Early Serum Biomarkers of Cardiovascular Disease in Elderly Patients with Chronic Kidney Disease

The global population is aging. It is estimated that the share of the global population aged 65 years or older will increase from 10% in 2022 to 16% in 2050 [1]. There is plenty of evidence that aging is associated with an increased prevalence of various chronic diseases, one of which is chronic kidney disease (CKD) [2]. CKD is defined as an abnormality of kidney structure or function present for more than 3 months and is a major public health issue disproportionately impacting elderly people [3]. The number of patients aged 65 years or older with kidney disease is growing, and this growth is continuing [4]. Elderly patients also have higher rates of death than younger patients with comparable levels of kidney function [5]. One of the reasons for this difference is that CKD increases the vulnerability of individuals to multiple chronic diseases and geriatric syndromes, especially cardiovascular disease (CVD) [6]. The incidence and mortality of CVD in elderly patients with CKD are both high, but the manifestation of such disease is not typical and can be easily misdiagnosed [7‒9]. In addition, the treatment options available for these patients are limited, particularly when the disease has progressed [10]. Consequently, early biomarkers for these people are needed. Recently, multiple studies have proposed several related biomarkers. Based on the above observations, this review aimed to summarize the early biomarkers of CVD in elderly patients with CKD to provide a basis for the prevention and treatment of this disease. The main relevant information of the early biomarkers included in this article is presented in the Table 1.

Suppression of tumorigenicity 2 (ST2), also called growth stimulation expressed gene 2, is a member of the interleukin (IL)-1 receptor family and is a novel circulating cardiac biomarker [30]. It is generally believed that the normal value of it is less than 35 ng/mL. Previous studies have indicated that ST2 may be correlated with cardiomyocyte fibrosis in response to subclinical cardiac ischemia [31]. In vitro studies have shown that ST2 is secreted from cardiac myofibroblasts induced by myocardial stretch. ST2 ligands bind to interleukins to exert their anti-inflammatory and antifibrotic effects in the damaged heart. A meta-analysis also described a correlation between elevated sST2 level and CV death (HR: 2.29; 95% CI: 1.41–3.73; p < 0.001) in 58–80 years old patients [32]. ST2 has recently been found to be correlated with CVD in CKD patients as well. A meta-analysis including 15 studies suggested that elevated sST2 levels were associated with CVD mortality (HR: 1.68; 95% CI: 1.35–2.09), total CVD events (HR: 1.88; 95% CI: 1.26–2.80), and heart failure (HF) (HR: 1.35; 95% CI: 1.11–1.64) in CKD patients aged 47–66 years [33]. For elderly patients, a retrospective study of 218 patients (age 68.31 [57.62–75.47]) showed that sST2 was associated with cardiac remodeling in patients at different stages of CKD (36 patients at stages 1–2, 42 patients at stage 3A, 57 patients at stage 3B, 62 patients at stage 4, and 21 patients at stage 5). These authors speculated that ST2 was likely involved in this process by decreasing the availability of IL-33 [11]. In addition, a study of 420 participants (age 70.13 ± 10.51, CKD stages 3–5) indicated that the predictive value of sST2 is also applicable to CVD in elderly CKD patients and that the optimal critical value of sST2 for detecting HF in these patients was 30.55 ng/mL [12]. Moreover, Mirna et al. [34] reported that there was no significant increase in sST2 in patients with CKD, even in those with advanced CKD (epidermal growth factor receptor [eGFR] <30 mL/min/1.73 m² BSA), and the level of sST2 showed no correlation with the eGFR. Various studies have also suggested that sST2 has low biological variability and is not easily disturbed by age, sex, diabetes, or dialysis. All of these findings indicate that ST2 can be used to assess the risk of CVD elimination caused by various interfering factors, even in elderly individuals [33]. However, higher levels of sST2 are not significantly related to electrocardiographic abnormalities in CKD patients, as suggested by cross-sectional analysis [35] and more research is needed to determine the reason for this contradiction.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is recognized as a traditional marker of myocardial stress, which may also increase in ischemic states [31]. For ruling in HF, age-adjusted cut points of NT-proBNP have been established: ≥450 pg/mL for patients under 50 years, ≥900 pg/mL for patients aged 50–75 years, and ≥1,800 pg/mL for patients over 75 years [36]. Its use as a predictive biomarker of CVD in CKD patients aged 52–88 has also been found for its noticeable elevation in such people, especially in hemodialysis ones [37, 38]. A prospective study even suggested that NT-proBNP was superior to echocardiographic parameters as a predictor of poor cardiovascular results in adjusted multivariate analysis [39]. For elderly patients, a cohort study of 120 elderly samples (age 69.5 ± 7.5, CKD stages 1–5) from China showed that serum NT-proBNP levels increased successively in normal control group, CKD without chronic heart failure (CHF) group, CKD combined with CHF group (p < 0.001) [13]. While another study of 269 patients (age 71.05 ± 8.44) suggested the threshold of NT-proBNP for diagnosing HF in elderly patients with CKD at different stages increases with the deterioration of renal function, namely, stage CKD 1: 407 pg/mL, stage CKD 2: 1,211.5 pg/mL, stage CKD 3: 3,482 pg/mL, and CKD stage 4∼5: 6,512 pg/mL [14]. The related mechanisms have been studied: the impaired kidney function results in a negative correlation between NT-proBNP and renalase plasma levels, accompanied by increased sympathetic nerve activity, which have an impact on the development of hypertension and cardiovascular complications [40]. The above content has shown the relationship between NT-proBNP and the kidney function. Some people may be reluctant to use NT-proBNP as a biomarker for CVD in CKD patients because they worry that the elevated level of NT-proBNP may only reflect the decrease in clearance resulting from the decrease in eGFR. However, several studies have suggested that although NT-proBNP has a definite correlation with eGFR, it can still be used as a biomarker of CVD in CKD patients [41, 42]. For instance, a study by Mahmood et al. [43] demonstrated that serum NT-proBNP concentrations in CKD patients far exceeded the increase expected due to reduced renal clearance alone. Therefore, the serum NT-proBNP level reflects the burden of CVD in this population. In addition, the combined model of sST2 and NT-proBNP was shown to be superior to the model of sST2 or NT-proBNP alone, and the difference was statistically significant (p < 0.05) in the study of Ma et al. [12], which provides a new idea for the combined application of these two indicators.

