Chronic kidney disease and the risk of cancer: An individual patient data meta-analysis of 32,057 participants from six prospective studies

Abstract

Background:
Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease but the relevance of reduced kidney function to cancer risk is uncertain.

Methods:
Individual patient data were collected from six studies (32,057 participants); including one population-based cohort and five randomized controlled trials. Participants were grouped into one of five CKD categories (estimated glomerular filtration rate [eGFR] ≥75 mL/min/1.73 m(2); eGFR ≥60 to <75 mL/min/1.73 m(2); eGFR ≥45 to <60 mL/min/1.73 m(2); eGFR <45 mL/min/1.73 m(2); on dialysis). Stratified Cox regression was used to assess the impact of CKD category on cancer incidence and cancer death.

Results:
Over a follow-up period of 170,000 person-years (mean follow-up among survivors 5.6 years), 2626 participants developed cancer and 1095 participants died from cancer. Overall, there was no significant association between CKD category and cancer incidence or death. As compared with the reference group with eGFR ≥75 mL/min/1.73 m(2), adjusted hazard ratio (HR) estimates for each category of renal function, in descending order, were: 0.98 (95 % CI 0.87-1.10), 0.99 (0.88-1.13), 1.01 (0.84-1.22) and 1.24 (0.97-1.58) for cancer incidence, and 1.03 (95 % CI 0.86-1.24), 0.95 (0.78-1.16), 1.00 (0.76-1.33), and 1.58 (1.09-2.30) for cancer mortality. Among dialysis patients, there was an excess risk of cancers of the urinary tract (adjusted HR: 2.34; 95 % CI 1.10-4.98) and endocrine cancers (11.65; 95 % CI: 1.30-104.12), and an excess risk of death from digestive tract cancers (2.11; 95 % CI: 1.13-3.99), but a reduced risk of prostate cancers (0.38; 95 % CI: 0.18-0.83).

Conclusions:
Whilst no association between reduced renal function and the overall risk of cancer was observed, there was evidence among dialysis patients that the risk of cancer was increased (urinary tract, endocrine and digestive tract) or decreased (prostate) at specific sites. Larger studies are needed to characterise these site-specific associations and to identify their pathogenesis.

Full text

R E S E A R C H A R T I C L E Open Access
Chronic kidney disease and the risk
of cancer: an individual patient data
meta-analysis of 32,057 participants
from six prospective studies
Germaine Wong
1,2*†
, Natalie Staplin
3†
, Jonathan Emberson
3
, Colin Baigent
3,4
, Robin Turner
5
, John Chalmers
6
,
Sophia Zoungas
6,7
, Carol Pollock
8
, Bruce Cooper
8
, David Harris
2
, Jie Jin. Wang
9
, Paul Mitchell
9
, Richard Prince
10
,
Wai Hon. Lim
10
, Joshua Lewis
10
, Jeremy Chapman
2
and Jonathan Craig
1
Abstract
Background: Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease but the relevance
of reduced kidney function to cancer risk is uncertain.
Methods: Individual patient data were collected from six studies (32,057 participants); including one population-based
cohort and five randomized controlled trials. Participants were grouped into one of five CKD categories (estimated
glomerular filtration rate [eGFR] ≥75 mL/min/1.73 m
2
;eGFR≥60 to <75 mL/min/1.73 m
2
;eGFR≥45 to <60 mL/min/1.
73 m
2
; eGFR <45 mL/min/1.73 m
2
; on dialysis). Stratified Cox regression was used to assess the impact of CKD category
on cancer incidence and cancer death.
Results: Over a follow-up period of 170,000 person-years (mean follow-up among survivors 5.6 years), 2626
participants developed cancer and 1095 participants died from cancer. Overall, there was no significant association
between CKD category and cancer incidence or death. As compared with the reference group with eGFR ≥75 mL/
min/1.73 m
2
, adjusted hazard ratio (HR) estimates for each category of renal function, in descending order, were: 0.98
(95 % CI 0.87–1.10), 0.99 (0.88–1.13), 1.01 (0.84–1.22) and 1.24 (0.97–1.58) for cancer incidence, and 1.03 (95 % CI 0.86–1.
24), 0.95 (0.78–1.16), 1.00 (0.76–1.33), and 1.58 (1.09–2.30) for cancer mortality. Among dialysis patients, there was an
excess risk of cancers of the urinary tract (adjusted HR: 2.34; 95 % CI 1.10–4.98) and endocrine cancers (11.65; 95 % CI: 1.
30–104.12), and an excess risk of death from digestive tract cancers (2.11; 95 % CI: 1.13–3.99), but a reduced risk of
prostate cancers (0.38; 95 % CI: 0.18–0.83).
Conclusions: Whilst no association between reduced renal function and the overall risk of cancer was observed, there
was evidence among dialysis patients that the risk of cancer was increased (urinary tract, endocrine and digestive tract)
or decreased (prostate) at specific sites. Larger studies are needed to characterise these site-specific associations and to
identify their pathogenesis.
