Relationship between brinogen/albumin ratio and early renal damage markers in patients with hypertension

Aim:To investigate the relationship between brinogen/albumin ratio (FAR) and early renal damage in hypertensive patients. Patients & methods:A retrospective study included 626 patients with hypertension, grouped according to the FAR tertiles and the presence or absence of early renal impairment. Early renal damage indicators[Serum cystatin c and β2 microglobulin] were detected in each group, and the differences between groups were compared, and the factors affecting early renal damage indicators were analyzed. Results:Serum cystatin c(CysC) and β2 microglobulin(β2-MG) levels in patients increased with FAR. In the renal impairment group, the brinogen and FAR were signicantly increased, and serum albumin was decreased. FAR was positively correlated with β2-MG and CysC. Regression analysis showed that FAR level was a factor affecting blood β2-MG(β=6.632, p(cid:0)0.001)and CysC(β=1.991, p(cid:0)0.001). Conclusion:Elevated FAR is an independent risk factor for early renal damage in hypertensive patients relationship between inammatory markers and early renal injury indicators by multiple linear regression with blood β2-MG serum cystatin C dependent variables age, FAR level independent variables. The results showed that FAR level higher than those in the normal renal function group. The serum albumin level was signicantly lower than in the normal renal function group. The FAR level had a positive correlation with β2-MG and serum CysC. The results of multiple linear regression analysis showed that: FAR level is a factor affecting blood β2-MG and serum CysC, suggesting that for patients with hypertension and increased levels of inammatory factors, early renal damage more signicant. FAR level is related to the changes of blood β2-MG and serum CysC.


Introduction
Hypertension is the most common chronic disease in clinic [1], and also the most important risk factor for cardiovascular and cerebrovascular diseases. Its main complications, such as coronary heart disease, heart failure, and stroke, not only cause disability and have a high mortality rate, but also severely consume medical and social resources. Thus it can be seen that hypertension has become an important public health problem worldwide. The kidney is one of the important target organs for damage caused by hypertension. The early clinical symptoms of hypertensive nephropathy are not signi cant, but usually they are only manifested as increased blood pressure, which brings di culties to clinical diagnosis and treatment [2]. With the development of the disease, patients successively show abnormal changes such as increased serum creatinine(Scr) and blood urea nitrogen(BUN), microalbuminuria(mALB) and persistent urine protein, nally causing chronic renal failure or uremia. At this time, the kidney damage is often irreversible [3]. Blood β2-microglobulin (β2-MG)and serum cystatin C(CysC) are sensitive and reliable indicators re ecting early renal damage, and signi cantly superior to serum creatinine, urea nitrogen and other markers of renal injury [4,5].
Low-grade in ammation is an important factor to cause and maintain elevated blood pressure, and the levels of circulating in ammatory factors are closely related to the degree of hypertension and target organ damage [6][7][8]. Elevated in ammatory markers, including neutrophils [9], tumor necrosis factor-α [10] and brinogen [11], are common in patients with hypertension. As a marker of in ammation in the acute phase, Fibrinogen is associated with hypertension [12] and diabetes [13], and has an important pathophysiological role in aggravating the progression of kidney disease [14]. Albumin is an important factor involved in systemic in ammatory response, and its decreased serum level can enhance the in ammatory response [15,16]. Epidemiological evidence suggests that low serum albumin levels are associated with many cardiovascular diseases, such as coronary heart disease, hypertension and heart failure [17,18]. Therefore, we have found a new in ammation-based risk index, brinogen to albumin ratio (FAR). The study has con rmed the correlation between this new index of FAR and many diseases such as cancer [19], end-stage renal disease [20] and coronary artery disease [21], with strong clinical value. However, there are few studies on the relationship between FAR and early renal impairment markers. The purpose of this study was to explore the relationship between FAR and early renal impairment indicators in patients with hypertension. The exclusion criteria are as follows: various acute and chronic infectious diseases; Patients with chronic hepatitis, cirrhosis of liver, liver cancer, liver failure and other liver diseases in the past, or those who have taken drugs that affect liver function in the near future; Patients with primary glomerular disease, renal artery stenosis, and severe renal impairment; Complicated with chronic consumptive diseases such as malignant tumor, autoimmune disease, hematological system disease, thyroid disease, and tuberculosis; Secondary hypertension, coronary heart disease, diabetes, acute cardiovascular and cerebrovascular diseases;

