Abstract
Background
The proportion of older patients awaiting liver transplantation (LT) is rising. While increased age and LT-MELD are known to increase the risk of graft loss, no studies have explored whether there is a synergistic effect between LT-age and LT-MELD.
Methods
All US adult, non-Status 1 recipients of primary deceased donor LT from 2/05–1/10 without MELD exceptions were included (n=15,677). Recipients were categorized by LT-age [18–59y (n=11,966), 60–64y (n=2,181), 65–69y (n=1,177), ≥70y (n=343)] and LT-MELD [low (<20, n=5,290), mid (20–27, n=5,112), high (≥28, n=5,265)]. Adjusted Cox models evaluated the 1) independent and 2) combined effects of LT-age and LT-MELD on graft loss (death or re-LT).
Results
LT-age ≥70y (HR=1.65, 95% CI 1.08–1.82) and LT-MELD ≥28 (HR=1.46, 95% CI 1.02–1.47) were independently associated with increased risk of graft loss (p<0.001). In a model allowing for the interaction between LT-age and LT-MELD, the risk of graft loss for recipients ≥70y with MELD ≥28 was higher than predicted by the additive model (HR=2.38, 95%CI 1.73–3.27, p<0.001) resulting in one-year graft survival of 56%. However, the increased risk of graft loss in recipients ≥70y was attenuated at lower LT-MELD <28. Furthermore, the interaction term was not significant for any other LT-age and LT-MELD combination.
Conclusion
Our analyses suggest that recipients should not be excluded solely based on age, however LT for recipients ≥70y at high LT-MELD scores should be undertaken cautiously.
Keywords: recipient age, MELD, graft loss
Introduction
From 2005 to 2009, the proportion of wait-list candidates for liver transplantation over 60 years of age increased from 27% to 34% (1). As the population with cirrhosis due to chronic hepatitis C (2) and non-alcoholic fatty liver disease ages (3), the proportion of older candidates on the wait-list is anticipated to grow. Exacerbating this problem is stagnant donor availability (1); as the gap between the number in need of transplant and the number of livers procured widens, candidates are waiting longer and undergoing transplant at older ages with higher MELD scores (1).
Older age at the time of transplant (LT-age) has been associated with worse post-transplant outcomes, including increased risk of graft loss (4–8). For this reason, some U.S. centers have set arbitrary maximum age cut-offs for liver transplantation, usually 65 or 70 years of age. However, a few single-center studies have suggested that comparable outcomes can be achieved in well-selected older recipients (9–12). Older candidates arguably undergo more stringent evaluation and consideration prior to transplantation in an effort to select those most appropriate to proceed to transplantation. However, data as to the optimal selection algorithm for older candidates is limited such that currently, consensus as to specific factors that predict favorable or unfavorable post-transplant outcomes are lacking.
The aim of this study was to evaluate post-transplant outcomes based on the combination of LT-age and MELD score at transplant (LT-MELD). We hypothesized that LT-MELD would be associated with a synergistic effect on post-transplant outcomes among older recipients. Therefore, we undertook this study to examine the interaction between LT-age and LT-MELD on the outcome of graft loss.
Results
Among the 15,677 liver transplant recipients who comprised our study cohort, 11,966 (76%) were 18–59 years, 2,181 (14%) were 60–64 years, 1,177 (8%) were 65–69 years, and 343 (2%) recipients were ≥70 years (Table 1). As LT-age increased, the proportion of African American recipients decreased while the proportion of Caucasians increased (p<0.001). Older recipients were more frequently transplanted for non-alcoholic fatty liver disease (NAFLD), cholestatic, or other liver diseases, whereas younger recipients were more frequently transplanted for hepatitis C virus (HCV) [p<0.001]. There were no significant differences between LT-age categories in the proportion of recipients on hemodialysis at the time of transplant (p=0.06). Median wait-list times were statistically different but clinically similar, ranging between 43 to 55 days (p<0.001).
Table 1.
