Outcome of Extended Right Lobe Liver Transplantations

Abbreviations BMI body mass index CI confidence interval CIT cold ischemia time CTS Collaborative Transplant Study EDC extended donor criteria ERL extended right lobe ERLT extended right lobe liver transplantation FSL full-size liver FSLT full-size liver transplantation HR hazard ratio labMELD laboratory Model for End-Stage Liver Disease score LT liver transplantation maEDC major extended donor criteria MELD Model for End-Stage Liver Disease PNF primary nonfunction SD standard deviation

The demand for liver grafts far exceeds the supply, so split-liver transplantation offers an elegant solution to the problem of organ shortage. It is an established procedure that allows 2 recipients to benefit from 1 deceased donor graft by creating size-matched grafts for pediatric patients without reducing the donor pool for adult recipients.(1-3) A mandatory split-liver transplantation policy was introduced in Italy in 2015, and since then waitlist mortality has reduced significantly from 4.5% to 2.5% in pediatric patients and from 9.7% to 5.2% in adult patients.(4) In the Eurotransplant region, the 50/50 rule promotes split-liver transplantations by considering every liver from a donor younger than 50 years and with a body weight ≥50 kg for splitting.(5) However, despite this regulation, the numbers of deceased donor split-liver transplantations remain suboptimal; in 2018, ~5% of liver transplantations (LTs) were split-liver transplantations, which is similar to the rates reported by the Organ Procurement and Transplantation Network.(6, 7)

In most cases, after the donor liver has been split conventionally, the extended right lobe (ERL), including Couinaud segments I and IV-VIII, is transplanted into an adult patient.(2) Liver segments I-IV (left lobe) and V-VIII (right lobe) can also be transplanted into 2 adults or adult-sized recipients. However, ERL and left lateral grafts are favored in ~74% of cases because they contain sufficient functional hepatocytes and because small-for-size grafts are at risk of portal hyperperfusion and infections.(3, 8)

Only high-quality organs are considered for split-liver transplantations, so the outcomes of extended right lobe liver transplantation (ERLT) should be at least comparable with those of full-size liver transplantation (FSLT).(8, 9) However, donor quality has continuously decreased since the Model for End-Stage Liver Disease (MELD) score–based allocation policy was introduced.(10) Consequently, decisions to perform split-liver transplantation are made on a case-by-case basis and the outcomes are controversial. Allocation of left lateral segments is prioritized to children at the center that performs the splitting procedure, while the allocation of ERL grafts is uncertain because these grafts are usually allocated to another transplantation center. This impairs the outcome by prolonging the cold ischemia time (CIT).(6, 8, 9) In a recent meta-analysis, ERL grafts were classified as major extended donor criteria (maEDC) organs because they had higher vasculobiliary complications and retransplantation rates and reduced graft survival in adult recipients.(11) However, the study could not address all aspects of the multifaceted ERLT because recipient data were not available.

In this multicenter Collaborative Transplant Study (CTS), we aimed to evaluate and compare graft and patient survival following ERLT and FSLT in adult recipients and to determine the donor and recipient risk factors associated with adverse outcomes after ERLT.

Patients and Methods

All data were obtained from the CTS (www.ctstransplant.org). Since 1982, the CTS has collected data from solid organ transplantations worldwide. It considers the confidentiality of patients as well as transplantation centers and continuously reports general information on transplantation outcomes and specific clinical issues. The well-structured follow-up concept and the incorporation of available registry data guarantee a high level of data integrity.(12)

Study Population

We analyzed 43,409 primary blood group–compatible deceased donor ERLTs and FSLTs performed in adults from January 1, 2000, to December 31, 2019, in 94 centers from 24 countries with available information on graft type, recipient and donor age and sex, and CIT. Multiorgan transplantations were excluded (Supporting Fig. 1). The MELD scores were available for transplantations performed from 2006 onward. To eliminate major confounding differences between ERLT and FSLT, a 1:2 match-paired analysis was performed using 3 methods: (1) exact matching for country, transplantation year periods (2000-2003, 2004-2007, 2008-2011, 2012-2015, 2016-2019), donor age (18-29, 30-39, 40-50, >50 years), recipient sex, and CIT (<10, 10-11, 12-13, ≥14 hours); (2) propensity score matching to obtain accurate confounding factors in the exact categories and to adjust for further factors with help of the score consisting of the fit of the linear model for graft size with the variables transplantation year, recipient and donor age, and CIT; and (3) Mahalanobis distance matching for categorized type of donor death.

