Traditional risk factors
Nontraditional risk factors
Hemodynamic factors
Metabolic factors
Old age
Volume overload
Proteinuria
Male sex
Anemia
Chronic inflammatory state
Menopause
Arteriovenous fistula
Malnutrition
Smoking habit
Arteriosclerosis
Disorders of lipid metabolism
Diabetes
Oxidative stress
Hypertension
CKD–MBD
Dyslipidemia
Thrombogenic factors
Physical inactivity
Family history of CVD
Progressive kidney damage leads to cardiac damage through a variety of mechanisms and factors, culminating in the unique risks that ESRD patients experience secondary to the dialysis procedure itself. Volume overload occurring in patients with ESRD may be attributable to diastolic dysfunction or circulatory congestion. As mentioned earlier, in terms of IHD and CAD, the relationship between CKD and CVD may involve shared risk factors, a reflection of widespread vascular disease and endothelial dysfunction, and/or the toxicity caused by the uremic milieu. Furthermore, IHD itself can contribute to CAD and predispose to arrhythmia. LVH and cardiac failure are the most common complications observed in patients with CKD, which are primarily attributable to fluid overload and, usually, hypertension. Myocardial fibrosis occurs secondary to impaired angio-adaptation, reduced capillary angiogenesis, myocyte-capillary mismatch, and micro-arteriopathy. The vascular tree is affected by both arteriosclerosis and atherosclerosis with widespread arterial media calcification and the deposition of lipid-rich plaques [3].
9.4 Clinical Manifestations of CVD in Patients with CKD
9.4.1 Cardiomyopathy
LVH is the most important cardiovascular structural change in patients with CKD, particularly in those with ESRD. LVH in patients with CKD is not only related to hypertension and volume load, but is also associated with activation of the local renin-angiotensin-aldosterone system and increased aortic wall stiffness. LVH is associated with diastolic dysfunction, which suggests an unfavorable prognosis in patients with CKD.
9.4.2 Coronary Atherosclerotic Heart Disease
Secondary to the occurrence of autonomic neuropathy in patients with CKD and the volume overload, myocardial ischemia may atypically present as asymptomatic acute myocardial infarction (AMI), which may be misdiagnosed, and thus patients may not receive prompt treatment.
9.4.3 Congestive Heart Failure
Patients with CKD, particularly those with ESRD undergoing dialysis, demonstrate the hypervolemia that can lead to LVH, LV enlargement, edema, and acute pulmonary edema.
9.4.4 Arrhythmia and Sudden Cardiac Death
Arrhythmia is a common clinical complication in patients with ESRD, particularly during the course of hemodialysis (HD). Sudden death is known to occur in patients with ESRD, primarily related to ventricular fibrillation, and approximately 20% of these cases are secondary to cardiac arrest. Cardiac arrhythmia is usually associated with hyperkalemia in patients with CKD.
9.4.5 Pericarditis
Untreated uremic pericarditis is rare, although dialysis-related pericarditis is common in patients with ESRD and usually occurs in those with insufficient dialysis. Echocardiography should be performed in patients presenting with pericardial pain and fever or when auscultation reveals pericardial friction sounds.
9.4.6 Heart Valve Disease
Disorders of calcium and phosphorus metabolism, long dialysis vintage, hypoalbuminemia, and old age are significant risk factors in patients with CKD complicated with valvular disease and calcification. Valvular calcification with regurgitation can cause stenosis and hemodynamic instability, as well as conduction disorders in patients with CKD.
9.4.7 Peripheral Vascular Diseases
Diabetic patients and those with atherosclerosis undergoing dialysis are at a high risk of peripheral vascular disease. The occurrence of peripheral vascular diseases in patients undergoing HD is related to dialysis vintage and hypoalbuminemia. Peripheral arterial calcification does not always lead to occlusive disease; however, occlusive small vessel disease causes gangrene.
9.5 Diagnosis of CVD in Patients with CKD
Although CVD is highly prevalent in patients with CKD, its clinical diagnosis remains challenging because of atypical signs and symptoms observed in patients. The diagnostic criteria used in the general population are not always applicable to patients with CKD owing to the decline in renal function in this patient population. For example, symptoms of heart failure (e.g., dyspnea, fatigue) and physical signs of volume overload are highly prevalent in patients with CKD even in the absence of cardiac dysfunction. It has also been reported that patients with ESRD with AMI may not always present with chest pain.
