Dyslipidemia in Dialysis Patients

Wajeh Y. QunibiDivision of Nephrology, Department of Medicine, University of Texas Health Sciences Center at San Antonio,San Antonio, Texas

ABSTRACT

Dyslipidemia is a well-established traditional risk factorfor cardiovascular events in the general population, par-ticularly those with preexisting cardiovascular disease(CVD). In this population, reductions in total and lowdensity lipoprotein cholesterol (LDL-C) levels are effectivein reducing coronary artery events and mortality. Dyslipi-demia is more common in patients with chronic kidneydisease (CKD) and is believed to contribute to the highprevalence of CVD in these patients. To date, the treat-ment of dyslipidemia in patients with CKD followed theguidelines recommended by the US National CholesterolEducation Program Adult Treatment Panel III (ATP III)for the treatment of lipid abnormalities. These guidelinesrecommend that initiation of lipid-lowering therapy bebased on LDL-C level and the projected 10-year risk for

coronary artery disease (CAD). However, we now recog-nize that the relationship between serum cholesterol andCVD is more complex in patients with CKD, particularlythose receiving maintenance hemodialysis. This has beendemonstrated by the failure of three large randomizedclinical trials to show a beneficial effect of lipid-loweringtherapy in reducing mortality in dialysis patients despitesignificant reduction in LDL-C levels. These results havecaused uncertainty among nephrologists about how bestto manage dyslipidemia in their patients. In this review,the role of dyslipidemia as a risk factor for atherosclerosisin ESRD patients and the results of the 3 clinical trialsand other studies, including their limitations will be dis-cussed, and a schema for treating dyslipidemia in dialysispatients will be proposed.

The number of patients with end-stage renal dis-ease (ESRD) who are receiving maintenance dialysisin the United States is approaching 500,000 (1). Car-diovascular disease (CVD), the leading cause ofdeath among these patients, accounts for 45% ofdeaths, a rate that is 10–30 times higher than that inthe general population (2–5). This relative risk is evengreater in younger dialysis patients (6). Atherosclero-sis is more common in dialysis patients than in thegeneral population (7) as is coronary artery disease(CAD) which has been documented by angiographicstudies in >50% of patients at the initiation of renalreplacement therapy (8). More disturbing is the highmortality rate in dialysis patients after a cardiovascu-lar event. In-hospital mortality after acute myocar-dial infarction (MI) among patients on dialysis isapproximately 30%; at 1-year the mortality rate is60% (9). Thus, risk factors for CAD must be identi-

fied and treated in an attempt to reduce the burdenof atherosclerosis in dialysis patients.Dyslipidemia, defined as increased levels of serum

cholesterol and/or triglycerides, is a well-establishedtraditional risk factor for atherosclerotic CAD inthe general population and in patients with mild-to-moderate CKD, particularly those with nephrotic-range proteinuria. Studies in the general populationhave documented a direct, strong, and dose-depen-dent relationship between total cholesterol level andCVD mortality. Moreover, the pathogenic role ofserum cholesterol as a risk factor in atheroscleroticCVD was confirmed by several randomized clinicaltrials (RCTs) which demonstrated that reductions intotal and LDL-C levels, primarily with statins, iseffective in reducing coronary artery events andmortality (10–13). Clinical trials have also shownthat lipid-lowering therapy is effective in reducingthe risk of atherosclerotic cardiovascular events inthe nondialyzed CKD population (14,15).As dyslipidemia is also frequent in dialysis

patients and is believed to represent a major riskfor CAD (16), treatment with lipid-lowering agentswas considered a plausible strategy for reducing car-diovascular events in dialysis patients. Managementof dyslipidemia in dialysis patients followed theguidelines recommended by the US National Cho-lesterol Education Program Adult Treatment PanelIII (ATP III) which base the initiation of treatment

Address correspondence to: Wajeh Y. Qunibi, MD, Profes-sor of Medicine, University of Texas Health Sciences Centerat San Antonio, 7703 Floyd Curl Drive, San Antonio, TX78229-3900, Tel.: 210-358-2962, Fax: 210-358-4710, e-mail:qunibi@uthscsa.edu.Conflict of interest: The author has no conflict of interestto declare.

Seminars in Dialysis—2015DOI: 10.1111/sdi.12375© 2015 Wiley Periodicals, Inc.

