Department of Medicine, McGill University, Montreal, Quebec, Canada
Correspondence to Dr. Sarah S. Prichard, Royal Victoria Hospital, 687 Avenue de Pins Ouest, Montreal, Quebec, Canada, H3A 1A7. Phone: 514-934-1934; Fax: 514-843-2815;
ABSTRACT. Heart disease is a major cause of morbidity and mortalityamong patients with renal failure. Premature atheroscleroticcoronary heart disease is driven by multiple risk factors, includingdyslipidemia and oxidative stress. In the nondialysis population,there is overwhelming evidence that treatment of dyslipidemiacan significantly improve cardiovascular outcomes. Accumulatingdata indicate that dialysis patients have atherogenic lipidabnormalities. Although LDL cholesterol (LDL-C) levels in patientswho undergo hemodialysis are normal or near normal, increasedoxidized LDL-C, triglycerides, and lipoprotein (a) [Lp(a)];decreased HDL cholesterol (HDL-C); and triglyceride-rich VLDLhave been noted. Patients who receive peritoneal dialysis havea more atherogenic lipid profile with increased LDL-C, apolipoproteinB, oxidized LDL-C, triglycerides, and Lp(a) and decreased HDL-C.Furthermore, the LDL particles of peritoneal dialysis patientsare small and dense. However, there is a dearth of informationregarding the goals, efficacy, and safety of dyslipidemia treatmentamong dialysis patients. Given the strong evidence of risk reductionand the benefits of lipid-lowering treatment in the nondialysispopulation, the emerging consensus is that dialysis patientsshould be treated aggressively for dyslipidemia to an LDL-Cgoal below 100 mg/dl. Although physicians and patients may bereluctant to add medications because of concerns about polypharmacy,potential decreased compliance, and increased cost, the useof agents such as sevelamer that can serve multiple functions,including phosphate control, lipid lowering (decreased LDL-Cand total cholesterol), and anti-inflammatory effects (decreasedhigh-sensitivity C-reactive protein), should be explored andconsidered for patients who would benefit from such treatment.E-mail: sarah.prichard@muhc.mcgill.ca
Regardless of age, heart disease is a major cause of morbidityand mortality among patients with renal failure. Mortality indialysis patients is dramatically higher than in the generalpopulation, and cardiovascular disease (CVD) is the leadingcause of mortality among these patients (1). Atheroscleroticheart disease is believed to account for approximately 55% ofmortality and contributes to a 20-fold increase in ischemicheart disease and to a 10-fold increase in risk of stroke amongpatients with ESRD (chronic kidney disease stage 5) (2). Therisk for heart disease or subclinical or clinical disease existseven as patients enter dialysis treatment. In the United StatesRenal Data System (USRDS) Wave 2 study, for example, the prevalenceof ischemic heart disease and cardiac failure was approximately40% before renal replacement, much higher than the 2 to 26%reported in the general population (3). In a Canadian study,baseline echocardiography identified 74% of patients enteringfirst-time dialysis treatment with left ventricular (LV) hypertrophy(4). In the same study, 32% of patients had LV dilation and15% had systolic dysfunction. It is likely that both preexistingand new-onset CVD contribute to the high mortality in patientswith ESRD. Identifying and reducing the causes of CVD and itsassociated risk factors in this patient population should goa long way toward improving outcomes in patients with ESRD.
Risk Factors for Coronary Artery Disease among Dialysis Patients
Patients with ESRD are at a particularly high risk for coronaryartery disease (CAD) or atherosclerotic coronary heart disease(ASCHD). There are traditional and nontraditional risk factorsthat contribute to the high incidence of CAD in this population(5). Multiple atherosclerotic risk factors recognized as "traditional"risk factors for ischemic heart disease exist in dialysis patients.These include hypertension, diabetes, dyslipidemia, and hyperhomocysteinemia(Table 1). In addition to these, other risk factors that maybe exaggerated in the uremic patient or are unique to uremiamust be considered and would be classified as nontraditional.These include disturbances of calcium and phosphate, inflammation,and oxidative stress.
