Approach to Cardiovascular Disease Prevention in Patients With Chronic Kidney Disease

Current Treatment Options in Cardiovascular Medicine (2012) 14:391–413DOI 10.1007/s11936-012-0189-2

Prevention (L Sperling, Section Editor)

Approach to CardiovascularDisease Prevention in PatientsWith Chronic Kidney DiseaseCristina Karohl, MD, PhD1,2

Paolo Raggi, MD*,1

Address*,1Division of Cardiology and Department of Medicine, Emory University,Atlanta, GA, USAEmail: [email protected] de Clínicas de Porto Alegre, Universidade Federal do Rio Grande doSul, Porto Alegre, RS, Brazil

Published online: 4 June 2012* Springer Science+Business Media, LLC 2012

Keywords Chronic kidney disease I Cardiovascular disease I Risk factors I Prevention

Opinion statement

Chronic kidney disease (CKD) is associated with a large burden of cardiovascular riskfactors ultimately leading to increased cardiovascular events and mortality. Preventionof cardiovascular disease (CVD) in CKD involves early identification of individuals athigh-risk of renal disease. In fact, substantial evidence points to a complex bidirec-tional relationship between CKD and CVD. Therefore, most interventions directed atCKD prevention should include multiple risk factor interventions with the goal of pre-venting CVD events while slowing progression of CKD. Clearly, prevention of CVD in CKDis a complex task and requires a multidisciplinary team approach, with a well-definedprogram, rational targets for each risk factor, and implementation of the most effectiveintervention strategies. Although several interventions to prevent CVD have proven ef-fective in the general population and in individuals at high risk for CVD, a true benefitin patients with CKD remains to be demonstrated for several of them. A few rationaltargets of intervention should be optimal blood pressure control, reduction of protein-uria, treatment of dyslipidemia, good control of diabetes, smoking cessation, dietarysalt restriction, achievement of normal body mass index, partial correction of anemia,and management of mineral metabolism abnormalities. Lifestyle modification andpharmacological therapy with renin-angiotensin blockers, β-blockers, diuretics, sta-tins, and aspirin should be encouraged in the early stages of CKD.

Introduction“Protect your kidneys, save your heart” was the 2011World Kidney Daymessage, calling attention to the inter-

action between chronic kidney disease (CKD) and cardio-vascular disease (CVD) [1•]. During the past decade, CKD

has received increasing recognition as a public healthproblem due to its increasing prevalence both in devel-oped and underdeveloped countries, the adverse out-come attached to its development, and the inherent costof caring for this disease. CKD is defined by progressiveand sustained decline of renal function or presence ofkidney damage detected mainly by urinary albumin ex-cretion for at least 3 months. To standardize the nomen-clature and to facilitate risk stratification, CKD has beenclassified in five stages (1:minimal damage to 5: predial-ysis and 5D: dialysis) according to the glomerular filtra-tion rate (GFR) estimated on the basis of serumcreatinine measurements [2]. The worldwide prevalenceof CKD is estimated to be about 7.2 % but may rangefrom 2.5–43%ormore depending on the study popula-tion and equation applied to estimate the GFR [3]. In theUnited States, the prevalence of CKD stages 1 to 4 in-creased from 10.0 % between 1988 and 1994 to 13.1 %between 1999 and 2004 [4]. The increased prevalence

has been mostly attributable to an aging populationand increased frequency of diabetes mellitus, hyperten-sion, and obesity [4]. Interestingly, worldwide a mi-nority of CKD patients progress to end-stage renalfailure and start dialysis. This may be due to theunavailability of renal replacement therapy and ear-ly mortality related to the burden of CKD comor-bidities [5] (Table 1).

CVD is the leading cause of mortality in patientswith CKD [6]. Even simply a GFR below 60 mL/min/1.73 m2 (CKD stage 2) has been associated witha significantly increased risk of cardiovascular eventsand death compared to the general population, andthe risk of adverse outcomes increases remarkably asthe GFR declines further [7]. In addition, albuminuriahas emerged as an important predictor of adverse car-diovascular events [8••]. In fact, slight reductions inGFR and increased albuminuria have been identifiedas independent and incremental prognostic risk factors

Table 1. Summary of the multiple interventions and targets to cardiovascular prevention in chronic kidneydisease patients

Intervention TargetLifestyle modification • Diet sodium restriction • G1.5 g/d (preferentially)

• Smoking cessation • Moderate intensity aerobic exercise30–60 min 4–7 days per week

• Physical activity • Body mass index between 18.5 and 25 kg/m2

• Weight reductionAlbuminuria ACE inhibitors or ARBs G500–1000 mg/dHypertension ACE inhibitors or ARBs and/or Diuretics,

β-blockers, calcium receptor antagonistBP ≤130/80 for diabetic patients withnephropathy and no diabetic CKD patients withproteinuria

Other antihypertensive drugs BP G140/90 for CKD patients without proteinuriaDyslipidemia Statins or Ezetimibe plus statin LDLc G70 to 100 mg/dL or 50 % reduction from

baseline valueDiabetes Diet HbA1c 6.5 to 7.5 %

Metformin (CKD stages 1 to 3)Oral antidiabetic agentInsulin

Antiplatelet therapy Aspirin (75–100 mg/d)Anemia Iron supplementation Hb 10–11

Erythropoiesis stimulator agentsMineral metabolism • Calcium supplementation • Calcium: normal range

• Phosphorus intestinal binding • Phosphorus: normal range• Calcitriol or analogous; paricalcitol • Serum 25(OH)D ≥30 ng/mL• Cholecalciferol or ergocalciferol

ACE angiotensin-converting enzyme, ARB angiotensin receptor blocker, BP blood pressure, CKD chronic kidney disease, LDLc low-densitylipoprotein cholesterol, HbA1c glycated hemoglobin, Hb hemoglobin, 25(OH)D 25-hydroxyvitamin D (calcifediol)

392 Prevention (L Sperling, Section Editor)

for CVD and all-cause mortality in several studies inthe general population [9–13, 14•].