9.5.1 Serological Tests
9.5.1.1 Cardiac Troponins
Although the estimation of single myocardial enzymes does not show high diagnostic specificity, the dynamic changes in levels of enzymes such as creatine kinase-MB and lactate dehydrogenase can effectively diagnose AMI. Positive serum cardiac troponin T (cTnT) and troponin I (cTnI) indicate acute ischemia, and the sensitivity of these tests in assessing the extent of myocardial infarction is greater than that of myocardial enzymes. High-sensitivity-cardiac troponin (hs-cTn) is the preferred cardiac marker to diagnose acute coronary syndrome (ACS). However, the upper reference limits for cTnT and cTnI were originally established in patients without CKD, and these biomarkers are elevated in approximately 80% of patients with asymptomatic CKD and ESRD. Notably, cTn elevation does not necessarily indicate acute ischemia secondary to coronary atherosclerosis. Elevated cTn levels may be secondary to decreased renal clearance or chronic myocardial injury. Multifactorial pathomechanisms are involved including myocardial strain from hemodynamic alterations, inflammation, endothelial dysfunction, and subendocardial ischemia. In contrast to cTnI, cTnT assays are standardized. In asymptomatic patients with CKD, cTn levels are associated with various surrogate markers such as LVH, doubling of serum creatinine levels, and CKD progression, as well as serious clinical outcomes such as death and cardiovascular events. Patients with ESRD presenting with an initial cTnT concentration >0.35 ng/mL demonstrate an unfavorable prognosis; therefore, a higher cutoff value is recommended for cTnT for prompt diagnosis and treatment in patients with ACS undergoing dialysis. Regular and close monitoring of hs-cTn is important in patients with CKD for clinical management rather than using a single value that is higher than the upper limit of normal [4].
9.5.1.2 Estimation of Brain Natriuretic Peptide and N-Terminal-pro-BNP
Brain natriuretic peptide (BNP) and N-terminal-pro-BNP (NT-pro-BNP) levels are commonly tested in symptomatic patients with suspected acute CHF exacerbation. Previous reports have shown elevated levels in 56% of asymptomatic patients with CKD. LV myocytes release BNP and NT-pro-BNP from precursors in response to increased stretch or tension. BNP is an active molecule with a short plasma half-life and is metabolized in the circulation by enzymatic action. NT-pro-BNP is the inactive form of BNP, with a longer half-life and primarily undergoes renal clearance. A reduced estimated glomerular filtration rate (eGFR) correlates with elevated plasma NT-pro-BNP levels to a greater extent than with elevated BNP levels. An increased NT-pro-BNP/BNP ratio shows a significant correlation with progression of CKD, particularly with eGFR <30 mL/min/1.73 m2. However, both BNP and NT-pro-BNP are associated with surrogate markers and serious clinical outcomes in asymptomatic patients with CKD [4]. A previous study involving 150 asymptomatic patients undergoing HD with a mean follow-up of 24 months showed that the correlation between NT-pro-BNP and all-cause and cardiovascular mortality was significantly stronger than that with cTnT. A recent cross-sectional study has shown that NT-pro-BNP levels of 6000 and 10,000 pg/mL are the optimal cutoff values to diagnose CAD and LV systolic dysfunction, respectively. Therefore, estimation of the NT-pro-BNP level prior to the initiation of dialysis is an important screening tool for cardiac abnormalities. A recent prospective cohort study involving 3483 patients with CKD without heart failure showed that the potential rate of heart failure was higher in patients with the highest levels of NT-pro-BNP (>433 pg/mL) with a risk ratio of 9.57. Therefore, NT-pro-BNP and BNP are useful biomarkers for LV dilatation, and systolic and diastolic dysfunction in patients undergoing dialysis. Notably, they serve as biomarkers for the prediction of cardiovascular mortality in patients with CKD not undergoing dialysis [5].
9.5.1.3 Serum Mineral and Bone Biomarkers
Patients with CKD-MBD demonstrate increased serum intact parathyroid hormone (iPTH) levels, vitamin D deficiency, and hyperphosphatemia, which serve as independent risk factors of CVD. The fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism and its levels increase progressively in early CKD, partially as an adaptation to the uremic environment and also as a primary pathophysiological event that may account for several clinical manifestations including bone and cardiovascular complications. Increased plasma FGF23 levels are associated with LVH, vascular calcification, cardiovascular dysfunction, and increased mortality in patients with CKD.