Table 1. Summary of risk factors for coronary artery disease among dialysis patients
In a cross-sectional study of 1041 dialysis patients, the prevalenceof atherosclerotic risk factors at the beginning of ESRD wascompared with estimates of risk factors in normal adults fromthe US population derived from the Third National Health andNutrition Examination (NHANES III) (6). That study found thatdialysis patients had a high prevalence of diabetes (54%), hypertension(96%), LV hypertrophy by electrocardiogram (EKG) criteria (22%),low physical activity (80%), hypertriglyceridemia (36%), andlow HDL cholesterol (HDL-C; 33%). These patients were also morelikely to be older, black, and male when compared with the non-ESRDNHANES III participants. After adjustment for age, race, gender,and atherosclerotic CVD, the prevalence of diabetes, hypertension,LV hypertrophy by EKG, low physical activity, low HDL-C, andhypertriglyceridemia were still found to be more common amongpatients with ESRD than among normal subjects. The projected5-yr atherosclerotic CVD risk among patients older than 40 yrand without atherosclerotic disease was more than twice as high(13%) for patients with ESRD compared with normal participants(6%).
Other risk factors that often are found to be present in ESRDand that may contribute to increased risk of ASCHD include inflammatorysyndromes (7), abnormalities of coagulation (8), hyperhomocysteinemia(9), and disturbance of calcium and phosphate metabolism, whichhas been linked to increased cardiovascular mortality risk inpatients with chronic renal failure (10–12). Thus, patientswith ESRD seem to have a greater number and prevalence of riskfactors than the general population, and these factors seemto contribute to an increased risk of subsequent atheroscleroticdisease. The relative contributions of these risk factors, appropriatetreatment strategies, and whether target goals should be differentin this population relative to the general population are questionsthat should be explored further. This article focuses on thequantitative and qualitative changes in lipid profiles as importantrisk factors for ASCHD among dialysis patients. It also providesan overview of the potential treatments for risk reduction asa result of dyslipidemia and how such treatment should be integratedinto the overall care of the patient who is on renal replacementtherapy.
Evidence for the importance of lipids as risk factors in CVDhas come from animal studies, studies of familial hypercholesterolemia,population studies, and clinical studies. Although these dataare not specifically from ESRD populations, they nonethelessserve to illustrate the importance of dyslipidemia as a riskfactor for atherosclerosis and highlight how lipid-normalizingtreatment can help lower such risk. New Zealand white rabbitsthat are fed a high-cholesterol (2%) diet develop atheroscleroticlesions more rapidly than those that are fed a normal diet andhave long been used as animal models of atherosclerosis. Inthe Watanabe heritable dyslipidemia (WHHL) model—a modelfor familial hypercholesterolemia—atherosclerosis developsprematurely from fatty streaks and has been attributed to lowLDL receptor levels. Recently, transgenic WHHL rabbits expressinghuman apolipoprotein (a) have been shown to develop more advancedlesions and vascular calcification than nontransgenic animals(13). Although a detailed review of animal models and the dataaccrued from them is beyond the scope of this article, thistype of data supports the importance of dyslipidemia in thecause of atherosclerotic lesions.
Further understanding of the molecular basis of cholesterolmetabolism and its critical effect on atherosclerosis has alsocome from studies of inborn errors of LDL metabolism, such asfamilial hypercholesterolemia, an inherited form of hypercholesterolemiathat is caused by a mutation of the LDL receptor gene leadingto an accumulation of LDL cholesterol (LDL-C) and the developmentof severe premature atherosclerosis. These patients are at highrisk for premature CVD, including myocardial infarction (MI)and death in the third to sixth decades of life (14).
The role of lipids in the cause of atherosclerosis and the importanceof therapies in the reduction of risk have been confirmed inpopulation studies and innumerable clinical studies. The UnitedStates National Heart, Lung, and Blood Institute’s Framinghamstudy, for example, demonstrated in the early 1960s that highcholesterol increases the risk of heart disease (15). Furtherstudies have defined a negative role for high triglycerides,LDL-C, and lipoprotein (a) (Lp[a]) as risk factors for heartdisease. Data have also shown that increasing HDL-C can decreasethe risk of death.
Clinical data corroborate the link between serum LDL-C and CADand support the reduction of cholesterol as a means of reducingcongestive heart disease (CHD) mortality and total mortality.Several quantitative angiographic studies have demonstrateda decreased rate of progression—or even regression—ofcoronary atherosclerotic lesions when LDL-C–reducing treatmentsare administered (16–20).
