Post on 18-Jan-2023
nature reviews | cardiology aDvanCe OnLine PuBLiCatiOn | 1
reviews
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.
nrcardio_121_SEP09.indd 1 14/7/09 15:32:01
© 2009 Macmillan Publishers Limited. All rights reserved
2 | aDvanCe OnLine PuBLiCatiOn www.nature.com/nrcardio
reviews
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.
nrcardio_121_SEP09.indd 2 14/7/09 15:32:02
© 2009 Macmillan Publishers Limited. All rights reserved
nature reviews | cardiology aDvanCe OnLine PuBLiCatiOn | 3
reviews
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).
nrcardio_121_SEP09.indd 3 14/7/09 15:32:05
© 2009 Macmillan Publishers Limited. All rights reserved
4 | aDvanCe OnLine PuBLiCatiOn www.nature.com/nrcardio
reviews
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.
nrcardio_121_SEP09.indd 4 14/7/09 15:32:12
© 2009 Macmillan Publishers Limited. All rights reserved
nature reviews | cardiology aDvanCe OnLine PuBLiCatiOn | 5
reviews
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.
nrcardio_121_SEP09.indd 5 14/7/09 15:32:13
© 2009 Macmillan Publishers Limited. All rights reserved
6 | aDvanCe OnLine PuBLiCatiOn www.nature.com/nrcardio
reviews
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.
nrcardio_121_SEP09.indd 6 14/7/09 15:32:15
© 2009 Macmillan Publishers Limited. All rights reserved
nature reviews | cardiology aDvanCe OnLine PuBLiCatiOn | 7
reviews
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
nrcardio_121_SEP09.indd 7 14/7/09 15:32:16
© 2009 Macmillan Publishers Limited. All rights reserved
8 | aDvanCe OnLine PuBLiCatiOn www.nature.com/nrcardio
reviews
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.
1. Go, A. s., Chertow, G. M., Fan, D., McCulloch, C. e. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).
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
disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure research, Clinical Cardiology, and epidemiology and Prevention. Circulation 108, 2154–2169 (2003).
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.
nrcardio_121_SEP09.indd 8 14/7/09 15:32:16
© 2009 Macmillan Publishers Limited. All rights reserved
nature reviews | cardiology aDvanCe OnLine PuBLiCatiOn | 9
reviews
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).
8. National Kidney Foundation. K/DOQi clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 39 (Suppl. 1), s1–s266 (2002).
9. Fox, C. s. et al. Predictors of new-onset kidney disease in a community-based population. JAMA 291, 844–850 (2004).
10. King, H., Aubert, r. e. & Herman, w. H. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 21, 1414–1431 (1998).
11. Greenlund, K. J. et al. Trends in self-reported multiple cardiovascular disease risk factors among adults in the United states, 1991–1999. Arch. Intern. Med. 164, 181–188 (2004).
12. Coresh, J. et al. Prevalence of chronic kidney disease in the United states. JAMA 298, 2038–2047 (2007).
13. UsrDs 2008 Atlas volume 2 Figure 11.4. United State Renal Data System [online], http://www.usrds.org/2008/view/esrd_11.asp (2008). The data reported here have been supplied by the United states renal Data system (UsrDs). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the Us government.
14. Mann, J. F., Gerstein, H. C., Pogue, J., Bosch, J. & Yusuf, s. renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPe randomized trial. Ann. Intern. Med. 134, 629–636 (2001).
15. weiner, D. e. et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J. Am. Soc. Nephrol. 15, 1307–1315 (2004).
16. McCullough, P. A. et al. independent components of chronic kidney disease as a cardiovascular risk state: results from the Kidney early evaluation Program (KeeP). Arch. Intern. Med. 167, 1122–1129 (2007).
17. Culleton, B. F. et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int. 56, 2214–2219 (1999).
18. Dries, D. L. et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J. Am. Coll. Cardiol. 35, 681–689 (2000).
19. Fried, L. F. et al. renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J. Am. Coll. Cardiol. 41, 1364–1372 (2003).
