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NDT Advance Access published online on May 25, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn296
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Cholesteryl ester transfer protein activity and cardiovascular events in patients with chronic kidney disease stage V

Sarah Seiler1,*, Axel Schlitt2,*, Xian-Cheng Jiang3, Christof Ulrich1, Stefan Blankenberg4, Karl J. Lackner4, Matthias Girndt1, Karl Werdan2, Michael Buerke2, Danilo Fliser1 and Gunnar H. Heine1

1 Department of Medicine IV, Saarland University, Homburg/Saar 2 Department of Medicine III, Martin Luther University, Halle-Wittenberg, Germany 3 Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center Brooklyn, NY, USA 4 Department of Medicine II and Institute of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University, Mainz, Germany

Correspondence and offprint requests to: Sarah Seiler, Department of Medicine IV, Saarland University, Homburg/Saar, Germany. Tel: +49-6841-1623000; Fax: +49-6841-1623545; E-mail: Sarahseiler{at}gmx.de



   Abstract
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 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular events (CVE). Uraemic dyslipidaemia, which is characterized by low HDL-cholesterol (HDL-C) and elevated triglycerides’ levels, may contribute to this elevated cardiovascular risk. Cholesteryl ester transfer protein (CETP) lowers HDL-C by transferring cholesterol esters to LDL and VLDL particles. We tested the hypothesis that CETP activity is associated with CVE in patients with CKD stage V.

Methods. We measured CETP activity and cholesterol levels in 69 haemodialysis patients. CVE and death were prospectively assessed over a follow-up period of 48 months.

Results. CETP activity was negatively correlated with HDL-C levels in patients without lipid-lowering medication (r = –0.379, P = 0.005). We found no difference in CETP activity in patients with cardiovascular disease at baseline compared to patients without cardiovascular disease. The same was true for incident CVE during the follow-up. When stratifying patients by median CETP activity, patients with high CETP activity did not have an increased risk for CVE (P = 0.901 by the log-rank test) or death (P = 0.615). Similarly, after stratifying patients by median HDL-C no increased risk for CVE (P = 0.780) or death (P = 0.838) was found in patients with low HDL-C.

Conclusions. In summary, although CETP activity correlated with HDL-C levels, neither high CETP activity nor low HDL-C was associated with CVE in CKD stage V patients. Thus, pharmacological modification of HDL-C by CETP inhibitors seems to be of questionable value in these patients.

Keywords: CETP; chronic kidney disease; CV events; haemodialysis treatment; HDL



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Cardiovascular events (CVE) are the most common cause of death in developed countries. CV mortality is 10–20 times higher in end-stage renal disease patients compared to age-matched controls with intact renal function [1]. A complex dyslipidaemia including low plasma levels of protective HDL-cholesterol (HDL-C) and elevated plasma triglycerides may contribute to this accelerated atherosclerosis [2], even though the exact pathophysiological pathway from uraemic dyslipidaemia to atherosclerosis remains obscure.

Current K/DOQI guidelines recommend treating patients suffering from chronic kidney disease (CKD) and dyslipidaemia with statins as first-line therapy [3]. As statins mainly lower LDL-cholesterol (LDL-C) and only slightly elevate HDL-C levels, they do not specifically target uraemic dyslipidaemia. Accordingly, in a recent randomized study, atorvastatin reduced neither CVE nor total mortality in diabetic patients on maintenance haemodialysis treatment [4].

Recently, lipid transfer proteins have become targets of growing interest for pharmacological intervention, as inhibition of the cholesteryl ester transfer protein (CETP) was shown to raise HDL-C serum levels [5]. The activity of lipid transfer proteins differs in CKD patients from subjects with intact renal function [6–8]. Results of cross-sectional studies suggest an association between CETP activity and the presence of cardiovascular disease in CKD stage V patients receiving haemodialysis therapy [9], but longitudinal studies verifying such an association are lacking. We therefore explored the association between CETP activity, HDL-C levels and prevalent cardiovascular disease in 69 patients with CKD stage V receiving haemodialysis treatment. Moreover, we followed these patients for 48 months and assessed incident CVE in this prospective follow-up period.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
We studied 69 patients with CKD stage V receiving haemodialysis in a prospective cohort study from November 2003 to October 2007. Patients were on haemodialysis treatment for 4.6 ± 5.5 years prior to inclusion. The causes of end-stage renal disease were diabetic nephropathy (n = 23), glomerulonephritis (n = 17), nephrosclerosis (n = 6), polycystic kidney disease (n = 5), interstitial nephritis (n = 5), other primary renal diseases (n = 9) or unknown (n = 4).

