| Abstract|| |
Chronic kidney disease (CKD) is one of the most important noncommunicable diseases. Abnormal concentration of some tumor markers were found in a spectrum of nonmalignant diseases such as benign ovarian tumors, breast diseases, chronic hepatitis, cirrhosis, diseases of the bile duct, and in CKD. Hence, the present study was undertaken to evaluate carbohydrate antigen (CA) 15-3, carcinoembryonic antigen (CEA), CA 19-9, and human chorionic gonadotropin (HCG) concentrations in advanced stages of CKD (Stage 4 and 5) patients who are not on dialysis and with no known malignancy. Patients included 40 CKD patients and 40 healthy controls. CA 15-3, CEA, CA 19-9, and HCG in serum were estimated by enzyme-linked immunosorbent assay method. The differences in tumor marker levels between the controls and advanced stages of CKD (Stage 4 and 5) were assessed using one-way analysis of variance using the Statistical Package for the Social Sciences for Windows version 16.5. CKD patients had significantly elevated levels of CEA, HCG, CA 19-9, and CA 15-3 compared to the control group (P = 0.001). There was no difference in the tumor markers levels between CKD Stage 4 and 5. Elevation in serum tumor markers may be a possibility in patients with CKD even in the situations of the absence of a malignancy. This may be due to an alteration in their metabolism in CKD and reduction of glomerular filtration rate leading to impaired excretion. Hence, it may be prudent to exercise caution in the interpretation of serum tumor markers as a representative for underlined malignancy in patients of CKD.
|How to cite this article:|
Rani B S, Suchitra M M, Srinivasa Rao P, Kumar V S. Serum tumor markers in advanced stages of chronic kidney diseases. Saudi J Kidney Dis Transpl 2019;30:898-904
|How to cite this URL:|
Rani B S, Suchitra M M, Srinivasa Rao P, Kumar V S. Serum tumor markers in advanced stages of chronic kidney diseases. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 17];30:898-904. Available from: http://www.sjkdt.org/text.asp?2019/30/4/898/265466
| Introduction|| |
Kidney failure is a worldwide public health problem, with increasing incidence and prevalence, high health-care costs involved, and with poor outcome. Chronic kidney disease (CKD) has now become one of the most important, chronic, noncommunicable diseases. The prevalence of CKD was observed to be 17.2% with about 6% in advanced stages of CKD in a cross-sectional study that screened 6120 Indian subjects all over the country. Dialysis and kidney transplantation are the most common effective treatment for renal diseases. However, an increased risk of cancer following kidney transplantation has been observed such as squamous cell carcinoma, basal cell carcinoma, in situ carcinoma of the cervix, carcinoma of lip, lymphoma, reticular cell carcinoma, which maybe due to prolonged use of immunosuppressive drugs., In contrast, renal failure can occur secondary to a malignancy which may be attributed to modalities used in the treatment of malignancies such as nephrotoxic chemotherapy agents or radiotherapy. The malignancy by itself may cause renal disease through mechanisms which includes postrenal obstruction, compression or infiltration, and metabolic or immunological changes. Malignancies observed in patients on dialysis are cancer of the kidney, bladder, thyroid, tongue, liver, cervix and uterus, and multiple myeloma. Tumor markers are biochemical substances that result as normal endogenous products that are produced at a greater rate in cancer cells or are the products of newly switched on genes that remained quiescent in the normal cells. Tumor markers are used for clinical purposes such as screening, early detection, diagnostic confirmation, prognosis and prediction of therapeutic response, and monitoring disease and recurrence. Human chorionic gonadotropin (HCG) is a glycoprotein composed of two dissimilar sub- units the alpha chain (14 KD) and beta-chain (24 KD). It contains 30% carbohydrate, and approximately 70% protein content. Carcino-embryonic antigen (CEA) is a glycoprotein with a molecular weight of 180 KD, the protein content of which is approximately 40% and the carbohydrate approximately 60%. Carbohydrate antigen (CA) 15-3 is a glyco-protein is expressed on the apical membrane of almost all glandular epithelia. CA 19-9 is a 210 KD tumor-associated glycoprotein antigen present as carbohydrate determinant on glycolipid and glycoprotein. Tumor markers CA 15-3, CEA, CA 19-9, and HCG are glyco- proteins, which undergo similar metabolism. Abnormal serum concentration of some tumor markers were found in a spectrum of benign conditions such as benign ovarian tumors, benign breast diseases, chronic hepatitis, liver cirrhosis, diseases of bile duct and in CKD.,
Tumor markers, such as tissue polypeptide antigen, CEA, and the tumor-associated antigens CA 19-9, CA 15-3 are reported to be increased in CKD, even in the absence of malignancy. Studies have reported normal levels of serum tumor markers in patients on dialysis and in kidney transplantation, whereas some studies found higher levels of tumor markers in patients who underwent kidney transplantation. It has been reported that stages of chronic kidney function, hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation can affect serum tumor marker levels variably. The serum concentration of the CA tumor markers is a balance between the rate of production by normal (as well as malignant) cells and the rate of clearance from the body. There are conflicting reports with regard to changes in tumor marker levels with some studies reporting no change and some studies reporting an increase in concentrations of CA 15-3, CEA, and CA 19-9 in CKD patients.,,, Hence, the comorbid presence of renal disease in patients with malignant conditions may pose a significant problem in the interpretation of concentration of tumor markers and making clinical judgment. Some studies done in CKD patients undergoing the dialysis have reported a decrease in serum tumor marker levels attributed to the dialysis process, whereas some studies found no change in tumor marker levels in HD patients.