9.5.1.4 Other Serum Biomarkers
In addition to cTnT and BNP, C-reactive protein, asymmetric dimethylarginine (ADMA), N-monomethyl-l-arginine (l-NMMA), plasminogen-activator inhibitor type I, homocysteine, serum amyloid A protein, ischemia modified albumin, and several others serve as biomarkers that progressively increase with a decline in the eGFR. Many of these are independently associated with CVD in patients with CKD. C-reactive protein is a well-known inflammatory biomarker that is strongly associated with vascular disease. In addition to being a biomarker, it is considered potentially causally related to vascular disease. ADMA and l-NMMA are endogenous inhibitors of nitric oxide synthases that attenuate nitricoxide production and enhance the generation of reactive oxidative species. Increased plasma levels of ADMA and/or l-NMMA are strong and independent risk factors for CKD and various types of CVD. The increased cardiovascular morbidity associated with CKD may be attributed to significantly increased levels of systemic ADMA and l-NMMA [6].
9.5.2 Instrumental Examinations
9.5.2.1 Electrocardiography and 24-H Dynamic Electrocardiography
Static electrocardiography (ECG) performed in patients undergoing HD show prolonged PR and QRS intervals and nonspecific ST-T segment changes. These changes are more pronounced during intra- and extracellular fluid shifts during dialysis. Typical ECG changes can be observed in patients with acute coronary ischemia. Monitoring with 24-h dynamic ECG is helpful to diagnose premature beats and other arrhythmias in patients with CKD.
9.5.2.2 Echocardiography and Doppler Ultrasonography
Echocardiography is the primary tool used to evaluate ventricular and valvular structures and cardiac function. This noninvasive diagnostic modality used in clinical practice performs real-time qualitative and quantitative evaluation. Echocardiography demonstrates signs of volume overload, particularly left and right ventricular dysfunction in patients with ESRD and those undergoing HD. Volume overload is indicated by increased atrial volumes or areas, pleural or pericardial effusion, and lung comets. Valvular calcification (related to secondary hyperparathyroidism) and features of right-sided cardiac dysfunction such as high pulmonary artery pressures or right chamber dilatation are commonly observed. Echocardiography and Doppler ultrasonography can also diagnose complications of uremic cardiomyopathy such as coronary and peripheral artery disease, LVH, vascular and valvular calcifications, and myocardial fibrosis. LVH is usually assessed by performing standard two-dimensional (2-D) echocardiography, which though not very accurate, is cost-effective. The accuracy of echocardiography depends upon the technique used, the timing of the test relative to the dialysis session, and the index used for “normalization” of the data generated. Estimation of the LV mass in patients with CKD and ESRD can be performed using 2-D and 3-D echocardiography techniques. Assessment of LV mass, volume, and EF using real-time 3-D echocardiography shows higher accuracy than that with 2-D echocardiography. The accuracy of this modality is close to that of cardiac magnetic resonance imaging (CMRI). Tissue Doppler imaging scores over conventional Doppler echocardiography in evaluating CKD-related cardiac complications and early diastolic dysfunction based on its ability to accurately record local and global myocardial velocity changes. With the development of advances in ultrasonographic technology might provide better and a greater number of radiological techniques to evaluate cardiac abnormalities in patients with CKD.
9.5.2.3 Cardiac Computed Tomography and Cardiac Magnetic Resonance Imaging
Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (CMRI) are useful to evaluate complications of uremic cardiomyopathy. Cardiac CT detects coronary artery calcifications and can diagnose coronary atherosclerosis in patients with CKD. CMRI is considered the gold standard for the accurate evaluation of the LV mass, to define the volume and pattern of LVH (eccentric, concentric or asymmetric), and to assess the magnitude of fibrosis. Compared with CMRI, classical echocardiography often overestimates the LV mass in patients undergoing dialysis; however, CMRI is not a practical option for widespread use owing to the higher costs. Therefore, echocardiography remains the primary tool to evaluate LV mass in clinical practice. CMRI allows complete assessment of arterial function through measurement of aortic distensibility (AD); a reduction in the AD is observed in the early stages of the evolution of CKD-related cardiomyopathy.
9.5.2.4 Coronary Angiography
Coronary angiography is the gold standard to diagnose CAD. Patients with CKD in the pre-dialysis stage are at a high risk of developing contrast nephropathy and deterioration of renal function following the administration of contrast agents. All patients with CKD are also at risk for cholesterol embolism. Therefore, coronary angiography should be cautiously performed in patients with CKD. Coronary angiography is warranted in patients with unstable angina or myocardial infarction prior to undergoing coronary angioplasty.
