Tumor markers are substances produced by cancer cells or by the body in response to cancer, measurable in blood, urine, or tissues. While initially developed for cancer detection and monitoring, their interpretation in chronic kidney disease (CKD) patients presents unique challenges due to altered metabolism and excretion (Amiri, 2016; Xiaofang et al., 2007).

Patients with end-stage renal disease (ESRD) on maintenance hemodialysis experience complex physiological changes including uremic toxin accumulation, chronic inflammation, oxidative stress, and altered protein metabolism. These factors may influence tumor marker levels independently of malignancy, potentially leading to false-positive results and unnecessary anxiety or investigations (Estakhri et al., 2013; Tzitzikos et al., 2010).

Previous studies have reported variable effects of renal dysfunction on different tumor markers. The prevalence of tumor marker elevations in hemodialysis patients varies widely across populations, with CEA elevations ranging from 24-66% (Ammon et al., 1988; Docci et al., 1984; Maoujoud et al., 2014; Cases et al., 1991), while AFP consistently shows the lowest elevation rates of 0-16% across different studies (Odagiri et al., 1991; Polenakovic et al., 1997; Maoujoud et al., 2014). While some markers like prostate-specific antigen (PSA) appear relatively unaffected, others such as CA125 and CA19-9 show frequent elevations in dialysis patients (Lye et al., 1994; Arik et al., 1996). Understanding these patterns is crucial for appropriate clinical interpretation and patient management.

This study aimed to comprehensively evaluate multiple tumor markers in a cohort of maintenance hemodialysis patients without known malignancy, establishing the prevalence of elevations and identifying associated factors.

Study Design and Population

This cross-sectional observational study was conducted at ESI-PGIMSR Maniktala, Kolkata, a tertiary care government hospital in Eastern India. The study protocol was approved by the Institutional Ethics Committee of ESI-PGIMSR Maniktala, and written informed consent was obtained from all participants.

Inclusion Criteria

• Adult (≥18 years) patients on >3 months maintenance hemodialysis

• Stable clinical condition

• No known history of malignancy

• No active infection or hospitalization in the preceding month

Exclusion Criteria

• Known malignancy or cancer treatment history

• Active infection or inflammatory conditions

• Pregnancy

• Recent surgery or invasive procedures (<3 months)

Sample Collection

Blood samples were collected pre-dialysis during routine monthly laboratory assessments. Serum was separated and stored at -80°C until analysis.

Laboratory Analysis

Tumor markers were measured using chemiluminescence immunoassay on Beckman Coulter Access 2:

• CEA (reference: <3 ng/ml)

• CA125 (reference: <35 U/ml)

• CA19-9 (reference: <35 U/ml)

• CA15-3 (reference: <31.3 U/ml)

• AFP (reference: <9 ng/ml)

• Total PSA (age-specific cutoffs)

• Free PSA

Anti-HCV antibodies were detected by ELISA. Routine biochemistry was performed on Beckman Coulter AU480.

Statistical Analysis

Data analysis was performed using R version 3.6.1 and SPSS v23. Continuous variables were expressed as mean ± SD or median (IQR) based on distribution. Categorical variables were presented as frequencies and percentages. Comparisons were made using Student's t-test or Mann-Whitney U test for continuous variables and chi-square test for categorical variables. Correlation analysis used Spearman's rank correlation. P-value <0.05 was considered significant.

Demographic Characteristics

The study included 123 maintenance hemodialysis patients. The mean age was 48.5 ± 12.5 years with median age 50 (39-58) years, range 23-77 years. Sex distribution showed 74 males and 49 females, yielding a male-to-female ratio of 1.5:1.

Table 1. Demographic Characteristics (n=123)

FIGURE 1: Box Plot of Male and Female Age distribution

(Males were significantly older than females, with Average age 52.5 versus 42.2 with p-value = 0.00003014 by Student's t-test)

Tumor Marker Elevations

A high proportion of patients demonstrated elevated tumor markers despite absence of known malignancy. CEA showed the highest rate of elevation (66.4%), followed by CA125 (22.5%) and CA19-9 (16.4%). AFP demonstrated the highest specificity with only 1.7% elevation rate.

