Research ArticleClinical Studies
Open Access

Role of High-sensitivity C-reactive Protein in Future Cardiovascular Events in Hemodialysis Patients

HIROSHI OSAWA, NORIO NAKAMURA, CHIKAKO TSUTAYA, HISAO SAITOH, MICHIKO SHIMADA, REIICHI MURAKAMI, TAKESHI FUJITA, IKUYO NARITA-KINJO, DAIKI NAGAWA, MASAMICHI NAKATA, TAKASHI YOKOTA, CHIKARA OHYAMA and HIROFUMI TOMITA
In Vivo May 2024, 38 (3) 1351-1358; DOI: https://doi.org/10.21873/invivo.13575

Abstract

Background/Aim: The pathogenesis of cardio-vascular disease (CVD) in hemodialysis (HD) patients involves inflammation and oxidative stress. High-sensitivity C-reactive protein (hs-CRP) is an established inflammatory biomarker associated with CVD. Several studies have suggested that the inflammatory biomarker pentraxin-3 (PTX-3) and the oxidative stress-related biomarker soluble lectin-like low-density lipoprotein receptor-1 (sLOX-1) are novel biomarkers for CVD in non-HD populations. This study aimed to clarify the association of these established and novel biomarkers with future cardiovascular (CV) events in HD patients. Patients and Methods: This was a single-center prospective cohort study that included 255 HD patients. The primary outcome was the composite of nonfatal and fatal CV events. The event-free survival rate between the two groups according to the median plasma level of each biomarker at baseline was evaluated using the Kaplan-Meier method. The risk for CV events at elevated levels of each biomarker was estimated using Cox proportional hazard model. Results: We observed 44 CV events during the median follow-up period of 743 days. The event-free survival rate significantly differed between the two groups in hs-CRP but not in PTX-3 or sLOX-1. The unadjusted hazard ratio (HR) for CV events in patients with hs-CRP levels above the median was 2.63 [95% confidence interval (CI)=1.37-5.02]. The HR remained significant after adjusting for age, sex, history of CVD, and diabetes (HR=2.30; 95%CI=1.20-4.43). Conclusion: In HD patients, hs-CRP may have a predictable role for future CV events, whereas PTX-3 and sLOX-1 do not.

Key Words:

Patients on hemodialysis (HD) have a high risk for morbidity and mortality due to cardiovascular disease (CVD) (1). Biomarkers that may predict future cardiovascular (CV) events may allow for the early recognition of high-risk patients and increase opportunities for appropriate therapy, improving their prognosis. Inflammation and oxidative stress are involved in the pathophysiology of CVD in patients on HD (2). Thus, biomarkers that reflect inflammation and oxidative stress may serve as predictors of future CV events in patients on HD.

High-sensitivity C-reactive protein (hs-CRP) is an established inflammatory biomarker, with elevated levels predicting CV events in the general population (3, 4). Although increased levels of hs-CRP are associated with all-cause or CV mortality in patients on HD (5, 6), its relationship with future CV events remains unknown. Pentraxin-3 (PTX-3) is an acute phase reactant belonging to the PTX superfamily, in which CRP belongs to, but its cellular source and regulation of production are different from those of CRP (7). PTX-3 may be closely associated with atherosclerosis as its expression was demonstrated in atherosclerotic lesions (8). Lectin-like low-density lipoprotein receptor-1 (LOX-1) is a receptor for oxidized low-density lipoprotein (OxLDL); binding of modified LDL, including OxLDL, to LOX-1 induces atherogenic changes (9). LOX-1 is detectable as soluble LOX-1 (sLOX-1), which is derived from proteolytic cleavage of the extracellular domain of LOX-1 (10). sLOX-1 is associated with vascular injury and is a potent oxidative stress-related biomarker (10, 11). PTX-3 and sLOX-1 have gained interest as novel biomarkers for CVD in nonHD populations (12, 13). However, information regarding the association of PTX-3 and sLOX-1 with CVD in patients on HD is limited. This study aimed to investigate the association of hs-CRP, PTX-3, and sLOX-1 levels with future CV events in patients on HD.

Patients and Methods

Study design and population. This single-center prospective cohort study enrolled patients undergoing HD for 3-4 h and three times per week at Oyokyo Kidney Institute Hirosaki Hospital, aged ≥20 years, and on HD for at least three months. The exclusion criteria included patients with complications due to infectious diseases, history of malignancy or autoimmune disease, kidney transplantation candidates, and having an unstable general condition. Each study participant was followed for two years from the date of baseline blood sampling. The primary outcome was CV events, which was the composite of nonfatal and fatal CV events, while the secondary outcome was all-cause mortality. This study was registered at University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR, study number UMIN000036598). Recently, we reported the relationship between CV events and serum lipid and plasma fatty acid profile among patients with diabetes in this study (14).

