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The Zena and Michael A. wiener Cardiovascular institute and Marie-Josée and Henry r. Kravis Cardiovascular Health Center (S. van der Zee, U. Baber, S. Elmariah, V. Fuster), Department of Nephrology (J. Winston), Mount sinai school of Medicine, New York, NY, UsA.

Correspondence: v. Fuster, The Zena and Michael A. wiener Cardiovascular institute, Mount sinai school of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029, UsA valentin.fuster@ mssm.edu

cardiovascular risk factors in patients with chronic kidney diseaseSarina van der Zee, Usman Baber, Sammy Elmariah, Jonathan Winston and Valentin Fuster

abstract | Patients with chronic kidney disease have a higher burden of cardiovascular disease, which increases in a dose-dependent fashion with worsening kidney function. Traditional cardiovascular risk factors, including advanced age, diabetes mellitus, hypertension and dyslipidemia, have an important role in the progression of cardiovascular disease in patients who have a reduced glomerular filtration rate, especially in those with mild-to-moderate kidney disease. in patients with severe kidney disease, nontraditional or ‘novel’ risk factors, including inflammation, oxidative stress, vascular calcification, a prothrombotic milieu, and anemia, seem to confer additional risk. in this review, we highlight factors that increase cardiovascular risk in patients with a reduced estimated glomerular filtration rate. in addition, we discuss therapeutic strategies for reducing cardiovascular risk in patients with kidney disease, whose unique atherosclerotic phenotype might require an approach that differs from traditional models developed in populations with normal kidney function. Therapeutic paradigms for patients with chronic kidney disease and cardiovascular risk factors must be evaluated in randomized trials, from which such patients have often been excluded.

van der Zee, s. et al. Nat. Rev. Cardiol. advance online publication 21 July 2009; doi:10.1038/nrcardio.2009.121

Introductionstudies have demonstrated a graded relationship between the degree of kidney disease and cardiovascular risk across a wide spectrum of populations of patients and clinical presentations.1–4 this observation has led to multi disciplinary statements recommending routine screening for chronic kidney disease (CKD) in patients with cardiovascular disease. the aHa and national Kidney Foundation support screening for kidney disease in all adult patients with established cardio­vascular disease or risk factors such as hypertension and diabetes mellitus.5,6

a commonly used metric to assess kidney function is the glomerular filtration rate (GFr). However, GFr is difficult to measure directly and, thus, equations that provide an estimated GFr (eGFr) have been adopted in clinical guidelines. Many early studies of cardiovascular risk excluded patients with CKD altogether or did not specify the degree of impairment in eGFr in the popula­tion studied. the aHa and national Kidney Foundation thus suggest a screening protocol that includes two tests: eGFr, based on the abbreviated Modification of Diet in renal Disease equation, and a random urine albumin:creatinine ratio.7 if eGFr is less than 60 ml/min/1.73m2 of body surface area or if the urine contains more than 30 mg of albumin per gram of creatinine for more than 3 months, the patient should be consi­dered as having CKD. recommendations from the national Kidney Foundation, which were published in 2002, strati fied CKD into five stages on the basis of eGFr

and the presence of urinary protein (table 1).8 stage 1 describes patients whose eGFr is normal or increased but have an elevated urine protein:creatinine ratio or other evidence of kidney damage; stages 2–4 encompass pro­gressive reductions in eGFr, from 60–15 ml/min/1.73m2 and stage 5 describes kidney failure, defined as an eGFr <15 ml/min/1.73m2 or renal replacement therapy.

the global burden of both cardiovascular disease and CKD is increasing, which is partially attributable to the growing prevalence of shared traditional risk factors, including advanced age, diabetes mellitus and hyper­tension.9–11 the 1999–2004 nHanes (national Health and nutrition examination survey) estimated the preva­lence of CKD stages 1–4 at 13.1%, compared with 10% in the 1988–1994 survey.12 the increase in overall preva­lence persisted after adjustment for the interim aging of the population and changes in method of CKD identi­fication. an increased prevalence of diabetes, hyper­tension and obesity accounted for the entire increase in the prevalence of microalbuminuria, but only part of the increase in overall prevalence of CKD. Patients with chronic kidney failure represent a smaller but rapidly expanding segment of the population. the prevalence of kidney failure exceeded 506,000 people in the us in 2006 and is projected to rise to more than 780,000 cases by 2020. the associated 2006 Medicare expenditure for treatment of chronic kidney failure was $23 billion, with an additional $10 billion spent by private insurers.13

this review highlights traditional and nontraditional cardiovascular risk factors in patients with varying degrees of kidney function and discusses thera peutic strategies for reducing cardiovascular risk in these patients.

competing interestsThe authors declare no competing interests.