Human hypersensitive troponin T (HsTnT) is considered a marker of myocardial ischemia and increases with severity [31]. Under normal circumstances, the level of it is less than 0.05 ng/mL. Compared with the traditional biomarker cardiac troponin T (cTnT), it has been found higher sensitivity and precision for the diagnosis of myocardial injury. Concretely speaking, hsTnT can detect clinically significant increases in 1–3 h after myocardial injury, without waiting for 2–4 h of the traditional cTnT. Hs-cTnT also has a higher detection rate on admission, which can enable 30% of patients to be diagnosed earlier. Besides, hs-cTn methods are characterized by a low intraindividual index of variation (<0.6) and reduced analytical imprecision (about 5% CV) at the clinical cutoff value (i.e., the 99th percentile URL value) [44, 45]. Recently, hsTnT was also found to be correlated with CVD, including HF, atherosclerosis, and stable coronary artery disease (CAD) in CKD patients of all ages [41, 46‒52]. Moreover, compared with NT-proBNP and ST2, hsTnT has the strongest association with atherosclerotic outcomes in CKD patients [31]. In contrast to ST2, it is also correlated with the ECG and echocardiographic measurements of CKD patients [35, 53]. For elderly patients, a study enrolling 489 participants (age 70.68 ± 13.43 CKD stages 2–5) indicated that hsTnT can be used as a diagnostic indicator for acute myocardial infarction in CKD patients, and the optimal cutoff value of hsTnT for diagnosis in such patients may be 129.45 ng/L. However, in different stages of CKD, eGFR range-specific optimal cutoff values of hsTnT are also different [15]. In addition, of the troponin assays, the hsTnT concentration appears to be most stable across eGFR categories and is associated with CVD mortality [54]. The study by Kang et al. [55] also suggested that hsTnT is strongly associated with alterations in left ventricular structure and diastolic dysfunction in CKD patients, regardless of the estimated glomerular filtration rate strata. The mechanism behind these relationships is not clear. Some researchers speculate that dysregulated oxidative stress could contribute to heart damage via cellular signaling disruption. Under oxidative stress conditions, a decrease in antioxidant enzyme activity increases hsTnT levels, indicating cardiac structural abnormalities [56]. However, there is a study contrary to the above findings. Their study revealed no association between changes in hsTnT and incident HF or atrial fibrillation (AF) in CKD patients [57]. As a consequence, more research is needed to determine the reasons for this discrepancy.

