Official reprint from UpToDate®

www.uptodate.com ©2013 UpToDate®

AuthorsMark Sarnak, MDC Michael Gibson, MS, MDWilliam L Henrich, MD, MACP

Section EditorsGary C Curhan, MD, ScDBernard J Gersh, MB, ChB, DPhil,FRCP, MACC

Deputy EditorJohn P Forman, MD, MSc

Chronic kidney disease and coronary heart disease

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Jun 2013. | This topic last updated: เม.ย. 3, 2556.

INTRODUCTION — Chronic kidney disease (CKD) is an independent risk factor for the development of coronary

artery disease, and for more severe coronary heart disease (CHD) [1-5]. CKD is also associated with adverse

outcomes in those with existing cardiovascular disease [6-8]. This includes increased mortality after an acute

coronary syndrome, after percutaneous coronary intervention (PCI) with or without stenting [9-16], and after

coronary artery bypass. In addition, patients with CKD are more likely to present with atypical symptoms, which

may delay diagnosis and adversely affect outcomes [17].

An overview of chronic kidney disease and coronary heart disease is presented in this topic review. Issues

related to coronary heart disease in patients with end-stage renal disease and general discussions of risk

factors for cardiovascular disease and interventions for secondary prevention are presented separately. (See

"Clinical manifestations and diagnosis of coronary heart disease in end-stage renal disease (dialysis)" and "Risk

factors and epidemiology of coronary artery disease in end-stage renal disease (dialysis)" and "Overview of the

risk equivalents and established risk factors for cardiovascular disease" and "Secondary prevention of

cardiovascular disease".)

CHRONIC KIDNEY DISEASE AS AN INDEPENDENT RISK FACTOR FOR CHD — Both decreased GFR and

increased proteinuria increase the risk of cardiovascular disease. These associations have been shown in both

community-based populations (ie, cohorts that were not selected specifically to enroll individuals with CKD or

cardiovascular disease), and in populations of patients at high cardiovascular risk (ie, cohorts in which patients

with preexisting cardiovascular disease or cardiovascular disease risk factors were specifically recruited).

Association between CKD and CHD in community-based populations — Numerous observational studies

have shown that a reduced glomerular filtration rate (GFR) and proteinuria are both independently associated

with an increased risk of cardiovascular events in community-based populations of patients who were not

selected based upon the presence of known kidney or cardiovascular disease [1,6,18-51].

The best data come from a meta-analysis of general population cohorts that included 105,872 participants with

urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants with urine protein dipstick

measurements; all had documented baseline estimated GFR [20]. Compared with participants whose estimated

GFR was 95 mL/min/1.73 m2, hazard ratios (HR) for all-cause mortality during 7.9 years of follow-up were 1.18

(95% CI 1.05-1.32), 1.57 (95% CI 1.39-1.78), and 3.14 (95% CI 2.39-4.13) for estimated GFRs of 60, 45, and 15

mL/min per 1.73 m2, respectively. Similar outcomes were observed for cardiovascular mortality, and similar

results were obtained in older and younger individuals (age greater than 65 years versus 65 years or less). A

higher risk for all-cause mortality was observed at estimated GFRs greater than 105 mL/min per 1.73 m2;

however, this association may reflect either reduced muscle mass from ill health leading to a lower creatinine

value, or a high prevalence of individuals with diabetes or obesity causing hyperfiltration and a low creatinine

[52].

Proteinuria was independently associated with increased all-cause and cardiovascular mortality in this study.

Compared to an albumin-to-creatinine ratio (ACR) of 0.6 mg/mmol (6 mg/g), the adjusted hazard ratio for all-

cause mortality was 1.20 (95% CI 1.15-1.26); 1.63 (95% CI 1.50-1.77); and 2.20 (95% CI 1.97-2.51) for ACRs of

1.1 (10 mg/g); 3.4 (30 mg/g); and 33.9 mg/mmol (300 mg/g), respectively. Similar findings were observed for

cardiovascular mortality. An ACR greater than 3.4 mg/mmol (30 mg/g) was associated with a greater than

twofold mortality risk for all levels of estimated GFR except the lowest (<30 mL/min per 1.73 m2). Among

participants with dipstick determination of proteinuria, a trace urine positive dipstick was also associated with

increased all-cause and cardiovascular mortality for all levels of kidney function, although large heterogeneity

was present between studies that provided only dipstick measurement of protein.

Given that CKD alone appears to increase the risk of CHD in the general population, it is not surprising that the

Framingham risk score, the traditional method to analyze future cardiovascular risk among individuals without

CKD, provides poor overall accuracy in predicting cardiovascular events in patients with CKD [53]. This may be

partly due to the markedly increased cardiac event rate and overall death rate among such patients. Although

altering the Framingham risk equations may increase their predictive accuracy, new prediction equations must

be developed to help predict future events among patients with CKD.

Despite the preponderance of evidence in favor of an increase in risk with CKD alone, a few studies have found

that less severe renal disease is not an independent risk factor for adverse cardiovascular outcomes [54,55].

Association between CKD and CHD among those at high cardiovascular risk — Numerous secondary

analyses of studies that enrolled patients with known risk factors for cardiovascular disease (such as

hypertension and diabetes), or preexisting cardiovascular disease, have shown that the presence or

development of various degrees of renal dysfunction is independently associated with cardiovascular events

[18,50,51,56-66].

The magnitude of this association was illustrated in a collaborative meta-analysis of 10 cohorts with 266,975

patients who had hypertension, diabetes, cardiovascular disease, or a combination of these disorders [56].

Compared with a reference estimated GFR of 95 mL/min per 1.73 m2, the hazard ratios for cardiovascular

mortality were 1.11 for an estimated GFR of 60 mL/min per 1.73 m2, 1.73 for an estimated GFR of 45 mL/min

per 1.73 m2, and 3.08 for an estimated GFR of 15 mL/min per 1.73 m2. Similar findings were noted for all-cause

mortality, and the associations were similar in younger and older patients. A monotonic association between

higher ACR and risk of both cardiovascular and all-cause mortality was also noted.

Even if CKD is an independent risk factor for cardiovascular disease among patients already at high

cardiovascular risk, it may not substantially improve the ability to risk-stratify patients beyond traditional risk

factors. This was shown in a pooled analysis of 27,620 patients in two randomized trials [67]. Lower GFRs and

higher urinary albumin excretions were each independent risk factors for cardiovascular events and death,

although their addition to a model with traditional cardiovascular risk factors did not significantly enhance the

model's ability to predict events.

CKD as a CHD risk equivalent — The above evidence that mild to moderate CKD is associated with an

adverse cardiovascular prognosis led both the National Kidney Foundation and the American College of

Cardiology/American Heart Association to recommend that CKD be considered a CHD risk equivalent [1,68-71].

Consistent with this, the number of cardiovascular events attributable to CKD in the Alberta Kidney Disease

Network and Atherosclerosis Risk In Communities (ARIC) studies were comparable to the number of events

attributable to diabetes, another factor considered to be a CHD risk equivalent [35,72].

In addition, the nine-year rates of cardiovascular death among 1899 individuals in the Cardiovascular Health

Study (CHS) were as follows (CKD was defined as an eGFR less than 60 mL/min per 1.73 m2) [73]:

History of myocardial infarction, but no diabetes or CKD: 15.7 percent

History of diabetes, but no myocardial infarction or CKD: 15.8 percent

History of CKD, but no myocardial infarction or diabetes: 13 percent

Although CKD was a powerful risk factor for cardiovascular disease in these and other studies, the

generalization that CKD is a CHD risk equivalent for all persons with CKD may not be warranted for several

reasons:

Some studies contradict the concept that CKD is a CHD risk equivalent. In the Alberta Kidney Disease

Network cohort, for example, the four-year incidence of myocardial infarction was nearly threefold higher

among those who had a prior history of myocardial infarction (7.7 percent) compared with those without a

prior history of myocardial infarction but who had CKD (2.8 percent) [72]. The incidence of myocardial

infarction among those who had a prior history of myocardial infarction but no diabetes and no CKD was

more than twice the incidence among those with CKD but not prior myocardial infarction. Similarly, a

secondary analysis from the ARIC study suggested that the risk associated with CKD was not

comparable to the risk associated with a prior myocardial infarction [74].

The risk of heart disease in those with CKD appears to vary based upon absolute level of renal function

and degree of proteinuria, as well as the rate at which these factors change. The simultaneous presence

of both decreased renal function and increased proteinuria further enhance the risk for cardiovascular

disease compared with the risk associated with either problem alone [19-21,56,72]. In addition, the rate

of decline of kidney function and the rate of increase of proteinuria also correlate with varying risks of

adverse cardiovascular events [75-77].