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Cardiovascular risk and outcomes in CKDa synergistic cycleMost studies have shown that CKD independently increases cardiovascular risk and is associated with a spectrum of adverse outcomes including cardio­vascular mortality, myocardial infarction, stroke and heart failure (Figure 1).1,7,14–16 However, some studies that included patients at lower risk did not demon­strate the same association.17 studies of patients with established vascular disease or high cardiovascular risk demonstrate an independent and graded relation­ship between reduced kidney function and adverse cardiovascular outcomes that is present at mild stages of kidney disease and becomes more marked at an eGFr <60 ml/min/1.73m2.14,17,18 in community­based longitudinal studies that included patients at lower cardiovascular risk, kidney disease—as manifest by elevated serum creatinine—was also associated with more cardiovascular events.15 in the prospective ariC (atherosclerotic risk in Communities) study of 15,250

Key points

with the growing prevalence of shared risk factors, the global burden of ■cardiovascular disease and chronic kidney disease is increasing rapidly

Most studies of patients with cardiovascular disease or high cardiovascular ■risk demonstrate a graded relationship between degree of kidney disease and adverse cardiovascular outcomes

Patients with cardiovascular disease or risk factors such as diabetes mellitus ■and hypertension should be screened for kidney disease via assessment of estimated glomerular filtration rate and urinary albumin:creatinine ratio

increased cardiovascular risk in patients with kidney disease is probably ■mediated by both traditional and novel risk factors

evidence-based therapeutic approaches to modification of cardiovascular risk ■in populations with preserved kidney function seem to be less effective in patients with kidney failure, who exhibit a unique vascular phenotype

Treatment paradigms targeted at both traditional and novel atherothrombotic risk ■factors must be evaluated in randomized trials in patients with kidney disease

patients aged 45–64, eGFrs of 60–89 ml/min/1.73m2 and 15–59 ml/min/1.73m2 were associated with hazard ratios (Hrs) for atherosclerotic cardio vascular events of 1.16 (95% Ci 1.00–1.34) and 1.38 (95% Ci 1.02–1.87), respectively, over 6.2 years.4 in the CHs (Cardiovascular Health study), a prospective, population­based study of individuals older than 65 years, 11.2% had elevations in serum creatinine and 25.1% experienced a cardio­vascular event in 5 years of follow­up.4,19 those with elevated serum creatinine had a significantly higher risk of all­cause and cardiovascular mortality, total cardio vascular disease, claudication and congestive heart failure that remained significant after adjusting for cardio vascular risk factors and subclinical vascular disease. although members of the Framingham Heart study and Framingham Offspring study (mean age 54 years for the subgroup whose creatinine was mea­sured) with moderate elevations in serum creatinine (1.5–3.0 mg/dl in men or 1.4–3.0 mg/dl in women) were not at increased risk for cardiovascular events after adjusting for traditional cardiovascular risk factors, men with kidney disease had a slight increase in all­cause mortality after multivariable adjustment (Hr 1.31, 95% Ci 1.02–1.67).17 the risk of cardiovascular events is increased markedly in patients with severe kidney disease, with a cardiovascular mortality in patients on hemodialysis that is 10 to 30­fold higher than that of age­matched controls.1,3,19,20

Conversely, patients with established cardio vascular disease are more likely to experience a decline in eGFr than those without cardiovascular disease (Figure 2). in the ariC and CHs studies, those with established cardio vascular disease—defined as prior stroke, tran­sient ischemic attack, angina, claudication, percutaneous coronary intervention, coronary artery bypass surgery, or myocardial infarction—constituted 13% of the study populations and were more likely to experi ence a decline in kidney function (defined as an increase in creati­nine of at least 0.4 mg/dl; odds ratio [Or] 1.28, 95% Ci 1.13–1.45) and to develop kidney disease (defined as an increase in creatinine of at least 0.4 mg/dl when the baseline creatinine was less than 1.4 mg/dl in men and 1.2 mg/dl in women; Or 1.54, 95% Ci 1.26–1.89).21 these data point to a cycle in which declining kidney function increases cardio vascular risk, which in turn accelerates a decline in kidney function (Figure 3).

Traditional versus nontraditional risk factorsintense research effort has been directed at establishing the mechanistic relationship between kidney disease and cardiovascular risk. traditional and nontraditional or ‘novel’ risk factors are thought to contribute to elevated risk of cardiovascular events in patients with a reduced eGFr (Figure 3);22,23 however, given that both traditional and novel risk factors are more prevalent among patients with kidney disease, compared with the general popula­tion, the relative contribution of each towards excess risk of cardiovascular events remains unclear.

Table 1 | stages of CKD and stage-specific action plan

cKd stage8

egFr (ml/min/1.73m2)

characteristics Prevalence in the US population8

Stage-specific action plan6

1 ≥90 Kidney damage with normal or increased eGFr

5.9% Diagnose and treat comorbid conditions, slow progression, reduce cardiovascular risk

2 60–90 Kidney damage with mildly decreased eGFr

4.0% estimate progression

3 30–60 Moderately decreased eGFr

4.3% evaluate and treat complications

4 15–30 severely decreased eGFr

0.2% Preparation for dialysis

5 <15 or dialysis

Kidney failure 0.2% replacement therapy if uremia present

Abbreviations: CKD, chronic kidney disease; eGFr, estimated glomerular filtration rate.

