274 Chin Med J 2013;126 (2)

Original article
Impact of chronic kidney disease on serum tumor markers
concentrations
TONG Hong-li, DONG Zhen-nan, WEN Xin-yu, GAO Jing, WANG Bo and TIAN Ya-ping

Keywords: retrospective study; kidney insufficiency; tumor marker

Background Serum tumor markers have always been of clinical importance in the diagnosis, monitoring disease
progression and therapy efficacy for patients with malignant diseases. However, elevated serum tumor markers are found
in some benign conditions, especially in chronic kidney disease (CKD). The elevation of them in CKD might cause
confusion and misuse of these tumor markers. We conducted this retrospective study to investigate which of the five
widely used tumor markers including carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), cytokeratin 19 fragment
antigen 21-1 (Cyfra21-1), squamous cell carcinoma antigen (SCC) and neuron specific enolase (NSE) are affected
markedly by CKD, in order to use them more effectively.
Methods Serum tumor marker concentrations, biochemical, hematological parameters, and urinalysis were measured
in CKD patients and healthy controls. The positive rate and median tumor markers’ level in CKD patients and controls,
and those in CKD patients stratified by CKD grade were compared using nonparametric rank tests. Correlation analysis
of serum tumor markers and other parameters in CKD patients were performed using the Spearman correlation
coefficient. Multivariate Logistic regression analysis was used to estimate the important variables that caused elevated
serum concentrations of these markers in CKD patients.
Results The overall positive rates and serum concentrations of Cyfra21-1, SCC, CEA in CKD group were significantly
higher than those in control group. Positive rate and serum concentrations of those tumor markers increased as kidney
function decreased. Both univariate analysis and multivariate regression analysis showed that the elevations of those
tumor markers were not only associated with kidney function, but also with nutritional status.
Conclusions Serum concentrations of Cyfra21-1, SCC, CEA are significantly influenced by kidney function, as well as
nutritional status. Therefore, in clinical work, the indices of kidney function and nutritional status could be simultaneously
measured to improve interpretation of the results of those tumor marker concentrations.
Chin Med J 2013;126 (2): 274-279

T umor markers are biochemical indicators for the

presence of tumor. They are used as important tools
for early diagnosis, monitoring disease progression and
therapeutic efficacy for patients with cancer in selected
sites.1-4 In clinical practice, elevated serum tumor marker
levels are also found in some benign conditions,
especially in chronic kidney disease (CKD). The
elevation of serum tumor markers in CKD might cause
confusion and misuse of these tumor markers. This
problem has been marked in the past several decades,
because the incidence of CKD has sharply increased
worldwide.5-10 Furthermore, most patients with cancer are
elderly and have various degrees of kidney insufficiency,
and their kidney function sometimes becomes worse
during therapy.11 Therefore, it is important to determine
the relations between the concentration of tumor markers
and the extent of kidney insufficiency to make the tumor
markers be used more effectively. At present, there are a
number of published reports that suggest kidney function
influences the blood concentrations of tumor markers.12-16
However, the effect of CKD on serum tumor marker
levels is not well understood. We conducted this
retrospective observational study to explore whether and
to what extent kidney insufficiency influences the serum
concentrations of five widely used tumor markers
(carcinoembryonic antigen (CEA), alpha-fetoprotein
(AFP), cytokeratin 19 fragment antigen 21-1 (Cyfra21-1),
squamous cell carcinoma antigen (SCC) and neuron
specific enolase (NSE)), in order to make better use of
these tumor markers in clinical practice.
METHODS
Study population
The study population consisted of 539 non-dialysis CKD
patients with varying degrees of kidney insufficiency, and
223 healthy individuals served as controls. They are all
Chinese. CKD patients were inpatients of the Department
of Nephrology, Chinese People’s Liberation Army
DOI: 10.3760/cma.j.issn.0366-6999.20121589
Department of Clinical Biochemistry, Chinese People’s Liberation
Army General Hospital, Beijing 100853, China (Tong HL, Dong
ZN, Wen XY, Gao J, Wang B and Tian YP)
Correspondence to: Dr. TIAN Ya-ping, Department of Clinical
Biochemistry, Chinese People’s Liberation Army General Hospital,
Beijing 100853, China (Tel: 86-10-66939374. Fax:
86-10-88217385. Email: tianyp61@gmail.com)
This study was supported by a grant from the National Science and
Technology Infrastructure Program of China (No.
2009BAI86B05).
Conflict of interests: None.
Chinese Medical Journal 2013;126 (2) 275

