CA 125 levels and left ventricular function in patients with end-stage renal disease on maintenance hemodialysis

Abstract

Purpose: The aim of this study was to analyze associations between serum cancer antigen 125 (CA 125) levels and left ventricular (LV) function in patients with end-stage renal disease on maintenance hemodialysis (HD). Methods: CA 125 levels, pro-brain natriuretic peptide (pro-BNP) and biochemical parameters were measured, and echocardiography was performed for 110 patients and 47 healthy controls. Results: The mean CA 125 level in patients, 38.78 ± 35.48 U/mL, was significantly higher than that found in healthy controls (9.20 ± 4.55 U/mL; p = 0.003). Patients with elevated CA 125 levels (n = 40) had significantly lower levels of albumin and reduced relative wall thickness, LV ejection fraction (EF) and fractional shortening but significantly higher levels of pro-BNP and a greater left ventricular end-diastolic diameter (LVEDd) and -systolic diameter (LVESd). CA 125 levels were positively correlated with pro-BNP (r = 0.596, p < 0.05) and C-reactive protein (CRP) levels (r = 0.439, p < 0.05), as well as LVEDd (r = 0.599, p < 0.001), LVESd (r = 0.750, p < 0.001) and LV mass index (r = 0.378, p < 0.05). In contrast, serum CA 125 levels were negatively correlated with albumin (r = −0.513, p < 0.05) and hemoglobin (r = −0.475, p < 0.05) as well as the EF (r = −0.878, p < 0.0001). A depressed EF (β = −1.121, p < 0.0001) and increased CRP levels (β = 0.247, p = 0.035) were independent predictors of high CA 125 levels in the whole group in the multivariate-model. Conclusions: Our study is the first to demonstrate an association between serum CA 125 levels and LV systolic dysfunction via inflammation in patients on maintenance HD.

• CA 125
• end-stage kidney failure
• echocardiography
• hemodialysis
• inflammation
• left ventricular systolic dysfunction

Introduction

The cardiovascular system is closely related to kidney function. Renal insufficiency can affect cardiac performance, leading to heart failure (HF) and further worsening of renal function. The ability of the impairment of one component of the cardio-renal system to aggravate dysfunction in the other has significant clinical ramifications.

HF is a specific term used to define the clinical syndrome in which the heart is unable to pump enough blood to supply the metabolic needs of the body.1 Subjects with myocardial failure can have symptomatic HF or asymptomatic ventricular dysfunction.

Thirty-seven percent of patients beginning kidney dialysis have had a previous episode of HF, doubling their risk of death.2 Approximately 10% of the remaining patients will develop HF per year.3 Systolic and/or diastolic function may be impaired. Fifteen percent of patients starting dialysis have systolic dysfunction of the left ventricle (LV).4 The prevalence of diastolic dysfunction at dialysis inception is unknown but is likely to be high.5 Either systolic or diastolic dysfunction can lead to clinically evident congestive HF (CHF). Risk factors for new-onset CHF include hypertension, older age, anemia and coronary heart disease.6 Hypertension and coronary artery disease are important causes of myocardial dysfunction in end-stage renal disease (ESRD).

Serum cancer antigen 125 (CA 125), a high-molecular weight glycoprotein, is a tumor marker widely used for the diagnosis and follow-up of patients with ovarian cancer.7 However, increased serum levels of CA 125 have been frequently observed in patients affected by malignancies other than ovarian cancer as well as those affected by different non-malignant diseases such as digestive tract cancer,8 acute leukemia,9 non-Hodgkin lymphoma,10 endometriosis,11 ascites,12 pelvic inflammatory diseases,13 tuberculous peritonitis,14 and pericarditis.15 Recently, CA 125 levels have been shown to be increased in patients with HF.16–21

The aim of this study was to measure the blood levels of CA 125 in hemodialysis (HD) patients with and without LV systolic dysfunction and to determine the potential relationship between this tumoral marker and echocardiographic measurements and biochemical parameters.

