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Keywords:

  • Liver graft survival;
  • risk factors;
  • split liver;
  • UNOS

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

When considering advocacy of split-liver transplantation, it is important to understand whether comparable outcomes can be achieved. The goal of this study was to identify donor and transplant characteristics predictive of comparable outcomes by risk factor analysis. Using the United Network for Organ Sharing/ Organ Procurement and Transplantation Network data base between January 1996 and May 2006, first time adult/child split cases (568 adults, 508 children) were examined. In multivariate analysis, recipient medical condition (hospitalization), status 1 assignment, ABO incompatibility, donor age (>40 years), donor body weight (≤40 kg), calculated whole graft volume to recipient body weight ratio (cGRWR ≤1.5%) and no sharing between centers were significant risk factors in adult recipients.

Recipient diagnosis of tumor, dialysis prior to transplant, recipient body weight (≤6 kg), donor age (>30 years), donor history of cardiac arrest after declaration of death and cold ischemia time (CIT > 6 h) increased the risk of graft failure in pediatric recipients. The livers from young donors showed comparable outcomes to whole deceased liver transplantation (LT) when other transplant-related risk factors were minimized in adult recipients. Reducing CIT is important to obtain comparable outcomes to living donor LT in pediatric recipients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

Split-liver transplantation (SLT) offers the potential for expanding the deceased donor pool for pediatric recipients. In general, livers are split into a left lateral sector graft (LLSG) for a child and a right tri-sector graft (RTSG) for an adult. The increased use of SLT in the pediatric population may decrease the need for living donor liver transplantation (LDLT) and the associated risk to live donors. However, SLT is still cautiously undertaken in the United States perhaps because RTSG may still be considered as ‘extended criteria grafts’ (1). In the American Society of Transplant Surgeons (ASTS) survey report, Renz et al. analyzed the United Network for Organ Sharing (UNOS), Scientific Registry for Transplant Recipients (SRTR) data and reported that RTSG, even when SLT is restricted to optimal donors, were comparable to whole deceased grafts from donors older than 60 years (1). Although one survey study has reported favorable attitudes of 60% of liver transplant (LT) candidates toward graft sharing even with the possibility of compromised survival benefit in SLT, the ethical questions surrounding SLT remain (2,3).

Therefore, when considering advocacy of SLT, it is important to understand whether comparable outcomes can be achieved in recipients of SLT. In this study, we evaluated the risk factors affecting graft survival and identified donor and transplant characteristics predictive of comparable outcomes.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

Live transplants reported to the UNOS/Organ Procurement and Transplantation Network (OPTN) between January 1996 and May 2006 were investigated. Cases with two recipients from one donor were considered as SLT. In analyzing adult recipients, we excluded adult/adult splits (n = 124). Similarly, in analyzing pediatric recipients, we excluded child/child SLT (n = 134). Among 1212 paired recipients (606 children (age < 18 years), 606 adults (age ≥ 18 years)) who received split grafts with an adult/child recipient combination, we limited our analysis to first-time transplant cases (568 adults, 508 children). Risk factor analyses were performed separately. In certain analyses where a reference group was needed, we used whole donation after brain death (DBD) LT for adult SLT and LDLT for pediatric SLT.

Potential recipient risk factors included age, gender, ethnicity, height, weight, body mass index (BMI), diagnosis, status 1 assignment, previous transplant history, medical condition (home, in the hospital or in the intensive care unit [ICU]), dialysis one week prior to transplant, use of mechanical ventilation or organ-perfusion support and laboratory findings including creatinine and bilirubin. Donor risk factors included age, gender, ethnicity, height, weight, BMI, cause of death, cardiac arrest since event that led to declaration of death, three or more inotropic agents at time of incision and laboratory findings including creatinine, bilirubin, alanine aminotranferase (ALT) and aspartate aminotransferase (AST). Other transplant variables included transplant year, ABO incompatibility, cold ischemia time (CIT), share type (local, regional, national), split method (in situ vs. ex vivo), graft sharing between centers, center volume and characteristics and calculated whole graft volume (L) to recipient body weight (kg) ratio (cGRWR). To calculate whole graft volume, Urata's formula (4) was used. Body surface area was calculated using Mostellar's formula (5). Large volume center was defined as more than 50 cases of LT per year. Pediatric-specific center was defined as pediatric LT to total LT number ratio > 0.9. Sharing was determined by comparing center codes between paired cases.