Growth differentiation factor 15 (GDF-15), a member of the TGF-β family, is a stress-responsive cytokine. It is highly expressed in cardiomyocytes, adipocytes, macrophages, endothelial cells, and vascular smooth muscle cells under normal and pathological conditions [58]. Clinical trials have reported that GDF-15 is a reliable biomarker for CVD and HF [15]. The more recognized GDF-15 level standard at present: normal range, less than 1,200 ng/L; slightly elevated, 1,200 ng/L–1,800 ng/L; significantly elevated, more than 1,800 ng/L. The association has also been found between GDF-15 and CVD in CKD patients recently [31, 59, 60]. For instance, a study of 2,372 participants aged 56 ± 11.6 indicated that the association between GDF-15 and atherosclerotic events in CKD patients was statistically significant (HR: 1.44; 95% CI: 1.19–1.73) [31]. Compared to controls, HF in 60.3 ± 17.6 years old CKD patients also demonstrated increased circulating levels of GDF-15 (p = 0.014), as indicated by the study of Claus et al. [60]. They suggested adding GDF-15 activity to a base model (consisting of clinical covariates and NT-proBNP) resulted in a significant increase of the AUC for the diagnostic value of HF from 0.785 to 0.902. For elderly patients, a study of 231 CKD patients (age 64 ± 7, CKD stages 3–5) showed that GDF-15 was significantly associated with major adverse cardiovascular events after adjustments for baseline age, sex, microalbuminuria, and kidney function (hazard ratio per standard deviation increase: 1.43 [95% CI: 1.03–1.98]) [16]. In terms of mechanism, it has been found that GDF-15 can protect the kidney by inhibiting the cardiomyocyte apoptosis through the PI3K/AKT signaling pathway [61]. For CVD, an animal study showed that GDF-15-overexpressing mice (MIC-1/GDF-15fms mice were crossed with syngeneic C57/BL6 ApoE^−/− mice so as to generate ApoE^−/−fmsMIC-1 mice, which were used in this study) had smaller atherosclerotic lesions when measured in the late stage of disease. Another animal study revealed that GDF-15 can improve myocardial infarction in reducing the infarct size and the mortality by inhibiting polymorphonuclear leukocyte infiltration [62]. Tang et al. [61] suggested that GDF-15 increases rapidly with the occurrence of myocardial ischemia or reperfusion injury and inhibits inflammatory mediators such as TNF-α and IL-1β to combat atherosclerosis and myocardial infarction. Another cohort study involving 1,823 participants (age 61 ± 10) reported that circulating GDF-15 was positively correlated with carotid-femoral pulse wave velocity and negatively correlated with after multivariate adjustment, which may also represent a protective mechanism in such patients [63].

However, several studies have reported opposite results. A post hoc biomarker study of 861 patients (mean age 64 ± 9) indicated that the ability of GDF-15 to predict renal and cardiovascular events in CKD patients was rather modest [64]. Another observational cohort study conducted by Courtney Tuegel et al. [65] suggested that although GDF-15 was associated with HF events (HR per 1-SD higher, 1.56; 95% CI: 1.12–2.16), no correlations were found between GDF-15 and atherosclerotic CVD in those with kidney disease. Some researchers have even professed that they did not find evidence for the association between GDF-15 and CVD comorbidity [66]. In brief, the relationship between GDF-15 and CVD in elderly CKD patients is still uncertain, and further studies are needed.

