Begin typing your search above and press return to search.
Volume: 15 Issue: 5 October 2017

FULL TEXT

ARTICLE
Donor Age Still Matters in Liver Transplant: Results From the United Network for Organ Sharing-Scientific Registry of Transplant Recipients Database

Objectives: Individuals older than 60 years represent a large proportion of the organs available for orthotopic liver transplant. However, the use of organs from older donors remains controversial. We hypothesized that the use of older donors would not affect patient and graft survival due to significant improvements in donor-recipient management.

Materials and Methods: We conducted a retrospective cohort analysis using the United Network for Organ Sharing database from February 2002 through December 2012, including non-HCV-infected adults (18 and older) who underwent primary orthotopic liver transplant. We compared patient and graft survival between 4 cohorts based on donor’s age (< 60, 60-69, 70-79, and 80+ years) using the Kaplan-Meier estimator. Cox proportional hazards models were constructed to adjust for recipient and donor characteristics to estimate the risk associated with organs from older donors.

Results: We identified 35 788 liver transplant recipients. Unadjusted analyses indicated that both patient and graft survival were similar among recipients of donors older than 60 years but significantly inferior compared with those recipients who received a liver from a donor younger than 60 years. Multivariate regression revealed that all 3 categories of donor age > 60 years old were significantly associated with worse patient and graft survival. Model for End-Stage Liver Disease score was not an effective modifier of the association between donor age and survival.

Conclusions: The use of liver grafts from elderly donors has a negative impact on both patient and graft survival. Recipient’s Model for End-Stage Liver Disease score did not change survival based on donor age.


Key words : Extended criteria donors, Liver trans­plantation, Outcomes

Introduction

Advances in the care of liver transplant patients have led to improvements in both patient and graft survival; however, an increase in the number of patients listed annually has outnumbered graft availability.1 Efforts to lessen this disparity has broadened donor selection criteria with the use of extended criteria donors.1 Donations having extended criteria refer to donor factors that are associated with poor graft function and increased risk for graft loss, including the use of grafts from elderly donors.2 The controversy of using older donor grafts is ongoing, mostly based on reports demonstrating increased risk of graft dysfunction or primary nonfunction and worse long-term outcomes especially in recipients who are hepatitis C virus (HCV) positive.3-6 One report with up to 15 years follow-up showed a stepwise decrease in recipient survival with inc­reasing donor age.7 Also, donor age greater than 60 years has been reported as an independent risk factor not only for decreased graft and patient survival but also for recipient quality of life.8 More recent studies have demonstrated, however, that grafts from old donors provide similar outcomes compared with grafts from younger donors when careful selection and ap­propriate donor and recipient management strategies are adopted and when donor age is not associated with additional risk factors for poor graft outcomes.9-11 Most of the available reports on older donors report only short-term follow-up data, which greatly limits the development of interpretive guidelines.

To validate these recent single center outcomes, we looked at the Scientific Registry of Transplant Recipients data set and hypothesized that the use of older grafts will not affect either patient or graft survival due to the significant improvements in donor-recipient matching and selection. Because of the well-established relation shown between donor age and outcomes in HCV-positive recipients, we excluded all patients with diagnosis of HCV as a cause of liver transplant.

Materials and Methods

We conducted a retrospective cohort analysis of adult non-HCV-infected transplant recipients in the United States who underwent primary orthotopic liver transplant between February 2002 and December 2012. We compared patient and graft survival between 4 cohorts based on donor’s age (< 60, 60-69, 70-79, and > 80 y old).

Data source
The Organ Procurement and Transplant Network (OPTN), under charter from the US Department of Health and Human Services, maintains a nationwide database of all patients awaiting matching for organ transplant and tracks the outcomes of those who receive a transplant. This database provides detailed clinical data about both recipients and donors, including patient status codes (reflecting degree of medical urgency), blood type, age, race, sex, number of previous transplants, serologies (hepatitis), histocompatibility, and organ recovery and pre­servation times.