Missing CIT values (16%) were imputed with the mean value for the geographic share type of the donor organ. Missing height (Recipients: 14.2%, Donor: 0.03%) and weight (Recipients: 11.3%, Donor: 0%) were imputed by the mean value of each age in pediatric recipients and the mean value of adult split group in adult recipients. The missing laboratory values (creatinine and bilirubin <3%) were imputed with the mean value of each group. Missing or unknown values in donor cardiac arrest (23.5%) and three inotropic agents (1.3%) were imputed as ‘No’. Missing split methods (in situ vs. ex vivo, 2.4%) were imputed by matched recipients' method.

Chi-square and Student's t-tests were used for comparison of proportions and means, respectively. Graft failure (not censored for death) was the primary outcome measure. Kaplan-Meier product-limit methodology was used for graft survival estimates. Continuous variables were categorized using exploratory data analysis and assumptions of proportional hazards were met by extended Cox regression models with time dependent covariates. Unadjusted comparison of survival was performed using the log-rank test. Hazard ratios (HR) were estimated using Cox proportional-hazards methodology and estimates are reported as HR (95% confidence interval). Multivariate Cox modeling was performed using potential risk factors and covariates that were found to be statistically significant in unadjusted Cox models. Forward stepwise selection using likelihood ratios for entry and exit criteria were used to develop the final multivariate Cox proportional-hazards model.

Recipient condition was divided into two groups (high-risk vs. low-risk) for subgroup analysis. High-risk condition was defined as status 1, 2 A in pre-MELD era, or MELD score > 30 in MELD era.

Statistical analysis was performed using SPSS 15.0 for Windows (Chicago, IL). Statistical significance was defined at the α= 0.05 level.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

Annual trend of SLT and center experience

Figure 1 shows the annual trend of SLT in the United States. SLT appeared in the UNOS data base beginning in 1988. Most splits were adult/child combination (80%). Starting in 1996, the number of SLT increased. However, the use of split-liver grafts has remained relatively unchanged in recent years. In the study period (1996–2006), 1212 adult/child SLT from 606 donors were identified. Among a total of 141 transplant centers that performed whole DDLT, 91 centers (64.5%) performed at least one adult/child SLT. Only 14 centers (10.1%) performed more than an average of two cases of adult/child SLT per year. Forty centers (28.4%) were classified as large volume centers. Eight hundred fourteen cases (67.2% of SLT cases) were performed at large volume centers, including 472 right-side grafts (RSG) (77.9% of total RSG) and 342 left-side grafts (LSG) (56.4% of total LSG). Eighteen centers (34.6% of centers that performed at least one pediatric SLT) were classified as pediatric-specific centers. Two hundred forty-two cases (40.0%) of pediatric SLT were performed by pediatric specific centers. Among 606 donors, grafts from 329 donors (54.3%) were shared between two different centers. Among 329 shared split donors, donation and two recipient operations seemed to be performed at the same or adjoining hospital (assessed by distance from donor hospital to transplantation hospital) in 18 cases (5.5%).

image

Figure 1. Annual trend of split-liver transplantation (SLT) in the United States. SLT is defined as the cases with two recipients from one donor. SLT appeared in the UNOS data base from 1988. Most splits were adult/child combination (80%). From 1996, the number of SLT increased. However, the use of split-liver grafts has remained relatively unchanged in recent years.

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RSG Outcome

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

Demographics

The characteristics of donors and recipients are presented in Table 1. A total of 568 RSG and 40 304 whole DBD graft recipients were compared. About 90% of donors were less than 40 years in SLT group. Compared to whole DBD LT, livers from younger (24.6 vs. 39.8 years), taller (171.6 vs. 169.4 cm), lower weight (70.3 vs. 76.1 kg) and male (70.1 vs. 59.1%) donors were selected for split. The RSGs were transplanted into relatively smaller recipients (height; 167.4 vs. 172.0, weight; 71.8 vs. 82.9). The preoperative recipient condition was similar or slightly worse in whole DBD group. The mean CIT was slightly longer in RSG (8.7 vs. 8.2 h, p = 0.018). A 52.2% of split procedures were performed in situ. Split grafts were shared between two centers in 54.2%.

