Triglyceride-rich lipoproteins: mediator of the association between chronic kidney disease and CVD

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5 January 2013

Chronic kidney disease (CKD) is strongly associated with cardiovascular disease (CVD). However, the underlying mechanisms for this association are poorly understood. New evidence from the Multi-Ethnic Study of Atherosclerosis (MESA) highlights a role for elevated triglyceride-rich lipoproteins, a key component of atherogenic dyslipidemia.

Lamprea-Montealegre JA, McClelland RL, Astor BC, Matsushita K, Shlipak M, de Boer IH, Szklo M. Chronic kidney disease, plasma lipoproteins, and coronary artery calcium incidence: the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol 2013;33:652-8.

STUDY SUMMARY

Objective

To investigate 1) the association between CKD and risk of incident coronary artery calcium (CAC), a marker of subclinical atherosclerosis; 2) typical lipoprotein profiles in patients with CKD; and 3) whether elevated lipoprotein concentrations contribute information on the association between CKD and CVD

Study design

Population-based cohort study

Study population

2,795 individuals from the MESA cohort with no CAC (calcium score=0) at baseline (enrolled between 2000-2002).

Primary variable

• Lipid and lipoproteins, including triglycerides, high-density lipoprotein cholesterol (HDL-C), total cholesterol, non-HDL-C
• Lipoprotein subfractions: small, medium and large very low-density lipoprotein (VLDL) particles, large and small low-density lipoprotein (LDL) particles; and small, medium and large HDL particles, assessed by nuclear magnetic resonance spectroscopy

Secondary variables

• Cardiac CAC, assessed by computed tomography. CAC incidence was defined as the development of a CAC Agatson score >0 in individuals with baseline score of 0.1,2
• Cystatin-c-estimated glomerular filtration rate (eGFR)

Methods

Renal function was categorised on the basis of eGFR (mL/min/1.73 m2) as normal (≥90); mildly reduced (60-89) and CKD (30-59). Individuals with eGFR <30 were excluded due to small sample size. The association between categories of renal function and plasma lipids and lipoproteins was investigated using generalised linear models.
The main lipids and lipoproteins were modelled independently and in combination with lipoprotein subfractions using principal component analyses. Wald tests for multiple interactions were used to compare the associations of lipids, lipoproteins and their combination with lipoprotein subfractions across categories of renal function.
All models were adjusted for age, sex, ethnicity, use of lipid-modifying therapy, urinary albumin:creatinine ratio and the presence of diabetes or hypertension.

Main results

The characteristics of the cohort are summarised in Table 1. Over the median 2.4 years follow-up, 444 (16%) developed incident CAC.

Table 1. Characteristics of the cohort, stratified by renal function

	eGFR ³90 (Normal)	eGFR 60-89 (Mild dysfunction)	eGFR 30-59 (CKD)
N	1,490	1,181	124
Median age, yr	53	61	65
Male, %	41	33	26`
White, %	31	39	41
Diabetes, %	8	8	15
Hypertension, %	26	42	57**
Lipid-lowering therapy, %	9	12	17**
Lipids, mg/dL, Median (interquartile range)
LDL-C	116 (96-135)	115 (96-135)	111 (91-131)
Triglycerides	98 (70-143)	113 (79-160)	121 (91-174)**
HDL-C	51 (43-61)	50 (41-61)	47 (39-60)*
LDL-P (nmol/L)	1197 (982-1428)	1206 (994-1436)	1192 (995-1483)
VLDL-P (nmol/L)	56.4 (35.9-81.5)	59.5 (39.3-87.6)	64.3 (44.9-80.3)*
HDL-P (mmol/L)	34.1 (30.1-38.7)	33.8 (29.6-38.9)	32.8 (28.2-29.5)
Incident CAC, %	12	19	27**

*p=0.01; **p<0.001 versus normal renal function
CAC coronary artery calcium; HDL-C high-density lipoprotein cholesterol; HDL-P high-density lipoprotein particles; LDL-C low-density lipoprotein cholesterol; LDL-P low-density lipoprotein particles; VLDL-P very low-density lipoprotein particles

There was a strong association between reduction in renal function and CAC incidence; risk ratio (95% CI) 1.26 (1.04-1.52) for mild dysfunction and 1.56 (1.11-2.20) for CKD, p=0.014, versus normal renal function.

Reduced renal function was significantly associated with progressively elevated levels of triglyceride-rich lipoproteins, characterised by higher levels of triglycerides and VLDL and an increase in small, dense LDL and small HDL (p<0.001). A 25% increase in triglyceride levels was associated with 4% increase in the risk ratio for incident CAC in individuals with mild renal impairment, and this was increased ~3-fold in individuals with CKD (risk ratio 1.13, 95% 0.98-1.30).

Author's conclusion

CKD is strongly associated with CAC incidence. Part of this association is mediated via a characteristic lipid phenotype comprising elevations in triglyceride-rich lipoproteins.

COMMENT

The association between CKD and CVD is well established.3 Atherogenic dyslipidemia characterised by elevated triglyceride-rich apolipoprotein B-containing lipoproteins and low HDL, together with compositional changes in the apoB-containing lipoproteins (including relative enrichment with apoC-III) is a feature of the dyslipidemia typically associated with CKD.4 This dyslipidemia shares many features with the alterations of the lipoprotein metabolism found in cardiometabolic disease. Thus, given that atherogenic dyslipidemia is a key driver of CV risk in patients with cardiometabolic disease, including type 2 diabetes,5 it is plausible that this dyslipidemic profile is also of importance for the development of atherosclerosis in patients with CKD. The results from this analysis of MESA would support this hypothesis. Indeed, the findings from this analysis provide evidence implicating elevated triglyceride-rich lipoproteins as a potential mediator of risk for subclinical atherosclerosis.

The authors of this report acknowledge the limitations of small sample size in this analysis, which did not permit testing of the multiplicative interactions in the association of lipids and CAC. Despite this, their findings add to a growing body of evidence linking an atherogenic dyslipidemic profile with both CKD and CVD.

Thus, the results of this analysis raise a pertinent question. Would agents that specifically target this dyslipidemic profile offer the possibility of reducing the residual burden of CVD in such individuals, despite best treatment? Statins are the cornerstone for managing dyslipidemia in CKD.6 In addition, an association of simvastatin plus ezetimibe was shown to be effective in reducing CVD in patients with advanced CKD.7 However, it is recognised that their effects on atherogenic dyslipidemia, characterised by an increase in triglyceride-rich lipoproteins, are more modest than on LDL-C. Whether additional therapy targeting this dyslipidemia, such as novel selective peroxisome proliferator-activated receptor agonists, offer added clinical benefit merits further study.

References

1. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–32.
2. Kronmal RA, McClelland RL, Detrano R, Shea S, Lima JA, Cushman M, Bild DE, Burke GL. Risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2007;115:2722–30.
3. Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2701–2081.
4. Ritz E, Wanner C. Lipid abnormalities and cardiovascular risk in renal disease. J Am Soc Neph 2008; 19:1065–70.
5. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
6. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
7. Baigent C, Landray MJ, Reith C, et al., the SHARP Investigators: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection):a randomised placebo-controlled trial. Lancet 2011;377:2181-92.