Keywords: Cancer epidemiology, Chronic kidney disease, Survival analyses
* Correspondence: Germaine.wong@health.nsw.gov.au
†
Equal contributors
1
Sydney School of Public Health, University of Sydney, Sydney, Australia
2
Centre for Transplant and Renal Research, Westmead Hospital, Westmead,
Australia
Full list of author information is available at the end of the article
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Wong et al. BMC Cancer (2016) 16:488
DOI 10.1186/s12885-016-2532-6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Background
The number of people affected by chronic kidney disease
(CKD) and end-stage kidney disease (ESKD) is substantial
and increasing. The number of new patients with ESKD
treated by renal replacement therapy has increased at an
average of 8 % per year over the past 10 years globally [1].
Currently, over one million patients are on dialysis
worldwide, a number that is estimated to exceed two
million over the next decade [2].
CKD is a risk factor for disease affecting other organs. It
is well established that people with CKD are at increased
risk of developing and dying from cardiovascular disease
compared to people without kidney disease [3]. There is
also evidence that cancer risk and cancer mortality may be
increased in people with CKD, although the associations
do appear to be site-specific. It has been reported that
reduced renal function is associated with an increased
risk of cancers of the kidney or urinary tract [4–7], lip
[8], digestive tract [9], lung [4] and some soft tissue and
haematological sites [10]. Among dialysis patients, there
have also been reports of an increased risk of cervical and
possibly thyroid cancers and a reduced risk of prostate
cancer [8, 9]. A dose-dependent relationship between al-
buminuria and bladder or lung cancer risk was observed
in a Scandinavian study [11].
Previous observational studies have not examined the
extent to which reduced kidney function is associated
with increased risk of cancer and cancer death across
the full spectrum of kidney disease and in different pop-
ulations. We hypothesize that reduced kidney function is
a risk factor for site-specific cancer and may be a prognos-
tic indicator of poor cancer outcomes. The objective of
this study was to determine the overall and site-specific
risk for incident cancer and cancer deaths from a broader
population of people with CKD, varying from mild to ad-
vanced stage disease requiring dialysis.
Methods
Study design and participants
Six studies were included in our analysis, of which one
was a prospective, population-based cohort study, and
five were randomized controlled trials (RCTs). These
studies were included because they provided details of
serum creatinine, age and gender for the estimation of
glomerular filtration rate (GFR), as well as information
on site-specific and overall cancer incidence and mor-
tality. Information on non-cancer related mortality was
also recorded. All studies were also available to the in-
vestigator team for inclusion and so represent a sample
of all possible datasets available for analysis.
The cohort study was the Blue Mountains Eye Study
(BMES) [12], which included a suburban Australian popu-
lation aged 49 years or older at baseline (n= 3654). The
other five RCTs included the Action in Diabetes and
Vascular disease: Preterax and Diamicron MR controlled
evaluation (ADVANCE) study [13], a multi-centre trial of
blood pressure lowering and glucose control in people
with type 2 diabetes mellitus (n= 11,140); the Perindopril-
based blood-pressure-lowering regimen (PROGRESS)
study [14], a multi-centre trial of intensive blood pressure
lowering using the mixed perindopril and indapamide and
placebo in patients with a history of stroke or transient is-
chaemic attack (n= 6105); the Calcium Intake Fracture
Outcome (CAIFOS) study [15], a trial of 1500 women that
assessed the effects of daily calcium supplements and the
risk of osteoporotic fractures in post-menopausal women;
the Study of Heart and Renal Protection (SHARP) [16], a
multi-centre trial of LDL cholesterol lowering in people
with CKD (n= 9270) and the Initiating Dialysis Early and
Late Study (IDEAL) [17], a trial that compared early and
later commencement of dialysis in patients with ESKD
(n= 828). Full details of each study are reported else-
where [12–17]. This study involved the use of existing
collections of data or records that contain only non-
identifiable data. As such, ethics approval was not re-
quired according to the National Health and Medical
Research Council ethical guidelines on low and negli-
gible risk [18]. Written, informed consent was provided
by all participants in each of the studies included in this
individual patient meta-analysis.
Study outcomes
Assessment of incident cancers and cancer deaths
Incident cancers were defined as the first cancer diag-
nosed after inception of the individual studies. Diagno-
ses of incident cancers and cancer deaths for individual
studies were coded according to the International
Classification of Diseases, Ninth and Tenth Revision for
cancers (C00 –C96).
The site-specific cancers were coded as follows: oral
cavity and pharynx (C00–C14), digestive (C15–C26),
respiratory (C30–C39), bone and cartilage (C40–C41),
melanomas (C43), soft tissue/connective tissue (C45–
C49), breast (C50), female genital organs (C51–C58),
male genital (C60, C62–C63), prostate (C61), urinary
tract (C64–C68), central nervous system (C69–C72),
endocrine (C73–C75), unknown origin (C76–C80),
haematological (C81–C96) and multiple primary sites
(C97–C98).
Non-melanocytic skin cancers were excluded from the
analyses because they were deemed less clinically im-
portant than other cancers and because the Central
Cancer Registry of New South Wales and the Western
Australia Data Linkage System do not hold information
about skin cancers other than melanomas. Information
on cancer incidence and mortality in BMES [12] and
CAIFOS [15] was obtained from the Central Cancer
Registry of New South Wales and the Western
Wong et al. BMC Cancer (2016) 16:488 Page 2 of 11
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Australia Data Linkage System. For all other studies,
cancer incidence and mortality were recorded as ad-
verse events during follow-up. Incident cancers and
cancer deaths were also categorized into pre-specified
groups of similar types to allow site-specific associa-
tions to be investigated. Participants known to have
been diagnosed with cancer before study commence-
ment were excluded from the analyses.