Even patients with the same degree of renal dysfunction may not have the same risk of cardiovascular

disease, since the risk of cardiovascular disease in a patient with CKD is in part related to the presence

and extent of significant comorbidities. As an example, the overall risk for a 25-year-old nonsmoking man

with moderate CKD due to IgA nephropathy is not the same as that of a 65-year-old man with a similar

degree of CKD but with a long history of smoking, hypertension, and elevated serum cholesterol levels.

Thus, the proper assessment of overall cardiovascular risk in patients with CKD requires an adequate

assessment for the presence and severity of the other major risk factors for cardiovascular disease. (See

"Overview of the risk equivalents and established risk factors for cardiovascular disease".)

The concept of CHD risk equivalency was developed by expert panels as a means to help clinicians make

decisions about how aggressively to treat their patients to prevent CHD [78]. As an example, while it is fairly

simple to identify a patient who has diabetes or CKD, and thus institute aggressive therapy for secondary

prevention of CHD, it is more cumbersome to calculate every patient's 10-year cardiovascular risk. About half of

adults in the United States with CKD have another CHD risk equivalent, specifically a prior history of myocardial

infarction or stroke, diabetes, angina, or a calculated Framingham 10-year CHD risk greater than 20 percent

[79]. Thus, the question of whether CKD is a CHD risk equivalent is germane to whether millions of additional

patients with CKD should receive aggressive therapy to lower their LDL cholesterol and blood pressure, and

whether they should receive antiplatelet therapy. These issues are discussed in detail below. (See 'Reduction of

CHD risk in patients with CKD' below.)

Limitations of the data — One possible limitation in nearly all of the above reports is that kidney function was

indirectly estimated. Since the various estimates provide results that may differ from each other, the association

between kidney function and cardiovascular risk is affected by the method selected to estimate kidney function.

The association may be further compromised because some of the formulas utilized are based directly upon

variables linked with cardiovascular risk, such as age, weight, and body mass index.

This difficulty was shown using data from 8592 participants in the PREVEND study, in which the association

between various cardiovascular risk factors and kidney function was examined [80,81]. Kidney function was

estimated using creatinine clearance (based upon two 24-hour urine collections), and the Cockcroft-Gault and

Modification of Diet in Renal Disease (MDRD) formulas [80]; the various cardiovascular risk factors examined

included blood pressure, serum cholesterol and glucose levels, age, sex, weight, waist-to-hip ratio, and body

mass index. (See "Assessment of kidney function", section on 'Estimation equations'.)

Markedly different relationships emerged when each method for estimating kidney function was plotted against

each cardiovascular risk factor. These varied relationships were most pronounced for age, weight, and body

mass index, and less pronounced (but still statistically significant) for blood pressure, and serum cholesterol

and glucose levels. As a result, caution must be exercised when studying the relationships among

cardiovascular risk factors, indirect estimates of kidney function, and cardiovascular risk.

Cystatin C and other markers of kidney function — Another potential limitation of kidney function

estimates in the vast majority of studies mentioned above is that level of glomerular filtration rate (GFR) may not

be accurately assessed using creatinine-based questions, particular in those with estimated GFR values greater

than 60 mL/min/1.73 m2. In these individuals, cystatin C and other markers of kidney function (such as beta-

trace protein and beta-2-microglobulin) may be a more sensitive measures of decreased GFR, and also more

strongly associated with fatal and nonfatal cardiovascular events than creatinine and creatinine-based estimated

of GFR [41-48,82]. As an example, the risk of death relative to the cystatin C concentration increased in a dose-

response fashion in one study [41]. Relative to the first quintile, the adjusted hazard ratio of cardiovascular death

for the third, fourth and fifth quintiles (the fifth quintile further subdivided into thirds) of cystatin C levels were

1.93, 1.99, and 2.48 to 2.83, respectively. By comparison, a significant association with adverse outcomes was

only observed among those in the lowest quintile of GFR estimated from the plasma creatinine concentration.

(See "Assessment of kidney function", section on 'Serum cystatin C'.)

These results suggest that elevated plasma cystatin C concentration may be a more accurate measure of

cardiovascular risk than elevated plasma creatinine concentration. However, some have postulated that non-

renal determinants of cystatin C levels, such as increased inflammation and other cardiovascular factors, may

underlie this association. In addition, cystatin C is not routinely used.

PRESENCE OF TRADITIONAL AND NONTRADITIONAL CARDIOVASCULAR RISK FACTORS IN

CKD — Patients with CKD often have numerous traditional and nontraditional risk factors for the development of

cardiovascular disease. Traditional risk factors appear to be associated with much larger absolute increases in

risk in the earlier stages of CKD [83].

Traditional risk factors — Traditional cardiovascular risk factors, such as hypertension (which may be

accompanied by left ventricular hypertrophy), smoking, diabetes, dyslipidemia and older age, are highly

prevalent in CKD populations [1,84,85]. The number of cardiovascular risk factors appears to correlate with the

severity of kidney dysfunction [85]. These are discussed in greater detail elsewhere. (See "Overview of

hypertension in acute and chronic kidney disease" and "Overview of the risk equivalents and established risk

factors for cardiovascular disease".)

Patients with CKD are also more likely to have the metabolic syndrome, which could contribute to the increase

in cardiovascular risk [3,86]. This syndrome is defined as some combination of insulin resistance, dyslipidemia,

elevated serum glucose, abdominal obesity, and hypertension. (See "The metabolic syndrome (insulin

resistance syndrome or syndrome X)".)

Nontraditional risk factors — Possible risk factors that are relatively unique to patients with moderate to

severe CKD include retention of uremic toxins, anemia, elevated levels of certain cytokines, increased calcium

intake, abnormalities in bone mineral metabolism, and/or an "increased inflammatory-poor nutrition" state [4,87].

How these risk factors may lead to cardiovascular disease is unclear. As an example, disorders of bone mineral

metabolism in patients with CKD have often been linked to coronary artery calcification. However, while there is

a consistent association between CKD and a higher burden of coronary artery calcification, the associations

among phosphorus, calcium, and parathyroid hormone with coronary artery calcification in these patients is

inconsistent [88-90]. (See "Risk factors and epidemiology of coronary artery disease in end-stage renal disease

(dialysis)" and "Inflammation in renal insufficiency" and "Diagnostic and prognostic implications of coronary

artery calcification detected by computed tomography".)

Elevated levels of C-reactive protein (CRP) and asymmetric dimethylarginine, both of which are typically found in

patients with CKD, were both independently associated with an increased risk of all cause and cardiovascular

mortality in the Modification of Diet in Renal Disease study [91,92], although a similar relation between CRP and

cardiovascular disease was not observed in the Irbesartan for Diabetic Nephropathy trial [93].

Hyperhomocysteinemia has also been inconsistently associated with increased cardiovascular risk [94-96].

There is also a relationship between cardiovascular disease and microalbuminuria among nondiabetic patients

with normal estimated glomerular filtration rate. However, some disagree with the K/DOQI and KDIGO working

groups that isolated microalbuminuria (ie, without a reduction in glomerular filtration rate or some other renal

abnormality) necessarily reflects kidney disease among nondiabetic patients [68]. It correlates best with

generalized endothelial dysfunction and is associated with an increase in cardiovascular risk. (See "Overview of

the management of chronic kidney disease in adults", section on 'Definition and classification' and "High

albuminuria (microalbuminuria) and cardiovascular disease".)

COMPETING RISKS OF CARDIOVASCULAR AND END-STAGE RENAL DISEASE — Morbidity and mortality

from cardiovascular disease among those with CKD is high. The risk of death, particularly due to cardiovascular

disease, is typically higher than the risk of eventually requiring renal replacement therapy. However, this risk

varies with age and other factors. In many studies, older patients with less severe CKD and lower levels of

proteinuria are more likely to die (usually due to cardiovascular disease) before needing renal replacement

therapy, while younger patients with proteinuria and diseases localized to the kidney are more likely to

ultimately need renal replacement therapy [18,63,97-101]. This is illustrated by the following examples:

The following three studies largely include older patients identified through Medicare participation or

through the Veteran's Affairs Network:

In a study of over 1,000,000 individuals enrolled in the Medicare program in the United States,

outcomes were reported for several groups, including those with CKD but no diabetes (2.2 percent)

and both CKD and diabetes (1.6 percent) [18]. After two years of follow-up, the rates for requiring

renal replacement therapy were 1.6 and 3.4 per 100 patient-years for patients with CKD alone and

those with both disorders, respectively; by comparison, the death rates were 17.7 and 19.9 per 100

patient-years. In addition, rates for atherosclerotic vascular disease for these two groups were 35.7

and 49.1, while heart failure rates were 30.7 and 52.3, respectively.