Lymphocytes, which play a crucial role in adaptive immunity and used as an important indicator of infection, have also been considered early diagnostic markers of CKD in many previous studies [67]. Lymphocytes account for 20%–40% of blood cells in normal condition. Recently, the presence of B lymphocytes, a member of the lymphocyte family, was thought to be associated with CVD in CKD patients [68]. For instance, a study of 104 patients (age 64.8 ± 15 years) revealed that a CD19(+) B-cell count <100 cells/mL at baseline was associated with CV mortality [69]. Another study including 219 elderly (age 81.9 ± 4.8, CKD stages 3–4) participants suggested that subclinical atherosclerosis (measured by intima-media thickness) was negatively correlated with total CD19(+), B lymphocytes (R = −0.209, p = 0.012), CD19(+), CD5(+), B lymphocytes (R = −0.195, p = 0.020), and CD19(+), CD5(−) B lymphocytes (R = −0.208, p = 0.013) in elderly CKD patients [17]. Several studies have shown that B cells have a protective effect on atherosclerosis, primarily via the production of IgM antibodies, which can recognize apoptotic cells, oxidize LDL, and limit foam cell formation and oxidize LDL-induced endothelial activation [68]. Moreover, it has also been reported that B lymphocytes are negatively correlated with ventricular hypertrophy-related echocardiographic parameters in elderly CKD patients, which indicates that B lymphocytes might also be involved in the cardiac remodeling process in these patients [17]. Overall, although studies on the relationship between B cells and CVD in elderly patients with CKD are limited and that B cells are only shown to be associated with limited types of CVD, these findings have provided a new idea for the diagnosis and treatment of CVD in these patients.

The neutrophil-to-lymphocyte ratio (NLR) is an emerging composite marker of systemic inflammation [70]. The NLR can be obtained from routine blood tests and has the advantages of wide availability and low cost, making it a novel biomarker for various chronic diseases. The normal range of NLR in healthy adults was 0.88–4.00. Multiple studies have also shown that the NLR is associated with various CVDs in CKD patients, including nighttime hypertension, cardiac valvular calcification, arterial stiffness, and peripheral artery disease [71‒77]. For example, the NLR is independently related to endothelial dysfunction and can predict composite cardiovascular endpoints independent of traditional confounding factors in patients with various stages of CKD, as suggested by a study of 225 participants aged 25–70 years old [78]. A meta-analysis of 10 cohort studies indicated that the NLR is a predictor of cardiovascular events in CKD patients (HR: 1.52, 95% CI: 1.33–1.72). For the elderly population, the subgroup analysis of this study showed that there was no statistically significant difference between the older and younger subgroups [18]. Another study of 220 elderly participants (age 75.98 ± 7.06, CKD stages 3–5) from China also indicated that the NLR of the CKD combined with HF group was 3.27 ± 0.70, which was greater than that of the non-HF group (2.23 ± 0.50), and the difference was statistically significant (t = 12.847, p < 0.001) [19]. The NLR affects the counts of neutrophils and lymphocytes involved in two immune pathways, resulting in an inflammatory imbalance and causing exacerbation in patients with CKD [18]. However, a study by Yuan et al. [79] suggested that there was no significant association between an abnormal NLR and the risk of CVD in CKD patients. The NLR may predict CVD and all-cause mortality only in stage 5 CKD patients. Chen and Yang [80] reported that CKD patients in the CVD event group had a high NLR (p < 0.01). The adjusted binary regression analysis showed that there was no relationship between a high NLR and CVD events (OR: 1.21; 95% CI: 0.52–2.85; p = 0.44). Even for patients with underlying severe CAD, no conspicuous increase in the NLR was found [81]. In summary, there remains controversy about the relationship between the NLR and CVD in elderly CKD patients. Nonetheless, because it is convenient and inexpensive, the NLR is still a candidate biomarker worthy of further research.

The platelet-to-lymphocyte ratio (PLR) is an integrated reflection of two opposite thrombotic/inflammatory pathways that have been extensively studied in various diseases, such as malignant tumors, hypertension, heart disease, and vascular disease [82‒85]. Multiple studies have also reported that the PLR has a predictive value for the progression of CKD and hemodialysis [86‒88]. Recently, a correlation has been found between the PLR and CVD in CKD stages 1–5 patients [89, 90]. For instance, a study of 70 CKD patients (age 49.83 ± 10.78) indicated that patients in the CVD group had a higher PLR than did those without CVD (t < 0.01), and the correlation between a high PLR and CVD events was significant (OR: 1.05; 95% CI: 1.02–1.08; p < 0.01) [80]. For elderly patients, Liu et al. [20] conducted a case-control study enrolling 106 hemodialysis patients (patient group: 49 patients with cardiovascular or cerebrovascular accidents; age 70.39 ± 7.16; control group: 57 patients without the two conditions; age 69.61 ± 5.99), which suggested that there were significant differences in the PLR between the two groups (p < 0.001). PLR has diagnostic value for such patients [20]. Mechanistically, various factors cause endothelial cell damage and local inflammation, promoting the formation of atherosclerotic plaques. The formation of plaques not only leads to vascular stenosis but also increases the risk of rupture, which releases plaque materials into the vascular lumen, causing platelet activation, aggregation, and thrombosis. High platelet counts are a reflection of this change in platelet count. A low lymphocyte count indicates a low immune response, which is associated with adverse outcomes of CVD [20, 91, 92]. In conclusion, the diagnostic value of the PLR has been proven in previous studies, but the specific threshold seems to be unclear and still needs more research.

