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Original Clinical ScienceGeneral

Impact of Cytomegalovirus on Long-term

Mortality and Cancer Risk After
Organ Transplantation
Rajeev Desai,1 Dave Collett,1 Christopher J. E. Watson,2 Philip J. Johnson,3,4 Paul Moss,5,6 and James Neuberger1
Background. There is conflicting evidence of the effect of cytomegalovirus (CMV) infection on survival and the risk of cancer
after transplantation. Methods. All recipients of kidney, liver, heart, and lung transplants in the United Kingdom between 1987
and 2007 with known CMV immunoglobulin G status were identified from the U.K. Transplant Registry. Based on the donorrecipient CMV status, recipients were grouped into: donor (D) negative recipient (R) negative (D R), DR+, D + R+ and D + R.
Cancer data were obtained from the Office for National Statistics. The impact of CMV infection on survival and cancer incidence
was assessed. Results. The 10-year posttransplant survival in DR recipients (73.6% [95%CI, 72.3, 74.9]) was significantly
higher (P < 0.0001) than in other recipients (66.1% [65.3, 66.9]). Compared with the D R group, the risk-adjusted hazard of
death within 10 years of transplantation for D+ R group was 14% higher for kidney recipients (P = 0.0495), 13% higher for liver
recipients (P = 0.16), 34% higher for heart recipients (P = 0.01), and 35% higher for lung recipients (P = 0.006). The proportion of
recipients with a cardiovascular cause of death was higher (P = 0.03) among the recipients exposed to CMV (18%) as compared
to the D R recipients (16%). The CMV status was not associated with an increased risk of cancer. Conclusions. The results
from this large study demonstrate that CMV is associated with a significantly increased long-term mortality in kidney and
cardiothoracic transplant recipients and an increased risk of cardiovascular death but not of posttransplant cancer.

(Transplantation 2015;99: 19891994)

lthough long-term survival after solid organ transplantation is continuing to increase, recipients remain at
increased risk of premature death,1-5 primarily because of
an increased mortality from cardiovascular disease, cancer,
infection, and recurrent disease. Cytomegalovirus (CMV) infection is common, affecting 50% to 80% of the adult population with an initial, often subclinical mild infection
followed by a state of lifelong chronic viral carriage.6 The
CMV infection is generally well controlled in an immune
competent host, but in the immunosuppressed, it is often
associated with significant morbidity. Whereas some studies both in the normal and the transplant population have
found an increased risk of cardiovascular disease and

death in CMV infected individuals,4,7-9 this has not been

confirmed by all.10-13 However, all the studies in the transplant population have been relatively short term (less than
5 years).
Some viruses, such as human papilloma virus, hepatitis B
and C, Epstein-Barr virus, and human herpes virus-8 have
an established role in the development of cancer both in the
immunocompetent and the immunosuppressed organ allograft recipient populations. Although CMV antigens have
been identified in cells of certain tumors, such as cancers of
the colon, prostate, lymphoma, and glioblastoma,14 it is not
known if the presence of CMV is an epiphenomenon or
whether there is a causative association. The role of CMV
in posttransplantation cancer is also controversial with

Received 3 February 2014. Revision requested 3 March 2014.

Accepted 26 November 2014.

National Health Service Blood and Transplant, Stoke Gifford, Bristol, United

University Department of Surgery, Addenbrooke's Hospital, Hills Road,

Cambridge, United Kingdom.

Department of Molecular and Clinical Cancer Medicine, University of Liverpool,

Liverpool, Merseyside, United Kingdom.

Clatterbridge Cancer Centre, Wirral, Merseyside, United Kingdom.

School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham,

United Kingdom.

University Hospitals Birmingham, Edgbaston, Birmingham, United Kingdom.

The Science, Technology, Engineering and Mathematics Ethical Review Committee

at the University of Birmingham, UK has granted full ethical approval for this project.
R.D. designed the study, conducted literature search, data collection, data analysis,
interpreted the results and drafted the manuscript. D.C. participated in data
collection, data analysis and interpretation of results. C.J.E.W. participated in data
collection and literature search. P.J.J. and P.M. participated in data analysis and
interpretation. J.N. designed the study and contributed to data collection and
interpretation. All authors contributed to the writing of the manuscript.
Correspondence: Rajeev Desai, MRCP, NHS Blood and Transplant, Fox Den Road,
Stoke Gifford, Bristol BS34 8RR, United Kingdom. (

Funding provided by NHS Blood and Transplant.