Baseline recipient characteristics by LT-age categories.
| Characteristic* | LT-age Categories | p value | ||||
|---|---|---|---|---|---|---|
| 18–59y n=11,966 |
60–64y n=2,181 |
65–69y n=1,177 |
≥70y n=343 |
|||
| LT-age, years | 51 (45–55) | 62 (60–63) | 66 (65–68) | 71 (70–73) | ||
| Female | 34% | 37% | 43% | 41% | <0.001 | |
| Race/ethnicity | African American | 11% | 6% | 5% | 3% | <0.001 |
| Caucasian | 72% | 77% | 78% | 82% | ||
| Hispanic | 13% | 12% | 12% | 9% | ||
| Asian | 3% | 3% | 4% | 4% | ||
| Other | 1% | 1% | 1% | 1% | ||
| Disease etiology | HCV | 45% | 27% | 17% | 18% | <0.001 |
| Alcohol | 16% | 21% | 20% | 12% | ||
| NAFLD | 6% | 15% | 18% | 17% | ||
| HBV | 3% | 3% | 2% | 3% | ||
| Cholestatic | 13% | 15% | 15% | 21% | ||
| Other | 17% | 20% | 28% | 28% | ||
| LT-MELD | 23 (18–31) | 22 (17–29) | 21 (17–28) | 20 (16–26) | <0.001 | |
| INR | 1.9 (1.5–2.4) | 1.7 (1.4–2.2) | 1.7 (1.4–2.1) | 1.6 (1.3–2.0) | <0.001 | |
| Total bilirubin, mg/dL | 5.9 (3.2–14.1) | 4.6 (2.6–10.1) | 4.2 (2.2–8.9) | 3.7 (2.1–6.9) | <0.001 | |
| Creatinine, mg/dL | 1.2 (0.8–1.8) | 1.3 (1.0–1.9) | 1.3 (1.0–1.9) | 1.3 (1.0–1.8) | <0.001 | |
| Hemodialysis at transplant | 9% | 8% | 8% | 6% | 0.06 | |
| Waitlist time, days | 43 (9–201) | 43 (9–201) | 55 (12–211) | 46 (11–170) | <0.001 | |
Median (interquartile range)
Donor and transplant characteristics are listed in Table 2. Median donor age for recipients who were 18–59 years, 60–64 years, 65–69 years, and ≥70 years of age was 43 years, 45 years, 46 years, and 51 years, respectively (p=0.001). The proportion of recipients who received livers from donors who died from cerebrovascular accident (CVA) increased with LT-age (p<0.001). Older recipients were more likely to receive donation after cardiac death (DCD) livers (p=0.007), whereas younger recipients were more likely to receive livers from donor classified as CDC high-risk (p=0.01). Recipient LT-age strata did not exhibit differences in split liver (p=0.70) or cold ischemia time (p=0.78).
Table 2.
Donor and transplant characteristics by LT-age categories.
| Characteristic* | LT-age Categories | p value | ||||
|---|---|---|---|---|---|---|
| 18–59y n=11,966 |
60–64y n=2,181 |
65–69y n=1,177 |
≥70y n=343 |
|||
| Donor age, years | 43 (25–54) | 45 (27–57) | 46 (29–60) | 51 (33–65) | 0.001 | |
| DCD | 5.2% | 5.9% | 6.5% | 7.5% | 0.007 | |
| CDC high risk donor | 8.2% | 7.6% | 6.6% | 5.5% | 0.01 | |
| Donor positive HCV antibody | 3.1% | 2.2% | 0.9% | 1.7% | <0.001 | |
| Partial/split | 1% | 1% | 1% | 2% | 0.70 | |
| Donor cause of death | Trauma | 39% | 35% | 32% | 26% | <0.001 |
| CVA | 42% | 46% | 47% | 51% | ||
| Anoxia | 17% | 16% | 18% | 19% | ||
| Other | 2% | 3% | 3% | 4% | ||
| Region (by MELD category) | Low | 40% | 44% | 43% | 38% | 0.33 |
| Mid | 37% | 34% | 24% | 36% | ||
| High | 23% | 22% | 23% | 26% | ||
| Share region | Local | 69% | 69% | 64% | 56% | <0.001 |
| Regional | 25% | 23% | 25% | 26% | ||
| National | 7% | 8% | 11% | 18% | ||
| Cold ischemia time, hours | 7.0 (5.1–8.9) | 6.9 (5.1–8.7) | 6.6 (5.1–8.5) | 7.0 (5.5–8.9) | 0.78 | |
Median (interquartile range)
Unadjusted and adjusted models evaluating the association of LT-age and LT-MELD on graft loss – independent of the interaction between the two factors – showed that older LT-age was associated with an increased risk of graft loss (Table 3). Specifically, compared to recipients 18–59 years of age, the adjusted hazard ratio for graft loss for recipients 60–64 years, 65–69 years, and ≥70 years of age was 1.26 (95% CI, 1.16–1.37), 1.28 (95% CI, 1.14–1.43), and 1.65 (95% CI, 1.38–1.97), respectively (p<0.001 for all). Similarly, higher LT-MELD was associated with an increased risk of graft loss compared to recipients with LT-MELD <20 (Table 3); the adjusted hazard ratio was 1.19 (95% CI, 1.11–1.29) for MELD 20–27 and 1.46 (95% CI, 1.02–1.46) for MELD ≥28 (p<0.001 for both).
