Fatty acid‐binding protein‐3 and renal function decline in patients with chronic coronary syndrome

Abstract Background Renal dysfunction is common in patients with coronary artery disease. Due to the shared vascular pathogenesis between the two conditions, novel biomarkers such as the fatty acid‐binding protein‐3 (FABP‐3) have been proposed for diagnosis and prognosis prediction. This multicentre prospective cohort study investigates the association between FABP‐3 and renal dysfunction. Hypothesis We hypothesized that higher FABP‐3 levels are correlated to worse renal outcome. Methods Patients with chronic coronary syndrome were classified into three groups based on the initial serum FABP‐3 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation was used to estimate the patient's renal function. Renal events were defined as >25% and >50% decline in estimated glomerular filtration rate (eGFR). Cox multivariable regression was employed to delineate the correlation between FABP‐3 and renal dysfunction. Results A total of 1606 subjects were included. During a mean follow‐up of 35.9 months, there were 239 patients with eGFR >25% reduction and 60 patients with >50% reduction. In the Kaplan–Meier survival curve and log‐rank test, increased levels of FABP‐3 were significantly correlated with eGFR >25% reduction (p < .001) and >50% reduction (p < .001). Multivariate Cox regression model revealed that subjects with higher FABP‐3 exhibited a greater risk of eGFR >25% reduction (Group 2: hazard ratio [HR] = 2.328, 95% confidence interval [CI] = 1.521–3.562, p < .001; Group 3: HR = 3.054, 95% CI = 1.952–4.776, p < .001) and >50% reduction (Group 3: HR = 4.838, 95% CI = 1.722–13.591, p = .003). Conclusions Serum FABP‐3 may serve as a novel biomarker to predict eGFR decline in patients with chronic coronary syndrome.


| INTRODUCTION
Chronic kidney disease (CKD), defined as abnormalities of kidney structure or a glomerular filtration rate (GFR) lower than 60 mL/min/ 1.73 m2 for more than 3 months, poses a significant public health burden with a global prevalence of around 13.4%. 1,2Despite the drastic increase in healthcare expenditure for the prevention and treatment of CKD, the number of patients suffering from end-stage kidney disease (ESKD) is expected to increase by 29%-68% in the United States by 2030. 3 Aside from the detrimental effect on the kidney, CKD is associated with a higher risk of cardiovascular disease (CVD). 4To delay the development of ESKD and improve CKD prognosis, early detection and management of CKD are crucial, especially for high-risk populations such as CVD patients. 5shared physiological mechanism underlying the pathogenesis of CKD and CVD is the disordered lipid metabolism. 6Recent studies have suggested that adipokines, such as the fatty acid-binding protein (FABP) family, are involved in the modulation of lipid metabolism and have the potential to serve as biomarkers or treatment targets for a variety of disorders, such as chronic inflammation, ischemic stroke, metabolic syndrome, atherosclerosis, and CVD. 7,8Among the FABP family, the heart-type FABP (H-FABP) or FABP-3 has been considered a possible biomarker for cardiac and renal injury.0][11] Also, patients with CKD are reported to have elevated levels of inflammatory and metabolic markers, such as omentin, 12 neuregulin, 13 serum uric acid, 14 kidney injury molecule, 15 prognostic nutritional index, 16 systemic inflammatory index, 17 uric acid/ HDL-cholesterol ratio, 18 and C-reactive protein, 19 indicating correlations between inflammatory markers and renal disease.Studies have shown that the elevation of serum FABP-3 concentration is associated with lower estimated GFR (eGFR) in type 2 diabetes mellitus (DM) patients 20 and a higher rate for acute kidney injury after cardiac surgery. 21However, most of the existing studies are cross-sectional or retrospective, which makes it difficult to infer the temporal relationship between FABP-3 and the decline of renal function.Also, the prognostic value of FABP-3 for kidney injury in high-risk population such as patients with CVD is unclear.
Since the relationship between FABP-3 and kidney injury in patients with CAD is still unclear, we aimed to examine the correlation between circulating FABP-3 and renal function decline in patients with chronic coronary syndrome.