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1.0 –

0.9 –

0.8 –

0.7 –

0.6 –

0 –

0 1 2 3

Time since baseline (years)

CKD (eGFR 15–60 ml/min/1.73 m2)

No CKD (eGFR 60–150 ml/min/1.73 m2)

Prop

ortio

n fr

ee o

f co

mpo

site

out

com

e

4 5 6 7 8 9 10

Figure 1 | Kaplan-Meier analysis of cardiovascular outcomes according to the presence of chronic kidney disease. Composite outcome includes myocardial infarction, fatal coronary heart disease, stroke and all-cause mortality. Bars represent 95% Cis. Abbreviation: CKD, chronic kidney disease; eGFr, estimated glomerular filtration rate. Permission obtained from American society of Nephrology © weiner, D.e. et al. J. Am. Soc. Nephrol. 15, 1307–1315 (2004).

Patients with mild-to-moderately reduced egFrTraditional risk factorstraditional Framingham risk factors are highly preva­lent in patients with a reduced eGFr and account for a significant proportion of cardiovascular risk.4,17,19,24 For example, in individuals in the ariC study whose eGFr was 15–59 ml/min/1.73m2, traditional risk factors remained predictive of coronary heart disease. the rela­tive risk (rr) of coronary heart disease was 3.06 (95% Ci 2.01–4.67) for those with diabetes mellitus, 2.02 (95% Ci 1.27–3.22) for those with hypertension, 1.65 (95% Ci 1.01–2.67) for those who were current smokers, 1.50 (95% Ci 1.25–1.71) for each standard deviation of higher total cholesterol, and 0.79 (95% Ci 0.62–1.01) for each standard deviation of higher HDL cholesterol.3 indeed, traditional risk factors substantially attenuate the unadjusted association between CKD and cardiovascular events in multiple studies (table 2).

the importance of traditional risk factors in medi­ating excess cardiovascular risk in those with mild­to­ moderate CKD is supported both by epidemiologic observations and biologic plausibility. in cross­sectional studies, impaired kidney function is associated with mul­tiple indices of subclinical cardiovascular disease, includ­ing abnormal carotid intima–media thickness and left ventri cular hypertrophy.2,25 in addition, the magnitude of association between CKD and cardiovascular end points seems to be higher in populations with a greater burden of pre­existing cardiovascular disease.14,26

these data suggest that kidney disease might be a marker of overall vascular disease, the magnitude of which may not be fully captured by traditional risk factors. in many cases, the presence of kidney disease might reflect diffuse and/or severe atherosclerosis, which places patients at high risk for future cardio­vascular events. in addition, current statistical models of cardiovascular risk might not reflect prolonged expo­sure to and/or poorer control of various risk factors in patients with CKD. indeed, traditional Framingham risk factors seem to carry a different weight in those with reduced eGFr compared to the original Framingham population.27 in a pooled study of individuals from ariC and CHs who had an eGFr 15–60 ml/min/1.73m2 and no pre­existing coronary disease (n = 944), the Framingham risk score tended to underpredict events at 5 and 10 years in both men and women. in men, dia­betes mellitus was a more significant risk factor than in the original Framingham cohort, hypertension and total cholesterol were less significant, and HDL levels had no effect on outcomes. in women, diabetes mellitus was also more significant, while a ‘J­shaped’ relationship between blood pressure and outcomes was observed. However, by refitting the Framingham prediction algo­rithm for CKD­specific coefficients, the discrimination for the Framingham function in the CKD population was comparable to a non­CKD population (at 5 years, C­statistic was 0.72 versus 0.73 in men, and 0.82 versus 0.79 in women).27

Novel risk factorsin addition to traditional risk factors, a high prevalence of nontraditional cardiovascular risk factors—including fibrinogen, calcium•phosphorus product and homo­cysteine—exists in patients with CKD.3,22,23 in a pro­spective analysis of individuals with an eGFr 15–60 ml/min/1.73m2, C­reactive protein, plasma fibrinogen, and low serum albumin were independently associated with adverse outcomes including myocardial infarc­tion, stroke and all­cause mortality.28 although some of these non traditional risk factors seem to be related to inflammation as well as disordered bone and mineral metabolism, their biologic role and clinical significance remain uncertain.

16 –

12 –

8 –

4 –

0 –

0 0.5 0.75 1.00

Baseline creatinine level (mg/dl)

CVD

No CVD

Prob

abili

ty o

f de

clin

e in

kid

ney

func

tion

(%)

1.25 1.50 1.75 2.00

Figure 2 | Adjusted estimated probability of kidney function decline as a function of baseline serum creatinine level in patients with and without cardiovascular disease. Abbreviation: CvD, cardiovascular disease. Permission obtained from American Medical Association © elsayed, e.F. et al. Arch. Intern. Med. 167, 1130–1136 (2007).

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Patients with kidney failurealthough most patients with CKD die from cardio­vascular causes before they develop kidney failure, cardio vascular mortality rates are also significantly higher in patients with kidney failure than in age­matched and sex­matched controls.20 this excess risk is probably medi­ated by both traditional and novel risk factors, which increase in prevalence as kidney function declines.