A longitudinal follow-up of nearly 30,000 older patients with estimated glomerular filtration rates

(GFRs) of less than 90 mL/min per 1.73 m2 reported the rate of renal replacement and death at five

years [97]. The rate of renal replacement therapy in those with stage 2, 3, or 4 disease was 1.1, 1.3,

and 19.9 percent, respectively; by comparison, the mortality rate was 19.5, 24.3, and 45.7 percent.

A higher incidence of coronary artery disease, heart failure, diabetes mellitus, and anemia was noted

in those who died.

In a report of over 12,000 older patients with diabetes, 48 percent had CKD defined as GFR less than

60 mL/min per 1.73 m2, or proteinuria [98]. After three years of follow-up, mortality rates were 6, 10,

20 and 30 percent for patients with CKD stages 2, 3, 4 and 5, respectively, compared to 5 percent

for those with preserved kidney function at baseline. Rates of progression to end-stage renal disease

(ESRD) were much lower, less than 1 percent for stages 2 and 3, and 14 percent for stage 4.

The nondiabetic patients enrolled in the MDRD study included a broad range of ages, causes of kidney

disease, baseline GFR, and baseline protein excretion. After nearly 12 years of follow-up, 936 patients

(56 percent) developed ESRD, and 369 (22 percent) died [102]. Death prior to ESRD was more likely to

occur in older as compared with younger individuals. In those patients older than 65 years, for example,

42 percent developed ESRD and 22 percent died before developing ESRD. However, in those 45 years or

younger, 65 percent developed ESRD and less than 1 percent died before developing ESRD.

The following are two studies with long-term observations from two cohorts of younger individuals with

type 1 diabetes and nephropathy:

The rate of ESRD incidence was substantially greater than the mortality rate (35.5 versus 9.5

percent) in a cohort of 592 young (median age 42 years) patients with type 1 diabetes followed for 10

years [99]. All patients in this study had at least 300 mg/day of proteinuria, and 60 percent of

patients had an estimated GFR less than 60 mL/min per 1.73 m2.

Similar results were observed in cohort of 423 young (median age 39 years) patients with type 1

diabetes, at least 300 mg/day of proteinuria, and a median baseline estimated GFR of 66 mL/min per

1.73 m2 [100]. During 15 years of follow-up, 41 percent of patients developed ESRD, while 7 percent

died without developing ESRD.

Although these data suggest that age differences determine whether or not patients with CKD will develop

ESRD before dying, this observation may be biased by study design. Patients enrolled into studies of

cardiovascular disease tend to be older and have less severe kidney disease than patients enrolled into studies

of kidney disease. In addition, older patients with severe renal dysfunction are more likely to develop ESRD

before dying, as was observed in 3228 older individuals with type 2 diabetes and nephropathy (mean age 59

years, estimated GFR 44 mL/min per 1.73 m2, and mean urine albumin-to-creatinine ratio 1.37 g/g) [103].

REDUCTION OF CHD RISK IN PATIENTS WITH CKD — In patients without CKD, risk factor modification and

beneficial lifestyle changes can substantially decrease morbidity and mortality in those with coronary,

cerebrovascular, or peripheral artery disease. These modalities include therapy with statins, control of

hypertension, cessation of smoking, maintaining ideal body weight and an active lifestyle, glycemic control in

diabetes, and the use of aspirin. A review of the data supporting these interventions is presented in detail

separately. (See "Secondary prevention of cardiovascular disease".)

In the past, patients with CKD were largely excluded from clinical trials of patients with coronary artery disease.

A 2006 survey of the published literature noted that 75 percent of coronary artery disease trials excluded

patients with CKD and only 7 percent reported baseline renal function [104]. Similar observations were reported

in a contemporaneous survey [105]. However, randomized trials have subsequently been performed specifically

in patients with CKD, particularly regarding statin therapy. (See 'CKD as a CHD risk equivalent' above.)

As noted above, we do not agree with the generalization that CKD is a CHD risk equivalent for all persons with

CKD. Our approach is instead based upon the available data and an assessment of future cardiovascular risk.

This evidence, which is presented below, supports the following approach to reduce the risk of atherosclerotic

cardiovascular disease in most patients with CKD not requiring dialysis:

Statin therapy (see 'Statin therapy' below).

In patients with proteinuric CKD (defined as proteinuria greater than 500 to 1000 mg/day), we recommend

angiotensin blockade as part of the antihypertensive regimen and a goal blood pressure of less than

130/80 mmHg. In patients with non-proteinuric CKD, we recommend a goal blood pressure of less than

140/90 mmHg. (See 'Blood pressure control' below.)

Low-dose aspirin therapy (see 'Antiplatelet therapy' below).

In all patients, smoking cessation, maintenance of an ideal body weight, an active lifestyle, and, in

patients with diabetes, glycemic control. (See 'Other issues' below.)

The KDIGO guidelines also consider persistent proteinuria, including microalbuminuria, to be part of CKD and

therefore associated with increased CHD risk even if estimated GFR is normal. We do not agree with applying

this paradigm to all patients. As an example, it is unknown whether a 25-year-old nonsmoker with IgA

nephropathy, normal serum creatinine concentration, and normal blood pressure is at increased cardiovascular

risk in the absence of progressive disease. Such patients should clearly be followed carefully and patient values

should be taken into account when considered how aggressively one would modify coronary risk factors. Issues

related to microalbuminuria are discussed separately. (See "High albuminuria (microalbuminuria) and

cardiovascular disease".)

Secondary prevention of cardiovascular disease and management of coronary artery disease in patients with

end-stage renal disease on maintenance dialysis or those with a kidney transplant are discussed elsewhere.

(See "Secondary prevention of cardiovascular disease in end-stage renal disease (dialysis)" and "Treatment of

coronary heart disease in end-stage renal disease (dialysis)" and "Hypertension after renal transplantation" and

"Lipid abnormalities after renal transplantation".)

Statin therapy — Most evidence for the use of statins in patients with mild to moderate CKD comes from post-

hoc sub-group analyses of randomized trials that were not intended to include patients with decreased kidney

function. (See "Lipid abnormalities in patients with chronic kidney disease not requiring dialysis", section on

'Cholesterol lowering with a statin'.) One randomized trial, the Study of Heart and Renal Protection (SHARP)

trial, specifically evaluated cholesterol lowering with a statin to prevent major vascular events in patients with

CKD.

The findings from the SHARP trial echoed the observations made in CKD subgroups from other randomized

trials: treatment of patients with CKD not requiring dialysis with a statin leads to a significant reduction in

cardiovascular events. Patients who received statin therapy in SHARP also received ezetimibe, although it is not

clear if ezetimibe contributed to the clinical benefit. A detailed discussion of these findings and

recommendations regarding statin use in CKD are presented elsewhere. (See "Lipid abnormalities in patients

with chronic kidney disease not requiring dialysis", section on 'Cholesterol lowering with a statin'.)

However, these trials mainly enrolled older patients with various comorbid conditions such as smoking,

diabetes, and hypertension. Whether statin therapy would be beneficial in younger patients who have CKD due

to primary kidney disease (such as IgA nephropathy or autosomal dominant polycystic kidney disease) rather

than a systemic disease (such as diabetes) is unclear. We would initiate statin therapy in patients who have an

estimated GFR less than 60 mL/min per 1.73 m2 if they are older than 40 years of age, since such patients are

similar to those enrolled in the SHARP trial. In addition, we suggest initiating statin therapy in patients with CKD

who have additional cardiovascular risk factors such as smoking, diabetes, hypertension, and proteinuria.

A related issue is whether statins provide cardiovascular protection due in part to their pleiotropic effects that are

independent of lipid-lowering in patients with and without CKD. (See "Mechanisms of benefit of lipid-lowering

drugs in patients with coronary heart disease".)

There are as yet no trials that have compared cardiovascular outcomes among patients with dyslipidemia who

were randomly assigned to specific target lipid levels rather than specific statin doses. When the results of

multiple trials are considered, each using a fixed atorvastatin dose, the rate of major cardiovascular events falls

linearly with the reduction in LDL cholesterol [106]. However, there is as yet no good evidence that titrating

statin therapy to achieve specific target LDL levels in patients at increased cardiovascular risk is associated

with improved cardiovascular outcomes. (See "Intensity of lipid lowering therapy in secondary prevention of

coronary heart disease", section on 'Statin dose versus goal LDL'.)