General Hospital, from January 2008 to January 2009. USA). Data were given as the mean ± standard deviation
CKD was diagnosed and classified according to Kidney (SD) in case of normal distributions and as median with
Disease: Improving Global Outcomes (KDIGO) clinical 25th and 75th percentiles in case of non-normal
practice guidelines.17 CKD was defined as either kidney distributions. The data with normal distributions were
damage or estimated glomerular filtration rate (eGFR) compared using Student’s t test. The tumor marker levels
<60 ml/min per 1.73 m2 for 3 or more months. eGFR was of the study population stratified by CKD grade were
calculated from pre-dialyzed serum creatinine using the compared by using nonparametric rank tests. Pearson’s
modified glomerular filtration rate estimating equation for chi-square test was used to compare the positive rate of
Chinese:18 eGFR=175 × (serum creatinine)−1.234× serum tumor markers between subgroups in the study
(age)−0.179× 0.79 (if the individual is female). CKD was populations. Multivariate Logistic regression analysis
classified according to eGFR in ml/min per 1.73 m2 of using a stepwise backward method was used to estimate
stage I ≥90, stage II 60–89, stage III 30–59, stage IV the important variables that caused elevated serum
15–29, and stage V <15. Kidney damage was defined as concentrations of these markers in CKD patients. The
an albumin-to-creatinine ratio >30 mg/g in two of three Spearman rank correlation coefficient was used for
spot urine specimens. The patients who met the diagnosis correlations between serum tumor markers and
criteria for CKD, and did not accept dialysis therapy are biochemical and hematological parameters. A value of P
eligible for inclusion. After systematic health examination, <0.05 was considered statistically significant.
patients with acute kidney function deterioration,
malignancy, pleural effusion or ascites, heart failure, RESULTS
hepatocirrhosis or liver failure were excluded. Healthy
controls were healthy individuals without known major Clinical characteristics of CKD patients and controls
disease who visited Chinese People’s Liberation Army The clinical characteristics of CKD patients and controls
General Hospital for a routine physical examination. are presented in Table 1. There were no significant
differences in age and gender distribution between CKD
Measurement of serum tumor markers, biochemical, patients and controls (P >0.05). Compared to healthy
hematological parameters and urinalysis
controls, CKD patients had higher serum urea, creatinine
In the morning, fasting venous blood and urine samples
levels, lower serum protein, albumin levels, lower
of patients and control were collected and labelled by
hemoglobin concentration and decreased eGFR (P
nurses and sent to clinical laboratories for measurement
<0.001).
in time. For each patient and control, 3 ml whole blood
with the coagulant EDTAK2 was used for hematological
Overall positive rate and median tumor markers’
parameters, 5 ml blood without coagulant was used for
levels in CKD patients and controls
detection of tumor markers and biochemical parameters,
and 3 ml urine was used for urinalysis. In control group, the serum levels of those five tumor
Chemiluminescence immunoassays were used to measure markers were all within their reference ranges. The
serum tumor markers (CEA, AFP, Cyfra21-1, NSE) using positive rates of those five tumor markers in the control
a Roche E170 automatic immune analyzer (Roche group were all 0. The overall positive rates of Cyfra21-1
Diagnostics, Shanghai, China). A microparticle enzyme (30.80%), SCC (26.72%), CEA (9.65%) in CKD group
immunoassay was used to measure serum SCC levels were significantly higher than those in control group (P
using an Abbott IMX immunoassay analyzer (Abbott <0.01). There were no statistically significant differences
Diagnostics Inc., Chicago, USA). Serum biochemical in the positive rates of AFP, NSE between two groups
parameters such as alanine aminotransferase (ALT), (P >0.05, Table 2). The median serum Cyfra21-1, SCC,
aspartate aminotransferase (AST), protein, albumin, urea, CEA,
creatinine were measured using a Hitachi 7600 automatic
Table 1. Clinical characteristics of CKD patients and controls
biochemistry analyzer (Hitachi Ltd., Tokyo, Japan).
CKD patients P
Hematological parameters were measured using a Characteristics
(n=539)
Controls (n=223)
values
Sysmex SE2100 Hematology Analyzer (Sysmex, Kobe, Gender (n)
Japan). Urinalysis was performed using the Max AX4280 Male 323 135 >0.05
(ARKRAY, Kyoto, Japan). All tests were performed Female 216 88
according to the manufacturers’ instructions of the Age (years) 51.12±14.64 51.01±9.78 >0.05
Serum creatinine (mg/dl) 2.47±2.67 0.76±0.14 <0.001
reagents and equipments within twenty-four hours. The
Serum urea (mmol/L) 11.33±8.44 5.53±1.02 <0.001
maximum value of reference range for serum tumor eGFR (ml/min per 1.73 m2) 68.94±55.41 115.67±21.68 <0.001
markers were defined as the cut-off values. The cut-off Hemoglobin (g/L) 120.28±28.05 151.73±12.04 <0.001
values for each tumor markers were 5 μg/L for CEA, 20 Serum protein (g/L) 59.46±11.85 74.62±4.08 <0.001
μg/L for AFP, 4 μg/L for Cyfra21-1, 24 μg/L for NSE and Serum albumin (g/L) 33.44±8.18 45.04±2.56 <0.001
1.5 μg/L for SCC. Measured values greater than or equal CKD stage
1 177 (32.84)
to the cut-off value were defined as positive. 2 84 (15.58)
3 110 (20.41)
Statistical analyses 4 53 (9.83)
Data were analyzed using SPSS17.0 software (SPSS Inc., 5 115 (21.34)
276 Chin Med J 2013;126 (2)

