In end stage kidney disease (ESKD) patients, mortality due to cardiovascular disease (CVD) is 10 to 30 times higher than in the general population. For example, a 30-year-old dialysis patient has a similar CVD mortality risk to that of an 80-year-old in the general population. This increased risk likely reflects the very high prevalence of CVD, increased prevalence and severity of diabetes, hypertension and left ventricular hypertrophy, and nontraditional risk factors such as chronic volume overload, hyperphosphatemia, anemia, oxidant stress, and other aspects of the uremic milieu (Table 38.1). In this chapter, we focus on epidemiology and management of traditional and nontraditional CVD risk factors, and on ischemic heart disease, heart failure, pericardial effusion, valvular disease, and arrhythmia.

 I.  TRADITIONAL RISK FACTORS

     A.  Blood pressure. Data on blood pressure targets and optimal strategies and agents for blood pressure management in dialysis remain insufficient (Inrig, 2010). These are discussed in further detail in Chapter 33.

     B.  Diabetes. Dialysis patients with diabetes are at higher risk for acute coronary syndromes and have worse outcomes following coronary interventions than those without diabetes. Additionally, there is increased prevalence of heart failure. Poor blood glucose control (as assessed by glycosylated hemoglobin levels) is associated with increased mortality in dialysis patients, although precise targets remain uncertain. Cohort data suggest that a hemoglobin A1C threshold of 8% may be a reasonable target in healthier dialysis patients for cardiovascular risk reduction (Ricks, 2012), while less stringent targets may be appropriate in those with more extensive comorbidity. See Chapter 32.

     C.  Smoking. Smoking is associated with progression in early stage CKD patients, and may well adversely impact residual kidney function in dialysis patients. Smoking strongly associates with all-cause mortality in dialysis patients and likely associates with CVD. Critically, in USRDS data, former smokers had a similar risk as lifelong nonsmokers, suggesting a benefit of smoking cessation and a role for directed intervention.

     D.  Dyslipidemia

        1.  Lipid profile patterns. Dyslipidemia is very common in all stages of kidney disease, including both hemodialysis and peritoneal dialysis patients. Dyslipidemia, particularly high low-density lipoprotein (LDL) cholesterol and high triglyceride levels, is particularly common in peritoneal dialysis, where the glucose-enriched milieu predisposes to a more atherogenic lipid profile. In dialysis, similar to many advanced chronic disease states, the relationship of total or LDL cholesterol to mortality is “U”-shaped; patients with high cholesterol levels, likely due to increased atherogenic risk, and also patients with low levels, likely due to associated malnutrition, both are at heightened risk (Kilpatrick, 2007). Total cholesterol and, in particular, high-density lipoprotein (HDL) cholesterol levels may be reduced, and atherogenic lipoprotein remnants and lipoprotein (a) are often increased.
    Nearly one-third of dialysis patients have hypertriglyceridemia, defined by levels above 200 mg/dL (2.26 mmol/L), with levels occasionally 600 mg/dL (6.8 mmol/L) or higher. The predominant underlying cause is a deficiency of lipoprotein lipase, resulting in reduced lipolysis of triglyceride (TG)-rich very low-density lipoproteins (VLDL) and yielding high quantities of atherogenic remnant lipoproteins. Enrichment of LDL particles with triglycerides also suggests partial deficiency of hepatic lipase. These basic defects may be enhanced by β-adrenergic blockers, high-carbohydrate diets, absorption of glucose from peritoneal dialysate, the use of heparin, and decreased hepatic blood flow from cardiac disease.

        2.  Measurement. If not previously assessed, it is likely worthwhile to evaluate a lipid profile at least once in all dialysis patients. This can establish a diagnosis of severe hypercholesterolemia or hypertriglyceridemia (i.e., 1,000 mg/dL [11.3 mmol/L] or higher) that may prompt focused treatment or evaluation for secondary causes of dyslipidemia (Miller, 2011). Lipid panels are optimally obtained in the fasting state, particularly for evaluation of serum triglyceride levels, although, as many dialysis patients receive treatments in the afternoon or evening and data on therapy efficacy are limited, a random screening may be most practical.
    The current KDIGO lipid guideline, similar to the recent American Heart Association guideline, notes limited data to support dose escalation of lipid-lowering therapies and therefore favors a “fire-and-forget” strategy (KDIGO Lipid Work group, 2013). Accordingly, in patients already treated with a high potency statin, there is no indication to routinely measure cholesterol. Similarly, in dialysis patients not currently treated with a statin, given the data discussed below on statin efficacy for CVD prevention, there is no indication to routinely measure cholesterol.

