Abstract
Background
Infants have the highest waitlist mortality of all liver transplant candidates. While previous studies have demonstrated that young children may be at increased risk when receiving partial grafts from adult and adolescent deceased donors (DD), with few size-matched organs available, these grafts have increasingly been used to expand the pediatric donor pool. We aimed to determine the current adjusted risk of graft failure and mortality in young pediatric recipients of DD partial livers, and to determine if these risks have changed over time.
Methods
We analyzed 2,683 first-time DD liver-alone recipients under the age of 2 years in the UNOS database (1995-2010), including 1,118 DD partial livers and 1,565 DD whole organs. Transplant factors associated with graft loss on bivariate analyses (p<0.1) were included in multivariable proportional hazards models of graft and patient survival. Interaction analysis was used to examine risks over time (time-periods:1995-2000, 2001-2005, 2006-2010).
Results
While there were significant differences in crude graft survival by graft type in 1995-2000 (p<.001), graft survival between partial and whole grafts was comparable in 2001-2005 (p=.43) and 2006-2010 (p=.36). Furthermore, while the adjusted hazards of partial graft failure and mortality were 1.40 (1.05-1.89) and 1.41 (.95-2.09) respectively in 1995-2000, the adjusted risk of graft failure and mortality was comparable between partial and whole organs in 2006-2010 (Graft failure HR .81 95%CI .56-1.18; Mortality HR 1.02 95%CI .66-1.71).
Conclusions
Deceased-donor partial liver transplantation has become less risky over time, and now has comparable outcomes to whole liver transplantation in infants and young children.
Keywords: Pediatrics, partial liver, risk factors, multivariate analysis, United Network of Organ Sharing
Introduction
With a severe shortage of size-matched whole organs, partial grafts from both living and deceased donors have increasingly been seen as an alternative means of expanding the pediatric organ pool. (1-5) Though living donor partial grafts have been shown to have superior graft survival to both types of deceased donor grafts, (1, 2) many pediatric patients do not have access to appropriate living donors.(6) Although the use of living donors has increased since the introduction of the PELD scoring system in 2002,(4) they still comprised less than 11% of pediatric liver transplants in 2010. (7) In contrast, since 2002 the use of deceased donor partial grafts, including “split grafts” (in which the remainder of the organ is used) and “reduced grafts” (in which the remainder of the organ is discarded), has increased almost eight-fold to between 25 and 32% of pediatric liver transplants. (4, 7, 8) Furthermore split livers have the potential to become even more common; fewer than 10% of adult livers that met criteria for splitting between 1996 and 2006 were actually made available for split liver transplantation.(2)
Infants and young children awaiting liver transplantation have the highest waitlist mortality of all liver transplant candidates, (2, 3, 8, 9) and young children may be at the greatest risk of long-term morbidities and growth delays associated with extended waiting time.(10-12) A significant increase in the number of deceased donor partial livers could dramatically shorten the length of time that a child spends on the waitlist, potentially decreasing this high waitlist morbidity and mortality. (13)
While infants could potentially benefit most from an expansion in the pediatric donor pool, they also may be at especially high risk when accepting partial deceased donor grafts. In one study prior to the initiation of PELD, deceased donor split liver recipients under the age of 2 years experienced a significantly greater risk of graft failure compared to recipients of whole grafts. Yet in older children, the risk of graft failure in split livers was comparable to that of whole livers.(1) An analysis from a single academic center even suggested that all pediatric recipients may be subject to this increased risk of adjusted graft failure and mortality when accepting split grafts.(14) Although other single center studies have shown that the risk of partial graft failure in pediatric patients may be more comparable to that of whole grafts,(15) there has been no recent national analysis of the specific risk of deceased donor partial grafts in infants and young children. As partial grafts become more common for infants on the waitlist, it will become increasingly important to understand the risk of accepting such a graft in this high-risk age group. The aims of this study were: (i) to determine the current risk of graft failure and mortality in young recipients (<24 months) of deceased donor partial and whole grafts, (ii) to determine if these risks have changed over time, (iii) and to identify the effects of other transplant characteristics on the risk of both graft failure and mortality in this age group.