Data expressed as mean ± standard deviation, or number (percentage). Table 2. Positive rate of serum tumor markers in CKD patients and
NSE levels were higher in CKD group than those in controls (n (%))
control group (P <0.05). The median serum AFP level in Tumor markers Controls (n=223) CKD patients (n=539) P values
Cyfra21-1 0 (0) 166 (30.80) <0.001
the CKD group was lower than that in control group (P
SCC 0 (0) 144 (26.72) <0.001
<0.01, Table 3). CEA 0 (0) 52 (9.65) <0.001
AFP 0 (0) 4 (0.74) 0.46
Positive rate and median tumor marker levels at NSE 0 (0) 0 (0) 1.00
different stages of CKD
The positive rates of serum Cyfra21-1, SCC increased Table 3. Serum tumor marker levels in CKD patients and controls
(μg/L, median (25th, 75th percentile))
progressively along with the worsening CKD. CEA
Tumor markers Controls (n=223) CKD patients (n=539) P values
showed a tendency similar to that of SCC, but the Cyfra21-1 1.59 (1.20, 2.10) 2.94 (2.07, 4.32) <0.001
tendency was weaker (Figure 1). The concentrations of SCC 0.30 (0.10, 0.50) 0.80 (0.50, 1.60) <0.001
Cyfra21-1, SCC, CEA increased with the worsening CKD CEA 1.46 (1.02, 2.21) 2.05 (1.35, 3.24) <0.001
(P <0.001). Serum AFP and NSE levels did not differ AFP 2.49 (1.85, 3.69) 2.26 (1.47, 3.21) <0.001
significantly among different stage of CKD (P >0.05, NSE 8.80 (7.70, 10.00) 9.23 (7.42, 11.77) 0.014

Table 4).