Table 3.
Hazard ratios for graft loss from univariable and multivariable models without the interaction between LT-age and LT-MELD
| Predictor | Univariable | Multivariable* | |||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | p-value | HR | 95% CI | p-value | ||
| LT-age | <60y | 1.0 (reference) | 1.0 (reference) | ||||
| 60–64y | 1.18 | 1.08–1.28 | <0.001 | 1.26 | 1.16–1.37 | <0.001 | |
| 65–69y | 1.16 | 1.04–1.29 | <0.001 | 1.28 | 1.14–1.43 | <0.001 | |
| ≥70y | 1.60 | 1.35–1.89 | <0.001 | 1.65 | 1.38–1.97 | <0.001 | |
| LT-MELD | <20 | 1.0 (reference) | 1.0 (reference) | ||||
| 20–27 | 1.11 | 1.03–1.19 | 0.005 | 1.19 | 1.11–1.29 | <0.001 | |
| ≥28 | 1.33 | 1.23–1.43 | <0.001 | 1.46 | 1.02–1.46 | <0.001 | |
| Recipient Race/ethnicity | Caucasian | 1.0 (reference) | 1.0 (reference) | ||||
| African American | 1.41 | 1.29–1.54 | <0.001 | 1.37 | 1.25–1.50 | <0.001 | |
| Hispanic | 0.99 | 0.91–1.08 | 0.76 | 0.95 | 0.86–1.04 | 0.24 | |
| Asian | 0.86 | 0.71–1.04 | 0.12 | 0.90 | 0.73–1.09 | 0.28 | |
| Other | 1.08 | 0.80–1.45 | 0.63 | 1.05 | 0.78–1.42 | 0.74 | |
| Recipient disease etiology | Alcohol | 1.0 (reference) | 1.0 (reference) | ||||
| HCV | 1.33 | 1.22–1.46 | <0.001 | 1.45 | 1.33–1.59 | <0.001 | |
| NAFLD | 1.05 | 0.92–1.20 | 0.43 | 1.05 | 0.92–1.20 | 0.46 | |
| HBV | 0.80 | 0.65–0.98 | 0.03 | 0.80 | 0.64–0.99 | 0.04 | |
| Cholestatic | 0.89 | 0.79–1.00 | 0.05 | 0.90 | 0.80–1.20 | 0.07 | |
| Other | 1.14 | 1.03–1.26 | 0.01 | 1.09 | 0.98–1.21 | 0.10 | |
| Donor age, per year | 1.01 | 1.00–1.01 | <0.001 | 1.01 | 1.00–1.01 | <0.001 | |
| Donation after Cardiac Death (DCD) | 1.56 | 1.40–1.75 | <0.001 | 1.79 | 1.60–2.00 | <0.001 | |
| Cold ischemia time, per hour | 1.03 | 1.02–1.04 | <0.001 | 1.03 | 1.02–1.03 | <0.001 | |
Each model is also adjusted for: recipient gender; donor age, height, and cause of death; split liver; and share region
Next, we investigated the combined effect of LT-age and LT-MELD on the risk of graft loss. Unadjusted Kaplan-Meier survival curves for each LT-age category are shown for LT-MELD <20 (Figure 1A), 20–27 (Figure 1B), and ≥28 (Figure 1C). One-year graft survival rates for each LT-age and LT-MELD combination are listed in Table 4. Within each LT-MELD stratum, one-year graft survival declines incrementally with increased LT-age category. Graft survival in 60–64 year old recipients was 86%, 83%, and 75% at low (<20), mid (20–27), and high (≥28) LT-MELD group, respectively. For recipients 65–69 years of age, survival was 85%, 83%, and 74% at low (<20), mid (20–27), and high (≥28) LT-MELD group. Within all three LT-MELD categories, graft survival was lowest for the oldest (≥70 year old) cohort. At low LT-MELD (<20) and mid LT-MELD (20–27), graft survival at one year was 85% and 75%; survival was particularly poor at 56% for ≥70 year old recipients with LT-MELD ≥28.
