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Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?
Original Article
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation? Narendra S. Choudhary *, Sujeet K. Saha *, Sanjiv Saigal *, Dheeraj Gautam y, Neeraj Saraf *, Amit Rastogi *, Prashant Bhangui *, Srinivasan Thiagrajan *, Arvinder S. Soin * * Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India and y Department of Histopathology, Medanta, the Medicity, Gurgaon, India
A
lthough human leukocyte antigen (HLA) matching between the donor and recipient in solid organ transplantation has a proven beneficial (decreases rejection and improves survival) role in kidney and heart transplantation, its role in liver transplantation is controversial. Several studies have shown that donor and recipient HLA mismatch increases risk of early graft dysfunction or disease recurrence while data about impact on graft survival is conflicting.18 Although cadaveric donors remain genetically unrelated, donors in living donor liver transplantation (LDLT) may be genetically related (thus higher chances of HLA matching) or genetically unrelated. LDLT is the main form of liver transplantation in Asia including India owing to shortage of cadaveric organs. The living donors are related to the recipient; however, they may be genetically related (parents or siblings) or genetically unrelated
Keywords: liver transplantation, living donor, acute rejection, chronic rejection, survival Received: 7.5.2019; Accepted: 16.12.2019; Available online: xxx Address for correspondence: Dr. Sanjiv Saigal Director, Transplant Hepatology Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurgaon, 122001, India. E-mail: [email protected] Abbreviations: ACR: acute cellular rejection; CMV: cytomegalovirus; HLA: human leukocyte antigen; LDLT: living donor liver transplantation https://doi.org/10.1016/j.jceh.2019.12.004
(spouse or relatives of the spouse). Unrelated donors in LDLT have higher chances of HLA mismatch than related donors. There is limited literature regarding impact of genetic relation on outcomes of LDLT. A recent LDLT study showed that chronic rejection (CR) was more common in genetically unrelated donors than in related donors.3 We aim to compare outcomes of LDLT between recipients of genetically related and unrelated donors in the present study.
MATERIALS AND METHODS The study was conducted at a tertiary care center in North India. The institute's ethical committee approved the study. The study is a retrospective analysis of a prospectively maintained database of all LDLT recipients. The following LDLT recipients were excluded from analysis: those aged <18 years at the time of transplantation, those who underwent ABO-incompatible transplantation, those who underwent deceased donor liver transplantation, and those of donors with unclear genetic relationship (cousins, siblings of parents). A total of 1372 LDLT recipients were included in final analysis. These LDLTs were performed from June 2010 to October 2017, and the patients were followed up until October 2018. The acceptable limits of age and body mass index limits for donors are 18–55 years and 17–34 kg/m2 at our center, respectively. All donors had
© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved. Journal of Clinical and Experimental Hepatology | - xxxx | Vol. xxx | No. xxx | xxx Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
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Background: There are few data on genetic relation of the donor and outcomes in living donor liver transplantation (LDLT) recipients. We compared outcomes of LDLT between recipients of genetically related and unrelated donors in a large single-center series. Methods: The study included 1372 adult, ABO-compatible, primary LDLT recipients, who received a graft from either a first-degree relative (parent, sibling, son, or daughter; n = 756) or unrelated donor (spouse or relative of the spouse; n = 616). Results: The mean age of the recipients with a related donor was 50.2 ± 10.8 years compared with 47.3 ± 9.3 years for recipients with unrelated donors (P = 0.000). Chronic rejection was significantly more common in the genetically unrelated donor group than in the genetically related donor group (28 [4.5%] versus 9 [1.1%]; P = 0.000) at a mean follow-up of 37 months (15–95 months). There were no significant differences in other outcomes between the 2 groups. The 12-month and 36-month survival between the unrelated and related groups was 87.6% versus 90%, and 86.3% versus 89.7% respectively (P = 0.115). The multivariate analysis revealed genetically unrelated donors (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.80–8.34, P = 0.001) and history of acute cellular rejection (OR: 3.39, 95% CI: 1.68–6.81, P = 0.001) as predictors of chronic rejection. Conclusion: Although chronic rejection was found to be more common in genetically unrelated donors, the patient survival after LDLT was similar. ( J CLIN EXP HEPATOL xxxx;xxx:xxx)
DONOR GENETIC RELATION AND OUTCOME OF LDLT
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psychiatric, pulmonary, cardiac, and anesthesia evaluation before donation. Noncontrast computed tomography of the abdomen of donors was carried out to calculate the liver attenuation index (difference between average liver and splenic attenuation at a minimum of 25 areas). Prospective donors with suspected steatosis (liver attenuation index #5, presence of $2 metabolic risk factors), with low remnant liver volume (<35%), or with a graft-to-recipient weight ratio <0.8 underwent liver biopsy during evaluation. The immunosuppression protocol consisted of calcineurin inhibitors (mainly tacrolimus), mycophenolate, and steroids. There was no change of immunosuppression protocol in the study period. The steroids were tapered in 3 months except in cases of autoimmune hepatitis (5 mg/ day to continue) and hepatitis C (before availability of direct-acting antivirals in 2015). We aimed to maintain a tacrolimus level of 7–10 ng/mL in the first month and 5– 8 ng/ml thereafter. Mycophenolate was stopped at 2 years in patients with stable graft functions except in patients with renal dysfunction or metabolic syndrome in which case mycophenolate was continued with a low dose of tacrolimus. CR was diagnosed in presence of graft dysfunction on liver biopsy after ruling out other causes. Acute cellular rejection (ACR) was treated with steroids boluses (500 mg of methylprednisolone x 3 doses, followed by tapering). The parents or siblings were considered genetically related donors, and the spouse or relatives of the spouse were considered unrelated donors. ACR was diagnosed on liver biopsy in presence of raised liver function tests. CR was diagnosed on biopsy as per Banff Working Group recommendations.9 Liver biopsies were carried out in case of raised liver function tests, and protocol liver biopsies (in case of normal liver function tests) were not carried out.