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DRUG THERAPY: SPECIAL CONSIDERATIONS IN DIALYSIS PATIENTS

and target LDL-cholesterol (LDL-C) level on theprojected 10-year risk for coronary artery eventsuch as myocardial infarction (MI) or coronarydeath (17). According to these guidelines, LDL-Cshould be reduced to <100 mg/dl in patients with aprojected 10-year risk of coronary artery event thatexceeds 20% such as those with CKD. However, aswill be discussed later, the underlying pathophysiol-ogy of CVD and the nature of atherosclerosis aredifferent in dialysis patients from that of the generalpopulation. Understanding these differences mayhelp in designing a rational approach for the treat-ment of dyslipidemia in these patients.

Role of Atherosclerosis in CardiovascularDisease in Dialysis Patients

In patients with early stages of CKD, dyslipidemiacontributes significantly to the pathogenesis of ath-erosclerotic CAD (16). This process was thought tobe accelerated in chronic hemodialysis patients aswas initially described by Lindner et al. in 1974 (18).Subsequently, Lowrie and Lew reported a U-shaperelationship between serum total cholesterol leveland the risk for all-cause mortality in dialysispatients (19). Other large observational studies haveconfirmed the negative relationship between serumtotal or LDL-cholesterol and CVD in dialysis (20)and nondialyzed CKD patients (21). In one study,serum LDL-C < 70 mg/dl was strongly associatedwith all-cause mortality risk, but black patients dis-played a more conventional association betweenhigh LDL-C and increased death risk (20). The highrisk associated with low cholesterol level was attrib-uted to malnutrition and inflammation. Clarifyingthis relationship further, Liu et al. reported thathypercholesterolemia is an independent risk factorfor all-cause and CVD mortality in a subgroup ofESRD patients without serologic evidence of inflam-mation or malnutrition (22). Given that statinsaffect inflammation in addition to cholesterol level,these authors stated that their findings support theuse of statins in preventing CVD in dialysis patients.

Effects of Stains in Patients with CKD

Observational Studies

Statins (3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitors) are highly effective for prevent-ing CV morbidity and mortality in the general pop-ulation, especially those at higher baseline CADrisk (10–12). In these patients, the reduction in mor-tality and in CAD events is proportional to thereduction in LDL-C level. The Third Adult Treat-ment Panel of the National Cholesterol EducationProgram recommended a target value of LDL-cho-lesterol of 70 mg/dl for individuals at very high riskof CVD (23). Subgroup analyses of large trials inthe general population suggest that the benefit ofstatin treatment is similar to, or even greater, in

patients with stage 3 CKD than that in individualswith normal kidney function (24). Moreover, retro-spective analyses of the U.S. Renal Data SystemDialysis Morbidity and Mortality Wave-2 studyshowed that in incident hemodialysis or peritonealdialysis patients, statin therapy was associated witha 32% decrease in total mortality and 37% decreasein cardiovascular mortality (25). A similar decreasein mortality associated with statin use was alsoreported in prevalent dialysis patients enrolled inDialysis Outcomes and Practice Patterns Study(DOPPS) (26).However, there were no major randomized clini-

cal trials that specifically examined the efficacy ofstatins in improving survival and cardiovascularevents or on safety of these drugs in patients withadvanced CKD or in dialysis patients. Thus, theKidney Disease Dialysis Outcome Quality Initiative(K/DOQI) guidelines stated that, in the absence ofstrong evidence to the contrary, it is reasonable toassume that statins will reduce LDL-C and therebyatherosclerotic CVD in most patients with CKD.Given the high mortality rate from CVD in CKDpatients, and based on results of studies in the gen-eral population as well as on observational studiesin CKD patients, the K/DOQI guidelines recom-mended a goal LDL-cholesterol <100 mg/dl inpatients with CKD, including those receiving main-tenance dialysis (27).Unfortunately, this approach proved to be contro-

versial because an increased risk of CVD is seen in alarge proportion of dialysis patients irrespective ofwhether their LDL-C levels were low, normal, or high.This suggests that the accelerated atherosclerosis andCVD in most dialysis patients may not be due to ele-vated LDL-C, and thus interventions that reduce CVevents in the general population may not be equallyeffective in dialysis patients (28,29). Adding to this isthe concern about possible increased risk of rhabd-omyolysis and liver function abnormalities due to sta-tins in patients with decreased renal function.To investigate the efficacy and safety of statins

and other lipid-lowering therapy in CKD patients,three large RCTs and a number of meta-analyseswere conducted during the last 9 years with the aimof ascertaining whether statins are beneficial, andsafe, in reducing CV risk and mortality from CVDin dialysis patients (Table 1). A brief description ofeach of these trial follows.