Table 1.  Demographics of donor and recipient (RSG vs. whole DBD grafts)
 RSG (n = 568)Whole DBD grafts (n = 40   304)p-value
  1. *Primary or secondary biliary cirrhosis, biliary atresia, neonatal hepatitis, etc.

  2. **Transplantation.

  3. ***Laboratory MELD score, MELD era only.

  4. $Status 1, 2 A in pre-MELD era, or MELD score >30 in MELD era.

  5. $$Calculated whole graft volume to recipient weight ratio.

Recipients
 Age (years)51.0 ± 10.751.2 ± 10.2 0.714
 Diagnosis 0.017 
   HCV29.931.9 
   Alcoholic18.722.2 
   HBV 6.2 4.7 
   Cholestatic* 7.4 5.2 
   Malignancy 4.1 3.0 
   Other33.733.0 
 Female (%)51.634.8<0.001
 Height (cm)167.4 ± 10.7172.0 ± 11.2<0.001
 Weight (kg) 71.8 ± 16.9 82.9 ± 19.7<0.001
 Status 1 (%)6.26.2  0.993
   Ventilated or organ-perfusion
   support@TX** (%)7.77.2 0.435
 Medical condition (home%)65.167.7 0.386
 MELD score***18.8 ± 8.920.6 ± 9.7 0.001
 High-risk condition (%)$19.721.6 0.305
Donors
 Age (years)24.6 ± 10.339.8 ± 17.6<0.001
   ≤18 (%)35.413.8 
   19–40 (%)55.336.6 
   41–60 (%) 9.236.0 
   61+ (%)0.213.6 
 Female (%)29.940.9<0.001
 Height (cm)171.6 ± 14.3169.4 ± 18.9<0.001
 Weight (kg) 70.3 ± 14.0 76.1 ± 19.2<0.001
 Creatinine > 2.0 mg/dL (%) 3.910.1<0.001
 Cause of death; head trauma(%)71.242.9<0.001
Others
 Cold ischemic time (h)8.7 ± 4.58.2 ± 4.0 0.018
 cGRWR$$1.9 ± 0.51.7 ± 0.5<0.001
 Split LT specific
   In situ (%)52.2 
   Sharing between centers (%)54.2 

Graft survival and risk factors affecting graft survival

The graft survival of RSG was 82.1% at 1 year, 72.3% at 3 years and 66.1% at 5 years, which was similar with that of whole DBD grafts in nonadjusted analysis (Figure 2 A). However, the RSG showed inferior outcomes to whole DBD grafts in adjusted analysis Figure 2B. This was related to the dramatic difference of demographics between two groups.

image

Figure 2. Graft survival between whole donation after brain death (DBD, solid line) graft and right-side split graft (RSG, dotted line). There was no significant survival difference in nonadjusted graft survival (A). However, RSG showed inferior outcomes in adjusted analysis (B).

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Table 2 shows significant risk factors for graft failure from the multivariate Cox analysis. Recipient medical condition (hospitalization), status 1 assignment and ABO incompatibility were predictors of graft failure. Donor age showed a stepwise increase of the graft loss at ages 18 and 40. cGRWR ≤ 1.5% and no sharing of split grafts also increased the risk of graft loss. Donor body weight ≤ 40 kg (1.2% of SLT donors) was a strong predictor of graft failure (HR = 6.901 [2.652–17.956], p < 0.001). Ex vivo split had a tendency to increase risk of graft failure, but did not reach statistical significance. However, 106 cases of uncertain split method were excluded, ex vivo split increased risk of graft failure significantly (HR: 1.473[1.017–2.132] p = 0.040). Donors with body weight ≤ 40 kg had somewhat less cGRWR than larger donors (1.50 ± 0.43% vs. 1.9 ± 0.50, p = 0.047). In sharing cases, center volume did not affect graft outcomes, but when two split grafts were used in one single center, RSG used in small centers showed higher risk than those used in large volume centers. There was no significant difference in CIT between in situ and ex vivo (8.5 ± 5.1 h vs. 8.8 ± 4.0, p = 0.570) and between sharing and nonsharing (8.6 ± 5.1 h vs. 8.7 ± 3.9, p = 0.706). There was no difference in waiting time between sharing and nonsharing (319.2 vs. 325.7 days, p = 0.837).