STATISTICAL METHODS Data are expressed as number, percentage, mean (standard deviation), and median (25–75 interquartile range). Two groups (genetically related and unrelated donors) were compared using Fisher's exact test or chi-square test (categorical data), Mann–Whitney test (nonparametric data), and Student's t test (parametric data). The Kaplan–Meier survival curve and log-rank (Mantel–Cox) test were used to look for survival of LDLT recipients between genetically related and unrelated donor groups. As CR was significantly different in genetically related and unrelated groups, we entered genetic relation with other factors known to cause CR (donor age, cytomegalovirus [CMV] viremia, autoimmune etiology, ACR, donor genetic relation)5,10,11 into a logistic regression model. The significant parameters from univariate analysis were entered in multivariate analysis. A 2-tailed P value < 0.05 was considered as significant.
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CHOUDHARY ET AL
Table 1 Baseline Characteristics of LDLT Recipients (n = 1372). Parameters
Genetically related donors (n = 756)
Unrelated donors (n = 616)
P value
Recipient age (years)
50.2 10.8
47.3 9.3
0.000
Recipient, male :female
588/168
553/63
0.000
Child's score
9.6 2.1
9.8 1.9
0.271
MELD score
19.3 6.5
19.4 6.3
0.825
Alcohol
184 (24.3%)
212 (34.4%)
0.000
Hepatitis C
172 (22.7%)
110 (17.8%)
0.026
Hepatitis B
99 (13%)
82 (13.3%)
0.936
Cryptogenic/ nonalcoholic steatohepatitis
190 (25.1%)
128 (20.7%)
0.062
Others
111 (14.6%)
84 (13.6%)
0.587
Donor age (years)
31.4 10.1
36.5 9.6
0.000
Donor sex as female
357 (47.2%)
416 (67.5%)
0.000
Graft-to-recipient weight ratio
0.98 0.21
0.96 0.19
0.134
Etiology of liver disease
LDLT, living donor liver transplantation; MELD, model for end-stage liver disease.
RESULTS The study group consisted of 231 women and 1141 men, with a mean age of 49 years. Among these 1372 adult LDLT recipients, 756 donors were genetically related, whereas 616 were genetically unrelated. The genetically related donors included brothers (n = 99), daughters (n = 198), fathers (n = 9), sisters (n = 107), mothers (n = 23), and sons (n = 320). The genetically unrelated donors included spouses and relatives of the spouse or daughterin-law/son-in-law (n = 616). The characteristics of the recipients are shown in table 1, and comparison of posttransplant outcomes between genetically related and unrelated donors is shown in table 2. The main etiologies of end-stage liver disease before liver transplantation were alcohol followed by hepatitis C, cryptogenic/nonalcoholic steatohepatitis–related cirrhosis, hepatitis B, and others (including autoimmune liver diseases), as shown in table 1. The proportion of LDLT recipients with alcohol as etiology was significantly more in the genetically unrelated group, and hepatitis C was more common in the genetically related group. The donors were of younger age in the genetically related group (as this group included sons and daughters). A significantly more number of women donated in the genetically unrelated group; this difference was due to donation by wives (n = 120) to husbands with alcoholic cirrhosis, as all alcoholics were men. There was
© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
Table 2 Outcomes in Genetically Related Versus Unrelated Donor Groups. Parameters
Genetically related donors (n = 756)
Hospital stay (days)
15 (12–18)
Unrelated donors (n = 616)
P value
15 (13–29)
0.335 0.359
ICU stay (days)
5 (5–6)
5 (5–6)
Acute cellular rejection
105 (13.8%)
108 (17.5%) 0.072
Chronic rejection
9 (1.1%)
28 (4.5%)
0.000
Vascular complications (hepatic artery/ portal vein)
20 (2.6%)
25 (4%)
0.170
History of 317 (41.9%) cytomegalovirus viremia
270 (35.2%) 0.510
ICU, intensive care unit.
