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|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|
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)
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 characteristics of the cohort are summarised in Table 1. Over the median 2.4 years follow-up, 444 (16%) developed incident CAC.
*p=0.01; **p<0.001 versus normal renal function
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.|
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.
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.