INTRODUCTION — The presence of cardiovascular disease is an important predictor of mortality in patients with end-stage kidney disease (ESKD) as it accounts for almost 45 percent of deaths [1,2]. Of these, approximately 10 percent can be attributed to the consequences of coronary heart disease (CHD). Patients with varying degrees of chronic kidney dysfunction but who are not dialysis dependent also have a markedly increased risk of morbidity and mortality from cardiovascular disease, including CHD. (See "Patient survival and maintenance dialysis" and "Chronic kidney disease and coronary heart disease".)
However, the relative prevalence of the various types of cardiac disease differs in patients on dialysis compared with the general population. As an example, the single, largest, specific cause of death is attributed to arrhythmic mechanisms or sudden cardiac arrest, accounting for approximately two-thirds of all cardiac deaths. Nevertheless, the rate of death from myocardial infarction and the incidence of CHD are increased among patients on dialysis versus those without kidney disease. (See "Evaluation of sudden cardiac arrest and sudden cardiac death in dialysis patients".)
This topic review will address the risk factors and epidemiology of CHD in patients on dialysis. The clinical manifestations, prevention, and treatment of CHD in these patients are presented separately:
●(See "Secondary prevention of cardiovascular disease in end-stage kidney disease (dialysis)".)
RISK FACTORS
Traditional risk factors — The difference in cardiovascular prognosis in patients on dialysis compared with those without kidney disease is related in part to the clinical status of patients when they are started on dialysis [1,3-5]. Based upon the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study, a large percentage of incident patients on dialysis have traditional risk factors for cardiovascular disease [4]. This includes diabetes (54 percent), low serum high-density lipoprotein (HDL) cholesterol (33 percent), hypertension (96 percent), left ventricular hypertrophy by electrocardiographic criteria (22 percent), low physical activity (80 percent), and increased age. It should be noted, however, that the influences of some of these traditional risk factors, such as hypertension, on cardiovascular disease in patients on dialysis are less clear than in patients not on dialysis.
Many patients on dialysis have more than one of these risk factors, resulting in an even higher risk of adverse outcomes [6]. (See "Hypertension in dialysis patients".)
Additional risk factors include the following [7-12] (see "Overview of established risk factors for cardiovascular disease"):
●Dyslipidemia – Although most patients on dialysis have normal or low total cholesterol levels, approximately 20 to 30 percent have serum total cholesterol levels greater than 240 mg/dL (6.2 mmol/L), while 10 to 45 percent have low-density lipoprotein (LDL) cholesterol levels greater than 130 mg/dL (3.4 mmol/L). In addition, hypertriglyceridemia, abnormalities in the composition and function of serum HDL particles, and elevated serum lipoprotein(a) (Lp(a)) levels are common in patients with chronic kidney disease (CKD) or end-stage kidney disease (ESKD). The risk associated with specific serum lipid and lipoprotein levels in patients on dialysis is, however, not well understood. This issue is discussed in detail separately. (See "Lipid management in patients with nondialysis chronic kidney disease".)
●Physical inactivity – Patients undergoing chronic dialysis are less active and perform at activity levels lower than those observed in sedentary healthy controls. The risk associated with low activity levels is discussed elsewhere. (See "Uremic myopathy and deconditioning in patients with chronic kidney disease (including those on dialysis)".)
●Smoking – As noted in those without kidney disease, smoking is associated with a markedly increased risk of heart disease in patients on dialysis [13,14]. (See "Cardiovascular risk of smoking and benefits of smoking cessation".)
Risk factors unique to chronic kidney disease — Some risk factors for atherosclerosis in patients with CKD result directly from the loss of kidney function and/or the utilization of measures aimed at replacing such function [15]. As examples:
Chronic kidney disease alone — Several studies suggest that the presence of CKD alone, even when the decrease in glomerular filtration rate or the increase in albuminuria is modest, is an independent risk factor for the development of coronary heart disease (CHD). As a result, practice guidelines from the National Kidney Foundation and the American College of Cardiology/American Heart Association task force have recommended that CKD be considered a CHD risk equivalent [16-18]. (See "Chronic kidney disease and coronary heart disease".)
However, whether CKD per se is a risk factor for CHD depends upon the completeness of adjustment for the nontraditional risk factors, including those that are unique to uremia.
Uremia and kidney replacement therapy — Uremia and kidney replacement therapies result in markedly enhanced oxidant stress, the production of proinflammatory cytokines, increased adhesion molecules on endothelial cells, carbamylated proteins, and other proinflammatory factors [19]. These factors may provide the proper milieu for the development of accelerated atherosclerosis [20-26]. As an example, carbamylation of LDL, a process that occurs in uremia, is associated with multiple proatherogenic effects, including smooth muscle proliferation [27]. In part, this process also appears to underlie atherogenesis in patients who smoke [28]. (See "Uremic toxins".)
Whether peritoneal dialysis is associated with increased cardiovascular risk compared with hemodialysis is unclear. The available evidence from a few studies, although limited due to bias, suggests that similar cardiovascular outcomes are likely between kidney replacement modalities among patients with ESKD and without pre-existing cardiovascular disease [29,30].
Inhibition of nitric oxide (NO) synthesis in those with ESKD may cause vasoconstriction and hypertension, thereby resulting in adverse cardiovascular outcomes. Asymmetrical dimethylarginine (ADMA), which is significantly increased in ESKD, is an endogenous inhibitor of NO [31,32]. Among patients on dialysis, ADMA may be a significant predictor of cardiovascular outcome and mortality [33]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Asymmetrical dimethylarginine' and "Uremic toxins".)