Statistical analyses
Primary analyses
All statistical analyses were conducted using SAS 9.3.
The main analyses of estimated glomerular filtration
rate (eGFR) used the Chronic Kidney Disease Epi-
demiology Collaboration (CKD-EPI) equation, but
they were repeated using the four-variable MDRD
equation [19, 20]. The relevance of baseline eGFR to
the risk of cancer incidence and cancer mortality was
estimated using Cox proportional hazards regression
models stratified by study. All regression analyses
were adjusted for age, sex, ethnicity and smoking
status. The shapes of the association between baseline
renal function and cancer risk and deaths were
assessed by grouping participants into five categories
defined by their baseline eGFR (eGFR ≥75; ≥60 to
<75; ≥45 to <60; <45 ml/min/1.73 m
2
but not on
dialysis; and on dialysis). Relative risks, estimated by
the hazard ratios from the Cox regression models, are
presented graphically with a group-specific confidence
interval (CI) derived only from the variance of the log
risk in that one category. Each relative risk, including
that for the reference group, is associated with a
group-specific CI that can be thought of as reflecting
theamountofdataonlyinthatonecategorywhich,
if desired, allows for an appropriate statistical com-
parison to be made between any two groups [21].
Throughout the text, all quoted relative risks are
provided with the CI for the comparison with the
specified reference group. Analyses were repeated
separately for men and women and also for specific
common groupings of cancer sites. To assess the
extent to which the observed associations may be the
result of reverse causality, the primary analyses were
repeated excluding cancers and cancer deaths that
occurred within the first 2 years of follow-up. Finally,
the potential relevance of the competing risk of non-
cancer related death was considered using a stratified
proportional sub-distribution hazard model [22].
Results
Baseline characteristics of participants
Among the 33,680 participants in the six studies, 1236
(3.6 %) were excluded because of missing values for age,
gender or eGFR and a further 387 (1.1 %) were excluded
because of a prior history of cancer, leaving a total of
32,057 participants. Of these, 18,427 (57.5 %) were men,
15,429 (48.1 %) were previous or current smokers and
22,263 (69.4 %) were of white race (Table 1 and Additional
file 1). A total of 9594 (29.9 %) participants had eGFR
≥75 ml per min per 1.73 m
2
; 6681 (20.8 %) had an eGFR
of at least 60 but less than 75 ml per min per 1.73 m
2
;
4931 (15.4 %) had an eGFR of at least 45 but less than
60 ml per min per 1.73 m
2
; 7828 (24.4 %) had an eGFR
less than 45 per min per 1.73 m
2
and 3023 (9.4 %) partici-
pants were on dialysis (Table 2). All participants on dialy-
sis were from SHARP [16].
Incidence of cancer and deaths from cancer
During an average follow-up (among survivors) of
5.6 years, 2626 participants developed cancer (average
incidence rate 15.4 per 1000 person-years [py]; Table 2)
and 1095 died from cancer (6.2 per 1000 py; Table 3).
Cancers of the digestive system (n= 706; 4.1 per 1000
py) were the most common cancers, followed by pros-
tate cancers (n= 332; 1.9 per 1000 py), cancers of the re-
spiratory system (n= 322; 1.9 per 1000 py), breast
cancers (n= 277; 1.6 per 1000 py), and cancers of the
urinary tract (n = 228; 1.3 per 1000 py). Cancers of the
digestive system were also the most common cause of
cancer death (n= 373; 2.1 per 1000 py), followed by can-
cers of the respiratory tract (n= 249; 1.4 per 1000 py).
Relevance of renal function to cancer incidence and
cancer death
Overall, there was no significant association between
baseline stage of kidney disease and cancer incidence or
cancer mortality. For cancer incidence, compared with
the reference category with eGFR ≥75 mL/min/1.73 m
2
,
adjusted hazard ratio (HR) estimates for the other renal
function categories, in order of declining renal function,
were 0.98 (95 % CI 0.87–1.10), 0.99 (0.88–1.13), 1.01
(0.84–1.22) and 1.24 (0.97–1.58) respectively (Fig. 1).
For cancer death, these four estimates were 1.03 (95 %
CI 0.86–1.24), 0.95 (0.78–1.16), 1.00 (0.76–1.33) and
1.58 (1.09–2.30) respectively. Estimates were largely un-
altered after exclusion of the first 2 years’follow-up 1.12
(95 % CI 0.97–1.29), 1.11 (0.95–1.30), 1.15 (0.92–1.44),
1.32 (0.97–1.81) for cancer incidence; 1.12 (0.91–1.38),
1.03 (0.82–1.29), 1.06 (0.77–1.47) and 1.78 (1.14–2.77)
for cancer death (Additional file 2).
