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Risk Factors for Refractory Ascites After Living Donor Liver Transplant
Risk Factors for Refractory Ascites After Living Donor Liver Transplant Koki Sato, Masahiro Ohira*, Seiichi Shimizu, Yuki Imaoka, Shinji Hashimoto, Hiroyuki Tahara, Tsuyoshi Kobayashi, Shintaro Kuroda, Kentaro Ide, Yuka Tanaka, and Hideki Ohdan Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
ABSTRACT Objectives. Refractory ascites after liver transplant commonly occurs in living donor liver transplant (LDLT). Refractory ascites is associated with postoperative complications and poor prognosis. This study sought to determine the risk factors of refractory ascites and discuss their perioperative management. Methods. A retrospective study of 122 living donor liver transplant recipients between 2008 and 2017 was performed to analyze the risk factors, incidence, and characteristics of refractory ascites. Refractory ascites post LDLT was defined as the production of ascites fluid >1000 mL/d on postoperative day 14 or required repeated drainage. Results. A total of 24 patients (19.6%) developed refractory ascites. The 1-year survival rate was significantly worse in the refractory ascites group compared with the nonrefractory ascites group (P < .001). In a univariate analysis, patients with refractory ascites had a higher Model for End-Stage Liver Disease (MELD) score, donor age, presence of left lobe graft, ascites at laparotomy, portal venous pressure just after surgery, cold ischemia time, and absence of hepatocellular carcinoma compared with patients without refractory ascites. Multivariate proportional regression analyses revealed that MELD score 20, left lobe graft, donor age 50 years or older, and ascites at laparotomy 350 mL were independently associated with refractory ascites. Postoperative complications, such as bleeding (P < .001), sepsis (P < .001), and bloodstream infection within 30 days after LDLT (P < .00), were significantly higher in the refractory ascites group. Conclusion. Refractory ascites is associated with reduced 1-year survival and increased postoperative complications. Four factors including MELD score 20, donor age 50 years or older, presence of left graft, and ascites at laparotomy 350 mL were independent predictors for refractory ascites.
P
OSTOPERATIVE ascites commonly occurs in living donor liver transplant (LDLT) recipients [1]. It is well accepted that refractory ascites after LDLT is a poor prognostic factor [2,3]. Despite recent advances in ascites treatment, including tolvaptan and transjugular intrahepatic portosystemic shunt, refractory ascites is still associated with renal impairment, increased incidence of abdominal infection, prolonged hospitalization, graft function deterioration, and reduced survival [4,5]. However, there are few studies that have investigated the independent risk factor of post-LDLT ascites in detail. In the present study, we investigated the risk factors for refractory ascites in patients 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.01.120
1516
who underwent LDLT by analyzing the perioperative donor and recipient characteristics. PATIENTS AND METHODS From April 2008 to September 2017, a total of 126 adult patients underwent initial LDLT at our hospital. Of these patients, 4
*Address correspondence to Masahiro Ohira, MD, PhD, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Tel: þ81-82257-5222; Fax: þ81-82-257-5224. E-mail: mohira@hiroshima-u. ac.jp ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 1516e1519 (2019)
REFRACTORY ASCITES AFTER LIVER TRANSPLANT
1517 Table 1. Characteristics Refractory Ascites Group n ¼ 24
Nonrefractory Ascites Group n ¼ 98
P Value
