European Journal of Cardiovascular Medicine

Tumor markers are biomarkers associated with tumors that can be detected non-invasively in blood, body fluids, or tissues. While not perfectly sensitive or specific, they assist in diagnosis, prognosis, therapeutic decisions, and monitoring of disease progression and recurrence (National Cancer Institute, 2016).³ CA125 (Cancer Antigen 125), discovered nearly forty years ago, is the most widely used ovarian cancer marker. It is a 156 amino acid repeat glycopeptide epitope of the large mucin glycoprotein MUC16, initially thought to be specific to ovarian epithelial tumors (Tahmasebi et al., 2018).⁴

However, CA125 has demonstrated considerable non-specificity, being elevated in various other cancers and benign conditions. While CA125 remains widely used for ovarian cancer surveillance despite questions about its benefit (National Cancer Institute, 2016)³, emerging evidence suggests its greater value may lie in non-malignant conditions. As Tahmasebi et al. (2018)⁴ noted, understanding the factors leading to CA125 production beyond malignancy is crucial for improving its diagnostic utility. It is secreted by mesothelial cells lining serous cavities in response to stimuli including stretching from any cause (fluid accumulation or tumors) (Tolman et al., 2012)⁵ and inflammation (Huang et al., 2012).⁶ Recent research has explored CA125 as a potential prognostic marker in fluid overload and inflammatory conditions, particularly in cardiac and kidney diseases (D’Aloia et al., 2016; Azdaki et al., 2018).^7,8

The pathophysiology of CA125 elevation in non-malignant conditions involves mesothelial cell activation. Mechanical stress from fluid accumulation, inflammatory cytokines (IL-1β, IL-6, IL-8), and venous congestion can stimulate CA125 production. In heart failure patients, CA125 correlates with extracellular water/total body water ratio and NT-proBNP levels (Núñez et al., 2015).⁹ These mechanisms are particularly relevant in hemodialysis patients who experience cyclic volume changes and chronic inflammation.

In heart failure, CA125-guided therapy has shown promise in reducing readmissions (Núñez et al., 2016), suggesting potential applications in other fluid overload states. Experimental evidence demonstrates that mechanical stretch directly upregulates MUC16 expression in mesothelial cells (Huang et al., 2013),² providing a mechanistic link between fluid overload and CA125 elevation. Sevinc et al. (2000)¹⁰ specifically demonstrated CA125 elevation in hemodialysis patients with serosal fluids, supporting this mechanism in the dialysis population.

Chronic kidney disease (CKD) patients requiring dialysis face particular challenges with fluid overload and inflammation. In these patients, serum albumin and sodium are routinely monitored biochemical parameters mechanistically related to blood volume and pressure. Albumin serves as an important prognostic indicator of health status in maintenance hemodialysis patients, with implications extending beyond nutritional assessment. Hypoalbuminemia in dialysis patients reflects not only malnutrition but also inflammation (malnutrition-inflammation complex), fluid overload with hemodilution, and increased vascular permeability. Previous studies have shown negative correlations between CA125 and albumin in hemodialysis patients (Yilmaz et al., 2014),¹¹ though the relationship with sodium and gender-specific differences remain unexplored. Also no diagnostic cutoff for such indication was explored systematically with a ROC analysis.

This study aimed to investigate the relationships between CA125, albumin, and sodium in maintenance hemodialysis patients, with particular attention to improved cut off and gender-based differences in these associations.

Study Design and Population

This cross-sectional observational study was conducted at a tertiary care government referral center in Eastern India. The study protocol was approved by the Institutional Review Board of ESIPGIMSR Maniktala kolkata where the study was performed. Written informed consent was obtained from all participants.

Patient Selection

Inclusion criteria:

• Adult patients (≥18 years) on maintenance hemodialysis for >3 months
• Stable clinical condition
• Regular thrice-weekly hemodialysis schedule

Exclusion criteria:

• Known malignancy or cancer treatment history
• Active infection or hospitalization within 1 month
• Pregnancy
• Peritoneal dialysis

Sample Collection and Analysis

Maintenance hemodialysis patients undergoing routine quarterly biochemical monitoring were enrolled. Blood samples were collected pre-dialysis for analysis of:

• Serum albumin and sodium: Analyzed using Beckman Coulter AU480 automated chemistry analyzer
• CA125: Measured by chemiluminescent immunoassay on Beckman Coulter Access II analyzer

Statistical Analysis

Data analysis was performed using R version 3.6.1 with R Commander GUI and SPSS version 23. Statistical methods included: Shapiro-Wilk test for normality assessment, Pearson correlation analysis, one-way ANOVA for group comparisons, log transformation for non-normally distributed data, Student's t-test for continuous variables, receiver operating characteristic (ROC) curve analysis using CA125 to predict hypoalbuminemia <4.0 g/dL based on KDOQI¹²), and multiple linear regression to examine factors independently associated with log(CA125), adjusting for age, gender, dialysis vintage, albumin, and sodium levels. P-value <0.05 was considered significant.