Table 2.  Factors affecting graft survival on multivariate analysis in RSG
Risk factorsHazard ratiop-value
  1. *cGRWR: Calculated whole graft volume (L) to recipient's body weight (kg) ratio.

  2. **Large volume center: annual LT volume > 50 cases.

Recipients
 Medical condition
   HomeReference 
   Hospital1.624 (1.163–2.269)  0.004
 Status 1
   NoReference 
   Yes1.897 (1.108–3.249)  0.020
Donors
 Age (years)
   ≤18Reference 
   18.1–401.644 (1.120–2.415)  0.011
   >402.662 (1.555–4.557)<0.001
 Donor body weight (kg)
   >40Reference 
   ≤406.901 (2.652–17.956)<0.001
Transplant factors
 cGRWR* (%)
   >1.5Reference 
   ≤1.51.517 (1.033–2.227)  0.033
 Split method
   In situ splitReference 
   Ex vivo split1.354 (0.975–1.880)  0.071
 Center sharing and center volume
   SharingReference 
   No sharing 
   Single large center**1.500 (1.081–2.080)  0.015
   Single small center**4.547 (2.140–9.664)<0.001
 ABO incompatibility
   Identical or compatibleReference 
   Incompatible 5.354 (1.808–15.856)  0.002

RSG recipients showed different risk by splitting according to donor age when compared to whole DBD recipients (Figure 3). RSG from donors ≤ 18 years old showed comparable outcomes to whole DBD grafts (Figure 3A). RSG from donors 19 to 40 years old showed minimal-to-moderate risk of graft failure (Figure 3B). However, RSG from donors 41 to 60 years old showed higher risk of graft failure compared to the matched DBD group (Figure 3C).

image

Figure 3. Graft survival difference between whole donation after brain death (DBD, solid line) graft and right side split graft (RSG, dotted line) according to donor age. There was no significant survival difference between two groups in donor age ≤ 18 (A). In the groups with donor age 19–40 (B), RSG showed mild-to-moderate risk compared to whole DBD graft. In the groups with donor age 41–60, (C), RSG showed higher risk. All analyses were adjusted for recipient, donor and transplant factors. Seven RSG from donors with body weight ≤ 40 kg were excluded in split group.

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To evaluate the difference of risk by splitting according to the recipient condition, RSG and whole DBD grafts were divided by donor age and recipient condition. RSG from donors ≤ 18 years old showed comparable outcome to whole DBD grafts in low-risk recipients (HR = 0.875 [0.597–1.282], p = 0.493) and high-risk recipients (HR = 1.200 [0.651–2.212], p = 0.560) in adjusted analysis. RSG from donors 19 to 40 years old showed inferior outcome to matched whole DBD grafts in low-risk recipients (HR = 1.301 [1.018–1.663, p = 0.036]) and high-risk recipients (HR = 1.493 [1.008–2.211], p = 0.045). RSG from donors 40 to 60 years old also showed inferior outcome to matched whole DBD grafts in both low-risk condition (HR = 1.695 [1.049–2.738, p = 0.031]) and high-risk condition (HR = 3.269 [1.335–8.005], p = 0.010). For subgroup analysis, RSG and whole DBD from donors ≤ 40 years old were divided by recipient condition and the number of transplant risk factors (cGRWR ≤ 1.5% and no sharing) (Figure 4). In the recipients with low-risk condition, RSG showed comparable overall outcome to whole DBD group (Figure 4A) and only the subgroup with two of transplant risk factors (4.5%) showed inferior outcome (Figure 4C). In the recipients with high-risk condition, RSG showed inferior outcome (Figure 4B), however, only the subgroup without any additional transplant risk factors (42.2%) showed comparable outcome to whole DBD grafts (Figure 4D).

