Association between fibrinogen/albumin ratio and severity of coronary artery calcification in patients with chronic kidney disease: a retrospective study

Introduction

Chronic kidney disease (CKD) is a widespread disease among the many chronic diseases that inflict great harm upon the world population. The incidence of CKD in China has reached 10.8% and is still on the rise (Sun et al., 2020), and has become a critical public health concern. Most CKD patients eventually die from cardiovascular-related complications due to the high mortality rate that is often related to coronary artery calcification (CAC) (Turakhia et al., 2018; Bundy et al., 2019). Vascular calcification (VC) occurs in the early stages of CKD and gradually worsens as the disease progresses. VC results in thickening and stiffness of the muscularis layer of the arterial wall, and is primarily caused by calcification of the medial layer. Unlike atherosclerosis, medial calcification is similar to osteogenesis and is mainly regulated by vascular smooth muscle cells (VSMCs) (Ottolini & Sonkusare, 2021). One of the main mechanisms of VC is the accelerated rate of VSMC synthesis and senescence, decreased contractile protein expression, and gradual transdifferentiation into an osteoblastic/chondrocyte phenotype that releases matrix vesicles (Chen, Zhou & Yang, 2021). When high phosphate levels are present, differentiation of VSMCs into a bone/chondrogenic phenotype can occur (Voelkl et al., 2018). In the clinical course of CKD patients, in addition to high levels of phosphate and parathyroid hormone, other factors that promote VC include oxidative stress and inflammation.

Coagulopathy is a common symptom of CKD patients. Clot formation is delayed, but at the same time there is a slower rate of clot decomposition and increased clot strength. Fibrinogen is a glycoprotein produced and secreted by the liver that eventually distributes to the serum. CKD leads to increased fibrinogen levels in the body, which ultimately mediates the increased clot strength (Nunns et al., 2017).

Many other studies have shown that hypoalbuminemia is closely related to CKD. Several recent studies have reported the relationship between cardiovascular disease (CVD) and the fibrinogen/albumin ratio (FAR), confirming the relationship between CVD and FAR, a marker of systemic inflammation. In addition, FAR has important prognostic value in the assessment of end-stage renal disease (Zou et al., 2020) and acute coronary syndrome (Çetin et al., 2020). Among them, Zou et al. (2020) believe that FAR can be used as a key indicator to provide a predictive program for peritoneal dialysis all-cause mortality and CVD mortality in assessing the prognosis of patients with end-stage renal disease. Studies related to coronary heart disease have found that contrast-induced nephropathy after carotid angiography is generally associated with patients who have high FAR values (Ertas, Avci & Kiris, 2019). In patients with stable coronary heart disease, high FAR values are also associated with the formation of coronary artery side branch circulation (Zhao et al., 2020). After a comprehensive consideration of the medical literature, we aimed to retrospectively study possible correlations between FAR and CAC in CKD patients.

Materials and Methods

Results

Discussion

In our study of CKD patients we found that if the FAR value is higher, the prevalence of CAC is higher. We detected CAC in 54.8% of the total samples. We found that older age and a longer time since beginning dialysis, as well as higher levels of BMI, serum phosphate, PTH, hs-CRP, NLR and FAR were significantly positively correlated with a higher detection rate of CAC. CKD patients who smoked or had disease stage 5d were more likely to be diagnosed with CAC. Our findings are consistent with those of other researchers. Mizuiri et al. (2021) showed that many factors significantly affect the probability of CAC in patients undergoing hemodialysis treatment, such as smoking, hs-CRP, diabetes, phosphate levels, gender, time on dialysis, age and blood calcium levels. Chen, Zhou & Yang (2021) studied the factors that affect radial artery calcification in patients with end-stage renal disease and found that calcium levels, HbA1c levels, duration of diabetes and duration of dialysis treatment are positively correlated with the degree of radial artery calcification.

Several studies have recently explored the relationship between FAR and CVD. Whether patients have ST-elevation myocardial infarction (STEMI) or non STEMI (NSTEMI), FAR can predict SYNTAX scores, and assess severity of cardiovascular diseases and prognosis (Erdoğan et al., 2021; Karahan et al., 2016a). In addition, an elevated FAR was significantly associated with no-reflow and short-term mortality in STEMI patients who had primary percutaneous coronary intervention (Xiao et al., 2019; Zhao et al., 2019). The FAR levels were significantly higher in patients with slow coronary blood flow and definitive coronary artery disease (CAD). It is evident that the FAR is very useful for predicting the course of the CAD process (Kayapinar, Ozde & Kaya, 2019). Zou et al. (2020) illustrated that the baseline FAR was a superior predictor of all-cause and CVD mortality in patients with continuous ambulatory peritoneal dialysis, compared to the established inflammatory markers.