Materials and methods

This study included 110 HD patients, with and without congestive heart failure (CHF) secondary to LV systolic dysfunction (left ventricular ejection fraction (LVEF) <50% by echocardiography), who regularly visited the nephrology clinic at Turgut Ozal University Hospital between October and December 2011. In addition, 47 healthy individuals were used as healthy controls. There were the same mean age, percentage of females in the patient and control groups. The patients were on maintenance dialysis due to ESRD. All of the patients were dialyzed three times per week using polysulfone membranes and bicarbonate-buffered dialysis fluid.

The diagnosis of CHF was based on clinical presentation and standard investigations (echocardiography, ECG and chest X-ray), stable pharmacological therapy during the three-month study period and significant LV systolic dysfunction defined by an ejection fraction (EF) <50%.22 The exclusion factors included the presence of primitive pathologies of the cardiac valves and/or congenital cardiomyopathies, recent acute coronary syndrome (within the last three months) and any evidence of active infection, peritonitis, pancreatitis, endometriosis, uterine leiomyomas, benign ovarian cysts, pelvic inflammatory disease, cancer, chronic liver disease or nephrotic syndromes. No patients enrolled showed serosal effusions, excluded by echocardiograms, chest X-ray and abdominal ultrasound.

The baseline demographic data, functional status, cardiovascular risk factors and medication history were also recorded. The HF patients were managed according to the guidelines of HF management.23

All patients underwent a two-dimensional Doppler echocardiographic examination and venous blood sampling for CA 125 and pro-brain natriuretic peptide (pro-BNP) analysis on the day of admission to the study. Two-dimensional echocardiography was performed with commercially available equipment. The two-dimensional guided M-mode echocardiographic study of the LV was performed using the parasternal long-axis view. The LVEF was calculated using the Simpson method from the apical four-chamber view. According to the recommendations of the American Society of Echocardiography European Association of Echocardiography,24 interventricular septal thickness (IVSD) and left ventricular posterior wall thickness (LVPWD) were obtained at diastole. The mean wall thickness (MWT) was calculated using the following formula: MWT (mm) = (IVS + PWT)/2, where IVS is the interventricular septum and PWT is the posterior wall thickness. The left ventricular end-diastolic diameter (LVEDd) was assessed during late diastolic phase. The relative wall thickness (RWT) was calculated using the following formula: RWT = PWDd + IVSd/LVEDd, where IVSd = IVS thickness in diastole. The LV mass (LVM) was calculated in grams as follows: LVM = 0.8 × {1.04 [(IVSD + EDLVD + LVPWD)³ – (EDLVD)³]} + 0.6 g, where IVSD is the diastolic interventricular septal thickness,25 EDLVD is the end-diastolic LV diameter and LVPWD is the diastolic LV posterior wall. The weight and height were measured within one hour of the end of dialysis. The left ventricular mass index (LVMI) was calculated and normalized by height^2.7 (LVMI = LVM/height^2.7). The LVH was defined as an LVMI greater than 100 g/m² in women and 132 g/m² in men.26

Venous blood sampling and echocardiography were both performed before a midweek dialysis session. Serum urea nitrogen, creatinine, calcium, phosphorous, albumin, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol triglyceride, C-reactive protein (CRP) and hemoglobin levels were measured by standard laboratory techniques using an autoanalyzer (Roche Diagnostics, COBAS INTEGRA 800, Indianapolis, IN). Intact parathyroid hormone (iPTH), serum pro-BNP and CA 125 levels were measured by a direct chemiluminescence assay (Siemens Healthcare Diagnostics Inc., ADVIA Centaur® XP Immunoassay System, Deerfield, IL); 35 U/mL was considered the upper normal limit for CA 125 levels.

Serum CA 125 groups were defined as median value of CA 125 (<26.6 U/mL) and (≥26.6 U/mL) in HD patients. Cardiac systolic function was then evaluated as LVEF ≤ 50% HD patients (group 1); LVEF > 50% HD patients (group 2); and LVEF > 50% healthy controls (group 3).