9/15 52.5 (2.18) 45.5 (2.3) 22.7 (1.45) 1/2/21 0.95 (0.04) 2/22 15/8/1 2/22 17/7 4/20 746 (27.8) 5013 (768) 145 (13.1) 1849 (482) 4/20 23.0 (1.17) 16.2 (0.88) 17.0 (0.89) 0.72 (0.02) 37.9 (5.31) 10.3 (2.19) 44.4 (5.11)
57/41 55.9 (1.08) 37.2 (1.1) 16.8 (0.75) 10/29/59 0.90 (0.02) 12/86 41/39/18 22/76 40/58 53/45 780 (13.7) 4867 (380) 112 (6.5) 1006 (237) 19/79 22.8 (0.59) 15.8 (0.45) 14.9 (0.45) 0.71 (0.01) 45.2 (2.85) 13.3 (1.17) 44.9 (2.74)
.07 .16 .002 <.001 .04 .26 .59 .10 .12 .59 .001 .28 .86 .03 .12 .76 .94 .69 .04 .77 .23 .21 .94
Male/Female Recipient age, mean (SD), y Donor age, mean (SD), y MELD, mean (SD), points Child-Pugh A/B/C GRWR, mean (SD), % ABO incompatibilities, þ/ Non/HCV/HBV Diabetes þ/ Left graft þ/ HCC þ/ Operative time, mean (SD), min Bleeding volume, mean (SD), mL Cold ischemia time, mean (SD), min Ascites at operation started, mean (SD), mL Splenectomy þ/ Pretransplant PVP, mean (SD), mm Hg Reflow PVP, mean (SD), mm Hg Posttransplant PVP, mean (SD), mm Hg Resistance index at POD 1, mean (SD) Systolic arterial flow at POD 1, mean (SD), mL/sec Diastolic arterial flow at POD 1, mean (SD), mL/sec Portal venous flow at POD 1, mean (SD), mL/sec
Abbreviations: GRWR, graft-to-recipient weight ratio; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; POD, postoperative day; PVP, portal vein pressure.
underwent portal infusion of prostaglandin E1 during the LDLT surgery and were excluded from the study, leaving 122 recruited patients. We retrospectively reviewed their medical records and created a computerized database inclusive of demographic, radiologic, and laboratory data related to each patient. This study was approved by the Independent Ethics committee of Hiroshima University. To identify the risk factors for developing refractory ascites, the following preoperative recipient variables were analyzed: age, sex, primary liver disease, Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, and presence of ABO incompatibilities. Intraoperative variables included the volume of ascites at laparotomy; operating time; cold ischemia time; blood loss; portal venous pressure at pretransplant, at reflow, and at post-transplant; and whether a left lobe graft and splenectomy had been performed previously. We also recorded postoperative resistance index, systolic arterial blood flow, diastolic arterial blood flow, and portal venous blood flow velocity on day 1 post LDLT. Donor factors that were
analyzed included sex, age, graft weight-to-recipient weight ratio, donor liver quality, portal vein graft diameter, hepatic artery graft diameter, and right hepatic vein graft diameter. Refractory ascites post LDLT was defined as the production of ascites fluid >1000 mL/d that lasted longer than 14 days after LDLT or required repeated drainage after LDLT. Patients were placed into either group 1 (n ¼ 24, refractory ascites) or group 2 (n ¼ 98, nonrefractory ascites) based on this definition.
Statistics Univariate analyses using the c2 test or Fisher exact test where appropriate were performed to compare categorical variables, and the Mann-Whitney test was used to compare continuous variables. A difference was considered significant if the P value was <.05. Statistical analyses were performed using JMP statistical software, version 13 (SAS Institute, Cary, NC, United States).
Table 2. Post-transplant Complications
Bile duct complication þ/ Abdominal abscess þ/ Thrombosis þ/ Pulmonary embolism þ/ Heart vascular complication þ/ Bleeding þ/ Acute rejection þ/ Sepsis þ/ BSI within 30 days þ/ CMV infection þ/
Refractory Ascites Group n ¼ 24
Nonrefractory Ascites Group n ¼ 98
P Value
3/21 6/18 1/23 0/24 2/22 12/12 7/17 10/14 12/12 16/8
32/66 13/85 6/92 1/97 4/94 15/83 20/78 11/87 16/82 46/52
.05 .16 .71 .62 .39 <.001 .35 <.001 <.001 .08
Abbreviations: BSI, blood stream infection; CMV, cytomegalovirus.
