Chapter 19. Cardiovascular Disease in Chronic Kidney Disease

• Cardiovascular disease (CVD) is highly prevalent among patients with chronic kidney disease (CKD) and is the most common cause of death in this population.
• The manifestations of CVD in CKD are variable and include left ventricular hypertrophy, ischemic heart disease, heart failure, and peripheral vascular disease.
• Traditional and nontraditional (or “uremia-related”) cardiac risk factors are common in CKD.
• Clinicians should maintain a high index of suspicion for the presence of CVD in patients with CKD, even when the presentation is atypical.
• An aggressive approach to diagnosis and treatment of CVD is recommended in patients with CKD.

CVD is highly prevalent among patients with CKD and is the most common cause of death in this population. Importantly, patients with impaired kidney function are more likely to die than to progress to end-stage renal disease (ESRD) requiring renal replacement therapy and those who do reach dialysis have a staggering mortality rate of about 20% per year. In dialysis patients of all ages, the mortality rate from CVD far exceeds that observed in the general population (Figure 19–1). Dialysis has the greatest impact on younger patients, whose mortality rate from CVD is more than 100 times greater than that of their counterparts with normal kidney function.

The burden of CVD begins to accumulate long before patients reach ESRD. For example, left ventricular (LV) hypertrophy (LVH) increases in prevalence with declining renal function and is present in 75% of patients beginning dialysis treatment. Ischemic heart disease (IHD) and heart failure also develop early, and are present in 40% and 35% of incident dialysis patients, respectively. Recent publications have demonstrated a profound impact of a reduced glomerular filtration rate (GFR) below 60 mL/minute on cardiovascular event rates.

In recent years both the National Kidney Foundation (NKF) and the American Heart Association (AHA) have recommended that patients with CKD be placed in the highest risk group for the development of CVD. However, while recognition of their high-risk status has improved, evidence from clinical trials evaluating the benefit of interventions aimed at reducing CVD risk in the CKD population is still largely lacking.

Recommendations by the NKF for the evaluation and treatment of CVD in dialysis patients were published in April 2005. The key to these guidelines is the recommendation that an aggressive approach to diagnosis and treatment is warranted in patients with ESRD due to the high risk of CVD in this patient group.

The spectrum of CVD in CKD is wide, and includes abnormalities of the heart and blood vessels, such as LVH, congestive heart failure (CHF), valvular heart disease, pericarditis, cardiac arrhythmias, IHD, and peripheral vascular disease (PVD). Those disorders that are most common and account for the majority of the morbidity and mortality in patients with CKD will be the focus of this chapter: LVH, IHD, heart failure, and PVD. In this chapter, the term CKD is used generically to refer to patients with all degrees of kidney dysfunction, including those on dialysis. Comments pertaining to a particular subgroup of patients (for example, predialysis patients or ESRD patients) are specified as such.

Cardiovascular Risk Factors in Chronic Kidney Disease

Traditional and nontraditional risk factors have been discussed in the literature as contributors to the high rate of CVD in CKD (Table 19–1). Certainly, traditional cardiac risk factors are highly prevalent in these patients. These include advanced age, diabetes mellitus, hypertension, low high-density lipoprotein (HDL), and LVH. However, the complexity of the relationship between some traditional cardiovascular risk factors and overall mortality in ESRD must be appreciated. For example, a “reverse epidemiology” or “U-shaped” mortality curve has been observed whereby ESRD patients with low cholesterol and low blood pressure paradoxically have an increased mortality. This increase in mortality is hypothesized to reflect underlying malnutrition and/or inflammation (in the case of low cholesterol) and advanced cardiomyopathy (in the case of low blood pressure). Thus, the benefits of strategies traditionally used to combat CVD in the general population, such as lowering of cholesterol and blood pressure, may be questioned in the setting of kidney disease.

Furthermore, there is accumulating evidence that a reduced GFR per se is an independent risk factor for CVD. It may be that lower GFR is associated with, or marks for, nontraditional or “uremic” risk factors. These nontraditional risk factors, outlined in Table 19–1, include anemia, abnormalities of calcium and phosphate metabolism, inflammation, prothrombotic factors, oxidative stress, and perhaps also hyperhomocysteinemia, and elevated levels of lipoprotein (a). However, despite strong associations between these factors and CVD in epidemiologic studies, a causal relationship has not been proven, nor have interventional studies been conducted that demonstrate changes in outcomes with treatment of these abnormalities.