Ethical approval. This study was approved by the Ethics Committees of Hirosaki University Graduate School of Medicine (approval number 2018-154-1) and was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all participants included in the study.

Data collection and laboratory measurements. Demographic and clinical information, including comorbidities and medications, at baseline were obtained from medical records. Hypertension was defined as the use of anti-hypertensive drugs or a predialysis systolic blood pressure >140 mmHg. Diabetes mellitus was defined as current use of insulin or oral hypoglycemic agents or history of diabetic treatment. History of CVD was defined as history of revascularization due to coronary artery disease (CAD) or peripheral vascular disease (PAD) and ischemic or hemorrhagic stroke. Baseline blood sampling was conducted before the first dialysis session of the week. The hs-CRP level was measured using JCA-ZS050 with latex agglutination immunoassay kit (LZ test “EIKEN” CRP-HG, Eiken Chemical Co., Ltd., Tokyo, Japan). Plasma levels of PTX-3 and sLOX-1 were measured using human PTX 3 ELISA kit (Perseus Proteomics Inc., Tokyo, Japan) and human LOX-1 ELISA kit (Cell Biolabs, Inc., San Diego, CA, USA) respectively.

Definition of CV events. Nonfatal CV events included revascularization for CAD or PAD, hospitalization due to congestive heart failure (HF), and nonfatal stroke. Nonfatal stroke was defined as acute onset of neurological symptoms associated with compatible imaging findings from computed tomography or magnetic resonance. Fatal CV events included fatal myocardial infarction, fatal stroke, and sudden cardiac death. Fatal myocardial infarction and fatal stroke were defined as death within seven days from the onset of the respective event. Sudden cardiac death was defined as death due to in-hospital cardiac arrest or sudden death in patients with a known history of CAD or low ejection fraction (<40%) as demonstrated by echocardiography.

Statistical analysis. Continuous variables are expressed as mean±standard deviation or median and interquartile range. Categorical variables are expressed as number and percentage. Patients were divided into two groups based on the median baseline levels of hs-CRP, PTX-3, and sLOX-1. The time to the first CV event or all-cause mortality for each biomarker between the two groups was estimated using the Kaplan-Meier method and compared with the log-rank test. Patients were censored if they moved to another hospital or reached the end of the 2-year follow-up period. The relative risk for future CV events or all-cause death in patients with higher levels of each biomarker was estimated using the Cox proportional hazards model, employing patients with lower levels as the reference. All statistical analyses were performed using SPSS version 27.0 (IBM Corporation, Armonk, NY, USA). A p-value <0.05 was considered significant.

Results

Patient characteristics. Overall, 462 patients were screened between May 2019 and May 2020. Of these, 131 patients declined to participate, two withdrew their consent, two with complications of infectious disease, 56 with a history of malignancy, 12 with a history of autoimmune disease, and one kidney transplantation candidate were excluded. Additionally, four patients were excluded because of an unstable general condition: one each had critical limb ischemia, decompensated liver cirrhosis, pleural effusion of unknown etiology, and ascites of unknown etiology. Finally, 255 patients were included in the analysis. The baseline characteristics of the study participants are summarized in Table I. The mean age was 65.6±11.6 years old, 67.1% were men, and the median duration on dialysis was 73 months. Furthermore, 77.6% had hypertension, 48.2% had diabetes, and 31.4% had a history of CVD. The median levels of each biomarker were as follows: hs-CRP, 0.14 (0.05-0.37) mg/dl; PTX-3, 3.66 (2.53-5.45) ng/ml; and sLOX-1, 63.1 (43.8-95.9) pg/ml.

View this table:
Table I.

Baseline characteristics of the patients (n=255).

Cardiovascular events and death. The outcomes of this study are shown in Table II. The median follow-up duration was 743 (645-752) days. We observed CV events in 44 (17.3%) patients; 37 had nonfatal CV events, including 16 with revascularization for CAD, three with revascularization for PAD, 16 with hospitalization for HF, and two with nonfatal stroke. Meanwhile, fatal CV events were observed in seven patients; one with fatal myocardial infarction, one with fatal stroke, and five with sudden cardiac death. A total of 30 participants died during the follow-up period. In addition to the seven patients who died of fatal CV events, non-CV related causes of death occurred in 23 patients; due to infection in 10, malignancy in two, bowel perforation in one, hepatic failure in one, general prostration in one, accident in one, and unknown in five patients.

