made with the JMP Pro software package (SAS Institute, Cary, North Carolina). The results were expressed as mean SE. Patients were studied from the date of operation until death or last follow-up. Kaplan-Meier survival curves were constructed for both study groups. The effects of management on overall survival were examined initially with the use of the KaplanMeier log-rank test (Breslow-Gehan-Wilcoxon test). A univariate analysis was performed with the use of the Fisher exact test for categoric variables and Mann-Whitney U test for continuous variables. The factors identified by univariate analysis to be associated with a P value of <.20 were then subjected to a multivariate regression analysis to identify the independent risk factors for recurrences. P < .05 was considered to be statistically significant.
RESULTS
The survival rates of group I and group II at 5 years were 69.0% and 81.5%, respectively. It was significantly better in group II than in the group I (P < .05; Fig 1). The occurrence rates of portal vein stenosis in group I and group II were 17.24% (5/29) and 4.84% (6/124), respectively. There were significant differences between the groups (P < .05). On univariate analysis, the risk factors identified to be associated with a P value of <.20 were old age (P ¼ .0385), heavy weight (P ¼ .1840), tall height (P ¼ .1122), small lumen Table 1. Background of the Patients Group I (n ¼ 29)
Age (years old) Sex (M:F) Weight (kg) Lumen diameter of the artery (mm) Bile leakage (cases) Graft lobe (L:R) Acute rejection (cases) ABO incompatible (cases) *Significant.
Group II (n ¼ 124)
8.83 4.08 26.25 1.98 12:17 54:70 22.74 4.52 38.35 2.20 10.0 0.7 14.9 0.4 4 29:0 7 3
7 61:63 28 10
P
.0002* 1.0000 .0023* .0001* .2216 .0001* .8110 .7131
Fig 1. Survival rates.
diameter of portal vein (P ¼ .1379), high volume of blood loss (P ¼ .0589), small amount of gabexate mesilate infusion (P ¼ .0103), and large graft weight (P ¼ .1326; Table 2). We then performed a multiple logistic regression analysis of the data and identified old age (P ¼ .0073) and small amount of gabexate mesilate infusion (P ¼ .0339) to be the independent risk factors for portal vein stenosis (Table 3). DISCUSSION
Portal vein thrombosis is a lethal complication of LDLT. To overcome these complications, we began systemic administration of gabexate mesilate, a strong serine protease inhibitor, because we thought that the key to preventing thrombosis is protecting endothelial cells. Our results suggest that treatment with gabexate mesilate at a full dose of 40 mg/kg/d seems to be safe for LDLT. Moreover, on the multiple logistic regression analysis, we found that gabexate mesilate infusion contributed to the reduction of portal vein stenosis. Table 2. Univariate Analysis of Risk Factors Variable
PV stenosis(e) (n ¼ 142)
PV stenosis(þ) (n ¼ 11)
Old age (years old) 21.9 1.9 36.7 6.9 Sex (M:F) 63:79 3:8 Heavy weight (kg) 34.6 2.1 45.0 7.5 Long height (cm) 120.5 3.6 142.0 12.9 Small lumen diameter of the 14.1 0.3 11.7 1.6 artery (mm) Bile leakage (cases) 11 0 High volume of blood 9809 1430 19959 5137 loss (mL) Graft lobe (L:R) 83:59 7:4 Applied dose of gabexate 36.3 0.7 29.1 2.7 mesilate (mg/kg) Acute rejection (cases) 32 3 ABO incompatible (cases) 12 1 Heavy graft weight (g) 394.8 15.4 456.5 54.3 Choledocojejunostomy:duct 117:25 11:0 to duct *Significant.
P
.0385* .3521 .1840* .1122* .1379* 1.0000 .0589* 1.0000 .0103* .7147 1.0000 .1326* .2129
RISK FACTORS FOR PORTAL VEIN STENOSIS
691
Table 3. Multivariate Analysis of Risk Factors Variable
Odds ratio
95% CI
P
Old age Heavy weight Long height Small lumen diameter of the artery (mm) High Volume of blood loss (ml) Small applied dose of gabexate mesilate Heavy graft weight (g)
0.8951 1.0008 0.9788 1.2580 1.0000 1.1656 1.0027
0.79e0.97 0.90e1.13 0.89e1.05 0.93e1.84 0.99e1.00 1.01e1.43 0.99e1.01
.0073* .9882 .5694 .1365 .6597 .0339* .5826
*Significant.