The study was approved by the ethical committee of the Turgut Ozal University Hospital, and all subjects gave informed consent.

The data in this study are expressed as the mean ± SD. For nonnormally distributed variables, comparisons between groups were performed using the Mann–Whitney U test, whereas unpaired Student’s t tests were used to compare normally distributed variables. A χ² test was used to compare categorical variables between groups. A correlation analysis between CA 125 levels and different parameters was performed, calculating Pearson’s or Spearman’s coefficient as appropriate. The groups were compared using one-way analysis of variance for variables that showed a normal distribution, followed by a post hoc Tukey multiple comparison test to estimate the significance of differences between groups, and the Mann–Whitney U test was used for variables that did not show a normal distribution. Univariable and multivariable logistic regressions were used to evaluate independent parameters affecting high CA 125 levels. A p value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS software (version 16.0; SPSS Inc., Chicago, IL).

Results

The baseline patient characteristics are given in Table 1. The underlying causes of ESRD were as follows: hypertension related nephropathy (n = 40), diabetic nephropathy (n = 48), chronic primary glomerulonephritis (n = 10), interstitial nephritis (n = 4), polycystic kidney disease (n = 4), obstructive nephropathy (n = 1) and unknown (n = 3). The control group included 47 healthy individuals, aged 60.21 ± 11.31 (22 men and 25 women). The mean serum CA 125 level in patients was 38.78 ± 35.48 U/mL (range, 7.1–140.6 U/mL) and was significantly higher than that measured in the control group (mean: 9.2 ± 4.55; range: 1.21–20.1 U/mL; p < 0.01; Table 1). There was no statistical difference between the HD patients and the healthy controls with respect to sex, age, body mass index (BMI) or smoking habits (Table 1).

Table 1. Baseline characteristics of study population.

	Hemodialysis patients	Healthy controls	p
Numbers	110	47	NS
Male/female, %	56 (50.9)/54 (49.1)	22 (46.8)/25 (53.2)	NS
Age, years	62.16 ± 12.59	60.21 ± 11.31	NS
Body mass index, kg/m^2	28.4 ± 5.65	29.25 ± 5.49	NS
Hemodialysis duration, months	50.23 ± 39.89	–	–
Smoking, %	29	27.6	NS
Hypertension, %	86	0	<0.001
Etiology of chronic renal failure
Diabetic nephropathy	48	–
Hypertension related nephropathy	40	–
Chronic primary glomerulonephritis	10	–
Interstitial nephritis	4	–
Polycystic kidney disease	4	–
Obstructive nephropathy	1	–
Unknown	3	–
CA 125 level, U/mL	38.78 ± 35.48	9.2 ± 4.55	<0.01

We created two groups in the HD patients based on serum CA 125 levels: the first group included patients with normal CA 125 levels (<26.6 U/mL, the median value) and the second group included patients with high CA 125 levels (≥26.6 U/mL). There was no significant difference between the two groups with respect to sex, age, BMI, systolic or diastolic blood pressure, weekly EPO dose, smoking habits or the serum levels of HDL, LDL, Ca, P, CaxP, iPTH, ferritin, Hb, CRP or uric acid (Table 2). The normal CA 125 group had higher albumin levels than the high CA 125 group (p = 0.005), whereas the high CA 125 group had higher pro BNP levels than the normal CA 125 patients (p = 0.017) as shown in Table 2.

Table 2. Biochemical parameters and erythropoietin dose by CA 125 groups in hemodialysis patients.