View this table:
Table II.

Cardiovascular (CV) events and non-CV death observed during the follow-up period.

Association of biomarkers with cardiovascular events. Figure 1 depicts the Kaplan-Meier curves for CV events between the two groups divided by the median baseline level of each biomarker. Based on the hs-CRP level, the CV event-free survival rate was significantly different between the two groups (Figure 1A, Log-rank test, p=0.004). Meanwhile, when based on the PTX 3 or sLOX-1 levels, the CV event-free survival rate was not significantly different between the two groups (Figure 1B and C). Table III shows the risk for future CV events in patients with biomarker levels above the median level for each biomarker as estimated by the Cox proportional hazard model. The hazard ratio (HR) of an hs-CRP level above the median was 2.63 [95% confidence interval (CI)=1.37-5.02] in the unadjusted model and 2.47 (95%CI=1.29-4.73) in the model adjusted for age and sex. The HR remained significant after adjusting for age, sex, history of CVD, and diabetes (HR=2.30; 95%CI=1.20-4.43).

Figure 1.
Figure 1.

Kaplan-Meier curve for cardiovascular events in patients with high-sensitivity C-reactive protein (hs-CRP) (A), pentraxin-3 (PTX 3) (B), and soluble lectin-like low-density lipoprotein receptor-1 (sLOX-1) (C) levels above or below the median values.

View this table:
Table III.

Cox proportional-hazard analysis for predicting cardiovascular (CV) events based on baseline concentrations of biomarkers.

Association of biomarkers with all-cause mortality. Kaplan-Meier curves for all-cause mortality are shown in Figure 2. The cumulative survival rate between the two groups divided by the median baseline level of each biomarker was significantly different except for sLOX-1. The HRs for hs-CRP or PTX-3 levels above the median values were significant in both the unadjusted and age-and-sex adjusted model (Table IV).

Figure 2.
Figure 2.

Kaplan-Meier curve for all-cause death in patients with high-sensitivity C-reactive protein (hs-CRP) (A), pentraxin-3 (PTX 3) (B), and soluble lectin-like low-density lipoprotein receptor-1 (sLOX-1) (C) levels above or below the median values.

View this table:
Table IV.

Cox proportional-hazard analysis for predicting all-cause mortality based on baseline concentrations of biomarkers.

Discussion

In this study, hs-CRP was associated with future CV events in patients on HD. In contrast, PTX-3 and sLOX-1, which have been suggested as novel biomarkers for CVD in nonHD populations, failed to show such an association.

Elevated levels of hs-CRP or CRP is a predictor for CV and all-cause mortality in both patients on HD and in the general population (5, 6, 15). However, few studies have reported an association between hs-CRP levels and CV events in patients on HD. Hs-CRP had predictive value for atherosclerotic events in a posthoc analysis of the AURORA study, which investigated the efficacy of rosuvastatin on composite CV endpoints (16). The cutoff value of hs-CRP for predicting CV events in HD patients is yet to be determined. Our study revealed that an hs-CRP level of ≥0.14 mg/dl carried a significant risk for future CV events. Notably, this value is within the proposed range of fluctuation of the CRP level associated with micro-inflammation linked to atherosclerosis in patients on HD without infection (17). Our cutoff value is higher than that in previous studies that aimed to identify individuals at high risk for future CAD events or ischemic stroke in the general population (3, 4). The difference in cutoff value may be reasonable, considering a previous report wherein a large proportion of clinically stable patients on HD had CRP levels higher than the upper limit of those in normal subjects (18).