Gabexate mesilate is one of the strongest serine protease inhibitors. In Japan, gabexate mesilate is sometimes used for the treatment of DIC, and in some cases it is more effective than heparin. In a previous study, we used nafamostat mesilate [3], the strongest serine protease inhibitor after gabexate mesilate in marginal-donor liver transplantation in rats. We observed that both serine protease inhibitors had cytoprotective effects on endothelial cells. Therefore, in the present study, we investigated the effects of gabexate mesilate on LDLT. In our results, the survival rate and the occurrence rate of portal vein stenosis of group II were significantly better than those of group I. In fact, the backgrounds of both groups were considerably different. Group I cases were mainly pediatric (left lobe graft only), and group II were mainly adult cases (left:right ¼ 61:63). Therefore, we thought that low body weight cases or pediatric cases might be risk factors for portal vein stenosis. But in our univariate analysis, those were not identified as risk factors for stenosis. Furthermore, the lobe of the liver graft was also not identified as a risk factor. Rather, heavy weight and old age were identified as risk factors. From these results, we thought that the treatment with full-dose gabexate mesilate infusion contributed to the reduction of portal vein stenosis. Why does the thinness of the lumen diameter of the portal vein and low body weight not become risk factors
for portal vein stenosis in our multiple logistic regression analyses? Generally, it is thought that these 2 factors become risk factors because of the technical difficulties for the operation. According to our results, the risk factor was rather older age. One explanation for this outcome is that the risk factor wasn’t influenced directly by the technical reason. In fact, we encountered a few older patients who had portal vein thrombosis because of developed collateral circulation, which made portal flow more decreased. Thus, portal vein stenosis often occurs in old age. In conclusion, based on our results of univariate analysis and multivariate analysis, treatment with full-dose gabexate mesilate infusion might be safe and contribute to the reduction of portal vein stenosis. REFERENCES [1] Mikami K, Goto T, Miura K, et al. Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachlorideinduced liver injury in rats. J Gastroenterol 2005;40:260e5. [2] Tsukamoto S, Ohkohchi N, Fukumori T, et al. Elimination of Kupffer cells and nafamostat mesilate rinse prevent reperfusion injury in liver grafts from agonal nonheart beating donors. Transplantation 1999;67:1396e403. [3] Miyagi S, Ohkohchi N, Oikawa K, et al. Effects of antiinflammatory cytokine agent (FR167653) and serine protease inhibitor on warm ischemia-reperfusion injury of the liver graft. Transplantation 2004;77:1487e93. [4] Luh SP, Tsai CC, Shau WY, et al. Effects of gabexate mesilate (FOY) on ischemia-reperfusion induced acute lung injury in dogs. J Surg Res 1999;87:152e63. [5] Aramoto H, Saito H, Shigematsu H, et al. Synthetic protease inhibitors in the treatment of disseminated intravascular coagulation. Nippon Rinsho 1993;51:93e8. [6] Isobe J. Inhibitory effects of gabexate mesilate (FOY) on experimental DIC. Adv Exp Med Biol 1979;120B:385e94. [7] Kaneko J, Sugawara Y, Akamatsu N, et al. Prediction of hepatic artery thrombosis by protocol Doppler ultrasonography in pediatric living donor liver transplantation. Abdom Imaging 2004;29:603e5.
I
N LIVING-DONOR liver transplantation (LDLT), the recipient’s portal vein is short and located deep in the abdominal cavity. Compared with that with a cadaveric donor, LDLT is difficult owing to the short vessels, severe intimal damage, and limited usable vessel grafts. Furthermore, portal vein thrombosis and stenosis can be lethal complications. To reduce portal vein stenosis, we began systemic administration of gabexate mesilate, a strong serine protease inhibitor [1e6]. This serine protease inhibitor has cytoprotective effects on endothelial cells and has been effective for the treatment of disseminated intravascular coagulation (DIC) compared with heparin [3e6]. The purpose of the present study was to examine the effects of gabexate mesilate and to reveal the risk factors for portal vein stenosis in LDLT. ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 689e691 (2014)
MATERIALS AND METHODS Informed consents were obtained from the donors and recipients. All of the procedures were reviewed and approved by the Ethical
From the Division of Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Supported by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan and Ministry of Welfare of Japan and a grant from Tohoku University Graduate School of Medicine. Address reprint requests to S. Miyagi, MD, Division of Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: [email protected] 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.042 689
690
MIYAGI, KAWAGISHI, MAIDA ET AL
Committee of Tohoku University School of Medicine and therefore performed in accordance with the ethical standards of the Declaration of Helsinki. From July 1991 to December 2012, we performed 153 LDLTs. For the present cohort study, patients were divided into 2 groups. Group I was treated with gabexate mesilate mildly (0e20 mg/kg/d; n ¼ 29). Group II was treated with gabexate mesilate at full dose (40 mg/kg/d for 7 days; n ¼ 124). Group I were mainly pediatric cases (left lobe graft only), and group II were mainly adult cases (left:right ¼ 61:63; Table 1). We examined portal vein stenosis with the use of ultrasonography every 8 hours for 14 days after transplantation [7]. On the 3rd week, we reduced the frequency of the ultrasonographic examinations to once per day until 21 days and eventually discontinued it as a routine diagnostic procedure. We investigated frequencies of the occurrence of portal vein stenosis and the survival rates of both groups. Furthermore, we investigated the cases retrospectively and performed univariate and multivariate analyses to identify the independent risk factors for portal vein stenosis.