Data Collection
Clinical data such as gender, age, body mass, smoking history, drinking history and hypertension course were recorded accurately, and body massindex (BMI) was calculated. BMI = body mass (kg)/ height (m)2.
All subjects were fasted for 10-12 hours one day before the experiment, and 4-5 ml venous blood was taken on an empty stomach in the early morning of the next day, and the serum was collected after centrifugation at 4 000 r/min. Blood biochemical tests were performed with Beckman AU5800 automatic biochemical analyzer, and the biochemical indexes such as serum albumin(Alb), urea nitrogen(BUN), serum creatinine(Scr), total cholesterol(TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), Serum uric acid(SUA) and blood β2 microglobulin(β2-MG) were measured. Serum brinogen(Fib) level was detected by coagulation method with Sysmex CS5100 automatic coagulation analyzer. The levels of brinogen and albumin were collected, and FAR was calculated as the ratio of brinogen to albumin. MDRD formula was used to calculate and estimate the glomerular ltration rate (eGFR) [22]: male: eGFR = 186×Scr(mg/dl) −1.154 × age (years) −0.203 ; Female: eGFR = 186×Scr(mg/dl) −1.154 × age (years) −0.203 ×0.742.

Statistical Analysis
Statistical analysis was performed using SPSS 26.0 (SPSS Inc.).Measurement data conforming to normal distribution were expressed as mean ± standard deviation. A Student , s t-test was used for comparison between two groups, one-way analysis of variance was used for comparison among multiple groups, and q test was used for pairwise comparison between groups. The measurement data of nonnormal distribution was expressed as M(P25, P75). The Kruskal-Wallis rank sum test was used for comparison among multiple groups, and Mann-whitney U test was used for pairwise comparison.
Enumeration data were compared using X 2 test; Pearson correlation analysis and Spearman rank correlation analysis were used for correlation analysis. Multifactor linear stepwise regression was used to analyze the in uencing factors of serum β2-microglobulin and cystatin C. The level of statistical signi cance for all the above tests was de ned at a probability value of less than 0.05 (P < 0.05).

Results
A total of 626 patients (mean age 58.98 ± 12.22 years, 360 men) with hypertension were included in the study.The baseline clinical characteristics and laboratory measurements of patients within the groups are presented in Table 1. Participants were grouped into tertiles, according to their FAR level.A signi cant positive association between age and FAR level was identi ed ( Table 1). The mean age in the lower group of FAR was 54.50 ± 11.12, which was signi cantly lower than the medium (59.68 ± 12.17) and high group   history, SBP, DBP, BMI, LDL-C, TC and HDL-C between the two groups (P > 0.05). The levels of Age, Duration of hypertension, Fib, FAR, SUA, BUN, blood β2-MG, CysC, Scr and mAlb in the renal impairment group were signi cantly higher than those in the normal renal function group. The levels of ALB and eGFR were signi cantly lower than those in the normal renal function group, and the differences were statistically signi cant (P < 0.05, Table 2, Fig. 2). Data are expressed as mean ± SD, or median (25th-75th percentiles), or number (percentage).FAR, brinogen/albumin ratio.
The results of correlation analysis showed that there was a negative correlation between FAR level and Alb in patients with hypertension (P < 0.05). They were positively correlated with Age, Duration of hypertension, LDL-C, Fib, blood β2-MG, CysC and mALB (p < 0.05). There is no correlation between FAR level and SBP, DBP, BMI, TC, HDL-C, Scr, BUN, eGFR and SUA. After adjusting Sex and Age, FAR was still positively correlated with β2-MG, CysC and mALB in blood (p > 0.05, Table 3). The relationship between in ammatory markers and early renal injury indicators was analyzed by multiple linear regression with blood β2-MG and serum cystatin C as dependent variables and age, disease course month and FAR level as independent variables. The results showed that FAR level was the in uencing factor of blood β2-MG(β = 6.632, p 0.001) and serum cystatin C(β = 1.991, p 0.001)( Table 4).