Randomized Placebo-Controlled ClinicalTrials

The 4D Study (Die Deutsche Diabetes DialyseStudie) was the first multicenter, double blind, pla-cebo-controlled RCT that examined the effects oflowering the level of LDL-C with statins on cardio-vascular events and mortality in 1255 German he-modialysis patients with type 2 diabetes. Patientswere randomized to receive 20 mg of atorvastatindaily or placebo (30). The primary end-point was acomposite of death from cardiac causes, fatal and

2 Qunibi

nonfatal stroke, and nonfatal MI. Secondary end-points comprised all-cause mortality, cardiac eventsand cerebrovascular events.

The trial succeeded in lowering the median LDL-C level by 42% within 4 weeks in the atorvastatingroup vs. 1.3% by placebo. Despite that, and dur-ing a median follow-up period of 4 years, there wasonly a nonsignificant 8% decrease in the primarycomposite end-point in the atorvastatin treatedgroup (relative risk (RR), 0.92; 95% confidenceinterval (CI) 0.77–1.10; p = 0.37). Atorvastatin sig-nificantly reduced the rate of all cardiac events com-bined by 18% (RR: 0.82; 95% CI: 0.68–0.99;p = 0.03) but not total mortality (RR: 0.93; 95%CI: 0.79–1.08; p = 0.33). There were no cases ofrhabdomyolysis or severe liver disease detected ineither group but, unexpectedly, there was 2-foldincrease in the relative risk of fatal stroke amongthose receiving atorvastatin compared with placebo(95% CI: 1.05–3.93; p = 0.04).

This study was limited by including only diabeticpatients and for excluding patients with LDL-C > 190 mg per deciliter. In addition, 15% of theplacebo arm patients received nonstudy statins and17% of the statin-treated group discontinued theirdrug therapy. Moreover, the mean baseline serumLDL-C was approximately 123 mg/dl and only13% of patients had serum LDL-cholesterol levels>160 mg/dl. Interestingly, a post hoc analysis of thetrial data that stratified patients into LDL-C levels<103, 104–122, 123–144, and >145 mg/dl, showedthat atorvastatin significantly reduced the rate offatal and nonfatal cardiac events and death fromany cause if pretreatment LDL-cholesterol was>145 mg/dl (31). Therefore, statins may still be con-sidered for diabetic HD patients with high LDL-Clevels.

AURORA (A Study to Evaluate the Use of Rosu-vastatin in Subjects on Regular Hemodialysis: AnAssessment of Survival and Cardiovascular Events)was published 4 years after the publication of the4D trial (32). AURORA was an international, mul-

ticenter, double-blind, placebo-controlled RCT thatrandomly assigned 2776 prevalent hemodialysispatients to receive rosuvastatin 10 mg daily or pla-cebo. The combined primary end-point was deathfrom cardiovascular causes, nonfatal myocardialinfarction, or nonfatal stroke. Secondary end-pointsincluded death from all causes and individual car-diac and vascular events. Similar to the 4D study,LDL-C levels decreased by 43% and total choles-terol levels decreased by 27% in the rosuvastatingroup. However, after a mean follow-up of3.8 years, intent-to-treat analysis revealed no signifi-cant difference in the combined primary endpointbetween the rosuvastatin and the placebo groups(hazard ratio (HR): 0.96; 95% CI: 0.84–1.11;p = 0.59) or all-cause mortality (HR: 0.96; 95% CI:0.86–1.07; p = 0.51). There was no increase in theincidence of muscle-related adverse events, rhabd-omyolysis, or liver disease in the rosuvastatin groupas compared with the placebo group but there wasa slight but significant increase in hemorrhagicstrokes in patients with diabetes who received rosu-vastatin, which is consistent with the findings of the4D study.Again, this study was limited by a 50% dropout

of patients in each treatment group before studycompletion which may have concealed the potentialbenefit of statin therapy. Of note, the mean baselineserum LDL-C was around 100 mg/dl. Moreover,AURORA excluded patients who had received astatin within the previous 6 months, a group thatrepresents 35–40% of all dialysis population whoare likely to benefit the most from statins. Finally,the study did not enroll patients who are youngerthan 50 years old, a group that have higher cardio-vascular risk and may potentially benefit from statintherapy.SHARP (Study of Heart and Renal Protection) is

the most recent trial. SHARP randomized 3023dialysis patients (2527 on hemodialysis and 496 onperitoneal dialysis) and 6247 CKD patients notrequiring dialysis to receive simvastatin 20 mg/day

