Umpredictable scientific research n.2: Effect of Donor Age and Sex on the Outcome of Liver Transplantation

Scientific research is fascinating and often unpredictable. I want to provide three examples of something that happened to me that demonstrates that imagination and curiosity are essential in discovering scientific development. Still, possibly, persistence is even more critical.

Today, I will describe how I was wrong in believing that the age and the sex of a liver donor do not have a significant impact on the outcome of liver transplantation. To demonstrate this concept with scientific proof, I examined a few hundred liver transplantations performed by our team in Pittsburgh. Quite differently from what I and others were expecting, our study demonstrated that both the age and sex of the donor have a significant impact on the outcome of liver transplantation with a significant difference in long-term survival. My mentor, Thomas Starzl, was unhappy with the data and asked me to run them by two prominent statisticians working at the Universities of Stanford and at Cambridge University. They confirmed our data, and we published a paper that became important in matching donors and recipients.

 

Effect of Donor Age and Sex on the Outcome of Liver Transplantation

by IGNAZIO ROBERTO MARINO,^1,2 HOWARD R. DOYLE, ^1,2 LUCA ALDRIGHETTI,¹ CATALDO DORIA,¹ JOHN MCMICHAEL,¹ TIMOTHY GAYOWSKI,^1,2 JOHN J. FUNG,¹ ANDREAS G.TZAKIS, ^1,3 AND THOMAS E. STARZL^1,2

 

We correlated donor and recipient factors with graft outcome in 436 adult patients who underwent 462 liver transplants. Donor variables analyzed were age, gender, ABO blood group, cause of death, length of stay in the intensive care unit, use of pressors or pitressin, need for cardiopulmonary resuscitation, terminal serum transaminases, and ischemia time. Recipient variables analyzed were age, gender, primary diagnosis, history of previous liver transplant, ABO blood group, cytotoxic antibody crossmatch, United Network for Organ Sharing (UNOS) status, and waiting time (except for the cross-match results, they were all known at the time of the operation). The endpoint of the analysis was graft failure, defined as patient death or retransplantation. Using multivariate analysis, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and UNOS 4 status of the recipient. The effect of donor age became evident only when they were older than 45 years. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55% (95% CI, 45% to 67%); female to female, 64% (95% CI, 54% to 77%); male to male, 72% (95% CI, 669’~ to 78%); and male to female, 780/0 (95% CI, 70% to 88%). The only donors identified as questionable for liver procurement were old (260 years) women in whom the adverse age and gender factors were at least additive. However, rather than discard even these livers, in the face of an organ shortage crisis, their individualized use is suggested with case reporting in a special category. (HEPATOLOG1Y9 95;22:1754-1762)

 

As of January 4, 1995, 37,751 transplant candidates were registered on the national waiting list operated by the United Network for Organ Sharing (UNOS), the agency that coordinates organ allocation in the United States. This was a 391% increase from the 9,632 waiting in December 1986. Of the 37,751 in 1995, 4,039
were liver candidates, up from 449 in 1987 (a 900% increase). The supply of all organ donors had undergone a marginal increase between 1988 and 1990 (from 4,085 to 4,514), but has remained relatively stable since then: 4,531 in 1991, 4,521 in 1992, 4,849 in 1993, and 4,891 in 1994.

The limited supply of organ donors has increasingly influenced the selection of candidates for liver transplantation, and is used at some institutions to justify restricting the availability of the procedure.¹ Although the exact magnitude of the organ deficit is not yet known,^2,3 the obvious gap between supply and need has stimulated the development of bioartificial liver assist devices,⁴ utilization of living related liver donors,^5,6 use of non-heart beating donors, ^7-9 and xenotransplantation.¹⁰ A more immediate impact on organ shortage already has come from the widespread use of livers from “marginal donors,” as first documented by Makowka
et al¹¹ and Pruim et al. ¹²
The definition of a marginal donor has varied in different reports, and recently has included obesity.^13,14 Two potential risk factors-age and gender-are relevant with all donors, no matter what the other circumstances of death. Although it has long been thought that the liver is less affected than other organs by senescence, ^15,16 poor experience with older donors in the original Denver series (including two who were 73 years of age) resulted in an upper donor age limitation of 45 years.¹⁷ The demonstration that satisfactory livers could be obtained from donors well into the seventh decade of life ^18,19 or beyond ²⁰ was followed by a flurry of confirmatory reports, ^13,14,21,22 countered by descriptions of degraded results using geriatric livers.^23-26

Less has been written about the effect of donor sex on outcome after liver transplantation, although there is an extensive literature, recently summarized by Neugarten and Silbiger,²⁷ showing poorer results with kidney allografts from female donors. We have reported similar findings with female livers in adults^28,29 but not in children.³⁰ The gender effect has been disputed by Stratta et al.³¹
In the current study, we have examined with univariate and multivariate analysis the effect on outcome of donor age and sex, singly and together, in a consecutive series of liver recipients, taking into account an array of other risk factors. A clear influence of both donor age and gender on outcome was identifiable.

 

Patients and Methods

From January 1, 1992 to June 30, 1993, 436 consecutive adult patients received 479 liver transplants at the University of Pittsburgh Medical Center and the Veterans Administration Medical Center, Pittsburgh, PA. The livers in 17 were part of multivisceral transplants that included intestine. These cases were excluded, leaving 419 recipients of 462 allografts who were entered for analysis. The information was obtained from the clinical database maintained by the Pittsburgh Transplantation Institute, and a review of the donor charts that are kept on file at the Center for Organ Recovery and Education (Western Pennsylvania Organ Procurement Organization) Pittsburgh, PA.
All grafts were flushed with the University of Wisconsin solution. No attempt was made to transplant older livers into older recipients, or vice versa. ABO compatibility, size match, and medical urgency (UNOS status, see later discussion), were the only criteria used in recipient selection. All recipients were treated with the same immunosuppressive protocol, based on tacrolimus (Prograf, formerly FK506, Fujisawa USA, Inc., Deerfield, IL) and prednisone, augmented by azathioprine and antilymphocyte globulin in a small minority of cases. Intravenous prostaglandin E¹ was routinely given perioperatively.³²

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