Beyond the traditional cardiovascular risk factorsobserved in the general population, factors specificallylinked with loss of renal function are probably con-tributing to the severe risk of CVD in CKD (Fig. 1)[5, 15]. Sudden death and congestive heart failure

are the most frequent causes of cardiovascular demisein advanced CKD [16]. Histopathologically, ischemicheart disease and cardiomyopathy are very commonin CKD and may coexist in the same patient. Cardio-myopathy is characterized by a combination of leftventricular hypertrophy, interstitial fibrosis, and mi-crovascular disease ultimately predisposing to systolic

Figure 1. Cardiovascular disease and risk factors associated with chronic kidney disease (CKD).

Approach to Cardiovascular Disease Prevention Karohl and Raggi 393

and diastolic dysfunction, arrhythmias, and suddendeath [17]. Coronary artery disease is characterizednot only by aggressive atherosclerotic disease, but alsodense calcification of the muscular medial layer of thevessel wall, which is associated with increased arterialstiffness. These conditions conduce to reduced perfu-sion and hypertrophy of the myocardium whose atten-dant effect is development of cardiomyopathy.

Hence, primary and secondary prevention of CVDin patients with CKD is challenging because multipletargets for intervention must be met. Luckily, moststrategies to reduce CVD risk overlap with those widely

implemented to retard progression of CKD. Certainly,early recognition and prevention of CKD representsthe best approach to prevent CVD. For example, earlyrecognition of albuminuria and reduced GFR facili-tates the identification of patients at high risk of CVD.

Prevention of CVD in CKD should encompass life-style changes and adequate implementation of drugtreatments targeting multiple cardiovascular risk fac-tors. Preventive strategies are similar to those forCVD risk reduction in the general population; howev-er, several of these approaches still await proof of effi-cacy in CKD.

Pharmacologic treatment of traditional risk factors

Hypertension& It is well recognized that blood pressure (BP) control is the mainstay

of therapy to reduce progression of CKD and prevent CVD. Untreatedhypertension is associated with several cardiovascular complicationssuch as left ventricular hypertrophy, cardiomyopathy, heart failure,atherosclerosis, cardiac ischemia, and stroke.Multiple factors play a rolein the pathogenesis of hypertension in CKD, including extracellularvolume expansion due to sodium and water retention and increasedperipheral vascular resistance, mediated by activation of the reninangiotensin system (RAS) and sympathetic nervous system.

& Achievement of good BP control often requires multiple drugs,and a large proportion of CKD patients have uncontrolled hy-pertension [18]. Therefore, BP control should be a consistent focusof therapy to improve cardiovascular and renal outcome. How-ever, how low the BP should be to achieve cardiorenal protectionin patients with CKD remains a matter of debate. In general, thetarget is the same as for the general population with hypertension(ie, 130/80mmHg or lower [2, 19, 20••]). However, this goal has beena matter of discussion.

& A recent meta-analysis concluded that a BP target under 140/90mmHgdid not achieve a substantial reduction in morbidity and mortality inCKD patients [21]. The African American Study of Kidney Disease andHypertension (AASK) showed no effect on CKD progression and acomposite outcome (reduction in GFR by 50% or more from baseline,progression to end-stage renal disease, or death) with intensive BPcontrol (BP goal G130/80 mmHg) [22]. In several studies, a systolic BPunder 120mmHgwas associatedwith a higher rate of adverse outcomesthan more moderate goals of therapy [23, 24]. However, it has beensuggested that intensive BP control may be beneficial in patients withbaseline proteinuria [25, 26•] and diabetes mellitus. Therefore, forpatients with CKD but no diabetes and no albuminuria, the recom-mended target of therapy is a BPunder 140/90mmHg, although studies


are required to prove that such BP target attains results similar to orbetter than those attainable with a BP of 130/80mmHg or lower [20••,26•, 27].

& For both nondiabetic patients with proteinuria and diabetic patients,the recommended BP target in the presence of CKD is 130/80 mmHgor lower [20••, 24, 27]. Angiotensin-converting enzyme inhibitors(ACE-I) or angiotensin II receptor blockers (ARBs) are the first line oftherapy in hypertensive nondiabetic and diabetic CKD patients, es-pecially in the presence of elevated albuminuria/proteinuria [19, 28,29]. Nevertheless, RAS blockers may cause further renal functiondeterioration in patients with renal artery stenosis. In such cases,alternative therapies include diuretics, β-blockers, and calciumantagonists or direct vasodilators.

Renin-angiotensin-aldosterone system blockers& It is recognized that increased renin-angiotensin-aldosterone activity is

one of the major contributing factors to hypertension and sustainedproteinuria and progression of CKD. Hence, drugs that block the renin-angiotensin-aldosterone system (RAAS) are considered a cardinal in-tervention in early CKD stages. ACE-Is and ARBs are the two antihy-pertensive classes recommended as first-line therapy formanagement ofhypertension and albuminuria in CKD. A recent meta-analysis and asystematic review, however, raised a concern that ACE-Is and ARBsmaynot reduce cardiovascular and all-cause mortality in patients with CKDstage 1 to 3 and in patients with albuminuria and at least one othercardiovascular risk factor [30, 31•]. Dual RAAS inhibition with ACE-Isand ARBs has failed to improve cardiovascular and renal outcomes inCKD patients. ONTARGET (Ongoing Telmisartan Alone and in Com-binationWith Ramipril Global Endpoint Trial) was a trial that enrolledpatients with hypertension and high cardiovascular risk, and demon-strated that both ramipril and telmisartan were independently effectiveat preventing major cardiovascular events in a wide range of high-riskpatients, including those with CKD. However, the combination therapywas not superior to monotherapy, and was associated with more sideeffects [32]. To date, ACE-Is remain the first choice andARBs can beusedas alternative to ACE-Is for cardiovascular protection in CKD patients.