In a meta-analysis of 38 studies using cholesterol loweringas an intervention, Gould et al. (21) found that for every 10%decrease in cholesterol, there is a 15% decrease in CHD mortality(P < 0.001) and an 11% decrease in total mortality (P <0.001). Even greater benefits have been noted in clinical trialsusing HMG-CoA reductase inhibitors or statins as lipid-loweringagents. In the Scandinavian Simvastatin Survival Study, cholesterollowering with simvastatin was found to reduce total cholesterolby 25%, LDL-C by 35%, and triglycerides by 10% and to increaseHDL-C by 8% (22). The overall reduction in total mortality asa result of treatment was 30% (relative risk [RR] = 0.70; 95%confidence interval [CI], 0.58 to 0.85; P = 0.0003). The studyalso showed a 34% RR reduction of a major coronary event withtreatment (RR = 0.66; 95% CI, 0.59 to 0.75; P < 0.00001).In the Cholesterol and Recurrent Events trial, pravastatin treatmentreduced total cholesterol by 20%, LDL-C by 28%, and triglyceridesby 14% and increased HDL-C by 5% (23). This translated to areduction in risk of a fatal coronary event or nonfatal MI of24% (P = 0.003).
It is clear that there is an association between high LDL-Cand CAD in the general population. A combination of elevatedLDL-C, elevated triglycerides, and low HDL-C seems to be particularlyatherogenic. In addition, high concentrations of Lp(a), a cholesterol-richlipoprotein with an LDL particle linked to apolipoprotein (a),has been associated with high risk for CAD (24,25). The compellingevidence linking dyslipidemia with CAD and showing benefitsof cholesterol reduction or lipid-normalizing strategies ledto the recommendation by the American Heart Association thatpatients with CAD be treated with lipid-lowering agents (26).The Adult Treatment Panel III (ATP III) guidelines recentlyissued by the National Cholesterol Education Program ExpertPanel on Detection, Evaluation, and Treatment of High BloodCholesterol in Adults focus on LDL-C as the chief target oflipid-lowering therapy. The ATP III report recommends an LDL-Ctarget of less than 100 mg/dl as optimal for all patients (27).
Among patients with ESRD and uremia, a number of lipid abnormalitieshave been identified. Although information remains incomplete,accumulating evidence indicates that the kind of dyslipidemiais often related to the type of renal replacement therapy: peritonealdialysis or hemodialysis (28) (Figure 1).
Figure 1. Diagrammatic view of lipoprotein profiles in normal subjects versus patients on hemodialysis and peritoneal dialysis. Note: The arrows show increasing atherogenicity from normal health to hemodialysis to peritoneal dialysis.
Hemodialysis
Hemodialysis patients often have normal or near-normal levelsof total cholesterol and LDL-C (28). Approximately 20 to 40%of hemodialysis patients have been estimated to have elevatedtriglycerides and reduced HDL-C (29,30) (Figure 1). In addition,increased oxidized LDL levels (31–33) and increased Lp(a)levels have been reported, with 34% of patients having levelsabove the 75th percentile (34). The elevations of Lp(a) levelsin hemodialysis patients are smaller than those seen in continuousambulatory peritoneal dialysis. The triglyceridemia in hemodialysispatients can be explained by the presence of triglyceride-richVLDL rather than an overproduction of VLDL (35).
Peritoneal Dialysis
Peritoneal dialysis seems to be associated with a relativelymore atherogenic lipid profile than hemodialysis. In reportedstudies, 20 to 40% of peritoneal dialysis patients have beenshown to have elevated total cholesterol and LDL-C (Figure 1),and 25 to 50% of patients have been reported to have elevatedtriglycerides and apolipoprotein B (apo B) and low HDL-C (34,36,37).The LDL-C has also been shown to be qualitatively differentfrom normal LDL-C in that there is an increased concentrationof small, dense particles together with the high apo B (38).In addition, increased oxidized LDL levels (31–33) andincreased Lp(a) levels have been reported in peritoneal dialysispatients, with 42% of patients having levels above the 75thpercentile (34). The hypertriglyceridemia in peritoneal dialysispatients may be partially explained by increased hepatic synthesisof VLDL, which binds triglycerides (38).
Development of Coronary Artery Plaque and Treatment Implications
What are the implications of atherogenic lipid profiles amongpatients with uremia or ESRD? To answer this question, the overallcause and development of atherosclerotic plaques and the superimpositionof factors unique to uremic patients must be considered. Ingeneral, plaque formation in CAD involves oxidation of LDL-C,inflammation, and calcification. Thus, any strategy to reducerisk of ASCHD should consider reduction of LDL-C, reductionof oxidative risk, and reduction of risk of calcification, particularlybecause abnormal calcium and phosphorus metabolism and vascularcalcification are significant contributors to mortality in patientswith ESRD (10–12). Strategies for the reduction of hyperphosphatemiaand calcification involve the use of phosphate binders, andavailable phosphate binders have different effects on the twotherapeutic goals (39).