20. Foley, r. N., Parfrey, P. s. & sarnak, M. J. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 32 (Suppl. 3), s112–s119 (1998).
21. elsayed, e. F. et al. Cardiovascular disease and subsequent kidney disease. Arch. Intern. Med. 167, 1130–1136 (2007).
22. shlipak, M. G. et al. Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. JAMA 293, 1737–1745 (2005).
23. Baber, U. et al. Non-traditional risk factors predict coronary calcification in chronic kidney disease in a population-based cohort. Kidney Int. 73, 615–621 (2008).
24. Parikh, N. i. et al. Cardiovascular disease risk factors in chronic kidney disease: overall burden and rates of treatment and control. Arch. Intern. Med. 166, 1884–1891 (2006).
25. shoji, T. et al. Advanced atherosclerosis in predialysis patients with chronic renal failure. Kidney Int. 61, 2187–2192 (2002).
26. Flack, J. M., Neaton, J. D., Daniels, B. & esunge, P. ethnicity and renal disease: lessons from the Multiple risk Factor intervention Trial and the Treatment of Mild Hypertension study. Am. J. Kidney Dis. 21 (Suppl. 1), 31–40 (1993).
27. weiner, D. e. et al. The Framingham predictive instrument in chronic kidney disease. J. Am. Coll. Cardiol. 50, 217–224 (2007).
28. weiner, D. e. et al. The relationship between nontraditional risk factors and outcomes in individuals with stage 3 to 4 CKD. Am. J. Kidney Dis. 51, 212–223 (2008).
29. Cheung, A. K. et al. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int. 58, 353–362 (2000).
30. Zager, P. G. et al. ‘U’ curve association of blood pressure and mortality in hemodialysis patients. Medical Directors of Dialysis Clinic, inc. Kidney Int. 54, 561–569 (1998).
31. Cooper, s. P. et al. The relation between degree of blood pressure reduction and mortality among hypertensives in the Hypertension Detection and Follow-Up Program. Am. J. Epidemiol. 127, 387–403 (1988).
32. Liu, Y. et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 291, 451–459 (2004).
33. Kilpatrick, r. D. et al. Association between serum lipids and survival in hemodialysis patients and impact of race. J. Am. Soc. Nephrol. 18, 293–303 (2007).
34. stidley, C. A. et al. Changing relationship of blood pressure with mortality over time among hemodialysis patients. J. Am. Soc. Nephrol. 17, 513–520 (2006).
35. Udayaraj, U. P. et al. Blood pressure and mortality risk on peritoneal dialysis. Am. J. Kidney Dis. 53, 70–78 (2009).
36. Jamison, r. L. et al. effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA 298, 1163–1170 (2007).
37. Kidney Disease Outcomes Quality initiative (K/DOQi) Group. K/DOQi clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am. J. Kidney Dis. 41 (Suppl. 3), i-iv, s1–s91 (2003).
38. [No authors listed] Third report of the National Cholesterol education Program (NCeP) expert Panel on Detection, evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel iii) final report. Circulation 106, 3143–3421 (2002).
39. Harper, C. r. & Jacobson, T. A. Managing dyslipidemia in chronic kidney disease. J. Am. Coll. Cardiol. 51, 2375–2384 (2008).
40. Heart Protection study Collaborative Group. MrC/BHF Heart Protection study of cholesterol
lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002).
41. Tonelli, M. et al. effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 110, 1557–1563 (2004).
42. shepherd, J. et al. intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J. Am. Coll. Cardiol. 51, 1448–1454 (2008).
43. Asselbergs, F. w. et al. effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation 110, 2809–2816 (2004).
44. Nishizawa, Y., shoji, T., ishimura, e., inaba, M. & Morii, H. Paradox of risk factors for cardiovascular mortality in uremia: is a higher cholesterol level better for atherosclerosis in uremia? Am. J. Kidney Dis. 38 (Suppl. 1), s4–s7 (2001).