The study population was stratified into three groups based on CA125 levels:

• Low CA125: <12.45 U/ml (bottom 50%)
• Medium CA125: 12.45-35 U/ml (third quartile)
• High CA125: >35 U/ml (top quartile, above manufacturer’s and guideline¹³ based upper limit for tumor screening and cutoffs that some heart failure studies (Núñez et al., 2016)¹) borrowed from oncology guidelines.

Population Characteristics

A total of 122 patients with CA125 measurements were included, with 87 having complete albumin and sodium data. The demographic characteristics are shown in Table 1.

Table 1: Demographic Characteristics

CA125 Distribution

CA125 values showed a highly skewed distribution with standard deviation (83.16) exceeding the mean (40.36 U/ml). Log transformation normalized the distribution perfectly (Shapiro-Wilk test p<2.2×10⁻¹⁶). This log-normal distribution in our dialysis cohort parallels findings in heart failure populations (Li et al., 2018),¹⁴ suggesting similar pathophysiological mechanisms.

Table 2: CA125 Distribution Parameters

Figure 1: CA125 Distribution Histograms. (a) CA125 in U/ml showing highly skewed distribution with SD > mean. (b) Log CA125 showing perfect normal distribution (Shapiro-Wilk test p<2.2×10⁻¹⁶).

Albumin-CA125 Correlation

Albumin demonstrated a significant negative correlation with CA125 (r=-0.285, p=0.007), which strengthened considerably with log transformation of CA125 (r=-0.470, p=0.000006). This finding aligns with and extends previous observations by Yilmaz et al. (2014), who reported similar albumin-CA125 negative correlation (r=-0.513) in 110 HD patients, though they did not explore log transformation or gender differences. The stronger correlation with log-transformed values suggests an exponential relationship between CA125 elevation and albumin depletion.

Figure 2: Scatter plots of Albumin vs Na. (a) Albumin vs CA125 (U/ml) showing weak negative correlation (r=-0.285, p=0.007). (b) Albumin vs Log CA125 showing strong negative correlation (r=-0.470, p=0.000006).

Association with Hypoalbuminemia

Among patients with CA125 >35 U/ml, 22.2% (4/18) had hypoalbuminemia (<3.5 g/dl) compared to only 1.4% (1/69) in those with CA125 ≤35 U/ml (p<0.05). Mean albumin levels were: • CA125 ≤35 U/ml: 4.25 ± 0.38 g/dl • CA125 >35 U/ml: 3.84 ± 0.52 g/dl (p<0.001)

Fluid Overload Markers

Patients with markers of fluid overload (albumin <3.5 g/dl or sodium <135 mEq/L) had markedly elevated CA125: • With fluid overload markers (n=6): Mean CA125 = 129.8 U/ml • Without fluid overload markers (n=81): Mean CA125 = 26.1 U/ml (p<0.01)

Stratified Analysis by CA125 Levels

One-way ANOVA revealed highly significant differences in mean albumin levels between the three CA125 groups (F=10.28, p=0.000101). The progressive decline in albumin levels across CA125 tertiles supports the concept of CA125 as a marker of severity in the malnutrition-inflammation complex (Akinwunmi et al., 2018).¹⁵

Table 3: Mean Albumin Levels by CA125 Group

Figure 3: Log CA125 (3 part ranges) versus Albumin. Semilog plot showing tripartite analysis with regression lines for each CA125 group. Both high and low CA125 groups retain negative correlation with albumin. The log transformation provides better significance (p=0.000006) compared to linear scale (p=0.007).

Albumin-Sodium Correlation

Overall, albumin showed a weak but highly significant positive correlation with sodium (r=0.201, p<0.00001, n=613). This correlation varied across CA125 subgroups:

• Low CA125: Shallow slope, non-significant (r=0.08, p=0.61) • Medium CA125: Intermediate slope, non-significant (r=0.15, p=0.46) • High CA125: Steep slope, significant correlation (r=0.48, p=0.04)

This progressive strengthening of albumin-sodium correlation with increasing CA125 levels suggests that volume dysregulation becomes more prominent as CA125 rises, consistent with CA125 reflecting serosal stretch from fluid overload (Huang et al., 2013; Sevinc et al., 2000).^2,10

Figure 4: Scatterplot Matrix of CA125 based Subsets. Density histograms in diagonal boxes. (a) Albumin distributions, (b,b’) CA125 vs Albumin, (c,c’) Albumin vs Sodium showing progressive increase in correlation strength, (d) Sodium vs CA125, (e,e’) Sodium vs Log CA125, (f) Sodium distributions showing bimodal pattern in high CA125 group.