Supplemental digital content (SDC) is available for this article. Direct URL citations
appear in the printed text, and links to the digital files are provided in the HTML text
of this article on the journals Web site (

The authors declare no conflicts of interest.

Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

The NHS Blood and Transplant played no role in the conduct of this study,
manuscript preparation, or the decision to submit for publication.

ISSN: 0041-1337/15/9909-1994


September 2015

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DOI: 10.1097/TP.0000000000000641

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conflicting evidence from recent studies: some have shown a

protective effect,15 whereas others, an increased risk.16
We therefore examined a large national cohort of solid allograft recipients for the impact of CMV in donors and recipients on the long-term posttransplantation survival. We have
also investigated for an association between CMV and the
risk of posttransplantation cancer.
Study Cohort

Using the data held by the U.K. Transplant Registry, the recipients of first solid organ (kidney, liver heart, and lung)
transplantation between January 01, 1987, and December
31, 2007 who were resident in England, Wales or Scotland
were identified. The transplants where the CMV status was
not recorded for the donor or the recipient were excluded
(n = 12228). Recipients of combined kidney-pancreas
(n = 764) were grouped with the kidney recipients and recipients of double-lung or heart-lung transplants (n = 553) were
grouped with the lung recipients. The recipients were divided
into 4 groups based on the combination of donor and recipient CMV immunoglobulin G status at the time of transplantation: both donor and recipient CMV positive (D+ R+) or
negative (D R), CMV-positive donor with CMV-negative
recipient (D+ R) and CMV-negative donor with CMVpositive recipient (D R+).

Transplant and CMV data were obtained from the U.K.

Transplant Registry. Cancer registration data were obtained
from the Office for National Statistics by matching the details
of the recipients (name, sex, date of birth/death, address, and
National Health Service [NHS] number). All types of cancers
other than non-melanoma skin cancer were included. The
data for the first diagnosed cancer after transplantation were
included. To ignore the cancers which may have been present
at the time of transplantation, all cancers other than Hodgkin
lymphoma or non-Hodgkin lymphoma diagnosed within a
month of transplantation were excluded.
Statistical Analysis

Kaplan-Meier analysis and log-rank test were used to

assess the long-term posttransplantation patient survival.
The risk-adjusted hazard of death was calculated using Cox
proportional hazards model, correcting for those risk factors
that have been identified by NHS Blood and Transplant as
having a significant impact on survival.17 Risk adjusted hazard of death for different solid organ recipients are shown

separately because the risk adjustment varies. Risk factors included were: donor age, recipient age, donor sex, recipient
sex, donor type (kidney and lung recipients), donor cause
of death (kidney and heart recipients), transplant year, primary
disease (kidney, liver and heart recipients), HLA mismatch
(kidney recipients), and ischemia time (cold ischemia for
liver, total for heart/lung). For this assessment, death of the
recipient within 10 years (or 1 year, when 1-year survival
was assessed) was considered as an event, and the recipients
who were alive at 10 years (or 1 year, when 1-year survival
was assessed) from transplantation and those who were lost
for follow-up were censored. During Cox regression, missing
data for a categorical covariate were grouped together as
unknown category. Recipients with missing ischemia time
(12% of liver recipients, 35% of cardiothoracic recipients)
were excluded from multivariate analysis using Cox regression only. Times to diagnosis of cancer in the 4 CMV groups
were compared using the log-rank test. Cox proportional
hazards modelling was also used to assess the relationship between various CMV groups and diagnosis of cancer within
10 years of transplantation. The factors used for risk adjustment in this analysis were recipient age and sex. For
this assessment, a diagnosis of cancer within 10 years of
transplantation was considered as an event and any other
end point in the absence of a diagnosis of cancer, such as
death or end of follow-up, was considered as censored.
While comparing the hazard of multiple types of cancers
in different CMV groups, the Bonferroni correction was
used to assess statistical significance to avoid inflating
the overall type I error above its nominal level for each
test. The causes of death between the D R groups and
other recipient group were compared using the 2 test.
All data were analyzed using SAS version 9.1.3 (SAS
Institute, Cary).
A total of 22461 recipients were studied, including 13,215
(59%) kidney recipients, 4814 (21%) liver recipients, 2686
(12%) heart recipients, and 1746 (8%) lung recipients. The
baseline characteristics of the recipients in different CMV
groups are shown in Table 1.
Survival curves for the recipients of all organ transplantation over 10 years from transplantation are shown in
Figure 1. At 10 years from transplantation, survival of
D R group (73.6 [95%CI, 72.3, 74.9]) was significantly higher (P < 0.0001) compared with the combined
survival of all the other recipients (66.1% [65.3, 66.9]).
The donor-recipient CMV matching was associated with