1518
SATO, OHIRA, SHIMIZU ET AL Table 3. Risk Factors of Refractory Ascites Univariate Refractory Ascites Group (n ¼ 24)
Factors
Donor age, y 50 <50 MELD 20 <20 Ascites at operation started 350 <350 Left graft Yes No HCC Yes No Posttransplant PVP 15 <15 CIT 164 <164 GRWR 0.8 <0.8 Operation time 745 <745 Bleeding volume 2570 <2570
Nonrefractory Ascites Group (n ¼ 98)
Multivariate P Value
.002 27 95
11 13
16 82
36 86
16 8
20 78
45 77
18 7
27 70
57 65
17 7
40 58
57 65
4 20
53 45
61 61
18 6
43 55
22 100
8 16
14 84
84 38
17 7
67 31
73 49
11 13
62 36
92 30
20 4
72 26
<.001
OR
6.04
12.8
95% CI
P Value
1.4e26.6
.02
3.1e52.5
<.001
<.001
4.69
1.3e17.1
.02
.008
6.09
1.3e28.5
.02
.001
.01
.03
.82
.12
.31
Abbreviations: CIT, cold ischemia time; GRWR, graft-to-recipient weight ratio; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; OR, odds ratio; PVP, portal vein pressure.
RESULTS
The cohort included 66 men and 56 women, with a mean age at the time of the transplant of 55.2 (SD, 10.7) years. The patients’ characteristics, stratified by presence or absence of refractory ascites, are summarized in Table 1. In the Kaplan-Meier survival curve analysis, the 1-year survival rate was significantly worse in the refractory ascites group compared with the nonrefractory ascites group (P < .001). The postoperative complications are summarized in Table 2. There were significant differences between the 2 groups in the presence of bleeding, sepsis, and blood stream infection within 30 days after LDLT. Univariate analysis revealed that a high donor age, elevated recipient MELD score, high volume of ascites at laparotomy, presence of left lobe graft, absence of hepatocellular carcinoma, high post-transplant portal vein pressure, and long cold ischemia time were statistically significant predictors of a poor prognosis. Several factors that were associated with a poor prognosis in the univariate analysis, such as donor age 50 years or older (odds ratio [OR], 6.0391; 95% CI, 1.3695e26.6305; P ¼ .02), recipient MELD score 20 (OR, 12.8064; 95% CI, 3.1231e52.5131;
P < .001), amount of ascites at laparotomy 350 mL (OR, 4.6904; 95% CI, 1.2881e17.0792; P ¼ .02), and presence of left lobe graft (OR, 6.0862; 95% CI, 1.2989e28.5171; P ¼ .02), remained independent risk factors after a multivariate logistic regression analysis (Table 3).
DISCUSSION
In this study, we have shown that MELD score 20, donor age 50 years or older, presence of left graft, and ascites at laparotomy 350 mL were independent risk factors for refractory ascites. Small-for-size graft syndrome and portal hypertension have been reported to be associated with ascites formation [6,7]. Post-transplant ascites is common in LDLT where the left lobe with a graft weight-to-recipient weight ratio <0.8% is used [8], and the major mechanism for massive ascites formation after transplant was suggested to be postsinusoidal portal hypertension secondary to hepatic vein outflow difficulty [5]. Patients with refractory ascites in the present study also exhibited more serious preoperative conditions, as shown by higher MELD and Child-Pugh
REFRACTORY ASCITES AFTER LIVER TRANSPLANT
scores, than the patients without refractory ascites. Li et al reported that a higher preoperative MELD score and a higher Child-Pugh score were independent predictors of refractory ascites after LDLT [1]. In addition, another independent risk factor for refractory ascites observed in our study was the presence of ascites at laparotomy. Ito et al [9] and Matsudaira et al [10] also reported that patients in the refractory ascites group had higher incidences of preoperative ascites compared with the control group, although the definition of refractory ascites was slightly different from our study. Because preoperative ascites seems to be the only independent risk factor that can be clinically controlled before LDLT, maximal effort should be made to decrease accumulation of preoperative ascites to avoid refractory ascites after LDLT. The incidence of massive ascites after liver transplant found in different studies is quite variable, ranging from 7.0% to 48.4% [4,9]. In our study, massive ascites developed in 24 patients (19.6%). Cirera et al [4] reported only a 7% incidence of ascites after whole liver