Parameters	CA 125 level <26.6	CA 125 level ≥26.6	p Value
Patient numbers	70	40
Age, years	62.00 ± 13.45	62.45 ± 11.24	0.900
Sex, male/female	17/18	11/9	0.781
BMI	28.47 ± 6.17	28.29 ± 4.76	0.904
SBP, mmHg	142.25 ± 11.24	145.63 ± 12.45	0.541
DBP, mmHg	91.38 ± 9.75	94.19 ± 10.62	0.432
Smoking, n (%)	10 (14.2)	6 (15)	0.627
Albumin, g/dL	3.78 ± 0.28	3.53 ± 0.26	0.005
Ca (corrected), mg/dL	8.82 ± 0.64	9.00 ± 0.55	0.122
P, mg/dL	5.49 ± 1.61	5.00 ± 1.59	0.282
Ca × P product mg^2/dL^2	46.29 ± 15.11	43.89 ± 14.61	0.593
iPTH, pg/mL	341.70 ± 301.04	331.57 ± 327.48	0.914
HDL-C, mg/dL	34.76 ± 14.52	32.43 ± 7.84	0.556
Triglycerides, mg/dL	179.48 ± 79.39	168.88 ± 156.56	0.764
LDL-C, mg/dL	110.69 ± 36.13	95.46 ± 39.49	0.206
Hb, g/dL	10.75 ± 0.97	10.65 ± 1.22	0.748
TSAT, %	26.77 ± 9.88	22.82 ± 12.43	0.283
Ferritin, ng/mL	522.43 ± 210.28	489.15 ± 186.17	0.586
Weekly Epo dose, IU	7468.8 ± 4234.9	7470.6 ± 4360.5	0.999
CRP, mg/L	13.75 ± 11.97	18.84 ± 22.3	0.302
proBNP, pg/mL	586.19 ± 1546.06	1947.7 ± 1590.7	0.017
UF, mL	3071 ± 752	3169 ± 1105	0.716
Uric acid, mg/dL	7.09 ± 1.28	6.68 ± 1.53	0.325

Note: Abbreviations: BMI, body mass index; Ca, calcium; DBP, diastolic blood pressure; Epo, erythropoietin; Hb, hemoglobin; HDL-C, high-density lipoprotein cholesterol; iPTH, intact parathyroid hormone; LDL-C, low-density lipoprotein cholesterol; P, phosphate; proBNP, pro brain natriuretic peptide; SBP, systolic blood pressure; SD, standard deviation; TSAT, transferrin saturation.

Table 3 shows detailed echocardiographic data for the HD patients according to their CA 125 levels. The EF, fractional shortening and RWT were significantly reduced (p < 0.001; p < 0.001 and p < 0.001, respectively) in the high CA 125 group compared with the normal CA 125 patient group. The LVEDd, left ventricular end-systolic diameter (LVESd) and LVMI were higher in the high CA 125 patient group than in patients with normal CA 125 levels (p < 0.001; p < 0.001; p = 0.013, respectively) (Table 3).

Table 3. Echocardiographic parameters by CA 125 groups in patients on hemodialysis.

Parameters	CA 125 level <26.6	CA 125 level ≥26.6	p Value
IVSd, mm	11.68 ± 2.15	10.85 ± 1.72	0.122
PWDd, mm	11.08 ± 1.77	10.30 ± 1.72	0.096
MWT, mm	11.38 ± 1.90	10.57 ± 1.44	0.105
LVEDd, mm	49.37 ± 6.77	58.70 ± 5.75	<0.001
LVESd, mm	32.02 ± 6.00	46.10 ± 8.08	<0.001
RWT, mm	0.46 ± 0.09	0.36 ± 0.06	<0.001
EF, %	59.48 ± 5.80	32.85 ± 7.42	<0.001
FS, %	35.16 ± 6.88	22.00 ± 7.67	<0.001
E/A	0.94 ± 0.17	1.05 ± 0.38	0.292
EDT, ms	202.97 ± 27.04	193.09 ± 36.15	0.275
LVMI, g/m^2	116.43 ± 36.17	141.20 ± 30.87	0.013

Note: Abbreviations: E/A, early/late diastolic mitral flow; EDT, deceleration time of early filling; EF, ejection fraction; FS, fractional shortening; IVSd, interventricular septum diameter; LVEDd, left ventricular end-diastolic diameter; LVESd, left ventricular end-systolic dimension; LVMI, left ventricular mass index; MWT, mean wall thickness; PWDd, posterior wall diastolic diameter; and RWT, relative wall thickness.