Although the evidence is weak, there are also data suggesting that lipid-lowering with statins may be associated

with a slower rate of loss of glomerular filtration rate in patients with mild to moderate CKD. (See "Statins and

chronic kidney disease", section on 'Statins and kidney function'.)

Blood pressure control — Numerous trials of patients with primary hypertension (formerly called "essential"

hypertension) have shown that blood pressure control improves cardiovascular outcomes. (See "Hypertension:

Who should be treated?".)

Post-hoc analyses of CKD subgroups from cardiovascular trials suggests that antihypertensive therapy

(typically with ACE inhibitors) reduces the risk of cardiovascular events [57,64,107]. The PROGRESS trial of

6105 patients with a prior stroke or transient ischemic attack, for example, compared the effect of perindopril-

based antihypertensive therapy with placebo; only one-half of patients were hypertensive [64]. A post hoc

analysis evaluated the 29 percent of patients with a creatinine clearance less than 60 mL/min. Antihypertensive

therapy reduced the risk of risk of all major cardiovascular events by 35 percent in the patients with CKD,

preventing one event among every 11 patients treated for five years. (See "Antihypertensive therapy to prevent

recurrent stroke or transient ischemic attack", section on 'PROGRESS trial'.)

The goal blood pressure is similar for patients with diabetic and non-diabetic CKD, differing primarily based upon

the presence or absence of proteinuria. The evidence for a lower blood pressure goal is stronger in patients with

proteinuric CKD. These issues are presented in detail elsewhere. (See "Antihypertensive therapy and

progression of nondiabetic chronic kidney disease in adults", section on 'Blood pressure goal' and "Treatment of

hypertension in patients with diabetes mellitus", section on 'Goal blood pressure'.)

Goal blood pressure in non-proteinuric CKD is a separate issue. There are no reliable data demonstrating that

targeting blood pressure to below 130/80 mmHg reduces the risk of progressive kidney failure or cardiovascular

disease. As a result, we recommend that a blood pressure of less than 140/90 mmHg be achieved in patients

with non-proteinuric CKD. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease

in adults", section on 'Blood pressure goal' and "Treatment of hypertension in patients with diabetes mellitus",

section on 'Goal blood pressure'.)

The desired degree of blood pressure control can usually be safely achieved with combined therapy. In

proteinuric patients, the regimen should include an ACE inhibitor or angiotensin II receptor blocker. (See

"Overview of hypertension in acute and chronic kidney disease", section on 'Choice of antihypertensive therapy'

and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Antiplatelet therapy — Long-term aspirin therapy reduces the risk of subsequent myocardial infarction (MI),

stroke, and vascular death among patients without CKD, but with a wide range of prior manifestations of

cardiovascular disease. (See "Benefits and risks of aspirin in secondary and primary prevention of

cardiovascular disease".)

There are fewer data related to the effectiveness and safety of antiplatelet therapy in patients with CKD

[108,109]. The best data come from a meta-analysis of 27,139 patients with CKD who participated in 50

randomized trials that tested the efficacy of antiplatelet agents (mostly aspirin) for prevention of CVD [108].

Antiplatelet therapy significantly reduced the incidence of fatal or nonfatal myocardial infarction as compared

with either placebo or no therapy (6.7 versus 7.0 percent, or 3 myocardial infarctions prevented for every 1000

patients treated). However, antiplatelet therapy also significantly increased the rate of major bleeding (4.4 versus

2.9 percent, or 15 additional major bleeding events for every 1000 patients treated). Antiplatelets had no effect

on stroke or mortality. The results were similar in patients of all CKD stages.

Based upon these data, we suggest that decisions about antiplatelet therapy to prevent cardiovascular disease

in patients with CKD be individualized depending upon the patient's overall risk for CHD (for example, a prior

history of myocardial infarction) and for bleeding, and also upon their preferences. This suggestion is broadly

consistent with guidelines made by the Kidney Disease Improving Global Outcomes (KDIGO) report on the

management of CKD [110]. (See "Benefits and risks of aspirin in secondary and primary prevention of

cardiovascular disease".)

In addition to cardiovascular disease, aspirin therapy may reduce the risk of cancer incidence. This should also

be considered in the decision about whether or not to use aspirin in patients with CKD. (See "Aspirin in the

primary prevention of cardiovascular disease and cancer".)

The prescription of low-dose aspirin is probably safe in most patients with CKD. The K/DOQI clinical practice

guidelines for controlling the epidemic of CV disease in CRD, as well as other K/DOQI guidelines, can be

accessed through the National Kidney Foundation's web site at

www.kidney.org/professionals/kdoqi/guidelines.cfm.

Other issues — In general, similar considerations apply to patients with and without renal dysfunction

concerning interventions for cessation of smoking, maintaining ideal body weight and an active lifestyle, and

glycemic control in diabetes. Recommendations concerning these issues are presented separately. (See

"Secondary prevention of cardiovascular disease".)

Measures aimed at correcting other nontraditional cardiovascular risk factors in those with CKD, such as

anemia, calcium-phosphate disorders, systemic inflammation and increased oxidative stress, may also improve

cardiovascular outcomes. This is also discussed separately. (See "Erythropoietin for the anemia of chronic

kidney disease among predialysis and peritoneal dialysis patients" and "Erythropoietin for the anemia of chronic

kidney disease in hemodialysis patients" and "Treatment of hyperphosphatemia in chronic kidney disease" and

"Overview of the management of chronic kidney disease in adults".)

TREATMENT OF CORONARY HEART DISEASE — Patients with CKD require drug dose adjustments and have

a higher risk of drug-related adverse effects. Despite the increased risk of adverse effects, the treatments used

for established coronary heart disease and acute coronary syndrome that are used in patients with normal

kidney function (eg, revascularization) may have similar benefits in patients with CKD. (See "Overview of the

care of patients with stable ischemic heart disease" and "Overview of the acute management of unstable angina

and non-ST elevation myocardial infarction" and "Overview of the acute management of ST elevation myocardial

infarction" and "Initial evaluation and management of suspected acute coronary syndrome in the emergency

department" and "Overview of the non-acute management of unstable angina and non-ST elevation myocardial

infarction" and "Coronary arteriography and revascularization for unstable angina or non-ST elevation acute

myocardial infarction" and "Coronary artery bypass graft surgery after acute ST elevation myocardial infarction".)

Multiple studies have reported that medical therapy commonly used in patients without CKD is employed

significantly less frequently in patients with CKD [13,14,111-116]. As an example, a study of 889 patients with

an acute coronary syndrome (ACS) evaluated the association between renal dysfunction, defined as an

estimated GFR below 60 mL/min per 1.73 m2, and in-hospital management and outcomes [14]. Renal

dysfunction was associated with a lower likelihood of receiving percutaneous coronary intervention, and a

reduction in the use of a GP IIb/IIIa inhibitor, although the frequency of coronary artery bypass grafting was

similar in those with and without renal dysfunction. Less frequent utilization of angiography, revascularization,

and standard medical therapy (eg, angiotensin converting enzyme inhibitors, beta blockers) in CKD patients

after ACS has also been observed in other studies [115,116].

However, it is not clear that the usual treatments used in patients with normal renal function should be

universally applied in patients with CKD. As an example, a meta-analysis of 9969 CKD patients who were

having an ACS or percutaneous coronary intervention found that the use of glycoprotein IIb/IIIa inhibitors or

clopidogrel increased major bleeding episodes without preventing cardiovascular events or death [109].

PROGNOSIS OF CORONARY HEART DISEASE IN PATIENTS WITH CKD — A pervasive finding among

patients who suffer coronary events or who have coronary interventions is that those with impaired kidney

function have a worse prognosis. The mechanisms which underlie the poor prognosis in patients with CKD are

not entirely clear.

One possibility is that patients who have a coronary event and abnormal kidney function are more likely to have

other predictors of adverse outcomes such as older age, hypotension, and lower body weight; these factors may

confound the associations observed in the various studies despite statistical adjustment. A second potential

explanation is that the adverse outcome (eg, death, recurrent vascular event) ascribed to worse kidney function

may instead reflect a more severe acute coronary syndrome (ACS). Because only baseline creatinine values (at

the time of presentation with an ACS) were used in most studies to define the presence of CKD, patients with

hemodynamic compromise would have been more likely to be defined as having CKD. The formulas used to

estimate GFR based upon serum creatinine are predicated on there being a stable creatinine concentration.

(See "Assessment of kidney function".)