Methods
Data
All deceased donor liver transplants reported in the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research Files were considered for analysis. IRB Approval was obtained from Children’s Hospital, Boston (IRB-P00002506).
All deceased donor transplants from 1995-2010, in which the recipient was under the age of 2 years, were analyzed. We excluded all re-transplants, and patients receiving organs from living donation and donation after death from circulatory arrest. All cases of multi-organ transplantation were also removed from the analysis. The follow-period extended from 1/1/1995-8/31/2011. Patient and graft survival was truncated at 1500 days post-transplant.
Variables
All variables in the standard UNOS database were considered to be possible risk factors for graft failure in previous analyses were considered (2, 16, 17). Transplants were categorized by whether they occurred during 1995-2000, 2001-2005 and 2006-2010. The time periods before and after the initiation of PELD in 3/2002 were also examined. No variable included in the analysis had over 20 percent missing data. Missing data was categorized as “missing” in order to maximize power in the multivariate analysis. Transplant type was defined according to the UNOS database as partial (in which the remainder of the organ was discarded), split (in which the remainder of the organ was transplanted), and whole. The regional volume of first-time transplant recipients aged 0-24 months was adjusted for in the final multivariate analysis. Primary diagnoses that accounted for less than 3% of total diagnoses were combined into “other diagnosis,” including parenteral nutrition related liver disease and cholestasis. The primary outcome variable of interest was time to graft loss as defined by re-transplant or death. Patients were followed until the date of graft failure or until they were lost to follow-up. Mortality was analyzed as a secondary outcome measure.
Analysis
Association of transplant type with all other variables was determined with bivariate analysis. Fisher’s exact tests were used to compare categorical variables. Normally distributed data were compared with ANOVA, while skewed continuous variables (e.g. waitlist time, MELD score, and cold ischemia time) were compared with rank sum tests.
Kaplan-Meier survival analysis (log-rank test) was used to examine the unadjusted association of risk factors with graft failure. As reduced and split grafts were noted to have similar crude outcomes, all DD partial grafts were combined to increase the power of the multivariate analysis. Variables with p-values < 0.1 on bivariate analysis were considered for multivariate analysis. Backwards-selection was used to build the final multivariable models (p<.1). Covariates that were investigated but excluded under backwards selection included: Lab and final PELD score, history of exception, donor diabetes, coronary artery disease, previous malignancy, hepatitis status, and number of vasopressors. Height and BMI were excluded because they were collinear with weight, and recipient creatinine was collinear with use of dialysis. Donor cause of death, ABO match, final status 1 designation, and regional transplant volume were forced into the final model, though these were not independently associated with outcome. Cox proportional hazards modeling was used to estimate the adjusted association of all variables with graft failure as a primary outcome. A second Cox proportional hazards model was used to estimate the adjusted associations of all variables with patient mortality. Interaction tests were performed to determine the effect of all significant independent risk factors on the adjusted risk of partial liver grafts. We then examined the possibility of effect modification of significant risk factors with transplant type using subset analyses. Ten-fold cross-validation was used to evaluate the stability of all estimates in the multivariate models.(18, 19) A p-value ≤.05 was considered to be significant. Analyses were performed with JMP Pro 10.0.0 (SAS Institute Inc, Cary, NC) and SAS 9.3 (SAS Institute Inc., Cary, NC).
Results
Transplant Characteristics
Deceased donors of partial grafts were significantly older than those of whole livers (Table 1, p<.001). As would be expected, donor weight was also significantly lower for whole grafts, compared to partial grafts (p<.001). Whole organs were also more likely to be shared nationally (p<.001). A larger proportion of partial grafts were given to recipients less than 1 year old, compared to whole grafts and the weight of these partial graft recipients was also lower. Recipients of partial grafts were “sicker” than recipients of whole grafts as measured by: (1) a greater proportion of partial graft recipients requiring a ventilator prior to transplant, (2) greater proportion designated as Status 1, and (3) higher lab PELD score. Waitlist-time in the PELD era also varied significantly by graft type; Young children who received a whole graft tended to wait much longer than those given partial grafts, a trend that was consistent when examining all recipients (p<.001) and just the subgroup designated Status 1 (p<.001). Only among recipients with a PELD over 30 was graft type not significantly associated with differences in waitlist time (p=.29). There were 698 graft failures and 345 deaths across the study cohort; 92% of these occurred within 1500 days post-transplant.