45. seliger, s. L. et al. HMG-CoA reductase inhibitors are associated with reduced mortality in esrD patients. Kidney Int. 61, 297–304 (2002).
46. wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, 238–248 (2005).
47. Fellstrom, B. C. et al. rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N. Engl. J. Med. 360, 1395–1407 (2009).
48. Davidson, M. H., Armani, A., McKenney, J. M. & Jacobson, T. A. safety considerations with fibrate therapy. Am. J. Cardiol. 99, 3C–18C (2007).
49. Goldfarb-rumyantzev, A. s., Habib, A. N., Baird, B. C., Barenbaum, L. L. & Cheung, A. K. The association of lipid-modifying medications with mortality in patients on long-term peritoneal dialysis. Am. J. Kidney Dis. 50, 791–802 (2007).
50. siamopoulos, K. C. et al. Lipid parameters including lipoprotein (a) in patients undergoing CAPD and hemodialysis. Perit. Dial. Int. 15, 342–347 (1995).
51. Xue, J. L. et al. Peritoneal and hemodialysis: i. Differences in patient characteristics at initiation. Kidney Int. 61, 734–740 (2002).
52. Agodoa, L. Y. et al. effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 285, 2719–2728 (2001).
53. wright, J. T. Jr et al. effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AAsK trial. JAMA 288, 2421–2431 (2002).
54. Klahr, s. et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in renal Disease study Group. N. Engl. J. Med. 330, 877–884 (1994).
55. ruilope, L. M. et al. renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J. Am. Soc. Nephrol. 12, 218–225 (2001).
56. sarnak, M. J. et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann. Intern. Med. 142, 342–351 (2005).
57. Parving, H. H. et al. The effect of irbesartan on the development of diabetic nephropathy in
nrcardio_121_SEP09.indd 9 14/7/09 15:32:18
© 2009 Macmillan Publishers Limited. All rights reserved
10 | aDvanCe OnLine PuBLiCatiOn www.nature.com/nrcardio
reviews
patients with type 2 diabetes. N. Engl. J. Med. 345, 870–878 (2001).
58. Brenner, B. M. et al. effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).
59. [No authors listed] effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPe study and MiCrO-HOPe substudy. Heart Outcomes Prevention evaluation study investigators. Lancet 355, 253–259 (2000).
60. Agrawal, v., Marinescu, v., Agarwal, M. & McCullough, P. A. Cardiovascular implications of proteinuria: an indicator of chronic kidney disease. Nat. Rev. Cardiol. 6, 301–311 (2009).
61. Jafar, T. H. et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann. Intern. Med. 135, 73–87 (2001).
62. Johnson, D. w., Craven, A. M. & isbel, N. M. Modification of cardiovascular risk in hemodialysis patients: an evidence-based review. Hemodial. Int. 11, 1–14 (2007).
63. Kalantar-Zadeh, K., Block, G., Humphreys, M. H. & Kopple, J. D. reverse epidemiology of cardiovascular risk factors in maintenance dialysis patients. Kidney Int. 63, 793–808 (2003).
64. vlagopoulos, P. T. et al. Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J. Am. Soc. Nephrol. 16, 3403–3410 (2005).
65. Foley, r. N. et al. impact of hypertension on cardiomyopathy, morbidity and mortality in end-stage renal disease. Kidney Int. 49, 1379–1385 (1996).
66. Zannad, F. et al. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int. 70, 1318–1324 (2006).
67. Heerspink, H. J. et al. effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials. Lancet 373, 1009–1015 (2009).
68. Block, G. A., Hulbert-shearon, T. e., Levin, N. w. & Port, F. K. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am. J. Kidney Dis. 31, 607–617 (1998).
69. st Peter, w. L., Liu, J., weinhandl, e. & Fan, Q. A comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: a secondary
analysis of the Dialysis Clinical Outcomes revisited (DCOr) randomized trial using claims data. Am. J. Kidney Dis. 51, 445–454 (2008).