Discussion
The mechanism of renal damage caused by hypertension has not been elucidated, including hemodynamic and non-hemodynamic mechanisms. The involvement of immune in ammatory response in the pathogenesis of hypertensive renal damage has gradually become a hot research topic in recent years [23]. The main purpose of this study was to investigate the effect of FAR, an in ammatory marker, on early renal damage in patients with hypertension. Samples consisted of patients with essential hypertension, grouped according to the FAR tertiles and the presence or absence of early renal impairment. The levels of early renal impairment indexes and in ammatory markers were compared among different groups. The results showed that the serum CysC and β2-MG levels of patients in the M-FAR group and H-FAR group were higher than those in the L-FAR group. The levels of brin and FAR in the renal impairment group were signi cantly higher than those in the normal renal function group. The serum albumin level was signi cantly lower than that in the normal renal function group. The FAR level had a positive correlation with β2-MG and serum CysC. The results of multiple linear regression analysis showed that: FAR level is a factor affecting blood β2-MG and serum CysC, suggesting that for patients with hypertension and increased levels of in ammatory factors, the early renal damage was more signi cant. FAR level is related to the changes of blood β2-MG and serum CysC.
Hypertension is a low-grade in ammatory state disease, and in ammation plays an important role in the occurrence, development and complications of hypertension [24]. Persistent in ammation is also a key feature of CKD, which can lead to progressive renal brosis, endothelial dysfunction and other aggravating renal damage [25]. Fibrinogen, a precursor of brin, is produced by the liver and has a serum concentration of 2.0-4.0 g/L, which plays an important role in thrombosis and in ammatory reaction [26]. A large number of studies have found that serum brinogen levels are related to cardiovascular risk factors or cardiovascular events [27], and brinogen has also been found to be signi cantly associated with renal impairment. For example, Lin et al. [28] in a cross-sectional study of 732 T2DM men found that serum brinogen was associated with decreased glomerular ltration rate, and another study reported [14] that elevated serum brinogen levels in T2DM patients were associated with end-stage renal disease. Fibrinogen has been identi ed as an independent risk factor for death and cardiovascular events in patients with chronic renal disease Stage 3 and 4 [29]. Celik et al. [30] found that serum brinogen levels were independently associated with the risk of contrast-induced acute kidney injury in patients with acute coronary syndrome receiving coronary intervention (OR 1.006,95% CI 1.003-1.009,p < 0.001). In summary, chronic in ammatory conditions, re ected in elevated serum brinogen levels, may have exacerbated renal impairment. This study found a signi cant increase in plasma brinogen levels in patients with early renal impairment compared to patients with normal renal function, demonstrating that mean concentrations in patients with renal impairment were signi cantly higher than in patients with normal renal function.
Serum albumin is a synthetic protein of the liver that maintains the plasma colloid osmotic pressure, transports lipids, and participates in the processes of acute and chronic in ammation [15,31]. Serum albumin concentration is related to the increase of in ammatory load in vivo, and in ammation is related to the decrease of albumin synthesis and increase of catabolism [16]. Studies have shown that serum albumin level is a useful and reliable prognostic indicator for acute kidney injury [32]. An independent predictor of acute kidney injury in patients after PCI for acute coronary syndrome when serum albumin reduction at admission was identi ed [33]. The mechanism of kidney injury caused by low serum albumin is considered to be multi-factorial, including inhibition of platelet aggregation, increase of blood viscosity, reduction of antioxidant capacity, in ammatory response and destruction of endothelial function [16,17,34]. This study found that serum albumin levels decreased with the increase in in ammatory index levels, and serum albumin levels in patients with renal impairment were lower than those in the normal renal function group, which was consistent with the results of the above study.
It has been recently found that FAR is a novel in ammatory indicator that combines brinogen and albumin, and can more sensitively re ect the in ammatory state. Many studies have revealed the relationship between FAR and many diseases, including cardiovascular diseases. For example, that study by Mahmut et al. [35] indicate that FAR is a powerful predictor of early morning blood pressure increase in newly diagnosed and treated patients with primary hypertension and may be a bet predictor than single brinogen and albumin. In addition, FAR is signi cantly associated with the severity and short-term prognosis of coronary artery stenosis in patients with st-segment elevation myocardial infarction [36,37]. Notably, a recent study found that FAR was independently associated with the occurrence of PC-Aki (postcontrast acute kidney disease) [38]. Jing JuanYang et al. [32] revealed that preoperative serum brinogen was associated with the risk of acute kidney injury after heart valve replacement (OR = 1.212, 95% CI 1.1089-1.347, P = 0.003).
At present, the markers used for evaluating renal impairment mainly include Scr, BUN, CysC, β2 -MG, etc. Among them, CysC, which is used to re ect glomerular function, is an effective indicator for the assessment of glomerular ltration rate at present. With high sensitivity and strong speci city, it is less affected by factors such as gender, age, and muscle content, and is one of the ideal indicators for the assessment of early renal injury [39]. Ozer et al. [40] found that compared with traditional renal injury markers Scr and BUN, CysC is the best indicator for predicting renal function in primary hypertension patients with mild decreased GFR. β2 -MG, a small molecular protein, has a low but constant content in the body, which is a sensitive indicator for assessing renal tubular function. In the early stage of decreased glomerular ltration function, serum β2 -MG level can be increased, and increases with the aggravation of renal impairment. It is a sensitive indicator re ecting early lesions of hypertensive renal injury [41]. In this study, the relationship between the new in ammatory marker FAR and early renal impairment was explored for the rst time. The results showed that as the level of FAR increased, the levels of β2 -MG and CysC also increased, and there was a signi cant positive correlation between them. FAR level was a factor affecting blood β2-MG and serum CysC. With the increase of the value of FAR, the levels of β2 -MG and CysC increased by 6.362 and 1.991 respectively. It indicated that in ammation was a risk factor for early renal injury in patients with hypertension, and monitoring of FAR could well assess early renal impairment.