& Two other RAAS inhibitor therapeutic classes are of potential value inCKD patients. Aldosterone antagonists, such as spironolactone, aresupposed to limit cardiac remodeling and prevent heart failure. Fur-thermore, aldosterone antagonists appear to enhance proteinuria re-duction in CKD patients already receiving ACE-Is and ARBs [33, 34].Nevertheless, this approach carries an increased risk of hyperkalemia.Currently, aldosterone antagonists are not recommended due to thelack of evidence that these drugs reduce CVD and mortality [34].

& Aliskiren, a novel direct renin inhibitor, prevents the formation of an-giotensin I and II and is considered an alternative to ACE-Is and ARBs as


an antihypertensive agent. Small clinical studies have demonstratedthat aliskiren reduces proteinuria in nondiabetic and diabetic CKDpatients [35, 36]. The combination of aliskiren with ARBs or ACE-Is hasbeen shown to promote greater reduction of albuminuria independentof BP control compared with monotherapy in type II diabetic patientswith CKD [36]. Additionally, prevention of CKD progression has beensuggested in a post hoc analysis of the AVOID (Aliskiren in the Evalu-ation of Proteinuria in Diabetes) study with a combination of aliskirenand losartan but at an increased risk of hyperkalemia in patients withdiabetic nephropathy [37]. Recently the U.S. Food and Drug Adminis-tration (FDA), based on preliminary data from the ALTITUDE (Aliski-ren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) study, hasrecommended against the combination of aliskiren with ARBs or ACE-Iin patients with diabetes because of the risk of renal impairment, hy-potension, and hyperkalemia. Additionally the FDA advised avoidingaliskiren in association with RAAS blockers in patients with GFR below60 mL/min (Food and Drug Administration. FDA drug safety com-munication: New warning and contraindication for blood pressuremedicines containing aliskiren (Tekturna). April 20, 2012). Furtherstudies are needed to evaluate the impact and safety of aliskiren aloneorin combination with other RAAS blockers on cardiovascular and renalprevention in CKD.

Standard dosage ACE-Is (per day): Captopril 25–150 mg; enalapril 2.5–40 mg; fosinopril 5–40 mg; lisinopril 5–40 mg; ramipril 1.25–20 mg; trandolapril 1–5 mg.ARBs (per day): Candesartan 4–32 mg; irbesartan 150–300 mg; losartan 25–100 mg; olmesartan 20–40 mg; telmisartan 20–80 mg; valsartan 40–320 mg.

Contraindications ACE-Is and ARBs present the same contraindications including presence ofbilateral renal artery stenosis or renal artery stenosis in a functioning solitarykidney, hyperkalemia, angioedema related to previous treatment with ACE-Isor ARBs, and pregnancy.

Main drug interactions Both RAS blocker classes may increase the risk of hypotension when asso-ciated with diuretics; hyperkalemia can occur when RAS blockers are asso-ciated with potassium-sparing diuretics, β-blockers, or potassiumsupplements; concomitant use of RAS blockers and cyclosporines enhancesthe nephrotoxicity of the latter drugs. Concurrent use of ACE-Is andARBs increases the risk of symptomatic hypotension, renal failure, andhyperkalemia.

Main side effects All agents share the same side effects: hypotension and postural hypoten-sion; acute renal failure or acute decline of renal function (mostly observedin patients with bilateral renal artery stenosis, renal artery stenosis in afunctioning solitary kidney, hypertensive nephrosclerosis, diabetic ne-phropathy, or CKD of any cause); hyperkalemia (K95.5 mEq/L) may bemore frequently observed in patients with CKD, diabetes, concurrent use ofpotassium-sparing diuretics, potassium supplements, or in combinationwith other RAAS blockers; cough is a frequent patient complain with ACE-Is;angioedema is a rare but potentially fatal side effect; anaphylactoid reactionsdue to increased bradykinin release may be seen with ACE-Is.

Special points Drugs should be initiated at a low dose and titrated to achieve the desiredeffect or maximum recommended dose.


Renal function should be checked 3 or 5 days after starting therapy inpatients with high risk for renal artery stenosis.Renal function and serum potassium should be checked about 1 month aftertherapy initiation.Consider discontinuing the drugs if hyperkalemia (K+95.5 mEq/L) occurs.Dose reduction, restriction of potassium in the diet, and diuretics aremeasures to counteract this complication.Consider discontinuing the drugs once GFR decreases more than 30 % frombaseline or hyperkalemia cannot be treated [38].Side effects are generally reversible after drug discontinuation.

Cost/cost-effectiveness Due to similar efficacy and side effects among ACE-Is and ARBs, cost andavailability should be taken into consideration when prescribing these drugs.

β-Blockers& β-Blockers can be added to ACE-Is and ARBs for hypertension

management. Additionally, they are associated with reduced cardio-vascular morbidity and mortality in heart failure and post-myocar-dial infarction [39]. Similar benefits have been suggested in patientswith CKD [40, 41].

Standard daily dosage Atenolol 50–100 mg; bisoprolol 10–20 mg; carvedilol 6.25–50 mg; meto-prolol 25–200 mg. Atenolol and bisoprolol need adjustment for renalfunction.

Contraindications Decompensated heart failure; cardiogenic shock; sick-sinus syndrome; sec-ond- or third-degree atrioventricular block; severe bradycardia; reactive air-way disease (bronchial asthma or related bronchospastic conditions); andsevere hepatic impairment (carvedilol) are the main contraindications.

Main drug interactions Special attention should be paid to the combination of β-blockers withagents that depress myocardial contractility and chronotropic function suchas other β-blockers, calcium antagonists, and antiarrhythmic agents. Otherimportant interactions include those with aminophylline, antidiabeticagents, clonidine, levodopa, methyldopa, and tricyclic antidepressants.

Main side effects Cardiovascular side effects may be enhanced in CKD patients and includeprecipitation of congestive heart failure, bradycardia, bradyarrhythmias,atrioventricular conduction delays, and hypotension. Other common sideeffects are dizziness, fatigue, increased airways resistance, asthma, broncho-spasm, hyperkalemia, hyperglycemia, and impotence.

Special points Abrupt suspension of β-blockers may precipitate a withdrawal syndrome.