no difference in median follow-up, as shown in table 1. Post-transplant outcomes such as stay in the intensive care unit/hospital, ACR, CMV viremia, and vascular complications were not statistically different in the 2 groups, as shown in table 2. There was no statistical difference between the two groups regarding biliary strictures. A total of 213 recipients had at least 1 episode of ACR at 3.3 (1.3– 23.7) weeks after LT. Forty-three recipients had 2 or more episodes of ACR. Thirty-seven (2.6%) recipients were diagnosed as having CR at 25 (11–45) months after LT. The etiology profile of recipients with or without ACR was not different. The percentage of recipients with ACR among main etiologies was as follows: 19 of 181 patients (10.49%) in hepatitis B, 54 of 282 (19.14%) in hepatitis C, 60 of 396 (15.15%) of alcoholic liver disease, 46 of 318 (14.46%) of non-alcoholic steatohepatitis/cryptogenic, and 14 of 73 (19.17%) of autoimmune liver diseases (P = 0.116). The comparison of patients with CR and without CR is shown in table 3. Similar to ACR, the etiology profile of recipients with or without CR was not different. The patients with CR had significantly higher chances of having an ACR episode or $2 ACR episodes. The follow-up period was
similar in transplant recipients with or without CR, 53 (23–72) months versus 48 (23–71) months (P = 0.744). The CR group had the first episode of ACR later than the non-CR group: 28 (2–90) weeks versus 3 (1–18) weeks (P = 0.008). The incidence of CR was not different in same gender versus different gender donation, as shown in table 3. Five patients (all in the genetically unrelated group, including 1 with alcohol recidivism) had history of noncompliance to immunosuppression. The association of CR with genetic relation of donors remained statistically significant after exclusion of these 5 patients also (P = 0.002). The incidence of CR was significantly more common in the genetically unrelated group (28 [4.5%] versus 9 [1.1%]) than in the genetically related group (P = 0.000). The 12-month actual survival between the unrelated and related groups was 87.6% versus 90%; the 36month actuarial survival was 86.3% versus 89.7% respectively (P = 0.115), as shown in Figure 1. The univariate and multivariate analysis for CR is shown in Tables 4 and 5. The factors with a significant P value in univariate analysis (genetically unrelated donors, CMV, and ACR) were included in multivariate analysis. The multivariate analysis revealed unrelated donors (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.80–8.34, P = 0.001) and history of ACR (OR: 3.39, 95% CI: 1.68–6.81, P = 0.001) as predictors of CR, as shown in table 4. The donor genetic relation remained statistically significant even when ACR after 3 or 6 months was included in multivariate analysis in place of any time history of ACR. Retransplantation was offered to patients with CR in case of no response to increased immunosuppression by addition of everolimus.
DISCUSSION In contrast to kidney and heart transplantation, where genetic matching (HLA) improves survival and lowers rejection rates, HLA matching is not routinely performed in liver transplantation as its importance is controversial, and several studies have shown contradicting results.4,7,8,10–17 In liver transplantation, organ allocation
Table 3 Comparison of CR and No CR Groups. No CR group (n = 1335)
P
4:8:15:7:2:1
177:274:381:311:71:121
0.738
Same gender:different gender donation
13:24
583:752
0.319
Any time history of ACR
17 (45.94%)
196 (14.68%)
0.000
2 or more episodes of ACR
6 (16.21%)
37 (2.77%)
0.001
ACR after 3 months of LT
11 (29.7%)
61 (4.5%)
0.000
ACR after 6 months of LT
10 (27%)
42 (3.1%)
0.000
Time of first ACR
28 (2–90) weeks
3 (1–18) weeks
0.008
History of ctomegalovirus viremia
22 (59.4%)
565 (42.3%)
0.043
Parameter
CR group (n = 37)
Etiology (hepatitits B: hepatitis C: alcoholic liver disease: non-alcoholic steatohepatitis/cryptogenic:autoimmune: others)
ACR, Acute cellular rejection; LT, liver transplantation.
Journal of Clinical and Experimental Hepatology | - xxxx | Vol. xxx | No. xxx | xxx
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Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
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DONOR GENETIC RELATION AND OUTCOME OF LDLT
DONOR GENETIC RELATION AND OUTCOME OF LDLT
CHOUDHARY ET AL
Table 5 Multivariate Analysis for Chronic Rejection. Parameters
OR
95% CI
P value
Lower Upper Genetically unrelated donor
3.884 1.807 8.349 0.001
Acute cellular rejection
3.392 1.689 6.812 0.001
History of cytomegalovirus viremia 1.783 0.880 3.612 0.108 OR, odds ratio; CI, confidence interval.
Figure 1 Patient survival between the unrelated and related donor groups.
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relies not on HLA but mostly on the ABO blood group, and outcomes are also affected by several other recipient, donor, and transplant factors such as the model for the end-stage liver disease score, previous infection and acute kidney injury, donor liver volume and quality, restoration of optimal inflow, and outflow to the graft, among others.7 However, there is some evidence that HLA matching may have a role in liver transplantation. Balan et al3 described long-term follow-up of 799 adults (883 liver transplantations). The mismatching negatively affected 10-year graft survival (hazard ratio: 1.6); mismatching also increased recurrence of autoimmune hepatitis, hepatitis C, primary sclerosing cholangitis, and primary biliary cirrhosis.3 A meta-analysis by Lan et al,4 including 16 studies, found lower rates of acute rejection with lower number of HLA mismatches (relative risk: 0.77) with no effect on 1-year and 5-year graft survival; however, most of the studies had a small proportion of transplant recipients. LDLT offers an option to study impact of genetic relationship as a significant proportion of donors are first-degree relatives (parents, siblings, and offspring), whereas others are totally genetically unrelated (e.g., spouse and relatives
of the spouse). Several studies have looked into this aspect and have shown variable results. Jakab et al18 showed no impact of genetic relationship (first-degree relative versus others) in a study including 1838 LDLTs; the authors had HLA matching data of 631 recipients, and matching had no impact on 5-year graft survival. Suehiro et al19 showed that positive crossmatching was associated with significantly more acute rejection and lower graft survival. A recent study by Ali et al5 compared 212 LDLT genetically related recipient–donor pairs with 96 unrelated pairs. The authors found significantly less CR (7% versus 14.7%; P = 0.03) in the related than in the unrelated group, but there was no difference in survival rates.5 Although we also found higher rates of CR in recipients with unrelated donors (4.5%) than in those with related (1.1%) donors; both these rates are much lower than those reported in the study by Ali et al.5 These lower rates may be related to the different etiology profile of LDLT recipients (HCV in the study by Ali et al5) or immunosuppression protocol (steroid-free in the study by Ali et al5). Although the present study is retrospective in nature, it assesses rejection rates and mortality, which are not subject to bias in a large cohort. The limitations of the study include absence of information on HLA matching and donor-specific antibodies. To conclude, we present outcomes of a large cohort (n = 1372) of LDLT recipients between genetically related and unrelated donor–recipient pairs. The CR rates were significantly higher in the genetically unrelated group, although the overall patient survival rates were similar.