Study subjects
All transplant procedures that occurred from February 2002 through December 2012 were eligible for this study. We limited the analysis to transplant recipients who were 18 years and older and who were seronegative for HCV. Diagnosis codes for organ recipients were categorized into 8 groups: acute hepatic necrosis, alcohol, cancer, cholestatic disease, metabolic, nonalcoholic steatohepatitis, viral, and other. Both the diagnosis variable and the diagnosis-free text descriptions were used for categorization.

Statistical analyses
The 4 cohorts of patients were compared de­scriptively in terms of demographic characteristics, diagnoses, and clinical status using the t test for continuous variables and the chi-squared test for categorical variables. In addition, the rate of older graft use was evaluated chronologically over the entire study period to investigate trends in overall use of elderly donors.

We compared the 4 patient cohorts in terms of patient and graft survival (defined as need for retransplant, mortality, or loss to follow-up) using the Kaplan-Meier estimator and the log-rank chi-squared test for equality. To evaluate sources for confounding factors, we constructed multivariate Cox pro­portional hazards models to evaluate the risk of death and graft failure associated with older donor age (donors > 60 y old) compared with those reci­pients who received younger grafts (donors < 60 y old). We estimated unadjusted risk and then adjusted for recipient age, sex, diagnosis category, United Network for Organ Sharing (UNOS) region, transplant type (whole or split), patient disposition at transplant (inpatient, intensive care unit, or outpatient), Model for End-Stage Liver Disease (MELD) score at transplant, international normalized ratio at transplant, serum creatinine level at transplant, and cold ischemia time, using robust sandwich-estimator variance estimates.

The University of Washington Human Subjects Division deems the OPTN database is de-identified and publicly available and thus not human subject data. Therefore, this study was exempt from human subject review. All analyses were performed with SAS 9.3 software (SAS Institute, Inc., Cary, NC, USA).

Results

We identified 35 788 liver transplant recipients. Demographic data are depicted in Table 1. Recipients from younger donors were more likely to have a higher MELD score, higher serum creatinine level, require dialysis at time of transplant, had received a partial liver, had been patients in an intensive care unit, and were ventilated or had inpatient status. In addition, they were more likely to be Black versus other races. Recipients from older donors were more likely to be female, to have hepatocellular carcinoma, and of White race. Younger donors were more likely to have received donations from donors after cardiac death and be Black or Hispanic. Older donors were more likely to be female and White.

We looked at the trend of graft use based on donor age and year from 2002 to 2012 (Figure 1). There was a small increase in use of grafts from donors who were 60 to 69 years old (from 9% to 12%). The use of grafts from donors who were ≥ 70 years old showed no change.

The prevalence of liver retransplant was 1069/29 766 (3.6%) in the group with donors < 60 years old, 72/4088 (1.8%) in the group with donors age 60 to 69 years, 26/1749 (1.5%) in the group with donors age 70 to 79 years, and 3/278 (1.1%) in the group with donors > 80 years (P = not significant). We also looked at the cause of retransplant among the different donor age groups. Biliary complications, hepatic artery throm­bosis, primary nonfunction, recurrence of the primary disease, and other were not significantly different among the different donor age groups (Table 2).

The distribution of donor age graft by UNOS region is depicted in Figure 2. The use of grafts from donors < 60 years and 60 to 69 years old is quite uniform among all of the regions. Use of grafts from donors in the 70- to 79-year range was more common in regions 1, 2, and 9. Use of grafts from donors ≥ 80 years old was scarce among all of the regions, except for region 9, which represented 3.5% of all of the donors.

Unadjusted analyses indicated that both patient and graft survival were similar among recipients of donors older than 60 years but significantly inferior compared with those recipients who received a liver from a donor younger than 60 years (Figures 3 and 4). Multivariate regression revealed that all 3 categories of donors > 60 years old were significantly associated with worse patient and graft survival. Other independent risk factors for patient and graft survival included recipient age and intensive care unit or inpatient stay at the time of the transplant (Table 3). Interestingly, the MELD score was not an effective modifier of the association between donor age and survival.

Discussion

In this large-scale study, overall patient and graft survival of all non-HCV patients who underwent primary liver transplant were significantly lower in those whose donor age was ≥ 60 years old versus younger donors. Among recipients whose donor age was ≥ 60 years old, patient and graft survival rates were not significantly affected by donor age. Moreover, we confirmed that donor age ≥ 60 years old is an independent risk factor for poor patient and graft survival, regardless of the recipient’s MELD score.