TABLE 1. Comparison of the three major randomized controlled trials: 4D, AURORA and SHARP

4D AURORA SHARP

Author/year Wanner et al./2005 Fellstr€om et al./2009 Baigent et al./2011# of patients 1255-all diabetic 2773 9270Age range (years) 18–80 50–80 62 � 12CKD stage 5D All All 3023 on maintenance HDDrugs Atorvastatin 20 mg daily vs. placebo Rosuvastatin 20 mg

daily vs. placeboSimvastatin plus ezetimibevs. placebo

Follow-up period(Median)

4 years 3.8 years 4.9 years

Main results No reduced risk of the compositeprimary end-point but significantreduction in subgroup withLDL-C > 145 mg/dl

No reduced risk of mortalityor primary and secondaryend-points

No significant reduction inmajor atherosclerotic eventsin dialysis patients

Risk of stroke 2-fold increase in relative risk offatal stroke among those receivingatorvastatin

Slight but significant increasein hemorrhagic strokes indiabetic patients receiving rosuvastatin

No significant differencebetween treatment groups

Other adverse events No cases of rhabdomyolysis orsevere liver disease detectedin either group

No increase in liver disease, orrhabdomyolysis in rosuvastatin group

No significant increase inmyalgia, rhabdomyolysis,transaminases, or hepatitis

HYPERLIPIDEMIA IN ESRD 3

with ezetimibe 10 mg/day or placebo (33). None ofthe patients had a history of MI or coronary arteryrevascularization. After a median duration of fol-low-up of 4.9 years, the study showed a 17% reduc-tion in major atherosclerotic events (RR: 0.83, 95%CI: 0.74–0.94; log-rank p = 0.0021), 25% reductionin nonhemorrhagic stroke (RR: 0.75, 95% CI: 0.60–0.94; p = 0.01), and 21% reduction in coronaryrevascularization (RR: 0.79, 95% CI: 0.68–0.93;p = 0.0036) among the simvastatin plus ezetimibe-treated patients. Moreover, there was a nonsignifi-cant 8% reduction in nonfatal MI or death fromCAD (RR: 0.92, 95% CI: 0.76–1.11; p = 0.37) inthe simvastatin and ezetimibe-treated group. How-ever, there was no overall reduction in the risk ofall-cause mortality. SHARP did not find a signifi-cant reduction in major atherosclerotic events fordialysis patients (RR: 0.90, 95% CI: 0.75–1.08)compared with CKD patients not on dialysis (RR:0.78, 95% CI: 0.67–0.91). Interestingly, the magni-tude of reduction in LDL-C was greater in nondial-ysis CKD patients compared to dialysis patients(37 mg/dl vs. 23 mg/dl, respectively).

Although the authors stated that there was notgood statistical evidence that the effects on majoratherosclerotic events differed between the dialysisand nondialyzed CKD patients, it is believed thatSHARP did not have sufficient power to assess theeffects on major atherosclerotic events separately indialysis and nondialysis patients. It is possible thatthe favorable results observed in the SHARP studywere largely related to the much larger number ofCKD patients not on dialysis enrolled in the study.Similar to the 4D and AURORA trials, there wasno significant difference between the two treatmentgroups with respect to the incidence of adverseevents such as myalgia, rhabdomyolysis, increasedtransaminases, or hepatitis. One criticism of thisstudy has been the inclusion of 3 different groups ofpatients; nondialysis CKD patients, hemodialysisand peritoneal dialysis patients.

Meta-analysis of trials in chronic kidney dis-ease

Despite the limitations of the above 3 trials, theyall have major strengths in being randomized, pla-cebo-controlled trials and in enrolling large numberof patients. However, because of their limitations, itwould be difficult to generalize their results to alldialysis patients.

