Associations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis

doi:10.1016/j.jacl.2017.12.007

Journal of Clinical Lipidology

Volume 12, Issue 2, March–April 2018, Pages 481-487.e14

https://doi.org/10.1016/j.jacl.2017.12.007 Get rights and content

Highlights

•
Low-density lipoprotein and apolipoprotein (Apo) B are inversely associated with infectious events in dialysis patients.
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Higher Apo A1, Apo B, and Apo C3 are associated with lower all-cause mortality.
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Lipoproteins are not associated with cardiovascular outcomes.

Background

In hemodialysis (HD) patients, higher lipid levels are associated with lower mortality. Lipid-lowering therapy does not reduce all-cause mortality or cardiovascular (CV) mortality. Lipoproteins play a role in the innate immune system. Our objective was to determine whether protection from infection might counterbalance adverse CV outcomes associated with lipoproteins.

Methods

We examined associations between serum apolipoprotein (Apo) A1, B, C2, C3, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol and triglyceride levels and infectious mortality or hospitalization, CV mortality or hospitalization, and all-cause mortality in 433 prevalent HD patients. Cox models with time-varying apolipoprotein concentrations collected every 6 months for up to 2 years were used for analyses.

Results

Median follow-up time for all-cause mortality was 2.7 years (25th–75th percentile range: 2.2–3.4 years). One hundred seventy-nine (41%) patients had an infection-related event. In multivariable models, higher Apo B and LDL were associated with lower risks of infection-related outcomes (hazard ratio Apo B 0.92 [95% confidence interval 0.86–0.99 per 10 mg/dL, P = .03]; hazard ratio LDL 0.93 [95% confidence interval 0.87–1.00 per 10 mg/dL, P = .05]). Sixty-three (15%) participants had a CV-related event. No significant associations were observed between lipoproteins and CV outcomes. Eighty-seven (20%) participants died. Higher Apo A1, Apo B, and Apo C3 were associated with lower risks of all-cause mortality. There was no interaction between the use of lipid-lowering medication and any of the outcomes.

Conclusion

Associations of lipoproteins with lower risk of serious infection accompanied by no significant association with CV events may help to explain the paradoxical association between lipids and survival and lack of benefit of lipid-lowering therapies in HD.

Introduction

Cardiovascular (CV) and infection-related events are the 2 leading causes of death among patients with end-stage renal disease (ESRD) receiving hemodialysis (HD).1, 2 By the United States Renal Data System (USRDS) estimates, CV mortality and CV events have stabilized, but the rates of infection-related hospitalization and death have increased.³ Total and low-density lipoprotein (LDL) cholesterol concentrations are associated with CV mortality among persons over age 50 years in the general population, but the associations between these lipoproteins and outcomes in individuals with ESRD are less certain,⁴ and mortality is actually higher among ESRD patients who have lower serum total cholesterol concentrations compared to those with higher serum cholesterol concentrations,5, 6, 7 Moreover, randomized controlled trials lowering LDL cholesterol concentrations in patients receiving HD have neither enhanced survival nor reduced the incidence of major CV events8, 9, 10 and have had no significant effect on all-cause mortality or CV mortality,¹⁰ suggesting that the paradigm linking lipoproteins and mortality operative in the general population may be altered in the setting of ESRD.

Lipoproteins and other protein constituents that compose lipoproteins are now understood to play roles in the innate immune system,11, 12, 13, 14, 15, 16 providing a potential mechanism for protection against leading causes of morbidity and mortality in a population with high risk of infection. To explore this hypothesis, we examined associations among serum lipoprotein concentrations and CV and infection-related outcomes in a prevalent HD cohort. We also examined all-cause mortality to determine whether any infection-related benefit observed among patients with higher lipoprotein concentrations was offset by adverse CV effects.