Disorders of mineral metabolism — Vascular calcification in patients on dialysis may be associated with increased calcium intake, increased serum calcium-phosphorus product, and abnormal bone metabolism. Deposition of calcium in arteries may occur in the intimal and medial layers (as observed in atherosclerotic plaques) or the medial layer alone. The latter is associated with stiffening of the vasculature but not atherosclerosis or luminal narrowing. (See "Vascular calcification in chronic kidney disease", section on 'Pathogenesis'.)
Even without atherosclerosis or luminal narrowing, coronary medial calcification may cause decreased diastolic filling, and peripheral medial calcification increases afterload to the heart.
In patients on dialysis, increased oral intake of calcium (which is given as a phosphate binder to treat hyperphosphatemia and may result in a high serum calcium-phosphorus product) may directly enhance coronary arterial calcification. These observations prompted the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines to recommend that the calcium-phosphate product be maintained below 55 mg2/dL2 in patients on dialysis. However, the recommendations related to this level are not based upon intervention trials showing benefits with lowering serum calcium-phosphate levels.
The KDOQI and Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for bone metabolism and disease in CKD are presented elsewhere [34,35]:
A detailed discussion related to vascular calcification in patients with CKD is presented separately. (See "Vascular calcification in chronic kidney disease".)
EPIDEMIOLOGY — The incidence and prevalence of coronary heart disease (CHD) in the dialysis population depend in part upon the definition that is used [36]. A confounding issue is that coronary disease often presents in atypical fashion in patients on dialysis. As a result, the presence of CHD is frequently overlooked due to the absence of classic symptoms and/or signs of heart disease. Overall, the prevalence of CHD is much higher than that observed in the general population.
The 2020 Annual Data Report of the United States Renal Data System (USRDS) reported the following for patients on dialysis [37]:
●The unadjusted prevalence of CHD in 2018 was 44 and 36 percent among patients on hemodialysis and peritoneal dialysis, respectively. When stratified by age, younger patients had a lower prevalence of CHD than older patients; for patients on hemodialysis, the prevalence of CHD was 22 percent among those ages 18 to 44 years and 41 percent among those ages 45 to 64 years. Similarly, for patients on peritoneal dialysis, the prevalence of CHD was 16 percent among those ages 18 to 44 years and 35 percent among those ages 45 to 64 years.
●The unadjusted prevalence of acute myocardial infarction in 2018 was 15 and 13 percent among patients on hemodialysis and peritoneal dialysis, respectively.
●In 2018, the adjusted mortality rate was 165 per 1000 patient-years for patients on hemodialysis and 132 per 1000 patient-years for patients on peritoneal dialysis. In patients receiving hemodialysis, cardiac disease accounted for 40 percent of deaths, of which 8 percent were attributed to acute myocardial infarction and CHD, while 85 percent were attributed to arrhythmia and cardiac arrest (which are likely attributable to nonischemic etiologies such as myocardial fibrosis and left ventricular hypertrophy), thus continuing a temporal trend of an increasing proportion of cardiac deaths attributable to arrhythmic mechanisms. The unadjusted two-year mortality rate between 2017 and 2018 was 43 percent for patients on dialysis with CHD compared with 23 percent in those without CHD.
The incidence also varies by race among patients on dialysis. In a retrospective study, the incidence of new-onset atherosclerosis was 147 per 1000 person-years and 119 per 1000 person-years among White patients and Black patients, respectively, in the United States [38]. A similar, relatively lower incidence of myocardial infarction in Black patients was observed in a study using the USRDS database [39].
Occult and/or silent myocardial ischemia is also observed in a significant number of patients on dialysis [1,13,40-43]:
●In one Japanese study, the presence of significant occult CHD using coronary angiography (greater than 50 percent stenosis) was found in 16 of 30 asymptomatic patients (53 percent) initiating kidney replacement therapy [44].
●In a second study of 67 asymptomatic patients, 28 (42 percent) had ≥50 percent stenosis in at least one vessel, while 19 (29 percent) had stenosis within the proximal third of an epicardial vessel [43].
●A third study of 67 patients on dialysis found that 16 (23 percent) demonstrated some evidence of silent ischemia during ambulatory Holter monitoring [42].
Silent ischemia is a concern clinically because it has been associated with an increased risk of myocardial infarction, serious arrhythmias, and sudden death in patients with and without end-stage kidney disease (ESKD). Several studies have confirmed a relationship between estimated glomerular filtration rate (eGFR) and the likelihood of chest pain with acute myocardial infarction [45-48]. As an example, one study that analyzed data from the USRDS and the third National Registry of Myocardial Infarction (NRMI 3) reported that only 44 percent of patients on dialysis reported chest pain with acute myocardial infarction, compared with 68 percent of patients not on dialysis [48]. (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis".)
SUMMARY AND RECOMMENDATIONS
●Traditional risk factors – A high percentage of patients undergoing maintenance dialysis have traditional risk factors for coronary heart disease (CHD), including diabetes, hypertension, left ventricular hypertrophy, dyslipidemia, increased age, smoking history, and physical inactivity. The effects of some of these traditional factors on CHD are less clear in the dialysis population than in the nondialysis population. (See 'Traditional risk factors' above.)
●Risk factors unique to chronic kidney disease – Some other proposed risk factors for CHD, including uremic toxins, carbamylated proteins, dialysis therapy, abnormalities in mineral metabolism, nonatherosclerotic arterial medial calcification, and other factors, are unique to those with kidney dysfunction. (See 'Risk factors unique to chronic kidney disease' above.)
●Epidemiology – The incidence and prevalence of coronary disease in the dialysis population depend in part upon the definition that is used. Overall, the burden of heart disease is much higher than that observed in the general population, although the precise contribution of CHD, in contrast to nonischemic heart disease, to cardiac mortality in the dialysis population is unclear. (See 'Epidemiology' above.)