The association between baseline category of renal func-
tion and cancer incidence and cancer death was also
unaffected by adjustment for competing risks from non-
cancer death, although the relative increase in cancer
death seen for dialysis patients was attenuated (Additional
file 3). Compared to participants with eGFR ≥75 ml/min
per 1.73 m
2
, the adjusted HRs for cancer incidence in de-
scending order of renal function category were 1.00 (95 %
Wong et al. BMC Cancer (2016) 16:488 Page 3 of 11
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Table 1 Baseline characteristics of 32057 eligible participants, by CKD status
CKD status (CKD EPI-estimated GFR (mL/min/1.73 m
2
)) Dialysis
(n= 3023)
Greater than
75 (n= 9594)
60 to 75
(n= 6681)
45 to 60
(n= 4931)
Less than 45
(n= 7828)
Age at baseline (years) 63 (8) 67 (8) 70 (9) 65 (12) 60 (12)
Male 5983 (62 %) 3739 (56 %) 2266 (46 %) 4521 (58 %) 1918 (63 %)
Ethnicity
White 5570 (58 %) 4985 (75 %) 3801 (77 %) 5744 (73 %) 2163 (72 %)
Asian 3847 (40 %) 1555 (23 %) 1035 (21 %) 1701 (22 %) 564 (19 %)
Other/not specified 177 (2 %) 141 (2 %) 95 (2 %) 381 (5 %) 298 (10 %)
Higher education 110 (1 %) 605 (9 %) 886 (18 %) 1835 (23 %) 660 (22 %)
Ever smoked 4683 (49 %) 3179 (48 %) 2221 (45 %) 3841 (49 %) 1505 (50 %)
Body mass index (kg/m
2
) 27.2 (4.9) 27.3 (4.8) 27.2 (4.9) 27.5 (5.5) 26.5 (5.9)
Systolic blood pressure (mm Hg) 144 (25) 145 (21) 146 (21) 142 (22) 138 (24)
Diastolic blood pressure (mm Hg) 83 (20) 82 (11) 82 (11) 80 (12) 78 (13)
MDRD-estimated GFR (mL/min/1.73 m
2
) 94.4 (22.0) 68.7 (4.5) 55.5 (4.5) 25.7 (12.2) -
CKD EPI-estimated GFR (mL/min/1.73 m
2
) 89.1 (9.6) 67.4 (4.3) 53.4 (4.2) 24.3 (11.7) -
Total cholesterol (mg/dL) 203 (44) 210 (47) 215 (48) 196 (48) 179 (45)
Triglycerides (mg/dL) 170 (121) 169 (115) 176 (113) 202 (136) 205 (164)
Follow-up time (years) 5.0 (4.4–5.1) 5.0 (4.4–5.5) 5.0 (4.4–10.4) 4.5 (3.9–54) 4.4 (3.2–5.4)
Mean (SD), median (IQR) or n (%) shown
Table 2 Number of incident cancers (annual rate per 1000 patients) by CKD status and cancer site
CKD status (CKD EPI-estimated GFR (mL/min/1.73 m
2
)) Dialysis
(n= 3023)
All
(n= 32057)
Greater than
75 (n= 9594)
60 to 75
(n = 6681)
45 to 60
(n= 4931)
Less than 45
(n= 7828)
Total person years 48216 41013 34630 35011 11948 170819
All sites 596 (13.9) 621 (14.0) 580 (15.7) 619 (18.5) 210 (22.2) 2626 (15.4)
Oral cavity and pharynx 12 (0.3) 12 (0.3) 12 (0.3) 11 (0.3) 9 (0.6) 56 (0.3)
Digestive 172 (4.0) 177 (3.8) 156 (4.0) 147 (4.3) 54 (6.6) 706 (4.1)
Respiratory 88 (1.9) 86 (2.0) 59 (1.7) 63 (1.9) 26 (2.9) 322 (1.9)
Melanomas 16 (0.4) 24 (0.5) 43 (1.2) 40 (1.2) 7 (0.8) 130 (0.8)
Breast 60 (1.4) 69 (1.8) 74 (1.7) 60 (1.7) 14 (1.2) 277 (1.6)
Female genital 17 (0.4) 20 (0.4) 19 (0.7) 23 (0.7) 8 (0.9) 87 (0.5)
Prostate 79 (1.7) 80 (1.9) 72 (2.1) 85 (2.8) 16 (1.9) 332 (1.9)
Male genital 1 (0.0) 0 (0.0) 1 (0.0) 2 (0.1) 1 (0.1) 5 (0.0)
Soft tissue/connective tissue 3 (0.1) 3 (0.1) 5 (0.1) 12 (0.4) 0 (0.0) 23 (0.1)
Urinary tract 40 (1.0) 30 (0.7) 35 (1.3) 83 (2.5) 40 (4.1) 228 (1.3)
Central nervous system 11 (0.3) 15 (0.3) 9 (0.2) 8 (0.2) 2 (0.3) 45 (0.3)
Endocrine 5 (0.1) 2 (0.1) 5 (0.2) 5 (0.2) 12 (0.7) 29 (0.2)
Haematological 47 (1.0) 53 (1.1) 43 (1.0) 42 (1.2) 16 (1.5) 201 (1.2)
Multiple primary sites 5 (0.2) 14 (0.3) 14 (0.3) 9 (0.2) 0 (0.0) 42 (0.2)
Unknown origin 17 (0.4) 10 (0.2) 10 (0.2) 18 (0.6) 5 (0.7) 60 (0.4)
Bone and cartilage 2 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.0)
Others 8 (0.2) 10 (0.3) 7 (0.3) 0 (0.0) 0 (0.0) 25 (0.1)
Site data not available 13 16 16 11 0 56
Rates in CKD status group directly standardized for age sex, using 10-year age intervals
Wong et al. BMC Cancer (2016) 16:488 Page 4 of 11
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CI 0.89–1.12), 1.01 (0.89–1.15), 0.95 (0.79–1.15) and 1.03
(0.80–1.31), while for cancer death the estimates were
1.06 (0.89–1.27), 0.98 (0.80–1.20), 0.93 (0.70–1.24) and
1.25 (0.86–1.82) for participants on dialysis.