Figure 1.
A. Unadjusted graft survival in recipients with low LT-MELD (<20) by LT-age categories
B. Unadjusted graft survival in recipients with mid LT-MELD (20–27) by LT-age categories
C. Unadjusted graft survival in recipients with high LT-MELD (≥28) by LT-age categories
Table 4.
One-year graft survival and hazard ratios for graft loss associated with each LT-age and LT-MELD category for univariable and multivariable models including the interaction between LT-age and LT-MELD
| LT-MELD | LT-age (years) | n (*) | Univariable | Multivariable† | 1y Graft Survival | ||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | p-value | HR | 95% CI | p-value | ||||
| <20 | 18–59 | 3,847 (24) | 1.0 (reference) | 1.0 (reference) | 88% | ||||
| 60–64 | 786 (5) | 1.10 | 0.95–1.28 | 0.18 | 1.14 | 1.01–1.33 | 0.07 | 86% | |
| 65–69 | 492 (4) | 1.15 | 0.97–1.38 | 0.10 | 1.22 | 1.02–1.46 | 0.03 | 85% | |
| ≥70 | 165 (1) | 1.53 | 1.19–1.98 | 0.001 | 1.41 | 1.08–1.82 | 0.01 | 85% | |
| 20–27 | 18–59 | 3,884 (25) | 1.0 (reference) | 1.0 (reference) | 87% | ||||
| 60–64 | 765 (5) | 1.21 | 1.05–1.39 | 0.008 | 1.28 | 1.11–1.48 | 0.001 | 83% | |
| 65–69 | 361 (2) | 1.13 | 0.93–1.38 | 0.21 | 1.21 | 1.01–1.48 | 0.06 | 83% | |
| ≥70 | 102 (0.5) | 1.46 | 1.06–2.03 | 0.02 | 1.51 | 1.08–2.09 | 0.02 | 75% | |
| ≥28 | 18–59 | 4,235 (27) | 1.0 (reference) | 1.0 (reference) | 82% | ||||
| 60–64 | 630 (4) | 1.30 | 1.13–1.50 | <0.001 | 1.36 | 1.18–1.57 | <0.001 | 75% | |
| 65–69 | 324 (2) | 1.29 | 1.07–1.57 | 0.008 | 1.40 | 1.15–1.69 | 0.001 | 74% | |
| ≥70‡ | 76 (0.5) | 2.37 | 1.73–3.25 | <0.001 | 2.38 | 1.73–3.27 | <0.001 | 56% | |
% of total recipient population
Adjusted for: recipient gender, ethnicity, and disease etiology; donor age, height, and cause of death; donation after cardiac death (DCD); split liver; cold ischemia time; and share region.