Table 1.
Donor and recipient characteristics by types of cadaveric liver grafts in infant recipients (aged less than 24 months). N=2683
| Characteristics |
DD Partial (n=1118) |
DD Whole (n=1565) |
p-value |
|---|---|---|---|
|
| |||
|
Donor
| |||
| DD Partial Graft Type | |||
| Reduced | 486 (43.5) | N/A | N/A |
| Split | 632 (56.5) | ||
|
| |||
| Age (years, Median, IQR) | 15 (8-21) | 1 (0-2) | <.001** |
|
| |||
| Weight (Kg, Median, IQR) | 56 (30-69.6) | 11 (7.8-14.5) | <.001** |
|
| |||
| Cause of Death (%) | <.001** | ||
| Anoxia | 188 (16.9) | 554 (35.5) | |
| Head Trauma | 716 (64.6) | 825 (53.0) | |
| Other | 54 (4.9) | 88 (5.7) | |
| Stroke | 153 (13.6) | 92 (5.9) | |
| Missing | 7 (0.6) | 6 (0.4) | |
|
| |||
| ABO Match (%) | .38 | ||
| Identical | 899 (80.4) | 1292 (82.5) | |
| Compatible | 180 (16.1) | 223 (14.3) | |
| Incompatible | 39 (3.5) | 50 (3.2) | |
|
| |||
| Share (%) | <.001** | ||
| Local | 541 (48.4) | 422 (31.8) | |
| Regional | 487 (43.6) | 639 (40.8) | |
| National | 86 (7.7) | 497 (31.8) | |
| Foreign | 4 (0.4) | 7 (0.5) | |
|
| |||
| Cold Ischemia Time | |||
| (Hrs, median, IQR) | 7.5 (6-9.8) | 7.7 (6-9.6) | .19 |
| Missing | 87 (7.8) | 163 (10.4) | .02** |
|
| |||
|
Recipient
| |||
| Age (yrs, %) | |||
| <1 | 739 (66.1) | 936 (59.8) | .001** |
| 1-2 | 379 (33.9) | 629 (40.2) | |
|
| |||
| Weight (Kg, median, IQR) | 7.3 (5.9-8.8) | 7.5 (6.2-9.3) | .001** |
|
| |||
| Medical Condition (%) | <.001** | ||
| Home | 500 (44.7) | 893 (57.0) | |
| Inpatient | 243 (21.7) | 335 (21.4) | |
| ICU without ventilator | 210 (14.6) | 183 (11.7) | |
| ICU with ventilator | 163 (14.6) | 150 (9.6) | |
| Missing | 2 (0.2) | 4 (0.3) | |
|
| |||
| Status 1 (%) | 417 (37.3) | 419 (26.8) | <.001** |
|
| |||
|
Lab PELD Score (2002-10) (median, IQR) |
20 (10-28) | 17 (7-25) | .02** |
|
| |||
| Dialysis (%) | 20 (1.8) | 32 (2.0) | .22 |
|
| |||
| Diagnosis (%) | <.001** | ||
| Biliary Atresia/Hypoplasia | 678 (60.6) | 1001 (64.0) | |
| Acute (Hepatitis/Necrosis) | 133 (11.9) | 110 (7.0) | |
| Primary Malignancy | 42 (3.8) | 77 (4.9) | |
| Metabolic | 121 (10.8) | 166 (10.6) | |
| Other | 144 (12.9) | 211 (13.5) | |
|
| |||
|
Waitlist Time, Days, Median (IQR), All Post-PELD era |
|||
| All | 42 (12-113) | 52.5 (19-114) | .004** |
| Lab PELD>30 | 16 (5-71) | 25 (6-70) | .29 |
| Status 1 | 13 (4-51.5) | 36.5 (11-75.8) | <.001** |
While there has not been a significant increase in the proportion of DD partial grafts over time (Table 2, p=.15), an increasing proportion of partial liver transplants have been split liver grafts (p<.001). The proportion of very small recipients (<6 kg), median cold ischemia time, organ sharing status, recipient medical condition, and the proportion of status 1 designees have all varied over time. While overall waitlist time has decreased in more recent time periods (p<.001), there has been no significant improvement in median waitlist time for status 1 designees (p=.24).