There was no significant association in either sex
between renal function and cancer incidence or cancer
mortality, nor did the overall associations differ by
gender (test for interaction between gender and renal
function p= 0.10 for incident cancer; p= 0.60 for cancer
death; Fig. 2).
Relevance of renal function to site-specific cancer risk
Associations between baseline category of renal function
and cancer risk were observed for specific cancer sites
(Fig. 3). With declining renal function, there was a non-
significant trend (p= 0.06, Fig. 3) towards an increased
risk of urinary tract cancer, with an increased risk of such
cancers among dialysis patients as compared with partici-
pants with eGFR ≥75 ml per min per 1.73 m
2
(adjusted
HR 2.34 [95 % CI: 1.10–4.97]). There was also a significant
trend towards an increased risk of other known/unknown
cancers (trend p= 0.01), which appeared to be chiefly
attributable to an increased risk of endocrine (mostly
thyroid) cancers, with an increased risk of endocrine
cancers among dialysis patients as compared to partici-
pants with eGFR ≥75 ml per min per 1.73 m
2
(adjusted
HR 11.65, 95 % CI 1.30–104.12; Additional file 4). With
declining renal function there was also a significant trend
towards reduced risk of prostate cancer (trend p=0.03,
Fig. 3). In addition, dialysis patients had a twofold higher
risk of death from cancers of the digestive tract (adjusted
HR: 2.11; 95 % CI: 1.13–3.99), however the excess in di-
gestive cancer incidence did not reach statistical signifi-
cance (HR 1.51, 95 % CI 0.94–2.42).
Discussion
We analysed individual patient data from six prospect-
ive studies of 32,057 participants with various levels of
renal function, followed for an average of 5 years. Al-
though in the pre-specified analyses there was no sig-
nificant association between renal impairment and the
overall risk of cancer or of cancer death, several notable
findings emerged when these findings were examined
in greater detail. First, as compared with people with
eGFR ≥75 ml/min/1.73 m
2
, patients on dialysis had a
non-significant excess risk of any cancer (HR 1.24, 95 %
CI 0.97–1.58) together with a statistically significant
increase in the risk of cancer death (HR 1.58, 95 % CI
Table 3 Number of cancer deaths (annual rate per 1000 patients) by CKD status and cancer site
CKD status (CKD EPI-estimated GFR (mL/min/1.73 m
2
)) Dialysis
(n= 3023)
All
(n= 32057)
Greater than
75 (n= 9594)
60 to 75
(n= 6681)
45 to 60
(n= 4931)
Less than 45
(n= 7828)
Total person years 49403 42615 36452 36538 12436 177443
All sites 240 (5.8) 272 (5.7) 247 (5.9) 246 (7.0) 90 (10.8) 1095 (6.2)
Oral cavity and pharynx 6 (0.2) 2 (0.0) 3 (0.1) 4 (0.1) 4 (0.2) 19 (0.1)
Digestive 84 (2.0) 94 (1.9) 78 (1.9) 81 (2.3) 36 (4.2) 373 (2.1)
Respiratory 71 (1.5) 67 (1.5) 44 (1.2) 47 (1.4) 20 (2.4) 249 (1.4)
Melanomas 3 (0.1) 3 (0.1) 8 (0.2) 6 (0.2) 5 (0.7) 25 (0.1)
Breast 5 (0.2) 10 (0.2) 6 (0.1) 11 (0.2) 0 (0.0) 32 (0.2)
Female genital 5 (0.2) 7 (0.1) 13 (0.3) 6 (0.2) 2 (0.3) 33 (0.2)
Prostate 9 (0.3) 13 (0.3) 22 (0.5) 11 (0.3) 1 (0.1) 56 (0.3)
Male genital 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Soft tissue/connective tissue 1 (0.0) 0 (0.0) 6 (0.1) 8 (0.3) 1 (0.1) 16 (0.1)
Urinary tract 10 (0.2) 7 (0.1) 7 (0.3) 18 (0.5) 5 (0.8) 47 (0.3)
Central nervous system 9 (0.2) 12 (0.2) 10 (0.2) 7 (0.2) 2 (0.3) 40 (0.2)
Endocrine 1 (0.0) 1 (0.0) 0 (0.0) 1 (0.0) 2 (0.3) 5 (0.0)
Haematological 14 (0.3) 29 (0.6) 26 (0.5) 20 (0.5) 7 (0.8) 96 (0.5)
Multiple primary sites 6 (0.2) 13 (0.3) 10 (0.2) 6 (0.1) 0 (0.0) 35 (0.2)
Unknown origin 11 (0.2) 12 (0.2) 11 (0.3) 16 (0.5) 5 (0.7) 55 (0.3)
Bone and cartilage 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Others 3 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 4 (0.0)
Site data not available 2 2 2 4 0 10
Rates in CKD status group directly standardized for age sex, using 10-year age intervals
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Cancer Incidence
0.75 1 1.5 2 3
Relative risk (95% CI)
20 40 60 80 100
Dialysis Not on dialysis
Renal function
(eGFR calculated using CKD−EPI formula (mL min 1.73m2))
1.00
596
0.98
621
0.99
580
1.01
619
1.24
210
Cancer Death
0.75 1 1.5 2 3
Relative risk (95% CI)
20 40 60 80 100
Dialysis Not on dialysis