Correlation of serum tumor markers and biochemical

and hematological parameters and urinalysis in CKD
patients
The Spearman rank correlation analysis showed that
serum Cyfra21-1, SCC positively correlated with age,
CKD grade, serum urea, creatinine, whole blood
leukocyte, urine erythrocyte, urine leukocyte, urine
protein and urine SEC, negatively correlated with eGFR,
serum protein, serum albumin, and hemoglobin (P <0.01).
Serum CEA positively correlated with age, CKD grade,
urea, creatinine, urine leukocyte, urine protein, urine SEC
and whole blood leukocyte, negatively correlated with
serum protein, albumin, hemoglobin, platelet, and eGFR
(P <0.01). Figure 1. Positive rate of serum Cyfra21-1, SCC and CEA
stratified by CKD grade.
Multivariate Logistic regression analysis using Cyfra21-1
test status (positive or negative) as a dependent variable, 1.127–5.399, P=0.024), age (OR=1.048, 95%
showed that CKD grade (OR=1.876, 95% CI= CI=1.048–1.075, P <0.001), serum urea (OR=1.108, 95%
1.306–2.696, P=0.001), urine protein (OR=1.328, 95% CI=1.047–1.172, P <0.001), serum creatinine (OR=1.014,
CI=1.076–1.639, P=0.008) were significant risk factors 95% CI=1.004–1.025, P=0.006) were significant
of elevated serum Cyfra21-1 level, serum protein predictors of elevated serum CEA level, while eGFR
(OR=0.944, 95% CI=0.906–0.983, P <0.001) was (OR=0.997, 95% CI=0.994–1.000, P=0.034), hemoglobin
protective factor. Using SCC test status as a dependent (OR=0.981, 95% CI=0.965–0.998, P=0.025) were
variable, Logistic regression analysis showed that CKD protective factors.
grade (OR=3.543, 95% CI=2.248–5.583, P <0.001), male
(OR=2.111, 95% CI=1.163–3.831, P=0.014) and urine DISCUSSION
protein (OR=1.269, 95% CI=1.014–1.587, P=0.028) were
risk factors of elevated serum SCC level, whereas serum Serum tumor marker levels can be influenced by a variety
albumin (OR=0.955, 95% CI=0.912–0.965, P=0.023) was of factors, the important one of which is kidney
protective factor. Using CEA test status as a dependent function.19 There have been a number of published
variable, results showed that CKD grade (OR=1.640, 95% reports that suggest kidney function may influence the
CI=1.013–2.656, P=0.044), male (OR=2.466, 95% CI= serum concentrations of tumor markers.12-16 The results
Table 4. Serum tumor marker levels stratified by CKD grade (μg/L, median (25th, 75th percentile))
Tumor markers CKD1 (n=177) CKD2 (n=84) CKD3 (n=110) CKD4 (n=53) CKD5 (n=114) P values
CEA 1.67 1.85 1.96 2.30 2.88 <0.001
(1.16, 2.71) (1.21, 2.91) (1.28, 2.90) (1.65, 3.81) (1.92, 4.22)
AFP 2.43 2.29 2.24 2.19 1.98 0.089
(1.67, 3.41) (1.57, 3.24) (1.53, 3.00) (1.53, 3.00) (1.17, 2.96)
Cyfra21-1 2.25 2.77 2.72 3.54 4.13 <0.001
(1.58, 3.40) (2.07, 4.10) (2.13, 4.24) (2.67, 4.55) (2.90, 5.01)
NSE 9.24 9.24 8.63 9.34 9.83 0.148
(7.38, 11.19) (7.54, 11.78) (7.40, 11.77) (6.03, 11.92) (8.03, 12.61)
SCC 0.50 0.70 0.90 1.30 1.90 <0.001
(0.20, 0.80) (0.40, 1.00) (0.50, 1.40) (0.70, 2.00) (1.18, 2.80)
Chinese Medical Journal 2013;126 (2)
are not entirely consistent. We used eGFR calculated
from serum creatinine using the modified glomerular
filtration rate estimating equation for Chinese as predictor
of kidney function, which is better than serum creatinine
alone or creatinine clearance rate. The CKD patients with
kidney insufficiency of varying degrees were classified
according to eGFR, with range from 3.07 to 309.87
ml/min per 1.73 m2. First, we compared the overall
positive rate and median tumor markers’ level in patients
with CKD and healthy control. Then, we compared the
positive rate and median tumor markers’ level in CKD
patients stratified by CKD grade. The results showed that
the serum concentrations of SCC, Cyfra21-1 and CEA
were affected markedly by kidney function. The positive
rates and concentrations of serum Cyfra21-1, SCC, CEA
increased progressively as the worsening CKD, but the
tendency was weaker for serum CEA. It is consistent to
the work by Nomura et al16 which showed the mean
concentration of CEA, SCC, Cyfra21-1 but NSE
significantly increased with the severity of renal failure.
In order to explore the possible mechanisms by which
kidney function or other factors affected serum tumor
markers concentration, we used Spearman rank
correlation analysis and multivariate Logistic regression
analysis to explore the relationship between serum
concentrations of these markers and kidney function, and
other biological parameters. The results showed that
serum concentrations of Cyfra21-1, SCC, CEA were not
only positively correlated with the indices of kidney
function and kidney damage, but also inversely correlated
with the indices of nutritional status. Multivariate
Logistic regression analysis using Cyfra21-1, SCC, CEA
test status (positive or negative) as a dependent variable
showed similar results.
What is the possible underlying mechanism to explain the
observed link between serum tumor marker levels and
indices of kidney function and other biological indices?
CKD is set in 5 stages of increasing severity with a
decrease in glomerular filtration rate. Direct injury, high