Table 2.
Donor and recipient characteristics of Liver Transplants for recipients aged 0-24 months, by time period: (1) 1995-2000, (2) 2001-2005, and (3) 2006-2010. N=2676.
| Characteristics |
1995-2000 (n=936) |
2001-2005 (n=827) |
2006-2010 (n=920) |
p-value |
|---|---|---|---|---|
|
| ||||
| DD Graft Type (%) | ||||
| Whole | 569 (60.8) | 467 (56.5) | 529 (57.5) | .15 |
| Partial | 367 (39.2) | 360 (43.5) | 391 (42.5) | |
| - Split | − 172 (46.9) | − 218 (60.6) | − 242 (61.9) | <.001** |
| - Reduced | − 195 (53.1) | − 142 (39.4) | − 149 (38.1) | |
|
| ||||
| Recipient Age (<1 year, %) | 593 (63.4) | 527 (63.7) | 555 (60.3) | .27 |
|
| ||||
| Recipient Weight (<6 kg, %) | 226 (24.2) | 204 (24.7) | 166 (18.0) | <.001** |
|
| ||||
| Cold Ischemia Time | <.001** | |||
| (Hrs, median, IQR) | 8.5 (6.5-11) | 7.4 (6-9.25) | 7 (5.5-9) | |
|
| ||||
| Share (%) | <.001** | |||
| Local | 366 (39.1) | 330 (39.9) | 267 (29.0) | |
| Regional | 357 (38.1) | 313 (37.9) | 456 (49.6) | |
| National | 207 (22.1) | 182 (22.0) | 194 (21.1) | |
| Foreign | 6 (0.6) | 2 (0.2) | 3 (0.3) | |
|
| ||||
| Medical Condition (%) | <.001** | |||
| Home | 468 (50.0) | 409 (49.5) | 516 (56.1) | |
| Inpatient | 200 (21.4) | 182 (22.0) | 196 (21.3) | |
| ICU without ventilator | 127 (13.6) | 151 (18.3) | 115 (12.5) | |
| ICU with ventilator | 135 (14.4) | 85 (10.3) | 93 (10.1) | |
| Missing | 6 (0.6) | 0 (0.0) | 0 (0.0) | |
|
| ||||
| Status 1 (%) | 287 (30.7) | 339 (41.0) | 210 (22.8) | <.001** |
|
| ||||
|
Lab PELD Score (2002-10) (median, IQR) |
N/A | 17 (9-25) | 19 (8-27) | .37 |
|
| ||||
|
Waitlist Time, Days, Median (IQR) |
||||
| All | 60 (16-144) | 57 (17-131) | 45 (14-100.5) | <.001** |
| PELD>30 | N/A | 22 (6-72.8) | 19.5 (6-70) | .73 |
| Status 1 | 17 (5-67) | 26 (7-73) | 32.5 (5.8-64.5) | .24 |
Kaplan-Meier Survival Analysis
On bivariate analysis, there was a significant improvement in graft survival in both whole and partial liver transplantation in the post-PELD era compared to the pre-PELD period (Figure 1, Left, p=.01 and p<.001 respectively). Additionally, while there were significant differences in graft survival between partial and whole grafts in the pre-PELD era (p=.002), there was no significant difference in graft survival by graft type in the post-PELD era (p=.68). Reduced and Split grafts had comparable survival in both the pre-PELD and post-PELD eras (p=.76 and p=.39 respectively). While there were significant differences in crude graft survival by graft type in 1995-2000 (Figure 1, Right, p<.001), graft survival between partial and whole grafts was comparable in 2001-2005 (p=.43) and 2006-2010 (p=.36).Only livers from donors over the age of 40 had significantly worse graft survival (p<.001). In the post-PELD era, donors less than 10 kilograms had significantly inferior graft survival compared to those in higher weight categories (p<.001) and recipients less than 6 kilograms also had diminished survival (p=.01). Patients who were in the ICU on a ventilator were at significantly higher risk of failure (p<.001). Graft survival also differed significantly by final status score, with status 1 recipients having a significantly increased risk of graft failure (p=.003).