        3.  Treatment

            a.  Principles. Treatment strategies for dyslipidemia include medications and lifestyle modifications. As in the general population, first-line therapy for most patients is dietary and lifestyle modification, including exercise whenever feasible. While the utility of lifestyle modifications for changing the lipid profile remains uncertain, there is little drawback to this strategy, particularly given other potential benefits, minimal risk, and a lack of benefit on hard outcomes associated with pharmacologic therapy.
    Dietary prescriptions are best accomplished with guidance from a nutritionist with experience in management of kidney disease patients. Recommendations listed in Chapter 31 should generally be followed. These include consumption of a diet containing about 25%–35% of total calories as fat; of this, about 20% should be monounsatured, 10% polyunsaturated, and <7% saturated fat. In patients with hypertriglyceridemia, mild restriction of total carbohydrate intake and limitation of the use of refined carbohydrate may be indicated. Additionally, alcohol ingestion should be discouraged. Despite the risk of malnutrition in many dialysis patients, there may be a minority where overall calorie restriction is indicated to achieve ideal body weight, especially among those receiving peritoneal dialysis. In PD patients, sodium restriction may reduce the use of higher dialysate glucose concentrations; this would yield less glucose absorption and decrease the stimulus for hypertriglyceridemia (see Chapter 29). If possible, physical training and regular exercise are recommended as they may result in an improved cardiovascular risk profile and an improved sense of well-being.

            b.  Statin therapy. Although dialysis patients are in the highest risk group for CVD events, several large clinical trials have failed to show a significant benefit with statin therapy, despite substantial LDL-C lowering with therapy in these trials. Accordingly, in contrast to the prior KDOQI guideline, the 2013 KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease suggests that statins or a statin/ezetimibe combination not be initiated in adults with dialysis-dependent CKD.
    In incident dialysis patients already being treated with statin therapy, these medications likely should be continued. This conclusion is based on results from the Study of Heart and Renal Protection (SHARP), which enrolled not only dialysis patients but also more than 6,000 individuals with stage 3b and 4 CKD, more than 2,000 of whom progressed to require dialysis or kidney transplant. In general, simvastatin/ezetimibe was continued during kidney replacement therapy, and, in analyses of SHARP participants who at baseline did not require dialysis, statin/ezetimibe therapy was associated with significant cardiovascular event reduction. As many of these individuals continued on therapy following dialysis initiation, it seems reasonable to continue statin therapy in individuals treated with statins at the time of dialysis initiation. Although there are no studies evaluating dialysis patients with an acute myocardial infarction (MI) who were not previously treated with a statin, it also seems reasonable to initiate statin therapy in those with a relatively good longer-term prognosis.
    One area of insufficient knowledge is peritoneal dialysis (PD). SHARP included 496 PD patients, but, aside from SHARP, PD patients have not been included in clinical trials. In SHARP, there was a trend to a benefit with lipid-lowering therapy versus placebo in this subgroup. Similarly, in a post hoc analysis of the US Renal Data System observation Dialysis Morbidity and Mortality Wave 2 cohort that used propensity score matching, lipid-lowering therapy in PD patients was associated with a significantly reduced risk of all-cause and cardiovascular death.
    In sum, based on available data, statins should be continued in those individuals already using these agents, with attention paid to dose and drug-drug interactions (Table 38.2). Additionally, in dialysis patients not previously prescribed a statin, in the opinion of the authors, statin treatment of those dialysis patients with longer life expectancies (i.e., individuals listed for transplantation) or those experiencing recent acute coronary syndromes may be appropriate. Given the paucity of data in peritoneal dialysis but physiology that suggests higher atherosclerosis risk, a “fire-and-forget” approach may also be beneficial in PD patients (Goldfarb-Rumyantzev, 2007).
    While statin use is generally safe in the dialysis population, a number of medications increase blood levels of statins via co-metabolism by hepatic cytochrome P450 enzymes; these include calcineurin inhibitors, macrolide antibiotics, azole antifungal agents, calcium channel blockers, fibrates, and nicotinic acid, and are best documented with simvastatin. Potential drug–drug interactions should be assessed in each patient. Statins may cause myopathy, and the risk of myopathy may be increased in CKD. This is particularly apparent with concurrent use of fibrates, and this combination should be avoided in CKD.

^a Statins may interact with other medications used in dialysis patients, including calcineurin inhibitors, several antibiotics, and, potentially, calcium channel blockers.

^b Based on package inserts, all fibrates are contraindicated in dialysis patients. Small short-term studies have safely utilized fibrates in dialysis patients, with one study using gemfibrozil 600 mg twice daily and another using fenofibrate 100 mg daily without any serious adverse effects. The FIELD trial of 9795 patients with type 2 diabetes evaluated fenofibrate 200 mg daily versus placebo and noted no adverse safety signals in the 519 patient subset with stage 3 CKD.