Haemodialysis was performed using bicarbonate dialysate and polyamide or polysulfone dialysers. All patients were of Caucasian ethnicity. Patients with any medical complication necessitating hospitalization at study initiation were excluded.

Systolic and diastolic blood pressure (BP sys and BP dia) was measured prior to a dialysis session. The mean blood pressure was defined as BP dia + (BP sys – BP dia)/3.

Patients with a history of diabetes mellitus, with a spontaneous plasma glucose level of >200 mg/dl and/or anti-diabetic treatment, and patients with self-reported diabetes mellitus were categorized as diabetic (n = 37, comprising 23 patients with clinical diagnosis of diabetic nephropathy and 14 patients with non-diabetic nephropathy). The body mass index (BMI) was calculated as body weight (kg)/height (m2).

We assessed cardiovascular co-morbidity and comedication in all patients by chart review and by standardized interviews. Prevalent cardiovascular disease was diagnosed in patients with coronary artery disease (a history of myocardial infarction or coronary artery angioplasty/stenting/bypass surgery), cerebrovascular disease (a history of major stroke or carotid endarterectomy/ stenting) or peripheral artery disease (a history of non-traumatic lower extremity amputation or lower limb artery bypass surgery/angioplasty/stenting). After completion of the cross-sectional part of the investigation we followed patients for 48 months.

The prespecified clinical endpoints were total mortality and CVE defined as myocardial infarction, coronary artery angioplasty/stenting/bypass surgery, major stroke, carotid endarterectomy/stenting, non-traumatic lower extremity amputation, lower limb artery bypass surgery/ angioplasty/stenting and death of any cause. Patients were censored at the time of renal transplantation (n = 13). No patient was lost to follow-up.

We drew blood samples for measurement of routine chemistry, serum lipoprotein concentrations and CETP activity under standardized conditions before the start of a haemodialysis session, without regard to time since last meal. Samples were placed on ice immediately and were centrifuged at 4000 rpm (3300 g) for 10 min at 4°C, and frozen at –80°C until further analysis. CETP activity was measured by a fluorescence method (Roar Biomedical, Inc.,NY, USA; intra- and interassay coefficients of variation <3%).

The study protocol was approved by the local ethics committee and was conducted in accordance with the declaration of Helsinki. All patients gave their written informed consent for study participation.

We performed statistical analysis using SPSS 12.0.1 (SPSS Inc., Chicago, USA). Categorical variables are presented as percentage of patients, and compared by Fisher's exact test. Continuous data are expressed as mean ± standard deviation and compared by the Mann–Whitney test. The relationship between CETP activity and HDL-C was assessed by Spearman's correlation coefficients. After stratifying patients by median CETP activity and by median HDL-C levels, survival curves were calculated by the Kaplan–Meier method and compared by log-rank testing. Additionally, in order to compare event-free and overall survival for extremes of CETP activity, survival curves were calculated after stratifying patients by CETP activity into tertiles.

Finally, Cox proportional hazards models were calculated with age, diabetes mellitus, statin intake, total cholesterol and CETP activity as independent variables, and total mortality and CVE as dependent variables. The level of significance was set at P < 0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Among the 69 patients with CKD stage V, 26 patients had prevalent cardiovascular disease at study initiation (Table 1). Those patients were older and had a higher prevalence of diabetes mellitus. However, they neither differed in CETP activity nor in total cholesterol or HDL-C serum concentrations from patients without prevalent cardiovascular disease. Out of the 69 patients, 54 did not receive lipid-lowering medication at study initiation. In these patients, we found a significant negative correlation between CETP activity and HDL-C levels (r = –0.379, P = 0.005; Figure 1). This correlation remained significant after exclusion of diabetic patients (r = –0.386, P = 0.047). In contrast, CETP activity and HDL-C did not correlate in the remaining 15 patients who received statin treatment (r = 0.131, P = 0.642). Furthermore, there was no significant correlation between CETP activity and plasma triglyceride levels (total cohort: r = –0.113, P = 0.355; patients without statin treatment: r = –0.033; P = 0.813).