image

Figure 4. Right-side split grafts (RSG) and whole donation after brain death (DBD) grafts from donors with age ≤ 40 year old were divided by recipients' condition and the number of transplant risk factors (nonsharing and cGRWR ≤ 1.5%). Severe recipient's condition included status I, status IIA (before MELD era) or laboratory MELD score > 30 (MELD era). In the recipients with low-risk condition, RSG (dotted line) showed comparable outcome to whole DBD group (solid line) (A) and only the subgroup with two transplant risk factors (3.8%, ▪) showed inferior outcome to whole DBD grafts (solid line) (C). In the recipients with high-risk condition, RSG (dotted line) showed inferior outcome to whole DBD grafts (solid line) (B), however, only the subgroup without any additional transplant risk factor (42.6%, ▴) showed comparable outcome to whole DBD grafts (solid line) (D). All analyses were adjusted for recipient, donor and transplant factors. Seven RSG from donors with body weight ≤ 40 kg were excluded in split group.

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LSG Outcomes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

Demographics

An 87.5% of the pediatric recipients were younger than 5 years, and only 5% of the recipients were older than 10 years. Table 3 shows the demographics of the recipients of LSG and LD grafts. Compared to LD grafts recipients, more LSG recipients were in severe medical condition at transplantation. About 40% of the split recipients were status 1 and in the ICU at transplantation. Donors were younger (24.4 vs. 31.9) and more likely to be male (70.1 vs. 40.7%) in the split group.

Table 3.  Demographics (LSG vs. LD grafts)
 Adult/child split (n = 508)Living donor LT (n = 758)p-value
  1. *Transplantation.

  2. **Laboratory PELD score, MELD era only.

  3. $Status 1, 2 A in pre-MELD era, or PELD score > 30 in MELD era.

Recipients
 Age (years)2.1 ± 3.42.5 ± 4.1  0.118
 Female (%)54.952.1  0.326
 Diagnosis (%)   0.742
 Cirrhosis78.876.8 
 Acute hepatitis13.514.9 
 Tumor 6.2 6.1 
 TPN/hyperalimentation-related liver disease 1.5 2.2 
 Others 0.70 
 Status 1 (%)44.123.6<0.001
 Organ-perfusion support@TX* (%)15.711.9  0.134
 Medical condition (ICU%)38.022.6<0.001
 PELD score**17.1 ± 14.216.9 ± 14.12  0.872
 High-risk condition$ (%)47.824.8<0.001
Donors
 Age (years)24.4 ± 10.431.9 ± 7.4<0.001
 Female (%)29.959.3<0.001
Other
 Cold ischemic time (h)7.6 ± 4.54.2 ± 6.4<0.001

The mean CIT was 7.6 h, which is shorter than that in RSG (8.7 h). The other donor demographics except split method were similar to RSG in Table 1. There were 100 LSG (19.7%) with reported discrepancy between RSG and LSG from the same donor in terms of split method in the UNOS data base. In LSG, 50.9% of split procedures were reported as performed in situ.

Graft survival and risk factors affecting graft survival

The graft survival of LSG was 75.5% at 1 year, 67.5% at 3 years and 64.4% at 5 years, which was inferior to that of LD grafts in nonadjusted analysis and adjusted analysis (Figure 5). However, the HR was reduced from 1.626 to 1.445 in adjusted analysis.

image

Figure 5. In nonadjusted analysis (A) and adjusted analysis (B), left side grafts (LSG, dotted lines) showed inferior outcomes to living donor (LD, solid lines) grafts. However, after multiple recipients factors and transplant years were adjusted (B), the hazard ratio was decreased. It is related to relatively severe medical condition in LSG recipients.

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Table 4 shows risk factors affecting graft survival in LSG. On multivariate analysis, recipient diagnosis of tumor and need for dialysis prior to transplant were predictors of graft failure. Very small children with body weight ≤ 6 kg showed inferior outcome to larger children. Donor age over 30 years was correlated with an increased risk of graft failure. History of cardiac arrest after declaration of death increased the risk significantly. CIT showed a stepwise increase of risk at 6 and 12 h. There was no significant graft survival difference between sharing and nonsharing cases when excluding the center specific variable. Pediatric specific centers that shared most LSG with other centers showed better outcomes than nonpediatric specific centers. However, if nonpediatric specific centers were subdivided by sharing status, shared LSG showed worse outcomes than nonshared LSG. Shared LSG had shorter CIT than nonshared LSG (7.8 ± 4.4 h vs. 8.5 ± 4.6 h, p = 0.026). CIT of LSG used in pediatric specific centers was similar with shared LSG in nonpediatric specific centers (7.0 ± 3.6 h in pediatric centers vs. 7.3 ± 3.2 h in nonpediatric centers, p = 0.511) and shorter than that of nonshared LSG in nonpediatric specific centers (8.2 ± 5.3, p = 0.009). There was no difference in waiting time between sharing and nonsharing cases (223.9 vs. 224.8, p = 0.963).