Characteristics of recipients in different CMV groups

Recipient details
CMV Status

D + R+

Age (95% CI)


Median follow-up in years (95% CI)

6666 (30%)
4520 (20%)
5754 (26%)
5521 (25%)
22461 (100%)

47.6 (47.3, 47.9)

41.3 (40.8, 41.8)
46.7 (46.3, 47.1)
37.6 (37.1, 38.0)
43.6 (43.4, 43.9)

3985 (60%)
2926 (65%)
3415 (59%)
3528 (64%)
13854 (62%)

8.0 (7.9, 8.1)

7.6 (7.2, 7.8)
7.8 (7.6, 7.9)
8.0 (7.9, 8.3)
7.9 (7.8, 7.9)

D, donor; R, recipient.

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Desai et al

2015 Wolters Kluwer

for D R+ group). Table 2 shows the risk-adjusted hazard

of death within 1 year and 10 years from transplantation,
assessed separately for the recipients of kidney, liver, heart,
and lung transplantation. A total of 6213 recipients died
within 10 years from transplantation. The recipients who
died within 30 days of transplantation (n = 897) were excluded because CMV is not likely to have contributed to
death in this group. A majority of these (471, 53%) died
within 8 days of transplantation, and the cause of death in
this group is more likely to be related to perioperative complications than CMV. The causes of death were studied in the
remaining 5316 recipients after dividing them into D R
group and others group, and the results are shown in
Figure 2.
The unadjusted incidence of all cancers was 8.8% (7.9,
9.6) among D+ R+ group, 7.0% (6.0, 7.9) among D+ R
group, 9.1% (8.1, 10.1) among D R+ group, and 6.4%
(5.5, 7.3) among D R group, and this difference was statistically significant (P < 0 0001). However, there was no statistically significant difference in the risk-adjusted hazard of
all cancers between these groups after correction for age
and sex (Figure 3). Similar results were obtained on comparing risk of cancer among DR group against the risk of cancer among all other recipients. The unadjusted hazard of
cancer among all other recipients was higher compared to
DR recipients (hazard ratio [HR] of 1.37 among other

FIGURE 1. U.K. organ recipients, 1987-2007: comparison of 10-year

recipient survival between 4 groups based on CMV status. D, donor;
R, recipient; + and indicate CMV immunoglobulin G status; UK,
United Kingdom.

significant survival advantage for CMV-negative recipients (10-year survival: 73.6% [72.3, 74.9] for D R
group and 68.4% [66.9, 69.9] for D+ R group) but not
for CMV-positive recipients (10-year survival: 64.6%
[63.3, 65.8] for D+ R+ group and 66.1% [64.7, 67.5]

U.K. Organ transplantation recipients, 1987-2007: 1-y and 10-y patient survival and risk-adjusted hazard of death
CMV status


1-y survival% 95%CL
Risk adjusted hazard of death within 1 y
10-y survival% 95%CL
Risk adjusted hazard of death within 10 y


1-y survival% 95%CL
Risk adjusted hazard of death within 1 y
10-y survival% 95% CL
Risk adjusted hazard of death within 10 y


1-y survival% 95%CL
Risk adjusted hazard of death within 1 y
10-y survival% 95% CL
Risk adjusted hazard of death within 10 y