For reduction of oxidative stress, high-dose supplementationwith 800 IU/d -tocopherol (vitamin E) can be useful. It hasbeen shown to reduce cardiovascular risk in the Secondary Preventionwith Antioxidants of Cardiovascular Disease in End-Stage RenalDisease study of hemodialysis patients with preexisting CVD(40). In that study, the primary end point was a composite variableof MI, ischemic stroke, peripheral vascular disease (excludingarteriovenous fistula), and unstable angina, and it showed a54% reduction with treatment (RR = 0.46; 95% CI, 0.27 to 0.78;P = 0.014). Confirmation of these results, as well as informationregarding the utility of other antioxidant agents, is neededto recommend their use conclusively. In ESRD, antioxidant therapymay be especially valuable in hemodialysis patients, who showgreater evidence of oxidative stress than the general populationand peritoneal dialysis patients (41).
Despite increased antioxidant defense, there seems to be a relationshipbetween the degree of lipid peroxidation and the severity ofCVD in hemodialysis patients (41). Lipid-lowering therapiesare important in patients with ESRD and should be included wheneverdiet and exercise are not sufficient to achieve target lipidgoals. However, use of antilipid therapies remains low in dialysispatients. It is clear that dialysis patients have a myriad oflipid abnormalities, with peritoneal dialysis patients havinga more atherogenic lipid profile than hemodialysis patients.By extension of the compelling data in the general populationand the high risk for lipid abnormalities and CVD in the dialysispopulation, most patients with ESRD should be treated with lipid-loweringagents. Supporting evidence for this approach comes from a recentlypublished analysis of data from the USRDS Dialysis Morbidityand Mortality Wave 2 study that shows that statin use is associatedwith a reduction in cardiovascular mortality (RR = 0.64; 95%CI, 0.45 to 0.91) and total mortality (RR = 0.68; 95% CI, 0.54to 0.87) (42). Further prospective studies are needed to confirmthe use of this strategy in dialysis patients. Large-scale,prospective, randomized trials (4-D Trial, HARP) to determinethe effects of statins on cardiovascular complications in diabeticand nondiabetic patients on hemodialysis are ongoing and shouldprovide further information on the effects of lipid loweringon reducing the risk of CVD in this patient population (43).Currently, there are no specific trials examining cholesterolreduction in dialysis patients.
Both the European Joint Task Force and the US National CholesterolEducation Program (27,44) have issued lipid guidelines for thegeneral population. In addition, specific recommendations onthe management of dyslipidemias in chronic kidney disease (CKD)have recently been published through the National Kidney Foundation’sKidney Disease Outcome Quality Initiative (45). In comparingthese guidelines with the ATP III guidelines (27), patientswith CKD should be considered to be in the highest risk category,meaning that the target LDL-C level for CKD patients is below100 mg/dl.
Let us examine the reality of lipid management in current practice.Are patients with ESRD receiving lipid-lowering treatment? Assumingthat at least 50% of patients who initiate dialysis have clinicalor subclinical ASCHD and that at least 80% of these patientshave dyslipidemia, it may be expected that at least 40% of dialysispatients should be receiving lipid-lowering therapy. In fact,the data show far less usage of lipid-lowering treatments. Ina Canadian study of patients with ESRD, a lipid-lowering agentwas used in 9.5% of patients with no ASCHD and in 29.4% of patientswith ASCHD (46); USRDS data indicate that as few as 15% of peritonealdialysis patients and 8% of hemodialysis patients are on lipid-loweringtreatments (47).
In examining the possible reasons for the underimplementationof lipid-management strategies among dialysis patients, thefollowing factors may be intuitively considered as potentialreasons: polypharmacy, cost, compliance, lack of published evidence,side effects, and normal LDL-C levels. It is hoped that a casehas been made here for the severity of consequences (ASCHD)in the absence of lipid control in the general population and,by extension, in the dialysis or uremic population. Althoughmore studies of dyslipidemia in ESRD are certainly needed, thepotential risk of nontreatment clearly indicates that more aggressivelipid-lowering strategies need to be implemented for these patients.In considering such therapy, LDL-C measurements alone are notsufficient to determine whether treatment is warranted. As wehave seen, quantitative differences in apo B protein, oxidizedLDL-C, HDL-C, and Lp(a) as well as qualitative differences inVLDL particles exist in dialysis patients relative to nondialysissubjects.