CONFLICTS OF INTEREST Table 4 Univariate Analysis for Chronic Rejection. Parameters
OR
95% CI
P value
Lower Upper Donor age
1.015 0.984 1.047 0.348
Autoimmune versus other etiologies
0.678 0.091 5.055 0.705
Genetically unrelated donor
4.105 1.920 8.776 0.000
Acute cellular rejection
3.979 2.024 7.823 0.000
History of cytomegalovirus viremia 2.249 1.134 4.460 0.020 OR, odds ratio; CI, confidence interval.
4
The authors have none to declare.
ACKNOWLEDGMENTS The authors thank Mr. Yogesh Saini and Mr. Manish K Singh (biostatistician). REFERENCES 1. Lee PC, Zhu L, TerasakiPI, Everly MJ. HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation. 2009;88:568–574.
© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
2. Kaczmarek I, Deutsch MA, Rohrer ME, et al. HLA-DR matching improves survival after heart transplantation: is it time to change allocation policies? J Heart Lung Transplant. 2006;25:1057– 1062. 3. Balan V, Ruppert K, Demetris AJ, et al. Long-term outcome of human leukocyte antigen mismatching in liver transplantation: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database. Hepatology. 2008;48:878–888. 4. Lan Xi, Zhang MM, Pu CL, et al. Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: a meta-analysis. World J Gastroenterol. 2010 Jul 21;16:3457–3464. 5. Ali MA, Elshobari MM, Salah T, et al. Impact of donor-recipient genetic relationship on outcome of living donor liver transplantation. Liver Transplant. 2017;23:43–49. 6. Kaneku H, O'Leary J, Banuelos N, et al. De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients. Am J Transplant. 2013;13:1541–1548. 7. Reddy MS, Varghese J, Venkataraman J, Rela M. Matching donor to recipient in liver transplantation: relevance in clinical practice. World J Hepatol. 2013;5:603–611. 8. Fan S, Zhang Z. Comparison of acute cellular rejection between living donor liver transplantation and cadaveric liver transplantation [in Chinese]. Zhonghua Yixue Zazhi. 2001;81:1092–1094. €bscher SG, et al. 2016 Comprehensive 9. Demetris AJ, Bellamy C, Hu update of the Banff working group on liver allograft pathology: introduction of antibody-mediated rejection. Am J Transplant. 2016;16:2816–2835. 10. Neumann UP, Langrehr JM, Lang M, et al. Impact of HLA matching upon outcome after liver transplantation. Transplant Proc. 2002;34:1499–1500.
11. Jain A, Demetris AJ, Kashyap R, et al. Does tacrolimus offer virtual freedom from chronic rejection after primary liver transplantation? Risk and prognostic factors in 1,048 liver transplantations with a mean follow-up of 6 years. Liver Transplant. 2001;7:623–630. 12. Choudhary NS, Saraf N, Saigal S, et al. Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: a single center experience. Clin Transplant. 2018;32:e13161. 13. Poli F, Frison S, Cardillo M, et al. A retrospective analysis of HLA matching and other factors on liver graft outcome. Transplant Proc. 2001;33:1368–1369. 14. Donaldson P, Underhill J, Doherty D, et al. Influence of human leukocyte antigen matching on liver allograft survival and rejection: “the dualistic effect”. Hepatology. 1993;17:1008–1015. 15. Nikaein A, Backman L, Jennings L, et al. HLA compatibility and liver transplant outcome. Improved patient survival by HLA and crossmatching. Transplantation. 1994;58:786–792. 16. Doran TJ, Geczy AF, Painter D, et al. A large, single center investigation of the immunogenetic factors affecting liver transplantation. Transplantation. 2000;69:1491–1498. 17. Liu LU, Bodian CA, Gondolesi GE, et al. Marked differences in acute cellular rejection rates between living-donor and deceased-donor liver transplant recipients. Transplantation. 2005;80:1072–1080. 18. Jakab SS, Navarro VJ, Colombe BW, Daskalakis C, Herrine SK, Rossi S. Human leukocyte antigen and adult living-donor liver transplantation outcomes: an analysis of the organ procurement and transplantation network database. Liver Transplant. 2007;13:1405–1413. 19. Suehiro T, Shimada M, Kishikawa K, et al. Influence of HLA compatibility and lymphocyte cross-matching on acute cellular rejection following living donor adult liver transplantation. Liver Int. 2005;25:1182–1188.