Traditional risk factorsseveral investigators have used observational studies to attempt to quantify the contribution of traditional risk factors towards cardiovascular outcomes in patients with kidney failure. advanced age and diabetes melli­tus remain predictors of adverse events in patients with kidney failure; however, hypertension and dyslipidemia have not been consistently associated with adverse out­comes and in certain circumstances even seem to be pro­tective.29 a ‘u­shaped’ curve has been observed between systolic blood pressure and cardiovascular mortality among patients on dialysis, in contrast to a ‘J­shaped’ curve in the general population.30,31

there are several possible explanations for the appar­ent ‘reverse epidemiology’ for traditional risk factors and

cardiovascular risk in patients with kidney failure. First, the association between risk factors and cardiac out­comes might be mediated by the presence or absence of mal nutrition and inflammation. in support of this hypo­thesis, Liu et al. demonstrated that cardiovascular risk increased with total cholesterol levels among patients on dialysis without evidence of malnutrition or inflamma­tion, whereas the opposite was observed in patients with either malnutrition or inflammation.32 these findings, however, were not reproduced in a subsequent, larger analysis.33 second, there might be a time­ dependent relationship between traditional risk factors and cardio­vascular outcomes in patients who develop kidney failure, which is not observed in the general population. For example, among incident hemodialysis patients, a low systolic blood pressure was associated with increased mortality during the first 2 years after starting dialysis, while a high systolic blood pressure was associated with increased mortality in patients who survived beyond 3 years.34 similar findings were observed in a prospective study of incident peritoneal dialysis patients.35

Novel risk factorsin addition to inflammation and calcification, other novel risk factors implicated as potential mediators of cardiovascular risk in patients with advanced CKD include malnutrition, anemia, hyperhomocysteinemia and oxidative stress. Despite robust associations between such risk factors and cardiovascular end points in obser­vational analyses, however, limited data support a causal relationship with cardiovascular events. interventions aimed at lowering homocysteine, for example, did not translate into improved outcomes among patients on hemodialysis.36

Therapeutic implicationsdyslipidemiaKDOQi (the national Kidney Foundation Disease Outcomes Quality initiative) clinical practice guidelines recommend treating adult patients with CKD with a goal of LDL­cholesterol levels less than 100 mg/dl or non­HDL­cholesterol levels less than 130 mg/dl.37 More­aggressive goals of LDL­cholesterol levels less than 70 mg/dl might be justified in those with coronary artery disease.38

However, data supporting the use of HMG Coa reductase inhibitors (that is, statins) for dyslipidemia to reduce cardiovascular risk in patients with CKD are limited (table 3).39 Posthoc subgroup analyses have sug­gested a protective effect of statin therapy in CKD. in the Heart Protection study, in high­risk patients with mild­to­moderate CKD (defined as creatinine 1.2–2.3 mg/dl for women and 1.5–2.3 mg/dl for men) and coronary disease, other occlusive arterial disease, or diabetes mel­litus, simvastatin (40 mg daily) was associated with a 28% reduction in risk of total mortality and fatal and nonfatal vascular events (rr 0.72, 95% Ci 0.72–0.85), compared with placebo.40 in the Pravastatin Pooling Project, which also studied a high­risk population, pravastatin (40 mg

Coronary heart disease

Chronic kidney disease

Traditional risk factorsAdvanced ageHypertension

Diabetes mellitusDyslipidemiaTobacco useFamily historyMale gender

Novel risk factorsAlbuminuria

Disordered bone and mineral metabolismAnemia

Vascular stiffnessProthrombotic milieu

Oxidative stressProtein-energy wasting

Figure 3 | relationship between chronic kidney disease and coronary heart disease. Traditional risk factors lead to both progression of atherosclerotic heart disease and reduction in glomerular filtration. The presence of coronary heart disease accelerates the reduction in glomerular function in chronic kidney disease, which, in turn, increases the risk of coronary events. Once kidney disease becomes more severe, novel risk factors, including disordered bone and mineral metabolism, vascular stiffness and altered lipid metabolism, emerge as additional mediators of cardiovascular risk.

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daily) significantly reduced the incidence of the com­bined primary outcome of time to myocardial infarction, coronary death, or coronary revascularization (Hr 0.77, 95% Ci 0.68–0.86) in patients with an eGFr of 30–59 ml/min/1.73m2.41 in 3,107 patients in the tnt (treating to new targets) study who had stage 3 or 4 CKD, aggres­sive lipid­lowering therapy with atorvastatin (80 mg daily) reduced the risk of major cardiovascular events by 32% (Hr 0.68, 95% Ci 0.55–0.84) compared to a lower dose of this statin (10 mg daily).42 intriguingly, a more­significant benefit of intensive lipid­lowering therapy was observed in patients with reduced eGFr than in those with normal eGFr (Hr 0.85, 95% Ci 0.72–1.00).42 However, results from trials devoted to patients with CKD have to date been negative. Pravastatin was not associated with a reduction in risk of cardiovascular mortality and hospitalization for cardiovascular mor­bidity in the PrevenD­it (Prevention of renal and vascular end­stage Disease intervention trial; rr 0.87, 95% Ci 0.49–1.57).43