Prognosis after acute coronary syndrome — An adverse association between mild to moderate renal

dysfunction and cardiovascular prognosis in patients with ACS has been reported, both in patients with ST

elevation myocardial infarction and non-ST elevation ACS. This is discussed in detail elsewhere. (See "Risk

factors for adverse outcomes after non-ST elevation acute coronary syndromes", section on 'Chronic kidney

disease' and "Risk factors for adverse outcomes after ST-elevation myocardial infarction", section on 'Chronic

kidney disease'.)

Prognosis after CABG — Although there are some reports of equivalent outcomes [117], most studies

demonstrate that decreased kidney function at the time of coronary artery bypass grafting (CABG) is associated

with higher risk of adverse outcomes [111,118]. As a consequence, renal function is included in a commonly

used risk prediction algorithm for cardiac surgical mortality (table 1). (See "Operative mortality after coronary

artery bypass graft surgery", section on 'Chronic kidney disease'.)

In-hospital complication rates and in-hospital as well as long-term mortality are highest among patients on

dialysis [119-122]. (See "Treatment of coronary heart disease in end-stage renal disease (dialysis)".)

Patients with CKD who develop acute kidney injury after CABG may require temporary or permanent dialysis.

This issue is discussed elsewhere. (See "Early noncardiac complications of coronary artery bypass graft

surgery", section on 'Acute kidney injury'.)

Prognosis after PCI — The presence of even mild CKD appears to predict an adverse prognosis after

percutaneous coronary intervention (PCI) with or without stenting [15,16,123-126], and renal function is

incorporated into a commonly used risk score that predicts one-year mortality following PCI in patients with

acute myocardial infarction (table 2). (See "Primary percutaneous coronary intervention in acute ST elevation

myocardial infarction: Determinants of outcome", section on 'Other risk factors' and "Intracoronary stent

restenosis", section on 'Chronic kidney disease'.)

The observation that revascularization for restenosis is required less frequently when stents are deployed has

been made in patients with CKD as it has in patients with normal renal function [127]. In addition, CKD does not

appear to mitigate the angiographic benefits observed with drug-eluting stents [128,129]. (See "Drug-eluting

intracoronary stents: General principles".)

A separate issue is whether the presence of CKD is associated with higher rates of restenosis. While some

studies have found an increased risk of restenosis in patients with CKD [126,130], other studies have reported

that CKD is not associated with increased restenosis [123,128].

PCI versus CABG in patients with CKD — No studies have compared outcomes with PCI versus CABG

specifically in patients with moderate to severe CKD. The relative efficacies of PCI with stenting and CABG in

patients with mild CKD was addressed in a subgroup analysis from the ARTS trial, which compared multivessel

PCI with bare metal stenting to CABG in patients with stable angina. Among the 1205 patients, 290 had CKD

as defined by an estimated creatinine clearance ≤60 mL/min (mean 50 mL/min) [124]. A more complete

description of this study is discussed elsewhere. (See "Bypass surgery versus percutaneous intervention in the

management of stable angina pectoris: Clinical studies", section on 'ARTS I trial'.)

After three years of follow-up, the rate of the primary composite end point of death, myocardial infarction, or

stroke was similar with PCI and CABG (adjusted hazard ratio 0.93) but, as in the patients without CKD, CABG

was associated with a much lower risk of subsequent revascularization (RR 0.28, 95% CI 0.14-0.54) [124]. This

difference persisted at five years, as the rate of a second revascularization procedure remained higher with PCI

than CABG (19 versus 8 percent) [131].

However, the applicability of the findings in ARTS to current practice is uncertain given the widespread use of

drug-eluting stents. Uncontrolled observations from ARTS II suggested that outcomes with drug-eluting stents

approached those with CABG but data in patients with CKD are not available. (See "Drug-eluting intracoronary

stents: General principles" and "Bypass surgery versus percutaneous intervention in the management of stable

angina pectoris: Clinical studies", section on 'ARTS I trial'.)

INCREASED SERUM CARDIAC ENZYMES AND ACUTE CORONARY EVENTS — Cardiac troponins are the

preferred marker for the diagnosis of myocardial injury among patients with normal renal function because of

their increased specificity compared with CK-MB and other markers. (See "Troponins and creatine kinase as

biomarkers of cardiac injury".)

Cardiac troponins are also used in the diagnosis of myocardial infarction in patients with CKD and a suspected

acute coronary syndrome, although minor chronic elevations in serum troponins are commonly observed in

patients with CKD who do not have clinical evidence of a myocardial infarction. These issues are discussed in

detail separately. (See "Serum cardiac enzymes in patients with renal failure".)

SUMMARY

Both decreased glomerular filtration rate (GFR) and increased proteinuria increase the risk of

cardiovascular disease. These associations have been shown in both community-based populations (ie,

cohorts that were not selected specifically to enroll individuals with chronic kidney disease [CKD] or

cardiovascular disease) and in populations of patients at high cardiovascular risk (ie, cohorts in which

patients with preexisting cardiovascular disease or cardiovascular disease risk factors were specifically

recruited). (See 'Chronic kidney disease as an independent risk factor for CHD' above.)

Patients with CKD often have numerous traditional and nontraditional risk factors for the development of

cardiovascular disease. Traditional risk factors (hypertension, smoking, diabetes, dyslipidemia, and older

age) appear to be more important risk factors during the earlier stages of CKD. Nontraditional risk factors

include uremic toxins, anemia, elevated levels of certain cytokines, an increased calcium load,

abnormalities in bone mineral metabolism, and/or an increased inflammatory-poor nutrition state. (See

'Presence of traditional and nontraditional cardiovascular risk factors in CKD' above.)

Among those with CKD, the risk of death, particularly due to cardiovascular disease, is typically higher

than the risk of eventually requiring renal replacement therapy. However, this risk varies with age and

other factors. In many studies, older patients with less severe CKD and lower levels of proteinuria are

more likely to die (usually due to cardiovascular disease) before needing renal replacement therapy, while

younger patients with proteinuria and diseases localized to the kidney are more likely to ultimately need

renal replacement therapy. (See 'Competing risks of cardiovascular and end-stage renal disease' above.)

Our general approach to reduce the risk of atherosclerotic cardiovascular disease in most patients with

CKD not requiring dialysis includes the following (see 'Reduction of CHD risk in patients with CKD'

above):

Statin therapy (see 'Statin therapy' above).

In patients with proteinuric CKD (defined as proteinuria greater than 500 to 1000 mg/day), we

recommend angiotensin blockade as part of the antihypertensive regimen and a goal blood pressure

of less than 130/80 mmHg. In patients with non-proteinuric CKD, we recommend a goal blood

pressure of less than 140/90 mmHg. (See 'Blood pressure control' above.)

Individualized decisions about antiplatelet therapy (see 'Antiplatelet therapy' above).

In all patients, smoking cessation, maintenance of an ideal body weight, an active lifestyle, and, in

patients with diabetes, glycemic control. (See 'Other issues' above.)

Patients with CKD require drug dose adjustments and have a higher risk of drug-related adverse effects.

Despite the increased risk of adverse effects, the treatments used for established coronary heart disease

(CHD) and acute coronary syndrome that are used in patients with normal kidney function (eg,

revascularization) may have similar benefits in patients with CKD. (See 'Treatment of coronary heart

disease' above.)

Patients with CKD who suffer an acute coronary syndrome or who have coronary interventions (ie,

coronary artery bypass grafting, percutaneous coronary intervention [PCI]) have a worse prognosis than

patients with normal kidney function who have similar events or procedures (table 1 and table 2). The

mechanisms which underlie the poor prognosis in patients with CKD are not entirely clear. (See

'Prognosis of coronary heart disease in patients with CKD' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development ofcardiovascular disease: a statement from the American Heart Association Councils on Kidney inCardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology andPrevention. Circulation 2003; 108:2154.

2. US Renal Data System. USRDS 2009 Annual Data report: Atlas of end-stage renal disease in the UnitedStates. Am J Kidney Dis 2010; 55(Suppl 1):S1.

3. Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults.Ann Intern Med 2004; 140:167.

4. Kaysen GA, Eiserich JP. The role of oxidative stress-altered lipoprotein structure and function andmicroinflammation on cardiovascular risk in patients with minor renal dysfunction. J Am Soc Nephrol2004; 15:538.

5. Ix JH, Shlipak MG, Liu HH, et al. Association between renal insufficiency and inducible ischemia inpatients with coronary artery disease: the heart and soul study. J Am Soc Nephrol 2003; 14:3233.

6. Muntner P, He J, Hamm L, et al. Renal insufficiency and subsequent death resulting from cardiovasculardisease in the United States. J Am Soc Nephrol 2002; 13:745.