Journal of Clinical and Experimental Hepatology | - xxxx | Vol. xxx | No. xxx | xxx
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Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
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DONOR GENETIC RELATION AND OUTCOME OF LDLT
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY
Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation? Narendra S. Choudhary *, Sujeet K. Saha *, Sanjiv Saigal *, Dheeraj Gautam y, Neeraj Saraf *, Amit Rastogi *, Prashant Bhangui *, Srinivasan Thiagrajan *, Arvinder S. Soin * * Institute of Liver Transplantation and Regenerative Medicine, Medanta, the Medicity, India and y Department of Histopathology, Medanta, the Medicity, Gurgaon, India
A
lthough human leukocyte antigen (HLA) matching between the donor and recipient in solid organ transplantation has a proven beneficial (decreases rejection and improves survival) role in kidney and heart transplantation, its role in liver transplantation is controversial. Several studies have shown that donor and recipient HLA mismatch increases risk of early graft dysfunction or disease recurrence while data about impact on graft survival is conflicting.18 Although cadaveric donors remain genetically unrelated, donors in living donor liver transplantation (LDLT) may be genetically related (thus higher chances of HLA matching) or genetically unrelated. LDLT is the main form of liver transplantation in Asia including India owing to shortage of cadaveric organs. The living donors are related to the recipient; however, they may be genetically related (parents or siblings) or genetically unrelated
Keywords: liver transplantation, living donor, acute rejection, chronic rejection, survival Received: 7.5.2019; Accepted: 16.12.2019; Available online: xxx Address for correspondence: Dr. Sanjiv Saigal Director, Transplant Hepatology Institute of Liver Transplantation and Regenerative Medicine, Medanta The Medicity, Gurgaon, 122001, India. E-mail: [email protected] Abbreviations: ACR: acute cellular rejection; CMV: cytomegalovirus; HLA: human leukocyte antigen; LDLT: living donor liver transplantation https://doi.org/10.1016/j.jceh.2019.12.004
(spouse or relatives of the spouse). Unrelated donors in LDLT have higher chances of HLA mismatch than related donors. There is limited literature regarding impact of genetic relation on outcomes of LDLT. A recent LDLT study showed that chronic rejection (CR) was more common in genetically unrelated donors than in related donors.3 We aim to compare outcomes of LDLT between recipients of genetically related and unrelated donors in the present study.
MATERIALS AND METHODS The study was conducted at a tertiary care center in North India. The institute's ethical committee approved the study. The study is a retrospective analysis of a prospectively maintained database of all LDLT recipients. The following LDLT recipients were excluded from analysis: those aged <18 years at the time of transplantation, those who underwent ABO-incompatible transplantation, those who underwent deceased donor liver transplantation, and those of donors with unclear genetic relationship (cousins, siblings of parents). A total of 1372 LDLT recipients were included in final analysis. These LDLTs were performed from June 2010 to October 2017, and the patients were followed up until October 2018. The acceptable limits of age and body mass index limits for donors are 18–55 years and 17–34 kg/m2 at our center, respectively. All donors had
© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved. Journal of Clinical and Experimental Hepatology | - xxxx | Vol. xxx | No. xxx | xxx Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
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Background: There are few data on genetic relation of the donor and outcomes in living donor liver transplantation (LDLT) recipients. We compared outcomes of LDLT between recipients of genetically related and unrelated donors in a large single-center series. Methods: The study included 1372 adult, ABO-compatible, primary LDLT recipients, who received a graft from either a first-degree relative (parent, sibling, son, or daughter; n = 756) or unrelated donor (spouse or relative of the spouse; n = 616). Results: The mean age of the recipients with a related donor was 50.2 ± 10.8 years compared with 47.3 ± 9.3 years for recipients with unrelated donors (P = 0.000). Chronic rejection was significantly more common in the genetically unrelated donor group than in the genetically related donor group (28 [4.5%] versus 9 [1.1%]; P = 0.000) at a mean follow-up of 37 months (15–95 months). There were no significant differences in other outcomes between the 2 groups. The 12-month and 36-month survival between the unrelated and related groups was 87.6% versus 90%, and 86.3% versus 89.7% respectively (P = 0.115). The multivariate analysis revealed genetically unrelated donors (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.80–8.34, P = 0.001) and history of acute cellular rejection (OR: 3.39, 95% CI: 1.68–6.81, P = 0.001) as predictors of chronic rejection. Conclusion: Although chronic rejection was found to be more common in genetically unrelated donors, the patient survival after LDLT was similar. ( J CLIN EXP HEPATOL xxxx;xxx:xxx)
DONOR GENETIC RELATION AND OUTCOME OF LDLT
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psychiatric, pulmonary, cardiac, and anesthesia evaluation before donation. Noncontrast computed tomography of the abdomen of donors was carried out to calculate the liver attenuation index (difference between average liver and splenic attenuation at a minimum of 25 areas). Prospective donors with suspected steatosis (liver attenuation index #5, presence of $2 metabolic risk factors), with low remnant liver volume (<35%), or with a graft-to-recipient weight ratio <0.8 underwent liver biopsy during evaluation. The immunosuppression protocol consisted of calcineurin inhibitors (mainly tacrolimus), mycophenolate, and steroids. There was no change of immunosuppression protocol in the study period. The steroids were tapered in 3 months except in cases of autoimmune hepatitis (5 mg/ day to continue) and hepatitis C (before availability of direct-acting antivirals in 2015). We aimed to maintain a tacrolimus level of 7–10 ng/mL in the first month and 5– 8 ng/ml thereafter. Mycophenolate was stopped at 2 years in patients with stable graft functions except in patients with renal dysfunction or metabolic syndrome in which case mycophenolate was continued with a low dose of tacrolimus. CR was diagnosed in presence of graft dysfunction on liver biopsy after ruling out other causes. Acute cellular rejection (ACR) was treated with steroids boluses (500 mg of methylprednisolone x 3 doses, followed by tapering). The parents or siblings were considered genetically related donors, and the spouse or relatives of the spouse were considered unrelated donors. ACR was diagnosed on liver biopsy in presence of raised liver function tests. CR was diagnosed on biopsy as per Banff Working Group recommendations.9 Liver biopsies were carried out in case of raised liver function tests, and protocol liver biopsies (in case of normal liver function tests) were not carried out.