9.5.2.5 Doppler Angiography and Intravascular Ultrasound Imaging
The development of ultrasound imaging technology has enabled the real-time analysis of blood vessels and vascular blood flow. Waveforms typically vary across vascular beds, and abnormal waveforms indicate arteriopathy. The lesions and plaques in surrounding vessels and the coronary arteries, as well as changes in the endovascular cavity, can be identified using high-frequency probes and intravascular imaging.
9.5.2.6 Ambulatory Blood Pressure Monitoring
Ambulatory blood pressure monitoring (ABPM) is essential for the accurate determination of BP levels, particularly in patients with CKD [7]. ABPM scores over traditional office BP measurements in that it can avoid the white coat effect and provide additional information regarding a patient’s BP including short-term BP variability and circadian rhythm (i.e., “dipping” or “non-dipping” status). It is also essential to diagnose “white coat hypertension” and “masked hypertension.” In our previous study, we observed that approximately 50% of the patients undergoing dialysis who were considered to show controlled BP actually demonstrated “masked uncontrolled hypertension” and that this condition is associated with hypertensive end-organ damage [7]. Therefore, physicians should routinely use ABPM in these patients.
9.5.2.7 Measures of Arterial Elasticity, Endothelial Function, and Pulse Wave Velocity
Previous studies have shown that a few noninvasive modalities that are not widely adopted in clinical practice are useful to assess cardiovascular health and for risk prediction in patients with CKD. Assessment of vascular function including the estimation of arterial elasticity and endothelial function serves as a potentially valuable indicator of cardiovascular health and should be considered in the care of patients with CKD [8, 9]. Measurement of pulse wave velocity is a standard measure of arterial stiffness and can be performed with several commercially available devices [10]. The “flow-mediated dilation” test is the traditional method to assess endothelial function; however, it requires a highly experienced operator, and its reproducibility is usually unsatisfactory. A device based on peripheral arterial tonometry has recently been developed for automatic measurement of peripheral endothelial function. We adopted this measurement method in a dialysis cohort to test if it could overcome the challenge of the fistula and predict cardiovascular outcomes in patients undergoing maintenance HD [11].
9.6 Treatment of CVD in Patients with CKD
9.6.1 Risk Factor Intervention
9.6.1.1 Intervention for the Management of Traditional Risk Factors
Antihypertensive treatment
Hypertension is highly prevalent among patients with CKD and contributes to the high burden of CVD-related morbidity and mortality. Strict volume control via sodium restriction constitutes the first-line approach for the treatment of hypertension in this patient population; however, antihypertensive drug therapy is often needed to control BP. Selection of an optimal antihypertensive regimen should be individualized. The latest 2018 European Society of Cardiology/European Society of Hypertension guidelines for the management of hypertension recommend initial combination therapy with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) or diuretics in patients with CKD. ACEIs/ARBs are more effective than other antihypertensive drugs in reducing proteinuria in patients with CKD. Serum potassium and creatinine levels should be closely monitored in patients with CKD who receive ACEIs or ARBs. Thiazide diuretics are contraindicated and loop diuretics can be used in patients with CKD demonstrating eGFR <30 mL/min/1.73m2. Probing dry weight can improve BP among hypertensive patients undergoing HD. Intra- and interdialytic pharmacokinetics, effect on cardiovascular reflexes, treatment of comorbidities, and the adverse effect profile are important factors that determine individualization of therapy. Beta-blockers and dihydropyridine CCBs constitute the first- and second-line antihypertensives, respectively, that are commonly prescribed. ACEIs and ARBs are third-line choices because there is limited evidence supporting their use in patients undergoing dialysis. Diuretics have little to no role in patients with ESRD [12].
Correction of abnormal lipid metabolism
The short-term efficacy and safety of statins have been confirmed in patients with CKD, and statins are the most effective drugs to reduce low-density lipoprotein (LDL)-cholesterol in these patients. The long-term effects of statins on cardiovascular outcomes in patients with CKD have also been well documented, and they are known to reduce proteinuria. Statins are recommended in patients presenting in the early stages of CKD because their use during this period significantly reduces the relative risk of CVD. The continued role of statins in patients who require dialysis is controversial because previous trials that investigated statin use in patients undergoing dialysis have shown negative results. All patients with CKD are considered to be at a high risk, and lipid-lowering therapy is indicated in patients with LDL-cholesterol >100 mg/dL except in patients undergoing dialysis.
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