transplant, although the definition of massive ascites was slightly different in their study. Li et al reported a 25.7% incidence and Ito et al reported a 48.4% incidence of ascites after LDLT. These data suggest that postoperative massive ascites is more common in LDLT than in deceased donor liver transplant. Post-transplant refractory ascites was associated with poor prognosis and postoperative complications in this study. To control preoperative ascites, diuretic drugs and albumin products were used at first. In case of failure, the transjugular intrahepatic portosystemic shunt procedure [11] or drainage or cell-free and concentrated ascites reinfusion therapy [12] were the other treatment strategies used. Since September 2017, we have introduced a novel and improved cell-free and concentrated ascites reinfusion therapy [13] as a treatment option of preoperative ascites. Safety procedures, effectiveness of the LDLT procedure, and the perioperative management that our hospital follows have been validated (Seiichi Shimizu, 2019, unpublished data). Our new concentrated ascites reinfusion therapy could be a promising option for the treatment of refractory ascites, and its further effectiveness as a treatment for preoperative ascites should be analyzed in a future study (Seiichi Shimizu, personal communication, 2019). In conclusion, we found that MELD score 20, donor age 50 years or older, presence of left graft, and ascites at laparotomy 350 mL were the independent risk factors for refractory ascites. It is important to reduce and control the
1519
preoperative ascites to reduce the occurrence rate of refractory ascites after LDLT. REFERENCES [1] Li C, Lu Q, Luo J, Zhang Z. Independent risk factors for massive ascites after living donor liver transplantation in adults. Transplant Proc 2014;46:883e7. [2] Gotthardt DN, Weiss KH, Rathenberg V, Schemmer P, Stremmel W, Sauer P. Persistent ascites after liver transplantation: etiology, treatment and impact on survival. Ann Transplant 2013;18:378e83. [3] Stewart CA, Wertheim J, Olthoff K, Furth EE, Brensinger C, Markman J, et al. Ascites after liver transplantation–a mystery. Liver Transpl 2004;10:654e60. [4] Cirera I, Navasa M, Rimola A, Garcia-Pagan JC, Grande L, Garcia-Valdecasas JC, et al. Ascites after liver transplantation. Liver Transpl 2000;6:157e62. [5] Shirouzu Y, Ohya Y, Suda H, Asonuma K, Inomata Y. Massive ascites after living donor liver transplantation with a right lobe graft larger than 0.8% of the recipient’s body weight. Clin Transplant 2010;24:520e7. [6] Kiuchi T, Tanaka K, Ito T, Oike F, Ogura Y, Fujimoto Y, et al. Small-for-size graft in living donor liver transplantation: how far should we go? Liver Transpl 2003;9:S29e35. [7] Soejima Y, Taketomi A, Yoshizumi T, Uchiyama H, Harada N, Ijichi H, et al. Feasibility of left lobe living donor liver transplantation between adults: an 8-year, single-center experience of 107 cases. Am J Transplant 2006;6(5 Pt 1):1004e11. [8] Yi NJ, Suh KS, Cho YB, Lee HW, Cho EH, Cho JY, et al. The right small-for-size graft results in better outcomes than the left small-for-size graft in adult-to-adult living donor liver transplantation. World J Surg 2008;32:1722e30. [9] Ito D, Akamatsu N, Togashi J, Kaneko J, Arita J, Hasegawa K, et al. Behavior and clinical impact of ascites after living donor liver transplantation: risk factors associated with massive ascites. J Hepatobiliary Pancreat Sci 2016;23: 688e96. [10] Matsudaira S, Ishizaki Y, Yoshimoto J, Fujiwara N, Kawasaki S. Risk factors for intractable ascites after adult-to-adult living donor liver transplantation using left lobe. Transplant Direct 2017;3:e138. [11] Bai M, Qi XS, Yang ZP, Yang M, Fan DM, Han GH. TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis. World J Gastroenterol 2014;20:2704e14. [12] Hanafusa N, Isoai A, Ishihara T, Inoue T, Ishitani K, Utsugisawa T, et al. Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in refractory ascites: post-marketing surveillance results. PLoS One 2017;12: e0177303. [13] Matsusaki K, Ohta K, Yoshizawa A, Gyoda Y. Novel cell-free and concentrated ascites reinfusion therapy (KMCART) for refractory ascites associated with cancerous peritonitis: its effect and future perspectives. Int J Clin Oncol 2011;16: 395e400.