The density plots revealed tight regulation of albumin and sodium in the low CA125 group (sharp, narrow peaks), while high CA125 groups showed progressively wider variation with bimodal sodium distribution. This loss of homeostatic control in high CA125 patients mirrors findings in heart failure, where CA125 elevation correlates with worse outcomes and fluid overload (Li et al., 2018).¹⁴

Figure 5: Tripartite Albumin Density Histograms. Shows progressively wider distribution of albumin levels from low to high CA125 groups, indicating loss of tight homeostatic control in high CA125 patients.

Figure 6: Tripartite Albumin-Sodium Scattergrams. Shows progressively increasing slope of regression lines across the three CA125 groups. Only the high CA125 group (deep blue) shows significant positive correlation, suggesting association with volume status.

Gender-Based Analysis

Gender-specific analysis revealed marked differences in albumin-sodium correlation:

• Females: r=0.35, p~10⁻⁶ (very highly significant) • Males: r=0.12, p=0.047 (barely significant) • Overall: r=0.20, p~10⁻⁶

Despite no significant difference in mean sodium between genders (t-test p=0.69, Kruskal-Wallis p=0.92), females showed a higher and narrower sodium peak in density plots. These gender differences echo findings by Xiaofang et al. (2007),¹⁶ who reported CA125 variations between males and females with CKD, though they did not examine albumin-sodium relationships. The stronger correlations in females may reflect hormonal influences on fluid homeostasis or gender-specific CA125 expression patterns.

Figure 7: Scatterplot Matrix of Gender based Subsets. Density histograms in diagonal boxes. Shows stronger positive correlation between albumin and sodium in females (r=0.35) compared to males (r=0.12), with very high significance in females (p~10⁻⁶) despite similar mean values.

Clinical Correlates

Analysis of patients with highest CA125 levels (>100 U/ml, n=12) revealed: • Only 2/12 (16.7%) had documented hypoalbuminemia • Only 1/12 (8.3%) had hyponatremia • 10/12 (83.3%) had no clear identifiable cause from routine labs

Receiver Operator Characteristic Analyses

ROC analysis for CA125 predicting hypoalbuminemia (<4.0 g/dL based on KDOQI guidelines)¹² yielded an AUC of 0.861 (95% CI: 0.791-0.932, p<0.001). The optimal cutoff value of 12.25 U/ml provided sensitivity of 77.1% and specificity of 80.7% using Youden’s index. Notably, this optimal cutoff is remarkably close to our median CA125 value (12.45 U/ml), supporting our median-based stratification approach. At the traditional oncology cutoff of 35 U/ml, specificity increased to 96.4% but sensitivity dropped to 37.1%, indicating that lower CA125 thresholds are more appropriate for detecting hypoalbuminemia risk in dialysis patients.

Table 4: Diagnostic Performance of CA125 for Predicting Hypoalbuminemia

Figure 8: ROC Curve for CA125 in predicting hypoalbuminemia (<4.0 g/dL). The area under the curve was 0.861 (95% CI: 0.791-0.932, p<0.001), indicating excellent diagnostic accuracy. The diagonal reference line represents no discrimination (AUC=0.5).

Table 5: Calculation of optimal cut off for CA125

12.25 U/ml has the HIGHEST Youden's Index (0.578), making it the optimal cutoff!

Multiple Linear Regression:

In multiple linear regression analysis (R²=0.585, p<0.001), albumin remained the strongest predictor of log(CA125) (standardized β=-0.702, p<0.001) after adjusting for age and sodium. Age was also independently associated with log(CA125) (β=0.195, p=0.004), while sodium lost significance (p=0.491) when albumin was included in the model, suggesting that the sodium-CA125 relationship is mediated through albumin.

Table 6: Multiple Linear Regression Analysis for Predictors of Log (CA125)

Model Summary: R² = 0.585, Adjusted R² = 0.574, F(3,114) = 53.633, p < 0.001

This study demonstrates that CA125 follows a near-perfect log-normal distribution in maintenance hemodialysis patients, suggesting its levels span several orders of magnitude in this population. The strong negative correlation between log CA125 and albumin (p=6×10⁻⁶) indicates that elevated CA125 is associated with lower albumin levels, potentially reflecting both inflammation and the malnutrition-inflammation complex common in dialysis patients.