Renal function
(eGFR calculated usin
g
CKD−EPI formula (mL min 1.73m2))
1.00
240
1.03
272
0.95
247
1.00
246
1.58
90
Fig. 1 Relevance of renal function to cancer incidence and cancer death after adjustment for age, sex, ethnicity and smoking status. Relative risks
are stated above 95 % CI and the number of events is given below 95 % CI
Wong et al. BMC Cancer (2016) 16:488 Page 6 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Male
0.75 1 1.5 2 3
Relative risk (95% CI)
20 40 60 80 100
Dialysis Not on dialysis
Renal function (eGFR calculated
using CKD−EPI formula (mL min 1.73m2))
1.00
376
0.90
337
1.03
288
1.07
378
1.37
137
Cancer Incidence (Interaction between sex and renal function*: χ2
2=4.55; p=0.10)
Female
0.75 1 1.5 2 3
Relative risk (95% CI)
20 40 60 80 100
Dialysis Not on dialysis
Renal function (eGFR calculated
using CKD−EPI formula (mL min 1.73m2))
1.00
220
1.06
284
0.99
292
1.06
241
1.21
73
Male
0.75 1 1.5 2 3
Relative risk (95% CI)
20 40 60 80 100
Dialysis Not on dialysis
Renal function (eGFR calculated
usin
g
CKD−EPI formula (mL min 1.73m2))
1.00
163
0.92
154
0.98
132
1.13
156
1.86
60
Cancer Death (Interaction between sex and renal function*: χ2
2=1.03; p=0.60)
Female
0.75 1 1.5 2 3
Relative risk (95% CI)
20 40 60 80 100
Dialysis Not on dialysis
Renal function (eGFR calculated
usin
g
CKD−EPI formula (mL min 1.73m2))
1.00
77
1.21
118
0.96
115
1.00
90
1.43
30
Fig. 2 (See legend on next page.)
Wong et al. BMC Cancer (2016) 16:488 Page 7 of 11
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(See figure on previous page.)
Fig. 2 Sex-specific relevance of renal function to cancer incidence and cancer death after adjustment for age, ethnicity and smoking status.
Relative risks are stated above 95 % CI and the number of events is given below 95 % CI. *Joint test of the significance of two interaction terms
(between sex and, respectively, a linear and quadratic term for ordered renal function group) done by comparing the difference in -2 log L
between the two nested models
0.1 110
Cancer type CKD status Hazard ratio (95% CI) P value
for trend
Digestive
[n=706 (27%)] 0.32
eGFR ≥75 1.00 (0.84 − 1.19)
eGFR ≥60 to <75 1.01 (0.87 − 1.18)
eGFR ≥45 to <60 0.96 (0.82 − 1.14)
eGFR <45 0.99 (0.75 − 1.31)
Dialysis 1.51 (0.99 − 2.28)
Respiratory
[n=322 (12%)] 0.64
eGFR ≥75 1.00 (0.78 − 1.28)
eGFR ≥60 to <75 1.08 (0.87 − 1.34)
eGFR ≥45 to <60 0.86 (0.66 − 1.13)
eGFR <45 0.69 (0.42 − 1.13)
Dialysis 1.05 (0.54 − 2.02)
Prostate
[n=332 (13%)] 0.03
eGFR ≥75 1.00 (0.77 − 1.31)
eGFR ≥60 to <75 0.78 (0.63 − 0.98)
eGFR ≥45 to <60 0.84 (0.66 − 1.07)
eGFR <45 0.72 (0.44 − 1.19)
Dialysis 0.38 (0.19 − 0.77)
Breast
[n=277 (11%)] 0.74
eGFR ≥75 1.00 (0.75 − 1.33)
eGFR ≥60 to <75 0.99 (0.78 − 1.26)
eGFR ≥45 to <60 1.07 (0.84 − 1.35)
eGFR <45 1.22 (0.80 − 1.86)
Dialysis 1.03 (0.50 − 2.12)
Urinary tract
[n=228 (9%)] 0.06
eGFR ≥75 1.00 (0.69 − 1.46)
eGFR ≥60 to <75 0.89 (0.61 − 1.31)
eGFR ≥45 to <60 1.35 (0.95 − 1.91)
eGFR <45 1.66 (1.02 − 2.70)
Dialysis 2.34 (1.31 − 4.18)
Haematological
[n=201 (8%)] 0.25
eGFR ≥75 1.00 (0.71 − 1.40)
eGFR ≥60 to <75 0.89 (0.67 − 1.17)
eGFR ≥45 to <60 0.71 (0.52 − 0.97)
eGFR <45 0.63 (0.35 − 1.12)
Dialysis 0.72 (0.33 − 1.58)
Other known/
unknown site
[n=560 (21%)]
0.01
eGFR ≥75 1.00 (0.81 − 1.24)
eGFR ≥60 to <75 1.01 (0.84 − 1.21)
eGFR ≥45 to <60 1.22 (1.02 − 1.45)
eGFR <45 1.41 (1.05 − 1.88)
Dialysis 2.11 (1.34 − 3.32)
Fig. 3 Relevance of renal function to site specific cancer incidence after adjustment for age, sex, ethnicity and smoking status
Wong et al. BMC Cancer (2016) 16:488 Page 8 of 11
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1.09–2.30). Second, closer inspection of data on cancer
risk in particular sites indicated that the lack of any overall
association masked clear associations for specific cancer
types: in particular, with declining renal function there
were trends towards increased risks of urinary tract and
endocrine (mostly thyroid) cancers but also lower risk of
prostate cancer. Taken together, our findings extend previ-
ous reports of associations between renal function and
cancer risk to people with a wider degree of renal dysfunc-
tion, and our findings for particular cancer sites are con-
sistent with these earlier reports [4, 5, 7, 8].
