Impact of Different Cadaveric Donor Age Cut-Offs on Adult Recipient Survival After Liver Transplantation: A Single-Center Analysis

Impact of Different Cadaveric Donor Age Cut-Offs on Adult Recipient Survival After Liver Transplantation: A Single-Center Analysis G. Santori, E. Andorno, N. Morelli, G. Bottino, R. Mondello, A. Gianelli Castiglione, and U. Valente ABSTRACT The increase in the number of patients awaiting liver transplantation (OLT) has forced the use of cadaveric donors (CD) with suboptimal characteristics. Of these, donor age is perhaps the most investigated parameter. Although excellent outcomes were observed for OLT using CD aged over 60 years, the European Liver Transplant Registry (ELTR) Group found an increased risk by using CD of more than 55 years. The Italian National Transplant Center has recently assumed that CD age more than 60 years is a potential risk factor for OLT. In this study, a single-center analysis was performed by stratifying CD by three age cut-offs (ⱕ55/⬎55, ⱕ60/⬎60, and ⱕ65/⬎65 years) to evaluate effects on OLT outcome. Although no significant difference in 6-month and 1-year patient or graft survival occurred after stratification for each donor age cut-off, a better survival was observed with OLT performed using livers procured from CD ⬎55 years. A significant increase in cold ischemia time (CIT) was observed among OLT performed with grafts procured from CD ⱕ55 and ⱕ65 years (P ⫽ .007), and there was an inverse correlation between overall CIT and donor age (R ⫽ ⫺0.300; P ⫽ .0022). However, no impact on 1-year patient survival was observed by introducing CIT in univariate logistic regression models as well as donor age, recipient age, donor/recipient age ratio, donor/recipient sex mismatch, ELTR diagnostic categories, and UNOS status. The results of this study suggest the suitability of CD of more than 55 years for OLT and the need to further investigate the cut-off value for CIT-related risk.

T

HE GROWING NUMBER of patients on the waiting lists for liver transplantation (OLT) and the persistent shortage of cadaveric liver donors (CD) have forced widening of donor acceptance criteria.1,2 Of these criteria, donor age represents maybe the most investigated parameter.3 Although the age limit for CD is controversial, current opinion advises use of grafts from donors older than 60 years.3,4 Despite the fact that advanced donor age may not be considered as a contraindication for liver procurement,5 both graft and recipient survival have been reported among OLT performed using elderly donors.6 A large study of data in the European Liver Transplant Registry (ELTR) showed an increased risk of using donors age ⱖ55 years.7 The Italian National Transplant Center has recently assumed the CD age more than 60 years is a potential risk factor for OLT.8 In contrast, excellent outcomes have been observed for LT performed with donors over 60 years,5 and since 1993, when the first successful OLT with a donor over 80 years was reported,9 other successes with elderly donors have been described.10 –12

With the aim to obtain more information on the impact of donor age on graft and liver recipient survival, this study was a single-center analysis stratifying CD for three age cut-offs (ⱕ55/⬎55, ⱕ60/⬎60, and ⱕ65/⬎65 years). PATIENTS AND METHODS Patients Between January 1, 2000, and September 30, 2003, 141 OLT procedures were performed as first transplants (full-size: 104; in situ split liver: 37). Only adult patients who underwent full-size OLT were considered in this study. Other enrollment criteria were complete recipient and cadaveric donor data set and no missing From the Department of Transplantation (G.S., E.A., N.M., G.B., R.M., U.V.) and Regional Coordination Center (A.G.C.), San Martino University Hospital, Genoa, Italy. Address reprint requests to Gregorio Santori, MD, PhD, Department of Transplantation, San Martino University Hospital, L.go R. Benzi 10, 16132 Genoa, Italy. E-mail: [email protected]/ [email protected]

0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.06.074

© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

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Donor age, recipient age, donor/recipient age ratio (1.10 ⫾ 0.48; median: 1.14), and CIT (392 ⫾ 151 minutes median:

⬍0.0001 .797 ⬍0.0001 .0071 72.52 ⫾ 4.95 50.52 ⫾ 9.52 1.5 ⫾ 0.42 341 ⫾ 119 43.23 ⫾ 14.13 51.2 ⫾ 9.56 0.87 ⫾ 0.35 420 ⫾ 161 ⬍0.0001 0.705 ⬍0.0001 0.0627 71.97 ⫾ 5.13 50.56 ⫾ 9.24 1.48 ⫾ 0.41 356 ⫾ 117 47.12 ⫾ 13.61 51.20 ⫾ 9.79 0.85 ⫾ 0.34 414 ⫾ 168 68.41 ⫾ 7.59 50.16 ⫾ 9 1.417 ⫾ 0.39 355 ⫾ 112

⬍0.0001 .272 ⬍0.0001 .0077

⬎65 Years (n ⫽ 38) ⱕ65 Years (n ⫽ 65) P ⬎60 Years (n ⫽ 41) ⱕ60 Years (n ⫽ 62)

37.56 ⫾ 11.99 51.85 ⫾ 10.13 0.744 ⫾ 0.28 433 ⫾ 179 Mean ⫾ SD Mann-Whitney test.

RESULTS

Donor age (years) Recipient age (years) Donor/recipient age ratio CIT (minutes)

Results are expressed as mean values ⫾ SD. The Shapiro-Wilk W test was used to test continuous variables for normality, rejecting the normal distribution hypothesis when the W statistic was significant.14 Mann-Whitney U-test and Fisher’s exact test were used for intergroup comparisons of continuous variables and contingency tables, respectively. In the contingency table analysis, odds ratio (OR) and its 95% confidence interval (CI) were also calculated. Spearman rank order correlation was calculated for continuous variables. Survival analyses were performed using the Kaplan-Meier product-limit estimator method, with a log-rank test for survival curve comparisons. The slope of the survival curves was measured by the hazard ratio (HR) and its 95%CI. A series of univariate logistic regression models with 1-year patient survivals assumed as the dependent variable were also performed. Only statistical analyses with a power ⱖ0.8 for the goodness of sample size were considered. The differences were assumed to be significant at P ⬍ .05 using a two-tailed null hypothesis. Statistical analyses were performed using the software packages STATISTICA 6.1 (StatSoft, Tulsa, Ok, USA) and Prism 3.02 (GraphPad Software, San Diego, Calif, USA).

P

Statistical Analysis

⬎55 Years (n ⫽ 55)

Acceptance criteria for CD (n ⫽ 103; men: 65%, women: 41%; age: 54 ⫾ 18.33 years; median: 57; range: 10 – 87) were consistent with the Nord Italia Transplant (NITp) counsel, national guidelines for solid organ procurement8 and the international literature: normality or slight modification in graft function markers and hemostatic parameters, administration of no more than one pressor during intensive care unit (ICU) stay, ICU stay ⱕ5 days, hemodynamic stability within the last 24 hours, normal portal blood flow evaluated by Doppler ultrasonography, Na⫹ ⬍160 mmol/L, absence of steatosis for donors ⱕ55 years old or macrosteatosis ⱕ30% for donors ⬎55 years, and cold ischemia time (CIT) preferably no more than 600 minutes. The donor evaluation protocol did not require any special invasive examination. Liver procurement was performed in the following Italian Regions: Liguria (n ⫽ 63), Lombardia (n ⫽ 12), Veneto (n ⫽ 8), Marche (n ⫽ 7), Trento Province-Trentino-Alto Adige Region (n ⫽ 4), other (n ⫽ 9). In one case, liver procurement was performed in Greece.