Fibrinogen can be viewed as a reactive protein that reflects the acute phase of systemic inflammation, and at the same time it plays an important role in the normal operation of blood coagulation (Karahan et al., 2016b). During coagulation, thrombin converts fibrinogen to fibrin, which polymerizes and forms the protein meshwork of the growing blood clot. The coagulation-fibrinolytic cascades and the inflammatory response are closely interconnected, and there is evidence that fibrinolysis is a marker for the onset of systemic inflammation (Cvachovec, Horácek & Vislocký, 2000). In the development of inflammation, fibrinogen is conducive to the production of pro-inflammatory cytokines and promotes the development of inflammation (Gobel et al., 2018). The systemic inflammatory response and coagulation are closely related to CKD (Gäckler et al., 2019). At the same time, lymphocytes, monocytes, platelets and endothelial cells will be affected by fibrinogen and its degradation products resulting in changes to the inflammatory response, thereby changing blood flow, causing vascular endothelial damage and thrombosis (Abdul & Sultan, 2019). Enia et al. (2005) found that death from CVD in peritoneal dialysis patients is independently related to fibrinogen.

Albumin is synthesized and secreted by liver cells, which can maintain nutrition and osmotic pressure of the body, transport many insoluble small molecules of organic matter and inorganic ions, and participate in the inflammation process. Inflammatory response can induce barrier dysfunction, resulting in endothelial cell and albumin hyperpermeability and increased tissue oedema (Chen et al., 2019). Serum albumin, as an anti-inflammatory protein, has a protective anti-inflammatory effect during acute inflammation (China et al., 2018). CKD patients lose a large amount of protein in the urine due to renal failure that is often accompanied by hypoalbuminemia. An inflammatory state could give rise to hypoalbuminemia, which is an independent risk factor for heart failure and acute coronary syndrome. Moreover, the severity of CAD and hospital mortality are higher in patients with lower serum albumin (Kumar & Banerjee, 2017).

The occurrence of CAC is closely related to the inflammatory response. Fibrinogen and albumin as inflammatory markers may reflect the process of CAC through the following mechanisms. First, pro-inflammatory cytokines such as interleukin-1 will accelerate the synthesis of tumor necrosis factors under the action of fibrinogen. Then, these cytokines act to promote the transformation of VSMCs from the contractile to the bone/chondrogenic phenotype and they eventually become chondrocytes or adulterants (Voelkl et al., 2018). Second, under the action of fibrinogen and metabolites, endothelial function may become damaged, ultimately affecting endothelial cell permeability. Previous studies have shown that the production and progression of CAC are critically affected by vascular endothelial cells. Vascular endothelial cell abnormalities (i.e., abnormal function of morphological changes) due to any cause will promote CAC (Yung et al., 2015). Third, when hypoproteinemia occurs, patients may experience increased oxidative damage and inflammation. At the same time, the presence of cytokines makes it difficult to eliminate oxygen free radicals. For example, interleukin-6 can block the albumin synthesis pathway and elevated TNF-α selectively inhibits albumin gene expression and ultimately reduces the albumin level (Xiao et al., 2019). Finally, when the serum albumin level decreases, the blood becomes more viscous, promoting LDL-C modification to oxidized LDL-C, thereby aggravating VC (Milan et al., 2016; Ding & Manson, 2021).

The FAR predicts CAC, which may be primarily related to inflammation. Microinflammation is widespread in CKD patients, and is closely related to the increased mortality in dialysis patients (Amdur et al., 2019). The biological incompatibility of the dialysate, abnormal intestinal function, continuous accumulation of toxins produced by uremia and abnormal renal function are closely related to microinflammation. The three factors of VC, oxidative stress and microinflammation influence each other and ultimately increase cardiovascular morbidity and mortality (Schley et al., 2019). Other studies have focused on ratios or evaluation systems to study the relationship between these markers or between the markers and the mortality of CKD patients, such as FAR (Zou et al., 2020), platelet to lymphocyte ratio (PLR) (Duan et al., 2021), neutrophil to lymphocyte ratio (NLR) (Zhang et al., 2021) and Glasgow Outcome Score (GPS) (Cai et al., 2018).

In our study we found that inflammation markers such as NLR and hs-CRP were related to CAC, which is consistent with the results of previous studies. Li et al. (2020) found that the hs-CRP value was positively correlated with VC and believed that the cause was inflammation. Previous studies have shown that excessive CRP causes abnormal endothelial dysfunction. The influence of CRP weakens the activity and expression of endothelial nitric oxide synthase, and the production of nitric oxide is inhibited. In terms of CAC and angiogenesis, nitric oxide plays a key role (Batko et al., 2020). Therefore, when CKD patients have high hs-CRP values, it may be due to a sharp decrease in the amount of nitric oxide and abnormal endothelial function (CRP-mediated). Chandra et al. (2020) also concluded that NLR could be used when predicting VC in end-stage renal disease patients. Nam, Kang & Song (2017) studied Behçet disease patients and believed that CAC and NLR were independently correlated, while CRP, carotid artery intima-media thickness, and NLR were positively correlated (moderate).

Limitations

This study has several limitations. It was conducted at a single center and included a relatively small number of patients. In addition, FAR is a dynamic index and could differ from day to day. Therefore, analyses based on a single FAR measurement may not reflect the long-term relationship between FAR and CAC score. Another limitation is that the retrospective study design makes it difficult to explain the underlying cause of the relationship between CAC and FAR.

Conclusion

Our study shows that the FAR is positively correlated with CAC score. In CKD patients, higher levels of FAR are independently associated with CAC. FAR may serve as an easily measurable laboratory index for the prevalence of CAC in patients with CKD.

Supplemental Information