Cost/cost-effectiveness Inexpensive to moderately expensive.

Diuretics& Thiazide and loop diuretics are indicated for treatment of hypertension,

volume overload, and hyperkalemia management in CKD patients[42]. Diuretics can be used as monotherapy or in combination withother antihypertensive agents for best achievement of BP.

Standard dosage Thiazides: hydrochlorothiazide 12.5–50 mg/day.Loop diuretics: furosemide 20–320 mg/day; torsemide 10–20 mg/day(maximum dose 200 mg/day), bumetanide 0.5–2 mg/day.


Contraindications Thiazides should be avoided in patients with worsening renal function andknown hypersensitivity to hydrochlorothiazide or any component of theformula. Loop diuretics should not be used in patients with volume deple-tion or anuria resistant to diuretics.

Main drug interactions Concomitant use of diuretics with any other antihypertensive agents mayenhance the hypotensive effect.

Main side effects Both thiazides and loop diuretics can increase the risk of hypotensionand orthostatic hypotension mainly with concurrent use of other anti-hypertensive agents. Hypokalemia is more common with loop diureticsthan thiazides. Thiazide diuretics are associated with risk of hypercalce-mia. Increases in serum glucose, triglycerides, and LDL cholesterol mayoccur, but are relatively minor with low doses. They may also precipitatephotosensitivity, allergic reactions, and gout crises. Volume depletionand pre-renal failure are mostly observed with loop diuretics. Other sideeffects of loop diuretics are hypocalcemia, hypomagnesemia, and hypo-natremia. Ototoxicity may occur when high doses are administrated inCKD patients.

Special points Thiazide diuretic are generally ineffective when GFR is below 30 mL/min/1.73 m2 except when used in combination with a loop diuretic.Hydrochlorothiazide in combination with a loop diuretic enhances the di-uretic effect but may cause severe hypokalemia and volume depletion.

Cost/cost-effectiveness All diuretics are inexpensive.

Albuminuria/proteinuria& Both urinary albumin excretion and proteinuria are surrogate

markers of kidney damage even when the GFR is in the normalrange. Albuminuria is grossly estimated as the albumin to creatinineratio (ACR) in a simple urine specimen [2]. The normal rate of al-bumin excretion is less than 20 mg/day. Microalbuminuria is definedas urinary albumin excretion between 30 and 300 mg/day andmacroalbuminuria (or overt proteinuria) as urinary albumin excre-tion higher than 300 mg/day. Albuminuria has been associated withincreased risk of CVD in the general population and a variety ofdisease states [10, 11, 13, 14•]. It is believed to reflect generalizedvascular endothelial dysfunction in addition to glomerular dysfunc-tion [43].

& RAS blockers (see above) are the preferred drugs to slow albu-minuria and delay progression of CKD both in diabetic as well asnondiabetic patients [44, 45]. Recently, several studies haveevaluated whether reduction of albuminuria with RAS blockerstreatment translates into cardiovascular and mortality benefits. Inthe Prevention of Renal and Vascular Endstage Disease Interven-tion Trial (PREVEND IT), 846 normotensive patients withmicroalbuminuria were randomly assigned to fosinopril treat-ment versus placebo. Fosinopril significantly lowered urinary al-bumin excretion and was associated with a nonsignificant trendtoward lower cardiovascular mortality and hospitalization for


cardiovascular events (HR 0.60, 95 % CI: 0.33–1.10; P=0.09)[46]. A benefit of reduced albuminuria on CVD also was ob-served in a secondary analysis of the LIFE trial (Losartan Inter-vention for Endpoint Reduction in Hypertension Study) in whichthe primary composite end point (risk of cardiovascular death,myocardial infarction, and stroke) was significantly reduced inpatients with hypertension and evidence of left ventricular hy-pertrophy whose microalbuminuria was reduced after 1 year oftreatment with losartan or atenolol. In that study, the reductionin albuminuria was significantly greater with losartan comparedto atenolol [47]. Cardiovascular protection associated with re-duction in rate of albuminuria with RAS blockers has been moreconsistently seen in diabetic patients with nephropathy [48].

& Recently a multicenter, prospective, double-blind, parallel-grouptrial comparing renal and cardiovascular outcomes in 281 hy-pertensive type 2 diabetic patients randomly assigned to verapa-mil/trandolapril or trandolapril alone demonstrated that ACE-Itherapy (trandolapril) reduced the incidence of cardiovascularevents in patients who had regression of albuminuria comparedto those without regression [49]. Therefore, accumulating evi-dence suggests that albuminuria is an important target of therapyto achieve cardiovascular protection. In the absence of overtcontraindications, RAS blockers should be considered the firstline of therapy for hypertension in patients with CKD and uri-nary protein excretion greater than 0.5 g/day.

Dyslipidemia& Patients with CKD present different types of dyslipidemias depend-

ing on the etiology of CKD. The most typical abnormalities includehypertriglyceridemia and low HDL cholesterol levels; elevated LDLcholesterol levels can be encountered in nephrotic syndromes andearly stages of CKD but not typically in end-stage kidney failure.Although recent guidelines suggested serum LDL should be keptbelow 100 mg/dL in advanced CKD [50], two randomized clinicaltrials failed to show reduction of cardiovascular morbidity andmortality with statins in patients on maintenance dialysis despiteeffective LDL lowering [51, 52].