A number of systematic reviews and meta-analy-ses pooled data from all available randomized clini-cal trials performed in CKD populations to allowfor sufficient power for assessing the treatmenteffects of LDL-C lowering therapy in these patients.In the first meta-analysis, Palmer and colleagues(34) showed that statins significantly reduced all-cause mortality and CV mortality in CKD patientsnot on dialysis. However, they did not find a signifi-cant effect of statins on all-cause mortality (RR:0.96; 95% CI: 0.88–1.04), cardiovascular mortality

(RR: 0.94; 95% CI: 0.82–1.07), major cardiovascu-lar events or fatal and nonfatal stroke in dialysispatients.A second meta-analysis by Upadhyay and col-

leagues (35) in 18 RCTs showed that lipid-loweringtherapy decreased the risk for cardiac mortality, car-diovascular events (including revascularization), andMI in patients with CKD. Significant benefit was alsoseen for all-cause mortality but was limited by a highdegree of heterogeneity. Subgroup analysis revealedthat the benefit for all-cause mortality was limited tostudies in nondialysis patients with CKD.A third meta-analysis by Barylski and colleagues

(36) of 11 RCTs with 21,295 CKD patients, includ-ing 6857 who were on dialysis, showed that use ofstatins in subjects with nondialysis-dependent CKDresulted in a marked reduction in death from allcauses, cardiac causes, cardiovascular events, andstroke. However, the use of statins in dialysis-dependent patients resulted in a nonsignificant effecton death from all causes and stroke, but had signifi-cant effect in reducing death from cardiac causesand cardiovascular events.A more recent Cochrane meta-analysis (37) on

dialysis patients in 25 studies with 8289 participantsconcluded that statins had little or no benefit onmajor cardiovascular events, all-cause mortality, car-diovascular mortality and MI and uncertain effectson stroke in adults treated with dialysis despite clini-cally relevant reductions in serum cholesterol levels.Finally, Hou and colleagues reported the results of

their meta-analysis of 31 trials that provided data for48,429 patients with CKD (38). Their results showedthat statin therapy produced a 23% risk reductionfor major cardiovascular events, an 18% reductionfor coronary events, and 8% reduction in cardiovas-cular or all-cause deaths, but had no significant effecton stroke. The observed beneficial effects appearedto be smaller in patients with advanced kidney dis-ease and those requiring dialysis. Interestingly, expe-rience from a Japanese dialysis population that hadlesser degrees of inflammation and a different lipo-protein particle pattern have indicated that statinsmay be helpful (39,40).

Why Lipid-Lowering Therapies are notEffective in Dialysis Patients?

Statins are remarkably effective in reducing therisk of atherosclerotic cardiovascular events in thegeneral population, particularly those with preexist-ing CAD. Thus, it would be reasonable to assumethat they will be at least equally effective in the popu-lation that are at even greater risk of CAD such asCKD patients including those who are receivingmaintenance dialysis. Unfortunately, as discussedabove, there is no definitive evidence from RCTs toindicate that statins or other lipid–lowering therapiesare as effective in reducing cardiovascular risk in dial-ysis patients as in the general population or eventhose with nondialysis CKD patients.

4 Qunibi

There are a multitude of reasons for the apparentfailure of these agents in reducing cardiovascularevents and mortality in the dialysis population. First,the pathophysiology and spectrum of CVD in dialy-sis patients is markedly different compared to that inthe general population or even to earlier stages ofCKD (41). Besides atherosclerosis, these patientsmay develop arterial stiffness, vascular calcification,left ventricular hypertrophy, left ventricular diastolicdysfunction, congestive cardiomyopathy, and suddencardiac death from arrhythmia. Lipid-lowering ther-apy would not be expected to have an impact on thevast majority of these conditions.

It is well recognized that most of the deaths inpatients with CAD in the general population arefrom MI (42), but only 12% of those in the 4D andAURORA trials died of MI, while almost twice asmany died from sudden cardiac death (30,32). Inaddition, death from noncardiac causes occurred in20% and 25% in 4D and AURORA trials, respec-tively. Indeed, only 20% of the underlying causes ofCVD in dialysis patients are due to atheroscleroticCAD (43). These findings suggest that the majorityof deaths in dialysis patients are not related toCAD and thus would not be modifiable by statin orother lipid-lowering therapy (42).