Neutrophil gelatinase-associated lipocalin (NGAL) is a protein secreted by activated neutrophils that has attracted much attention as a novel indicator of AKI and CKD [93, 94]. The average concentration of NGAL in plasma of healthy people was 63 ng/mL and the normal range is 3–106 ng/mL. NGAL has also been reported to be associated with CVD, even in elderly patients [95]. Recently, it has been found that NGAL plays a significant role in vascular remodeling, atherosclerotic plaque stability and thrombus formation in CKD patients. An increase in NGAL can be used to detect CVD and CVD progression in elderly people [96‒99]. A cohort study of 186 elderly patients (age 65.58 ± 2.89 CKD stages 3–5) revealed that serum NGAL levels were significantly greater in patients in the CKD-CVD group than in those in the CKD-NCVD group (p < 0.05) [21]. Several studies have focused on the underlying mechanism involved. NGAL can mediate epidermal growth factor receptor (EGFR) signaling, which activates and stimulates hypoxia-inducible factor (HIF-1α) and ultimately enhances renal injury and CKD progression. In CVD, NGAL can be connected to MMP-9, which increases the activity of MMP-9 and protects against its degradation, ultimately contributing to fibrosis in the heart. NGAL is also involved in the development of cardiorenal syndrome, which may also explain its mediating role between the two diseases [94]. In brief, NGAL is correlated with CKD complicated with CVD, which provides a new direction for subsequent research.

α-Klotho (Klotho) is a type I transmembrane protein that is mainly expressed in the kidney (in both the proximal and distal tubules) [100]. It was initially considered to have an anti-aging effect, and later studies revealed its predictive value for CKD. The normal range of klotho protein in adult blood is 300–1,200 pg/mL. Recently, multiple studies have indicated that a decrease in Klotho may be directly pathogenic for CKD-associated CVD, suggesting that it can be used as an independent early biomarker for such patients [98, 101, 102]. Furthermore, it has been proven to have the same value for elderly individuals. A study by Li et al. [22] involving 80 elderly CKD patients (experimental group: patients with CKD and cardiovascular complications, mean age 68.57 ± 6.53 years; control group: patients with CKD without cardiovascular complications, mean age 67.72 ± 6.25 years) indicated that the level of Klotho in the experimental group was significantly lower than that in the control group (p = 0.00). The authors also reported that the level of Klotho was negatively correlated with cardiac function classification (p = 0.00) [22]. Another study including 103 patients (age 67.3 ± 7.9 CKD stages 3–4) showed that compared with CKD patients without subclinical atherosclerosis, CKD patients with this clinical status had decreased serum and mRNA expression levels of Klotho in their PBCs. The optimal cutoff value for serum Klotho for subclinical atherosclerosis in these patients was 553.04 pg/mL (a specificity of 56.8% and a sensitivity of 88.1%) [23]. In the cardiovascular system, Klotho appears to regulate intracellular calcium homeostasis as well as inhibit reactive oxygen species, thereby reducing myocardial hypertrophy, fibrosis, and cardiotoxicity, as reported by an animal experiment [103]. Another study demonstrated that Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress by regulating the LOX-1 and PI3K/Akt/eNOS pathways, which attenuates endothelial dysfunction and ameliorates atherosclerosis [104]. Consequently, the onset of CVD often means that the protective function of Klotho has been impaired and inhibited. Some researchers have also studied the genetic mechanism and reported that the presence of the T allele of the SNP rs495392 in the Klotho gene is associated with a decrease in the odds of progression of atheromatosis in CKD patients [105]. However, several studies have indicated that Klotho deficiency is not related to left ventricular hypertrophy development and arterial stiffness [106]. The relationship between klotho and several CVDs is still controversial, and the underlying mechanism is not yet clear; further studies are needed.