Statistics All calculations were made with the JMP Pro software package (SAS Institute, Cary, North Carolina). The results were expressed as mean SE. Patients were studied from the date of operation until death or last follow-up. Kaplan-Meier survival curves were constructed for both study groups. The effects of management on overall survival were examined initially with the use of the KaplanMeier log-rank test (Breslow-Gehan-Wilcoxon test). A univariate analysis was performed with the use of the Fisher exact test for categoric variables and Mann-Whitney U test for continuous variables. The factors identified by univariate analysis to be associated with a P value of <.20 were then subjected to a multivariate regression analysis to identify the independent risk factors for recurrences. P < .05 was considered to be statistically significant.
RESULTS
The survival rates of group I and group II at 5 years were 69.0% and 81.5%, respectively. It was significantly better in group II than in the group I (P < .05; Fig 1). The occurrence rates of portal vein stenosis in group I and group II were 17.24% (5/29) and 4.84% (6/124), respectively. There were significant differences between the groups (P < .05). On univariate analysis, the risk factors identified to be associated with a P value of <.20 were old age (P ¼ .0385), heavy weight (P ¼ .1840), tall height (P ¼ .1122), small lumen Table 1. Background of the Patients Group I (n ¼ 29)
Age (years old) Sex (M:F) Weight (kg) Lumen diameter of the artery (mm) Bile leakage (cases) Graft lobe (L:R) Acute rejection (cases) ABO incompatible (cases) *Significant.
Group II (n ¼ 124)
8.83 4.08 26.25 1.98 12:17 54:70 22.74 4.52 38.35 2.20 10.0 0.7 14.9 0.4 4 29:0 7 3
7 61:63 28 10
P
.0002* 1.0000 .0023* .0001* .2216 .0001* .8110 .7131
Fig 1. Survival rates.
diameter of portal vein (P ¼ .1379), high volume of blood loss (P ¼ .0589), small amount of gabexate mesilate infusion (P ¼ .0103), and large graft weight (P ¼ .1326; Table 2). We then performed a multiple logistic regression analysis of the data and identified old age (P ¼ .0073) and small amount of gabexate mesilate infusion (P ¼ .0339) to be the independent risk factors for portal vein stenosis (Table 3). DISCUSSION
Portal vein thrombosis is a lethal complication of LDLT. To overcome these complications, we began systemic administration of gabexate mesilate, a strong serine protease inhibitor, because we thought that the key to preventing thrombosis is protecting endothelial cells. Our results suggest that treatment with gabexate mesilate at a full dose of 40 mg/kg/d seems to be safe for LDLT. Moreover, on the multiple logistic regression analysis, we found that gabexate mesilate infusion contributed to the reduction of portal vein stenosis. Table 2. Univariate Analysis of Risk Factors Variable
PV stenosis(e) (n ¼ 142)
PV stenosis(þ) (n ¼ 11)
Old age (years old) 21.9 1.9 36.7 6.9 Sex (M:F) 63:79 3:8 Heavy weight (kg) 34.6 2.1 45.0 7.5 Long height (cm) 120.5 3.6 142.0 12.9 Small lumen diameter of the 14.1 0.3 11.7 1.6 artery (mm) Bile leakage (cases) 11 0 High volume of blood 9809 1430 19959 5137 loss (mL) Graft lobe (L:R) 83:59 7:4 Applied dose of gabexate 36.3 0.7 29.1 2.7 mesilate (mg/kg) Acute rejection (cases) 32 3 ABO incompatible (cases) 12 1 Heavy graft weight (g) 394.8 15.4 456.5 54.3 Choledocojejunostomy:duct 117:25 11:0 to duct *Significant.