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  		Table 1 Baseline characteristics of the study cohort, stratified by prevalent cardiovascular disease (CVD)

 

Figure 1
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  		Fig. 1 Relationship between CETP activity and HDL-cholesterol levels in patients not receiving statins.

 
During the prospective follow-up, 36 patients suffered a CVE, and 32 patients died. Patients who had a CVE during the follow-up were older and had a higher prevalence of diabetes mellitus than patients without an incident CVE (Table 2), but both groups did not differ with respect to total cholesterol or HDL-C levels. When we stratified patients by CETP activity into two groups (patients above versus below the median), patients with high CETP activity had neither an increased risk for subsequent CVE (P = 0.901; Figure 2a) nor higher overall mortality (P = 0.615; Figure 2b) than patients with CETP activity below the median. The same holds true when stratifying patients by CETP activity into tertiles and comparing patients with the highest and lowest CETP activity in order to compare event-free and overall survival for extremes of CETP activity (CVE: P = 0.478; overall mortality: P = 0.837). In addition, CETP activity above the median predicted neither future CVE nor overall mortality in a subgroup of non-diabetic dialysis patients (CVE: P = 0.871; overall mortality: 0.968).


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  		Table 2 Characterization of patients who suffered a cardiovascular event (CVE) during the follow-up

 

Figure 2
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  		Fig. 2 (a) CETP activity and survival without cardiovascular events. Patients were stratified by CETP activity (below versus above median; Kaplan–Meier analysis with the log-rank test). (b) CETP activity and total survival. Patients were stratified by CETP activity (below versus above median; Kaplan–Meier analysis with the log-rank test).

 
Similarly, when stratifying patients by HDL-C levels into two groups, patients with low HDL-C levels differed neither in event-free survival (P = 0.780; Figure 3a) nor in total survival (P = 0.838; Figure 3b), from patients with higher HDL-C levels.


Figure 3
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  		Fig. 3 (a) HDL-cholesterol (HDL-C) and survival without cardiovascular events. Patients were stratified by HDL-C (below versus above median; Kaplan–Meier analysis with the log-rank test). (b) HDL-C and total survival. Patients were stratified by HDL-C (below versus above median; Kaplan–Meier analysis with the log-rank test).

 
In a Cox regression analysis, age and total cholesterol levels were independent predictors of CVE, and age was the only independent predictor of total mortality (Table 3).


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  		Table 3 Cox regression analysis for cardiovascular events/death

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
It is postulated that dyslipidaemia contributes to accelerated atherogenesis and premature CVE in CKD patients. This ‘uraemic’ dyslipidaemia is characterized by low plasma levels of HDL-C and elevated plasma triglycerides, whereas total cholesterol and LDL-C levels are normal or even low [2,6]. Its pathophysiology is poorly understood, and conventional drug treatment failed to reduce CVE in CKD patients receiving haemodialysis [4]. Ongoing clinical trials now focus on pharmacological lowering of LDL-C by combining statins and ezetimibe [2]. However, with regard to the lipoprotein patterns in uraemic dyslipidaemia, it seems more promising to raise HDL-C than to lower LDL-C levels. CETP regulates human lipoprotein metabolism and facilitates the transfer of cholesterol esters from HDL particles to VLDL and LDL particles in exchange for triglycerides. As a consequence, high CETP activity leads to low HDL-C levels, an increased content of cholesterol esters in VLDL and an enhanced generation of small dense LDL particles, which may promote atherosclerosis [10,11].

Pharmacological CETP inhibition was initially considered an epoch-making new strategy to raise HDL-C levels. Surprisingly, recently published clinical trials on the efficacy and safety of the CETP inhibitor Torcetrapib in the general population reported disappointing long-term results [5,12,13]. Nevertheless, CKD stage V patients who suffer from dyslipidaemia with low HDL-C levels might selectively benefit from raising HDL-C by CETP inhibition. However, before designing clinical trials with CETP inhibitors in these patients, it must be clarified whether CETP activity in CKD patients is associated with low HDL-C levels as well as increased cardiovascular morbidity and mortality. To the best of our knowledge, we are the first group to analyse the association of CETP activity with CVE and mortality in a longitudinal study in CKD patients. Interestingly, even though CETP activity negatively correlated with HDL-C levels in our study, it was not associated with prevalent cardiovascular disease. Moreover, CETP activity did not predict future CVE in our patient cohort during a follow-up period of 48 months. These results corroborate the finding that high HDL-C levels are not protective against CVE in patients with CKD stage V. Kimura et al. recently reported on a cross-sectional study in which they initially found a high prevalence of cardiovascular disease among CKD patients receiving haemodialysis with low CETP serum concentration and low HDL-C levels [9]. In a later publication, however, the same group reported contradictory data [14]. Compared to our patient cohort, the patients studied by Kimura et al. were younger, had a longer vintage of haemodialysis treatment and had a different ethnic background.