STATISTICAL METHODS Data are expressed as number, percentage, mean (standard deviation), and median (25–75 interquartile range). Two groups (genetically related and unrelated donors) were compared using Fisher's exact test or chi-square test (categorical data), Mann–Whitney test (nonparametric data), and Student's t test (parametric data). The Kaplan–Meier survival curve and log-rank (Mantel–Cox) test were used to look for survival of LDLT recipients between genetically related and unrelated donor groups. As CR was significantly different in genetically related and unrelated groups, we entered genetic relation with other factors known to cause CR (donor age, cytomegalovirus [CMV] viremia, autoimmune etiology, ACR, donor genetic relation)5,10,11 into a logistic regression model. The significant parameters from univariate analysis were entered in multivariate analysis. A 2-tailed P value < 0.05 was considered as significant.
2
CHOUDHARY ET AL
Table 1 Baseline Characteristics of LDLT Recipients (n = 1372). Parameters
Genetically related donors (n = 756)
Unrelated donors (n = 616)
P value
Recipient age (years)
50.2 10.8
47.3 9.3
0.000
Recipient, male :female
588/168
553/63
0.000
Child's score
9.6 2.1
9.8 1.9
0.271
MELD score
19.3 6.5
19.4 6.3
0.825
Alcohol
184 (24.3%)
212 (34.4%)
0.000
Hepatitis C
172 (22.7%)
110 (17.8%)
0.026
Hepatitis B
99 (13%)
82 (13.3%)
0.936
Cryptogenic/ nonalcoholic steatohepatitis
190 (25.1%)
128 (20.7%)
0.062
Others
111 (14.6%)
84 (13.6%)
0.587
Donor age (years)
31.4 10.1
36.5 9.6
0.000
Donor sex as female
357 (47.2%)
416 (67.5%)
0.000
Graft-to-recipient weight ratio
0.98 0.21
0.96 0.19
0.134
Etiology of liver disease
LDLT, living donor liver transplantation; MELD, model for end-stage liver disease.
RESULTS The study group consisted of 231 women and 1141 men, with a mean age of 49 years. Among these 1372 adult LDLT recipients, 756 donors were genetically related, whereas 616 were genetically unrelated. The genetically related donors included brothers (n = 99), daughters (n = 198), fathers (n = 9), sisters (n = 107), mothers (n = 23), and sons (n = 320). The genetically unrelated donors included spouses and relatives of the spouse or daughterin-law/son-in-law (n = 616). The characteristics of the recipients are shown in table 1, and comparison of posttransplant outcomes between genetically related and unrelated donors is shown in table 2. The main etiologies of end-stage liver disease before liver transplantation were alcohol followed by hepatitis C, cryptogenic/nonalcoholic steatohepatitis–related cirrhosis, hepatitis B, and others (including autoimmune liver diseases), as shown in table 1. The proportion of LDLT recipients with alcohol as etiology was significantly more in the genetically unrelated group, and hepatitis C was more common in the genetically related group. The donors were of younger age in the genetically related group (as this group included sons and daughters). A significantly more number of women donated in the genetically unrelated group; this difference was due to donation by wives (n = 120) to husbands with alcoholic cirrhosis, as all alcoholics were men. There was
© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
Table 2 Outcomes in Genetically Related Versus Unrelated Donor Groups. Parameters
Genetically related donors (n = 756)
Hospital stay (days)
15 (12–18)
Unrelated donors (n = 616)
P value
15 (13–29)
0.335 0.359
ICU stay (days)
5 (5–6)
5 (5–6)
Acute cellular rejection
105 (13.8%)
108 (17.5%) 0.072
Chronic rejection
9 (1.1%)
28 (4.5%)
0.000
Vascular complications (hepatic artery/ portal vein)
20 (2.6%)
25 (4%)
0.170
History of 317 (41.9%) cytomegalovirus viremia
270 (35.2%) 0.510
ICU, intensive care unit.