Figure 1.
Kaplan-Meier Analysis of graft survival comparing (Left) Reduced, Split and Whole Grafts before and after the introduction of PELD (Pre PELD 1995-2/2002, Post PELD 3/2002-2010); (Right) Partial versus Whole Grafts by Time Period (1995-2000, 2001-2005, 2006-2010).
Multivariable Models
Graft Failure
The multivariate adjusted associations of selected donor and recipient characteristics are shown in Table 3. Partial liver transplants were associated with a case-mix adjusted HR of graft failure of 1.14 (.89-1.44, p=.30) compared with whole livers over the entire study cohort. Donor age was an independent predictor of graft failure (p<.001). Similar to bivariate analysis, low donor weight (≤10 kilograms) low recipient weight (≤6 kilograms) and longer cold ischemia time (CIT, over 9 hours) also had an increased risk of failure. The earliest time period in the study (1995-2000) appeared to be associated with a 63% increased risk of graft failure compared to the most recent time period (2006-2010), even after controlling for other factors (p<.001). The age of recipients was not independently associated with outcome. Pre-transplant medical status, as measured by both ventilator status in the ICU and dialysis, also independently affected graft outcome.
Table 3.
Adjusted association of selected donor and recipient variables with graft and patient survival between 1995 and 2010. 2545 patients remained in the model. HR = Hazard Ratio.
| Risk Factors | Graft Failure HR (95% CI) / p-value |
Mortality HR (95% CI) / p-value |
|---|---|---|
|
| ||
|
Donor Factors
| ||
| Transplant Type | ||
| Whole | 1.00 / Reference | 1.00 / Reference |
| Partial | 1.14 (.89-1.44) / .30 | 1.35 (.97-1.89) / .08 |
|
| ||
| Age (/additional 10y) | 1.15 (1.04-1.27) / .007 | 1.18 (1.03-1.34) / .01** |
|
| ||
| Weight ≤ 10 (Kg) | 1.48 (1.19-1.84) / <.001** | 1.47 (1.06-2.03) / .02** |
|
| ||
| Cold Ischemia (Hours) | ||
| < 5 | 1.00 / Reference | 1.00 / Reference |
| 5-9 | 1.16 (.89-1.52) / .27 | 1.28 (.86-1.91) / .22 |
| >9 | 1.27 (.95-1.69) / .11 | 1.57 (1.04-2.38) / .03** |
| Missing | 1.42 (.99-2.04)/ .06 | 1.32 (.76-2.29)/ .32 |
|
| ||
| Share Type | ||
| Local | 1.17 (.91-1.50)/ .23 | 1.46 (1.01-2.10)/ .04** |
| Regional | 1.14 (.90-1.44)/ .29 | 1.32 (.94-1.86)/ .11 |
| National | 1.00/Reference | 1.00/Reference |
|
| ||
| Year | ||
| 1995-2000 | 1.63 (1.32-2.01) / <.001** | 1.79 (1.34-2.39) / <.001** |
| 2001-2005 | 1.18 (.95-1.48)/ .14 | .93 (.67-1.30) / .68 |
| 2006-2010 | 1.00 / Reference | 1.00 / Reference |
|
| ||
| Recipient Factors | ||
|
| ||
| Age (years) | ||
| < 1 | 0.88 (.72-1.08) / .21 | 0.89 (.66-1.19) / .42 |
| 1-2 | 1.00/Reference | 1.00/Reference |
|
| ||
| Weight (Kilograms) | ||
| ≤ 6 | 1.50 (1.15-1.94) / .002** | 1.97 (1.37-2.84) / <.001** |
| 6.1-9 | 1.02 (.81-1.29) / .85 | 1.09 (.78-1.53) / .62 |
| >9 | 1.00 / Reference | 1.00 / Reference |
|
| ||
| Diagnosis | ||
| Biliary Atresia | 1.00/Reference | 1.00/Reference |
| Primary Malignancy | 1.30 (.88-1.91) / .19 | 1.18 (.64-2.17) / .59 |
| Acute Hepatitis/Necrosis | 1.15 (.86-1.53) / .35 | 1.46 (.99-2.13) / .06 |
| Metabolic | 1.10 (.83-1.44) / .52 | 1.24 (.84-1.83) / .27 |
| Other (includes PN-LD) | 1.05 (.81-1.36) / .72 | 1.55 (1.11-2.18) / .01* |
|
| ||
| Medical Condition | ||
| Home | 1.00 / Reference | 1.00 / Reference |
| Inpatient | 1.16 (.93-1.44) / .19 | 1.15 (.84-1.58) / .38 |
| ICU without ventilator | 1.08 (.80-1.45) / .62 | .89 (.58-1.37) / .60 |
| ICU with ventilator | 1.71 (1.29-2.28) / .001** | 1.96 (1.33-2.89) / <.001** |
|
| ||
| Dialysis | 1.56 (.97-2.49) / .07 | 2.08 (1.17-3.70) / .01** |
Models were also adjusted for Donor cause of death, ABO match, status 1 designation of recipients and regional transplant volume, however these were not independently associated with outcome.