In patients with residual kidney function (ie, those not yet on dialysis), the issue of proteinuria and cardiovascular risk merits specific comment. First, microalbuminuria is associated with an increased risk of cardiovascular events in both diabetic and nondiabetic subjects, even in the absence of renal insufficiency. While patients with microalbuminuria often have an increased prevalence of traditional cardiac risk factors, it is also thought that microalbuminuria may be a marker of generalized endothelial dysfunction or inflammation. Second, individuals with the nephrotic syndrome are known to have an increased risk of myocardial infarction (MI). Among the potential explanations for this are that hyperlipidemia, hypercoagulability, and hypertension are common in the nephrotic syndrome and these may contribute to the increased risk of IHD. In addition, recent publications describe clear associations between proteinuria and increased rates of CVD at all levels of kidney dysfunction.

Given the documented burden of CVD in CKD, the association with adverse outcomes in patients where the two coexist, and the biologically plausible explanations as to the impact of traditional and nontraditional risk factors in CKD populations, it is important for the practicing clinician to understand the complexity of this area, what is known and where gaps in our knowledge base exist.

Left Ventricular Hypertrophy

The work performed by the LV in each cardiac cycle is equal to the product of the ventricular pressure and stroke volume. In kidney disease, the work of the LV is increased due to both pressure and volume overload. Hypertension, arteriosclerosis, and aortic stenosis contribute to pressure overload, while volume overload occurs as a result of factors such as anemia, increased extracellular fluid volume, and the presence of arteriovenous fistulas. These and potentially other factors, such as hyperparathyroidism and the “uremic milieu,” contribute to the development of LVH, an independent risk factor for mortality in all CKD patients, independent of dialysis status.

The LVH that occurs intitially as an adaptive response to physiologic stimuli (pressure or volume) eventually becomes maladaptive. At the cellular level, the metabolically active myocytes begin to experience an energy deficit, partly due to ischemia, resulting in cell death. In addition, cardiac fibroblasts proliferate, expanding the extracellular matrix of the myocardium and causing myocardial fibrosis. From a functional point of view, the hypertrophied ventricle becomes stiff, impairing relaxation and resulting primarily in diastolic dysfunction, at least initially. These changes may partially explain the high prevalence of heart failure in this patient group.

Heart Failure

Heart failure is common in CKD and is present in about one-third of incident dialysis patients. Patients may have systolic dysfunction, diastolic dysfunction, or both. The pathogenesis of heart failure is multifactorial with contributions from LVH, IHD, valvular heart disease, and other abnormalities specific to the uremic state such as chronic extracellular fluid volume expansion, disturbances in divalent ion metabolism, anemia, and the presence of arteriovenous (AV) fistulas.

Vascular Disease: Atherosclerosis and Arteriosclerosis

There are two general types of arterial vascular disease in CKD: Atherosclerosis and arteriosclerosis. Atherosclerosis is a disease of the intima and is characterized by plaques and vessel occlusion. The most common vessels affected are the medium-sized arteries, such as the coronary, femoral, and carotid arteries. There are many contributors to atherosclerosis, including the high prevalence of cardiac risk factors such as advanced age, dyslipidemia, hypertension, and the metabolic syndrome.

Patients with CKD also have a high prevalence of arteriosclerosis, or stiffening of the arteries; this may occur in the presence or absence of significant atherosclerosis. Although it normally occurs with aging, the process appears to be accelerated in kidney disease. The intima and media of the large, elastic arteries such as the aorta and the common carotid are affected in particular. The vessel wall is remodeled and becomes thickened and stiff, reducing compliance. These stiff vessels contribute to hemodynamic changes, including an increase in systolic blood pressure, a decrease in diastolic blood pressure, and as a result, a widened pulse pressure and increased pulse wave velocity. The raised systolic blood pressure increases LV afterload and contributes to the development of LVH, while the reduced diastolic pressure compromises coronary artery perfusion and contributes to myocardial ischemia. Recent data from both dialysis and predialysis patients have confirmed the association among an elevated pulse pressure, a clinical manifestation of arterial stiffness, and adverse outcomes.

