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Chin Med J 2013;126 (2)274

Original article

Impact of chronic kidney disease on serum tumor markers

concentrationsTONG 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

umor markers are biochemical indicators for thepresence of tumor. They are used as important tools

for early diagnosis, monitoring disease progression andtherapeutic efficacy for patients with cancer in selectedsites.1-4 In clinical practice, elevated serum tumor markerlevels are also found in some benign conditions,especially in chronic kidney disease (CKD). Theelevation of serum tumor markers in CKD might causeconfusion and misuse of these tumor markers. This

problem has been marked in the past several decades,because the incidence of CKD has sharply increasedworldwide.5-10 Furthermore, most patients with cancer areelderly and have various degrees of kidney insufficiency,and their kidney function sometimes becomes worseduring therapy.11 Therefore, it is important to determinethe relations between the concentration of tumor markersand the extent of kidney insufficiency to make the tumormarkers be used more effectively. At present, there are anumber of published reports that suggest kidney functioninfluences the blood concentrations of tumor markers.12-16However, the effect of CKD on serum tumor marker

levels is not well understood. We conducted thisretrospective observational study to explore whether andto what extent kidney insufficiency influences the serumconcentrations 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 neuronspecific enolase (NSE)), in order to make better use ofthese tumor markers in clinical practice.

METHODS

Study population

The study population consisted of 539 non-dialysis CKDpatients with varying degrees of kidney insufficiency, and223 healthy individuals served as controls. They are allChinese. CKD patients were inpatients of the Departmentof Nephrology, Chinese Peoples Liberation Army

T

DOI: 10.3760/cma.j.issn.0366-6999.20121589Department of Clinical Biochemistry, Chinese Peoples LiberationArmy General Hospital, Beijing 100853, China (Tong HL, DongZN, Wen XY, Gao J, Wang B and Tian YP)Correspondence to: Dr. TIAN Ya-ping, Department of ClinicalBiochemistry, Chinese Peoples Liberation Army General Hospital,Beijing 100853, China (Tel: 86-10-66939374. Fax:86-10-88217385. Email: [email protected])

This study was supported by a grant from the National Science andTechnology Infrastructure Program of China (No.2009BAI86B05).Conflict of interests: None.


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Chinese Medical J ournal 2013;126 (2) 275

General Hospital, from January 2008 to January 2009.CKD was diagnosed and classified according to KidneyDisease: Improving Global Outcomes (KDIGO) clinicalpractice guidelines.17 CKD was defined as either kidneydamage or estimated glomerular filtration rate (eGFR)0.05Serum creatinine (mg/dl) 2.472.67 0.760.14


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Chin Med J 2013;126 (2)276

Data expressed as mean standard deviation, or number (percentage).

NSE levels were higher in CKD group than those incontrol group (P


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are not entirely consistent. We used eGFR calculatedfrom serum creatinine using the modified glomerularfiltration rate estimating equation for Chinese as predictorof kidney function, which is better than serum creatininealone or creatinine clearance rate. The CKD patients withkidney insufficiency of varying degrees were classified

according to eGFR, with range from 3.07 to 309.87ml/min per 1.73 m2. First, we compared the overallpositive rate and median tumor markers level in patientswith CKD and healthy control. Then, we compared thepositive rate and median tumor markers level in CKDpatients stratified by CKD grade. The results showed thatthe serum concentrations of SCC, Cyfra21-1 and CEAwere affected markedly by kidney function. The positiverates and concentrations of serum Cyfra21-1, SCC, CEAincreased progressively as the worsening CKD, but thetendency was weaker for serum CEA. It is consistent tothe work by Nomura et al16 which showed the mean

concentration of CEA, SCC, Cyfra21-1 but NSEsignificantly increased with the severity of renal failure.