ABSTRACT Objectives. Refractory ascites after liver transplant commonly occurs in living donor liver transplant (LDLT). Refractory ascites is associated with postoperative complications and poor prognosis. This study sought to determine the risk factors of refractory ascites and discuss their perioperative management. Methods. A retrospective study of 122 living donor liver transplant recipients between 2008 and 2017 was performed to analyze the risk factors, incidence, and characteristics of refractory ascites. Refractory ascites post LDLT was defined as the production of ascites fluid >1000 mL/d on postoperative day 14 or required repeated drainage. Results. A total of 24 patients (19.6%) developed refractory ascites. The 1-year survival rate was significantly worse in the refractory ascites group compared with the nonrefractory ascites group (P < .001). In a univariate analysis, patients with refractory ascites had a higher Model for End-Stage Liver Disease (MELD) score, donor age, presence of left lobe graft, ascites at laparotomy, portal venous pressure just after surgery, cold ischemia time, and absence of hepatocellular carcinoma compared with patients without refractory ascites. Multivariate proportional regression analyses revealed that MELD score 20, left lobe graft, donor age 50 years or older, and ascites at laparotomy 350 mL were independently associated with refractory ascites. Postoperative complications, such as bleeding (P < .001), sepsis (P < .001), and bloodstream infection within 30 days after LDLT (P < .00), were significantly higher in the refractory ascites group. Conclusion. Refractory ascites is associated with reduced 1-year survival and increased postoperative complications. Four factors including MELD score 20, donor age 50 years or older, presence of left graft, and ascites at laparotomy 350 mL were independent predictors for refractory ascites.
P
OSTOPERATIVE ascites commonly occurs in living donor liver transplant (LDLT) recipients [1]. It is well accepted that refractory ascites after LDLT is a poor prognostic factor [2,3]. Despite recent advances in ascites treatment, including tolvaptan and transjugular intrahepatic portosystemic shunt, refractory ascites is still associated with renal impairment, increased incidence of abdominal infection, prolonged hospitalization, graft function deterioration, and reduced survival [4,5]. However, there are few studies that have investigated the independent risk factor of post-LDLT ascites in detail. In the present study, we investigated the risk factors for refractory ascites in patients 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.01.120
1516
who underwent LDLT by analyzing the perioperative donor and recipient characteristics. PATIENTS AND METHODS From April 2008 to September 2017, a total of 126 adult patients underwent initial LDLT at our hospital. Of these patients, 4
*Address correspondence to Masahiro Ohira, MD, PhD, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Tel: þ81-82257-5222; Fax: þ81-82-257-5224. E-mail: mohira@hiroshima-u. ac.jp ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 1516e1519 (2019)
REFRACTORY ASCITES AFTER LIVER TRANSPLANT
1517 Table 1. Characteristics Refractory Ascites Group n ¼ 24
Nonrefractory Ascites Group n ¼ 98
P Value
9/15 52.5 (2.18) 45.5 (2.3) 22.7 (1.45) 1/2/21 0.95 (0.04) 2/22 15/8/1 2/22 17/7 4/20 746 (27.8) 5013 (768) 145 (13.1) 1849 (482) 4/20 23.0 (1.17) 16.2 (0.88) 17.0 (0.89) 0.72 (0.02) 37.9 (5.31) 10.3 (2.19) 44.4 (5.11)
57/41 55.9 (1.08) 37.2 (1.1) 16.8 (0.75) 10/29/59 0.90 (0.02) 12/86 41/39/18 22/76 40/58 53/45 780 (13.7) 4867 (380) 112 (6.5) 1006 (237) 19/79 22.8 (0.59) 15.8 (0.45) 14.9 (0.45) 0.71 (0.01) 45.2 (2.85) 13.3 (1.17) 44.9 (2.74)
.07 .16 .002 <.001 .04 .26 .59 .10 .12 .59 .001 .28 .86 .03 .12 .76 .94 .69 .04 .77 .23 .21 .94
Male/Female Recipient age, mean (SD), y Donor age, mean (SD), y MELD, mean (SD), points Child-Pugh A/B/C GRWR, mean (SD), % ABO incompatibilities, þ/ Non/HCV/HBV Diabetes þ/ Left graft þ/ HCC þ/ Operative time, mean (SD), min Bleeding volume, mean (SD), mL Cold ischemia time, mean (SD), min Ascites at operation started, mean (SD), mL Splenectomy þ/ Pretransplant PVP, mean (SD), mm Hg Reflow PVP, mean (SD), mm Hg Posttransplant PVP, mean (SD), mm Hg Resistance index at POD 1, mean (SD) Systolic arterial flow at POD 1, mean (SD), mL/sec Diastolic arterial flow at POD 1, mean (SD), mL/sec Portal venous flow at POD 1, mean (SD), mL/sec
Abbreviations: GRWR, graft-to-recipient weight ratio; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; MELD, Model for End-Stage Liver Disease; POD, postoperative day; PVP, portal vein pressure.