A contributor to the arterial stiffening in kidney disease that has recently been given some attention is calcification of the intimal and medial layers of these vessels. It has been observed that this calcification is a key feature of the arterial disease in CKD, especially in ESRD. The calcification is more extensive and is observed much earlier in ESRD than in the general population. Abnormalities of bone mineral metabolism, including elevations in serum phosphorus, calcium, and calcium × phosphorus product, among other factors, are intimately involved in promoting vascular calcification.

This unique contribution of specific factors to arterial calcification and measured arterial stiffness, in conjunction with anemia (also common in CKD), may explain in part the high prevalence of CVD in CKD patients.

Symptoms and Signs

Left Ventricular Hypertrophy

LVH may be asymptomatic or patients may present with diastolic dysfunction, which is discussed in further detail in the next section.

On physical examination, hypertension is common. Particular attention should be paid to the pulse pressure as a surrogate measure of arterial stiffness, where “normal values” are <40–60 mm Hg. Precordial palpation may reveal a left ventricular heave and a sustained and diffuse cardiac apical impulse. On auscultation, a fourth heart sound may be heard.

Due to the lack of sensitivity of symptoms and physical examination findings, echocardiography is usually used for diagnosis and clinical follow-up of patients with LVH.

Heart Failure

Heart failure may occur as a result of systolic dysfunction, diastolic dysfunction, or both. It may be asymptomatic or patients may present with shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, reduced exercise tolerance, and progressive extracellular fluid volume expansion. In addition, patients with LV dysfunction on hemodialysis often tolerate dialysis treatments poorly and episodes of intradialytic hypotension may occur.

On physical examination, the signs of heart failure include pulmonary vascular congestion such as jugular venous distention and crackles due to pulmonary edema. LVH is the most common cause of diastolic dysfunction in CKD and these patients would be expected to have the cardiac findings discussed under that section. However, findings in patients with predominantly systolic heart failure include cardiomegaly, manifested by an inferiorly and laterally displaced apical pulsation, and the presence of a third heart sound on auscultation.

Due to the insensitivity of the physical examination, echocardiography is usually used for the diagnosis of heart failure. In addition to evaluating left ventricular function and geometry, echocardiography also has the advantage of providing other useful information, such as the presence of valvular heart disease, which may also contribute to left ventricular dysfunction.

Ischemic Heart Disease

The main symptom of cardiac ischemia is angina, which may be accompanied by symptoms of CHF. In CKD, the high proportion of patients with a concomitant diagnosis of diabetes mellitus means that atypical presentations of cardiac ischemia, such as shortness of breath without chest pain, may occur. In addition, patients with CKD may experience episodes of silent cardiac ischemia. For example, asymptomatic ST segment depression has been observed during hemodialysis treatments.

Findings on physical examination of acute cardiac ischemia may be relatively few. Signs of left and/or right heart failure may be observed depending on the size and location of the vascular territory affected. In general, the diagnosis of an acute coronary syndrome (ACS) relies on laboratory findings, including serial cardiac enzyme determinations and an electrocardiogram (ECG).

In the CKD population, a number of factors may interfere with the timely diagnosis of IHD, including diabetes, atypical presentations, and the relative lack of utility of specific tests in dialysis patients. Thus, a high index of suspicion in patients at high CVD risk is imperative.

Peripheral Vascular Disease

PVD, also a result of the atherosclerotic process, is common in CKD. The symptoms and signs depend on the vascular territory affected. Carotid artery disease causes neurologic changes during a transient ischemic attack or stroke. When the arteries supplying the lower extremities are affected, intermittent claudication with exertion may result. However, given the poor tolerance to exercise in the CKD population in general, this symptom probably lacks sensitivity. Chronic ischemia of the legs results in skin changes, hair loss, and muscle atrophy. Other signs include pallor, reduced or absent pulses, and bruits. Without treatment, skin ulceration and gangrene can occur when ischemia becomes critical.