Second, although dialysis patients have a higherprevalence of many of the traditional Framinghamrisk factors for atherosclerosis such as older age,hypertension, diabetes, obesity, inflammation, andlipid abnormalities, these patients are also exposedto uremia-related risk factors. These include anemia,hyperphosphatemia, oxidative stress, inflammation,and accumulation of the endogenous inhibitor ofnitric oxide (NO) synthase, asymmetric dimethylarg-inine (ADMA) which results in reduced NO synthe-sis and significantly contribute to CVD (Table 2).Again, none of these factors is amenable to lipid-

lowering therapy with statins and their managementrequires specific therapy that is not expected toimpact dyslipidemia.Third, the nature of atherosclerosis in dialysis

patients is different from that of the general popula-tion (44). Hypertriglyceridemia is present in approx-imately 50% of CKD patients but total serumcholesterol and LDL-C are either normal or low,whereas HDL-C is decreased due to reduced plasmalevels of apolipoprotein A-I, the principal apolipo-protein constituent of HDL-C. Moreover, LDL-C,which is a major CVD risk factor for CAD in thegeneral population, may not be a good marker forassessing cardiovascular risk in dialysis patientsbecause even those with low levels are still at a veryhigh risk of cardiovascular mortality. The explana-tion for this is that coexisting malnutrition andinflammation may modify the relationship betweencholesterol and CVD. The prevalence of malnutri-tion and inflammation is higher than that of ele-vated cholesterol levels in dialysis patients (22).Moreover, malnutrition and inflammation are moreimportant risk factors for CVD in dialysis patientsthan high serum cholesterol level (45–48). In the 4Dstudy, hs-CRP level was an important risk factorassociated with CVD events. However, in both the4D and AURORA trials, statins, which have pleio-tropic effects in reducing inflammation, were onlyminimally effective in reducing the hs-CRP levels indialysis patients (30,32).Fourth is the accumulation of the highly athero-

genic lipoproteins which are not amenable to statintherapy. In dialysis patients, decreased metabolismof chylomicrons due to deficiency of lipoproteinlipase, hepatic lipase and LDL receptor-related pro-tein leads to accumulation of highly atherogeniclipoproteins and their fragments such as very lowdensity lipoprotein (VLDL), small dense-LDL,intermediate-density lipoproteins, oxidized LDL,and lipoprotein (a) (49–51) (Table 3). Moreover, theinflammatory state in ESRD may lead to transfor-mation of the protective HDL cholesterol to a pro-atherogenic inflammatory HDL (52). Theseabnormalities are also not amenable to lipid-lower-ing therapy. Finally, hyperparathyroidism inpatients with ESRD may lead to accumulation ofcalcium in the liver and other tissues and inducesdeficiency of the enzymes involved in lipid metabo-lism such as lipoprotein lipase and hepatic lipase(53). Despite these issues, it remains possible thatthe lack of demonstrated benefit from statin therapyin the recent RCTs in hemodialysis patients may, atleast in part, be due to limitations in the design andor conduct of these trials as discussed above.

Adverse Effects of Statins in Dialysis Patients

Concern about the safety of statins in patientswith advanced CKD was based on the recognitionthat a decrease in renal excretion of statin mayincrease the risk of myopathy or rhabdomyolysis.

TABLE 2. Risk factors for cardiovascular disease in dialysis

patients

Traditional Framingham risk factors:

• Older age

• Male sex

• Hypertension

• Diabetes

• Obesity

• Smoking

• High LDL-cholesterol

• Low HDL cholesterol

• Physical inactivity

• Genetic predisposition

Uremia-related risk factors:

• Uremic milieu

• Anemia

• Abnormal mineral metabolism (Hyperphosphatemia,calcium load and elevated PTH levels)

• Dialysis vintage

• Fluid overload

• Oxidative stress

• Malnutrition

• Chronic inflammation (C-reactive protein and interleukin 6)

• Increased asymmetric dimethylarginine (ADMA)

HYPERLIPIDEMIA IN ESRD 5

However, as discussed earlier, this notion has notbeen confirmed in various clinical trials. In theFirst United Kingdom Heart and Renal Protection(UK-HARP-1) study, simvastatin use was not asso-ciated with an increased risk of abnormal liver func-tion tests or creatine kinase elevation (54). Also, inUK-HARP-II, simvastatin plus ezetimibe was notassociated with increased incidence of transaminitisor creatine kinase elevation (55). Furthermore, datafrom the recent 3 RCTs discussed above indicatethat the rate of statin-related adverse events is simi-lar among patients with CKD and individuals fromthe general population, and also not different fromthose assigned to placebo. The exception is that ahigher risk of fatal stroke was reported from the 4D(30) and in hemorrhagic stroke in AURORA (32).Although in SHARP, significantly more patients inthe simvastatin plus ezetimibe discontinued the drugdue to myopathy than the placebo group, there wasno evidence for increased risk of rhabomyolysis orliver dysfunction.