no difference in median follow-up, as shown in table 1. Post-transplant outcomes such as stay in the intensive care unit/hospital, ACR, CMV viremia, and vascular complications were not statistically different in the 2 groups, as shown in table 2. There was no statistical difference between the two groups regarding biliary strictures. A total of 213 recipients had at least 1 episode of ACR at 3.3 (1.3– 23.7) weeks after LT. Forty-three recipients had 2 or more episodes of ACR. Thirty-seven (2.6%) recipients were diagnosed as having CR at 25 (11–45) months after LT. The etiology profile of recipients with or without ACR was not different. The percentage of recipients with ACR among main etiologies was as follows: 19 of 181 patients (10.49%) in hepatitis B, 54 of 282 (19.14%) in hepatitis C, 60 of 396 (15.15%) of alcoholic liver disease, 46 of 318 (14.46%) of non-alcoholic steatohepatitis/cryptogenic, and 14 of 73 (19.17%) of autoimmune liver diseases (P = 0.116). The comparison of patients with CR and without CR is shown in table 3. Similar to ACR, the etiology profile of recipients with or without CR was not different. The patients with CR had significantly higher chances of having an ACR episode or $2 ACR episodes. The follow-up period was
similar in transplant recipients with or without CR, 53 (23–72) months versus 48 (23–71) months (P = 0.744). The CR group had the first episode of ACR later than the non-CR group: 28 (2–90) weeks versus 3 (1–18) weeks (P = 0.008). The incidence of CR was not different in same gender versus different gender donation, as shown in table 3. Five patients (all in the genetically unrelated group, including 1 with alcohol recidivism) had history of noncompliance to immunosuppression. The association of CR with genetic relation of donors remained statistically significant after exclusion of these 5 patients also (P = 0.002). The incidence of CR was significantly more common in the genetically unrelated group (28 [4.5%] versus 9 [1.1%]) than in the genetically related group (P = 0.000). The 12-month actual survival between the unrelated and related groups was 87.6% versus 90%; the 36month actuarial survival was 86.3% versus 89.7% respectively (P = 0.115), as shown in Figure 1. The univariate and multivariate analysis for CR is shown in Tables 4 and 5. The factors with a significant P value in univariate analysis (genetically unrelated donors, CMV, and ACR) were included in multivariate analysis. The multivariate analysis revealed unrelated donors (odds ratio [OR]: 3.88, 95% confidence interval [CI]: 1.80–8.34, P = 0.001) and history of ACR (OR: 3.39, 95% CI: 1.68–6.81, P = 0.001) as predictors of CR, as shown in table 4. The donor genetic relation remained statistically significant even when ACR after 3 or 6 months was included in multivariate analysis in place of any time history of ACR. Retransplantation was offered to patients with CR in case of no response to increased immunosuppression by addition of everolimus.
DISCUSSION In contrast to kidney and heart transplantation, where genetic matching (HLA) improves survival and lowers rejection rates, HLA matching is not routinely performed in liver transplantation as its importance is controversial, and several studies have shown contradicting results.4,7,8,10–17 In liver transplantation, organ allocation
Table 3 Comparison of CR and No CR Groups. No CR group (n = 1335)
P
4:8:15:7:2:1
177:274:381:311:71:121
0.738
Same gender:different gender donation
13:24
583:752
0.319
Any time history of ACR
17 (45.94%)
196 (14.68%)
0.000
2 or more episodes of ACR
6 (16.21%)
37 (2.77%)
0.001
ACR after 3 months of LT
11 (29.7%)
61 (4.5%)
0.000
ACR after 6 months of LT
10 (27%)
42 (3.1%)
0.000
Time of first ACR
28 (2–90) weeks
3 (1–18) weeks
0.008
History of ctomegalovirus viremia
22 (59.4%)
565 (42.3%)
0.043
Parameter
CR group (n = 37)
Etiology (hepatitits B: hepatitis C: alcoholic liver disease: non-alcoholic steatohepatitis/cryptogenic:autoimmune: others)
ACR, Acute cellular rejection; LT, liver transplantation.
Journal of Clinical and Experimental Hepatology | - xxxx | Vol. xxx | No. xxx | xxx
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Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
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DONOR GENETIC RELATION AND OUTCOME OF LDLT
DONOR GENETIC RELATION AND OUTCOME OF LDLT
CHOUDHARY ET AL
Table 5 Multivariate Analysis for Chronic Rejection. Parameters
OR
95% CI
P value
Lower Upper Genetically unrelated donor
3.884 1.807 8.349 0.001
Acute cellular rejection
3.392 1.689 6.812 0.001
History of cytomegalovirus viremia 1.783 0.880 3.612 0.108 OR, odds ratio; CI, confidence interval.
Figure 1 Patient survival between the unrelated and related donor groups.
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relies not on HLA but mostly on the ABO blood group, and outcomes are also affected by several other recipient, donor, and transplant factors such as the model for the end-stage liver disease score, previous infection and acute kidney injury, donor liver volume and quality, restoration of optimal inflow, and outflow to the graft, among others.7 However, there is some evidence that HLA matching may have a role in liver transplantation. Balan et al3 described long-term follow-up of 799 adults (883 liver transplantations). The mismatching negatively affected 10-year graft survival (hazard ratio: 1.6); mismatching also increased recurrence of autoimmune hepatitis, hepatitis C, primary sclerosing cholangitis, and primary biliary cirrhosis.3 A meta-analysis by Lan et al,4 including 16 studies, found lower rates of acute rejection with lower number of HLA mismatches (relative risk: 0.77) with no effect on 1-year and 5-year graft survival; however, most of the studies had a small proportion of transplant recipients. LDLT offers an option to study impact of genetic relationship as a significant proportion of donors are first-degree relatives (parents, siblings, and offspring), whereas others are totally genetically unrelated (e.g., spouse and relatives
of the spouse). Several studies have looked into this aspect and have shown variable results. Jakab et al18 showed no impact of genetic relationship (first-degree relative versus others) in a study including 1838 LDLTs; the authors had HLA matching data of 631 recipients, and matching had no impact on 5-year graft survival. Suehiro et al19 showed that positive crossmatching was associated with significantly more acute rejection and lower graft survival. A recent study by Ali et al5 compared 212 LDLT genetically related recipient–donor pairs with 96 unrelated pairs. The authors found significantly less CR (7% versus 14.7%; P = 0.03) in the related than in the unrelated group, but there was no difference in survival rates.5 Although we also found higher rates of CR in recipients with unrelated donors (4.5%) than in those with related (1.1%) donors; both these rates are much lower than those reported in the study by Ali et al.5 These lower rates may be related to the different etiology profile of LDLT recipients (HCV in the study by Ali et al5) or immunosuppression protocol (steroid-free in the study by Ali et al5). Although the present study is retrospective in nature, it assesses rejection rates and mortality, which are not subject to bias in a large cohort. The limitations of the study include absence of information on HLA matching and donor-specific antibodies. To conclude, we present outcomes of a large cohort (n = 1372) of LDLT recipients between genetically related and unrelated donor–recipient pairs. The CR rates were significantly higher in the genetically unrelated group, although the overall patient survival rates were similar.