the risk reduction associated with treating dyslipi­demia in kidney failure is controversial owing to the confounding effects of comorbidities, inflammation and nutritional deficiencies seen in these patients.39,44 although observational studies have demonstrated signifi cant relative risk reduction with statin therapy in kidney failure,45 randomized clinical trials have refuted these results. in the randomized 4D study (Die Deutsche Diabetes Dialyze studie) of patients with diabetes (with baseline LDL >130 mg/dl) on dialysis, treatment with atorvastatin (20 mg daily) had no significant effect on the composite primary end point of cardio vascular death, nonfatal myocardial infarction and stroke (rr 0.92, 95% Ci 0.77–1.10) compared with placebo, despite a 42% reduction in LDL­cholesterol levels in this high­risk population.46 investigators in the aurOra (a study to evaluate the use of rosuvastatin in subjects on regular Hemodialysis: an assessment of survival and

Cardiovascular events) trial randomly assigned 2,776 patients on maintenance hemodialysis to rosuvastatin (10 mg daily) or placebo.47 Despite a 42.9% reduction in LDL­cholesterol levels, from a mean baseline value of 100 ± 35 mg/dl, and an 11.5% reduction in median high­sensitivity C­reactive protein levels, rosuvastatin had no effect on the combined primary end point of death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke (Hr 0.96, 95% Ci 0.84–1.11) or on its individual components.47 therapy with statins thus far seems to be generally safe in patients with kidney failure although dose reduction is required with some agents; however, it is important to note that the combi­nation of statins and fibrates are contraindicated in this group. Other therapies directed at the treatment of dys­lipidemia, including exercise and omega­3 fatty acids, can be prescribed according to usual practice in patients with kidney failure; however, a niacin dose reduction of 50% is recommended.39,48

notably, these trials focused primarily on patients with kidney failure who were on maintenance hemo­dialysis. Patients on peritoneal dialysis might poten­tially derive a greater reduction in cardiovascular risk from treatment of dyslipidemia as they tend to have more atherogenic lipid panels49,50 and, when beginning dialysis, are generally healthier than their counterparts starting hemo dialysis; on average, patients on perito­neal dialysis are younger and have a lower BMi but have higher hematocrit and albumin levels.51 Consequently, a secondary analysis of the observational us renal Data system prospective Dialysis Morbidity and Mortality wave 2 study was performed evaluating the effects of lipid­modifying medications on patients on perito­neal dialysis.49 the authors demonstrated a signifi­cant decrease in all­cause mortality (Hr 0.74, 95% Ci 0.56–0.98) and cardio vascular mortality (Hr 0.67, 95% Ci 0.47–0.95) with lipid­modifying medications, 93% of which were statins.

Table 2 | Association of CKD and Cv events in community-based studies

Population Number of patients

definition of cKd cV end points Unadjusted cV hazard ratio (95% ci)

adjusted cV hazard ratio (95% ci)*

AriC4 15,350 eGFr: 15–59 ml/min/1.73m2 Fatal CHD, Mi, stroke and cardiac procedure

2.89 (2.22–3.77)

1.38 (1.08–1.87)

CHs92 4,893 eGFr: 15–59 ml/min/1.73m2 Cardiac death, Mi, percutaneous transluminal coronary angioplasty, CABG, angina, CHF, peripheral vascular disease, stroke, and transient ischemic attack

2.29 (1.93–2.72)

1.31 (1.06–1.62)

FHs/FOs men17

2,837 serum creatinine: 136–265 μmol/l

CHD (coronary insufficiency, recognized Mi, fatal CHD), CHF, and ischemic stroke

1.17 (0.88–1.57)

1.06 (0.79–1.43)

FHs/FOs women17

3,386 serum creatinine: 120–265 μmol/l

CHD (coronary insufficiency, recognized Mi, fatal CHD), CHF, and ischemic stroke

2.19 (1.70–2.83)

1.04 (0.79–1.37)

*Adjusted for traditional risk factors: age, gender, diabetes mellitus, hypertension, low HDL cholesterol, left ventricular hypertrophy, tobacco use. Abbreviations: CHD, coronary heart disease; CHF, congestive heart failure; CKD, chronic kidney disease; Cv, cardiovascular; eGFr, estimated glomerular filtration rate; Mi, myocardial infarction.