The key to the diagnosis of PVD is serial assessment of peripheral arterial function through clinical examination and laboratory investigations. Reluctance to evaluate PVD in a timely manner may have led to an increase in morbidity and mortality in this particular cohort of patients.

Laboratory Findings

Cardiac Disease

Cardiac Troponins

Troponins comprise part of the contractile apparatus of myocytes in both cardiac and skeletal muscle. They consist of three subunits: Troponin C, troponin T, and troponin I. While cardiac and skeletal troponin C are identical, cardiac troponin T (cTnT) and I (cTnI) are encoded by genes different from their skeletal counterparts, and the molecules are also different. The assays currently in use for detection of cTnT and cTnI are specific for troponin released from the heart muscle. They are also highly sensitive to even small amounts of myocardial damage. The degree of troponin elevation in patients presenting with a suspected ACS provides important prognostic information, even in the presence of renal dysfunction. For these reasons, cTnT and cTnI are the preferred markers for the diagnosis of acute cardiac injury.

Interpretation of cardiac troponin concentration in the setting of ESRD is complicated by the fact that the levels, particularly of cTnT, may be elevated in apparently asymptomatic individuals. The reasons for elevations in troponin in the absence of cardiac symptoms and the significance of the levels are still debated, but the finding of an elevated troponin concentration in a patient with ESRD cannot necessarily be dismissed as a false-positive result even if unaccompanied by cardiac symptoms.

What is even less clear is why asymptomatic troponin elevations in ESRD are observed more frequently with cTnT than with cTnI. Proposed explanations for this include differences in release patterns from damaged cardiac myocytes, circulating half-life, and dialyzability, in addition to the particular characteristics of the assays themselves.

Despite these controversies and uncertainties, patients with renal failure suspected of having an ACS should be followed with serial cardiac troponin assessments. A troponin level rising over time suggests an acute injury, especially if accompanied by other cardiac symptoms or ECG changes. A positive but unchanging level may not indicate acute damage, but it has prognostic implications in ESRD patients nonetheless. On the other hand, obtaining serial “normal” or “negative” results has an excellent negative predictive value and is therefore useful for excluding an ACS.

Cardiac Imaging Studies

Electrocardiography

All patients suspected of having an ACS should be evaluated with an ECG. However, the interpretation can be complicated by preexisting abnormalities on the baseline tracing. In the absence of acute cardiac ischemia, ST-T segment morphology can be altered by LVH, electrolyte disturbances, and medications such as digoxin. In a patient presenting with possible cardiac ischemia, obtaining an old ECG for comparison can be extremely helpful. Aside from abnormalities of the baseline study, ischemic changes are expected to have an appearance the same as in individuals without kidney disease.

Exercise Treadmill Testing

In screening for coronary artery disease (CAD), detection of exercise-induced ischemia with exercise treadmill testing is of limited utility in renal failure. Patients are often unable to attain their target heart rate for reasons that include poor exercise tolerance, autonomic neuropathy, and use of medications that impair the chronotropic response to exercise, such as β-blockers and calcium channel blockers. Abnormalities of the resting ECG further compromise the sensitivity and specificity of this test. For these reasons, pharmacologic stress testing is generally preferred in renal failure.

Echocardiography

Two-dimensional echocardiography has multiple uses in the renal failure population. It can be used to assess for abnormalities of cardiac structure, such as LVH and valvular heart disease, and also provides a good estimate of systolic and diastolic LV function. Ideally, patients on dialysis should be as close to their estimated dry weight as possible at the time of this study or at least have studies performed at the same time in their dialysis cycle for comparison purposes.

Dobutamine stress echocardiography (DSE) can be used as a noninvasive screening test for ischemic heart disease. Studies in the renal failure population are limited in number and comparisons between studies are difficult because of inconsistencies in methodology. Overall, DSE appears to be a useful, but imperfect, screening test for CAD in CKD.

Nuclear Scintigraphy

Nuclear scintigraphy has uses similar to echocardiography in patients with kidney disease: Assessment of ventricular function, screening for CAD, and prediction of future cardiac events.