A review of the medical literature by an expertpanel concluded that statin therapy is safe inpatients with CKD (56). However, since pharma-cokinetic studies suggest that the blood levels ofsome statins may be increased in patients withCKD, and that drug interactions may also increaseblood levels, dose adjustment should be consid-ered. Atorvastatin and fluvastatin have the lowestrenal excretion (<2% and <6%, respectively), rosu-vastatin has 10% urinary excretion, whereas sim-vastatin and pravastatin have higher urinaryexcretion at 13% and 20%, respectively (57,58).Atorvastatin, lovastatin, and simvastatin are allmetabolized by CYP-3A4 and thus are more proneto have drug–drug interactions with macrolides,azole antifungals, and nondihydropyridine calciumchannel blockers (59). However, except for lova-statin, it seems that no dose adjustments arerequired for most of the lipid-lowering drugs forreduced kidney function (56). KDIGO guidelinesrecommend measuring levels of transaminasesbefore initiating statin therapy (60). However, fur-ther measurements are not necessary unless thepatient has suggestive symptoms. Given that sta-tin-treated CKD patients are at higher risk ofadverse events when receiving concomitant fibrates,the above report as well as the more recent KDI-

GO Work Group recommend against administer-ing fibrates with statins in these patients.

What Should Nephrologists Do?

Collective evidence from RCTs and various meta-analyses argues against a significant benefit fromuse of statins or other lipid-lowering agents inreducing major cardiovascular events or mortalityin dialysis patients. Based on these results, theWork Group of the KDIGO Clinical PracticeGuideline for Lipid Management in Chronic KidneyDisease has issued the following guidelines for lipidmanagement in dialysis and CKD patients (60):

1 In adults with newly identified CKD (includingthose treated with chronic dialysis or kidneytransplantation), we recommend evaluationwith a lipid profile (total cholesterol, LDL-cho-lesterol, HDL cholesterol, and triglycerides)(1C). Although there is no direct evidence indi-cating that measurement of lipid status willimprove clinical outcomes, the KDIGO WorkGroup recommend that patients with fasting tri-glyceride levels above 1000 mg/dl or LDL-Clevels above 190 mg/dl should be referred to aspecialist for further management (Table 4).

2 In adults with CKD (including those treatedwith chronic dialysis or kidney transplantation),follow-up measurement of lipid levels is notrequired for the majority of patients (notgraded). As higher cardiovascular risk and notelevated LDL-C is now the primary indicationto initiate or adjust lipid-lowering treatment inCKD patients, follow-up monitoring of LDL-C(after an initial measurement) may not berequired for many patients. In the judgment ofthe KDIGO Work Group, follow-up measure-ment of lipid levels should be reserved forinstances where the results would alter manage-ment such as assessment of adherence to statintreatment; change in renal replacement therapymodality or concern about the presence of newsecondary causes of dyslipidemia or to assess10-year cardiovascular risk in patients aged<50 years and not currently receiving a statin.The group also recommends not measuring

TABLE 3. Lists the various lipid abnormalities in nondialyzed CKD patients and dialysis patients

CKD stages 1–4 Hemodialysis patients Peritoneal dialysis patients

Triglycerides Normal or high High Very highTotal cholesterol High, normal or low Normal, low or rarely high Commonly highLDL-C High, normal or low Normal, low or rarely high Commonly highHDL-C Normal or low Low LowVLDL High High HighSmall dense-LDL High High HighIDL cholesterol High High HighLp (a) High High High

CKD, chronic kidney disease; LDL, low density lipoprotein; HDL, high density lipoprotein; VLDL, very low density lipoprotein;IDL, intermediate dense lipoprotein; Lp (a), Lipoprotein (a).

6 Qunibi

LDL-C in situations where the results likelywould not change management such as inpatients already receiving a statin. Also, sinceclinical experience suggests that triglyceride lev-els >1000 mg/dl is rare in CKD patients, rou-tine measurement of fasting triglycerides levelsis not recommended except in patients withknown severe hypertriglyceridemia.