metabolic demands, or stimuli from renal dysfunction
activate tubular cells. They produce cytokines, support
inflammatory responses, causing further pathologic
changes in the renal parenchyma.20,21 SCC is a sub
fraction of glycoprotein TA-4 isolated from squamous
cell carcinoma of the uterine cervix.22 It is widespread in
the epithelium, especially in squamous epithelial cells.
The serum SCC level in healthy people is less than 1.5
μg/L. Cyfra21-1, a soluble fragments of cytokeratin 19
identified by BM 12.21 and KS19.1 antibodies, is a new
tumor marker of non-small cell lung cancer developed in
recent years.23 It is also used as an independent predictor
for definitive chemoradiotherapy sensitivity in
esophageal squamous cell carcinoma.24 CK19 is a
characteristic protein component of intermediate
filaments of epithelial cell, and it exists in a variety of
malignant tissues as well as normal epithelia. In healthy
persons, the serum level of Cyfra21-1 is very low without
277
any influence of sex, age and smoking habits. 25 After cell
death, proteolytic enzymes can degrade and solubilize
cytokeratin. Cyfra21-1, the soluble fragment of CK19,
can be released into the blood. Experiment in vitro
showed that Cyfra21-1 can be abundantly released into
the extracellular space during the intermediate stage of
epithelial cell apoptosis.26 Kashiwabara et al27 reported
that in patients with diabetic nephropathy, increased
serum Cyfra21-1 levels attribute to metabolic abnormality
in the kidney itself rather than the decreased urinary
excretion per se. So we speculate that inflammatory
response, dedifferentiation or dying of kidney epithelium
cells may play important role in elevation of serum
Cyfra21-1, SCC levels in CKD patients. Additionally,
both SCC22 and Cyfra21-125 are metabolized in the
kidney. Declined kidney function could reduce the
clearance of SCC and Cyfra21-1 by kidney. Therefore,
this could be another mechanism of how CKD affects
serum SCC and Cyfra21-1 levels. Our data, the stable
increased positive rate and serum SCC, Cyfra21-1 level
with increasing CKD grade, the strong association
between serum SCC, Cyfra21-1 levels and the indices of
renal function and kidney damage, support this
hypothesis.
On the other hand, patients with CKD frequently have a
compromised nutritional status. In our study, the serum
protein level ((59.46±11.85) vs. (74.62±4.08) g/L for the
CKD and control groups, P <0.001), the serum albumin
level ((33.44±8.18) vs. (45.04±2.56) g/L for the CKD and
control groups, P <0.001) and hemoglobin concentration
((120.28±28.05) vs. (151.73±12.04) g/L for the CKD and
control groups, P <0.001) were significantly lower than
control. Studies have confirmed that albuminuria and
eGFR associate with anemia, hypoalbuminemia, and
other complications of CKD.28 And anemia is an
independent risk factor for end-stage renal disease
(ESRD).29,30 Albumin is not only an indice of nutritional
status, but also an important transport protein for
non-water-soluble protein-bound drugs and uraemic
toxins. Its transport capacity is reduced in patients with
CKD and unbound fractions of uraemic toxins are related
to complications of CKD.31 Therefore, hemoglobin and
albumin are important renal protective factors. In our
study, univariate analysis showed positive associations
between serum SCC, Cyfra21-1 levels and urine protein,
negative associations between serum protein, albumin
and hemoglobin, the associations remaining valid after
multivariate regression analysis. These findings indicate
that the elevation of serum SCC, Cyfra21-1 levels could
also relate to anemia, hypoalbuminemia, albuminuria or
proteinuria, in addition to renal function.
CEA, an oncofetal glycoprotein is widely used as a tumor
marker due to its high expression in adenocarcinomas,
particularly in colorectal cancer.32 However, CEA levels
can be affected by many factors, including chronic
inflammatory disease, renal and hepatic insufficiency,
aging, and smoking.33,34 In our study, the prevalence of
278
elevated CEA was 9.65%, significantly lower than that of
Cyfra21-1 (30.80%), SCC (26.72%). The maximum value
was 14.12 μg/L, no more than two times above the upper
reference limit. Elevated CEA levels in CKD patients
were associated with not only renal function and
nutritional status, but also age and male gender, and the
associations were weaker. Because of without considering
the primary disease and smoking status and other
potential confounders, further studies are needed to
validate those associations.
In summary, serum Cyfra21-1, SCC, CEA levels were
markedly influenced by kidney function. Elevated serum
Cyfra21-1, SCC, CEA levels in CKD patients were not
only associated with kidney function, but also nutritional
status. Therefore, in clinical work, the indices of kidney
function and nutritional status could be simultaneously
measured to improve interpretation of the results of those
tumor marker concentrations and to prevent diagnostic
errors derived from false positive results.
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(Received June 13, 2012)
Edited by WANG Mou-yue and LIU Huan