Primary nonfunction (PNF) was defined as nonrecoverable liver function requiring retransplantation or causing death within 15 days after primary transplantation.(13) Graft survival was a combined endpoint, defined as the time from LT to either patient’s death or retransplantation (whichever came first). Patient survival was defined as the time between initial LT and death or last known contact. Patients with a MELD score <20 were considered low risk and patients with a MELD score ≥20 were considered high risk.(10) Graft and patient survival after ERLT and FSLT were analyzed in low- and high-risk patients 1 year and 2-5 years after transplantation.

Statistical Analysis

R (R Foundation for Statistical Computing, Vienna, Austria, 2019; https://www.R-project.org) was used for statistical analysis.(14) To compare demographics, a χ2 or Wilcoxon-Mann-Whitney U test was used for categorical and continuous variables, respectively. Univariate analysis was performed using the Kaplan-Meier estimator, and groups were compared using the log-rank test. Cox regression analysis was used considering the following confounders: graft type (ERL or FSL), transplantation period, donor and recipient age (linear), donor and recipient sex, donor hypertension, cause of donor death, original disease leading to transplantation, patient evaluation, urgency, induction therapy, initial medication (calcineurin inhibitor, antimetabolites, steroids), marginal donor (yes/no), and CIT (categorized). To minimize possible selection bias in favor of ERLT, ERLT cases were matched to FSLT cases according to country, transplantation year periods, donor age, recipient age, sex, and CIT in a 1:2 relation. R packages “Matching” and “Survival” were used for matching and survival analyses, respectively.(15-17) A 2-sided P value of less than 0.05 was considered statistically significant for all analyses.

Ethics Statement

The work of the Collaborative Transplant Study was approved by the Ethics Committee of the Medical Faculty of Heidelberg University (No. 083/2005) and performed in accordance with the current World Medical Association Declaration of Helsinki Ethical Principles.

Results Study Population

Demographic parameters were different in the ERLT (n = 756) and FSLT (n = 42,653) group. For example, donor age was significantly lower in the ERLT group and FSLTs had significantly shorter CIT than ERLTs did (Table 1). ERLT recipients had significantly lower mean ± standard deviation (SD) MELD scores than FSLT recipients did (23.3 ± 9.73 versus 25.2 ± 10.9, P = 0.008). To compare ERLT and FSLT outcomes directly, 612 primary adult ERLT cases with a mean observation period of 4.9 years were compared with 1224 matched FSLT cases. The demographics of the matched collective are shown in Supporting Table 1. No statistically significant differences in indication for transplantation were observed between ERLT and FSLT recipients (Supporting Table 1), and the mean ± SD MELD scores were comparable between the 2 groups (25.5 ± 9.69 versus 25.9 ± 10.7, P = 0.51).

TABLE 1. Demographic Characteristics of ERLT and FSLT Recipients Characteristic ERLT (n = 756) FSLT (n = 42,653) P value Geographical region Europe 733 (97%) 38,403 (90%) <0.001 Other 23 (3%) 4250 (10%) Year of transplantation 2000-2009 251 (33%) 21,556 (51%) <0.001 2010-2019 505 (67%) 21,097 (49%) Donor age, years 30.8 ± 11.6 51.4 ± 17.6 <0.001 Donor sex Female 335 (44%) 19,311 (45%) 0.62 Male 421 (56%) 23,342 (55%) Cause of donor death* Cerebrovascular 375 (51%) 25,376 (62%) Trauma 194 (26%) 8267 (20%) <0.001 Other 164 (22%) 6973 (17%) Recipient age, years 49.1 (±13.6) 52.5 ± 10.8 <0.001 Recipient sex Female 388 (51%) 13,225 (31%) <0.001 Male 368 (49%) 29,428 (69%) CIT, hours 11.1 ± 3.1 8.2 ± 2.9 <0.001 NOTE: Statistically significant results are indicated in bold. Data are presented as mean ± SD or n (%). Graft Survival