The association of PTX-3 and sLOX-1 levels with CVD has been demonstrated in nonHD populations. Higher levels of PTX-3 were associated with an increased risk for myocardial infarction, combined CVD events, and combined CAD events in adults without prevalent CVD (19). Elevated levels of PTX-3 and sLOX-1 may be related to plaque rupture and may have prognostic value in patients with CAD (20, 21). Additionally, higher PTX-3 levels were associated with the severity and prognosis of HF (22). sLOX-1 levels were elevated in patients with HF and negatively correlated with systolic cardiac function (23). Furthermore, PTX-3 levels are positively correlated with the severity of PAD (24), and sLOX-1 levels are inversely correlated with the ankle-brachial index in patients with type 2 diabetes mellitus (25). PTX-3 levels also have prognostic value in patients with ischemic stroke (26). LOX-1 polymorphism, which is associated with higher sLOX-1 levels, may be a risk factor for cerebral infarction (27). However, the present study failed to show an association between PTX-3 and sLOX-1 with future CV events in patients on HD, which may be due to several factors. The first point may be the differences in atherosclerotic lesions between patients on HD and not on HD. Analysis of coronary plaque morphology using virtual histology-intravascular ultrasound revealed a lower percentage of fibrous plaque in patients on HD compared to those with normal or mildly diminished renal function (28). This may suggest the limited role of PTX-3 and sLOX-1 as a marker for vulnerable coronary artery plaques in patients on HD because the association of elevated PTX-3 and sLOX-1 levels with rupture of thin-cap fibrous plaques has been demonstrated in patients not on HD (20, 29). Second, PTX-3 has potent anti-atherosclerotic effects; the protective effect has been demonstrated in experimental models of atherosclerosis (30). Whether PTX-3 exerts such effects on humans remains unknown, an association between annual decline of PTX-3 levels and incident of vascular access troubles has been shown in HD patients (31). In the complement activation pathway, PTX-3 activates the classical pathway by binding with immobilized C1q, whereas PTX-3 inhibits complement activation when it binds C1q in the fluid phase (32). Hence, PTX-3 may exert protective effects on the vascular system under several conditions. Third, involvement of the LOX-1 ligand may be important when employing sLOX-1 as a CVD biomarker. LOX-1 ligand containing apoB (LAB) is thought to represent the activity of modified LDL (9). The LOX-1 index, which is the product of sLOX-1 and LAB, has predictive value for CVD events in the general population (33). The authors reported that higher quartiles of the LOX-index revealed significant risk for future stroke and CAD events, while only the third quartile of sLOX-1 levels showed a significant risk for CAD events. Thus, the LOX-index may be superior to sLOX-1 as a predictable biomarker for CV events; this assumption should be confirmed in patients on HD.

There is a paucity of studies dealing with the association of PTX-3 and sLOX-1 with CVD in patients on HD. Previous cross-sectional analyses showed an association between PTX-3 and CVD comorbidity (34, 35), and a positive correlation of sLOX-1 levels with echocardiographic parameters of left ventricular hypertrophy and carotid artery intima-media thickness (36). Additionally, few prospective studies have shown the association between high PTX-3 levels and CV mortality (37). However, the results of our prospective study cast doubt on the association of PTX-3 and sLOX-1 with CV events. Future studies are necessary to confirm the role of PTX-3 and sLOX-1 as CVD biomarkers in patients on HD.

This study suggests that elevated levels of hs-CRP and PTX-3 are risk factors for all-cause mortality, in accordance with previous reports (5, 34), whereas sLOX-1 is not. Recently, sLOX-1 was shown to be associated with malignancy (38). During the 2-year follow-up period, we observed two cases of death due to malignancy. This low number of deaths in the present study suggests that a longer follow-up period may be necessary to evaluate the association between sLOX-1 and all-cause mortality.

Study limitations. First, this was a single-center prospective study with a relatively small sample size; our results may not be applied to other HD populations. Second, our definition of CV events included revascularization for CAD or PAD; we may have missed patients with CAD or PAD that did not undergo revascularization despite having clinical significance.

Conclusion

Hs-CRP may be predictive for future CV events in patients on HD. PTX-3 and sLOX-1, which have been recognized as novel CVD-related biomarkers in nonHD populations, may lack predictive value for future CV events in patients on HD.

Acknowledgements

The Authors would like to appreciate Enago (www.enago.jp) for English language editing.

Footnotes

  • Authors’ Contributions

    HO and NN designed the study. Material preparation, data collection, and analysis were performed by HO, NN, CT, HS, MS, RM, TF, INK, DN, MN, and TY. CO and HT supervised this study. HO drafted the manuscript and all Authors commented on previous versions of the manuscript. All Authors read and approved the final manuscript.

  • Funding

    The Authors received no funding for this study.

  • Conflicts of Interest

    The Authors declare that no conflicts of interest exist in relation to this study.

  • Received January 16, 2024.
  • Revision received February 25, 2024.
  • Accepted February 26, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Role of High-sensitivity C-reactive Protein in Future Cardiovascular Events in Hemodialysis Patients
HIROSHI OSAWA, NORIO NAKAMURA, CHIKAKO TSUTAYA, HISAO SAITOH, MICHIKO SHIMADA, REIICHI MURAKAMI, TAKESHI FUJITA, IKUYO NARITA-KINJO, DAIKI NAGAWA, MASAMICHI NAKATA, TAKASHI YOKOTA, CHIKARA OHYAMA, HIROFUMI TOMITA
In Vivo May 2024, 38 (3) 1351-1358; DOI: 10.21873/invivo.13575
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