It is well known that the lifespan of people on dialysis is
reduced as a consequence of premature death from both
cardiovascular and non-cardiovascular causes [23–25].
Our study findings suggest that cancer is a contributing
factor to the increased risk of non-vascular death among
patients on dialysis. A 1.5-fold increase in the risk of can-
cer death is broadly consistent with previous observational
studies that have reported an excess risk of cancer in the
range of 1.2 and 1.4-fold among those on dialysis using
registry analyses [8, 10], but our findings make clear that
the magnitude of any relative excess of cancer in a given
dialysis population will be determined by the relative
frequency of different cancers which, depending on the
subtype, may be associated (positively or negatively) or
unassociated with declining renal function. The distribu-
tion of cancer types will in turn depend on the gender,
age, and ethnicity of the population, as well as other
factors.
Some previous studies have reported an association
between renal function and any cancer [4, 8] whilst
others did not [5, 9]. For dialysis patients, other studies
have reported an increased risk of cancer, especially of
the kidney and urinary tract [8, 9] but also of thyroid
cancer [8] and some digestive tract cancers [8, 9]. Previ-
ous studies have also shown that the risk of prostate
cancer is reduced among dialysis patients [9]. In contrast
to previous studies [9] we did not observe an increased
risk of oral cavity, respiratory or haematological cancers
among those with reduced kidney function. Moreover,
whilst a previous study suggested that women on dialysis
were at increased risk of cervical cancer [8, 9], we did
not observe a significantly higher risk of female genital
cancers for dialysis patients. This apparent heterogeneity
of the available literature is consistent with the observa-
tion that associations between declining renal function
and cancer risk are dependent on cancer subtype, which
may vary between different study populations, and it im-
plies that studies (or meta-analyses of studies) involving
much larger numbers of cancers with detailed subtyping
information are needed to gain a better understanding
of these associations.
The present study adds to the current evidence that
the excess cancer observed in people on dialysis may not
be driven solely by viral carcinogenesis as previously sug-
gested [8], but could also be influenced by the uraemic
milieu associated with severe renal dysfunction. Uraemia
is often characterized as a state of immune dysfunction.
The different types of uraemic toxins may exert antagonis-
tic interactions of pro-inflammatory and immunosuppres-
sive responses, leading to increased risks of infections and
malignancy [26]. In addition, people on dialysis retain
solutes, which may impair the anti-tumour activity of
certain immune cell types such as natural killer and den-
dritic cells, promote angiogenesis and enhance accelerated
growth of aggressive tumours [26]. Future studies that
explore the relationship between impaired renal function
and risk for particular cancer subtypes (rather than for
cancer of all types) may be able to provide a better under-
standing of these processes.
Our study has several strengths. The present meta-
analysis represents one of the largest cohorts of individ-
uals with diverse patient characteristics to have exam-
ined the effects of reduced kidney function and risk of
cancer and cancer death. The availability of individual
data allowed for an assessment of the potential influence
on estimates of competing risks and reverse causality
bias. There are also some potential limitations. First, we
may not have had sufficient follow-up time to reliably
detect a small but significant effect among those with
moderate stage CKD, particularly for cancers such as
colorectal, breast and prostate cancer which have a long
latency period relative to the period of observation in
the included studies. Second, our study was not powered
to detect a statistically significant interaction between
gender and the effects of reduced kidney function on
cancer incidence and death, or to reliably investigate the
relevance of renal function to site specific cancer risk.