| Study design
The research is based on the "Development of New Biosignatures for Atherosclerosis Cardiovascular Diseases" study, a multicentre cohort registry that prospectively enrolled a series of patients with the chronic coronary syndrome.This study protocol has been published previously. 22The patients with stable coronary artery disease (CAD) after successful percutaneous coronary intervention (PCI) were included from nine tertiary referral centers in Taiwan from 2012 to 2017.

| Patient
Subjects who fulfilled the inclusion criteria were enrolled: the presence of a significant CAD history after at least one PCI with coronary ballooning or stenting and remained clinically stable under medical treatment for at least 1 month before this enrolment.
Individuals who met any of the following circumstances were excluded: under treatment with a non-steroid anti-inflammatory drug, steroid, disease-modifying antirheumatic drug, or other biological immunosuppressants at enrolment or any time-point during follow-up, with underlying autoimmune diseases, had been hospitalized due to acute coronary syndrome in the recent 3 months, anticipated to receive coronary or other cardiac interventions in the following 1 year, undergoing therapy for compelling malignancy, mandatorily hospitalized for other systemic diseases in the following 1 year, with a life expectancy of fewer than 6 months, and failed to cooperate with clinical follow-up.
The study complied with the principles of the Declaration of Helsinki.Approvals from each hospital's independent ethics committees and review boards were obtained (IRB: AS-IRB01-19007).Informed consent was obtained from all subjects before participating in this study.

| Clinical assessment
A specially trained nurse documented demographic information following a standardized protocol from the chart or structured questionnaires.After being well-rested, the blood pressure (BP) values were measured using an electronic BP monitor operated by a trained nurse and recorded as the average of three consecutive measurements at the outpatient clinic ante meridiem.Hypertension was defined as a BP level exceeding 140/90 mmHg or using antihypertensive agents.All subjects were followed on an outpatient basis at the respective institutions.

| Biomarker measurement
Peripheral blood samples (20 cc) were collected for biochemical assessments.The samples were centrifuged before the sera were thawed for assessment.The levels of FABP-3, as well as baseline serum chemistry, including high-density lipoprotein-cholesterol (HDL-C), lowdensity lipoprotein-cholesterol (LDL-C), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP), were assessed at enrolment.Whereas renal function with creatinine was evaluated at the initial visit, every 3 months in the first year, and then at 6-month intervals.

| Renal events
Renal function, eGFR, was derived from serum creatinine level and demographic parameters based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). 18[28]

| Statistical analysis
Statistical Package for Social Sciences software (Version 21.0, SPSS Inc.) was used for analysis.Continuous variables were presented as mean ± SD, while categorical parameters were presented as numbers with percentages.All patients were divided into three groups (low, middle, and high) according to the FABP-3 tertile.Parametric continuous data between the three groups were compared using a one-way analysis of variance.Categorical data between the three groups were compared with a chi-square test or Fisher's exact test.The Kaplan-Meier curve and log-rank test were employed to assess the renal event rate based on FABP-3 levels.Multivariate analysis in conjunction with the Cox proportional hazard regression model was used to evaluate the independent association between FABP-3 levels and renal function decline.An adjustment was performed for potential confounding factors, including age, sex, BMI, systolic BP, diastolic BP, hypertension, DM, heart failure, use of antihypertensive agents, statins, baseline eGFR, HDL-C, LDL-C, NT-pro-BNP, and FABP-3.Each parameter's hazard ratios (HRs) and 95% confidence intervals (CIs) were presented.A twosided p value less than .05was considered statistically significant.

| Baseline characteristics according to the FABP-3 level
A total of 1606 patients with chronic coronary syndrome were included in this cohort study.The patients were categorized into three groups according to the baseline serum FABP-3 levels.The patients with the highest FABP-3 levels were the oldest (p < .001),having the highest systolic BP (p = .007),lowest diastolic BP (p = .047),highest rates of hypertension (p < .001),DM (p < .001),and heart failure (p < .001).They used more calcium channel blockers (p = .006)and diuretics (p < .001)but fewer statins (p = .002).In addition to the lowest LDL-C levels (p = .018)and the highest NT-pro-BNP levels (p < .001),patients with the highest FABP-3 levels had the highest creatinine levels (p < .001)and the lowest eGFR levels, which were consistent in eGFR values derived from CKD-EPI (p < .001),MDRD (p < .001),and CG equations (p < .001).Detailed information on the patients is listed in Table 1.2).
T A B L E 1 Baseline characteristics according to FABP-3 levels.