underwent portal infusion of prostaglandin E1 during the LDLT surgery and were excluded from the study, leaving 122 recruited patients. We retrospectively reviewed their medical records and created a computerized database inclusive of demographic, radiologic, and laboratory data related to each patient. This study was approved by the Independent Ethics committee of Hiroshima University. To identify the risk factors for developing refractory ascites, the following preoperative recipient variables were analyzed: age, sex, primary liver disease, Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, and presence of ABO incompatibilities. Intraoperative variables included the volume of ascites at laparotomy; operating time; cold ischemia time; blood loss; portal venous pressure at pretransplant, at reflow, and at post-transplant; and whether a left lobe graft and splenectomy had been performed previously. We also recorded postoperative resistance index, systolic arterial blood flow, diastolic arterial blood flow, and portal venous blood flow velocity on day 1 post LDLT. Donor factors that were
analyzed included sex, age, graft weight-to-recipient weight ratio, donor liver quality, portal vein graft diameter, hepatic artery graft diameter, and right hepatic vein graft diameter. Refractory ascites post LDLT was defined as the production of ascites fluid >1000 mL/d that lasted longer than 14 days after LDLT or required repeated drainage after LDLT. Patients were placed into either group 1 (n ¼ 24, refractory ascites) or group 2 (n ¼ 98, nonrefractory ascites) based on this definition.
Statistics Univariate analyses using the c2 test or Fisher exact test where appropriate were performed to compare categorical variables, and the Mann-Whitney test was used to compare continuous variables. A difference was considered significant if the P value was <.05. Statistical analyses were performed using JMP statistical software, version 13 (SAS Institute, Cary, NC, United States).
Table 2. Post-transplant Complications
Bile duct complication þ/ Abdominal abscess þ/ Thrombosis þ/ Pulmonary embolism þ/ Heart vascular complication þ/ Bleeding þ/ Acute rejection þ/ Sepsis þ/ BSI within 30 days þ/ CMV infection þ/
Refractory Ascites Group n ¼ 24
Nonrefractory Ascites Group n ¼ 98
P Value
3/21 6/18 1/23 0/24 2/22 12/12 7/17 10/14 12/12 16/8
32/66 13/85 6/92 1/97 4/94 15/83 20/78 11/87 16/82 46/52
.05 .16 .71 .62 .39 <.001 .35 <.001 <.001 .08
Abbreviations: BSI, blood stream infection; CMV, cytomegalovirus.