ⱕ55 Years (n ⫽ 48)

Cadaveric Liver Donors

Table 1. Comparison of Donor Age, Recipient Age, Donor/Recipient Age Ratio, and Cold Ischemia Time, Grouped for Different Donor Age Cut-Offs

recipient follow-up. Adopting these criteria, 103 adult patients (male: 75%, female: 25%) were considered for the analyses (age: 50 ⫾ 9.59 years; median: 52; range: 19 – 67). The main ELTR diagnostic categories among the patients listed for OLT were: virus C related cirrhosis (18.26%), alcoholic cirrhosis (11.53%), virus BD related cirrhosis (9.61%), hepatocellular carcinoma and virus B related cirrhosis (6.73%), virus B related cirrhosis (4.8%), virus C related cirrhosis and alcoholic cirrhosis (2.88%). At the time of surgery, the patients were in the United Network of Organ Sharing (UNOS) status 1 (n ⫽ 2), 2A (n ⫽ 11), 2B (n ⫽ 88), and 3 (n ⫽ 5). Liver recipients were from the following Italian Regions: Campania (n ⫽ 43), Liguria (n ⫽ 32), Lombardia (n ⫽ 9), Sicily (n ⫽ 5), Piemonte (n ⫽ 3), Abruzzo (n ⫽ 3), and other (n ⫽ 8). All patients informed about the details of the procedure consented to OLT, repeating their consent when called for surgery. OLT was performed using previously described surgical techniques.13

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P

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398 minutes) were analyzed for normality with the ShapiroWilk test. All variables showed statistical significance (donor age, P ⫽ .0009; recipient age, P ⫽ .00004; donor/ recipient age ratio, P ⫽ .00004; CIT, P ⫽ .0005), forcing us to reject the normal distribution hypothesis and to use nonparametric tests for intergroup comparisons. CD were stratified as: ⱕ55 years (n ⫽ 48); ⬎55 years (n ⫽ 55) to ⱕ60 years (n ⫽ 62); ⬎60 years (n ⫽ 41) to ⱕ65 years (n ⫽ 65); and ⬎65 years (n ⫽ 38). Comparisons between cadaveric donor ages in these groups showed statistically significant differences for each evaluation (Table 1). Conversely, no difference was observed among recipient ages grouped for these donor age cut-offs, producing a significant difference in the donor/recipient age ratios in all intergroup comparisons (Table 1). By grouping CIT values for donor age cut-offs, statistical significance was observed in ⱕ55/⬎55 years (P ⫽ .0077) and ⱕ65/⬎65 years groups (P ⫽ .0071; Table 1), although only in six cases was CIT ⬎600 minutes. In over-CIT cases, CIT mean value was 756 ⫾ 175 minutes (median: 693 minutes; range: 607–1080 minutes); of these, CIT remained within the range from 600 to 700 minutes in three cases. Two patient deaths occurred at 1-year in the over-CIT subgroup, involving one patient who received a graft from a ⬍55 year donor and another from a ⬎65 year donor. A significant correlation between overall CIT increase and decrease in donor age was observed (R ⫽ ⫺0.300; P ⫽ .0022). Liver procurement was performed mainly in the Liguria region (n ⫽ 63; 61.16%) when compared with grafts outside the Liguria region (n ⫽ 40; 38.84%). Among donors grouped at the 55 year age cut-off, 23 livers were obtained outside Liguria (57.50% of extraregional livers) from do-

Fig 1. (A) Six-month-patient survival (upper left) and graft survival (upper right) for donor age ⱕ55/⬎55 years (solid line: donors ⱕ55 years; broken line: donors ⬎55 years). (B) Oneyear-patient survival (bottom left) and graft survival (bottom right) for donor age ⱕ55/⬎55 years (solid line: donors ⱕ55 years; broken line: donors ⬎55 years).