To screen for myocardial ischemia, a radionuclide is injected and fixed or reversible perfusion defects are detected by comparing cardiac single-photon emission computed tomography (SPECT) images at rest and following stress (exercise or pharmacologic). Dipyridamole is a pharmacologic agent that acts by blocking the cellular reuptake of adenosine, thereby increasing its levels and causing vasodilation. In patients with markedly impaired kidney function, baseline levels of adenosine are increased, thus a reduced vasodilatory response to exogenously administered dipyridamole may occur, thereby potentially producing a false-negative result.

Several studies have evaluated the use of nuclear scintigraphy in patients with renal failure; however, the reported results are variable, likely due to inconsistencies in methodology. Like DSE, nuclear scintigraphy appears to be a moderately useful but suboptimal screening test for CAD in this group of patients.

Both thallium scintigraphy and DSE have prognostic implications in the renal failure population. In a recent meta-analysis of these myocardial perfusion studies for stratifying cardiac risk among patients with ESRD who were candidates for kidney or kidney–pancreas transplantation, compared to patients with negative test results, patients with positive tests had a relative risk of myocardial infarction of 2.73 and of cardiac death of 2.92 following transplantation.

Currently, there is no literature to guide the choice between nuclear scintigraphy and DSE in screening for CAD in CKD, as there are no studies directly comparing the two modalities. Therefore, it is reasonable to consider local expertise, availability, and cost to guide test selection.

Computerized Tomography Scanning

Electron beam computerized tomography (EBCT) and helical CT scanning methods can be used to assess the degree of coronary artery calcification (CAC). In the general population, where calcification occurs in the intima in association with atherosclerotic deposits, CAC scores have been found to correlate with angiographic plaque burden and to predict future cardiac events. However, their utility in CKD populations is less clear.

Vascular calcification of both the intimal and medical layers is common in renal failure. The CAC scores of ESRD patients in particular are often several times greater than those found in the general population. However, CT scanning cannot distinguish between intimal and medial calcification, and there are conflicting reports as to whether there is a correlation between CAC scores and atherosclerotic plaque burden. Furthermore, while data demonstrate an association between higher CAC scores and mortality in ESRD, debate still exists as to the utility of this test in routine clinical care or as an endpoint in clinical trials. Until the appropriate long-term and interventional studies are undertaken, CT scanning is not recommended as a screen for CAD in the CKD population.

Percutaneous Coronary Angiography

While IHD is most commonly a result of atherosclerotic CAD, a substantial proportion of patients with CKD experience cardiac ischemia without significant coronary artery stenosis. It is likely that these patients, particularly those with LVH, have microvascular insufficiency that limits myocardial perfusion and causes ischemia.

The gold standard for diagnosis of CAD is angiography; however, the cost and the potential for morbidity make it impractical as a screening test. In general, it is reserved for patients whose noninvasive screening tests are positive, those who present with an ACS, or those with known CAD who have developed recurrent symptoms despite optimal management.

In predialysis patients, angiography may worsen renal function by causing contrast nephropathy or cholesterol embolization. Invasive examinations should be undertaken only after careful consideration of their necessity, and whether the results will alter patient management. Contrast nephropathy generally produces a transient and reversible decline in renal function and in the modern era, with low osmolality contrast dyes, improved technology, and some evidence of renoprotective effects of specific agents, the risk may be lower than previously described. On the other hand, the decline in renal function caused by cholesterol emboli is usually permanent and can render patients with earlier stages of CKD dialysis dependent.

Peripheral Vascular Disease

In general, the initial approach to investigating PVD is with noninvasive testing, as is done in the general population. An ankle–brachial index (ABI)(at rest plus or minus postexercise) is a simple test that can be performed in the physician's office to confirm the suspicion of PVD. An ABI of <0.90 suggests PVD and further investigations with segmental limb pressures, plethysmography, and various ultrasound techniques or magnetic resonance angiography are indicated.

Conventional angiography is generally performed in patients with significant ischemia as part of the workup for a revascularization procedure in suitable candidates.