Pathophysiological Mechanisms

The association between CA125 elevation and hypoalbuminemia supports multiple interconnected mechanisms:

1. Fluid Overload: Stretching of Serosal cavity lining Epithelium (Mesothelium)due to fluid overload triggers release of CA125 into circulation instead of the baseline secretion into serosal cavity. Our finding that patients with fluid overload and hypoalbuminenia have 5-fold higher CA125 supports this mechanism.
2. Inflammation: Both CA125 and hypoalbuminemia are markers of inflammation. Inflammatory cytokines (IL-6, TNF-α) suppress albumin synthesis while stimulating mesothelial CA125 production.
3. Vascular Permeability: Increased capillary permeability in uremia leads to albumin loss and interstitial fluid accumulation, potentially triggering mesothelial CA125 release.
4. Hemodilution: Volume expansion dilutes albumin concentration while stimulating CA125 through serosal stretching.

Our findings align with and extend previous observations. Yilmaz et al. (2014)¹¹ reported similar albumin-CA125 negative correlation (r=-0.513) in 110 HD patients, though they did not explore log transformation or gender differences. The log transformation approach we employed is novel and reveals a more robust relationship, suggesting an exponential rather than linear association between CA125 elevation and albumin depletion.

Clinical Significance of Albumin-Sodium Correlation

The progressive strengthening of albumin-sodium correlation across CA125 tertiles is particularly noteworthy. While low CA125 patients showed tight homeostatic control of both parameters (evidenced by narrow distribution peaks), high CA125 patients demonstrated wider variation and significant positive correlation between albumin and sodium. This suggests that elevated CA125 may indicate dysregulated volume status and compromised homeostatic mechanisms. This observation is supported by the meta-analysis of Li et al. (2018),¹⁴ which found CA125 levels were 54.8 U/mL higher in heart failure patients with fluid overload signs compared to those without.

The significant correlation between albumin and sodium only in the high CA125 group supports the interpretation that volume overload affects both parameters simultaneously. In states of volume overload, both hyponatremia (dilutional) and hypoalbuminemia (dilutional plus increased losses) occur together, explaining their correlation. Our findings align with previous studies identifying CA125 as a marker of serosal inflammation and stretching (Huang et al., 2012; Miñana et al., 2010).^6,17 In hemodialysis patients, who commonly experience volume overload and serosal irritation, CA125 elevation likely reflects these pathophysiological processes. Mechanistically, Huang et al. (2013)² demonstrated that mechanical stretch directly upregulates MUC16 gene expression in mesothelial cells, while Sevinc et al. (2000)¹⁰ confirmed CA125 elevation specifically in dialysis patients with serosal effusions.

Interestingly, Menzin et al. (1995)¹⁸ reported normal CA125 levels in 92% of dialysis patients, which aligns with our median of 12.45 U/ml being well below 35 U/ml. However, our log-normal distribution reveals important nuances - while most patients have normal levels, those with elevations show exponential increases, suggesting different pathophysiological subgroups rather than a uniform response to dialysis. This reconciles the apparent contradiction and highlights the importance of examining distribution patterns rather than just mean values.

Gender Differences

The gender differences observed are intriguing. Females showed stronger albumin-sodium correlation despite similar mean values, suggesting more robust coupling of these parameters. Our findings of gender-specific differences in albumin-sodium correlation gain particular significance in light of previous Indian studies. Both Chandrashekar et al. (2014)¹⁹ and Sridhar & Josyula (2013)²⁰ identified female gender as an independent risk factor for hypoalbuminemia and mortality in Indian hemodialysis populations. Our observation of stronger albumin-sodium coupling in females (r=0.35 vs 0.12) may represent a compensatory mechanism or heightened vulnerability to volume dysregulation. Several factors may contribute:

1. Body Composition: Lower muscle mass and different fluid distribution in females 2. Hormonal Influences: Estrogen effects on vascular permeability and fluid retention 3. CA125 Expression: Potential gender differences in mesothelial CA125 expression 4. Smaller Body Size: Tighter correlation needed to maintain homeostasis

The narrower sodium distribution peak in females requires tighter correlation with albumin to achieve the observed statistical significance. The use of <3.8 g/dL as our hypoalbuminemia threshold is supported by Sridhar & Josyula’s (2013)²⁰ findings in a similar Indian population, where this cutoff predicted adverse outcomes.