Table 2. Tumor Marker Results

*Age-specific cutoffs applied

Multiple Marker Elevations

Analysis of concurrent elevations revealed:

• No elevation: 30 patients (24.4%)

• At least one or more markers elevated: 93 patients (75.6%)

• One marker elevated: 52 patients (42.3%)

• Two markers elevated: 25 patients (20.3%)

• Three markers elevated: 12 patients (9.8%)

• Four or more markers elevated: 4 patients (3.3%)

The most common pattern was isolated CEA elevation (36.6%), followed by combined CEA and CA125 elevation (12.2%).

Age and Sex Stratification

No significant differences in tumor marker elevations were observed between age groups (<50 vs ≥50 years) or between sexes (Table 3).

Table 3. Age and Sex Stratified Analysis

HCV Status and Tumor Markers

Only 2 patients (1.6%) were HCV reactive. One female patient had all tumor markers within normal limits. The other patient had elevated CEA (3.55 ng/ml) and CA125 (190.4 U/ml), but these values were not exceptional compared to the HCV-negative cohort—64 patients had higher CEA and 5 had higher CA125 values.

Comparison with Literature

Table 4. Comparison of Tumor Marker Elevations Across Studies

HD = hemodialysis; CRF = chronic renal failure; NR = not reported

Our study, demonstrates that tumor marker elevations are extremely common in maintenance hemodialysis patients without malignancy, with two-thirds showing elevated CEA levels. These findings have important implications for cancer screening and monitoring in the dialysis population.

The high prevalence of CEA elevation (66.4%) in our study exceeds previously reported rates from Morocco (51%) (Maoujoud et al., 2014), Greece (39%) (Tzitzikos et al., 2010), and Japan (26%) (Odagiri et al., 1991), suggesting that standard reference ranges are inappropriate for dialysis patients. This variation may reflect differences in dialysis adequacy, population genetics, or assay methods. CEA is normally cleared by the liver and kidneys; thus, reduced renal clearance likely contributes to accumulation (Coppolino et al., 2014). Additionally, chronic inflammation and oxidative stress in uremia may stimulate CEA production by various tissues (Holley, 2007). Docci et al. (1984) concluded that CEA measurement cannot be recommended as a reliable test for cancer screening in hemodialysis patients due to its poor specificity.

CA125 elevation (22.5%) likely reflects mesothelial cell activation from uremic serositis or subclinical fluid overload rather than malignancy (Bastani & Chu, 1995). The large ratio of standard deviation (83.2) to mean (40.94 U/ml) suggests varied mechanisms affecting individual patients differently. Sevinc et al. (2000) demonstrated that CA125 levels are particularly elevated in hemodialysis patients with serosal fluids, further supporting a non-malignant etiology for these elevations.

AFP also demonstrated remarkable retention of specificity with only 1.7% elevation rate, supporting its continued utility for hepatocellular carcinoma screening in dialysis patients. This finding aligns with multiple reports showing AFP as the most specific marker in hemodialysis patients, with several studies reporting 0% elevation (Odagiri et al., 1991; Tzitzikos et al., 2010). This contrasts with other markers and suggests that AFP metabolism is less affected by renal failure (Filella et al., 1990).

The absence of high-risk PSA ratios despite some total PSA elevations is reassuring and suggests that free PSA proportions remain interpretable in dialysis patients. This maintains the clinical utility of PSA screening, though age-specific cutoffs should be applied (Djavan et al., 1999). Several studies have confirmed that PSA remains reliable for prostate cancer detection in hemodialysis patients (Sasagawa et al., 1992; Tzanakis et al., 2002).