CONFLICTS OF INTEREST Table 4 Univariate Analysis for Chronic Rejection. Parameters
OR
95% CI
P value
Lower Upper Donor age
1.015 0.984 1.047 0.348
Autoimmune versus other etiologies
0.678 0.091 5.055 0.705
Genetically unrelated donor
4.105 1.920 8.776 0.000
Acute cellular rejection
3.979 2.024 7.823 0.000
History of cytomegalovirus viremia 2.249 1.134 4.460 0.020 OR, odds ratio; CI, confidence interval.
4
The authors have none to declare.
ACKNOWLEDGMENTS The authors thank Mr. Yogesh Saini and Mr. Manish K Singh (biostatistician). REFERENCES 1. Lee PC, Zhu L, TerasakiPI, Everly MJ. HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation. 2009;88:568–574.
© 2019 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
2. Kaczmarek I, Deutsch MA, Rohrer ME, et al. HLA-DR matching improves survival after heart transplantation: is it time to change allocation policies? J Heart Lung Transplant. 2006;25:1057– 1062. 3. Balan V, Ruppert K, Demetris AJ, et al. Long-term outcome of human leukocyte antigen mismatching in liver transplantation: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database. Hepatology. 2008;48:878–888. 4. Lan Xi, Zhang MM, Pu CL, et al. Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: a meta-analysis. World J Gastroenterol. 2010 Jul 21;16:3457–3464. 5. Ali MA, Elshobari MM, Salah T, et al. Impact of donor-recipient genetic relationship on outcome of living donor liver transplantation. Liver Transplant. 2017;23:43–49. 6. Kaneku H, O'Leary J, Banuelos N, et al. De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients. Am J Transplant. 2013;13:1541–1548. 7. Reddy MS, Varghese J, Venkataraman J, Rela M. Matching donor to recipient in liver transplantation: relevance in clinical practice. World J Hepatol. 2013;5:603–611. 8. Fan S, Zhang Z. Comparison of acute cellular rejection between living donor liver transplantation and cadaveric liver transplantation [in Chinese]. Zhonghua Yixue Zazhi. 2001;81:1092–1094. €bscher SG, et al. 2016 Comprehensive 9. Demetris AJ, Bellamy C, Hu update of the Banff working group on liver allograft pathology: introduction of antibody-mediated rejection. Am J Transplant. 2016;16:2816–2835. 10. Neumann UP, Langrehr JM, Lang M, et al. Impact of HLA matching upon outcome after liver transplantation. Transplant Proc. 2002;34:1499–1500.
11. Jain A, Demetris AJ, Kashyap R, et al. Does tacrolimus offer virtual freedom from chronic rejection after primary liver transplantation? Risk and prognostic factors in 1,048 liver transplantations with a mean follow-up of 6 years. Liver Transplant. 2001;7:623–630. 12. Choudhary NS, Saraf N, Saigal S, et al. Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: a single center experience. Clin Transplant. 2018;32:e13161. 13. Poli F, Frison S, Cardillo M, et al. A retrospective analysis of HLA matching and other factors on liver graft outcome. Transplant Proc. 2001;33:1368–1369. 14. Donaldson P, Underhill J, Doherty D, et al. Influence of human leukocyte antigen matching on liver allograft survival and rejection: “the dualistic effect”. Hepatology. 1993;17:1008–1015. 15. Nikaein A, Backman L, Jennings L, et al. HLA compatibility and liver transplant outcome. Improved patient survival by HLA and crossmatching. Transplantation. 1994;58:786–792. 16. Doran TJ, Geczy AF, Painter D, et al. A large, single center investigation of the immunogenetic factors affecting liver transplantation. Transplantation. 2000;69:1491–1498. 17. Liu LU, Bodian CA, Gondolesi GE, et al. Marked differences in acute cellular rejection rates between living-donor and deceased-donor liver transplant recipients. Transplantation. 2005;80:1072–1080. 18. Jakab SS, Navarro VJ, Colombe BW, Daskalakis C, Herrine SK, Rossi S. Human leukocyte antigen and adult living-donor liver transplantation outcomes: an analysis of the organ procurement and transplantation network database. Liver Transplant. 2007;13:1405–1413. 19. Suehiro T, Shimada M, Kishikawa K, et al. Influence of HLA compatibility and lymphocyte cross-matching on acute cellular rejection following living donor adult liver transplantation. Liver Int. 2005;25:1182–1188.
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Please cite this article as: Choudhary et al., Do Recipients of Genetically Related Donors Have Better Outcomes After Living Donor Liver Transplantation?, Journal of Clinical and Experimental Hepatology, https://doi.org/10.1016/j.jceh.2019.12.004
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DONOR GENETIC RELATION AND OUTCOME OF LDLT