Left Ventricular Hypertrophy

LVH is an independent predictor of morbidity and mortality in patients with ESRD. LV growth begins early in CKD and is associated with a number of potentially modifiable risk factors, such as anemia and hypertension. Partial regression of LVH has been associated with reduced mortality in observational studies, but randomized studies have yet to convincingly demonstrate this. It may be that primary prevention of LVH by earlier treatment of risk factors is a better approach; however, there is a paucity of randomized data supporting this as well. The following sections will outline the current evidence for the prevention and treatment of LVH with a focus on treatment of anemia and hypertension.

Anemia

In observational studies, declining hemoglobin, particularly <10–11 g/dL, is associated with the development of LVH and increased cardiovascular mortality. Uncontrolled studies have also shown that treatment of anemia is associated with partial regression of LVH and reduced mortality. Unfortunately, the data available from randomized controlled trials are less convincing. Although quality of life and exercise capacity certainly improve, there is no conclusive evidence that hemoglobin levels >10–11 g/dL improve LVH and other important clinical outcomes such as cardiovascular events and mortality.

Early randomized trials focused on the progression of LV structural abnormalities in the ESRD population with preexisting asymptomatic cardiac disease. The findings suggest that normalization of hemoglobin does not lead to regression of established LVH; however, prevention of LV dilation may occur with normalization of hemoglobin.

The predialysis population has also been evaluated for changes in cardiac dimensions with treatment of anemia. At the end of the 2-year follow-up period in the major study in this regard, there was no difference between the two groups with respect to the primary outcome, change in LVMI. It has been hypothesized that perhaps the development and progression of LVH were not clearly affected because the actual observed difference in hemoglobin between the two groups was relatively small. However, another study with a similar design demonstrated similar findings: A lack of change in LVMI with control of hemoglobin and other parameters. Additional clinical trials are ongoing to further explore the effects of various degrees of anemia correction on cardiac structure in CKD patients not yet on dialysis.

Hypertension

In the general population with essential hypertension, lowering blood pressure is associated with a regression of LVH. A meta-analysis evaluating the relative efficacy of various antihypertensive agents found that the reduction in LVMI was greatest with angiotensin II receptor blockers (ARBs), followed by angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Diuretics and β-blockers were least effective. In addition, it has recently been shown that ARBs can reduce the myocardial fibrosis observed in LVH, indicating that these medications have a direct effect on the myocardium, beyond their ability to lower blood pressure.

Data are limited in kidney disease, but some small studies support regression of LVH when hypertension is treated with pharmacologic inhibition of the rennin–angiotensin–aldosterone system (RAAS), although this has not been an entirely consistent finding. In most studies, it is difficult to ascertain how much of the effect is due to blood pressure reduction per se and how much is related to a specific effect of RAAS blockade. Nonetheless, because of the clinical and basic science evidence demonstrating that ACE inhibitors and ARBs are associated with delay of progression of kidney disease and fibrotic processes as well as other cardiovascular benefits, they are recommended as first-line antihypertensives in the CKD population.

Finally, blood pressure control has been associated with regression of LVH in observational studies of hemodialysis patients receiving either nocturnal or short daily hemodialysis compared to standard three times weekly hemodialysis.

Ischemic Heart Disease

Primary Prevention

There have been few randomized controlled trials conducted in the CKD population addressing primary prevention of ischemic heart disease. In addition, elevated serum creatinine is often a criterion for exclusion from interventional studies of the general population, which further contributes to the scarcity of data in patients with kidney disease. Nonetheless, given that CKD patients are in the highest risk group for development of CVD, it seems reasonable to apply the same general treatment recommendations applied for other patients at similar CV risk. This includes lifestyle modification, such as smoking cessation, exercise, and maintenance of ideal body weight. Glycemic control in diabetic patients and treatment of hypertension to a target blood pressure of <130/80 mm Hg (<140/90 mm Hg predialysis in hemodialysis patients) are also recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) group for CV risk reduction in CKD.

Aspirin has been recommended for primary prevention of myocardial infarction in the general population when CVD risk is high. However, these recommendations are based on the CV benefits outweighing the risk of major (intracranial or gastrointestinal) bleeding events. Although individuals with CKD have a propensity for bleeding, in the recently published First United Kingdom Heart and Renal Protection (UK-HARP-1) Study only an increased risk of minor, not major, bleeding episodes was observed with use of low-dose aspirin in CKD. However, patients with severe renal failure, who would be expected to be at highest risk of bleeding complications, represented a minority of patients in this study. Well-conducted clinical trials in heterogeneous populations of both dialysis and predialysis populations need to be conducted before aspirin can be adopted into clinical practice on a routine basis.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) appear to be safe and effective in reducing LDL cholesterol levels in renal failure; however, the evidence regarding their benefit in CKD populations is conflicting, particularly in primary prevention of CVD.