Table 4.  Factors affecting graft survival on multivariate analysis in LSG
Risk factorsHazard ratio (95% CI)p-value
  1. *Transplantation.

  2. **Pediatric liver transplantation to total liver transplantation number ratio > 0.9.

Recipients
 Diagnosis
 NontumorReference 
 Tumor1.904 (1.068–3.410)0.030
 Dialysis within 1 week of TX*
 NoReference 
 Yes2.935 (1.421–6.064)0.004
 Body weight (kg)
   > 6 
   ≤ 62.052 (1.367–3.081)0.001
Donors
 Age (years)
   ≤ 30Reference 
   >301.448 (1.014–2.068)0.041
 Arrest after declaration of death
   NoReference 
   Yes3.792 (1.666–8.634)0.001
Transplant factors
 Cold ischemia time (h)
 ≤ 6Reference 
 6–121.688 (1.145–2.490)0.008
 > 123.003 (1.585–5.689)0.001
 Center characteristics and sharing
   Pediatric specific center**Reference 
   Nonpediatric specific center
 No sharing1.666 (1.139–2.436)0.009
 Sharing2.231 (1.357–3.667) 0.002 

To evaluate the different risk of CIT according to recipient body weight and donor age, adjusted graft survival was calculated according to those variables (Figure 6). LSG with CIT ≤ 6 h showed comparable outcomes to LD grafts in both of very small recipients (body weight ≤ 6 kg, Figure 6A) as well as other recipients (body weight > 6 kg, Figure 6C). Long CIT showed a stepwise increase in graft failure. However, the risk by CIT was higher in very small recipients. Donor age did not affect the risk of graft failure when CIT was short (≤6 h). However, grafts from donor age > 30 years showed inferior outcomes to those from young donors (age ≤ 30 years) in the long CIT group, especially in very small recipients (Figure 6B, D).

image

Figure 6. Adjusted graft survival according to recipient body weight, donor age and cold ischemia time. Left-side grafts (LSG) with cold ischemia time (CIT) ≤ 6 h (▴) showed comparable outcomes to living donor (LD, solid line) grafts in both very small recipients (body weight ≤ 6 kg, (A)) and the other recipients (body weight > 6 kg, (C)). Long CIT showed stepwise increase of graft failure. However, the risk by CIT is higher in very small recipients. Donor age did not affect on the risk of graft failure when CIT was short (≤6 h). However, grafts from donor age > 30 years showed inferior outcomes to those from younger donor (age ≤ 30 years) in long CIT group, especially in very small recipients (B, D). All analyses were adjusted for recipient and transplant factors. Twelve LSG from donors who had history of cardiac arrest since event that led to declaration of death were excluded in split groups.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References

SLT has been shown to be an effective procedure to expand the donor pool for adults and children, although the application of SLT has been limited in the United States. While excellent single-center and statewide data exist (6,7), ASTS survey data and SRTR data demonstrated inferior outcomes of SLT when applied to adults in urgent need of LT (1). SRTR data suggested that the performance of SLT, presumably in ‘optimal’ donors, delivered right graft outcomes comparable to ‘marginal grafts’ (1). The impact of SLT will be lessened if these data prove true (1).

The UNOS data base had inaccuracy of graft type coding which is important in SLT analysis. In our study, to overcome potential inaccuracies of the UNOS data base, cases with two recipients from one donor were considered SLT regardless of graft type coding. Among them, paired cases with adult/child recipient combinations were selected and studied under the assumption that RTSG were given to adults and LLSG were given to a child. However, we acknowledge that a few of the pediatric recipients in the cohort may have received left hemi-livers instead of LLSG.