Section snippets

Materials and methods

The ACTIVE/ADIPOSE (A Cohort Study to Investigate the Value of Exercise in ESRD/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD) study enrolled 771 prevalent HD patients who had been receiving HD for at least 3 months from 14 centers in the San Francisco CA and Atlanta GA metropolitan areas from June 2009 through August 2011.¹⁷ The study was approved by the institutional review boards at the University of California, San Francisco, and at Emory University. All

Patient characteristics

Median or mean values for each parameter are presented in Table 1. The mean age was 56.6 years, 41.1% were women, 15.9% were white, and 53.6% had diabetes. During follow-up, 63 (15%) participants had a CV-related event, 179 (41%) had an infection-related event, and 87 (20%) died. The median follow-up time for all-cause mortality was 2.7 years (25th–75th percentile range 2.2−3.4 years). Patients prescribed lipid-lowering medication had significantly lower LDL cholesterol (64.9 ± 28.7 vs

Discussion

The 2 leading causes of death and hospitalization in patients on maintenance HD are related to CV disease and infection,1, 2 and we hypothesized that higher lipoprotein concentrations might provide protection from infection, which might offset potential adverse CV effects. We found that higher concentrations of some lipoproteins, specifically LDL and its associated apolipoprotein, Apo B, were associated with lower risk of infection-related outcomes. In contrast to data from the general

Acknowledgments

This work was supported by funding from the National Institutes for Diabetes and Digestive and Kidney Diseases to Dr. Johansen (R01 DK107269 and K24 DK085153) and Dr. Ishida (K23DK103963) and from the Department of Veterans Affairs fellowship support to Dr. Chiang and Clinical Science Research and Development Program (Career Development Award 1IK2CX000527) to Dr. Delgado.

The data reported here have been supplied in part by the United States Renal Data System (USRDS). The interpretation and

References (33)

V. Krane et al.
Association of LDL cholesterol and inflammation with cardiovascular events and mortality in hemodialysis patients with type 2 diabetes mellitus
Am J Kidney Dis
(2009)
E.G. Lowrie et al.
Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities
Am J Kidney Dis
(1990)
C. Baigent et al.
The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial
Lancet
(2011)
M.M. Peterson et al.
Is an innate barrier against invasive Staphylococcus aureus infection
Cell Host Microbe
(2008)
X. Zhang et al.
(Milano) protects endotoxin-challenged rats from multiple organ injury and dysfunction
Biol Chem
(2015)
K.L. Johansen et al.
Comparison of self-report-based and physical performance-based frailty definitions among patients receiving maintenance hemodialysis
Am J Kidney Dis
(2014)
L. Guo et al.
High density lipoprotein protects against polymicrobe-induced sepsis in mice
J Biol Chem
(2013)
M.M. Peterson et al.
Is an innate barrier against invasive Staphylococcus aureus infection
Cell Host Microbe
(2008)
S. Bhakdi et al.
Binding and partial inactivation of Staphylococcus aureus alpha-toxin by human plasma low density lipoprotein
J Biol Chem
(1983)
E. Esteve et al.
Dyslipidemia and inflammation: an evolutionary conserved mechanism
Clin Nutr
(2005)

U S Renal Data System

USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

(2011)

X. Cheng et al.

Mortality rates among prevalent hemodialysis patients in Beijing: a comparison with USRDS data

Nephrol Dial Transplant

(2013)

U S Renal Data System

USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

(2013)

R.D. Kilpatrick et al.

Association between serum lipids and survival in hemodialysis patients and impact of race

J Am Soc Nephrol

(2007)

Y. Liu et al.

Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition

JAMA

(2004)

C. Wanner et al.

Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis

N Engl J Med

(2005)

