Atherosclerosis which refers to an intimal disease, more frequent in CKD/ESRD than in nonrenal populations, is characterized by the presence of plaques and occlusive vascular lesions [12, 18, 19]. Calcifications, when present, involve the intima [18, 19]. However, in CKD, the atherosclerotic lesions have a distinct morphology. They are frequently calcified with a relatively increased media thickness, whereas in the general population, they are fibroatheromatous with thickening of the intima [18, 19].

Intimal calcification is observed in older patients with a clinical history of atherosclerotic complications and even before the initiation of dialysis therapy [20]. In contrast, medial calcification occurs more frequently in young and middle-aged patients with CKD, and its severity increases with the degree of uremia-related cardiovascular risk profile [20, 21].

In CKD, as in the general population, traditional cardiovascular risk factors have been postulated to initiate the atherosclerotic process [5, 11]. Among these factors, dyslipidemia appears to be a major determinant [22–24]. However the atherogenic dyslipidemia pattern, which is characterized by increased triglycerides, low high-density lipoprotein cholesterol (HDL-C), and normal or near-normal total serum cholesterol levels, plays a critical role in the pathogenesis of the atherosclerotic process only in patients with mild renal functional impairment [25, 26]. In contrast, in patients with more severe renal functional impairment, the atherogenic dyslipidemia pattern becomes a weaker predictor of atherosclerosis and cardiovascular disease [25, 26]. In moderate to severe renal insufficiency, there appears to be no relationship between renal function and progression of the atherosclerotic process [27]. No difference in atheroma plaque volume and growth could be demonstrated in patients with GFR >60 ml/min/1.73 m² versus those with GFR <60 ml/min/1.73 m². These observations suggest that in more severe renal functional impairment, pathobiologic processes other than or in addition to the known traditional factors may be involved in the initiation and progression of cardiovascular disease [26–28].

Atherosclerotic lesions tend to be patchy in distribution along the length of the artery and more frequent in the CKD population and tend to be more occlusive [25–28]. Clinical presentations include ischemic heart disease (angina, myocardial infarction, and sudden cardiac death), cerebrovascular disorders, and heart failure [25, 26].

Arteriosclerosis is a frequent vascular lesion in CKD/ESRD. It is defined as hardening or stiffening of the arteries, particularly the elastic arteries (aorta/major branches and common carotid artery), and is characterized by increased luminal diameter, media thickness, and extracellular matrix, destruction of the elastic lamellae, and extensive medial calcification [20, 21, 29, 30]. These structural modifications, often referred to as remodeling, reduce elasticity and compliance and increase stiffness of the elastic arteries, impairing the cushion function and capacity to smooth out the pulsatile flow associated with intermittent ventricular ejection [29, 30].

Arterial aging impaired renal function and elevated BP levels are the major determinants of increased arterial stiffness [29].

Factors that link arterial stiffness to renal function have not been completely elucidated. Disturbed mineral metabolism associated with renal functional impairment has been postulated to account for remodeling process [20, 28]. In CKD/ESRD, the mineral metabolism, characterized by hyperphosphatemia, increased calcium phosphorous product, hyperparathyroidism, and reduced 1,25 vitamin D(OH) 25, appears to induce medial calcification and arterial stiffening [20, 28, 31–33]. However the relationship between increased arterial stiffness and renal function is not limited to patients with substantially impaired renal function and ESRD. An inverse relationship between arterial stiffness and renal function has been reported in a group of never-treated individuals with mild renal insufficiency (serum creatinine ≥1.47 mg/dl) and normal or mildly elevated BP levels [34]. It has been postulated that in such individuals changes in serum phosphate levels, although still within the normal reference range, may trigger arterial calcification and cause increased arterial stiffness [34].

Ejection of left ventricular stroke volume into stiff elastic arteries results in an increase in amplitude of the systolic and a decrease in diastolic blood pressures, enhanced pulse wave velocity and early return of the reflected pulse wave into late systole, and a wide pulse pressure [35, 36]. Clinically, these alterations in arterial function are associated with isolated systolic hypertension, left ventricular hypertrophy, coronary hypoperfusion, and damage to highly perfused target organs such as the brain and the kidneys. These patients are prone to develop coronary events, heart failure, impaired cognitive function and dementia, and renal dysfunction [35, 36].