7. Drey N, Roderick P, Mullee M, Rogerson M. A population-based study of the incidence and outcomes ofdiagnosed chronic kidney disease. Am J Kidney Dis 2003; 42:677.

8. Shlipak MG, Stehman-Breen C, Vittinghoff E, et al. Creatinine levels and cardiovascular events in womenwith heart disease: do small changes matter? Am J Kidney Dis 2004; 43:37.

9. Shlipak MG, Heidenreich PA, Noguchi H, et al. Association of renal insufficiency with treatment andoutcomes after myocardial infarction in elderly patients. Ann Intern Med 2002; 137:555.

10. Wright RS, Reeder GS, Herzog CA, et al. Acute myocardial infarction and renal dysfunction: a high-riskcombination. Ann Intern Med 2002; 137:563.

11. Al Suwaidi J, Reddan DN, Williams K, et al. Prognostic implications of abnormalities in renal function in

patients with acute coronary syndromes. Circulation 2002; 106:974.

12. Gibson CM, Pinto DS, Murphy SA, et al. Association of creatinine and creatinine clearance onpresentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol 2003; 42:1535.

13. McCullough PA, Nowak RM, Foreback C, et al. Emergency evaluation of chest pain in patients withadvanced kidney disease. Arch Intern Med 2002; 162:2464.

14. Freeman RV, Mehta RH, Al Badr W, et al. Influence of concurrent renal dysfunction on outcomes ofpatients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors. J AmColl Cardiol 2003; 41:718.

15. Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency on clinical outcomes in patientsundergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39:1113.

16. Reinecke H, Trey T, Matzkies F, et al. Grade of chronic renal failure, and acute and long-term outcomeafter percutaneous coronary interventions. Kidney Int 2003; 63:696.

17. Sosnov J, Lessard D, Goldberg RJ, et al. Differential symptoms of acute myocardial infarction in patientswith kidney disease: a community-wide perspective. Am J Kidney Dis 2006; 47:378.

18. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renalreplacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005;16:489.

19. Hallan S, Astor B, Romundstad S, et al. Association of kidney function and albuminuria withcardiovascular mortality in older vs younger individuals: The HUNT II Study. Arch Intern Med 2007;167:2490.

20. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, et al. Association ofestimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in generalpopulation cohorts: a collaborative meta-analysis. Lancet 2010; 375:2073.

21. Tonelli M, Muntner P, Lloyd A, et al. Using proteinuria and estimated glomerular filtration rate to classifyrisk in patients with chronic kidney disease: a cohort study. Ann Intern Med 2011; 154:12.

22. Pinkau T, Hilgers KF, Veelken R, Mann JF. How does minor renal dysfunction influence cardiovascularrisk and the management of cardiovascular disease? J Am Soc Nephrol 2004; 15:517.

23. Manjunath G, Tighiouart H, Coresh J, et al. Level of kidney function as a risk factor for cardiovascularoutcomes in the elderly. Kidney Int 2003; 63:1121.

24. Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney function as a risk factor for atheroscleroticcardiovascular outcomes in the community. J Am Coll Cardiol 2003; 41:47.

25. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events,and hospitalization. N Engl J Med 2004; 351:1296.

26. Wong TY, Coresh J, Klein R, et al. Retinal microvascular abnormalities and renal dysfunction: theatherosclerosis risk in communities study. J Am Soc Nephrol 2004; 15:2469.

27. Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular andnoncardiovascular mortality in general population. Circulation 2002; 106:1777.

28. Knight EL, Rimm EB, Pai JK, et al. Kidney dysfunction, inflammation, and coronary events: a prospectivestudy. J Am Soc Nephrol 2004; 15:1897.

29. Henry RM, Kostense PJ, Bos G, et al. Mild renal insufficiency is associated with increased cardiovascularmortality: The Hoorn Study. Kidney Int 2002; 62:1402.

30. Fox CS, Larson MG, Keyes MJ, et al. Kidney function is inversely associated with coronary arterycalcification in men and women free of cardiovascular disease: the Framingham Heart Study. Kidney Int2004; 66:2017.

31. Weiner DE, Tighiouart H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovasculardisease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol 2004;15:1307.

32. Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and mortality risk: a systematic review. JAm Soc Nephrol 2006; 17:2034.

33. Hallan SI, Dahl K, Oien CM, et al. Screening strategies for chronic kidney disease in the generalpopulation: follow-up of cross sectional health survey. BMJ 2006; 333:1047.

34. Van Biesen W, De Bacquer D, Verbeke F, et al. The glomerular filtration rate in an apparently healthy

population and its relation with cardiovascular mortality during 10 years. Eur Heart J 2007; 28:478.

35. Weiner DE, Tighiouart H, Griffith JL, et al. Kidney disease, Framingham risk scores, and cardiac andmortality outcomes. Am J Med 2007; 120:552.e1.

36. McCullough PA, Jurkovitz CT, Pergola PE, et al. Independent components of chronic kidney disease as acardiovascular risk state: results from the Kidney Early Evaluation Program (KEEP). Arch Intern Med2007; 167:1122.

37. van Domburg RT, Hoeks SE, Welten GM, et al. Renal insufficiency and mortality in patients with known orsuspected coronary artery disease. J Am Soc Nephrol 2008; 19:158.

38. Choi AI, Li Y, Deeks SG, et al. Association between kidney function and albuminuria with cardiovascularevents in HIV-infected persons. Circulation 2010; 121:651.

39. Irie F, Iso H, Sairenchi T, et al. The relationships of proteinuria, serum creatinine, glomerular filtration ratewith cardiovascular disease mortality in Japanese general population. Kidney Int 2006; 69:1264.

40. Tonelli M, Jose P, Curhan G, et al. Proteinuria, impaired kidney function, and adverse outcomes in peoplewith coronary disease: analysis of a previously conducted randomised trial. BMJ 2006; 332:1426.

41. Shlipak MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events amongelderly persons. N Engl J Med 2005; 352:2049.

42. Sarnak MJ, Katz R, Stehman-Breen CO, et al. Cystatin C concentration as a risk factor for heart failure inolder adults. Ann Intern Med 2005; 142:497.

43. Fried LF, Katz R, Sarnak MJ, et al. Kidney function as a predictor of noncardiovascular mortality. J AmSoc Nephrol 2005; 16:3728.

44. Seliger SL, Longstreth WT Jr, Katz R, et al. Cystatin C and subclinical brain infarction. J Am Soc Nephrol2005; 16:3721.

45. Bibbins-Domingo K, Chertow GM, Fried LF, et al. Renal function and heart failure risk in older black andwhite individuals: the Health, Aging, and Body Composition Study. Arch Intern Med 2006; 166:1396.

46. Menon V, Shlipak MG, Wang X, et al. Cystatin C as a risk factor for outcomes in chronic kidney disease.Ann Intern Med 2007; 147:19.

47. Astor BC, Levey AS, Stevens LA, et al. Method of glomerular filtration rate estimation affects prediction ofmortality risk. J Am Soc Nephrol 2009; 20:2214.

48. Peralta CA, Katz R, Sarnak MJ, et al. Cystatin C identifies chronic kidney disease patients at higher riskfor complications. J Am Soc Nephrol 2011; 22:147.

49. Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverseoutcomes. JAMA 2010; 303:423.

50. Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality andend-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380:1662.

51. Mahmoodi BK, Matsushita K, Woodward M, et al. Associations of kidney disease measures withmortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis.Lancet 2012; 380:1649.

52. Leoncini G, Viazzi F, Pontremoli R. Overall health assessment: a renal perspective. Lancet 2010;375:2053.

53. Weiner DE, Tighiouart H, Elsayed EF, et al. The Framingham predictive instrument in chronic kidneydisease. J Am Coll Cardiol 2007; 50:217.

54. Culleton BF, Larson MG, Wilson PW, et al. Cardiovascular disease and mortality in a community-basedcohort with mild renal insufficiency. Kidney Int 1999; 56:2214.

55. Garg AX, Clark WF, Haynes RB, House AA. Moderate renal insufficiency and the risk of cardiovascularmortality: results from the NHANES I. Kidney Int 2002; 61:1486.

56. van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higheralbuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis ofhigh-risk population cohorts. Kidney Int 2011; 79:1341.

57. Mann JF, Gerstein HC, Pogue J, et al. Renal insufficiency as a predictor of cardiovascular outcomes andthe impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134:629.

58. Segura J, Campo C, Gil P, et al. Development of chronic kidney disease and cardiovascular prognosis inessential hypertensive patients. J Am Soc Nephrol 2004; 15:1616.