Several correlations were observed between CA 125 levels and the parameters of LV systolic function. Serum CA 125 levels were positively correlated with pro-BNP (r = 0.596, p < 0.05) and CRP levels (r = 0.439, p < 0.05) (Figure 1) as well as LVEDd (r = 0.599, p < 0.001), LVESd (r = 0.750, p < 0.001) (Figure 2) and LVMI (r = 0.378, p < 0.05). Serum CA 125 levels were negatively correlated with albumin (r = −0.513, p < 0.05) and hemoglobin (r = −0.475, p < 0.05) as well as with the EF (r = −0.878, p < 0.001) (Figure 3). In contrast, no correlation was found between CA 125 levels and diastolic function indices.

Figure 1. Correlation between serum CA 125 and CRP.

Figure 2. Correlation between serum CA 125 and LVESd.

Figure 3. Correlation between serum CA 125 and EF.

In this study, patients were divided into three groups according to their cardiac status: systolic HF in HD patients (group 1, n = 46), normal systolic heart function in HD patients (group 2, n = 64) and normal healthy controls (group 3, n = 47), as shown in Table 4. Groups 1 and 2 did not differ significantly from the normal controls with regard to age, sex and BMI. The serum levels of CRP, pro-BNP and CA 125 (Figure 4) of the patient group 1 were significantly higher than those of the healthy control, group 3 (18.77 ± 20.48 vs. 3.63 ± 2.37 mg/L, p < 0.001; 1784.6 ± 1569.6 vs. 15.78 ± 11.27 pg/mL, p < 0.001; and 74.47 ± 27.74 vs. 9.20 ± 4.55 U/mL, p < 0.001, respectively). Statistically significant differences were also found in the pro-BNP and CA 125 levels and the LVEF between groups 1 and 2 (1784.6 ± 1569.6 vs. 599.46 ± 643.5 pg/mL, p < 0.001; 74.47 ± 27.74 vs. 13.14 ± 4.84 U/mL, p < 0.001; and 34.65 ± 8.47 vs. 60.68 ± 4.29%, p < 0.001, respectively).

Figure 4. Serum CA 125 in HD patients with systolic heart failure (group 1), without systolic heart failure (group 2) and healthy controls (group 3).

Table 4. Comparison among three groups.

Parameters	Group I	Group II	Group III	p
Male/female	24/22	32/32	22/25	ns
Age, years	63.60 ± 11.49	61.12 ± 13.40	60.21 ± 11.31	ns
BMI, kg/m^2	29.26 ± 5.31	27.79 ± 5.89	29.25 ± 5.49	ns
Albumin, g/dL	3.57 ± 0.26‡	3.78 ± 0.29†	4.38 ± 0.35
CRP, mg/L	18.77 ± 20.48‡	13.28 ± 12.47†	3.63 ± 2.37
proBNP, pg/mL	1784.6 ± 1569.6‡,§	599.46 ± 643.5	15.78 ± 11.27
Hemoglobin, g/dL	10.74 ± 1.18‡	10.70 ± 0.97†	14.11 ± 1.32
CA 125, U/mL	74.47 ± 27.74‡,§	13.14 ± 4.84	9.20 ± 4.55
EF, %	34.65 ± 8.47‡,§	60.68 ± 4.29	63.06 ± 3.72
LVEDd, mm	59.08 ± 5.61‡,§	48.21 ± 5.75	48.53 ± 4.64
LVESd, mm	46.08 ± 7.69‡,§	30.71 ± 4.10	30.06 ± 3.35
ACE or ARB, n (%)	35 (76)	50 (78)	–
β-blockers, n (%)	13 (30.4)	19 (29.6)	–
CCB, n (%)	13 (30.4)	20 (31.2)	–
Alpha-blockers, n (%)	5 (10.8)	7 (10.9)	–

Notes: Group I: hemodialysis patients with systolic cardiac failure.

Group II: hemodialysis patients with normal systolic cardiac function.