A limitation of our work might be the rather small study cohort. However, neither any tendency for an increase in CVE nor a relevant tendency for shorter survival in patients with higher CETP activity was seen after following 69 haemodialysis patients for 4 years. Thus, even though we cannot exclude that a much larger, multicentre evaluation might reveal a certain, albeit small, impact of CETP activity on CVE and total survival, we expect that such a small statistical difference would be of limited clinical importance.

In summary, we present the first longitudinal data on the association between CETP activity and CVE in a sizable cohort of patients with CKD stage V. CETP activity was neither associated with prevalent CV disease nor did it predict event-free survival. Thus, a beneficial effect of raising HDL-C by CETP inhibitors in patients with CKD stage V seems questionable.

Conflict of interest statement. None declared.



   Notes
 
* Both authors contributed equally to the work. Back



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis (1998) 32:112–119.
  2. Uhlig K, Levey AS, Sarnak MJ. Traditional cardiac risk factors in individuals with chronic kidney disease. Semin Dial (2003) 16:118–127.[CrossRef][Web of Science][Medline]
  3. Kidney Disease Outcomes Quality Initiative (K/DOQI) Group. K/DOQI clinical practice guidelines for management of dyslipidemia in patients with kidney disease. Am J Kidney Dis (2003) 4:1–91.[Medline]
  4. Wanner C, Krane V, März W. for the German Diabetes and Dialysis study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med (2005) 353:238–248.[Abstract/Free Full Text]
  5. Nissen SE, Tardif J-C, Nicholls SJ. for the ILLUSTRATE investigators. Effect of Torcetrapib on the progression of coronary atherosclerosis. N Engl J Med (2007) 356:1304–1316.[Abstract/Free Full Text]
  6. Schlitt A, Heine GH, Jiang X-C, et al. Phospholipid transfer protein in hemodialysis patients. Am J Nephrol (2007) 27:138–143.[CrossRef][Web of Science][Medline]
  7. Kimura H, Gejyo F, Suzuki S, et al. A common mutation of cholesteryl ester transfer protein gene in dialysis patients. Kidney Int (1999) 71:186–189.
  8. Reade V, Mezdour H, Reade R, et al. Neutral-lipid transfers and cholesteryl ester transfer protein in hemodialyzed patients. Am J Nephrol (1996) 16:394–401.[Web of Science][Medline]
  9. Kimura H, Miyazaki R, Suzuki S, et al. Cholesteryl ester transfer protein as a protective factor against cardiovascular disease in hemodialysis patients. Am J Kidney Dis (2001) 38:70–76.[CrossRef][Web of Science][Medline]
  10. Dullaart RPF, Dallinga-Thie GM, Wolffenbuttel BHR, et al. CETP inhibition in cardiovascular risk management: a critical appraisal. Eur J Clin Invest (2007) 37:90–98.[CrossRef][Web of Science][Medline]
  11. Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med (2007) 356:1364–1366.[Free Full Text]
  12. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and intima-media thickness in mixed dyslipidemia (RADIANCE 2 study): a randomized, double-blind trail. Lancet (2007) 370:153–160.[CrossRef][Web of Science][Medline]
  13. Barter PJ, Caulfield M, Eriksson M. for the ILLUMINATE investigators. Effects of Torcetrapib in patients at high risk for coronary events. N Engl J Med (2007) 357:2109–2122.[Abstract/Free Full Text]
  14. Kimura H, Miyazaki R, Imura T, et al. Hepatic lipase mutation may reduce vascular disease prevalence in hemodialysis patients with high CETP levels. Kidney Int (2003) 64:1829–1837.[CrossRef][Web of Science][Medline]
Received for publication: 31. 1.08
Accepted in revised form: 30. 4.08


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