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      Apolipoproteins A and B and PCSK9: Nontraditional Cardiovascular Risk Factors in Chronic Kidney Disease and in End-Stage Renal Disease

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          Abstract

          Purpose

          Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase the prevalence of cardiovascular mortality in chronic kidney disease (CKD) or in end-stage renal disease (ESRD) through quantitative alterations. This review is aimed at establishing the biomarker (ApoA, ApoB, and PCSK9) level variations in uremic patients, to identify the studies showing the association between these biomarkers and the development of cardiovascular events and to depict the therapeutic options to reduce cardiovascular risk in CKD and ESRD patients.

          Methods

          We searched the electronic database of PubMed, Scopus, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins and PCSK9 in CKD and ESRD. Randomized controlled trials, observational studies (including case-control, prospective or retrospective cohort), and reviews/meta-analysis were included if reference was made to those keys and cardiovascular outcomes in CKD/ESRD.

          Results

          18 studies met inclusion criteria. Serum ApoA-I has been significantly associated with the development of new cardiovascular event and with cardiovascular mortality in ESRD patients. ApoA-IV level was independently associated with maximum carotid intima-media thickness (cIMT) and was a predictor for sudden cardiac death. The ApoB/ApoA-I ratio represents a strong predictor for coronary artery calcifications, cardiovascular mortality, and myocardial infarction in CKD/ESRD. Plasma levels of PCSK9 were not associated with cardiovascular events in CKD patients.

          Conclusions

          Although the “dyslipidemic status” in CKD/ESRD is not clearly depicted, due to different research findings, ApoA-I, ApoA-IV, and ApoB/ApoA-I ratio could be predictors of cardiovascular risk. Serum PCSK9 levels were not associated with the cardiovascular events in patients with CKD/ESRD. Probably in the future, the treatment of dyslipidemia in CKD/ESRD will be aimed at discovering new effective therapies on the action of these biomarkers.

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          Most cited references51

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          Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences.

          N. Vaziri (2006)
          Chronic renal failure (CRF) results in profound lipid disorders, which stem largely from dysregulation of high-density lipoprotein (HDL) and triglyceride-rich lipoprotein metabolism. Specifically, maturation of HDL is impaired and its composition is altered in CRF. In addition, clearance of triglyceride-rich lipoproteins and their atherogenic remnants is impaired, their composition is altered, and their plasma concentrations are elevated in CRF. Impaired maturation of HDL in CRF is primarily due to downregulation of lecithin-cholesterol acyltransferase (LCAT) and, to a lesser extent, increased plasma cholesteryl ester transfer protein (CETP). Triglyceride enrichment of HDL in CRF is primarily due to hepatic lipase deficiency and elevated CETP activity. The CRF-induced hypertriglyceridemia, abnormal composition, and impaired clearance of triglyceride-rich lipoproteins and their remnants are primarily due to downregulation of lipoprotein lipase, hepatic lipase, and the very-low-density lipoprotein receptor, as well as, upregulation of hepatic acyl-CoA cholesterol acyltransferase (ACAT). In addition, impaired HDL metabolism contributes to the disturbances of triglyceride-rich lipoprotein metabolism. These abnormalities are compounded by downregulation of apolipoproteins apoA-I, apoA-II, and apoC-II in CRF. Together, these abnormalities may contribute to the risk of arteriosclerotic cardiovascular disease and may adversely affect progression of renal disease and energy metabolism in CRF.
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            Arterial stiffness and pulse pressure in CKD and ESRD.

            We recognize that increased systolic pressure is the most challenging form of hypertension today and that pulse pressure as an independent cardiovascular risk factor has focused attention on arterial stiffness and wave reflections as the most important factors determining these pressures. In recent years, many studies emphasized the role of arterial rigidity in the development of cardiovascular diseases, and it was shown that stiffening of arteries is associated with increased cardiovascular mortality and morbidity. Moreover,arterial stiffening is linked to decreased glomerular filtration rate, and is predictive of kidney disease progression and the patient’s cardiovascular outcome. Premature vascular aging and arterial stiffening are observed with progression of chronic kidney disease (CKD) and in end-stage renal disease(ESRD). This accelerated aging is associated with outward remodeling of large vessels, characterized by increased arterial radius not totally compensated for by artery wall hypertrophy. Arterial stiffening in CKD and ESRD patients is of multifactorial origin with extensive arterial calcifications representing a major covariate. With aging, the rigidity is more pronounced in the aorta than in peripheral conduit arteries, leading to the disappearance or inversion of the arterial stiffness gradient and less protection of the microcirculation from high-pressure transmission. Various non-pharmacological or pharmacological interventions can modestly slow the progression of arterial stiffness,but arterial stiffness is, in part, pressure dependent and treatments able to stop the process mainly include antihypertensive drugs.
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              Dyslipidemia in patients with chronic kidney disease: etiology and management

              Patients with chronic kidney disease (CKD), including those with end-stage renal disease, treated with dialysis, or renal transplant recipients have an increased risk for cardiovascular disease (CVD) morbidity and mortality. Dyslipidemia, often present in this patient population, is an important risk factor for CVD development. Specific quantitative and qualitative changes are seen at different stages of renal impairment and are associated with the degree of glomerular filtration rate declining. Patients with non-dialysis-dependent CKD have low high-density lipoproteins (HDL), normal or low total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, increased triglycerides as well as increased apolipoprotein B (apoB), lipoprotein(a) (Lp (a)), intermediate- and very-low-density lipoprotein (IDL, VLDL; “remnant particles”), and small dense LDL particles. In patients with nephrotic syndrome lipid profile is more atherogenic with increased TC, LDL, and triglycerides. Lipid profile in hemodialysis (HD) patients is usually similar to that in non-dialysis-dependent CKD patients. Patients on peritoneal dialysis (PD) have more altered dyslipidemia compared to HD patients, which is more atherogenic in nature. These differences may be attributed to PD per se but may also be associated with the selection of dialytic modality. In renal transplant recipients, TC, LDL, VLDL, and triglycerides are elevated, whereas HDL is significantly reduced. Many factors can influence post-transplant dyslipidemia including immunosuppressive agents. This patient population is obviously at high risk; hence, prompt diagnosis and management are required to improve their clinical outcomes. Various studies have shown statins to be effective in the cardiovascular risk reduction in patients with mild-to-moderate CKD as well as in renal transplant recipients. However, according to recent clinical randomized controlled trials (4D, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Dialysis: an Assessment of Survival and Cardiovascular Events, and Study of Heart and Renal protection), these beneficial effects are uncertain in dialyzed patients. Therefore, further research for the most suitable treatment options is needed.
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                Author and article information

                Contributors
                Journal
                J Diabetes Res
                J Diabetes Res
                JDR
                Journal of Diabetes Research
                Hindawi
                2314-6745
                2314-6753
                2019
                14 December 2019
                : 2019
                : 6906278
                Affiliations
                1Department of Nephrology, “Dr. C. I. Parhon” Clinical Hospital Iasi, Iasi, Romania
                2Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania
                3Department of Cardiology, “Sf. Spiridon” Clinical Hospital Iasi, Iasi, Romania
                Author notes

                Academic Editor: Guanghong Jia

                Author information
                https://orcid.org/0000-0002-7558-0711
                https://orcid.org/0000-0002-3138-126X
                Article
                10.1155/2019/6906278
                6931031
                31915710
                52de59fb-64c6-4c22-9fbc-de9c3cb65d31
                Copyright © 2019 Cristiana-Elena Vlad et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 June 2019
                : 9 September 2019
                : 26 November 2019
                Categories
                Review Article

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