Finally, dialysis patients are among a group of chronicallyill patients who remain on long-term multiple pharmacotherapies,and it is understandable that there may be reluctance, on thepart of both the physician and the patient, to add one moremedication to the regimen. This reluctance may be related tocost and/or compliance, as well as fear of side effects anddrug interactions. Any strategy to reduce the number of medicationswould only serve to improve compliance, reduce cost, and reducerisk of adverse events. In this regard, it is interesting tonote that the calcium-free, metal-free phosphate binder sevelamerhydrochloride (mean dose, 6.5 g/d) has been shown in a randomizedtrial (n = 200) to reduce serum LDL-C concentrations by 37%(37 mg/dl) and total cholesterol by 22% (40 mg/dl; P < 0.0001versus calcium binders for both) in addition to decreasing serumphosphate levels by 33% (Figure 2) (48). Sevelamer did not seemto affect HDL-C or triglyceride levels in this study, althougha separate open-label study has shown a 30% reduction in LDL-Cand an 18% increase in HDL-C relative to baseline (P < 0.0001for both) after 46 wk of sevelamer treatment (49). In contrast,calcium-based phosphate binders were not shown to have any effecton total cholesterol or LDL-C levels (Figure 2) (48).
Figure 2. Effect of daily treatment with sevelamer hydrochloride on lipid profile in 200 hemodialysis patients. LDL-C, LDL cholesterol. *P < 0.0001 versus calcium.
Sevelamer treatment has also been shown to produce a reductionin highly sensitive C-reactive protein, a key marker of inflammation.In contrast, calcium-containing binders may increase highlysensitive C-reactive protein levels. Thus, data indicate thatsevelamer may have additional benefits beyond phosphate reductionin patients who undergo hemodialysis: namely, LDL-C reductionand anti-inflammatory effects. The contribution of either orboth of these effects to a reduction in calcification or atherosclerosisin sevelamer-treated patients is currently unclear. Additionalstudies are needed to elucidate further these benefits of treatmentwith sevelamer. However, this medication may be especially usefulin meeting lipid targets in patients with ESRD without the needfor additional specific lipid-lowering agents.
Dyslipidemia is an important risk factor for ASCHD. In the generalor nonuremic population, there is overwhelming evidence thatthe treatment of lipid abnormalities markedly improves cardiovascularoutcomes. Emerging data indicate that dialysis patients alsohave a number of lipid abnormalities and that the specific abnormalitiesoften differ between patients who receive hemodialysis versusperitoneal dialysis. In either case, the abnormal lipid profilesare atherogenic, with the dyslipidemia being more atherogenicin peritoneal dialysis patients. However, there is a dearthof information regarding the goals, efficacy, and safety oftreatment for lipid optimization among dialysis patients. Noprospective randomized studies have examined lipid-loweringstrategies in this specific patient population. One analysisof USRDS data indicates that statin therapy can reduce cardiovascularmortality and total mortality among hemodialysis patients (42).Given the strong evidence showing the benefit of lipid-loweringtherapy in the general population, the current consensus isthat until further data are available, dialysis patients shouldbe treated aggressively—with an LDL-C goal less than 100mg/dl—to reduce the risk of CVD. Although shortcomingsof added medications, compliance issues, and increased costmay hinder the addition of lipid-lowering therapies to the overalltreatment strategy of dialysis patients, the use of a singlemedication such as sevelamer to control hyperphosphatemia, reducelipid levels, and reduce some aspects of inflammatory processesis an interesting option that should be explored further. Preliminarydata in this regard are encouraging and should be confirmed.
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C. L. Weber, J. Frohlich, J. Wang, R. A. Hegele, and C. Chan-Yan Stability of lipids on peritoneal dialysis in a patient with familial LCAT deficiency
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C. Wanner, V. Krane, W. Marz, M. Olschewski, J. F.E. Mann, G. Ruf, E. Ritz, and the German Diabetes and Dialysis Study Investigato Atorvastatin in Patients with Type 2 Diabetes Mellitus Undergoing Hemodialysis
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Abstract
Epidemiology
-tocopherol (vitamin E) can be useful. It has been shown to reduce cardiovascular risk in the Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease study of hemodialysis patients with preexisting CVD (40). In that study, the primary end point was a composite variable of MI, ischemic stroke, peripheral vascular disease (excluding arteriovenous fistula), and unstable angina, and it showed a 54% reduction with treatment (RR = 0.46; 95% CI, 0.27 to 0.78; P = 0.014). Confirmation of these results, as well as information regarding the utility of other antioxidant agents, is needed to recommend their use conclusively. In ESRD, antioxidant therapy may be especially valuable in hemodialysis patients, who show greater evidence of oxidative stress than the general population and peritoneal dialysis patients (41). 
