Abstract
Proprotein convertase subtilisin/kexin 9 (PCSK9) plays an important role in lipid metabolism while available literature regarding its involvement in the pathogenesis of atherosclerosis and in the expression of genes associated with apoptosis and inflammation is constantly increasing. Patients with chronic kidney disease (CKD) experience disproportionately increased cardiovascular morbidity and mortality due to dyslipidemia, accelerated atherosclerosis, inflammation, oxidative stress, and other risk factors. In the present cross-sectional study, we investigated the possible association of serum PCSK9 levels with markers of inflammation, oxidative stress, and endothelial damage in patients with CKD. Patients and Methods. Ninety-two patients with CKD stages II-ΙV (eGFR CKD-EPI 47.3 ± 25.7 ml/min/1.73 m2, mean age 66 years, 51 men) were included in the study. Plasma PCSK9 levels were correlated with comorbidities (arterial hypertension, diabetes mellitus, and history of cardiovascular disease), renal function indices (eGFR, proteinuria–UPR/24 h), lipid parameters (LDL-cholesterol, HDL-cholesterol, triglycerides, Lp(a), APO-A1, and APO-B), and soluble biomarkers of inflammation, oxidative stress, and endothelial damage (hs-CRP, fibrinogen, 8-epiPGF2a, ox-LDL, IL-6, TNF-α, sICAM-1, and sVCAM-1). Results. The mean plasma value of PCSK9 was 278.1 ng/ml. PCSK9 levels showed direct correlation with serum triglycerides (p = 0.03), Lp(a) (p = 0.01), and sICAM-1 levels (p = 0.03). There was no significant correlation between PCSK9 levels and indices of the renal function, other lipid profile parameters, inflammatory markers, or comorbidities. Multiple regression analysis showed a significant effect of Lp(a) on PCSK9 levels, and for each unit of higher Lp(a), an increase by 3.082 is expected (95% CI: 0.935-5.228, p = 0.006). At the same time, patients receiving statins are expected to have on average 63.8 ng/ml higher PCSK9 values compared to patients not receiving statins (95% CI: 14.6-113.5, p = 0.012). Conclusion. Plasma levels of PCSK9 in nondialysis CKD patients are correlated with endothelial dysfunction and lipid metabolism parameters. Statin intake increases PCSK9 levels significantly in this patient population. PCSK9 levels are not correlated with the severity of kidney disease. Major prospective studies are necessary to investigate the role of PCSK9 in the atherosclerotic cardiovascular outcome in CKD.
Highlights
Chronic kidney disease (CKD) has been characterized as an atherosclerosis multiplier increasing disproportionally the incidence of fatal and nonfatal cardiovascular events from the early stages [1]
Systolic BP, UPR, uric acid, PTH, and LV mass index (LVMI) increased with decreasing eGFR
This study shows that in nondialysis CKD patients, plasma levels of Proprotein convertase subtilisin/kexin type 9 (PCSK9) are directly associated with the endothelial dysfunction biomarker sICAM-1 and with Lp(a), an established risk factor for myocardial infraction and cardiovascular death in CKD patients [35]
Summary
Chronic kidney disease (CKD) has been characterized as an atherosclerosis multiplier increasing disproportionally the incidence of fatal and nonfatal cardiovascular events from the early stages [1]. Atherosclerosis, beyond being a lipid disorder, is characterized by major inflammatory properties and has been implicated in the pathogenesis of arterial plaque formation and rupture and in clinical outcomes [4, 5]. Oxidative stress, and endothelial dysfunction separately and through their crosstalk have direct implications in the pathogenesis of atherosclerosis in CKD patients and have been established as nontraditional cardiovascular risk factors in this frail population [6,7,8,9]. In CKD patients, existing literature is conflicting about possible association of PCSK9 plasma levels with the renal function. PCSK9i manage to reduce LDL-C to target levels and Lp(a) levels by 20-30% with additional cardiovascular benefit when added to statin treatment in high-risk populations [14]. Efficacy of the PCSK9i alirocumab in CKD stage 3 patients was estimated in an analysis that pooled data from eight phase III ODYSSEY trials showing an efficacy and safety profile similar to that of patients with preserved eGFR [15]
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