C-reactive protein (CRP), an acute phase protein, is primarily produced and secreted by the liver. It has been found as an important indicator associated with aging-related diseases including CVD, hypertension, diabetes mellitus, kidney disease and cognitive decline [107, 108]. The normal range of C-reactive protein is 0.068–8.2 mg/L and exceeding this range often indicates the occurrence of infection or certain diseases. Various studies have also found the correlation between CRP and CVD in CKD patients recently [109‒112]. For example, a case-control study of 200 participants (mean age 54) in India suggested that higher mean values of hs-CRP (34.28 mg/dL) were found to be an independent predictor for the assessment of CV events in patients with CKD stages III and IV as determined by χ² test [113]. For elderly patients, a study of 3,166 participants (age 69.42 ± 7.74 CKD stages 3–5) showed that the majority of cardiovascular events occurred in CKD patients with high hs-CRP levels according to Kaplan-Meier survival curves [24]. Another study of Tokuda enrolling 516 patients (age 72.5 ± 9.7 CKD stages 3–5) also suggested that CRP level ≥2.0 mg/L was found to be a significant predictor of major adverse cardiovascular event in CKD patients with stable CAD undergoing percutaneous coronary intervention (HR: 1.54, 95% CI: 1.04–2.28, p = 0.003), as well as estimated glomerular filtration rate (HR: 0.98, 95% CI: 0.97–0.99, p < 0.01) [25].

Many researchers have studied the related mechanisms involved. A study suggested that CRP activates TGF-β/Smad signaling through TGF-β1-dependent and TGF-β1-independent mechanisms, mediating tissue fibrosis in many cardiovascular and renal diseases [108]. Henze et al. [114] conducted in vitro and animal experiments and suggested that vascular CRP expression was increased in a klotho-hypomorphic mouse model of aging and in human aortic smooth muscle cells under calcifying conditions. They also found that CRP promoted osteo-/chondrogenic transdifferentiation and aggravated phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of primary human aortic smooth muscle cells. These effects were paralleled by increased cellular oxidative stress and corresponding pro-calcific downstream signaling. Antioxidants or p38 MAPK inhibition can suppress CRP-induced osteo-/chondrogenic signaling and mineralization. In addition, silencing of the Fc fragment of IgG receptor IIa (FCGR2A) was also found to blunt the pro-calcific effects of CRP, which may also be involved in the progression of vascular calcification [114].

However, a study of 80 participants revealed a significant difference in hs-CRP between the ESRD and ESRD/CVD groups from the CON group (p < 0.0001) but not between the ESRD and ESRD/CVD groups [115]. There was also no significant difference in hs-CRP levels between HD patients with and without CVD (p > 0.05). Univariate analysis of variance showed that there was no significant relationship between hs-CRP and CVD (p > 0.05), as indicated by a study of 120 CKD patients [116]. In short, although researchers have long studied the function of CRP as a biomarker for CVD in CKD patients, this relationship is still controversial, and more mechanistic studies are needed to elucidate the underlying reasons.

Patients with CKD often exhibit endothelial dysfunction and increased coagulation [117]. Common coagulation and fibrinolysis indicators include coagulation factor VIII (FVIII), D-dimer, antithrombin-III (ATIII), plasminogen, and fibrinogen. These genes are correlated with CVD in CKD patients.

Coagulation FVIII is an essential cofactor in the coagulation cascade and a strong risk factor for general venous thromboembolism (VTE). The normal value of it is 50 U/L–135 U/L. Prospective studies have also shown that FVIII activity can predict the occurrence of CKD and a rapid decrease in the eGFR [118, 119]. A prospective cohort study of 1,233 participants (294 patients with VTE, age 69 ± 8, CKD stages 3–5) indicated that both FVIII and D-dimer play roles in the association of CKD with VTE, while FVIII plays an even greater role [26]. Ocak et al. [120] reported that FVIII may mediate the association between renal function and VTE. FVIII functions mainly as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. In addition to coagulation, FVIII is also involved in HSC maturation, macrophage function (which contributes to joint health), bone formation, and potential angiogenesis. However, the specific mechanism underlying its relationship with CVD remains to be studied.