In order to explore the possible mechanisms by whichkidney function or other factors affected serum tumormarkers concentration, we used Spearman rankcorrelation analysis and multivariate Logistic regressionanalysis to explore the relationship between serumconcentrations of these markers and kidney function, andother biological parameters. The results showed thatserum concentrations of Cyfra21-1, SCC, CEA were notonly positively correlated with the indices of kidneyfunction and kidney damage, but also inversely correlated

with the indices of nutritional status. MultivariateLogistic regression analysis using Cyfra21-1, SCC, CEAtest status (positive or negative) as a dependent variableshowed similar results.

What is the possible underlying mechanism to explain theobserved link between serum tumor marker levels andindices of kidney function and other biological indices?CKD is set in 5 stages of increasing severity with adecrease in glomerular filtration rate. Direct injury, highmetabolic demands, or stimuli from renal dysfunctionactivate tubular cells. They produce cytokines, support

inflammatory responses, causing further pathologicchanges in the renal parenchyma.20,21 SCC is a subfraction of glycoprotein TA-4 isolated from squamouscell carcinoma of the uterine cervix.22 It is widespread inthe epithelium, especially in squamous epithelial cells.The serum SCC level in healthy people is less than 1.5g/L. Cyfra21-1, a soluble fragments of cytokeratin 19identified by BM 12.21 and KS19.1 antibodies, is a newtumor marker of non-small cell lung cancer developed inrecent years.23 It is also used as an independent predictorfor definitive chemoradiotherapy sensitivity inesophageal squamous cell carcinoma.24 CK19 is acharacteristic protein component of intermediatefilaments of epithelial cell, and it exists in a variety ofmalignant tissues as well as normal epithelia. In healthypersons, the serum level of Cyfra21-1 is very low without

any influence of sex, age and smoking habits. 25 After celldeath, proteolytic enzymes can degrade and solubilizecytokeratin. Cyfra21-1, the soluble fragment of CK19,can be released into the blood. Experiment in vitroshowed that Cyfra21-1 can be abundantly released intothe extracellular space during the intermediate stage of

epithelial cell apoptosis.26 Kashiwabara et al27 reportedthat in patients with diabetic nephropathy, increasedserum Cyfra21-1 levels attribute to metabolic abnormalityin the kidney itself rather than the decreased urinaryexcretion per se. So we speculate that inflammatoryresponse, dedifferentiation or dying of kidney epitheliumcells may play important role in elevation of serumCyfra21-1, SCC levels in CKD patients. Additionally,both SCC22 and Cyfra21-125 are metabolized in thekidney. Declined kidney function could reduce theclearance 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 stableincreased positive rate and serum SCC, Cyfra21-1 levelwith increasing CKD grade, the strong associationbetween serum SCC, Cyfra21-1 levels and the indices ofrenal function and kidney damage, support thishypothesis.

On the other hand, patients with CKD frequently have acompromised nutritional status. In our study, the serumprotein level ((59.4611.85) vs. (74.624.08) g/L for theCKD and control groups, P


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Chin Med J 2013;126 (2)278

elevated CEA was 9.65%, significantly lower than that ofCyfra21-1 (30.80%), SCC (26.72%). The maximum valuewas 14.12 g/L, no more than two times above the upperreference limit. Elevated CEA levels in CKD patientswere associated with not only renal function andnutritional status, but also age and male gender, and the

associations were weaker. Because of without consideringthe primary disease and smoking status and otherpotential confounders, further studies are needed tovalidate those associations.

In summary, serum Cyfra21-1, SCC, CEA levels weremarkedly influenced by kidney function. Elevated serumCyfra21-1, SCC, CEA levels in CKD patients were notonly associated with kidney function, but also nutritionalstatus. Therefore, in clinical work, the indices of kidneyfunction and nutritional status could be simultaneouslymeasured to improve interpretation of the results of those

tumor marker concentrations and to prevent diagnosticerrors derived from false positive results.

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(Received June 13, 2012)Edited by WANG Mou-yue and LIU Huan

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