Effect of renal function on high-density lipoprotein particles in patients with coronary heart disease

High-density lipoprotein (HDL) has been acknowledged as a protective factor for cardiovascular disease, as there is unequivocal evidence of the inverse association between the HDL-C level and the occurrence and mortality of cardiovascular disease [1]. However, in recent years, several clinical trials aiming to increase plasma high-density lipoprotein cholesterol (HDL-C) concentrations, such as the ILLUMINATE study, AIM-HIGH study and HPS2-THRIVE study, have failed to consistently obtain satisfying results, indicating that HDL particles and HDL function may play a more important role than the HDL-C level in plasma [2‐4]. HDL lipoproteins are in fact not intact particles, but consisting of components that differ in composition and function, yet the exact relationship between HDL particles, HDL function and cardiovascular diseases remains unclear.

Dyslipidemia is also closely associated with renal insufficiency. Chronic kidney disease is believed to be related to systemic inflammatory responses, and in recent years, evidence has shown that dyslipidemia may contribute to the development of kidney dysfunction [5]. Alterations in the distribution and quality of lipoproteins have been reported in multiple studies, but the findings appear to be inconsistent and even contradictory due to the complex nature of lipid metabolism. Large, mature HDL particles are generally considered to be anti-inflammatory and cardiovascular protective, and recently, studies have reported decreased amounts of larger HDL particles in patients with end stage kidney disease (ESRD) [6].

Due to the complicated compositions of HDL, nuclear magnetic resonance imaging (NMRI) is usually used to measure the diameter of HDL particles [7]; however, this specific method can be difficult to apply. In 2013, in a study based on the Women's Health study, the ratio of HDL-C to apolipoprotein A-I (apoA-I) was discovered to be linearly correlated with actual HDL diameter measured by NMRI, indicating that HDL-C/apoA-I can serve as a reliable biomarker representing HDL particle size [8].

In this study, the potential effect of kidney function on the value and size of HDL, represented by HDL-C/apoA-I, was explored in patients with coronary heart disease.

Dyslipidemia is an independent risk factor for cardiovascular disease, which is the leading cause of death in chronic kidney disease patients [9]. Renal deficiency has also been identified as an independent risk factor for coronary heart disease, as kidney deficiency may contribute to the development of atherosclerosis and is related to premature cardiovascular events [10]. Stack [11] et al. have reported that patients on hemodialysis had a 38% higher incidence of cardiovascular diseases, and other studies have also reported that for every 10 mL/(min·1.73 m²) reduction in eGFR, the occurrence of cardiovascular diseases can increase by 19% [12].

HDL has been widely acknowledged as a protective factor in both cardiovascular disease and chronic kidney disease patients, as it acts as an acceptor of cellular cholesterol and initiates reverse cholesterol transport by transferring peripheral cholesterol back to the liver. Lower plasma HDL-C levels are known to be associated with an increased occurrence of major cardiovascular events.The Framingham study has reported that in a healthy population, for every 1 mg/dl increase in HDL-C levels, the incidence of coronary heart disease was reduced by 2% to 3% [1]. However, in recent years, studies aimed at elevating HDL-C levels have successively failed to reduce cardiovascular events, and it has been reported that high HDL-C levels are not always correlated with reduced cardiovascular death [13]. Therefore, an increasing number of studies have shifted their focus from the HDL-C level to HDL function and HDL particle size.

HDL is mainly composed of larger HDL2 and smaller HDL3. In the process of reverse cholesterol transport (RCT), small, flat pre-β-HDL gradually matures into large, spherical HDL2; thus, larger HDL particles are generally considered to be more mature and have greater cardiovascular protective effects [14]. In cardiovascular disease, the subpopulations of HDL may be altered due to a disrupted or even hindered RCT process [15]. Both HDL dysfunction and altered HDL distribution are likely to be related to oxidative stress and inflammation [16, 17], which also contribute to endothelial dysfunction and account for their association with the acceleration of chronic kidney disease.

In our study, lower HDL-C/apoA1 was shown to be closely related to coronary artery stenosis in coronary heart disease patients with normal kidney function; however, in coronary heart disease patients with a moderately decreased eGFR, HDL-C/apoA-1 grew larger, and the original association with coronary artery stenosis was also lost. Since HDL-C/apoA-I was used to represent HDL particle sizes in our study, our results demonstrated the same association between HDL particle sizes and coronary artery stenosis. Similar phenomenons has been reported in several studies [18‐20]. In the past, it was believed that lipoproteins cannot pass the glomerular filtration barrier. Despite HDL being the smallest of all lipoproteins, containing the least lipids but the most protein, there is no evidence of intact HDL particles filtering through the glomerular filtration barrier. However, subfractions of HDL particles metabolize separately¹⁸. Albumin, which has a molecular weight of 66.5 kD, has already been proven to cross the glomerular filtration barrier,; thus, apoA-I, weighted 28 kD, and pre-β-HDL, weighted 60 to 85 kD, can both cross a normally functioning glomerular filtration barrier theoretically, while larger subfractions are likely to be filtered in individuals with injured kidney function [21]. Therefore, it is reasonable to assume that increased HDL particle size in chronic kidney disease patients is a result of the loss of smaller HDL particles through the glomerular filtration barrier.

Our results also reported the loss of association between HDL particle size and Gensini score in the context of comorbidity of coronary heart disease with renal insufficiency. In our study, renal defficiency was defined as an eGFR < 90 mL/(min·1.73 m²), as renal damage and related dyslipidemia have already started in early stages of chronic kidney disease [22]. Chronic kidney disease is known to be an independent risk factor for cardiovascular disease, so it is reasonable to assume that with renal insufficiency in the picture, the size shifting of HDL particles, which reflects only an imbalance in HDL metabolism, is no longer a strong predictor of the severity of coronary heart disease [23, 24]. In coronary heart patients with renal insufficiency, the protective effects of larger HDL particles may be weakened; thus, lipid-targeting therapy may not be as essential in these patients.

Our study explored the still-debated effect of renal function on HDL particle size in patients with coronary artery disease using HDL-C/apoA-I to represent HDL particle size. However, as a single-center retrospective study, the sample size was relatively small, and further confirmation of our theory would require analysis of urine protein profiles. Additionally, HDL-C/apoA-I represents only the average size of HDL particles; thus, HDL subfraction analysis is still needed if the specific alterations in HDL subpopulations in chronic kidney disease patients are to be explored in the future.

In our study, lower HDL-C/apoA-1was shown to be associated with more severe coronary artery stenosis in coronary heart disease patients with normal kidney function. However, in coronary heart disease patients with renal insufficiency, an inverse correlation of eGFR with HDL-C/apoA-1was found as eGFR declined to 60 ml/min·1.73 m², accompanied by a loss of association between HDL-C/apoA-I and coronary artery stenosis.