SANTORI, ANDORNO, MORELLI ET AL

nors ⱕ55 years (47.92% within ⱕ55 years group); whereas, 17 extraregional graft procurements (42.50%) were performed from donors ⬎55 years (30.91% within age group; P ⫽ .105; OR: 2.056; 95%CI: 0.919 to 4.6). For 60 year-donor age cut-off, extraregional liver procurement occurred in 29 cases (72.50%) from donors ⱕ60 years (46.77% within age-group) and in 11 cases (27.50%) from donors ⬎60 years (26.83% within age group; P ⫽ .062; OR: 2.39; 95%CI: 1.022 to 5.621). With the cut-off of 65 years, livers procured outside Liguria were 30 (75%) from donors ⱕ65 years (46.15% within age group), and 10 (25%) from donors ⬎65 years (26.32% within group; P ⫽ .0598; OR: 2.40; 95%CI: 1.004 to 5.737). The frequency of overall donor-recipient sex mismatch was 35.57%, whereas female donor-male recipient mismatch occurred at 25.96%. Putting overall donor-recipient sex mismatch in contingency tables for the donor age cut-offs revealed no significant difference for ⱕ55/⬎55 years (P ⫽ .6804; OR: 1.273; 95%CI: 0.564 to 2.868); ⱕ60/60 years (P ⫽ .678; OR: 1.219; 95%CI: 0.537 to 2.769), or ⱕ65/65 years (P ⫽ .397; OR: 1.489; 95%CI: 0.65 to 3.412). No statistical significance was observed in contingency tables arranged for female donor-male recipient mismatch (data not shown). Overall 6-month patient and graft survivals were 83.50% and 79.61%, respectively, whereas overall survival at 1-year for patients and grafts was 78.64% and 74.76%, respectively. By stratifying liver recipients for donor age ⱕ55/⬎55 years, 6-month patient survival was 77.08% vs 88.08%, respectively (P ⫽ .1426; HR: 2.095; 95%CI: 0.7799 to 5.617), whereas the corresponding graft survival was 72.92% vs 85.45%, respectively (P ⫽ .0935; HR: 2.086;

DONOR AGE AND ADULT RECIPIENT SURVIVAL

95%CI: 0.882 to 4.970; Figure 1A). For the same donor-age cut-off, 1-year patient survival was 75% with livers procured from CD ⱕ55 years and 81.82% for livers procured from CD ⬎55 years (P ⫽ .317; HR: 1.53; 95%CI: 0.662 to 3.57); whereas, 1-year graft survival was 68.75% vs 80% (P ⫽ .149; HR: 1.757; 95%CI: 0.814 to 3.85), respectively (Fig 1B). Adopting donor age ⱕ60/⬎60 years as the cut-off, 6-month patient survival was 80.65% vs 87.80% (P ⫽ .319; HR: 1.688; 95%CI: 0.6217 to 4.293), while 6-month graft survival was 75.81% vs 85.37% (P ⫽ .216; HR: 1.8; 95%CI: 0.725 to 4.12), respectively (Fig 2A). With the same donor-age cut-off, 1-year patient survival was 77.42% vs 80.49% (P ⫽ .647; HR: 1.224; 95%CI: 0.521 to 2.85), and 1-year graft survival was 70.97% vs 80.49% (P ⫽ .711; HR: 1.178; 95%CI: 0.5 to 2.757; Fig 2B). Last, for donor age ⱕ65/⬎65 years, 6-month patient survival was 81.54% vs 86.84% (P ⫽ .459; HR: 1.479; 95%CI: 0.543 to 3.85) with a graft survival of 76.92% and 84.21% (P ⫽ .344; HR: 1.571; 95%CI: 0.633 to 3.685), respectively (Fig 3A). With the donor age ⱕ65/ ⬎65 years as cut-off, 1-year patient survival was 76.92% vs 81.58% (P ⫽ .542; HR: 1.32; 95%CI: 0.552 to 3.09), and

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1-year graft survival was 70.77% vs 81.58% (P ⫽ .217; HR: 1.712; 95%CI: 0.746 to 3.627) (Fig 3B). No significant differences in patient or graft survival was found adopting sex mismatches, liver extraregional procurement, and CIT median value as grouping variables (data not shown). A simple series of univariate logistic regression models with 1-year liver recipient survival assumed as a dependent variable did not show statistical significance for the following variables: donor age (P ⫽ .531), recipient age (P ⫽ .726), overall sex mismatch (P ⫽ .134), female donor-male recipient mismatch (P ⫽ .525), ELTR codes (P ⫽ .999), UNOS status (P ⫽ .934), and CIT (P ⫽ .998). No significance was observed in the other end-point survival for patients and grafts (data not shown). DISCUSSION