D-dimer, the end product of the plasmin-mediated degradation of cross-linked fibrin, is a marker of coagulation state dependent on fibrin generation and subsequent degradation by the endogenous fibrinolytic system [121]. It is generally believed that the normal value of D-dimer is less than 0.5 mg/L. Various disorders involving excessive activation of the coagulation system are associated with highly elevated D-dimer levels. For CKD individuals, D-dimer is also one of the key predictors of thrombotic complications in them, as indicated by a study of 90 participants (CKD patients, age 66 ± 13) [122]. We did not find many studies focusing on the underlying mechanism, and the following possible mechanisms may partly account for the prognostic value of D-dimer elevation. First, elevated D-dimer levels can reflect hypercoagulability and a prothrombotic state. Second, the D-dimer level may serve as an indirect marker of the inflammatory state. Finally, a higher D-dimer level was also correlated with the extent of coronary stenosis and a larger myocardial infarct size [123].

ATIII is a pleiotropic molecule with anticoagulant and anti-inflammatory effects [124]. According to study of Sun et al. [27] including 4,197 CKD patients (age 64.18 ± 13.81 CKD stages 1–5), ATIII may also serve as a mediator between chronic renal insufficiency and chronic CAD.

Soluble urokinase plasminogen activator receptor (suPAR) is a new biomarker involved in many intracellular reactions, including cell adhesion, differentiation, proliferation, and migration [125]. It is generally believed that the normal value of it is less than 1.5 ng/mL. As a multifunctional cell signaling coordinator, suPAR is also related to various diseases, including chronic and acute kidney disease [126‒128]. Various studies have shown that suPAR is correlated with cardiovascular complications in CKD patients [28, 129‒131]. For instance, a study of 64 hemodialysis patients (age 66.4 ± 13, undergoing hemodialysis treatment) suggested that patients with a history of CAD had considerably greater suPAR levels (14.9 vs. 9.6 ng/L; p = 0.012). They also detected differences between baseline suPAR levels in patients with and without diagnosed HF (15.1 vs. 9.1 ng/mL; p = 0.0004) [129]. In terms of mechanism, SuPAR can activate β3 integrin by binding to β3 integrin, leading to podocyte disappearance and podocyte apoptosis [28]. An animal study suggested that a mouse model with high suPAR levels possessed aortic tissue with a proinflammatory phenotype, including monocytes with enhanced chemotaxis similar to that observed in atherogenesis, which may reflect several potential mechanisms [132].

Fibrinogen is synthesized mainly by hepatocytes and is a biomarker of thrombosis and inflammation [133]. Higher fibrinogen levels have been identified as a risk factor for cardiovascular events in the general population [134‒136]. The normal range of fibrinogen is 2–4 g/L. Several studies have also suggested that fibrinogen is an independent predictor of cardiovascular events in patients with CKD [113, 137]. A study of 978 elderly CKD patients (age 73.6 ± 8.6 years) suggested that serum levels of fibrinogen were greater in patients with CAD than in non-CAD patients (p < 0.05). Fibrinogen-to-albumin ratio levels were independently associated with the presence and severity of CAD in stages 3–5 pre-dialysis CKD patients [29]. Previous studies have shown that higher plasma concentrations of γ-fibrinogen lead to the formation of blood clots that are highly resistant to fibrinolysis, thereby increasing the risk of CVD [138]. However, fibrinogen was not significantly associated with apparent treatment-resistant hypertension according to the study of Chen et al. [139]. Therefore, its relationship with specific CVDs still needs more research. In brief, although several studies related these coagulation and fibrinolysis indicators to CVD in patients with CKD, more studies still need to be conducted to prove their universal feasibility.

This review outlines four categories of potential early biomarkers of CVD in elderly CKD patients, including circulating cardiac, blood cell, protein, coagulation, and fibrinolysis indicators. Most of them have been shown to be correlated with such patients and can be used in their diagnosis and treatment. However, as we can see from the above, there are also controversies and unclear findings impairing the predictive and curative value of several biomarkers, such as contrary results in other studies, a lack of studies on elderly individuals, and unclear mechanisms underlying the results. Thus, more studies are needed, particularly mechanistic studies and larger scale clinical trials. Nonetheless, an increasing number of serum biomarkers have been identified and confirmed for these patients, providing new methods for their diagnosis, evaluation, and treatment, which will greatly improve the prognosis of CVD in elderly CKD patients.

No potential conflict of interest was reported by the authors.

The authors have no funding sources to declare.

Bohua Zhang contributed to conceptualization and writing the manuscript. Ruoxi Liao critically revised the manuscript. All authors approved the final manuscript.