The minimal impact of HCV status on tumor marker levels (only 2 reactive patients) indicates that viral hepatitis is not a major contributor to marker elevations in our population. The one HCV-positive patient with elevated markers had values within the range seen in HCV-negative patients.

Based on our findings and the literature, we propose the following hierarchy of tumor marker reliability in hemodialysis patients:

1. AFP and PSA: Largely reliable (0-16% false positives)
2. CA15-3: Moderately reliable (4-24% false positives)
3. CA125 and CA19-9: Use with caution (6-46% false positives)
4. CEA: Least reliable (24-66% false positives)

Clinical Implications

1. Baseline Assessment: Establish individual baseline tumor marker levels when initiating dialysis
2. Serial Monitoring: Emphasize trends over absolute values
3. Multiple Markers: Avoid relying on single elevated markers for cancer diagnosis
4. AFP Reliability: AFP remains the most specific marker for cancer screening
5. PSA Utility: Free/total PSA ratio maintains diagnostic value
6. Consider Alternative Methods: Given the poor specificity of most markers, imaging techniques may be preferred for cancer screening in this population (Maisonneuve et al., 1999)

Study Limitations

• Cross-sectional design limits assessment of temporal changes
• Lack of long-term follow-up for cancer development
• Single-center study may limit generalizability
• The wide variation in tumor marker elevations across studies (e.g., CEA 24-66%) suggests the need for population-specific reference ranges

Traditional tumor markers, particularly CEA, are frequently elevated in maintenance hemodialysis patients without malignancy. These elevations appear independent of age, sex, or HCV status, likely reflecting decreased clearance and uremia-related inflammation. AFP demonstrates the highest specificity, while PSA ratios maintain diagnostic utility. Clinicians should interpret tumor markers cautiously in dialysis patients, considering baseline values and trends rather than isolated elevations. Development of dialysis-specific reference ranges is urgently needed to improve cancer screening accuracy in this vulnerable population. Future multicenter studies should standardize assay methods and dialysis parameters to better understand the variations in tumor marker elevations across different populations.

ACKNOWLEDGMENTS

The data was earlier presented as an abstract/poster at the American Association for Clinical Chemistry (AACC) 2017 annual scientific meeting USA.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