59. Ruilope LM, Salvetti A, Jamerson K, et al. Renal function and intensive lowering of blood pressure inhypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 2001;12:218.

60. Beddhu S, Allen-Brady K, Cheung AK, et al. Impact of renal failure on the risk of myocardial infarction anddeath. Kidney Int 2002; 62:1776.

61. Knobler H, Zornitzki T, Vered S, et al. Reduced glomerular filtration rate in asymptomatic diabeticpatients: predictor of increased risk for cardiac events independent of albuminuria. J Am Coll Cardiol 2004;44:2142.

62. Kong AP, So WY, Szeto CC, et al. Assessment of glomerular filtration rate in addition to albuminuria isimportant in managing type II diabetes. Kidney Int 2006; 69:383.

63. Rahman M, Pressel S, Davis BR, et al. Cardiovascular outcomes in high-risk hypertensive patientsstratified by baseline glomerular filtration rate. Ann Intern Med 2006; 144:172.

64. Perkovic V, Ninomiya T, Arima H, et al. Chronic kidney disease, cardiovascular events, and the effects ofperindopril-based blood pressure lowering: data from the PROGRESS study. J Am Soc Nephrol 2007;18:2766.

65. Schneider CA, Ferrannini E, Defronzo R, et al. Effect of pioglitazone on cardiovascular outcome indiabetes and chronic kidney disease. J Am Soc Nephrol 2008; 19:182.

66. Weiner DE, Tighiouart H, Stark PC, et al. Kidney disease as a risk factor for recurrent cardiovasculardisease and mortality. Am J Kidney Dis 2004; 44:198.

67. Clase CM, Gao P, Tobe SW, et al. Estimated glomerular filtration rate and albuminuria as predictors ofoutcomes in patients with high cardiovascular risk: a cohort study. Ann Intern Med 2011; 154:310.

68. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation,classification, and stratification. Am J Kidney Dis 2002; 39:S1.

69. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients withST-elevation myocardial infarction--executive summary: a report of the American College ofCardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revisethe 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004;110:588.

70. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronicrenal disease: what do we know? What do we need to learn? Where do we go from here? National KidneyFoundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32:853.

71. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidneydisease: evaluation, classification, and stratification. Ann Intern Med 2003; 139:137.

72. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney diseasecompared with those with diabetes: a population-level cohort study. Lancet 2012; 380:807.

73. Rashidi A, Sehgal AR, Rahman M, O'Connor AS. The case for chronic kidney disease, diabetes mellitus,and myocardial infarction being equivalent risk factors for cardiovascular mortality in patients older than 65years. Am J Cardiol 2008; 102:1668.

74. Wattanakit K, Coresh J, Muntner P, et al. Cardiovascular risk among adults with chronic kidney disease,with or without prior myocardial infarction. J Am Coll Cardiol 2006; 48:1183.

75. Matsushita K, Selvin E, Bash LD, et al. Change in estimated GFR associates with coronary heart diseaseand mortality. J Am Soc Nephrol 2009; 20:2617.

76. Shlipak MG, Katz R, Kestenbaum B, et al. Rapid decline of kidney function increases cardiovascular riskin the elderly. J Am Soc Nephrol 2009; 20:2625.

77. Schmieder RE, Mann JF, Schumacher H, et al. Changes in albuminuria predict mortality and morbidity inpatients with vascular disease. J Am Soc Nephrol 2011; 22:1353.

78. Tonelli M. Should CKD be a coronary heart disease risk equivalent? Am J Kidney Dis 2007; 49:8.

79. Hyre AD, Fox CS, Astor BC, et al. The impact of reclassifying moderate CKD as a coronary heart diseaserisk equivalent on the number of US adults recommended lipid-lowering treatment. Am J Kidney Dis 2007;49:37.

80. Verhave JC, Gansevoort RT, Hillege HL, et al. Drawbacks of the use of indirect estimates of renal functionto evaluate the effect of risk factors on renal function. J Am Soc Nephrol 2004; 15:1316.

81. Verhave JC, Hillege HL, Burgerhof JG, et al. The association between atherosclerotic risk factors andrenal function in the general population. Kidney Int 2005; 67:1967.

82. Astor BC, Shafi T, Hoogeveen RC, et al. Novel markers of kidney function as predictors of ESRD,cardiovascular disease, and mortality in the general population. Am J Kidney Dis 2012; 59:653.

83. Shlipak MG, Fried LF, Cushman M, et al. Cardiovascular mortality risk in chronic kidney disease:comparison of traditional and novel risk factors. JAMA 2005; 293:1737.

84. Muntner P, He J, Astor BC, et al. Traditional and nontraditional risk factors predict coronary heart diseasein chronic kidney disease: results from the atherosclerosis risk in communities study. J Am Soc Nephrol2005; 16:529.

85. Foley RN, Wang C, Collins AJ. Cardiovascular risk factor profiles and kidney function stage in the USgeneral population: the NHANES III study. Mayo Clin Proc 2005; 80:1270.

86. Kobayashi S, Maesato K, Moriya H, et al. Insulin resistance in patients with chronic kidney disease. AmJ Kidney Dis 2005; 45:275.

87. Becker B, Kronenberg F, Kielstein JT, et al. Renal insulin resistance syndrome, adiponectin andcardiovascular events in patients with kidney disease: the mild and moderate kidney disease study. J AmSoc Nephrol 2005; 16:1091.

88. Russo D, Palmiero G, De Blasio AP, et al. Coronary artery calcification in patients with CRF notundergoing dialysis. Am J Kidney Dis 2004; 44:1024.

89. Tomiyama C, Higa A, Dalboni MA, et al. The impact of traditional and non-traditional risk factors oncoronary calcification in pre-dialysis patients. Nephrol Dial Transplant 2006; 21:2464.

90. Dellegrottaglie S, Saran R, Gillespie B, et al. Prevalence and predictors of cardiovascular calcium inchronic kidney disease (from the Prospective Longitudinal RRI-CKD Study). Am J Cardiol 2006; 98:571.

91. Menon V, Greene T, Wang X, et al. C-reactive protein and albumin as predictors of all-cause andcardiovascular mortality in chronic kidney disease. Kidney Int 2005; 68:766.

92. Young JM, Terrin N, Wang X, et al. Asymmetric dimethylarginine and mortality in stages 3 to 4 chronickidney disease. Clin J Am Soc Nephrol 2009; 4:1115.

93. Friedman AN, Hunsicker LG, Selhub J, et al. C-reactive protein as a predictor of total arterioscleroticoutcomes in type 2 diabetic nephropathy. Kidney Int 2005; 68:773.

94. Ducloux D, Motte G, Challier B, et al. Serum total homocysteine and cardiovascular disease occurrencein chronic, stable renal transplant recipients: a prospective study. J Am Soc Nephrol 2000; 11:134.

95. Menon V, Sarnak MJ, Greene T, et al. Relationship between homocysteine and mortality in chronickidney disease. Circulation 2006; 113:1572.

96. Shishehbor MH, Oliveira LP, Lauer MS, et al. Emerging cardiovascular risk factors that account for asignificant portion of attributable mortality risk in chronic kidney disease. Am J Cardiol 2008; 101:1741.

97. Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population withchronic kidney disease in a large managed care organization. Arch Intern Med 2004; 164:659.

98. Patel UD, Young EW, Ojo AO, Hayward RA. CKD progression and mortality among older patients withdiabetes. Am J Kidney Dis 2005; 46:406.

99. Forsblom C, Harjutsalo V, Thorn LM, et al. Competing-risk analysis of ESRD and death among patientswith type 1 diabetes and macroalbuminuria. J Am Soc Nephrol 2011; 22:537.

100. Rosolowsky ET, Skupien J, Smiles AM, et al. Risk for ESRD in type 1 diabetes remains high despiterenoprotection. J Am Soc Nephrol 2011; 22:545.

101. Nicola LD, Minutolo R, Chiodini P, et al. The effect of increasing age on the prognosis of non-dialysispatients with chronic kidney disease receiving stable nephrology care. Kidney Int 2012; 82:482.

102. Menon V, Wang X, Sarnak MJ, et al. Long-term outcomes in nondiabetic chronic kidney disease. KidneyInt 2008; 73:1310.

103. Packham DK, Alves TP, Dwyer JP, et al. Relative incidence of ESRD versus cardiovascular mortality inproteinuric type 2 diabetes and nephropathy: results from the DIAMETRIC (Diabetes Mellitus Treatmentfor Renal Insufficiency Consortium) database. Am J Kidney Dis 2012; 59:75.