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Hypertensionstudies evaluating blood­pressure control in patients with kidney disease have compared various blood­ pressure goals in addition to the efficacy of different classes of antihypertensive regimens.52–55 the aasK (african american study of Kidney Disease and Hypertension) and the MDrD (Modification of Diet in renal Disease) studies found no difference in mean decline in eGFr between patients randomly assigned to a lower target of systolic blood pressure (92 mmHg or less) and those assigned to a standard blood pres­sure treatment goal of 102–107 mmHg at 3 and 4 years, respectively. However, in the MDrD study, a signifi­cant reduction in the incidence of kidney failure and in the composite end point of kidney failure or all­cause mortality was observed at the 10­year follow­up in the group with the lower target blood pressure.56 in addi­tion, Parving et al. demonstrated that microalbuminuria normalized in 20% of patients with both diabetes melli­tus and hypertension when blood pressure was reduced

to less than 140/90 mmHg with diuretics, β­blockers, or vasodilators.57

in addition to the benefits of blood­pressure control in patients with kidney disease, multiple studies have demonstrated that reducing albuminuria is both cardio­protective and renoprotective.58,59 a full discussion of therapeutic strategies for reducing albuminuria has been published in a previous issue of this journal.60 the renaaL (reduction of endpoints in non­insulin dependent diabetes mellitus with the angiotensin ii antagonist Losartan) study randomly assigned patients with diabetic nephropathy on conventional anti­hypertensive regimens to losartan (50–100 mg daily) or placebo.58 Cardiovascular morbidity and mortality were similar in the treatment groups; however, losar­tan reduced the rate of first hospitalization for heart failure by 32% (P = 0.005) and the degree of albumin­uria by 35% (P <0.001).58 another study in patients with diabetes, the iDnt (irbesartan Diabetic nephropathy trial), demon strated superiority of irbesartan over

Table 3 | studies evaluating statin use in patients with CKD

Study Study type n Population of patients intervention clinical end point rr (95% ci)

CKD

PreveND-iT43 Prospective, randomized trial

864 Patients with microalbuminuria

Pravastatin 40 mg daily vs placebo and fosinopril 20 mg daily vs placebo

Cardiovascular mortality and hospitalization for cardiovascular morbidity

0.87 (0.49–1.57)

Heart Protection study40

subgroup of a prospective, randomized trial

1,329 Patients with coronary disease, other occlusive arterial disease, or diabetes and mild-to-moderate CKD

simvastatin 40 mg daily vs placebo

Total mortality and fatal and nonfatal vascular events

0.72 (0.72–0.85)

Pravastatin Pooling study41

Post-hoc analysis of data from wOsCOPs, CAre and LiPiD trials

4,491 High-risk patients with moderate CKD defined as eGFr 30–59.99 ml/min/1.73 m2

Pravastatin 40 mg daily vs placebo

Time to myocardial infarction, coronary death, or coronary revascularization

0.77 (0.68–0.86)

TNT42 Post-hoc subgroup of a prospective, randomized trial

3,107 Patients with coronary disease and eGFr <60 ml/min/1.73 m2

Atorvastatin 80 mg daily vs atorvastatin 10 mg daily

Major cardiovascular event

0.68 (0.55–0.84)

CAre93 Post-hoc subgroup of a prospective, randomized trial

1,711 Patients with a prior myocardial infarction, hyperlipidemia, and GFr <75 ml/min1.73 m2

Pravastatin 40 mg daily vs placebo

Death from coronary disease or symptomatic nonfatal myocardial infarction

0.72 (0.55–0.95)

Kidney failure

Us rDsD Morbidity & Mortality study49

retrospective 3,716 Patients initiating dialysis in 1996

Any statin use compared to nonusers

Cardiovascular mortality 0.64 (0.45–0.91)

DOPPs94 retrospective 17,221 Patients on chronic hemodialysis

Possession of a statin prescription

Cardiovascular mortality 0.77 (no 95% Ci provided), P = 0.03

4D46 randomized, controlled trial

1,255 Patients with type 2 diabetes mellitus on chronic hemodialysis

Atorvastatin 20 mg daily vs placebo

Composite of death from cardiac causes, nonfatal myocardial infarction and stroke

0.92 (0.77–1.10)

AUrOrA47 randomized, controlled trial

2,776 Patients on chronic hemodialysis

rosuvastatin 10 mg daily vs placebo

Composite of death from cardiac causes, nonfatal myocardial infarction and nonfatal stroke

0.96 (0.84–1.11)

Abbreviations: CKD, chronic kidney disease; eGFr, estimated glomerular filtration rate; n, number of patients; rr, relative risk.

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amlodipine in preventing the composite primary end point of doubling of serum creatinine, renal failure, or death (rr 0.76, 95% Ci 0.63–0.92). similarly, fosinopril (20 mg daily) was associated with a 40% decrease in cardiovascular mortality and hospitalization compared to placebo in the PrevenD­it study in patients with microalbuminuria (Hr 0.60, 95% Ci 0.33–1.10).43 in the MiCrO­HOPe substudy of the HOPe (Heart Outcomes Prevention evaluation) trial, ramipril (10 mg daily) signifi cantly reduced patients’ albumin:creatinine ratios (P = 0.001 at 1 year and 0.02 at 4.5 years), compared with placebo, and lowered the risk of overt nephropathy in patients without baseline microalbuminuria, despite only a small reduction in blood pressure (2–3 mmHg).59 Moreover, a reduction in the primary end point of myocardial infarction, stroke and cardiovascular death in the ramipril group (25% reduction, 95% Ci 12–36, P = 0.0004) remained significant after adjusting for the change in blood pressure.