Patients on renal replacement therapy often exhibit both atherosclerosis and arteriosclerosis. Both lesions are more severe and more widespread. A significantly higher prevalence of calcified plaques has been reported in the common carotid artery [23, 24, 28, 29, 37].

The arteriosclerotic changes which involve the large central elastic arteries are characterized by luminal dilatation, increased intima-media thickness, and significant increase in arterial stiffness. In uremic patients, the altered arterial stiffness appears to be more apparent in younger than in older individuals, since aging may mask the uremia-related elevation in the wall properties of the vessel [7, 28, 29].

The high incidence of cardiovascular events in dialyzed and uremic patients has been attributed to the severe macrovascular disease in this population [37, 38].

Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare life-threatening microvascular calcific disorder which affects predominantly adult patients with ESRD and uremia or with CKD [39, 40]. It is characterized both by specific histopathologic findings and clinical presentation. Histopathologic findings include media calcification of the small- and medium-sized vessels, extravascular calcification, intimal proliferation, microthrombus formation, epidermal ulceration, and subdermal and dermal necrosis [39]. The obliterative vasculopathy also involves both venules and capillaries [39]. The clinical manifestations are characterized by painful, violaceous, mottled skin lesions which may progress to tissue necrosis, nonhealing ulcers, and gangrene, possibly leading to amputation, sepsis, and/or death [39]. Multiple risk factors, such as female gender, diabetes, obesity, warfarin use, hyperphosphatemia, hyperparathyroidism, use of calcium-containing phosphate binders, and severe CKD, have been postulated to act as pathophysiologic factors [39–41]. The prognosis of CUA is poor, being determined by the underlying cardiovascular disease [39, 40].

Cardiovascular disease (CVD), the leading cause of mortality in patients with end-stage renal disease (ESRD), accounts for over 40 % of all deaths [42]. Of all of these various complications, heart failure, often referred to as uremic cardiomyopathy, appears to be the most frequent [43–46].

The pathophysiologic mechanism of uremic cardiomyopathy has not been completely elucidated. In contrast to the general population, the contribution of atherosclerotic coronary artery disease is less important in CKD [43–46]. In an autopsy study of 94 uremic patients dying from heart failure, presence of coronary heart disease was absent to minimal in 40 % [42].

Hemodynamic, structural, and uremia-related humoral and metabolic factors have been postulated to account for uremic cardiomyopathy. With worsening renal function and onset of heart failure, uremic patients often exhibit hypertension, anemia, and overactive circulation associated with the creation of an arteriovenous fistula in those on hemodialysis treatment, increased arterial stiffening, left ventricular hypertrophy, and dilatation resulting from pressure and volume overload [45, 46]. Structural changes in autopsied uremic hearts include intracardiac coronary artery thickening, decreased myocardial capillary density, increased myocardial fibrosis, and inhibition of apoptosis in hearts of experimental uremic animals [42–46]. Clinically these patients present heart failure resistant to therapy, evidence of myocardial ischemia and arrhythmias, and sudden cardiac death [45].

Endothelial dysfunction, a major determinant of cardiovascular disease, is frequently reported in CKD/ESRD [47].

Endothelial function is assessed by dilatation of the brachial artery in response to hyperemia or administration of sublingual glyceryl trinitrate (nitroglycerine) [48]. Maximal brachial artery dilatation to hyperemia assesses endothelium-dependent vasodilatation while the response to nitroglycerine evaluates the endothelium-independent vascular function [48].

In CKD, the endothelium-dependent vasodilatation is defective, while the endothelium-independent vascular function remains intact [48].

In CKD, impairment of endothelial function has been reported even in mild decrease in renal function and becomes progressively severe with further deterioration in renal function [48].

Several factors have been implicated in the pathophysiology of endothelial function in CKD [47–50]: (1) impaired nitric oxide release or bioavailability due to accumulation and elevation of asymmetric dimethylarginine (ADMA) levels, (2) oxidative stress associated with accumulation of oxidative stress markers, (3) activation of renin-angiotensin system which induces oxidative stress, (4) chronic inflammation, (5) homocysteinemia, (6) hyperuricemia, (7) dyslipidemia, and (8) deficiency of endothelial progenitor cells.

Changes in the structural properties of the microcirculation have been documented in CKD and ESRD. These structural modifications are characterized by remodeling of the resistance arteries and arterioles and capillary rarefaction.