| FABP-3 level and eGFR decline according to MDRD and CG equations
During a mean follow-up of 35.9 ± 23.2 months, 274 and 286 patients had eGFR >25% reduction according to MDRD and CG equations, respectively.There were 60 and 58 patients with eGFR >50% reduction according to MDRD and CG equations, respectively.
In the Kaplan-Meier survival curve and log-rank test, increased levels of FABP-3 were significantly correlated with eGFR >25% reduction (p < .001for both equations) (Figures S1A and S2A) and >50% reduction (p < .001for both equations) (Figures S1B and S2B).Also known as the heart FABP (H-FABP), the FABP-3 is abundantly expressed in the myocardium and is released into circulation after a cardiac injury, such as myocardial infarction. 29searchers have suggested the potential of FABP-3 as a biomarker for CVDs, including heart failure and myocardial infarction. 9In our cohort, albeit with wide variation, the mean serum concentration of FABP-3 is slightly higher than that of the normal population. 30In combination with the fact that FABP-3 is cleared by the kidney and reports implicating FABP-3's renal toxicity, 21,31,32 we hypothesized that the elevation of FABP-3 in patients after cardiac damage might lead to deterioration of renal function.After correcting the baseline renal function and other potential confounders, the patient groups with higher baseline circulating FABP-3 have significantly higher risks of the deterioration of renal function, whatever formula is used for deriving the eGFR (Table 3, S1 and S2).

Multivariate analysis with the
Although causality is difficult to infer from a prospective cohort study, our findings met several elements of the Bradford Hill criteria for causality, such as temporality (i.e., high FABP-3 concentration precedes the renal event), dose-response (i.e., groups with higher FABP-3 concentration have higher HR for the renal event), and biological plausibility. 33Hence, one possible mechanistic interpretation of our results is that the FABP-3 released from the myocardial injury leads to further injury.Further studies must disentangle the relationship between FABP-3 and cardiovascular and renal dysfunction.
From the clinical perspective, the direct implication of this study is that physicians may consider to follow FABP-3 levels for patient with chronic coronary syndrome to assess the risk of renal damage.
Early renal-protective interventions can be initiated for high risk population to prevent the comorbidities of subsequent CKD. was the only parameter used to assess renal function.We did not include albuminuria into our study.More metrics for renal function, such as urinary albumin excretion, may provide additional information.Third, the dynamic changes in FABP were not documented, compromising the interpretation of the longitudinal effect of the post-CAD inflammatory burden.An extended follow-up period is also

| CONCLUSIONS
We revealed a clear relationship between elevated FABP-3 levels, inflammatory markers released after myocardial injury, and future decay of renal function in patients with chronic coronary syndrome.The results not only demonstrate that the FABP-3 might serve as a predictor for the clinician to prevent the progression to CKD for these high-risked patients but also suggest that FABP-3 itself may be a pharmacological target for preventing renal damage.

F
I G U R E 1 (A) Kaplan-Meier curve for >25% estimated glomerular filtration rate (eGFR) change based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.(B) Kaplan-Meier curve for >50% eGFR change based on the CKD-EPI equation.investigated the relationship between FABP-3 and the deterioration of renal function in patients with the chronic coronary syndrome.We found that increased serum FABP-3 concentration is significantly associated with future eGFR reduction estimated by the three most commonly used formulas.
necessary to observe the eventual prognosis of renal function impairment.Finally, contrast-induced nephropathy might confound the interrogation of renal dysfunction after PCI.Since the study enrolled only clinically stable patients under medical treatment for at least 1 month and excluded those who anticipated receiving coronary or other cardiac interventions in the following year, such an effect is considered minimized.
Cox regression model revealed that subjects with higher FABP-3 exhibited a greater risk of eGFR (MDRD) >4 | DISCUSSIONEarly detection of renal injury in high-risked populations such as patients with CVD is crucial to prevent CKD or ESRD; however, reliable predictors or biomarkers are lacking.In this prospective cohort study, weT A B L E 2 Cox regression (CKD-EPI equation).