& A meta-analysis [53] and a post hoc analysis of a study that in-cluded patients with CKD demonstrated that statins reduce car-diovascular morbidity and mortality [54] suggested that statinsreduce risk of major cardiovascular events and death in pre-di-alysis patients (GFR 15–60 mL/min/1.73 m2). An ad hoc analysisof the JUPITER study (Justification for the Use of statins in Pre-vention-an Intervention Trial Evaluating Rosuvastatin) demon-strated that rosuvastatin was associated with a 45 % reduction inrisk of myocardial infarction, stroke, hospital admission for un-stable angina, coronary revascularization, or cardiovascular death


(HR: 0.55, 95 % CI: 0.38–0.82, P=0.002) and a 44 % reductionin all-cause mortality (HR: 0.56, 95 % CI: 0.37–0.85, P=0.005)in patients with moderate CKD [55]. The recently reported ran-domized placebo-controlled SHARP trial (Study of Heart andRenal Protection) compared the effect of simvastatin plus ezeti-mibe versus simvastatin alone versus placebo in 9270 patientswith CKD (3023 on dialysis and 6247 not on dialysis) followedfor a median of 4.9 years from randomization. The simvastatin–ezetimibe combination was associated with a significant reduc-tion in the incidence of major atherosclerotic events defined asnonfatal myocardial infarction, nonhemorrhagic stroke, and cor-onary revascularization but there was no benefit on mortality andthe effects were mitigated in patients on dialysis [56••]. Theguidelines for management of dyslipidemia of the European So-ciety of Cardiology and the European Atherosclerosis Societyrecommend statins as monotherapy or in combination with otherdrugs to achieve an LDL cholesterol target below 70 mg/dL or50 % or greater reduction from baseline when the target cannotbe reached in patients with moderate to severe CKD [57]; this isa lower target compared to previous K/DOQI (The Kidney Dis-ease Outcomes Quality Initiative) recommendations [50].

Statins and other lipid lowering drugs

Statins

Standard dosage Simvastatin: 5–40 mg/d; atorvastatin: 10–80 mg/d; fluvastatin: 20–80 mg/d; pitavastatin: 1–4 mg/d; lovastatin: 20–80 mg/d; rosuvastatin:5–20 mg/d (GFRG30 mL/min/1.73 m2: 5–10 mg/d); pravastatin: 10–80 mg/d (maximum recommended dose for patients using cyclosporineis 20 mg/d). Dose adjustment is not required in mild-to-moderate renaldysfunction.

Contraindications Hypersensitivity to statins; active liver disease; persistent elevation of hepatictransaminases; pregnancy; breastfeeding. The combination of simvastatinwith CYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole,ketoconazole, and HIV protease inhibitors), cyclosporine, and gemfibrozilshould be avoided to decrease the incidence of side effects.

Main drug interactions Statins interact with several drugs that predispose to the development ofside effects such as myopathy and hepatic dysfunction. Simvastatin,lovastatin, and atorvastatin carry a higher risk of drug interaction withCYP3A4 inhibitors (eg, clarithromycin, erythromycin, itraconazole,ketoconazole, and HIV protease inhibitors) and should be used withcaution. Other drug interactions can be seen with amiodarone, amlodi-pine, antifungal agents (azole derivatives), colchicine, cyclosporine, dil-tiazem, gemfibrozil, niacin, phenytoin, quinine, verapamil, and warfarinamong others.

Main side effects Side effects are mostly dose dependent. Rhabdomyolysis, myopathy,myalgia, increased creatine kinase, and elevation of hepatic transaminases are


the most common concern with statin treatment in CKD patients.Nonetheless, though few studies have addressed the side-effect profileof statins in CKD, the overall incidence appears to be low [56••, 58,59]. Minor hematuria and proteinuria have been observed withrosuvastatin.

Special points Statins differ in their absorption, bioavailability, plasma protein binding,excretion, and solubility.Atorvastatin, fluvastatin, and pitavastatin are the preferred statins to treatpatients with CKD due to their hepatic metabolism.It is recommended that statins, mostly those with short half-life, be ad-ministrated in the evening due to the greater cholesterol synthesis at nightduring fasting.Pravastatin is more expensive than simvastatin but is the recommendedstatin for renal transplant patients that receive cyclosporine.In general, these agents do not require dose adjustment for patients withCKD.

Cost/cost-effectiveness Several statins are now generic and therefore inexpensive.

Ezetimibe

Standard dosage Standard dose is 10 mg daily. No dosage adjustment is necessary in patientswith CKD.

Contraindications When combined with statins, consider the same contraindications as statins.

Main drug interactions Fibrates

Main side effects Headache, abdominal pain, diarrhea, nausea, fatigue, elevation of hepatictransaminases, and myalgia.

Special points Ezetimibe reduces cholesterol intestinal absorption, therefore lowering cho-lesterol delivery to the liver.Ezetimibe can be used as a second-line therapy in association with statins.Recommendations for ezetimibe therapy are achievement of therapeutictarget in addition to maximum statin dose; statin intolerance; and contra-indications to statins.

Cost/cost-effectiveness Relatively inexpensive

Diabetes mellitus& Diabetes is considered the leading cause of CKD in Western

nations and a strong predictor of CVD in patients with mild-to-moderate CKD [6]. A few clinical trials demonstrated a benefitwith aggressive, multifactorial treatment of diabetes and intensivediabetes control aiming at glycated hemoglobin (HgbA1c) below6.5 % with improved cardiovascular outcome [60, 61]. However,other studies have raised a serious concern with intensive dia-betes control (HgbA1cG6.5 %), which has been associated with agreater rate of adverse events, suggesting that aggressive inter-ventions should not be generalized to all diabetic patients [62].K/DOQI recommended a target HbA1c below 7.0 % for patientswith diabetes mellitus, irrespective of the presence or absenceof CKD [28]. The recent Renal Association Clinical Practice


Guideline on Cardiovascular Disease in CKD [20••] suggests atarget HbA1c of 6.5 %–7.5 % for CKD patients

Thrombotic risk and aspirin& Aspirin is a well-established and effective antiplatelet therapy

recommended for secondary prevention of thrombotic cardiovas-cular events and mortality in high-risk individuals [63]. However,there is no agreement as to whether aspirin is effective in CKDpatients. In addition, a concern with excess bleeding due toplatelet dysfunction in CKD has led to its underutilization. Re-cently a post hoc analysis of the HOT (Hypertension OptimalTreatment) study compared efficacy and risk of aspirin (75 mg) in18,597 hypertensive patients with diastolic dysfunction withdifferent levels of GFR (3.619 patients [16.6 %] had a GFRG60 mL/min/1.73 m2). Aspirin was associated with a 66 % reduc-tion in risk of major cardiovascular events (a composite of myo-cardial infarction, stroke, and cardiovascular death) and 49 %reduction in risk of all-cause mortality in individuals with GFRbelow 45 mL/min/1.73 m2 (a greater benefit than for those withnormal renal function). Major bleeding events were not signifi-cantly increased in the patients with the lowest GFR compared tothose with normal renal function [64]. These findings suggest thataspirin should be considered more widely in CKD patients forprimary cardiovascular prevention.