1-y survival% 95%CL
Risk adjusted hazard of death within 1 y





10-y survival% 95% CL

Risk adjusted hazard of death within 10 years HR





P value for patient survival

95.2 0.7
1.27 (0.96, 1.67)
70.9 1.6
1.11 (0.99, 1.25)
87.7 1.7
0.99 (0.77, 1.28)
63.2 2.8
1.03 (0.88, 1.22)
80.2 3.0
1.16 (0.83, 1.61)
55.3 3.8
1.31 (1.05, 1.65)
73.6 4.1
1.29 (0.93, 1.80)
28.8 4.5
1.27 (1.03, 1.57)

95.0 0.8
1.74 (1.30, 2.31)
76.8 1.8
1.14 (1.00, 1.30)
85.3 2.3
1.20 (0.92, 1.57)
63.4 3.5
1.13 (0.94, 1.34)
79.1 3.6
1.34 (0.96, 1.87)
56.2 4.7
1.34 (1.06, 1.70)
69.9 5.0
1.41 (1.02, 1.96)
29.9 5.6
1.35 (1.09, 1.68)

95.6 0.7
1.26 (0.95, 1.68)
73.4 1.8
1.05 (0.93, 1.19)
86.2 1.8
1.15 (0.89, 1.47)
66.1 2.8
0.99 (0.84, 1.17)
84.1 2.6
0.91 (0.65, 1.27)
57.6 3.7
1.09 (0.87, 1.36)
77.1 3.8
1.02 (0.73, 1.43)
34.6 4.8
1.04 (0.84, 1.29)

97.6 0.5


N, number at risk on day 0; HR for recipient death after correction for risk factors; CL, confidence limits.

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82.5 1.5
89.3 1.8
71.3 3.0
83.4 2.7
64.1 3.8
76.8 3.6
35.4 4.8










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FIGURE 2. Causes of death (in %) among 6213 recipients of

all organs who died within 10 years of transplantation, divided into
DR recipients and all other recipients. Cardiac and vascular group includes cardiac causes, cerebral causes and thromboembolic causes.
Others include miscellaneous, unspecified and unknown causes.

recipients compared to DR group, P < 0.0001) but after

adjustment for age and sex, the difference in hazard of cancer
between the 2 groups was not statistically significant (HR of
1.036 among other recipients, P = 0.63). In our cohort, along
with adjustment of risk for age (which is a recognized risk
factor for cancer), we also adjusted for sex because male
sex was found to be an independent risk factor for cancer
even after excluding those cancers which are sex-specific,
such as cancer of cervix, ovary uterus, and prostate (HR for
male sex, 1.36; P < 0.0001).
The impact of CMV status was studied on the risk of kidney cancer among kidney recipients: there were 72 cases of
kidney cancers among 13,215 kidney recipients. Compared
with DR recipients, other recipients had a higher unadjusted hazard of developing kidney cancer after kidney transplantation (HR, 2.33; P = 0.036) but after adjustment for age
and sex, the difference in the hazard was not statistically significant (risk adjusted HR, 1.98; P = 0.096).
(Table S1, SDC, shows the frequency and unadjusted incidence of 23 types of cancers among
the recipients in different CMV groups. The risk-adjusted hazard of developing different types of cancers is shown as forest
plots in (Figure S1, SDC,
This study found that the use of organs from donors who
are CMV-positive for recipients who are CMV-negative is associated with an increased long-term posttransplantation
mortality in kidney, heart, and lung transplant recipients.
The effect of CMV on posttransplantation patient survival
has been studied among recipients of different organs with
conflicting results. The published reports assessing patient
survival after transplantation include studies of kidney recipients11 (no effect), kidney-pancreas recipients12 (no effect),
liver recipients13 (no effect), and heart recipients9 (7.05 times
increased hazard of mortality at 1 year). Most of these studies
have assessed short-term survival, often limited to less than
5 years from transplantation. The data assessing the longterm survival are limited. One of the larger reports is the
study by Johnson and colleagues,11 which included 8228
recipients of deceased donor kidney transplantation in the
United Kingdom between 2000 and 2007, partly overlapping
with our present cohort. Johnson demonstrated no effect of