From subgroup and post hoc analyses, it appears that statin therapy may be of benefit in primary prevention in patients with mild to moderate CKD. While these analyses are encouraging, it is difficult to draw firm conclusions without corroborative data from well-designed prospective studies.

In fact, one prospective randomized trial of statin therapy for primary prevention of CVD in kidney transplant recipients yielded somewhat less optimistic results with the use of Lescol in renal transplant patients.

Data from ongoing prospective trials should help to clarify the question of whether statin use is of benefit in primary prevention of CVD in CKD. Until data from these studies become available, recommendations for treatment of dyslipidemia are taken from trials performed in the general population and summarized in K/DOQI guidelines for the treatment of dyslipidemias. As for other very high risk patients, treatment to a target LDL of <100 mg/dL (2.59 mmol/L) is recommended. The potential benefit of even further reductions in LDL levels has not yet been evaluated in CKD.

Although there are some reports that CKD increases the risk of statin toxicity, recently published studies do not confirm this. An initial dose reduction is generally recommended in severe renal failure (creatinine clearance <10 mL/minute) and caution is required in renal transplant recipients given the potential for drug interactions that may result in increased toxicity.

Acute Coronary Syndromes

CKD patients presenting with an ACS should be managed in the same way as the general population, recognizing that patients with severe renal insufficiency have generally been excluded from most trials of therapy. There are some important caveats with respect to the use of low-molecular-weight heparin (LMWH) and GPIIb-IIIa antagonists in CKD. Unlike unfractionated heparin, the clearance of LMWH is primarily renal, therefore elimination is slower and less predictable, and bleeding complications may be increased. Thus, unfractionated heparin is generally preferred in patients with significant renal insufficiency. There are some reports of an increased risk of bleeding with the use of GPIIb-IIIa antagonists; however, their use is still generally recommended in appropriate individuals. Dose adjustments may be necessary for some of the preparations as their excretion is partially renal.

Secondary Prevention

Because of a lack of evidence specific to the renal failure population, patients with CKD should receive the same secondary prevention measures employed in the general population. This includes lifestyle modification (smoking cessation, exercise, and maintenance of ideal body weight), aspirin, β-blockers, statins, ACE inhibitors, and revascularization procedures in suitable candidates.

Anemia can contribute to exercise-induced ischemia and exacerbation of angina in CKD. The target hemoglobin currently recommended by K/DOQI is 11–12 g/dL in patients with IHD. While there may be theoretical benefits to achieving a “normal” hemoglobin level, one well-known prospective randomized study in hemodialysis patients with a history of IHD or CHF showed that a more normal hematocrit (˜40%) was associated with an increased risk of nonfatal MI and death compared to the group with a lower target hematocrit (˜30%).

Coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is sometimes necessary in suitable candidates with CAD. When CKD patients are compared to the general population with CAD, patients with renal failure are more likely to experience postprocedure hemorrhagic complications, and they have higher rates of in-hospital mortality as well as poorer long-term survival with both PCI and CABG. In addition, PCI restenosis rates appear to be increased with angioplasty alone, but are likely improved if accompanied by stenting. The role of drug-eluting stents in renal failure is not yet well known. Finally, while there are no prospective randomized studies guiding the choice of revascularization method in CKD, a retrospective analysis of data from the United States Renal Data System (USRDS) favors CABG over PCI in dialysis patients, particularly in those with diabetes. Ideally, prospective studies are needed to answer this question.

In general, the decision for revascularization must be individualized and assessed on a case-by-case basis. Unfortunately, current decision making often reflects a pervasive therapeutic nihilism on the part of the general medical community toward patients with renal failure, which may lead to a postponement of testing and interventions and ultimately adversely impact the long-term outcomes of this group of patients.