70. suki, w. N. et al. effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int. 72, 1130–1137 (2007).
71. Chertow, G. M., Burke, s. K. & raggi, P. sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 62, 245–252 (2002).
72. raggi, P. & Kleerekoper, M. Contribution of bone and mineral abnormalities to cardiovascular disease in patients with chronic kidney disease. Clin. J. Am. Soc. Nephrol. 3, 836–843 (2008).
73. Teng, M. et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J. Am. Soc. Nephrol. 16, 1115–1125 (2005).
74. Teng, M. et al. survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N. Engl. J. Med. 349, 446–456 (2003).
75. Tentori, F. et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int. 70, 1858–1865 (2006).
76. Palmer, s. C. et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann. Intern. Med. 147, 840–853 (2007).
77. Boaz, M. et al. secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (sPACe): randomised placebo-controlled trial. Lancet 356, 1213–1218 (2000).
78. Mann, J. F. et al. effects of vitamin e on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: results of the HOPe study. Kidney Int. 65, 1375–1380 (2004).
79. Tepel, M., van der Giet, M., statz, M., Jankowski, J. & Zidek, w. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Circulation 107, 992–995 (2003).
80. wrone, e. M. et al. randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J. Am. Soc. Nephrol. 15, 420–426 (2004).
81. Drueke, T. B. et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N. Engl. J. Med. 355, 2071–2084 (2006).
82. singh, A. K. et al. Correction of anemia with epoetin alfa in chronic kidney disease. N. Engl. J. Med. 355, 2085–2098 (2006).
83. Besarab, A. et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N. Engl. J. Med. 339, 584–590 (1998).
84. Fleischmann, e. H., Bower, J. D. & salahudeen, A. K. Are conventional cardiovascular risk factors predictive of two-year mortality in hemodialysis patients? Clin. Nephrol. 56, 221–230 (2001).
85. Becker, B. N., Himmelfarb, J., Henrich, w. L. & Hakim, r. M. reassessing the cardiac risk profile in chronic hemodialysis patients: a hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J. Am. Soc. Nephrol. 8, 475–486 (1997).
86. Takeda, A. et al. Discordance of influence of hypertension on mortality and cardiovascular risk in hemodialysis patients. Am. J. Kidney Dis. 45, 112–118 (2005).
87. Herzog, C. A., Littrell, K., Arko, C., Frederick, P. D. & Blaney, M. Clinical characteristics of dialysis patients with acute myocardial infarction in the United states: a collaborative project of the United states renal Data system and the National registry of Myocardial infarction. Circulation 116, 1465–1472 (2007).
88. wright, r. s. et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann. Intern. Med. 137, 563–570 (2002).
89. Patel, U. D. et al. Hospital performance and differences by kidney function in the use of recommended therapies after non-sT-elevation acute coronary syndromes. Am. J. Kidney Dis. 53, 426–437 (2009).
90. Goldberg, r. J., ismailov, r. M., Patlolla, v., Lessard, D. & spencer, F. A. Therapies for acute heart failure in patients with reduced kidney function: a community-based perspective. Am. J. Kidney Dis. 51, 594–602 (2008).
91. winkelmayer, w. C., Levin, r. & setoguchi, s. Associations of kidney function with cardiovascular medication use after myocardial infarction. Clin. J. Am. Soc. Nephrol. 3, 1415–1422 (2008).
92. Manjunath, G. et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int. 63, 1121–1129 (2003).
93. Tonelli, M., Moye, L., sacks, F. M., Kiberd, B. & Curhan, G. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann. Intern. Med. 138, 98–104 (2003).
94. Andreucci, v. e. et al. Dialysis Outcomes and Practice Patterns study (DOPPs) data on medications in hemodialysis patients. Am. J. Kidney Dis. 44, 61–67 (2004).
nrcardio_121_SEP09.indd 10 14/7/09 15:32:19
© 2009 Macmillan Publishers Limited. All rights reserved