The 1-, 3-, and 5-year graft survival rates of the matched collective were lower in the ERLT group than in the FSLT group (81.1%, 84.9%, and 78.0% versus 79.3%, 73.8%, and 74.7%, respectively), but only 1-year survival was significantly lower (P = 0.05, 0.37, and 0.40, respectively). The risk of graft loss was 25% higher after ERLT than after FSLT during the first posttransplantation year (data not shown). PNF was 18.5% more prevalent in the ERLT group (32 of 580 cases) than in the FSLT group (54 of 1170 cases), but this difference was not statistically significant (P = 0.51). Graft survival was also significantly lower in the ERLT group than in the FSLT group 1 year after transplantation but not 2-5 years after transplantation (P = 0.05 and 0.14, respectively; Fig. 1). This finding was confirmed by multivariable Cox regression analysis. The risk of graft loss was 39% higher in the ERLT group than in the FSLT group 1 year after transplantation (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.08-1.79; P = 0.01; Table 2) but not 2-5 years after transplantation (HR, 0.68; 95% CI, 0.45-1.03; P = 0.07; data not shown).

image

Univariate Kaplan-Meier analysis of (A and B) graft and (C and D) patient survival in 1:2 matched ERLTs and FSLTs (A and C) 1 year and (B and D) 2-5 years after transplantation. The P value in (A) is statistically significant.

TABLE 2. Multivariable Cox Regression Analysis of 1-Year Graft Loss in 1:2 Matched ERLTs and FSLTs Graft Loss n (ERLT; FSLT) HR (ERLT Versus FSLT) 95% CI P value All patients 1836 (612; 1224) 1.39 1.08-1.79 0.01 Donor sex Female 789 (281; 508) 1.16 0.81-1.67 0.41 Male 1047 (331; 716) 1.74 1.08-2.13 0.02 Donor age, years <18 144 (48; 96) 2.21 1.06-8.30 0.10 18-50 1581 (527; 1054) 1.41 1.07-1.86 0.01 18-29 678 (226; 452) 1.83 1.19-2.84 0.006 30-39 480 (160; 320) 1.12 0.67-1.88 0.66 40-50 423 (141; 282) 1.04 0.64-1.67 0.88 >50 110 (37; 74) 1.89 0.67-5.34 0.23 Recipient sex Female 885 (295; 590) 1.15 0.79-1.66 0.46 Male 951 (317; 634) 1.68 1.34-2.59 <0.001 CIT, hours <10 672 (224; 448) 0.71 0.42-1.22 0.22 10-13 879 (293; 586) 1.79 1.26-2.53 0.001 ≥14 160 (95; 190) 1.96 1.02-3.78 0.04 Recipient MELD <20 130 (90; 40) 0.67 0.67-3.63 0.20 ≥20 318 (211; 107) 1.88 1.09-3.27 0.03 NOTE: Statistically significant results are indicated in bold.

Female donor and recipient sex, CIT <10 hours, and MELD score of <20 increased 1-year graft survival, whereas livers from 18- to 29-year-old donors, donor and recipient male sex, CIT ≥ 10 hours, and recipient MELD score ≥20 significantly reduced 1-year graft survival in the matched collective (Table 2). There was an almost 2-fold higher risk of 1-year graft loss in ERLT patients than in FSLT patients after receiving a graft from donors older than 50 years, but this difference was not statistically significant, possibly because the number of cases was low (HR, 1.89; 95% CI, 0.67-5.34; P = 0.23). The risk of 1-year graft loss was significantly higher in ELRT patients who received a graft from 18- to 50-year-old donors (HR, 1.41; 95% CI, 1.07-1.86; P = 0.01). This risk was also 2-fold higher in ERLT patients who received a graft from donors younger than 18 years, but this difference was not statistically significant, possibly because the number of cases was low (HR, 2.21; 95% CI, 1.06-8.30; P = 0.10; Table 2).