Patient Mortality
Overall there was a trend towards an increased risk of patient mortality in recipients of DD partial grafts compared to recipients of DD whole grafts (Table 3, HR 1.35, p=.08). As with graft failure, variables such as older age, low weight (≤10 kilograms), and longer CIT (>9 hours) were significantly associated with greater adjusted risks of mortality. The earliest time period of 1995-2000 was associated with a 79% increased case-mix adjusted hazard of mortality compared to the most recent time period of 2006-2010,(p<.001). Recipient factors such as low weight (≤6 kilograms), a primary diagnosis of “other”, ventilator status, need for dialysis and previous transplantation were all independently associated with increased risks of mortality. While local sharing was associated with a slightly increased risk of patient mortality overall (p=.04), local shares had comparable adjusted risk of mortality to national shares in the most recent time period (HR 1.33 95%CI .65-2.7). Furthermore, the risk of graft failure was comparable across all share types in all time periods. Final status score was not independently associated with either graft failure or mortality. We did not find an independent association with regional volume of transplants (for young recipients aged 0-24 months) and either type of outcome. Except for time period, we did not identify any significant effect modification between the use of partial grafts and any other risk factors considered in the model, including final status score, age of recipient, medical condition, diagnosis, or CIT.
Effect of Time Period
While the adjusted hazards of partial graft failure and mortality were 1.40 (1.05-1.89) and 1.41 (.95-2.09) respectively in 1995-2000, the adjusted risks of graft failure and mortality were comparable between partial and whole organs in 2006-2010 (Table 4; Graft failure HR .81 95%CI .56-1.18; Mortality HR 1.02 95%CI .66-1.71). Interaction analysis demonstrated that there was a significant change in the risk of partial graft failure over time, even after case-mix adjustment (p=.009). We did detect a trend towards an increased risk of patient mortality for partial grafts in the 2001-2005 time period, but confidence intervals were wide (HR 1.70 95% CI .99-2.92). Furthermore, this was not found to be significantly different than the current time period on interaction analyses.
Table 4.
The effect of time period on the Hazard of Partial Grafts: Interaction Analyses
| Risk Factors | Graft Failure HR (95% CI) |
Interaction p-value |
Mortality HR (95% CI) |
Interaction p-value |
|---|---|---|---|---|
|
| ||||
| Tx Year 1995-2000 | ||||
| Whole | 1.00 / Reference | .009* | 1.00 / Reference | .26 |
| Partial | 1.40 (1.05-1.89) | 1.41 (.95-2.09) | ||
|
|
|
|||
| Tx Year 2001-2005 | ||||
| Whole | 1.00 / Reference | .20 | 1.00 / Reference | .13 |
| Partial | 1.08 (.76-1.53) | 1.70 (.99-2.92) | ||
|
|
|
|||
| Tx Year 2006-2010 | ||||
| Whole | 1.00 / Reference | 1.00 / Reference | ||
| Partial | .81 (.56-1.18) | Reference | 1.02 (.66-1.71) | Reference |
Ten-fold cross-validation of both multivariable models indicated that these estimates were highly stable across our study samples (Table 5).
Table 5.