1. Amiri, F.S. (2016). Serum tumor markers in chronic kidney disease: as clinical tool in diagnosis, treatment and prognosis of cancers. Renal Failure, 38(4), 530-544.
2. Ammon, A., Eiffert, H., Weber, M.H., Rummel, J., & Niemann, J. (1988). Tumor markers in dialysis-dependent renal failure. A comparison of the mucin-like carcinoma antigen, CA 15-3, CA 125, CA 19-9 and CEA antigens. Onkologie, 11(6), 260-262.
3. Arik, N., Adam, B., Akpolat, T., Hasil, K., & Tabak, S. (1996). Serum tumour markers in renal failure. International Urology and Nephrology, 28(4), 601-604.
4. Bastani, B., & Chu, N. (1995). Serum CA-125 level in end-stage renal disease patients maintained on chronic peritoneal dialysis or hemodialysis: the effect of continuous presence of peritoneal fluid, peritonitis, and peritoneal catheter implantation. American Journal of Nephrology, 15(6), 468-472.
5. Cases, A., Filella, X., Molina, R., Ballesta, A.M., Lopez-Pedret, J., & Revert, L. (1991). Tumor markers in chronic renal failure and hemodialysis patients. Nephron, 57(2), 183-186.
6. Coppolino, G., Bolignano, D., Rivoli, L., Presta, P., & Fuiano, G. (2014). Tumour markers and kidney function: a systematic review. BioMed Research International, 2014, 647541.
7. Djavan, B., Shariat, S., Ghawidel, K., Guven-Marberger, K., Remzi, M., Kovarik, J., ... & Marberger, M. (1999). Impact of chronic dialysis on serum PSA, free PSA, and free/total PSA ratio: is prostate cancer detection compromised in patients receiving long-term dialysis? Urology, 53(6), 1169-1174.
8. Docci, D., Turci, F., & Pistocchi, E. (1984). High levels of carcinoembryonic antigen (CEA) in the serum of uremic patients under hemodialysis treatment. Quaderni Sclavo di Diagnostica Clinica e di Laboratorio, 20(4), 435-439.
9. Estakhri, R., Ghahramanzade, A., Vahedi, A., & Nourazarian, A. (2013). Serum levels of CA15-3, AFP, CA19-9 and CEA tumor markers in cancer care and treatment of patients with impaired renal function on hemodialysis. Asian Pacific Journal of Cancer Prevention, 14(3), 1597-1599.
10. Filella, X., Cases, A., Molina, R., Jo, J., Bedini, J.L., Revert, L., & Ballesta, A.M. (1990). Tumor markers in patients with chronic renal failure. International Journal of Biological Markers, 5(2), 85-88.
11. Holley, J.L. (2007). Screening, diagnosis, and treatment of cancer in long-term dialysis patients. Clinical Journal of the American Society of Nephrology, 2(3), 604-610.
12. Lye, W.C., Tambyah, P., Leong, S.O., & Lee, E.J. (1994). Serum tumor markers in patients on dialysis and kidney transplantation. Advances in Peritoneal Dialysis, 10, 109-111.
13. Maisonneuve, P., Agodoa, L., Gellert, R., Stewart, J.H., Buccianti, G., Lowenfels, A.B., ... & Disney, A.P.S. (1999). Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet, 354(9173), 93-99.
14. Maoujoud, O., Machtani, S.E., Asseraji, M., Atbib, Y., Zajjari, Y., Taoufik, A., ... & Tellal, S. (2014). Serum tumor markers in hemodialysis patients. International Journal of Artificial Organs, 37(2), 126-132.
15. Odagiri, E., Jibiki, K., Takeda, M., Sugimura, H., Iwachika, C., Abe, Y., ... & Demura, H. (1991). Effect of hemodialysis on the concentration of the seven tumor markers carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma-related antigen, neuron-specific enolase, CA 125, CA 19-9 and CA 15-3 in uremic patients. American Journal of Nephrology, 11(5), 363-368.
16. Polenakovic, M., Sikole, A., Dzikova, S., Polenakovic, B., & Gelev, S. (1997). Acquired renal cystic disease and tumor markers in chronic hemodialysis patients. International Journal of Artificial Organs, 20(2), 96-100.
17. Sasagawa, I., Nakada, T., Hashimoto, T., Ishigooka, M., Kubota, Y., Hirano, K., ... & Suzuki, Y. (1992). Serum prostatic acid phosphatase, gamma-seminoprotein and prostatic specific antigen in hemodialysis patients. Urologia Internationalis, 48(2), 181-183.
18. Sevinc, A., Buyukberber, S., Sari, R., Turk, H.M., & Ates, M. (2000). Elevated serum CA-125 levels in hemodialysis patients with peritoneal, pleural, or pericardial fluids. Gynecologic Oncology, 77(2), 254-257.
19. Tzanakis, I., Kazoulis, S., Girousis, N., Kagia, S., Spiliopoulou, C., Paphitis, K., ... & Kallivretakis, N. (2002). Prostate-specific antigen in hemodialysis patients and the influence of dialysis in its levels. Nephron, 90(2), 230-233.
20. Tzitzikos, G., Saridi, M., Filippopoulou, T., Makri, A., Goulioti, A., Stavropoulos, T., & Stamatiou, K. (2010). Measurement of tumor markers in chronic hemodialysis patients. Saudi Journal of Kidney Diseases and Transplantation, 21(1), 50-53.
21. Xiaofang, Y., Yue, Z., Xialian, X., & Zhibin, Y. (2007). Serum tumour markers in patients with chronic kidney disease. Scandinavian Journal of Clinical and Laboratory Investigation, 67(6), 661-667.