The discrepancy between the continuous increase in patients awaiting OLT and the lack of parallel growth in the cadaveric donor pool has forced us to consider suboptimal donors. On the other hand, what in the past was understood

Fig 2. (A) Six-month-patient survival (upper left) and graft survival (upper right) for donor age ⱕ60/⬎60 years (solid line: donors ⱕ60 years; broken line: donors ⬎60 years). (B) One-year-patient survival (bottom left) and graft survival (bottom right) for donor age ⱕ60/⬎60 years (solid line: donors ⱕ60 years; broken line: donors ⬎60 years).

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Fig 3. (A) Six-month-patient survival (upper left) and graft survival (upper right) for donor age ⱕ65/⬎65 years (solid line: donors ⱕ65 years; broken line: donors ⬎65 years). (B) One-year-patient survival (bottom left) and graft survival (bottom right) for donor age ⱕ65/⬎65 years (solid line: donors ⱕ65 years; broken line: donors ⬎65 years).

as suboptimal or marginal currently may be termed as normal,3 making suboptimal donor an evolving concept. In this context, the potential impact of donor age on OLT outcome represents perhaps the most investigated parameter.1,3– 6 Although donor age has been approached in heterogeneous liver recipient populations by using a plethora of statistical methods, there is a general belief that it may be a risk factor, but not per se a contraindication for donation.3 In fact, excellent outcomes were reported in OLT using CD of increasing age.5,9,10 –12 Conversely, a large study performed on the ELTR showed an increased risk for OLT by using donors of age ⱖ55 years.7 The Italian National Transplant Center has assumed a donor age more than 60 years to be a potential risk factor.8 Thus, in this retrospective study we evaluated the relationship between different donor age cut-offs and OLT survival. The analysis started in January 1, 2000 because at that time our department began a project funded by Italian Ministry of Health to progressively improve information management of CD in the Liguria region.15,16 Three different donor age cut-offs (ⱕ55/⬎55, ⱕ60/⬎60, and ⱕ65/⬎65 years) were chosen on the basis of ELTR results, Italian National Transplant

Center indications, and international literature.3 CD were selected in agreement with NITp counsel and national guidelines for solid organ procurement.8 In view of the fact that only donors with normal or negligible alterations in laboratory values may be used for liver procurement and that these data are poorly reliable because they are not specific for liver injury,3 this study investigated potential suboptimal factors that are not rigorously formalized in national guidelines, such as donor/recipient sex mismatch, extraregional liver procurement, and CIT. Although no significant difference in patient or graft survival occurred after stratification for the donor age cut-offs, a trend toward better survival was observed among OLT performed with livers procured from CD ⬎55 years (Figs 1–3). This finding was noted especially for 6-month graft survivals (Figs 1–3), and in recipient and graft survivals stratified by the ⱕ55/ ⬎55 donor age cut-off (Fig 1). To clarify these data, we initially considered a possible role of both overall sex mismatch and female donor-male recipient mismatch, which have been reported to be risk factors for graft failure in adult recipients.17 However, neither overall sex mismatch nor female donor-male recipient mismatch was related to