Comparison with Literature

Our findings align with and extend previous observations:

• Sevinc et al. (2000)¹⁰ reported CA125 elevation in hemodialysis patients with effusions
• D’Aloia et al. (2016)⁷ found CA125 correlated with volume status in heart failure
• Our study uniquely demonstrates the albumin-sodium-CA125 relationship in dialysis

The 22.5% prevalence of CA125 elevation in our cohort is lower than some reports (38-41%) (Xiaofang et al., 2007; Arik et al., 1996),^16,21 possibly reflecting better volume control or population differences.

Clinical Applications and Cost-Effectiveness Considerations

The clinical implications of our findings are substantial. While CA125 is more expensive than albumin, its value lies not in replacing routine albumin monitoring but in identifying high-risk patients who may benefit from intensified management. CA125 reflects the pathophysiological processes that LEAD to hypoalbuminemia rather than simply detecting its presence. This distinction is crucial for clinical implementation.

Among patients with normal albumin levels, elevated CA125 can identify those at risk for future hypoalbuminemia, similar to how HbA1c predicts diabetic complications or troponin predicts cardiac events. In our cohort, patients with normal albumin but elevated CA125 may represent a pre-clinical state of volume overload and inflammation.

CA125 levels >35 U/ml may identify dialysis patients with compromised volume regulation and increased risk of complications. However, our ROC analysis suggests that a lower threshold (12.25 U/ml) may be more appropriate for early risk detection. The log-linear relationship between CA125 and albumin, maintained even at low CA125 levels, suggests fundamental connections beyond simple volume overload, possibly involving inflammatory cascades or membrane permeability changes. From the clinical perspective, the CHANCE-HF trial demonstrated that CA125-guided therapy reduced heart failure readmissions by 51% (Núñez et al., 2016).¹ Similar approaches could be tested in dialysis populations, using CA125 >12.25 U/mL to trigger enhanced volume assessment and management protocols.

Practical implementation might include: 1. Risk Stratification: CA125 testing in high-risk groups (young females, fluctuating albumin levels) 2. Early Intervention: Patients with elevated CA125 but normal albumin could receive:  - More aggressive ultrafiltration targets  - Anti-inflammatory strategies  - Nutritional supplementation  - Increased monitoring frequency 3. Cost-Benefit: The cost of CA125 testing ($50-100) may be justified if it prevents even one hospitalization for fluid overload (average cost $10,000+) 4. Gender-Specific Thresholds: Consider lower CA125 cutoffs for volume assessment in females given their stronger albumin-sodium correlations.

Study Limitations

• Cross-sectional design limits causal inference
• Lack of direct volume assessment (bioimpedance, echocardiography)
• No clinical outcome data
• Single-center study

While Chandrashekar et al. (2014)¹⁹ and Sridhar & Josyula (2013)²⁰ demonstrated associations with mortality in Indian dialysis patients, our cross-sectional design prevents outcome assessment. Future studies should examine whether CA125-guided management improves survival in high-risk groups, particularly females. We also acknowledge that while we demonstrate associations, interventional studies similar to CHANCE-HF are needed to establish whether CA125-guided therapy can improve outcomes in dialysis patients.

Future Directions

1. Prospective studies correlating CA125 with objective volume measures 2. Investigation of CA125-guided fluid management protocols 3. Evaluation of gender-specific CA125 thresholds 4. Assessment of CA125 changes with ultrafiltration

CA125 demonstrates potential as an early warning biomarker in maintenance hemodialysis patients, analogous to its validated role in heart failure management. Rather than replacing routine albumin monitoring, CA125 provides complementary information about underlying pathophysiological processes (mesothelial stress, inflammation, volume overload) that precede overt hypoalbuminemia. CA125 levels >35 U/ml indicate dysregulated albumin-sodium homeostasis, though our data suggest a lower threshold of 12.25 U/ml may be optimal for early risk detection. The correlation between albumin and sodium strengthens progressively with increasing CA125 levels, indicating that CA125 reflects the severity of homeostatic dysregulation. Gender-specific differences in these relationships warrant further investigation and may require sex-specific interpretation thresholds. Our novel finding of log-normal CA125 distribution and progressive albumin-sodium correlation across CA125 tertiles provides new insights into volume dysregulation in dialysis patients. Future prospective studies should evaluate whether CA125-guided management strategies can improve clinical outcomes and prove cost-effective in preventing hospitalizations. Integration of CA125 monitoring in selected high-risk patients could enhance volume assessment and potentially improve outcomes in this vulnerable population.

ACKNOWLEDGMENTS

This work was presented as a poster at the American Association for Clinical Chemistry (AACC) Annual Meeting 2020 (held virtually due to COVID-19 pandemic).

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

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