It is important to determine the effect of CKD on the levels of tumor markers in blood, to avoid misinterpretation of tumor markers in arriving at the diagnosis of malignancy in CKD patients. The utility of tumor markers in the diagnostic workup of cancer in patients with renal insufficiency remains controversial.,,, Hence with this background, the present work was taken up to study the changes if any in the serum levels of tumor markers (CEA, CA 15-3, CA 19-9, and HCG ) in advanced stages of CKD who are not undergoing dialysis.
| Materials and Methods|| |
Patients attending the Department of Nephrology, Sri Venkateswara Institute of Medical Sciences, Tirupati, diagnosed with advanced stages of CKD – Stage 4 and Stage 5 based on the Kidney Diseases Initiatives and Global Outcome guidelines who are not undergoing dialysis during the study period from April 2015 to February 2016 were included in the study. A total of 40 CKD patients (aged 49.8 ± 9.77 years; males n = 29) along with 40 healthy controls (aged 49.7 ± 7.10 years; males n =28) without malignancy and willing to participate in the study were recruited in the study. Patients with acute kidney injury, malignancies, pregnant women, and patients who were unwilling to participate in the study were excluded from the study. Both the groups were matched for age and sex. The study was approved by the Institutional Ethics Committee. Written informed consent was obtained from all the participants in the study. All patients were screened to rule out malignancy by ultrasound abdomen, mammo-gram, stool for occult blood, chest X-ray, and liver function tests were assessed.
A total of 5 mL of venous blood was collected from patients who were fasting for 8–12 h in additive-free test tubes. The blood samples were allowed to stand for 30 min and centri-fuged at 2000 rotations/min for 15 min. The separated serum was aliquoted and stored at -80°C in the deep freezer until analysis.
Biochemical analysis: CA 19-9 (NovaTec Immunodiagnostica, Dietzenbach, Germany), CA 15-3 (NovaTec Immunodiagnostica, Dietzenbach, Germany), CEA (Omega Diagnostics, Scotland, UK), HCG (Alkor Bio Company, St. Petersburg, Russia) was determined by enzyme-linked immunosorbent assay method on Chemwell auto analyzer systems (CPC diagnostics), urea was determined by enzymatic timed endpoint method (RANDOX laboratories, United kingdom), creatinine was determined by Modified Jaffe’s method (Beckman system pack Brea, USA) on Beckman Synchron DXC600 autoanalyzer.
| Statistical Analysis|| |
The data distribution of continuous variables was analyzed using the Kolmogorov–Smirnov test. According to data distribution, parametric independent sample t-test and nonparametric Mann-Whitney U-test was used to test the significance of the difference in means between cases and controls for the data which were normally distributed and for data which were not normally distributed, respectively. Continuous variables were expressed as a mean ± standard deviation for variables with normal distribution and median inter quartile range (IQR) for variables with nonnormal distribution. A P <0.05 was considered statistically significant. Statistical analysis was performed using Microsoft excel spread sheets and the Statistical Package for the Social Sciences (SPSS) for Windows version 16.5 (SPSS Inc., Chicago, IL, USA).
| Results|| |
Serum creatinine, urea, alanine transaminase, and estimated glomerular filtration rate (eGFR) were found to be significantly elevated (P = 0.001) in cases when compared to controls, whereas total bilirubin, conjugated bilirubin, alkaline phosphatase, albumin, aspartate trans-aminase, showed no significant difference between cases and controls [Table 1]. CKD patients had significantly higher levels of serum tumor markers CEA, HCG, CA 19-9, and CA 15-3 (P = 0.001) compared to the control group [Table 2].
| Discussion|| |
Tumor markers have a role in clinical decisions such as in screening, treatment, and follow-up of malignancy. It has been found that the concentration of some tumor markers in CKD is elevated even in the absence of malignancies. This could be due to disturbed renal metabolism and excretion as it has been reported that GFR reduction can lead to impaired excretion of most tumor markers such as CEA, CA 19-9, CA 15-3, and HCG., In the present study, CKD patients had significantly higher levels of serum CEA (P = 0.001) with a 1.4-fold increase when compared to that of the control group. This is in agreement with previous studies which have shown elevated levels of CEA in CKD., Direct injury, high metabolic demands or stimuli from renal dysfunction activate tubular cells, which produce cytokines, support inflammatory responses, causing further pathological changes in the renal parenchyma. Thus, both changes in renal parenchyma metabolism and declining kidney function could reduce the renal clearance of CEA, leading to elevated serum CEA levels in CKD when compared to that of the control group. Similar observations have been reported where serum CEA and CA19-9 levels were found to be higher in predialysis, HD, and continuous ambulatory PD patients than in control group.