1518
SATO, OHIRA, SHIMIZU ET AL Table 3. Risk Factors of Refractory Ascites Univariate Refractory Ascites Group (n ¼ 24)
Factors
Donor age, y 50 <50 MELD 20 <20 Ascites at operation started 350 <350 Left graft Yes No HCC Yes No Posttransplant PVP 15 <15 CIT 164 <164 GRWR 0.8 <0.8 Operation time 745 <745 Bleeding volume 2570 <2570
Nonrefractory Ascites Group (n ¼ 98)
Multivariate P Value
.002 27 95
11 13
16 82
36 86
16 8
20 78
45 77
18 7
27 70
57 65
17 7
40 58
57 65
4 20
53 45
61 61
18 6
43 55
22 100
8 16
14 84
84 38
17 7
67 31
73 49
11 13
62 36
92 30
20 4
72 26
<.001
OR
6.04
12.8
95% CI
P Value
1.4e26.6
.02
3.1e52.5
<.001
<.001
4.69
1.3e17.1
.02
.008
6.09
1.3e28.5
.02
.001
.01
.03
.82
.12
.31
Abbreviations: CIT, cold ischemia time; GRWR, graft-to-recipient weight ratio; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; OR, odds ratio; PVP, portal vein pressure.
RESULTS
The cohort included 66 men and 56 women, with a mean age at the time of the transplant of 55.2 (SD, 10.7) years. The patients’ characteristics, stratified by presence or absence of refractory ascites, are summarized in Table 1. In the Kaplan-Meier survival curve analysis, the 1-year survival rate was significantly worse in the refractory ascites group compared with the nonrefractory ascites group (P < .001). The postoperative complications are summarized in Table 2. There were significant differences between the 2 groups in the presence of bleeding, sepsis, and blood stream infection within 30 days after LDLT. Univariate analysis revealed that a high donor age, elevated recipient MELD score, high volume of ascites at laparotomy, presence of left lobe graft, absence of hepatocellular carcinoma, high post-transplant portal vein pressure, and long cold ischemia time were statistically significant predictors of a poor prognosis. Several factors that were associated with a poor prognosis in the univariate analysis, such as donor age 50 years or older (odds ratio [OR], 6.0391; 95% CI, 1.3695e26.6305; P ¼ .02), recipient MELD score 20 (OR, 12.8064; 95% CI, 3.1231e52.5131;
P < .001), amount of ascites at laparotomy 350 mL (OR, 4.6904; 95% CI, 1.2881e17.0792; P ¼ .02), and presence of left lobe graft (OR, 6.0862; 95% CI, 1.2989e28.5171; P ¼ .02), remained independent risk factors after a multivariate logistic regression analysis (Table 3).
DISCUSSION
In this study, we have shown that MELD score 20, donor age 50 years or older, presence of left graft, and ascites at laparotomy 350 mL were independent risk factors for refractory ascites. Small-for-size graft syndrome and portal hypertension have been reported to be associated with ascites formation [6,7]. Post-transplant ascites is common in LDLT where the left lobe with a graft weight-to-recipient weight ratio <0.8% is used [8], and the major mechanism for massive ascites formation after transplant was suggested to be postsinusoidal portal hypertension secondary to hepatic vein outflow difficulty [5]. Patients with refractory ascites in the present study also exhibited more serious preoperative conditions, as shown by higher MELD and Child-Pugh
REFRACTORY ASCITES AFTER LIVER TRANSPLANT
scores, than the patients without refractory ascites. Li et al reported that a higher preoperative MELD score and a higher Child-Pugh score were independent predictors of refractory ascites after LDLT [1]. In addition, another independent risk factor for refractory ascites observed in our study was the presence of ascites at laparotomy. Ito et al [9] and Matsudaira et al [10] also reported that patients in the refractory ascites group had higher incidences of preoperative ascites compared with the control group, although the definition of refractory ascites was slightly different from our study. Because preoperative ascites seems to be the only independent risk factor that can be clinically controlled before LDLT, maximal effort should be made to decrease accumulation of preoperative ascites to avoid refractory ascites after LDLT. The incidence of massive ascites after liver transplant found in different studies is quite variable, ranging from 7.0% to 48.4% [4,9]. In our study, massive ascites developed in 24 patients (19.6%). Cirera et al [4] reported only a 7% incidence of ascites after whole liver transplant, although the definition