Kaplan-Meier analysis showed that the survival of grafts from both <18-year-old and >50-year-old donors was somewhat lower than those from 18- to 50-year-old donors in all unmatched recipients during the first month following transplantation (P = 0.06 and 0.30, respectively). However, these differences disappeared later on (global P = 0.42; Fig. 2). Multivariable subgroup analysis of matched-paired ERLT recipients of grafts from 18- to 50-year-old donors revealed significantly higher graft loss in the subgroup of ERLT patients who received grafts from 18- to 29-year-old donors (HR, 1.83; 95% CI, 1.19-2.84; P = 0.006; Table 2). Recipient age and MELD scores did not differ between ERLT and FSLT patients who received grafts from 18 to 29-year-old and 30-50-year-old donors (P = 0.10 and 0.86, respectively; data not shown).

image

One-year Kaplan-Meier estimates of graft survival in all ERLT recipients stratified by donor age.

Interestingly, combining male donors with male recipients increased the risk of 1-year graft loss 2-fold in ERLT patients compared with the matched FSLT patients (HR, 2.44; 95% CI, 1.54-3.88; P = 0.006; Supporting Table 2A). This was not the case in other donor-recipient gender combinations. Male recipients who received grafts from male donors had significantly higher MELD scores than FSLT recipients did (P = 0.004), which may explain this poorer outcome.

Patient Survival

The significantly higher graft loss rates in ERLT patients did not translate into lower patient survival. In the matched collective, Kaplan-Meier univariate analysis revealed a 1-, 3-, and 5-year patient survival rate of 87.1%, 84.1%, and 80.2% in the ERLT group versus 88.9%, 84.1%, and 79.7% in the FSLT group, respectively (all P > 0.05; data not shown). Besides, patient survival at 1 year and 2-5 years after transplantation was not significantly different between matched ERLT and FSLT recipients when analyzed separately (P = 0.31 and 0.21; Fig. 1).

Multivariable Cox analysis in the matched collective showed that 1-year survival was not significantly lower in ERLT patients than in FSLT patients (Table 3), but a trend toward lower patient survival was still observed (HR, 1.29; 95% CI, 0.95-1.74; P = 0.09). In ERLT patients, 1-year patient survival was significantly affected by donor age in recipients of grafts from 18 to 29-year-old donors (HR, 2.16; 95% CI, 1.26-3.70, P = 0.005). Similar to graft survival, patient survival at 2-5 years after transplantation was unaffected by ERLT (HR, 0.74; 95% CI, 0.48-1.14; P = 0.18; data not shown). Similar to the graft survival results, a MELD score of <20 and a CIT <10 hours increased 1-year patient survival (Table 3).

TABLE 3. Multivariable Cox Regression Analysis of 1-Year Patient Death in 1:2 Matched ERLTs and FSLTs Patient Death n (ERLT; FSLT) HR (ERLT Versus FSLT) 95% CI P value All patients 1836 (612; 1224) 1.29 0.95-1.74 0.09 Donor sex Female 789 (281; 508) 0.99 0.62-1.58 0.97 Male 1047 (331; 716) 1.53 1.01-2.32 0.05 Donor age, years <18 144 (48; 96) 1.01 0.33-3.13 0.98 18-50 1581 (527; 1054) 1.38 0.99-1.91 0.06 18-29 678 (226; 452) 2.16 1.26-3.70 0.005 30-39 480 (160; 320) 1.02 0.49-2.13 0.95 40-50 423 (141; 282) 1.14 0.60-2.15 0.70 >50 110 (37; 74) 1.14 0.41-3.14 0.80 Recipient sex Female 885 (295; 590) 0.97 0.62-1.52 0.89 Male 951 (317; 634) 2.01 1.36-2.96 <0.001 CIT, hours <10 672 (224; 448) 0.83 0.44-1.54 0.55 10-13 879 (293; 586) 1.84 1.20-2.80 0.005 ≥14 160 (95; 190) 1.42 0.59-3.37 0.43 Recipient MELD <20 130 (90; 40) 1.26 0.36-4.38 0.71 ≥20 318 (211; 107) 2.03 1.10-3.76 0.02 NOTE: Statistically significant results are indicated in bold.