A significant elevation of serum HCG (P = 0.001) with a 1.7-fold increase was found in CKD patients when compared to controls. About 30% of HCG being produced is said to be cleared by the kidney and an additional fraction metabolized by renal catabolic process in the tubules by which, proteins are rapidly eliminated by glomerular filtration. About 99.9% of this filtered amount is taken up by proximal tubular cells by megalin-dependent endocytosis. As renal tubules contribute to the destruction of HCG, a reduction in GFR and tubular activity would contribute to increase in serum HCG concentration in CKD patients., A case report also found an elevation of β-HCG levels in a patient with Stage 5 CKD.
Significantly higher levels of serum CA 19-9 (P = 0.001) with a 3.4-fold increase in CKD cases when compared with controls was observed. CA 19-9 is reported to be cleared through kidneys and hence, reduction in GFR and reduced tubular activity may affect the clearance of CA 19-9. Increased levels of CA 19-9 in CKD patients have been reported., A study reported that the increase in the serum levels of CA 19-9 in patients with CKD affects the specificity of these markers in the diagnosis of cancer in CKD patients. It was reported that HD does not eliminate tumor markers as both patients receiving HD and also those not on HD had elevated levels of ferritin, CA 19-9, and CA 125 when compared to controls. Some studies did not notice differences in patients with chronic renal failure compared to normal subjects., CA 19-9 is also reported to be cleared by hepatic metabolism and excreted in bile and hence alterations in liver functions may also contribute to alterations in CA 19-9. In our study, as the liver functions were normal, the elevated CA 19-9 may be solely attributed to the presence of CKD.
We found CKD patients had significantly higher levels of serum CA 15-3 (P = 0.001) with a 1.7-fold increase when compared to that of the control group. In the normal kidney, CA 15-3 is localized in the distal convoluted tubules and in the collecting ducts. Kidneys have an important role in the metabolism and excretion of CA 15-3. In CKD patients, declining kidney function could reduce the clearance of CA 15-3. Studies have found elevated levels of serum CA 15-3 in CKD when compared to controls with a significant correlation between creatinine clearance and CA 15-3. No change in CA 15-3 was reported in CKD patients who were not on dialysis when compared with patients on maintenance HD indicating that HD does not contribute to the clearance of tumor markers.
In our study on advanced stages of CKD (Stage 4 and 5), we found elevated levels of tumor markers CEA, CA 15-3, CA 19-9, and HCG even in the absence of malignancy when compared to normal controls. We found an increase in tumor markers with age in both patients and controls. In patients elevation of tumor markers was noticed with decrease in eGFR and increase in creatinine. The tumor markers were within the normal range in controls, whereas in advanced CKD we found elevated levels of all the tumor markers studied, most of them were in the higher end of given upper reference range as was found for CEA, HCG, CA 19-9 (<5 ng/mL, <10 IU/mL, <35 IU/mL, respectively), which has to be borne in mind when considering the cutoff values for these tumor markers in the diagnosis of malignancy in CKD. We have compared our findings with other studies, with a few studies reporting similar elevations in the studied tumor markers [Table 3]. Patients with these findings we propose that further studies need to be conducted to study the changes in tumor marker levels with reference to failing renal function in CKD and the same may be compared with CKD patients with malignancy to observe the degree of elevation of tumor markers in malignancy.
|Table 3:Comparison of our observations of tumor markers in chronic kidney disease with other studies|
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| Conclusion|| |
Detection of tumor markers in the biological specimens including blood as a marker of the presence of a tumor are presaging ongoing tumor process in the body is of paramount importance in the diagnosis and management of the neoplasms. However, in the paucity of available clarity on information on this aspect in scientific literature, it may be prudent to follow the patients of CKD with tumor marker values in the high normal range with periodic monitoring so as not to miss any hidden malignancy in the patients. Keeping in view of these observations, there is a need to identify the ranges of cut off values for tumor markers CEA, HCG, CA 19-9, CA 15-3 in situations of compromised renal function such as CKD alone with no evidence of association with malignancy as a disease entity, so as not to confuse with early or preneoplastic stages of malignancy.
Conflict of interest: None declared.
| Source(s) of support|| |
Sri BalajiArogya Varaprasadhini scheme of Sri Venkateswara Institute of Medical Sciences
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M M Suchitra
Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
[Table 1], [Table 2], [Table 3]