indeed, in the PrevenD­it and MiCrO­HOPe studies, the significant reduction in albuminuria and cardio vascular end points occurred despite modest blood­ pressure reduction. the magnitude of the observed benefits mediated by blockade of the renin–aldosterone system, using angiotensin­converting­enzyme inhibitors (aCei) or angiotensin ii receptor blockers (arBs), seems to be out of proportion to the blood­pressure­lowering effect, and the most consistent benefit with blockade of the renin–aldosterone system is seen in individuals with albuminuria. the renoprotective effects of blockade of the renin–aldosterone system were reinforced in a meta­analysis by the aiPrD (aCe inhibition in Progressive renal Disease) study group, which demon strated that antihypertensive regimens that included aCei were more effective than those without an aCei in slowing the progression of nondiabetic renal disease, defined as pro­gression to renal failure or doubling of serum creatinine (rr 0.70, 95% Ci 0.55–0.88).61

Data regarding the management of hypertension in patients with kidney failure has been confusing, as both high and low blood pressure have been associated with adverse outcomes.62,63 Current KDOQi guidelines recom­mend a blood­pressure goal of less than 140/90 mmHg in the absence of symptomatic hypotension;64 however, the recommendations are based primarily on data from patients with less­severe CKD62,64 and on an observa­tional study in which normal blood pressure was associ­ated with less left ventricular hypertrophy and death.65 Data from randomized, placebo­controlled trials demon­strating a benefit of strict blood­pressure control in patients are lacking.

in one of the few randomized trials to evaluate blood­pressure control in kidney failure, the FOsiDiaL (effects of Fosinopril on Cardiovascular Morbidity and Mortality in Hemodialysis Patients) trial demonstrated that, compared with placebo, treatment with fosinopril (5–20 mg daily) in addition to conventional treatment did not reduce cardiovascular events in patients with left

ventricular hypertrophy on hemodialysis.66 However, in a prespecified secondary analysis adjusting for identified risk factors, the authors noted a trend towards reduced cardiovascular events with fosinopril therapy (rr 0.79, 95% Ci 0.59–1.10). Because of low event rates, the trial lacked the statistical power to definitively determine the effect of fosinopril in this population of patients.

a meta­analysis has been performed to evaluate the effects of lowering blood pressure on risk of cardio­vascular events and mortality in patients on mainte­nance dialysis.67 in eight randomized, placebo­controlled trials including a total of 1,679 patients, blood­pressure lowering was associated with a significant reduction in cardiovascular events (rr 0.71, 95% Ci 0.55–0.92) and all­cause mortality (rr 0.80, 95% Ci 0.66–0.96). notably, however, patients included in the analysis represented diverse physiological states that included hemo dialysis, peritoneal dialysis, and heart failure. additionally, various pharmacologic agents were evaluated, including β­blockers, calcium­channel blockers, aCeis and arBs, and much of the benefit with regard to cardiovascular events seems to result from arB trials. as such, whether blood pressure reduction is helpful in patients with renal failure, or whether arBs hold a specific beneficial effect, remains unclear.

Novel risk factorsBone and mineral disorders—including hyperphos­phatemia, hypercalcemia, secondary hyperparathyroid­ism and elevated calcium•phosphorus product—are associated with elevated cardiovascular risk in patients with kidney failure.68 therapeutic interventions designed to modify this risk have yielded mixed results. in two randomized studies evaluating the efficacy of sevelamer compared with calcium­based phosphate binders, seve­lamer was not associated with a reduction in mortal­ity.69,70 Despite negative results in randomized trials, smaller analyses have suggested a benefit to sevelamer in reducing the surrogate marker of atherosclerosis. For example, compared with calcium­based phosphate binders, sevelamer was associated with an attenuation of coronary and aortic valve calcification in a randomized trial of patients on dialysis (n = 200).71

treatment of secondary hyperparathyroidism with activated injectable vitamin D analogs—primarily pari­calcitol or calcitriol—has been shown to prolong survival in patients on dialysis.72 in a retrospective analysis of 51,037 incident hemodialysis patients, the 37,173 patients who received injectable vitamin D had a 20–26% survival advantage and reduced cardiovascular­related mortality compared with those who did not receive the agents.73 additional observational studies also suggest a survival benefit, which might be superior with paricalcitol and doxercalciferol compared with calcitriol.74,75 However, in a meta­analysis of 76 small, randomized, controlled trials, which included 3,667 patients, vitamin D analogs had no effect on cardiovascular mortality. importantly, the authors note that only eight of the included studies

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reported patient mortality and only five used new vitamin D compounds.76 More data for new agents are needed to confirm or refute the cardiovascular benefits of vitamin D analogs.