104. Charytan D, Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials incoronary artery disease. Kidney Int 2006; 70:2021.

105. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized

controlled trials of cardiovascular disease. JAMA 2006; 296:1377.

106. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stablecoronary disease. N Engl J Med 2005; 352:1425.

107. Solomon SD, Rice MM, A Jablonski K, et al. Renal function and effectiveness of angiotensin-convertingenzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events withACE inhibition (PEACE) trial. Circulation 2006; 114:26.

108. Palmer SC, Di Micco L, Razavian M, et al. Antiplatelet agents for chronic kidney disease. CochraneDatabase Syst Rev 2013; 2:CD008834.

109. Palmer SC, Di Micco L, Razavian M, et al. Effects of antiplatelet therapy on mortality and cardiovascularand bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis.Ann Intern Med 2012; 156:445.

110. KDIGO. Chapter 1: Definition and classification of CKD. Kidney Int Suppl 2013; 3:19.http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf

111. Gibney EM, Casebeer AW, Schooley LM, et al. Cardiovascular medication use after coronary bypasssurgery in patients with renal dysfunction: a national Veterans Administration study. Kidney Int 2005;68:826.

112. Newsome BB, Warnock DG, Kiefe CI, et al. Delay in time to receipt of thrombolytic medication amongMedicare patients with kidney disease. Am J Kidney Dis 2005; 46:595.

113. Han JH, Chandra A, Mulgund J, et al. Chronic kidney disease in patients with non-ST-segment elevationacute coronary syndromes. Am J Med 2006; 119:248.

114. Patel UD, Ou FS, Ohman EM, et al. Hospital performance and differences by kidney function in the use ofrecommended therapies after non-ST-elevation acute coronary syndromes. Am J Kidney Dis 2009;53:426.

115. Charytan D, Mauri L, Agarwal A, et al. The use of invasive cardiac procedures after acute myocardialinfarction in long-term dialysis patients. Am Heart J 2006; 152:558.

116. Fox CS, Muntner P, Chen AY, et al. Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patientswith chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatmentand Intervention Outcomes Network registry. Circulation 2010; 121:357.

117. Tabata M, Takanashi S, Fukui T, et al. Off-pump coronary artery bypass grafting in patients with renaldysfunction. Ann Thorac Surg 2004; 78:2044.

118. Zakeri R, Freemantle N, Barnett V, et al. Relation between mild renal dysfunction and outcomes aftercoronary artery bypass grafting. Circulation 2005; 112:I270.

119. Anderson RJ, O'brien M, MaWhinney S, et al. Renal failure predisposes patients to adverse outcome aftercoronary artery bypass surgery. VA Cooperative Study #5. Kidney Int 1999; 55:1057.

120. Dacey LJ, Liu JY, Braxton JH, et al. Long-term survival of dialysis patients after coronary bypass grafting.Ann Thorac Surg 2002; 74:458.

121. Liu JY, Birkmeyer NJ, Sanders JH, et al. Risks of morbidity and mortality in dialysis patients undergoingcoronary artery bypass surgery. Northern New England Cardiovascular Disease Study Group. Circulation2000; 102:2973.

122. Massad MG, Kpodonu J, Lee J, et al. Outcome of coronary artery bypass operations in patients with renalinsufficiency with and without renal transplantation. Chest 2005; 128:855.

123. Pinkau T, Mann JF, Ndrepepa G, et al. Coronary revascularization in patients with renal insufficiency:restenosis rate and cardiovascular outcomes. Am J Kidney Dis 2004; 44:627.

124. Ix JH, Mercado N, Shlipak MG, et al. Association of chronic kidney disease with clinical outcomes aftercoronary revascularization: the Arterial Revascularization Therapies Study (ARTS). Am Heart J 2005;149:512.

125. Lemos PA, Arampatzis CA, Hoye A, et al. Impact of baseline renal function on mortality afterpercutaneous coronary intervention with sirolimus-eluting stents or bare metal stents. Am J Cardiol 2005;95:167.

126. Attallah N, Yassine L, Fisher K, Yee J. Risk of bleeding and restenosis among chronic kidney diseasepatients undergoing percutaneous coronary intervention. Clin Nephrol 2005; 64:412.

127. Stigant C, Izadnegahdar M, Levin A, et al. Outcomes after percutaneous coronary interventions in patients

with CKD: improved outcome in the stenting era. Am J Kidney Dis 2005; 45:1002.

128. Halkin A, Mehran R, Casey CW, et al. Impact of moderate renal insufficiency on restenosis and adverseclinical events after paclitaxel-eluting and bare metal stent implantation: results from the TAXUS-IV Trial.Am Heart J 2005; 150:1163.

129. Charytan DM, Varma MR, Silbaugh TS, et al. Long-term clinical outcomes following drug-eluting or bare-metal stent placement in patients with severely reduced GFR: Results of the Massachusetts DataAnalysis Center (Mass-DAC) State Registry. Am J Kidney Dis 2011; 57:202.

130. Charytan D, Forman JP, Cutlip DE. Risk of target lesion revascularization after coronary stenting inpatients with and without chronic kidney disease. Nephrol Dial Transplant 2007; 22:2578.

131. Aoki J, Ong AT, Hoye A, et al. Five year clinical effect of coronary stenting and coronary artery bypassgrafting in renal insufficient patients with multivessel coronary artery disease: insights from ARTS trial. EurHeart J 2005; 26:1488.

Topic 7190 Version 17.0

GRAPHICS

EuroSCORE risk prediction algorithm for cardiac surgical mortality

Predictor DefinitionRisk

points*

Age Per 5 years or part thereof over 60 years 1

Sex Female 1

Chronic pulmonarydisease

Long-term use of bronchodilators or steroids for lungdisease

1

Extracardiacarteriopathy

Any one or more of the following: 2

claudication

carotid occlusion or >50 percent stenosis

previous or planned intervention on the abdominal aorta,limb arteries or carotids

Neurologicaldysfunction

Disease severely affecting ambulation or day-to-dayfunctioning

2

Previous cardiacsurgery

Requiring opening of the pericardium 3

Serum creatinine >200 micromol/L (2.3 mg/dL) preoperatively 2

Active endocarditis Patient still under antibiotic treatment for endocarditisat the time of surgery

3

Criticalpreoperative state

Any one or more of the following: 3

ventricular tachycardia or fibrillation or aborted suddendeath

preoperative cardiac massage

preoperative ventilation before arrival in the anestheticroom

preoperative inotropic support

intraaortic balloon counterpulsation

preoperative acute renal failure (anuria or oliguria <10mL/hour)

Unstable angina Rest angina requiring IV nitrates until arrival in theanesthetic room

2

LV dysfunction Moderate or LV ejection fraction 30 to 50 percent 1

Poor or LV ejection fraction <30 percent 3

Recent myocardialinfarct

<90 days 2

Pulmonaryhypertension

Systolic pulmonary artery pressure >60 mmHg 2

Emergencyoperation

Carried out on referral before the beginning of thenext working day

2

Other thanisolated CABG

Major cardiac procedure other than or in addition toCABG

2

Surgery onthoracic aorta

For disorder of ascending, arch or descending aorta 3

Postinfarct septal 4

rupture

IV: intravenous; LV: left ventricle; CABG: coronary artery bypass grafting.* To calculate the estimated perioperative mortality risk, the sum of the risk points isdetermined. Scores are stratified into low risk (0 to 2 points; estimated mortality 1.3 percent),medium risk (3 to 5 points; estimated mortality 2.9 percent) and high risk (≥6 points;estimated mortality 10.9 to 11.5 percent).Reproduced with permission from: Nashed SA, Roques F, Michel P, et al. European system forcardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16:9. Copyright ©1999 Elsevier.

CADILLAC risk score for 30-day and one-year mortality after primarypercutaneous coronary intervention for ST elevation myocardialinfarction

Risk factor Points

LVEF <40 percent 4

Killip class 2/3 3

Renal insufficiency (estimated creatinine clearance <60 mL/min) 3

TIMI flow grade after PCI of 0 to 2 2

Age >65 years 2

Anemia (hematocrit <39 percent in men and <36 percent inwomen)

2

Triple-vessel disease 2

Risk score 30-day mortalityOne-yearmortality

Low risk (score 0 to 2) 0.1 to 0.2 percent 0.8 to 0.9 percent

Intermediate risk (score 3 to 5) 1.3 to 1.9 percent 4.0 to 4.5 percent

High risk (score ≥6) 6.6 to 8.1 percent 12.4 to 13.2 percent

Data from Halkin A, Singh M, Nikolsky E, et al, J Am Coll Cardiol 2005; 45:1397.