DONOR AGE AND ADULT RECIPIENT SURVIVAL

posttransplant survival. With increasing donor age, the number of trauma donors decreases while donors with brain hemorrhage rise.3 Our series confirmed no significance for posttransplant survival (data not shown). Moreover, patient ELTR codes and UNOS status did not reach significance for 1-year patient survival in univariate logistic regression models, as well as donor age, recipient age, and donor/recipient age ratio. Considering the extraregional liver procurement, there was a prevalence of the lower donor age cut-offs in all comparisons, with an almost significant P value for the ⱕ60/60 and ⱕ65/65 cut-offs. These data reflect the demography of the Liguria region, where the Italian Institute of Statistics has registered the presence of one of the most aged populations in Italy.18 Thus, significant differences were noted for CIT grouped according to the donor age cut-offs of ⱕ55/55 and ⱕ65/65 years, whereas an almost significant P value was calculated for ⱕ60/60 donor-age group (Table 1). The Italian National Transplant Center considers CIT ⬎600 minutes as a potential risk factor. In our series, CIT mean and median values were below this value, exceeding it in only six cases. A significant inverse correlation between overall CIT and donor age was observed, although overall CIT did not reach significance when entered as an independent variable in a logistic regression model for 1-year patient survival. Taken together, the results of this study support the suitability of livers procured from cadaveric donors of more than 55 years for OLT procedures. Although overall donor age was not an independent predictor for patient or graft survival, better survival occurred in OLT performed with grafts obtained from donors aged over 55 years. By stratifying donor age for different cut-offs, a significant CIT increase was noted with livers procured from donors aged below 55 and 65 years. These findings suggest that analyses about cadaveric donor age should be performed by assuming CIT cut-off values as potential risk factors for LT. REFERENCES 1. Norrby J, Liden M, Gäbel M, et al: Early outcome of liver transplantation using donor over 60 years of age. Transplant Proc 33:2516, 2001

2581 2. Gibbons RD, Meltzer D, Duan N: Waiting for organ transplantation. Science 287:237, 2000 3. Loinaz C, González EM: Marginal donors in liver transplantation. Hepato-Gatroenterology 47:256, 2000 4. Washburn WK, Johnson LB, Lewis WD, et al: Graft function and outcome of older (ⱖ60 years) donor livers. Transplantation 61:1062, 1996 5. Emre S, Schwartz ME, Altaca G, et al: Safe use of hepatic allografts from donors older than 70 years. Transplantation 62:62, 1996 6. Busquets J, Xiol X, Figueras J, et al: The impact of donor age on liver transplantation: influence of donor age on early liver function and on subsequent patient and graft survival. Transplantation 71:1765, 2001 7. Adam R, Cailliez V, Majno P, et al: Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study. Lancet 356:621, 2000 8. http://www.ministerosalute.it/trapianti. Accessed October 2004 9. Wall W, Grant D, Roy A, et al: Elderly liver donor. Lancet 341:121, 1993 10. Mazziotti A, Cescon M, Grazi GL, et al: Successful liver transplantation using an 87 year-old donor. Hepato-Gastroenterology 46:1819, 1999 11. Romero CJ, González EM, Ruíz FC, et al: Use of octogenarian livers safely expands the donor pool. Transplantation 68: 572, 1999 12. Santori G, Cottalasso D, Antonucci A, et al: Orthotopic liver transplantation in a young adult (33 years old) using an 84-year-old donor. Hepato-Gastroenterology 48:1138, 2001 13. Tzakis A, Todo S, Starzl TE: Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 210:649, 1989 14. Shapiro SS, Wilk MB, Chen HJ: A comparative study of various tests of normality. J Am Stat Ass 63:1343, 1969 15. Santori G, Valente R, Cambiaso F, et al: Preliminary results of an expert-opinion elicitation process to prioritize an informative system funded by Italian Ministry of Health for cadaveric donor management, organ allocation, and transplantation activity. Transplant Proc 36:433, 2004 16. Valente R, Cambiaso F, Santori G, et al: First results of Liguria-Trento Transplant Network Project: A model for a macroregional network and real-time registry in Italy. Transplant Proc 36:442, 2004 17. Marino IR, Doyle HR, Aldrighetti L, et al: Effect of donor age and sex on the outcome of liver transplantation. Hepatology 22:1754, 1995 18. http://www.demo.istat.it/pop2003/index.html. Accessed October 2004