http://www.jhltonline.
org
“Please Sir, I want some more?”… Charles Dickens, Oliver
Twist
Adriana Luk, MD, and Heather J. Ross, MD
From the Department of Medicine, Division of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada
Since the first pediatric heart transplant in 1967, more
than 100,000 pediatric transplants (ages newborn–18 years)
have been performed to date.1 With improved immunosup-
pressive therapy, as well as peri-operative and post-
transplant management, median survival has increased from
9.1 years for transplant eras 1982 through 1989 to 13.9
years for 1990 through 1999.1 Pediatric retransplantation
accounts for 5% of total transplants,1 with an increasing
prevalence of retransplantation as patients get further from
the date of the primary transplant.2 Given the improved
survival with primary transplant, assessment for retrans-
plantation can be expected to increase. Coronary allograft
vasculopathy (CAV) was the commonest indication for
retransplantation, accounting for more than 50% of cases.3–5
Earlier series revealed comparable 3-year survival rates
in the retransplantation and primary pediatric transplantation
population (81.9% ⫾ 8.9% vs 77.3% ⫾ 2.6%, respectively,
p ¼ 0.70).5,6 More recently, long-term survival has been
found to be lower in the retransplantation group,3,4 with
retransplant survival rates of 79%, 53%, and 44% at 1, 5,
and 10 years compared with primary transplant survival of
83%, 70%, and 58% ,respectively (p o 0.001).3 Poor
outcomes have been described in retransplant patients with
an inter-transplant interval of o 3 years (5-year survival,
50%), especially when the retransplant occurred o 180
days compared with 4 5 years (5-year survival, 71%).1,3
Limited published data and lack of uniformity amongst
case series has made it difficult to distinguish between
appropriate candidates and those at increased risk for death
with retransplantation. In this issue of the Journal of Heart
and Lung Transplantation, Conway et al2 present a large and
sophisticated analysis of pediatric retransplantation, focusing
on the risk factors for morbidity (rejection, CAV, renal
failure, development of cancer) and death. Between 1998 and
2010, 9,248 patients underwent primary transplantation at age
o 18 years, and 602 patients (6.1%) were a median age of 14
years at retransplantation (23.1% at age 4 18). The authors
found that despite similar 1-year survival, retransplantation
was associated with decreased long-term survival and
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved.
http://dx.doi.org/10.1016/j.healun.2013.12.021
increased rates of late rejection, CAV, and renal failure.
Survival after primary transplantation was 84%, 72%, 60%,
and 42% at 1, 5, 10, and 20 years compared with the
retransplantation group, where survival was 81%, 63%, 46%,
and 26%, respectively (p o 0.001). Median survival was 15
years for primary transplantation compared with 8.7 years for
retransplantation. In addition, median graft failure occurred at
2 years in the retransplant group compared with 4.7 years in
the primary transplant group (p o 0.001).2
Given the significant mismatch between donor availability
and recipients in need, how does one decide to allocate a graft
for retransplant over a primary transplant candidate?
Currently, 3,661 patients are waiting (3,513 primary
transplant, 148 retransplant) for heart transplantation in the
United States alone. Of these, 316 (295 primary transplant, 21
retransplant) are pediatric patients (aged o 18 years).7 The
pediatric waiting list mortality rate is 15% to 20% in pediatric
candidates within 2 months of listing as United Network of
Organ Sharing (UNOS) Status 18–10 and is at a 3% to 8% risk
by 12 months of listing in UNOS Status 2, with an additional
risk of deterioration of status.11 Important data from this
review, which the authors excluded, were the outcomes of 32
patients who were receiving a third or fourth graft.
Internationally, organs suitable for both an adult and
pediatric recipient are allocated differently than UNOS.
Eurotransplant allocation prioritizes appropriate size- and
blood group–matched hearts to pediatric patients over adult
recipients if they are aged o 16 years and documented to
still be in maturation, with this high-urgency status granted
yearly.12 Because this is part of their allocation algorithm,
there is no mandatory discussion between the adult and
pediatric programs if there are equal-status candidates.
Current international allocation systems appear to
disadvantage primary adult heart transplant candidates,
who have a longer median survival than that seen with
pediatric retransplant (13 vs 8.7 years).2,13 How and who
should decide where a donor heart is allocated when there
are 2 equal-status candidates? What would the clinical
indication be and the ethical framework used to justify the
232 The Journal of Heart and Lung Transplantation, Vol 33, No 3, March 2014
allocation of a graft to a retransplant candidate who has a
lower anticipated survival than a primary transplant?
Cost effectiveness and quality-adjusted life-years (QALYs)
gained amongst these 2 groups should also be addressed.
Willingness-to-pay thresholds indicate a medical intervention
with a cost-effectiveness ratio of o $50,000 per QALY is
acceptable, $50,000 to $100,000 per QALY is marginal, and 4
$100,000 is deemed too costly.14 Dayton et al15 reported that
the cost per QALY gained in 95 pediatric patients undergoing
primary transplantation was $49,679 and retransplantation was
$87,883. 15 With a marginal cost-effectiveness benefit, should
this affect medical decision making for retransplant candidates?
Overall, retransplantation portends worse outcomes; how-
ever, a select group of patients appear to benefit from
retransplantation. Current guidelines suggest that retransplanta-
tion is indicated in children with abnormal ventricular function
(Class I, Level of Evidence [LOE] B) or normal ventricular
function (Class IIa, LOE B) with at least moderate graft
vasculopathy. The Conway et al2 findings would support these
indications. Transplantation is not useful during an episode of
acute allograft rejection, even in the presence of graft
vasculopathy (Class III, LOE B) and should not be performed
within the first 6 months after the initial transplant (Class III,
LOE B).16 The Conway et al analysis shows that CAV as an
indication for retransplant is protective, whereas the inter-
transplant time interval was not significantly associated with
outcomes on multivariable analysis. This would suggest, as the
authors have stated, that the etiology of graft failure requiring
retransplant is more important than the interval since transplant,
calling into question the current guideline recommendations.
Conway et al2 identify patient, donor, and post-transplant
risk factors for adverse outcomes that differ from those
previously identified.3,4 On the basis of the size of the data
set, the authors missed an opportunity to develop a risk score
to predict retransplant outcomes. This would entail using the
recipient factors for death identified within their cohort (non-
specific graft failure, intensive care unit before transplant,
creatinine at time of evaluation and preceding year, history of
non-adherence, cancer history) and factors associated with
better retransplant outcomes (CAV diagnosis, later year of
retransplantation).2 A retransplant risk score might enable
programs to determine candidacy and distinguish when a
patient may be too high risk for retransplantation. By using a
risk score, once a patient is deemed an “acceptable risk” for
retransplant, then the identified donor risk factors may
improve judicious donor selection (cytomegalovirus-nega-
tive, non-diabetic, normotensive male, blood group O)2 for
this sub-group, hence optimizing outcomes.
Understanding that transplant programs have a fiduciary
responsibility to the individual patient, we must not forget
that as transplant professionals, we also have a duty to the list
and to be good stewards of the donor organ. Risk stratifying
those candidates who would derive the most benefit from
retransplant would be an excellent start. At this time, the
current guidelines for retransplant need to be revisited with
international discussion to determine appropriate candidate
selection, taking into account risk for death, and to ensure
judicious allocation of the limited donor resource.
Disclosure statement
The authors acknowledge Andreas Zuckermann and Leah
Edwards.
This work was supported in part by Health Resources and
Services Administration contract 234-2005-37011C. 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.
Neither author has a financial relationship with a commercial
entity that has an interest in the subject of the presented manuscript
or other conflicts of interest to disclose.
References
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