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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
National Health Service Blood and Transplant, Stoke Gifford, Bristol, United
Kingdom.
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 (www.transplantjournal.com).
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
Transplantation
September 2015
Volume 99
Number 9
DOI: 10.1097/TP.0000000000000641
www.transplantjournal.com
1989
1990
Transplantation
September 2015
Volume 99
Number 9
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+).
Data
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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).
RESULTS
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
TABLE 1.
D + R+
D+R
DR+
DR
Total
Male
6666 (30%)
4520 (20%)
5754 (26%)
5521 (25%)
22461 (100%)
3985 (60%)
2926 (65%)
3415 (59%)
3528 (64%)
13854 (62%)
D, donor; R, recipient.
1991
Desai et al
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]
TABLE 2.
U.K. Organ transplantation recipients, 1987-2007: 1-y and 10-y patient survival and risk-adjusted hazard of death
CMV status
Organ
Kidney
N
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
Liver
N
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
Heart
N
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
Lung
N
1-y survival% 95%CL
Risk adjusted hazard of death within 1 y
HR
P
HR
P
HR
P
HR
P
HR
P
HR
P
HR
P
D+R+
D+R
DR+
DR
4072
95.2 0.7
1.27 (0.96, 1.67)
0.10
70.9 1.6
1.11 (0.99, 1.25)
0.08
1445
87.7 1.7
0.99 (0.77, 1.28)
0.94
63.2 2.8
1.03 (0.88, 1.22)
0.71
696
80.2 3.0
1.16 (0.83, 1.61)
0.38
55.3 3.8
1.31 (1.05, 1.65)
0.019
453
73.6 4.1
1.29 (0.93, 1.80)
0.12
28.8 4.5
1.27 (1.03, 1.57)
0.028
2797
95.0 0.8
1.74 (1.30, 2.31)
0.0002
76.8 1.8
1.14 (1.00, 1.30)
0.044
896
85.3 2.3
1.20 (0.92, 1.57)
0.18
63.4 3.5
1.13 (0.94, 1.34)
0.19
499
79.1 3.6
1.34 (0.96, 1.87)
0.08
56.2 4.7
1.34 (1.06, 1.70)
0.014
328
69.9 5.0
1.41 (1.02, 1.96)
0.04
29.9 5.6
1.35 (1.09, 1.68)
0.0058
3120
95.6 0.7
1.26 (0.95, 1.68)
0.11
73.4 1.8
1.05 (0.93, 1.19)
0.44
1375
86.2 1.8
1.15 (0.89, 1.47)
0.29
66.1 2.8
0.99 (0.84, 1.17)
0.87
789
84.1 2.6
0.91 (0.65, 1.27)
0.57
57.6 3.7
1.09 (0.87, 1.36)
0.47
470
77.1 3.8
1.02 (0.73, 1.43)
0.89
34.6 4.8
1.04 (0.84, 1.29)
0.72
3226
97.6 0.5
1
<0.0001
N, number at risk on day 0; HR for recipient death after correction for risk factors; CL, confidence limits.
82.5 1.5
1
1098
89.3 1.8
1
71.3 3.0
1
702
83.4 2.7
1
64.1 3.8
1
495
76.8 3.6
1
35.4 4.8
1
<0.0001
0.036
0.002
0.037
0.009
0.054
0.01
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Transplantation
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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.
Desai et al
1993
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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Transplantation
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Number 9
ACKNOWLEDGMENTS
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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