of massive ascites was slightly different in their study. Li et al reported a 25.7% incidence and Ito et al reported a 48.4% incidence of ascites after LDLT. These data suggest that postoperative massive ascites is more common in LDLT than in deceased donor liver transplant. Post-transplant refractory ascites was associated with poor prognosis and postoperative complications in this study. To control preoperative ascites, diuretic drugs and albumin products were used at first. In case of failure, the transjugular intrahepatic portosystemic shunt procedure [11] or drainage or cell-free and concentrated ascites reinfusion therapy [12] were the other treatment strategies used. Since September 2017, we have introduced a novel and improved cell-free and concentrated ascites reinfusion therapy [13] as a treatment option of preoperative ascites. Safety procedures, effectiveness of the LDLT procedure, and the perioperative management that our hospital follows have been validated (Seiichi Shimizu, 2019, unpublished data). Our new concentrated ascites reinfusion therapy could be a promising option for the treatment of refractory ascites, and its further effectiveness as a treatment for preoperative ascites should be analyzed in a future study (Seiichi Shimizu, personal communication, 2019). In conclusion, we found that MELD score 20, donor age 50 years or older, presence of left graft, and ascites at laparotomy 350 mL were the independent risk factors for refractory ascites. It is important to reduce and control the
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preoperative ascites to reduce the occurrence rate of refractory ascites after LDLT. REFERENCES [1] Li C, Lu Q, Luo J, Zhang Z. Independent risk factors for massive ascites after living donor liver transplantation in adults. Transplant Proc 2014;46:883e7. [2] Gotthardt DN, Weiss KH, Rathenberg V, Schemmer P, Stremmel W, Sauer P. Persistent ascites after liver transplantation: etiology, treatment and impact on survival. Ann Transplant 2013;18:378e83. [3] Stewart CA, Wertheim J, Olthoff K, Furth EE, Brensinger C, Markman J, et al. Ascites after liver transplantation–a mystery. Liver Transpl 2004;10:654e60. [4] Cirera I, Navasa M, Rimola A, Garcia-Pagan JC, Grande L, Garcia-Valdecasas JC, et al. Ascites after liver transplantation. Liver Transpl 2000;6:157e62. [5] Shirouzu Y, Ohya Y, Suda H, Asonuma K, Inomata Y. Massive ascites after living donor liver transplantation with a right lobe graft larger than 0.8% of the recipient’s body weight. Clin Transplant 2010;24:520e7. [6] Kiuchi T, Tanaka K, Ito T, Oike F, Ogura Y, Fujimoto Y, et al. Small-for-size graft in living donor liver transplantation: how far should we go? Liver Transpl 2003;9:S29e35. [7] Soejima Y, Taketomi A, Yoshizumi T, Uchiyama H, Harada N, Ijichi H, et al. Feasibility of left lobe living donor liver transplantation between adults: an 8-year, single-center experience of 107 cases. Am J Transplant 2006;6(5 Pt 1):1004e11. [8] Yi NJ, Suh KS, Cho YB, Lee HW, Cho EH, Cho JY, et al. The right small-for-size graft results in better outcomes than the left small-for-size graft in adult-to-adult living donor liver transplantation. World J Surg 2008;32:1722e30. [9] Ito D, Akamatsu N, Togashi J, Kaneko J, Arita J, Hasegawa K, et al. Behavior and clinical impact of ascites after living donor liver transplantation: risk factors associated with massive ascites. J Hepatobiliary Pancreat Sci 2016;23: 688e96. [10] Matsudaira S, Ishizaki Y, Yoshimoto J, Fujiwara N, Kawasaki S. Risk factors for intractable ascites after adult-to-adult living donor liver transplantation using left lobe. Transplant Direct 2017;3:e138. [11] Bai M, Qi XS, Yang ZP, Yang M, Fan DM, Han GH. TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis. World J Gastroenterol 2014;20:2704e14. [12] Hanafusa N, Isoai A, Ishihara T, Inoue T, Ishitani K, Utsugisawa T, et al. Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in refractory ascites: post-marketing surveillance results. PLoS One 2017;12: e0177303. [13] Matsusaki K, Ohta K, Yoshizawa A, Gyoda Y. Novel cell-free and concentrated ascites reinfusion therapy (KMCART) for refractory ascites associated with cancerous peritonitis: its effect and future perspectives. Int J Clin Oncol 2011;16: 395e400.