Ten-fold Cross-Validation of the Adjusted Hazard Ratio of Partial and Whole Liver Transplantation in Young Children. 2006-2010.
| Risk Factor | Graft Failure Adjusted Hazard Ratio |
Mortality Adjusted Hazard Ratio |
|---|---|---|
|
| ||
| Whole (Reference): | 1.00 | 1.00 |
| Partial: | ||
| Mean HR | .82 | 1.03 |
| Range of HR | .72-.89 | .88-1.24 |
Discussion
Whole deceased donor livers, especially those that are size matched for young recipients, continue to be a severely limited resource. Infants and young children have been shown to have the highest morbidity and mortality on the waitlist for liver transplantation. (3, 8-12) While partial deceased donor liver grafts could be used to expand the pediatric donor pool (4), past analyses have suggested an increased risk of graft failure when these organs are transplanted into high-risk recipients, including adults with a high risk of waitlist mortality based on the MELD scoring system (2, 14, 20) and infants and young children.(1, 14)
In the present study we noted that while there was an increased risk of graft failure of partial grafts in infants in 1995-2000 as has been suggested by previous analyses, this risk has become negligible in the most recent time period of 2006-2010. On both crude and adjusted analyses, we found that DD partial grafts have become significantly safer over time. Both split and reduced DD grafts now have comparable outcomes to whole grafts, in terms of both graft and patient survival. While several other risk factors were independently predictive of graft failure and patient mortality, none of these variables were found to be associated with disproportionate risk in partial grafts compared to whole grafts, signifying that all infants, regardless of their status score, medical condition, diagnosis, age or weight, could accept a deceased donor partial liver graft without increasing their relative risk of graft failure or death compared to accepting a deceased donor whole liver.
We found that although median waitlist time appears to have decreased in the most recent time period, there have been no significant improvements in waitlist time for the highest risk status 1 designees or those with elevated lab PELD scores. With the demand for whole organs presumably outpacing supply for this young recipient cohort, we also noted that recipients of whole livers tended to wait significantly longer before transplant than recipients of partial livers despite the fact that more whole organs are shared nationally.(21) It is possible that differences in waitlist time could suggest an underlying preference for whole grafts over partial grafts for risk-equivalent patients. This preference would make sense given the increased relative risk of DD partial grafts noted on analyses of the pre-PELD era. However as we found that DD partial grafts had comparable outcomes to whole grafts in the most recent era of 2006-2010, we believe that both grafts should now be preferred equally for all young pediatric candidates. If the grafts are considered comparable, it is likely that there will be fewer differences in waitlist time by graft type in the future.
Recipients of partial grafts tended to have higher median lab PELD scores than those receiving whole grafts and a greater proportion of partial liver recipients were designated status 1 compared to whole liver recipients. Indeed, reduced and split liver recipients were also more likely to be in the ICU or on a ventilator prior to transplant compared to whole liver recipients. The longer waitlist-time for whole livers, even by status 1 recipients, would imply that for “sick” pediatric patients partial livers may be a more expedient means of obtaining an organ. As size-matched whole livers are relatively scarce compared to the large number of adult livers, sicker candidates may not have the time to wait for a whole size-matched organ to become available. Fortunately, despite the fact that partial livers tended to be transplanted into “sicker” pediatric recipients, we found that partial grafts had comparable unadjusted and adjusted graft survival to whole grafts, and a similar adjusted risk of mortality. While previous studies have suggested that adults with higher final status scores (status 1) are associated with a higher risk of graft failure when accepting a partial or split graft,(2, 14, 20) we found no evidence that status 1 designation, ventilator status or dialysis use was associated with a disproportionate risk of graft failure or mortality in young pediatric recipients of partial liver grafts compared to whole liver grafts.
While recipients who were designated as status 1 appeared to be associated with worse graft survival on unadjusted analysis, status score was not predictive of outcome in the full multivariate models. Conversely, medical status, including the need for a ventilator or dialysis, was highly associated with both graft failure and patient mortality in adjusted models. Previous studies have also suggested that the need for life support may increase the risk of graft failure (22, 23). As status 1 designees are more likely to require life support, it may be that status score is simply confounded by medical status. While recipient age was not shown to affect graft or patient survival, we did note that low donor or recipient weight was associated with diminished outcomes on both unadjusted and adjusted analysis. Previous studies have also suggested that low donor or recipient weight may be associated with an increased risk of graft failure and mortality, (2, 23) possibly because of the increased rate of vascular thrombosis in the small caliber vessels of these grafts. (24) As whole grafts are rare for this small cohort, it is notable that we did not find a difference in risk when these patients were given partial grafts compared to size matched whole grafts.