p value for the interaction term = 0.01; no other interaction terms for LT-age and LT-MELD combinations were significant
Lastly, we evaluated unadjusted and adjusted models that included the interaction between LT-age and LT-MELD, using LT-age <60 years as the reference group (Table 4). Within each LT-MELD category, the hazard ratio for graft loss increased with LT-age. The adjusted hazard ratio for graft loss in 60–64 year old recipients at low, mid, and high LT-MELD was 1.14 (95% CI, 1.01–1.33; p=0.07), 1.28 (95% CI, 1.11–1.48; p=0.001), and 1.36 (95% CI, 1.18–1.57; p<0.001), respectively. For recipients 65–69 years of age, the adjusted hazard ratio for graft loss at low, mid, and high LT-MELD was 1.22 (95% CI, 1.02–1.46; p=0.03), 1.21 (95% CI, 1.01–1.48; p=0.06), and 1.40 (95% CI, 1.15–1.69; p=0.001), respectively. In the oldest cohort, recipients ≥70 years of age, the adjusted hazard ratio for graft loss was 1.41 (95% CI, 1.08–1.82; p=0.02), and 1.51 (95% CI, 1.08–2.09; p=0.01) at low and mid LT-MELD. However, the adjusted hazard ratio for graft loss in recipients ≥70 years old transplanted at high LT-MELD (≥28) was markedly higher when compared to all other LT-age and LT-MELD strata (HR=2.38, 95% CI 1.73–3.27; p<0.001). This finding was supported by the fact that the interaction term for LT-age and LT-MELD was statistically significant only for recipients with LT-age ≥70 years and LT-MELD ≥28 (p=0.01). No interaction was detected for any other LT-age and LT-MELD combination (Table 4).
Discussion
Although chronologic age alone cannot be used as a sole criterion for liver transplantation for a particular candidate (13), there exists strong selection bias against offering transplantation to older candidates through the application of exclusion criteria – variably applied – such as the presence of multiple medical co-morbidities and poor functional status. As a result, only 10% of liver transplant recipients are ≥65 years old, and 2% are ≥70 years old. However, given the rising age of wait-listed candidates, determining specific factors beyond age alone that are associated with poor – or acceptable – outcomes in the oldest recipients is becoming increasingly more important.
In this study, we specifically evaluated whether the combined effect of older LT-age and higher LT-MELD was associated with an increased risk of graft loss. Using national registry data, we found that the risk of graft loss for all but one combination of LT-age and LT-MELD approximated the predictions of the independent models for all recipients (i.e., there was no interaction between LT-age and LT-MELD). Only for the unique combination of the oldest (LT-age ≥70 years) and sickest (LT-MELD ≥28) recipients did the risk of graft loss correspond to an unacceptably low one-year graft survival rate of 56%. It is noteworthy that this occurred despite strong selection bias against transplanting older recipients, as evidenced by the fact that this group represented only 0.5% of recipients during the five year study period. In other words, these individuals had been deemed “fit for transplantation” by their clinicians after undergoing rigorous testing, and yet, nearly half of those who underwent transplant at LT-MELD ≥28 died within the first post-transplant year.
What we also found through our analyses is that there were patients within the older LT-age categories who were able to achieve acceptable post-transplant survival rates. For recipients ≥70 years undergoing transplant at LT-MELD <20 and LT-MELD 20–27, there was no significant interaction between LT-age and LT-MELD, with one-year graft survival rates of 85% and 75%, respectively. Furthermore, while recipients 60–64 years and 65–69 years, compared to those <60 years, also experienced an increase in risk of graft loss, this decrement was not synergistic at higher LT-MELD categories.
Our study is limited by characteristics of the UNOS/OPTN registry. First, we were unable to adjust for additional factors that likely impact graft loss particularly among older recipients, such as coronary artery disease, complications of long-standing diabetes, and other medical co-morbidities as these factors are subject to inconsistencies in data definitions from center to center or are not collected at all. However, the evaluation and selection process for liver transplantation is stringent, such that we would anticipate that the prevalence of these conditions was relatively low. This is further supported by the modest number of ≥70 year old liver transplant recipients. The absence of the strong selection bias inherent in our study cohort would, almost certainly, exacerbate the impact of increased age on post-transplant survival for high disease severity candidates.