CMV on the posttransplantation patient survival at 1, 3,

and 5 years. In comparison, our study showed an increased
risk of patient death at 10 years after transplantation among
recipients of kidney as well as heart and lung transplantations.
This difference is likely to be due to larger numbers and longer
follow-up. A direct comparison between our cohort and the
cohort studied by Johnson could not be performed due to
inherent differences between the 2 cohorts, such as different
inclusion criteria and unspecified duration of follow-up. In
our study, an increased mortality was observed in the D+R
group at 10 years (14% increase in risk of death in comparison
to DR group among kidney recipients, 34% increase
among heart recipients and 35% increase among lung
recipients) possibly highlighting the effect of the new
CMV infection acquired during transplantation. An increased
mortality was also observed among D+R+ group of heart
recipients (31% increase) and lung recipients (27% increase).
It is difficult to explain the processes by which CMV may
be contributing to increased posttransplantation mortality
in a retrospective registry study, such as ours. The most common causes of death within 10 years after transplantation included cardiovascular events, cerebrovascular events, infections,
and single or multiorgan failure. The analysis of causes of death
showed a small (2%) increase in cardiovascular death among
CMV-infected recipients; however, it should also be noted that
causes of death in more than a third of recipients were unspecified or others. The CMV infection has been shown to be
associated in the nontransplantation population with an increased cardiovascular mortality.4,5,8 Among solid organ
transplantation recipients, CMV has been shown to be associated with a variety of conditions, such as acute rejection,18
tubulointerstitial nephritis and glomerulopathy after kidney
transplantation,19 hepatic artery thrombosis and accelerated
hepatitis C virus infection20 after liver transplantation, allograft vasculopathy after heart transplantation and bronchiolitis obliterans after lung transplantation,7 bacterial, fungal,
and viral infections,21,22 and new onset diabetes mellitus.23
The rates of these complications and their impact on posttransplantation mortality could not be assessed in the present cohort due to lack of relevant data in the retrospective
audit. The increased mortality observed among CMVinfected transplantation recipients in our cohort may be interplay of some or all of these diseases.

FIGURE 3. U.K. organ transplantation recipients, 1987-2007: comparison of risk-adjusted hazard of cancer compared with the DR
group, within 10 years of transplantation. D, donor; R, recipient; +
and indicate Cytomegalovirus immunoglobulin G status. Bars indicate 95% confidence intervals. Risk adjusted for age and sex.

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Desai et al

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In the general population, especially the healthy elderly

population, CMV is described as a driver of age-associated
immune alterations leading to a reduction in naive T cells.24
Reactivation of CMV may result in increased levels of proinflammatory cytokines, such as interleukin-6 and tumour necrosis factor-. C-reactive protein levels also increase as a
consequence of leakage of the virus from host cells via the action of interleukin-6. These inflammatory markers have been
linked to both all-cause and cardiovascular diseaserelated
mortality. Recently, Savva et al25 found in a cohort of 511
healthy individuals aged at least 65 years followed up for
18 years that CMV infection was associated with an increased mortality rate and a near doubling cardiovascular
death, whereas there was no increase in mortality from other
causes. Simanek et al,26 in a large and younger representative
American population, aged 25 years or older with up to
18 years of follow-up, showed that CMV seropositivity was
independently associated with an increased all-cause mortality (adjustment for CRP level did not attenuate this relationship). However, after confounder adjustment, they failed to
associate CMV serostatus with cardiovascular mortality.
Another study by Courivaud et al27 showed that CMV exposure was an independent risk factor for atherosclerotic
events, whereas posttransplantation CMV replication was
an independent risk factor for both atherosclerotic events
and death in kidney transplant recipients. Their results suggested that CMV was associated with immune exhaustion
and inflammation in favor of an indirect effect of CMV on
atherosclerotic progression. These results, along with the results of our study, provide evidence toward a complex interaction between aging, CMV infection, and cardiovascular
disease/death both in general population as well as recipients
of organ transplantation.