Group III: healthy controls.

†p < 0.001 between group III and II.

‡p < 0.001 between group III and I.

§p < 0.001 between group II and I.

After Univariate analysis, a depressed EF (B = −1.121, p < 0.0001) and increased CRP levels (B = 0.247, p = 0.035) were independent predictors of high CA 125 levels within the whole group in the multivariate-model (Table 5).

Table 5. Univariate and multivariate linear regression analysis with high serum CA 125 as the dependent variable.

	Univariate		Multivariate
	r	p Value	β	p Value
Age, year	−0.063	0.646
BMI, kg/m^2	−0.032	0.841
ProBNP (pg/mL)	0.596	0.018	−0.100	0.440
Albumin (g/dL)	−0.513	0.006	0.022	0.863
HDL (mg/L)	−0.182	0.233
LDL (mg/L)	−0.116	0.453
WBC (/µL)	−0.294	0.040	−0.020	0.873
Hb (g/dL)	−0.215	0.139
CRP (mg/L)	0.439	0.046	0.272	0.037
UF (mL)	0.170	0.216
LVEF (%)	−0.878	<0.001	−1.085	<0.001
LVEDd (mm)	0.599	<0.001	0.351	0.155
LVESd (mm)	0.750	<0.001	−0.503	0.145

Note: β, standardized regression coefficients.

Discussion

CA 125 is a sensitive but not specific tumor marker of particular use in monitoring the efficacy of ovarian cancer therapy and facilitating early detection of recurrence. High CA 125 values have also been observed in patients with lung, breast, uterine and gastrointestinal tract cancer. Furthermore, some non-malignant diseases such as peritonitis, pancreatitis, endometriosis, uterine leiomyomas, benign ovarian cysts, pelvic inflammatory disease, nephrotic syndrome and hepatic cirrhosis, as well as their concomitant serosal effusions (i.e., fluid accumulation in the pleural, peritoneal or pericardial space) may be associated with elevated serum levels of CA 125 and even higher CA 125 levels in the serosal fluids.

Contradictory results have been reported regarding serum CA 125 levels in patients with chronic renal failure (CRF). Elevated27–29 and normal29–32 serum CA 125 levels in patients with CRF on chronic HD or chronic ambulatory peritoneal dialysis have been reported. In our study, HD patients with CHF had higher levels of CA 125 than HD patients without CHF, despite the absence of serosal fluid accumulation.

Subsequent studies have demonstrated that among tumor markers, CA 125 is significantly elevated in patients with chronic CHF. The first study investigating possible clinical and hemodynamic associations of tumor markers with chronic HF was published by Nagele et al.16 The authors investigated various tumor markers in patients with severe HF both before and after cardiac transplantation and showed a direct correlation between CA 125 levels and right atrial pressure (r = 0.41, p = 0.0001) and pulmonary capillary wedge pressure (r = 0.27, p = 0.001). They also demonstrated an increase in serum CA 125 levels in both advanced HF patients with possible fluid accumulation and mild HF patients with no expected serosal effusion compared with healthy controls. Subsequent studies found CA 125 levels to be elevated in patients with chronic CHF compared with healthy controls.17–19 Kouris et al.18 demonstrated an association between CA 125 levels and the clinical severity of chronic CHF as well as a weak correlation between CA 125 levels and pulmonary artery pressure. In a recent study, it was shown that CA 125 levels are associated with left atrial volume index and BNP levels.33 A study by D’Aloia et al.17 showed that the CA 125 level is not only related to right atrial pressure, systolic pulmonary artery pressure and pulmonary artery capillary wedge pressure but also to LV diastolic function parameters. However, they did not detect a significant correlation between CA 125 levels and LV EF or LVEDd, although CA 125 levels were associated with the New York Heart Association Class of HF patients. D’Aloia et al.17 showed elevated serum CA 125 levels in both the relatively few patients with pleural, pericardial or peritoneal effusion as well as in patients with moderate to severe HF with no effusion. In contrast, Vizzardi et al. demonstrated that CA 125 levels were related to many parameters of systolic and diastolic functions in a study that included a well-defined echocardiographic approach.34 In another recent study, CA 125 levels correlated with LVEF and were associated with the presence of pericardial effusion and RV and RA dilatations.35 In their multiple regression analysis, the CA 125 level was independently associated with RV dilatation, pericardial effusion and LVEF.35