Despite these limitations, our study, which encompasses the U.S. national experience of liver transplantation for older recipients, has important implications for the consideration of chronologic age in liver transplant decision-making. While recipients 64–69 years of age experienced higher rates of graft loss when compared to younger candidates, one-year graft survival rates remained acceptable regardless of MELD at the time of transplant. Furthermore, recipients ≥70 years of age with lower disease severity (MELD <28) also experienced acceptable rates of graft loss at one year post-transplant. However, our findings urge extreme caution with respect to transplantation for candidates ≥70 years of age with high disease severity. The overall one-year graft survival rate of 56% was sobering, approaching the five year 50% graft survival rates embraced as a minimum threshold of acceptability. The current shortage of deceased donor livers translates into a high opportunity cost for every transplant performed. As such, the broader community will need to grapple with the wisdom of transplanting elderly and sick candidates. Clearly, setting absolute age limits for liver transplant candidacy rings of arbitrariness and thereby engenders disfavor. Our study highlights the need for an accurate and objective assessment of physiologic age to supplement or perhaps even replace chronologic age to optimally select recipients for liver transplantation.
Methods
Study population and data
All adult (≥18 years of age), non-Status 1 recipients of primary deceased donor liver transplants in the United States between February 1, 2005 and January 31, 2010 were included. In order to objectively evaluate the physiologic effect of liver disease severity on transplant outcomes, we excluded recipients who received MELD exception points, including those with hepatocellular carcinoma (HCC). Age at the time of transplant (LT-age) was categorized into four groups: 18–59 years, 60–64 years, 65–69 years, and ≥70 years. These categorizations were chosen based on clinical relevance, as deemed by the investigators. MELD score at the time of transplant (LT-MELD) was categorized into three groups based on LT-MELD tertiles in this cohort: <20 (low), 20–27 (mid), and ≥28 (high). Region risk was defined based on median LT-MELD for all recipients within a region; regions were divided by LT-MELD tertiles: low (LT-MELD 22), mid (LT-MELD 25), and high (LT-MELD 27).
All data were obtained from The United Network for Organ Sharing (UNOS) / Organ Procurement Transplantation Network (OPTN) registry as of April 30, 2012. Approval to perform this research was obtained by the Institutional Review Board at the University of California, San Francisco.
Statistical analysis
Descriptive continuous and dichotomous characteristics were compared using the Kruskall-Wallis and Chi-square tests, respectively. The primary outcome was graft loss, defined as death or re-transplantation. Graft survival curves were calculated using the Kaplan-Meier method. Univariable and multivariable Cox regression models were used to investigate the independent effects of LT-age and LT-MELD on graft loss. Models were then re-run allowing for the interaction between LT-age and LT-MELD categories. All multivariable models were adjusted for recipient (gender, ethnicity, and disease etiology), donor (age, height, cause of death, donation after cardiac death (DCD) status, and split liver), and transplant (cold ischemia time and share region) factors. Given the difference in receipt of DCD grafts by LT-age strata, we performed a sensitivity analysis which did not change our results. Again, recipients ≥70 years of age with LT-MELD>28 were the only group to experience a synergistic effect on graft loss with a hazard ratio of 2.62 (95% CI 1.89–3.62, p value <0.001) and a significant interaction term (p=0.008).
For all tests, statistical significance was defined as a p value ≤ 0.05. Statistical analyses were performed using STATA (SE Version 12.0, College Station, TX).
Acknowledgments
None
Abbreviations
- DCD
donation after cardiac death
- ECD
expanded criteria donor
- HBV
hepatitis B virus
- HCV
hepatitis C virus
- HCC
hepatocellular carcinoma
- INR
international normalized ratio
- LT
liver transplantation
- MELD
Model for End Stage Liver Disease
- NAFLD
non-alcoholic fatty liver disease
- LT-age
recipient age at time of transplantation
- LT-MELD
recipient laboratory MELD at time of transplantation
Contributor Information
Suzanne R. Sharpton, Email: suzanne.sharpton@ucsf.edu.
Sandy Feng, Email: sandy.feng@ucsfmedctr.org.
Bilal Hameed, Email: bilal.mameed@ucsf.edu.
Francis Yao, Email: francis.yao@ucsf.edu.
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