Third, none of the included studies considered cancer as
their primary outcome, so cancer reports may not have
been confirmed, for example, by pathology reports. The
reliability of the cancer outcomes may also have varied
between the individual studies. In general, cancer inci-
dence and mortality data were recorded by the treating
physicians who confirmed the cancer diagnoses and/or
deaths. It is likely that systematic coding errors may have
occurred for the different studies and resulted in over or
under-estimation of the causes and/or the potential
missing causes of death. Fourth, only one study
(SHARP) contributed data evaluating the link between
dialysis and cancer, whereas all studies contributed data
for earlier stage CKD. Finally, while adjustments were
made for potential confounders, residual confounding
from unmeasured factors may exist.
Conclusion
In summary, this study indicates that reduced renal
function is associated with an increased risk of urinary
Wong et al. BMC Cancer (2016) 16:488 Page 9 of 11
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

tract, digestive tract and thyroid cancers, but also with a
reduced risk of prostate cancer in men. The risk is most
marked among dialysis patients, but our study did not
have sufficient power to exclude an increase in risk of
particular cancers among patients with less severe renal
impairment. Much larger studies are needed to facilitate
an understanding of the association between renal func-
tion and the risk of specific cancers, and to identify pos-
sible mechanisms through which renal impairment may
modulate cancer risk.
Additional files
Additional file 1: Baseline characteristics of 32057 eligible participants,
by study. (PDF 160 kb)
Additional file 2: Relevance of renal function to cancer incidence and
cancer death, after adjustment for age, sex, ethnicity and smoking status,
excluding events in the first 2-years of follow-up. (PDF 9 kb)
Additional file 3: Relevance of renal function to cancer incidence and
cancer death, after adjustment for age, sex, ethnicity and smoking status,
using Fine and Gray regression. (PDF 9 kb)
Additional file 4: Relevance of renal function to site specific cancer
incidence after adjustment for age, sex, ethnicity and smoking status.
(PDF 157 kb)
Abbreviations
ADVANCE, action in diabetes and vascular disease: preterax and diamicron
mr controlled evaluation study; BMES, blue mountains eye study; CAIFOS,
calcium intake fracture outcome study; CI, confidence interval; CKD, chronic
kidney disease; CKD-EPI, chronic kidney disease epidemiology collaboration;
eGFR, estimated glomerular filtration rate; ESKD, end stage kidney disease;
HR, hazard ratio; PROGRESS, perindopril-based blood-pressure-lowering regimen
study; RCTs, randomised controlled trials; SHARP, study of heart and renal
protection
Acknowledgements
The authors thank the study participants in each of the individual studies for
their involvement.
Funding
SHARP was funded by Merck & Co., Inc., (Whitehouse Station, NJ, USA), with
additional support from the Australian National Health Medical Research
Council, the British Heart Foundation, and the UK Medical Research Council.
The study was funded by the National Health and Medical Research Council
of Australia.
Availability of data and materials
Data Access and Sharing requests for the SHARP trial data should be made by
email through the Richard Doll Centenary Archive Data Access Coordinator (see
https://www.ceu.ox.ac.uk/policies2). Applications for use of other study data
should be made in writing to the study principal investigators.
Authors’contributions
GW conceived of and designed the study, performed the statistical
analyses and wrote the manuscript. NS designed the study, performed
the statistical analyses and wrote the manuscript. JE designed the study,
supervised the statistical analyses and contributed to the writing of the
manuscript. CB supervised the statistical analyses and contributed to the
writing of the manuscript. JCC conceived of and designed the study and
contributed to the writing of the manuscript. JRC designed the study and
contributed to the writing of the manuscript. RT, JC, SZ, CP, BC, DH, JJW,
PM, RP, WL and JL all contributed to the conception of the study,
participated in the design, contributed the data, interpretation of the
data, advised on the presentation of results, and revised the manuscript.
All authors read and approved the manuscript.
Competing interests
The Clinical Trial Service Unit and Epidemiological Studies Unit, which is part
of the University of Oxford, has a staff policy of not accepting honoraria or
consultancy fees.
None declared for all authors.
Consent for publication
Written, informed consent for publication was provided by all participants in
each of the studies included in this individual patient meta-analysis.
Ethics approval and consent to participate
This study involved the use of existing collections of data or records that
contain only non-identifiable data. As such, ethics approval was not required
according to the National Health and Medical Research Council ethical
guidelines on low and negligible risk [18]. Written, informed consent
was provided by all participants in each of the studies included in this
individual patient meta-analysis.
Author details
1
Sydney School of Public Health, University of Sydney, Sydney, Australia.
2
Centre for Transplant and Renal Research, Westmead Hospital, Westmead,
Australia.
3
Clinical Trial Service Unit and Epidemiological Studies Unit,
Nuffield Department of Population Health, Oxford, UK.
4
Medical Research
Council Population Health Research Unit, Nuffield Department of Population
Health, Oxford, UK.
5
School of Public Health and Community Medicine,
University of New South Wales, Sydney, Australia.
6
The George Institute for
Global Health, Sydney, Australia.
7
Faculty of Medicine, Nursing & Health
Sciences, Monash University, Clayton, VIC, Australia.
8
Northern Clinical School,
Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
9
Centre for Vision Research, Westmead Millennium Institute of Medical
Research, University of Sydney, Sydney, Australia.
10
School of Medicine and
Pharmacology, The University of Western Australia, Crawley, WA, Australia.
Received: 30 October 2015 Accepted: 6 July 2016
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