although insufficient, the available data suggest a benefit of many routine pharmacological and behavioral interventions for cardiovascular­risk­factor modifica­tion in patients with mild­to­moderate CKD. Patients with kidney failure present a unique challenge in that no intervention has definitely been found to be beneficial in reducing cardiovascular risk. even aspirin, which is often used to reduce cardiovascular risk in other patients, has only been found to reduce mortality in patients on dialysis who have had a myocardial infarction.62 Other therapeutic interventions to reduce cardiovascular mortality have been evaluated in this high­risk popu­lation of patients. vitamin e and acetylcysteine have been used to limit oxidative stress with promising but inconclusive results.77–79 therapy with folate for hyper­homocysteinemia has also yielded conflicting results.62,80 Correction of anemia, which is associated with increased mortality in patients on dialysis, has shown no utility in reducing mortality in patients with CKD, and might even cause harm if anemia is aggressively corrected to hemo globin levels above 13.5 g/dl.62,81,82 in the only adequately powered, randomized, controlled trial of anemia correction in hemodialysis, patients with clini­cal evidence of ischemic heart disease or congestive heart failure assigned to receive epoietin to maintain a target hematocrit level of 42% (n = 618) had a relative risk of 1.3 (95% Ci, 0.9–1.9) of death or nonfatal myocardial infarc­tion compared to those with a target of 30% (n = 615).83 although the difference in event­free survival did not reach the prespecified statistical stopping boundary, the study was stopped early and the authors concluded that administration of epoietin to a target hemoglobin of 42% was not recommended in patients on hemodialysis.83

the challenge for physicians is to decide whether to treat or withhold therapies that are known to be effective in early CKD, even though studies to date have shown no benefit in patients with kidney failure. whether the failure of contemporary therapy is due to cardiovascular disease that is simply too advanced to allow for mean­ingful reversal of active pathologic processes, whether our understanding of the relevant risk factors remains deficient, and/or whether more comprehensive trials are needed to unearth missed effects, remains unclear.62 Multiple competing risks, many of which are non­cardiovascular in nature, might also render modification

of overall prognosis via cardiovascular inter ventions alone difficult.

Conclusionsrisk­factor modification is required to interrupt the syner­gistic cycle of cardiovascular disease and declining kidney function. traditional cardiovascular risk factors, includ­ing advanced age, diabetes mellitus, hypertension and dyslipidemia, mediate the progression of cardio vascular disease in CKD, particularly in patients with mild­to­moderate kidney disease. Patients with kidney failure exhibit a unique vascular phenotype— characterized by aggressive vascular calcification, inflammation, oxida­tive stress, altered lipid metabolism, a pro thrombotic milieu, and anemia—which seems to be less responsive to current evidence­based treatments. in addition, novel risk factors seem to have a more­ significant role in medi­ating excess cardiovascular morbidity and mortality in these patients.29,84–86 Despite a higher risk­factor burden than those with normal kidney function, patients with CKD are less likely to receive evidence­based therapies to modify cardiovascular risk factors and to achieve guideline­ recommended treatment goals.87–91

Careful attention must be given to the relative bene­fits of pharmacologic interventions to modify cardio­vascular risk in patients with CKD, as several common risk­ modifying therapies have not shown benefit in this high­risk population of patients. additionally, factors of particular importance in CKD, such as albuminuria and bone and mineral metabolism, must be considered when managing patients at different stages of CKD. the conventional therapeutic approach to modifying cardio­vascular risk has evolved in populations with preserved kidney function. treatment paradigms targeted at both traditional and novel atherothrombotic risk factors must be evaluated in randomized trials in patients with CKD.

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2. shlipak, M. G. et al. Cardiovascular disease risk status in elderly persons with renal insufficiency. Kidney Int. 62, 997–1004 (2002).

3. Muntner, P., He, J., Astor, B. C., Folsom, A. r. & Coresh, J. Traditional and nontraditional risk

factors predict coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study. J. Am. Soc. Nephrol. 16, 529–538 (2005).

4. Manjunath, G. et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J. Am. Coll. Cardiol. 41, 47–55 (2003).

5. sarnak, M. J. et al. Kidney disease as a risk factor for development of cardiovascular

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6. vassalotti, J. A., stevens, L. A. & Levey, A. s. Testing for chronic kidney disease: a position statement from the National Kidney Foundation. Am. J. Kidney Dis. 50, 169–180 (2007).

Review criteria

we searched for pertinent papers published since 1990 in PubMed using combinations of the following terms: “cardiovascular risk”, “non-traditional cardiovascular risk factors”, “novel cardiovascular risk factors”, “chronic kidney disease”, “renal insufficiency”, “renal disease” and “hemodialysis”. Only full-text papers written in english were reviewed. Only relevant papers were included in this review, based on information in identified abstracts. The reference lists of identified papers were reviewed for relevant manuscripts.

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7. Brosius, F. C. 3rd et al. Detection of chronic kidney disease in patients with or at increased risk of cardiovascular disease: a science advisory from the American Heart Association Kidney and Cardiovascular Disease Council; the Councils on High Blood Pressure research, Cardiovascular Disease in the Young, and epidemiology and Prevention; and the Quality of Care and Outcomes research interdisciplinary working Group: Developed in Collaboration with the National Kidney Foundation. Hypertension 48, 751–755 (2006).

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57. Parving, H. H. et al. The effect of irbesartan on the development of diabetic nephropathy in

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