            c.  Hypertriglyceridemia management. Statins have some effect in lowering serum triglyceride level, although they are less effective than fibrates and/or nicotinic acid for this purpose. In contrast, bile acid resins may actually increase triglyceride levels. There are no data supporting a benefit of fibrates or nicotinic acid on outcome improvement in dialysis patients, particularly in those with only modest elevations in serum triglyceride level (<500 mg/dL [<5.7 mmol/L]), and these agents should not be first-line therapy in this setting. Based on this paucity of data, the 2013 KDIGO guidelines state that: “Fibric acid derivatives are not recommended to prevent pancreatitis or reduce cardiovascular risk in adults with CKD and hypertriglyceridemia.” There are no data to guide treatment decisions in dialysis patients with very high TG levels (>500 mg/dL [>5.7 mmol/L]); accordingly, treatment decisions need to balance potential risks associated with severe hypertriglyceridemia with the risks and benefits associated with therapy. Of note, adequate data do not exist to guide fibrate dosing in dialysis patients as the safety of this class has not been assessed sufficiently in dialysis patients. Small studies and reports suggest that fibrates may be safe, although some dose reduction may be prudent if these agents are used in dialysis (Table 38.2) and concurrent use with a statin is contraindicated. Available fibrates include gemfibrozil, bezafibrate, ciprofibrate, clofibrate, and fenofibrate.

            d.  Other lipid-lowering agents. Alternatives to statins and fibrates include bile acid sequestrants (including the phosphate binder, sevelamer), nicotinic acid, and ezetimibe. Bile acid sequestrants can interfere with absorption of other medications; bile acid sequestrants should not be used when triglycerides (TG) are >400 mg/dL (>4.5 mmol/L), and their use is relatively contraindicated when TG are >200 mg/dL (>2.3 mmol/L) since they may increase triglycerides in some patients. Doses do not need to be reduced in dialysis patients (Table 38.2). Sevelamer acts by the same mechanism to lower both total and LDL cholesterol, and may be a good choice when phosphorus binding is also desired. While not as effective for LDL lowering, nicotinic acid has the greatest favorable effects on HDL cholesterol levels of available drug therapies, and also lowers serum triglyceride levels. However, there are no data to support a benefit of nicotinic acid on CVD or mortality outcomes. Dosage should be reduced by about 50% in ESKD, given its substantial renal excretion. The potential of nicotinamide as a phosphorus binder has been advocated, but data are inadequate to support this indication. Adverse effects can include hyperglycemia and hepatotoxicity in individuals with underlying liver disease or when high doses are used. Flushing may be attenuated with concurrent aspirin use or by giving longer-acting preparations. Nicotinic acid is more often used as a first-line therapy when severe hypertriglyceridemia (>500 mg/dL, or 5.8 mmol/L) needs to be treated to protect against pancreatitis, or when a statin is contraindicated. Ezetimibe is a drug that inhibits cholesterol absorption. There are few data available on its use in kidney failure, although its use in conjunction with simvastatin in SHARP suggests safety.

     E.  Left ventricular hypertrophy

        1.  Epidemiology. Left ventricular hypertrophy (LVH) is highly prevalent, frequently developing prior to the need for kidney replacement therapy, and likely reflecting pressure and volume overload (KDOQI CVD, 2005). Over 30% of participants in the Frequent Hemodialysis Network studies, a group that overall was healthier than the general dialysis population, had LVH at study entry (defined using cardiac magnetic resonance imaging), with other studies showing prevalence rates of (50%–75%) patients. LVH in dialysis patients is an independent risk factor for subsequent adverse cardiovascular events and death.
    Most LVH is initially concentric, representing a uniform increase in wall thickness secondary to pressure overload from hypertension, stiffened blood vessels, or aortic stenosis. Anemia and volume overload resulting from chronic inability to effectively remove ingested sodium and fluid may each result in eccentric hypertrophy. The endpoint is often a dilated cardiomyopathy with eventual reduction in systolic function. These end-stage patients typically have low blood pressure and may be responsible for the “J”-shaped (or “U”-shaped) relationship observed between blood pressure and mortality in dialysis patients.
    LVH most often is diagnosed with echocardiography, an inexpensive, noninvasive widely available test. Cardiac function should be assessed in the euvolemic state, as both significant volume depletion and overload may reduce left ventricular inotropy. Accordingly, in dialysis patients, two-dimensional echocardiography is likely to be most informative if performed on a day during the interdialytic interval. While three-dimensional echocardiography may be useful to assess left ventricle (LV) structure as it avoids the use of geometric assumptions of LV shape that are required to estimate LV mass and volume, the increasing availability of cardiac magnetic resonance imaging likely provides the most accurate assessment of LV structure. Screening echocardiography is currently recommended for incident dialysis patients; however, there is no evidence that this improves clinical outcomes.

        2.  Prevention and management. Some data suggest that with modification of risk factors, including anemia and systolic blood pressure, strict management of volume, management of mineral and bone disorder, and use of ACE inhibitor or angiotensin receptor blocker therapy, regression of LVH may occur in dialysis patients. Data are inconsistent on whether high flow arteriovenous fistulas may lead to maladaptive cardiac remodeling. That regression of LVH results in reduced CV events and decreased mortality risk appears likely, as multiple post hoc analyses have shown a lower risk of adverse events in participants in whom LVH regressed over the course of clinical trials. Accordingly, in dialysis populations, LVH has been used both as a factor in determining study eligibility and as a surrogate outcome to infer subsequent CV and mortality risk reduction.
    

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