The present knowledge regarding advanced age as a composite surrogate of poor liver function was confirmed by Feng and associates, who showed that donor age > 65 years was the strongest predictor of graft failure.5 Several other studies have also shown an adverse effect on outcomes after transplants from advanced age donors, and the effect is even more marked for recipients with HCV infection.2-6 Because of the shortage of donor organs, many transplant centers have to accept organs from older donors to expand the donor pool. During the past decade, some investigators have shown excellent early and middle-term results with older donors, especially when optimal donor and recipient matching and selection strategies are used and in the absence of additional risk factors for graft loss.9-11 Chedid and associates looked at 109 patients who received livers from donors older than 70 years and found no difference in patient and graft survival among HCV-negative recipients.11 Ghinolfi and associates found no difference in patient and graft survival among HCV-negative recipients who received a graft from donors ≥ 80 years old.10

Some authors have argued that older donors should ideally be used in less sick patients to improve outcomes and organ use.12 Our results showed that MELD score was not an effective modifier of the association between donor age and survival; therefore, this suggests that grafts from older donors should be used cautiously regardless of the MELD score. Elderly grafts are more susceptible to ischemia/reperfusion injury because of hemo­dynamic instability.13 Shorter cold ischemia time and reduction of long-distance organ travel could contribute to improving their outcomes and overall utilization. Some authors have suggested that minimization of organ manipulation, rapid aortic cannulation and cold perfusion, topical cooling, and rapid hepatectomy have protective effects for older liver grafts.14

Another major concern regarding the use of old grafts is the potential increased rate of vascular and biliary complications due to underlying athero­sclerosis of these donors.14 Our findings indicate that the rate of retransplant due to hepatic artery thrombosis is not different in older donors. Ghinolfi and associates had the same findings in their study.10 Careful assessment of vessel quality and patency at the back table along with a low threshold for graft discarding in the presence of occlusive athero­sclerosis play pivotal roles in reducing the incidence of vascular complications with these grafts. Unlike previous observations,10 we found that the rate of retransplant due to biliary complications was not affected by donor age. There is currently ongoing research regarding the role of microvascularization of the biliary tree as a surrogate for potential biliary complications, especially when donations after cardiac death are used; however, the effect of donor age on microvasculature of the biliary tree is still unknown.

Despite the increasing data encouraging the use of older donors, the utilization of older grafts has almost not changed over the course of the study period. There has been a small increase in the use of grafts from donors between 60 and 69 years old from 9% to 12%, but the use of grafts from donors ≥ 70 years old is still scarce. When we looked at donor age by region, it was also shown that grafts from older donors are barely used in almost all regions, except for regions 1, 2, and 9, which have the highest rate of use of grafts from donors older than 70 years old, likely related to the long wait times in these regions. Despite the higher use of older donors in these regions, on a regression analysis, the UNOS region was not an independent predictor of patient and graft survival.

Our study has several limitations that must be cautiously considered when interpreting these findings. First are those limitations inherent to a retrospective observational study. As with all observation studies, unmeasured confounders may be influencing our results. However, the breadth of clinical data available from the OPTN database has allowed us to control for many more variables than a traditional claims-based analysis. Second, our study may not be generalizable to international settings; however, it does represent the entire US non-HCV-positive adult transplant experience and thus should be reasonable to guide care across the country. A shift in the treatment of HCV infection is underway, with favorable treatment outcomes. We considered it more appropriate for the present analysis to exclude this patient population due to the overwhelming data showing the adverse effects of donor age on HCV recurrence. However, we foresee that the course and treatment of HCV infection will change quickly, with medical management becoming the predominant treatment strategy. As a consequence, grafts from older donor may be usable in this patient population without significantly affecting outcomes.