P
.0385* .3521 .1840* .1122* .1379* 1.0000 .0589* 1.0000 .0103* .7147 1.0000 .1326* .2129
RISK FACTORS FOR PORTAL VEIN STENOSIS
691
Table 3. Multivariate Analysis of Risk Factors Variable
Odds ratio
95% CI
P
Old age Heavy weight Long height Small lumen diameter of the artery (mm) High Volume of blood loss (ml) Small applied dose of gabexate mesilate Heavy graft weight (g)
0.8951 1.0008 0.9788 1.2580 1.0000 1.1656 1.0027
0.79e0.97 0.90e1.13 0.89e1.05 0.93e1.84 0.99e1.00 1.01e1.43 0.99e1.01
.0073* .9882 .5694 .1365 .6597 .0339* .5826
*Significant.
Gabexate mesilate is one of the strongest serine protease inhibitors. In Japan, gabexate mesilate is sometimes used for the treatment of DIC, and in some cases it is more effective than heparin. In a previous study, we used nafamostat mesilate [3], the strongest serine protease inhibitor after gabexate mesilate in marginal-donor liver transplantation in rats. We observed that both serine protease inhibitors had cytoprotective effects on endothelial cells. Therefore, in the present study, we investigated the effects of gabexate mesilate on LDLT. In our results, the survival rate and the occurrence rate of portal vein stenosis of group II were significantly better than those of group I. In fact, the backgrounds of both groups were considerably different. Group I cases were mainly pediatric (left lobe graft only), and group II were mainly adult cases (left:right ¼ 61:63). Therefore, we thought that low body weight cases or pediatric cases might be risk factors for portal vein stenosis. But in our univariate analysis, those were not identified as risk factors for stenosis. Furthermore, the lobe of the liver graft was also not identified as a risk factor. Rather, heavy weight and old age were identified as risk factors. From these results, we thought that the treatment with full-dose gabexate mesilate infusion contributed to the reduction of portal vein stenosis. Why does the thinness of the lumen diameter of the portal vein and low body weight not become risk factors
for portal vein stenosis in our multiple logistic regression analyses? Generally, it is thought that these 2 factors become risk factors because of the technical difficulties for the operation. According to our results, the risk factor was rather older age. One explanation for this outcome is that the risk factor wasn’t influenced directly by the technical reason. In fact, we encountered a few older patients who had portal vein thrombosis because of developed collateral circulation, which made portal flow more decreased. Thus, portal vein stenosis often occurs in old age. In conclusion, based on our results of univariate analysis and multivariate analysis, treatment with full-dose gabexate mesilate infusion might be safe and contribute to the reduction of portal vein stenosis. REFERENCES [1] Mikami K, Goto T, Miura K, et al. Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachlorideinduced liver injury in rats. J Gastroenterol 2005;40:260e5. [2] Tsukamoto S, Ohkohchi N, Fukumori T, et al. Elimination of Kupffer cells and nafamostat mesilate rinse prevent reperfusion injury in liver grafts from agonal nonheart beating donors. Transplantation 1999;67:1396e403. [3] Miyagi S, Ohkohchi N, Oikawa K, et al. Effects of antiinflammatory cytokine agent (FR167653) and serine protease inhibitor on warm ischemia-reperfusion injury of the liver graft. Transplantation 2004;77:1487e93. [4] Luh SP, Tsai CC, Shau WY, et al. Effects of gabexate mesilate (FOY) on ischemia-reperfusion induced acute lung injury in dogs. J Surg Res 1999;87:152e63. [5] Aramoto H, Saito H, Shigematsu H, et al. Synthetic protease inhibitors in the treatment of disseminated intravascular coagulation. Nippon Rinsho 1993;51:93e8. [6] Isobe J. Inhibitory effects of gabexate mesilate (FOY) on experimental DIC. Adv Exp Med Biol 1979;120B:385e94. [7] Kaneko J, Sugawara Y, Akamatsu N, et al. Prediction of hepatic artery thrombosis by protocol Doppler ultrasonography in pediatric living donor liver transplantation. Abdom Imaging 2004;29:603e5.