Aspirin

Standard dosage 75–100 mg once daily.

Contraindications The most important contraindications are hypersensitivity to salicylates; Reye’ssyndrome; bleeding disorders; pregnancy (especially in the third trimester).

Main drug interactions Concomitant use of aspirin and NSAIDs increases the risk of bleeding andgastrointestinal complications. Aspirin associated with other antiplateletagents, heparin, and anticoagulants also increases the risk of bleeding.

Main side effects Aspirin increases the risk of minor and major bleeding that may occur at anysite. Rash and angioedema may occur due to hypersensitivity to salicylates.Gastrointestinal side effects such as nausea, dyspepsia, heartburn, stomachpain, and gastrointestinal ulceration are common but can be prevented bytaking aspirin with meals. Importantly, side effects are uncommon with lowaspirin doses.

Special points Aspirin should be avoided for 1–2 weeks before any invasive procedure ifpossible.

Cost/cost-effectiveness Inexpensive.

Diet and lifestyle& Smoking cessation should be strongly recommended. It is well

established that smoking is an important risk factor for CVD and isassociated with increased risk of progressive renal failure [65].


Smoking cessation reduces cardiovascular risk [66] and slows renalfunction deterioration [67].

& Physical activity should be encouraged. Regular, moderate intensityexercise reduces the risk of CVD in people with cardiovascular riskfactors and in the general population [68, 69]. Cardiovascular benefitof regular exercise has not been confirmed in early CKD stages butappears plausible due to the increased cardiovascular risk in thispopulation.

& Maintenance of normal body weight. Weight control should be en-couraged in the presence of obesity. Both overweight and obesity areassociated with multiple comorbidities including type II diabetes andCVD [70]. Weight loss interventions seem to reduce proteinuria andsystolic BP in patients with CKD [71].

& Limitation of dietary sodium intake to less than 2,300 mg/day andfurther reduction intake to 1,500 mg has been recently recommended[72].

Mineral metabolism and bone disease& Mineral metabolism and bone disorder are common and develop

early in the course of CKD. This syndrome is characterized by dis-ruption of normal mineral hemostasis ultimately leading to abnor-mal serum concentration of calcium, phosphorus, and hormonessuch as 25-hydroxyvitamin D [25(OH)D], 1.25-dihydroxyvitamin D[1.25(OH)D2], parathyroid hormone (PTH), and bone-derived fi-broblast growth factor 23 (FGF23) [73]. Such abnormalities may bedetected in several patients with CKD stage 3 and almost universallyin CKD stage 5 and 5D.

& Several observational studies have noted an association of mineraland bone disorders with adverse outcomes, most notably with in-creased phosphate levels (increased risk of vascular calcification,cardiomyopathy, and mortality) [74–76]. Suboptimal serum 25(OH)D concentration is also commonly identified in all stages ofCKD and appears associated with CVD and mortality [77–79]. Fur-thermore, elevated FGF23 levels appear to be independently associ-ated with an adverse cardiovascular outcome and mortality inadvanced CKD [80]. Finally, secondary hyperparathyroidism (SHPT),the principal consequence of mineral metabolism derangement, is afrequent complication of advanced renal failure.

& Phosphate retention, hypocalcemia, decreased levels of 25(OH)Dand 1.25(OH)D2, and likely the increase in FGF23 levels are themain factors contributing to its pathogenesis [81•]. Besides skeletalconsequences, SHPT has been associated with several cardiovascularcomplications and mortality in CKD [82]. Therefore, early recogni-tion and management of abnormalities of mineral metabolismappears to be an additional target of CVD prevention in CKD.

& The KDIGO (Kidney Disease – Improving Global Outcomes)clinical practice guidelines for the diagnosis, evaluation,


prevention, and treatment of CKD-Mineral and Bone Disorder[73] recommended monitoring and treating abnormal serumlevels of calcium, phosphorus, and PTH as early as CKD stage 3.Serum calcium, phosphorus, and PTH should be measured every6–12 months; in more advanced CKD stages, such measurementsshould be even more frequent. In patients with CKD stage 3–5,serum calcium and phosphorus levels should be maintained inthe normal range. However, the goal for PTH level is not clearand the experts of the KDIGO workgroup suggested detectionand treatment for hyperphosphatemia, hypocalcemia, and vita-min D deficiency instead.

& Limiting dietary phosphate intake, reducing phosphate intestinalabsorption with phosphate-binding agents, supplementing vita-min D (cholecalciferol or ergocalciferol) once deficiency is pres-ent, and using calcitriol or analogues when serum PTH ispersistently above the upper limits of normal are the maininterventions recommended in CKD stages 3–5 [73]. Thesemeasures are aimed at preventing worsening of SHPT with itsattendant bone and cardiovascular disease risk. However, thereare no firm data to demonstrate that this approach is effective inpreventing untoward outcomes.

Phosphate-binding agents& Intestinal phosphate-binding agents decrease intestinal absorption

of phosphorus, ultimately reducing serum phosphorus level. Se-rum phosphorus is often maintained within normal ranges untillate CKD stages by the combined effect of PTH and FGF23,which enhance phosphate renal excretion [81•]. Serum phos-phate concentrations increase when GFR is below 25–30 mL/min/1.73 m2; at this level, the renal function is insufficient toeliminate excessive phosphate originated from the diet and boneturnover. Several observational studies showed an associationbetween increased serum phosphate levels and adverse cardio-vascular outcomes [74–76, 83]. Therefore, interventions tocounteract phosphate overload seem to be a supplementary andlikely important step, in combination with other risk factorsmanagement, to prevent CVD in CKD.