Donor age and condition were the most important criteria for selecting donors for splitting. Ideal donor age thresholds for splitting are not well defined, but many authors suggested that donors older than 40–50 years or younger than 10 years should not be considered (8,9). In this analysis, RSG from young donors ≤ 18 years old showed no additional risk by splitting regardless of recipient condition in primary LT. Furthermore, this group seemed to be less affected by other transplant related factors such as split methods, graft volume to recipient body-weight ratio, or center specific characteristics. RSG from donors 19 to 40 years old showed minimal to moderate risk by splitting. However, this risk can be reduced by minimizing other transplant related risk factors mentioned above. Low-risk recipients seemed to tolerate other transplant related risk factors. However, in high-risk recipients, both a relatively large graft (cGRWR > 1.5%) and well-coordinated sharing are necessary to show comparable outcomes to matched whole DBD grafts. Therefore, if high-risk adult recipients were included, splits should be performed very cautiously.

RSG from younger donors showed better outcomes. However, RSG from too small of young donors showed markedly increased risk of graft failure. Donor body weight 40 kg should be considered as lower threshold for SLT. Donors with body weight ≤ 40 kg had relatively small whole liver volume to recipient body weight that might induce small for size syndrome. However, the problems related to the small graft volume seemed not to be enough to explain the poor outcomes considering the smaller paired recipients and better quality of grafts from younger donors. Similarly, an Italian multi-center study also reported poor outcome in grafts from donors with body weight ≤ 40 kg, even though GRWR was above the safety limit in all cases (10). The problems related to the small vasculature and biliary tract seem responsible for the increased incidence of postoperative complications (10).

The minimum graft volume for successful LT is controversial. Living donor grafts of less than 40–50% of standard liver volume, corresponding to a GRWR of 0.8–1.0%, are associated with worse outcomes (11). These thresholds are less well defined for deceased SLT, but presumably, an even larger graft volume is necessary due to additional factors such as brain death and longer preservation injury (12). In this study, RSG from donors with less than 1.5% of cGRWR showed inferior outcomes. Generally, RTS to LLS volume ratio is 3:1. However, most of segment IV in RTSG is inevitably ischemic because of loss of left portal vein inflow. Therefore, functional volume of RTSG will be similar or slightly larger than that of the right hemi-liver with middle hepatic vein, which is about 65–70% of the whole liver. Roughly, according to this calculation, the threshold to show inferior outcome is 0.98–1.05% of GRWR. This threshold should be flexible according to recipient condition and graft condition. In our analysis, this relative graft size had a more important role in high-risk recipients. On the other hand, the formula used in graft volume calculation can affect the threshold value. In this study, if Heinemann's formula (13) was used to calculate graft volume, the threshold of cGRWR was 1.7. Indeed, it may be difficult to do volumetric CT scan before procurement for assessment of graft size and appropriate liver mass in most cases. Combined with intraoperative visual assessment, cGRWR can be helpful to select appropriate recipients.

There are two split methods and an ongoing debate regarding which procedure is better (7,14–16). In situ split offers the advantage of decreasing CIT and bleeding from the cut surface. In our study, split method showed no significance in terms of graft survival of primary SLT in both of RSG and LSG. However, there was a tendency of superior outcomes of in situ to ex vivo in RSG, and CIT was significantly shorter in the in situ split group in LSG. Because long CIT was very strong predictor in LSG, in situ split may be the preferable method.

Sharing rates reported in previous studies were low. In the ASTS survey, sharing occurred with only 5% of grafts (1). The UCLA group reported a 15% sharing rate (14), however, Washburn et al. reported a 37% sharing rate in the Texas region. In our study of a national data base, 54% of split grafts were shared between two centers. We acknowledge that the analysis on sharing using the UNOS data base may be somewhat inaccurate given that there are multiple scenarios where adult and pediatric hospitals may have different provider numbers even though the same team is involved. Nonetheless, this level of sharing is higher than any other single center reports. Sharing showed better outcomes in RSG. Furthermore, considering sharing cases in LSG had shorter CIT than nonsharing cases, sharing seemed to be helpful in LSG, too. However, if LSG were used in nonpediatric specific centers, the outcome was worse even with shorter ischemic time than that of nonshared graft. In this study, sharing combinations with LSG used in pediatric specific centers and RSG used in large volume centers showed the best outcome in both recipient groups. Therefore, stimulation of sharing between collaborative centers should be encouraged.