The combination of male donor and male recipient increased the risk of death within 1 year 3-fold in ERLT patients compared with the matched FSLT patients (HR, 3.41; 95% CI, 1.93-6.01; P < 0.001; Supporting Table 2B), most probably because MELD scores were higher in these patients.

CIT and ERLT

Ischemia/reperfusion injury negatively affected the outcome of both ERLT and FSLT, but the effect was more prominent on ERLT outcome. In matched patients with a prolonged CIT of 10-13 hours, ERLT recipients had a 79% higher risk of graft loss during the first posttransplantation year than FSLT recipients did (HR, 1.79; 95% CI, 1.26-2.53; P = 0.001; Table 2). In the subgroup of patients with an even longer CIT of ≥14 hours, the risk of graft loss increased by 96% in ERLT patients (HR, 1.96; 95% CI, 1.02-3.78; P = 0.04). We also assessed the impact of CIT in ERLT and FSLT separately without comparing ERLT and FSLT directly in the larger unmatched collective. This analysis showed that every additional hour of CIT increased the risk of 1-year graft loss by 10% in recipients of ERLT and by 3% in recipients of FSLT (HR, 1.10; 95% CI, 1.03-1.17; P = 0.003 and HR, 1.03; 95% CI, 1.03-1.04; P < 0.001; Table 4). A CIT ≥14 hours had the highest risk of graft loss in both ERLT and FSLT patients (HR, 2.26; 95% CI, 1.28-4.02; P = 0.005 and HR, 1.46; 95% CI, 1.31-1.64; P < 0.001; Table 4).

TABLE 4. Multivariable Cox Regression Analysis of the Impact of CIT and MELD Score on 1-Year Graft Loss After ERLTs and FSLTs in the Unmatched Collective Subgroup n HR 95% CI P ERLT, per hour CIT 756 1.10 1.03-1.17 0.003 <10 hours 1.00 (Reference) — — 10-11 hours 1.75 1.00-3.08 0.05* 12-13 hours 2.01 1.15-3.51 0.01 ≥14 hours 2.26 1.28-4.02 0.005 FSLT, per hour CIT 42,653 1.03 1.03-1.04 <0.001 <10 hours 1.00 (Reference) — — 10-11 hours 1.10 1.03-1.17 0.004 12-13 hours 1.37 1.26-1.49 <0.001 ≥14 hours 1.46 1.31-1.64 <0.001 ERLT, per point MELD 194 0.98 0.95-1.02 0.38 High versus low MELD 0.82 0.38-1.77 0.61 FSLT, per point MELD 9459 1.01 1.01-1.02 <0.001 High versus low MELD 1.15 1.03-1.28 0.01 NOTE: Statistically significant results including the 0.05 value* are indicated in bold.

Univariate Kaplan-Meier analysis showing the influence of CIT on 1-year graft survival in unmatched ERLT and FSLT patients is shown in Fig. 3. Prolonged CIT had a negative effect on 1-year graft survival in both groups (P < 0.001 for both) and the risk of 1-year graft loss increased with longer CIT. This risk was more pronounced in the ERLT group. However, graft survival was higher in ERLT patients than in FSLT patients when the CIT was less than 10 hours. Multivariable Cox regression analysis of 1-year graft survival in matched FSLT and ERLT showed that ERLT and FSLT outcomes are similar if the CIT is under 10 hours (HR, 0.71; 95% CI, 0.42-1.22; P = 0.22; Table 2). After a CIT of 10-13 hours, ERLT negatively affected 1-year patient survival compared with FSLT (HR, 1.84; 95% CI, 1.20-2.80; P = 0.005; Table 3). However, we did not observe a significant effect in the CIT ≥14 hours subgroup, probably because of the low number of cases (HR, 1.42; 95% CI, 0.59-3.37; P = 0.43; Table 3).

image

Univariate Kaplan-Meier a

留言 (0)

沒有登入
gif