& The KDIGO workgroup suggested maintaining serum phosphorus inthe normal range in patients with CKD stages 3 to 5. Dietary phos-phate restriction and phosphate binders are recommended once se-rum phosphorus rises above the normal range [73]. However, theappropriate time to initiate phosphate binders is a matter of debate.Recently, it has been argued that interventions to control serumphosphorus should begin before the occurrence of hyperphospha-temia to prevent later complications [84••].

& Phosphate-binding agents can be classified into two categories: cal-cium-based phosphate binders such as calcium acetate or calcium


carbonate and non–calcium and non–aluminum-based phos-phate binders, such as sevelamer and lanthanum. Calcium saltsare generally inexpensive, largely available, and effective in re-ducing serum phosphorus and are usually employed as firstchoice for stages 3 to 5 CKD patients. However, a positive cal-cium balance may increase the risk of calcium overload andcardiovascular calcification and it should be taken into accountwhen calcium salts are prescribed [85]. In view of these concerns,discontinuation or dose reduction of calcium-based phosphatebinders is suggested in the presence of hypercalcemia, cardio-vascular calcification, adynamic bone disease, and/or low serumPTH levels [73]. Non–calcium-based phosphate binders are ex-cellent alternatives and have been recently evaluated in pre-dial-ysis CKD patients [86, 87].

& The impact of different phosphate binders on the cardiovascularsystem and overall mortality has been addressed mainly in dial-ysis patients and in a few clinical studies in CKD stage 3 to 5.Yilmal et al. [88] evaluated patients with CKD stage 4 and ob-served a significant increase in flow-mediated vasodilatation insevelamer-treated patients and no change in calcium acetate–treated patients. Russo et al. [89] evaluated progression of coro-nary artery calcification in 90 patients with CKD stages 3–5.Patients randomly assigned to sevelamer (30 patients) showed noprogression of coronary artery calcification compared with thosereceiving low phosphorus diet alone or diet associated with cal-cium carbonate. In a recent pilot study of 212 patients with CKDstage 3–4, all-cause mortality and the composite end point ofdeath or dialysis inception were lower in a group of patientsrandomly assigned to sevelamer (n=107) compared to the groupreceiving calcium carbonate (n=105) [90••]. A clinical trialaddressing the cardiovascular outcome of patients treated withsevelamer carbonate is ongoing [91].

Standard dosage Calcium acetate: 1–6 g/d; calcium carbonate: 3–6 g/d; sevelamer-HCl andsevelamer-carbonate: 2400–4800 mg/d (phosphate binders must to be takenduring meals containing protein/phosphate to be effective).

Contraindications Calcium-based: hypercalcemia, severe hypercalciuria, nephrocalcinosis, renalcalculi.Sevelamer: intestinal occlusion.

Main drug interactions Calcium-based: concurrent use with digoxin increases the risk of digoxintoxicity. Decreased intestinal absorption of medications such as bisphosph-onates, thyroxine, quinolones, and iron compounds when taken with calci-um salts. Thiazide diuretics decrease urinary calcium excretion, and usedconcomitantly with calcium-based binders, may predispose to risk of hy-percalcemia.Sevelamer: may reduce intestinal absorption of other drugs.

Main side effects Calcium-based: main side effects are hypercalcemia followed by gastroin-testinal distress (nausea, vomiting, constipation, diarrhea, abdominal


cramping). High doses and concomitant use of vitamin D predispose tohypercalcemia.Sevelamer: Gastrointestinal side effects are common and include nausea,vomiting, dyspepsia, abdominal pain, flatulence, diarrhea, constipation;promotes lower intestinal absorption of vitamins K, D, E, and folic acid.Sevelamer-HCl may cause mild acidemia and caution should be taken inCKD patients not on dialysis (sevelamer carbonate has been evaluated forthis population due to absence of acidemia risk).

Cost/cost-effectiveness Calcium-based phosphate binders are inexpensive. Sevelamer and lan-thanum are expensive. All phosphate binders are effective in reducinghyperphosphatemia. Therefore, the individual risk-benefit ratio shouldbe taken into consideration: calcium salts should be avoided inpatients with hypercalcemia, extra-osseous calcification (mainly vascu-lar and cardiac valve calcification), adynamic bone disease, and lowPTH level.

Vitamin D and vitamin D analogues& Vitamin D supplementation either with cholecalciferol or ergocalci-

ferol is recommended whether serum 25(OH)D concentration islower than 30 ng/mL in patients with CKD stages 3 to 4. In patientswith CKD stages 3 to 5 and adequate serum 25(OH)D levels butelevated serum level of PTH, calcitriol or vitamin D analogues arerecommended [17, 73].

& Suboptimal serum 25(OH)D concentration defined as vitamin Dinsufficiency is highly prevalent worldwide, affecting varioussegments of the population including CKD patients [92, 93].Several studies have shown an association of low vitamin Dlevels with several chronic diseases including CVD [94]. Low 25(OH)D levels are associated with increased all-cause and cardio-vascular mortality in CKD patients [79]. Additionally, vitamin Ddeficiency has been associated with cardiovascular events andmortality in dialysis and incident hemodialysis patients [95, 96].These data suggest that low vitamin D might be considered a riskmarker for CVD and correction of vitamin D deficiency a po-tential target to prevent CVD risk. However, interventional studieswith vitamin D supplementation are needed to evaluate whethervitamin D supplementation improves outcome in CKD patients.