To our knowledge, this study is the first to examine the relationship between serum CA 125 levels and LV hypertrophy and the level of systolic dysfunction in HD patients. In this study, we detected elevated CA 125 levels in HD patients with low LVEF and increased LV dimensions. We also found that CA 125 levels did not increase as the level of diastolic dysfunction increased in HD patients.

We found elevated serum CA 125 levels in HD patients with CHF without serosal fluid accumulation (pleural, peritoneal or pericardial) compared as HD patients without CHF. According to our results, there was a significant correlation between CA 125 serum levels and HF, including the correlation between this tumoral marker and BNP values. Many reports12,14,19,36,37 have suggested that serosal fluids occurring in patients with HF are directly responsible for elevated serum CA 125 levels and that the presence of serosal fluid may stimulate the release of CA 125 rather than its cytopathological content. Recent studies have suggested that CHF may, in part, be an inflammatory disease. Cytokines, as inflammatory mediators, play a pivotal role in the pathogenesis of HF.38–41 The determination of serum cytokine levels facilitates monitoring of the immune and inflammatory responses to HF. Circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and circulating anti-inflammatory cytokines such as interleukin-10 (IL-10) are increased in patients with CHF.42–45 A recent study by Kosar et al.46 reported that CA 125 levels are elevated and positively correlated with serum TNF-α, IL-6 and IL-10 levels in HF patients. Interestingly, it has been reported that CA 125 is produced and released from ovarian cancer cells and lymphoma cells when the cells are stimulated by cytokines such as IL-6 and TNF-α, which are also elevated in HF.47,48 In addition, in vitro experiments have shown that cytokines may stimulate the secretion of CA 125 from mesothelial cells.49,50 We postulated that bowel congestion due to HF may stimulate the peritoneal endotoxin and cytokine pathways and hence CA 125 production. Furthermore, chronic inflammatory processes are common in individuals with chronic renal disease, especially ESRD. Deteriorating renal function may enhance overall inflammatory responses because of the decreased renal clearance of factors that are directly or indirectly involved in inflammation. In humans, declining renal function may also affect the levels of inflammatory molecules because serum CRP, IL-6 and hyaluronan levels are inversely correlated with creatinine clearance.51,52 Vascular congestion due to fluid overload in patients with renal insufficiency may result in an altered permeability of the gastrointestinal tract, thereby leading to the accumulation of endotoxins such as lipopolysaccharides and bacteria. These processes may in turn stimulate monocytes and the increased release of proinflammatory cytokines.53 This is due to many underlying factors, including the uremic milieu, elevated levels of oxidative stress, carbonyl stress, protein-energy wasting, an enhanced incidence of infections (especially dialysis-access related), less biocompatible dialysis membranes, poor quality of dialysis water and an intravenous catheter. Our striking finding was that the increase in serum CA 125 levels in HD patients was positively correlated with serum CRP levels, suggesting that serum CA 125 levels have a strong positive relationship with serum CRP levels in HD patients. In this sense, our study supports the hypothesis that elevated serum CA 125 levels are closely associated with inflammatory mediators or cytokines.

Our study demonstrated that serum CA 125 levels are elevated in HD patients with HF. In addition, this increase in serum CA 125 levels correlates with CRP and pro-BNP levels, LVEF and LV dimensions. These data suggest that elevated serum CA 125 levels may be secondary to the activation of these cytokines in HD patients. In particular, CA 125 values can be accepted as an additional non-invasive, low cost, independent marker for the detection of systolic HF that is easy to measure during routine follow-up with these patients, as is already well accepted with pro-BNP. Further studies are required to validate our data.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.