We found that both partial and whole pediatric liver transplants have become safer in the most recent pest-PELD time period. Previous studies have also shown that the outcomes of pediatric liver transplantation have improved since the initiation of PELD, possibly due to improvements in recipient and donor selection, organ allocation, surgical techniques, post-operative care and immunosuppression.(3, 4) However we noted that the relative outcomes of partial liver transplants have also greatly improved over time. While there was a significant difference in graft survival between partial and whole liver transplants in the earliest time periods of our study, outcomes now appear comparable. Interaction analyses suggest that the risk of graft failure in partial grafts has become significantly safer over time, even after adjusting for other significant donor and recipient factors. We found that outcomes appear to have gradually improved between 1995 and 2010. Although the initiation of PELD may be a part of the explanation for improved outcomes – the gradual nature of this progress across three time periods suggest that it is most likely due to numerous improvements in pediatric transplantation over time.
Given the large sample size, the UNOS database can provide power for more extensive multivariate analyses compared to many single center studies. Nevertheless, the database is retrospective and is limited to the risk factor and outcome variables collected for the allocation process. While the findings of the present study suggest that partial and whole grafts have comparable primary outcomes such as graft and patient survival, we could not accurately compare graft types by the relative proportion of specific complications and the causes of death due to the limitations of missing data. Additionally, as there were relatively fewer deaths in the study compared to graft failures, we had less power to detect differences in the risk of mortality. Further prospective evaluation will be required to validate our findings.
Infants continue to have the highest mortality rate on the liver waitlist. While this mortality rate has improved over time, it remains almost twice that of adult recipients.(25) As size matched whole livers remain a scarce resource, maximizing the use of partial livers from both deceased and living donors will be the key to decreasing this high mortality rate. However we noted that there has been no increase in the proportion of DD partial grafts over time. While we firmly believe that living donors should continue to be pursued, the use of split grafts from adult donors should also be used to optimally expand the pediatric donor pool. Despite an increase in the number of adult livers that were split since the introduction of PELD/MELD, the current liver allocation system is not designed to optimize the use of this valuable resource; fewer than 10% of donors that met criteria for splitting between 1996 and 2006 were actually split.(2) Studies have suggested that if even half of appropriate donor livers are split the pediatric waitlist could be eliminated.(13) We believe that split liver transplants have comparable outcomes to transplants of size matched whole grafts in all young pediatric recipients, making them a safe alternative to size matched whole organs. By expanding the use of partial liver grafts in young recipients it may be possible to reduce the unacceptably high morbidity and mortality of high-risk pediatric transplant candidates.
Acknowledgements
We would like to thank Naomi Shatz for her support and editorial assistance.
Funding Disclosure: This work was supported in part by Health Resources and Services Administration (HRSA) contract 231-00-0115, Agency for Healthcare Research and Quality (AHRQ) Grant number 1T32HS019485-01, and National Institute of Child Health and Human Development (NICHD) Grant number 1K24HD060786. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S Government.
This study supports the use of partial DD liver grafts in young children in an attempt to significantly increase the pediatric organ pool.
Abbreviations
All abbreviations used in this manuscript are explained directly within the text.
- BMI
Body Mass Index
- CIT
Cold Ischemia Time
- DD
Deceased Donor
- HR
Hazard Ratio
- ICU
Intensive Care Unit
- MELD
Model for End-Stage Liver Disease
- PELD
Pediatric End-Stage Liver Disease Model
- UNOS
United Network of Organ Sharing
Footnotes
Author Contributions: RC, KV, JF and HK contributed to the study design, data collection, study analysis and the drafting of this article. DG contributed to the study design, data collection, study analysis and editing of the manuscript. NF and KP contributed to the study design, analysis and drafting of this article.
Conflicts of Interest: The authors of this manuscript are not supported by any commercial associations and have no conflicts of interest to disclose.
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