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COVID-19 infections decrease total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I, A-II, and B levels while triglyceride levels may be increased or inappropriately normal for the poor nutritional status. The degree of reduction in total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I are predictive of mortality. With recovery lipid/lipoprotein levels return towards pre-infection levels and studies have even suggested an increased risk of dyslipidemia post-COVID-19 infection. The potential mechanisms for these changes in lipid and lipoprotein levels are discussed. Decreased HDL-C and apolipoprotein A-I levels measured many years prior to COVID-19 infections are associated with an increased risk of severe COVID-19 infections while LDL-C, apolipoprotein B, Lp (a), and triglyceride levels were not consistently associated with an increased risk. Finally, data suggest that omega-3-fatty acids and PCSK9 inhibitors may reduce the severity of COVID-19 infections. Thus, COVID-19 infections alter lipid/lipoprotein levels and HDL-C levels may affect the risk of developing COVID-19 infections.
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Citation Excerpt :
Lipid abnormalities in the CKD population are characterized by decreased HDL-C and increased TG and non-HDL-C.7,8 Whereas, low HDL-C and high TG and non-HDL-C levels are thought to be risk factors for CVD in CKD patients on HD,2,9 those disorders are not always associated with clinical outcomes in the HD population.10,11 Metabolism of HDL-C in patients on HD is influenced by increased catabolism due to decreased hepatic TG lipase and chronic inflammation,7,12,13 while increased TG is related to reduced activities of enzymes such as lipoprotein lipase in lipoprotein metabolism.8
Adiposity influences lipid metabolism and atherosclerotic cardiovascular disease (CVD) in the general population. The aim of the present study was to assess the association between fat mass (FM) and lipid metabolism and CVD events among patients on hemodialysis (HD).
This prospective observational study examined 240 patients on prevalent HD. Blood samples were obtained before dialysis at baseline to measure lipids, high-sensitivity C-reactive protein (hs-CRP), interleukin-6, and adiponectin. Lipids and hs-CRP were measured every 3 months for 12 months. FM was estimated by dual energy x-ray absorptiometric scan at baseline and 12 months later. Patients were then prospectively followed up for 36 months after the 1-year measurement period, and composite CVD events were estimated.
Truncal FM was positively correlated with body mass index, hs-CRP, interleukin-6, total cholesterol, low-density lipoprotein-C, triglyceride, and negatively correlated with high-density lipoprotein (HDL)-C and adiponectin at baseline. HDL-C levels were repeatedly decreased, and triglyceride and non-HDL-C were serially increased in the patient group with truncal FM > 7,000 g at both baseline and 12 months (large truncal FM group) compared with the other groups. Cox proportional hazards models adjusted for confounders showed composite CVD events occurred significantly in patients with large truncal FM and continuous low HDL-C levels.
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The question raised then now is not why LDL-C levels do not increase mortality risk, but what is the mechanism whereby LDL-C is protective in this population? It has been observed that among patients with normal renal function, both LDL-C and other apo B-associated lipoproteins are associated with lower risk of infection (42) and improved survival among patients with sepsis (43). However, many of these observations were based on lipid levels at the time of hospitalization for septic events, which might be confounded by severity of inflammation, because greater inflammation is expected to reduce lipid levels more (24, 26, 44, 45).
Cardiovascular (CV) events are increased 36-fold in patients with end-stage renal disease. However, randomized controlled trials to lower LDL cholesterol (LDL-C) and serum total cholesterol (TC) have not shown significant mortality improvements. An inverse association of TC and LDL-C with all-cause and CV mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and triglycerides (TGs) with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, and 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death, and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non-CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.
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The Correlation between Serum Lipoprotein(a) and Risk of Mortality in Patients on Peritoneal Dialysis
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View all citing articles on Scopus

: None of the authors have a conflict of interest.

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Original ArticleAssociations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis

Highlights

Background

Methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Patient characteristics

Discussion

Acknowledgments

Am J Kidney Dis

Am J Kidney Dis

Lancet

Cell Host Microbe

Biol Chem

Am J Kidney Dis

J Biol Chem

Cell Host Microbe

J Biol Chem

Clin Nutr

USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

Mortality rates among prevalent hemodialysis patients in Beijing: a comparison with USRDS data

Nephrol Dial Transplant

USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

Association between serum lipids and survival in hemodialysis patients and impact of race

J Am Soc Nephrol

Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition

JAMA

Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis

N Engl J Med

Original Article
Associations of lipoproteins with cardiovascular and infection-related outcomes in patients receiving hemodialysis