3 In adults with dialysis-dependent CKD, we sug-gest that statins or statin/ezetimibe combinationnot be initiated (2A). The KDIGO WorkGroup recommend against using LDL-C levelsto identify CKD patients who should receivecholesterol-lowering treatment. Rather, theysuggest focusing on the absolute risk of coro-

nary events and the evidence that such treat-ment is beneficial.

Summary and Recommendations

A proposed schema for treatment of dyslipidemiain hemodialysis patients is shown in Fig. 1. Evi-dence from RCTs indicates that lipid-loweringagents should not be initiated for primary preven-tion in dialysis patients, as recommended by KDI-GO guidelines (60). However, this recommendationmay not be applicable to patients with high LDL-Clevels or those who have documented atherosclerotic

TABLE 4. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease (CKD) patients

Grade

Assessment of lipid status in adults with CKD1C 1.1: In adults with newly identified CKD (including those treated with chronic dialysis or kidney transplantation),

we recommend evaluation with a lipid profile (total cholesterol, LDL-cholesterol, HDL cholesterol, triglycerides)Not graded 1.2: In adults with CKD (including those treated with chronic dialysis or kidney transplantation), follow-up measurement

of lipid levels is not required for the majority of patients

Pharmacological cholesterol-lowering treatment in adults1A 2.1.1: In adults aged ≥ 50 years with eGFR <60 ml/min per 1.73 m2 but not treated with chronic dialysis or kidney

transplantation (GFR categories G3a–G5), we recommend treatment with a statin or statin/ezetimibe combination1B 2.1.2: In adults aged ≥ 50 years with CKD and eGFR ≥ 60 ml/min per 1.73 m2 (GFR categories G1–G2), we recommend

treatment with a statin2A 2.2: In adults aged 18–49 years with CKD but not treated with chronic dialysis or kidney transplantation, we suggest

statin treatment in people with one or more of the following (2A):

• Known coronary disease (myocardial infarction or coronary revascularization)

• Diabetes mellitus

• Prior ischemic stroke

• Estimated 10-year incidence of coronary death or nonfatal

• Myocardial infarction 410%

2.3.1: In adults with dialysis-dependent CKD, we suggest that statins or statin/ezetimibe combination not be initiated2B In adult kidney transplant recipients, we suggest treatment with a statin2C 2.3.2: In patients already receiving statins or statin/ezetimibe combination at the time of dialysis initiation, we suggest

that these agents be continued2D 5.1: In adults with CKD (including those treated with chronic dialysis or kidney transplantation) and hypertriglyceridemia,

we suggest that therapeutic lifestyle changes be implemented

Treatment of dyslipidemia in ESRD patients

Incident dialysis patients Prevalent dialysis patients

Patients already Patients notreceiving statin receiving statin

Continue statins Patients with low LDL-C and no

recent MI or strokePatients prefer to

receive statin

or

Patients with low LDL-C and no

recent MI or stroke

Patients with LDL-C > 150 mg/dl or recent

MI or stroke

Patients with recent MI or stroke

Do not start statins

Start statins

Start statins

Fig. 1. Schema for the treatment of dyslipidemia in ESRD patients.

HYPERLIPIDEMIA IN ESRD 7

CVD. The small percentage of patients with highLDL-C levels in some of these trials suggests thatthe potential benefits of statins in such patients werenot satisfactorily investigated. Thus, nephrologistsmay be justified in initiating lipid-lowering therapyfor primary prevention in dialysis patients withLDL-C level greater than 150 mg/dl and in main-taining therapy for secondary prevention in CKDpatients who were treated with these drugs beforeinitiating dialysis.

The KDIGO Work Group does not recommenda specific on-treatment LDL-C target and thus doesnot recommend adjusting the dose of statins basedon LDL-C levels. Statins have pleotropic effects,particularly on inflammation and arterial stiffness,which should be taken into consideration whendeciding on treatment with these drugs (61,62).

Finally, given that only 20% of cardiovasculardeaths in dialysis patients are due to atheroscleroticCAD while the rest is due to arrhythmia, suddencardiac death or heart failure (43), it would be unre-alistic to expect a dramatic reduction in cardiovas-cular events or mortality from statin monotherapy.These patients are best managed by a multifacetedapproach designed to address the multitude of tra-ditional as well as uremia-related risk factors forCVD that are so prevalent in dialysis patientsincluding anemia, hypertension, malnutrition,inflammation, abnormal mineral metabolism, anddyslipidemia in selected patients.

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