significant on multivariate analysis after correction for age

and sex (Figure 3). This result highlights the fact that age is a
risk factor for both CMV positivity and cancer.
The size of the cohort is a clear strength of our study and is
likely to be the reason for the differences in findings between
our study and the 2 other recent reports assessing a similar
question.15,16 Couzi and colleagues15 retrospectively studied
a cohort of 105 kidney recipients followed up for a median of
5 years, 23 of whom had developed a posttransplantation
cancer. They concluded that CMV naive recipients had a
5.28 times increased risk of posttransplant cancer as compared to recipients exposed to CMV before or after transplantation and attributed this to CMV-mediated increase in
the number of a subset of T lymphocytes which possess
antitumor activity. In contrast, Courivaud and colleagues16
reported from a cohort of 455 recipients of kidney transplantation that both pretransplantation exposure (HR = 1.8) and
posttransplantation replication (HR = 2.17) of CMV were
associated with an increased risk of posttransplantation cancer as compared to CMV naive recipients and attributed this
to immune exhaustion related to exposure to CMV. Compared to these studies, our cohort was substantially larger
resulting in increased statistical power to detect any association between CMV and posttransplantation cancer. As
shown in (Table S1, SDC,,
despite the cohort size, the number of individual types of
cancers is relatively small; so studies with a smaller cohort
would have very small numbers of individual types of cancer
and are likely to produce results which cannot be generalized
to all transplantation recipients. Despite the limitations of
our study, as listed below, we believe that the validity of
our results is enhanced by the large cohort size.
Limitations of our Study

CMV Does Not Have an Effect on the Risk of

Posttransplantation Cancer

The cancer risk of a transplantation recipient is influenced

by complex interactions between recipient factors (age, ethnicity, social status, premalignant conditions, pre-existing infections, smoking, alcohol intake, possibly genetic factors),
donor factors (diseases transmitted from donor organ), and
posttransplant factors (medical follow-up, long-term immunosuppression, drug toxicity, de novo infections). The recipient factors, which are associated with an increased risk of
cancer, such as age, social status, and smoking, are also associated with higher CMV seroprevalence,28 and it can be difficult to tease out any independent effect exerted by CMV. A
higher risk of cancer among CMV-positive recipients as compared to DR recipients observed on univariate analysis of
our cohort may also be explained by the fact that CMVpositive recipients were older than CMV-negative recipients.
This difference in the risk was not statistically significant after
correction for recipient's age and sex.
From this large cohort of solid organ recipients, we demonstrated that the donor-recipient CMV statuses have no independent association with the risk of posttransplantation
cancer in general or with the specific risk of developing 23
types of posttransplantation cancers. On univariate analysis,
the incidence of posttransplantation cancer was higher among
the groups with a CMV-positive recipient (D+R+ and DR+)
as compared to the groups with a CMV-negative recipient
(D+R and DR), but this difference was not statistically

As with all retrospective registry studies, our study has several important limitations. The CMV data were not available
for 12,228 (35%) recipients, and these were excluded. The
CMV status was recorded at the time of transplantation,
and any recipients with posttransplantation acquisition of
de novo CMV infection were not identified. Furthermore,
in a significant proportion of patients, no case of death was
specified. The data regarding pharmacological prophylaxis
against CMV infection was not available. The risk of cancer
would be underestimated in cases where the recipient had
multiple cancers because the data for the first diagnosed posttransplantation cancer only was included. The cause of death
data was obtained from the Office for National Statistics,
which is the United Kingdom's largest independent producer
of official statistics and is the most widely recognized national statistical institute in the United Kingdom. Multiple
robust internal and external quality control measures are in
place to maintain the high quality of data produced by the
Office for National Statistics. Despite of this, some inaccuracy
of data may be inevitable.
In summary, in this large cohort of solid organ recipients,
there was no association between the donor-recipient CMV
status and the risk of posttransplantation cancer as a whole,
or the risk of 23 individual types of cancers. Novel findings
also include the negative impact of the D+R CMV mismatch on the long-term survival of recipients of kidney,
lung, or heart transplantations but not the recipients of
liver transplantation.

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September 2015

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Number 9

The authors are grateful to NHS Blood and Transplant for
funding and the data relating to the donors and the recipients, and to the Office for National Statistics for providing
the cancer data.
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