The role of lipoprotein (a) in chronic kidney disease

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Abstract

Lipoprotein (a) [Lp(a)] and its measurement, structure and function, the impact of ethnicity and environmental factors, epidemiological and genetic associations with vascular disease, and new prospects in drug development have been extensively examined throughout this Thematic Review Series on Lp(a). Studies suggest that the kidney has a role in Lp(a) catabolism, and that Lp(a) levels are increased in association with kidney disease only for people with large apo(a) isoforms. By contrast, in those patients with large protein losses, as in the nephrotic syndrome and continuous ambulatory peritoneal dialysis, Lp(a) is increased irrespective of apo(a) isoform size. Such acquired abnormalities can be reversed by kidney transplantation or remission of nephrosis. In this Thematic Review, we focus on the relationship between Lp(a), chronic kidney disease, and risk of cardiovascular events.

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Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

Nicholas Viney, Julian C van Capelleveen, Richard S Geary … (2016)

Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations.

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Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors.

David Siscovick, Teri A. Manolio, Mary Cushman … (2005)

Elderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown. To compare traditional and novel risk factors as predictors of cardiovascular mortality. A total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years. Cardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2. Among the participants, 1249 (22%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95% confidence interval, 0.71-0.78; P for difference = .15). Traditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.

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Safety of anacetrapib in patients with or at high risk for coronary heart disease.

Christopher Cannon, Sukrut Shah, Hayes Dansky … (2010)

Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001)--a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)--a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).

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Author and article information

Journal

Journal ID (nlm-ta): J Lipid Res

Journal ID (iso-abbrev): J. Lipid Res

Journal ID (hwp): jlr

Journal ID (pmc): jlr

Journal ID (publisher-id): jlr

Title: Journal of Lipid Research

Publisher: The American Society for Biochemistry and Molecular Biology

ISSN (Print): 0022-2275

ISSN (Electronic): 1539-7262

Publication date (Print): April 2018

Publication date (Electronic): 29 January 2018

Publication date PMC-release: 29 January 2018

Volume: 59

Issue: 4

Pages: 577-585

Affiliations

Clinical Trial Service Unit & Epidemiological Studies Unit, [* ] Nuffield Department of Population Health, University of Oxford , Oxford, United Kingdom

Medical Research Council Population Health Research Unit , [† ] Oxford, United Kingdom

Author notes

[1 ]To whom correspondence should be addressed. e-mail: Jemma.Hopewell@ 123456ndph.ox.ac.uk

Article

Publisher ID: r083626

DOI: 10.1194/jlr.R083626

PMC ID: 5880503

PubMed ID: 29378781

SO-VID: 31a3285e-3eca-4ad1-9357-a3e1469e1785

License:

Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license.

History

Date received : 19 January 2018

Funding

Funded by: British Heart Foundation, open-funder-registry 10.13039/501100000274;

Award ID: FS/14/55/30806

Funded by: Medical Research Council, open-funder-registry 10.13039/501100000265;

The role of lipoprotein (a) in chronic kidney disease

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A Sustainable Future

Most cited references 98

Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors.

Safety of anacetrapib in patients with or at high risk for coronary heart disease.

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