In conclusion, donor age should still be con­sidered an independent predictor of worse patient and graft survival in non-HCV patients regardless of the MELD score. We believe that most of the single center experiences demonstrating good outcomes with the use of older donors reflect appropriate donor and recipient matching/selection. Based on our data, we do not discourage the use of older donors in the present era of significant organ shortage; however, new strategies should be developed to optimize the use and function of these grafts. The introduction of novel strategies for assessment of liver graft quality/function, such as ex vivo machine perfusion and organ preservation, may promote further expansion of the current donor graft acceptance criteria.


References:

  1. Busuttil RW, Tanaka K. The utility of marginal donors in liver transplantation. Liver Transplant. 2003;9(7):651-663.
    CrossRef - PubMed
  2. Attia M, Silva MA, Mirza DF. The marginal liver donor-an update. Transpl Int. 2008;21(8):713-724.
    CrossRef - PubMed
  3. Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al. Risk factors for primary dysfunction after liver transplantation. A multivariate analysis. Transplantation. 1993;55(4):807-813.
    CrossRef - PubMed
  4. Cameron AM, Ghobrial RM, Yersiz H, et al. Optimal utilization of donor grafts with extended criteria. A single center experience in over 1000 liver transplants. Ann Surg. 2006;243(6):748-755.
    CrossRef - PubMed
  5. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: The concept of a donor risk index. Am J Transplant. 2006;6(4):783-790.
    CrossRef - PubMed
  6. Berenguer M, Prieto M, San Juan F, et al. Contribution of donor age to the recent decrease in patient survival among HCV infected liver transplant recipients. Hepatology. 2002;36(1):201-210.
    CrossRef - PubMed
  7. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a single-center experience. Ann Surg. 2005;241(6):905-916.
    CrossRef - PubMed
  8. Moore DE, Feurer ID, Speroff T, et al. Impact of donor, technical, and recipient risk factors on survival and quality of life after liver transplantation. Arch Surg. 2005;140(3):273-277.
    CrossRef - PubMed
  9. Anderson CD, Vachharajani N, Doyle M, et al. Advanced donor age alone does not affect patient or graft survival after liver transplantation. J Am Coll Surg. 2008;207(6):847-852.
    CrossRef - PubMed
  10. Ghinolfi D, Marti J, De Simone P, et al. Use of octogenarian donors for liver transplantation: A survival analysis. Am J Transplant. 2014;14(9):2062-2071.
    CrossRef - PubMed
  11. Chedid MF, Rosen CB, Nyberg SL, Heimbach JK. Excellent long-term patient and graft survival are possible with appropriate use of livers from deceased septuagenarian and octogenarian donors. HPB. 2014;16(9):852-858.
    CrossRef - PubMed
  12. Segev DL, Maley WR, Simpkins CE, et al. Minimizing risk associated with elderly liver donors by matching to preferred recipients. Hepatology. 2007;46(6):1907-1918.
    CrossRef - PubMed
  13. D’Amico F, Vitale A, Gringeri E, et al. Liver transplantation using suboptimal grafts: Impact of donor harvesting technique. Liver Transpl. 2007;13(10):1444-1450.
    CrossRef - PubMed
  14. Gurusamy KS, Naik P, Abu-Amara M, et al. Techniques of flushing and reperfusion for liver transplantation. Cochrane Database Syst Rev. 2012;14;(3):CD007512.
    CrossRef - PubMed


Volume : 15
Issue : 5
Pages : 536 - 541
DOI : 10.6002/ect.2016.0011


PDF VIEW [202] KB.

From the 1Department of Surgery, Division of Transplantation and the 2Pharmaceutical Outcomes Research and Policy Program, School of Pharmacy, University of Washington, Seattle, Washington; and the 3Division of Pediatric Transplantation, Seattle Children’s Hospital, Seattle, Washington, USA
Acknowledgements: The authors have no conflict of interest to disclose. M Montenovo, the principal author, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in study concept and design and critical revision of the manuscript; MI Montenovo, RN Hansen, and AA Dick participated in acquisition of data, analysis and interpretation, and drafting of the manuscript.
Corresponding author: Martin I. Montenovo, 1959 NE Pacific Street, Box 356175, Department of Surgery, Division of Transplantation, University of Washington Medical Center, Seattle, WA 98195, USA
Phone: +1 206 598 2608
E-mail: martinm@uw.edu