& It is well known that calcitriol and vitamin D analogues are ef-fective in the prevention and treatment of SHPT in CKD patients[17, 81•]. Activated vitamin D binds to and activates vitamin Dreceptors (VDR) expressed in parathyroid cells, thus inhibitingPTH synthesis and secretion. Beyond the classical effects of vita-min D compounds on mineral metabolism in CKD, activated vi-tamin D (ie, calcitriol or analogues) reduces proteinuria inpatients with stage 2–5 CKD without an increased risk of adverseevents [97]. Several retrospective and observational studies havereported improved survival in CKD patients treated with calcitriol oranalogues [98, 99]. However, whether vitamin D supplementation


plays a crucial role in the prevention of CVD or improved outcomeof established CVD in CKD remains to be demonstrated. Recently,Lishmanov et al. [100] evaluated 126 old male patients with CKDstages 3 and 4 and serum level of 25(OH)D below 30 ng/mL. In thisstudy, 90 patients were successfully treated with ergocalciferol suf-ficient to increase serum 25(OH)D level by 25 % from baselinewithin 6 months and were compared to untreated control patients(n=36). During a mean follow-up of 27.2 months, 21 % of thepatients in the treatment group had cardiovascular events comparedto 44 % in the control group (P=0.001). Paricalcitol treatment wasprovided to 227 CKD stage 3 and 4 patients enrolled in a recentclinical trial; active therapy did not alter left ventricular mass indexor improve measures of left ventricular diastolic dysfunction com-pared to placebo [101•].

Cholecalciferol and ergocalciferol

Standard dosage Cholecalciferol and ergocalciferol dose and time for replacement ofsuboptimal 25(OH)D level is dependent of the severity of insufficiency/deficiency. An oral dose of 50,000 IU per week for 12 and 4 weeks andthen monthly per 6 months is suggested when the serum 25(OH)D islower than 5 ng/mL and 5 to 15 ng/mL, respectively; while 50, 000 IUmonthly per 6 months should be provided when the serum 25(OH)Dlevel is 16–29 ng/mL [102].

Contraindications Hypercalcemia, elevated serum 25(OH)D level, or vitamin D toxicity.

Main drug interactions Use with digoxin increases risk of digoxin toxicity due to hypercalcemia.

Main side effects Hypercalcemia and hypercalciuria are the main consequences of vitamin Dtoxicity. Toxicity symptoms are often related to hypercalcemia includinganorexia, nausea, vomiting, polyuria, dehydration, constipation, weakness,neurologic disturbances, kidney stone, and vascular calcification. Therefore,25(OH)D levels should be monitored in patients taking vitamin D.

Special points Serum calcium and phosphorus levels should be checked at least every3 months.

Cost/cost-effectiveness Moderately inexpensive.

Calcitriol and vitamin D analogs

Standard dosage Calcitriol: 0.25–0.5 μg/d is the recommended dose to prevent SHPT in pre-di-alysis CKD patients. Paricalcitol: initial oral dose should be based on baselinePTH for CKD stages 3 and 4 patients. SerumPTHof 500 pg/mL or less: 1 μg/dayor 2 μg three times perweek; serumPTH above 500 pg/mL: 2 μg/d or 4 μcg threetimes per week. The dose is adjusted based on serum PTH response: increasedose by 1 μg/d or 2 μg three times per week if PTH level decreases less than 30%frombaseline or increases despite drug administration. Dose should be reducedif PTH decreases more than 60 % from baseline. The intravenous route isindicated for patients on dialysis. Doxercalciferol: initial oral dose is 1 μg/dayand titrated according to serum PTH levels. Alfacalcidol:0.25–0.5 μg/d.


Contraindications Hypercalcemia and hyperphosphatemia.

Main drug interactions Cardiac glycosides (digitalis toxicity is potentiated due to hypercalcemiarisk). Enhanced hypercalcemia risk with calcium salts.

Main side effects Hypercalcemia and hyperphosphatemia due to enhanced intestinal absorp-tion. Excessive calcitriol or analogs administration may predispose to extra-osseous calcifications, including Vascular Calcification (VC) and cardiacvalve calcifications, excessive PTH suppression, and adynamic bone disease.

Special points Treatment should be started only with serum calcium and phosphoruswithin normal range.Serum calcium and phosphorus levels should be checked within 2–4 weeksof starting treatment or following a dose adjustment. Thereafter, serum cal-cium and phosphorus should be monitored every 1–3 months.

Cost/cost-effectiveness Calcitriol is less expensive than vitamin D analogues and is the drug ofchoice due to lack of clear evidence that analogs are superior to calcitriol forSHPT prevention in CKD stages 3–5.

Cinacalcet& Cinacalcet is a type II calcimimetic agent that acts as an allosteric

modulator of the calcium-sensing receptor (CaSR), increasingsensitivity of the parathyroid glands to extracellular calcium,which leads to inhibition of PTH secretion. Cinacalcet is an ef-fective and well-tolerated oral therapy for the management ofSHPT in chronic dialysis patients [103]. The CaSR expression inseveral cardiovascular cells such as cardiomyocytes, endothelialcells, and vascular smooth muscle cells suggests that this receptormay constitute a potential therapeutic target for CVD prevention[104]. Cinacalcet was associated with lower cardiovascular andall-cause mortality in a prospective, observational study of 19,186patients undergoing maintenance hemodialysis (5976 receivingcinacalcet) [105]. In a prospective, randomized clinical trial of he-modialysis patients with SHPT, cinacalcet with low-dose vitamin Dtreatment was associated with a statistically significant smaller pro-gression of aortic valve calcification (P=0.014) and a trend towardslower progression of mitral valve and thoracic aorta calcification(P=0.053 and P=0.055, respectively) [106].

& Although effective for SHPT treatment in dialysis patients, cinacalcetis not approved for CKD stages 3 to 5. In a phase 3 study, patientswith CKD stages 3 and 4 were randomly assigned to cinacalcet versusplacebo. Cinacalcet was effective to reduce serum PTH, but hypo-calcemia and increased serum phosphate were observed [107]. In arecent experimental study, cinacalcet promoted hypocalcemia andhyperphosphatemia in uremic rats. Though the mechanisms areunclear, cinacalcet reduced PTH and FGF23 levels, which could leadto lower urinary phosphorus excretion, ultimately resulting in in-creased serum phosphorus [108]. Further studies are needed toclarify these findings.


DisclosuresC. Karohl: none. Dr. Paolo Raggi has received grants and honoraria from Amgen and Genzyme.

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Approach to Cardiovascular Disease Prevention in Patients With Chronic Kidney Disease

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