Heart Failure

The two variants of heart failure, diastolic and systolic, can coexist in patients with CKD. Those CKD patients with predominantly diastolic heart failure often have significant LVH. In this case, attention should be focused on potentially modifiable contributing factors, which include hypertension and anemia.

Systolic heart failure has been studied extensively in the general population, but much less so in CKD patients. Thus studies in the general population are the only basis upon which to guide treatment in CKD. Salt restriction and diuresis are the mainstays of therapy to attain euvolemia. While loop diuretics are the diuretics of choice, a thiazide may be added to potentiate diuresis in resistant patients. Drug dose modification is often necessary in those with GFR <60 mL/minute. The dose of loop diuretics must often be increased while medications that rely on renal excretion, including certain β-blockers (eg, atenolol) and digoxin, require a dose reduction. Close follow-up is required for potentially dangerous complications that may be more common in CKD, such as hyperkalemia with the use of ACE inhibitors, ARBs, or aldosterone antagonists, and cardiac toxicity with digoxin. In addition, sotalol has been recognized as a particularly problematic antiarrythmic in CKD patients and should probably be avoided.

While patients with CKD are underrepresented in studies of heart failure, recent observational studies seem to indicate that patients with CHF and mild to moderate CKD derive a mortality benefit from medications including ACE inhibitors and β-blockers.

Finally, while correction of anemia to a target of 11–12 g/dL is important, current evidence suggests that further normalization of hemoglobin may be associated with adverse outcomes, at least in hemodialysis patients with CHF.

Peripheral Vascular Disease

PVD is a significant source of morbidity in CKD patients. The medical management of PVD generally focuses on treatment of cardiovascular risk factors such as sedentary lifestyle, smoking, diabetes, hypertension, and dyslipidemia. Revascularization, either with percutaneous intervention or with bypass surgery, is often required and amputations are common.

Given that calcification is a key feature of the vascular pathology of CKD, attempts to reduce this should theoretically be of benefit in attenuating the progression of vascular disease. This is currently an area of active research. Perhaps rigorous attention to bone mineral metabolism and maintenance of appropriate levels of serum calcium, phosphorus, and parathyroid hormone through judicious use of calcium and non-calcium-containing phosphate binders, vitamin D, and calcimimetics will attenuate the progression of vascular calcification and improve clinical outcomes in CKD.

The prognosis for CKD patients with CVD is uniformly poor. The mortality rate of dialysis patients is an astounding 20% per year, with CVD representing the most common cause. LVH is an independent risk factor for mortality in ESRD. Declining GFR is associated with increased mortality following an acute myocardial infarction. In a recent study, patients with an estimated GFR >75 mL/minute had a 3-year mortality rate from MI of 14% compared to almost 46% in patients with an estimated GFR <45 mL/minute. The outcome for patients with CHF and/or PVD in conjunction with lower GFR is also much worse than that observed in the general population.

The evidence base for treating CVD in CKD is far from complete. However, it now appears that patients with concurrent CKD and CVD likely benefit from many of the interventions implemented in individuals with CVD alone. In addition, most of these interventions can be used safely with appropriate monitoring in the CKD setting. Nonetheless, it has been consistently demonstrated that patients with CKD are less likely to receive these potentially beneficial therapies than their counterparts with normal kidney function. This has been termed “therapeutic nihilism” by some and may represent a further contribution to the poor outcomes observed with CVD in CKD.

In summary, CVD in patients with CKD is prevalent, and is likely due to a combination of both traditional and nontraditional risk factors. These factors are present to variable extents and for varying durations over the lifespan of patients with reduced GFR, and their effects are likely multiplicative rather than additive. Current data describing methods of investigation and treatment fail to give adequate direction to physicians caring for patients throughout the entire spectrum of CKD. Nonetheless, this chapter attempts to synthesize the current state of knowledge, identify gaps in the evidence base, and describe reasonable strategies based on the data available.

Given the increasing recognition of CKD as a risk factor for CVD, ongoing trials will need to explore more completely the mechanisms by which lower GFR or dialysis therapies impact the natural history of CVD. Therapeutic strategies will then be evaluated in the context of a more complete understanding of the complexity of this disease.