Limitations
Of course, the study has some limitations. First, our study results are based on a retrospective study design, and selection bias is inevitable. Second, this study was conducted in Chinese patients with hypertension, and no normal subjects were recruited as the control group. The results need to be veri ed in a healthy population and other ethnic groups. Third, the majority of the subjects included in the study with hypertension were in Grade 3 hypertension, and the proportion of other subjects was small, which limited the intensity of the results and conclusions of this study. Finally, we only measured albumin, brinogen, and FAR levels at admission; we did not perform continuous measurements of these parameters.

Conclusion& future perspective
This study has shown that elevated FAR levels are an independent risk factor for early renal damage in hypertensive patients and baseline FAR can provide a useful indicator of early renal damage in hypertensive patients and is superior to established in ammatory markers. Therefore, for patients with hypertension, in order to prevent target organ damage, we should pay attention to the treatment of in ammation while strictly controlling the blood pressure to reach the standard, in order to delay the occurrence of renal damage and reduce the risk of cardiovascular and cerebrovascular complications.

Declarations
Author Contributions: JD: Data collection, analyses and interpretation, and writing of the nal manuscript.
JD and YZ: Study design, Data interpretation and revising manuscript. The author(s) read and approved  Comparison of FAR between normal renal function group and Renal impairment group FAR brinogen/albumin ratio