According to the current UNOS allocation policy, donors less than 40 years of age, on a single vasopressor or less, transaminases no greater than three times normal, BMI of 28 or less, would be identified on every OPO match run as potential splittable donors, concurrently the match run will identify regional recipients willing to accept a segmental graft (17). This study may support and help to refine the UNOS allocation policy. Donor body weight ≤ 40 kg, history of cardiac arrest after declaration of death might be added in UNOS exclusion criteria. Figure 7 shows potential split donors among DBD donors allocated for primary adult recipients. ‘Splittable’ donors were defined as the DBD donors who met the UNOS split criteria, body weight > 40 kg and no history of cardiac arrest. When a splittable donor ≤ 18 years old was identified, a mandatory split allocation program might be activated (Figure 7A). When a splittable donor 19–40 years old is identified and a high-risk patient is active in the list, selective split allocation might be necessary (considering cGRWR, technical experience and sharing system between two centers) (Figure 7B). Therefore, UNOS allocation policy should allow for flexibility between centers, in particular allow organ sharing between two centers with well collaboration in this subgroup. If there is no high-risk patient in the list, a mandatory split program might be activated (Figure 7C). According to this policy, SLT might be extended to 28.1% of the DBD grafts in adult primary LT (Figure 7D). In implementing an SLT program, there needs to be a formal policy on the consent procedure for patients offered a split-liver grafts (18). Patients should be informed of SLT (UNOS policy, ethical responsibility of transplant centers to increase use of deceased allografts, outcomes and so on) at either the time of listing or prior to ascension to the top of the transplant list.

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Figure 7. Potential split donors among donation after brain death (DBD) donors allocated for primary adult recipients.‘Splittable’ donors were defined as the DBD donors who met the UNOS split criteria (donors less than 40 years of age, on a single vasopressor or less, transaminases no greater than three times normal, BMI of 28 or less), body weight > 40 kg and no history of cardiac arrest. When a splittable donor with age ≤ 18 years identified, mandatory split allocation program can be activated (A). When a splittable donor with age 19–40 is identified and a high-risk patient is active in the list, selective split allocation is necessary (considering cGRWR, technical experience and sharing system between two centers) (B). ‘Mandatory splittable’ donors in (B) was defined as ‘splittable’ donors with cGRWR > 1.5% and allocated in large volume center. If there is no high-risk patient in the list, mandatory split program can be activated (C). According to this policy, split-liver transplantation (SLT) can be extended theoretically up to 28.1% of the DBD grafts in adult primary LT (D). ‘Split’ donors were actual split donors and belong to ‘mandatory splittable’ donors. ‘Total split’ donors were actual split donors in the cohorts.

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In this study, we found that the risk of graft failure was increased in very small recipients (body weight ≤ 6 kg). This seems not to be related to technical difficulty in very small infants but to be related to higher risk by prolonged CIT because there was no difference of graft survival in LDLT by recipient body weight. Very small infants were more sensitive to prolonged CIT. And LSG from young donors reduced the risk of prolonged CIT, especially in very small recipients. Therefore, more caution is needed when LSG are allocated to very small recipients.

We recognize both potential advantages and limitations of this study that uses a large national data base. Despite the large number of SLT cases, some important variables such as duration of ICU stay, degree of steatosis that may influence graft outcome may not be captured in the data base. And there might be a selection bias in this analysis even with statistical adjustment between SLT and other type of grafts (whole DBD or LD). For example, the patients who receive splits are more likely to be less sick in general than those who receive whole DBD organs. However, the large sample size provides sufficient power to detect meaningful risk factors that may be missed by single-center studies.

In conclusion, we identified risk factors for poor outcomes following SLT. Using these factors, we identified selective conditions that showed comparable outcomes to whole DBD in adults or LDLT in pediatrics. RSG from young (age ≤ 40 years) donors are suitable to split when other transplant related risk factors were minimized. Reducing CIT is important in LSG. In situ split and well coordinated sharing between specialized centers is preferable to reduce CIT and improve the outcomes. cGRWR can be used to select the appropriate RSG recipients preoperatively. In very small children and urgent adult recipients, more careful donor selection and graft management is needed.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. RSG Outcome
  7. LSG Outcomes
  8. Discussion
  9. References