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Introduction

Recent data indicate that the burden of chronic kidney disease (CKD) is steadily increasing in the United States [1]. Cardiovascular (CV) disease (CVD) is the leading cause of morbidity and mortality in patients with CKD [2]. Both decreased glomerular filtration rate (GFR) and increased proteinuria are independent CV risk factors in community-based populations as well as in patients at high CV risk [3–5]. Notably, CVD-associated mortality rates increase progressively with increasing CKD stages and are extremely high in end-stage renal disease (ESRD) patients receiving dialysis (10–30 times higher than age-adjusted CV mortality in the general population) [5–7]. It has been reported that 39 % of incident dialysis patients have ischemic heart disease [8], whereas the annual rate of myocardial infarction and/or angina is approximately 10 % [9]. It is well established that dyslipidemias play a pivotal role in the pathogenesis of CVD in the general population [10]. However, the association of dyslipidemia and CVD in CKD patients is confounded by the presence of the so-called non-traditional CV risk factors (inflammation, vascular calcification, anemia, increased oxidative stress, and endothelial dysfunction), rendering the answer to the question of whether and which CKD patients might benefit from lipid-lowering treatments of major importance [11].

Definition and Classification of CKD

CKD is defined based on the presence of either kidney damage (structural or functional abnormalities other than decreased GFR) or decreased kidney function (GFR <60 mL/min/1.73 m2) for 3 or more months, irrespective of cause. Kidney damage refers to pathologic abnormalities detected by a renal biopsy or imaging studies, urinary albumin excretion >30 mg/day, urinary sediment abnormalities, or renal transplant status. Decreased kidney function refers to a decreased GFR, which is usually estimated (eGFR) using serum creatinine and one of several available equations such as the Modification of Diet in Renal Disease (MDRD) and, more recently, the CKD-Epi formula [12]. The definition and classification of CKD were introduced by the National Kidney Foundation (NKF) Kidney Disease Outcomes Initiative (KDOQI) in 2002 [13] and adopted with minor changes by the international guideline group Kidney Disease Improving Global Outcomes (KDIGO) in 2004 [14]. Until recently, staging of CKD was based on eGFR and a five-stage classification was used (Table 5.1). This classification has been recently modified to an 18-stage classification by adding albuminuria stage, subdivision of stage 3, and the cause of CKD (Table 5.2) [5, 15]. By using this modified 18-stage classification, an improved stratification of CKD progression and its major complications has been achieved, thus providing a better guidance for the monitoring and management of CKD patients. However, as most studies have been based on the original classification, we will refer to this one in this chapter.

Table 5.1 The five stages of CKD as defined by the National Kidney Foundation
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Table 5.2 Revised chronic kidney disease staging
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Association Between CKD and CVD-Epidemiological Data

It is well established that CV mortality rates increase dramatically with advanced CKD stages. In fact, individuals with CKD are more likely to die of CVD than to develop ESRD [6, 16]. Intriguingly, younger ESRD patients (25–34 years old) exhibit 500-fold greater CV mortality rates than age-matched controls with normal renal function [6]. Accumulating evidence suggests that the link between CKD and increased CV morbidity and mortality holds across populations with various degrees of baseline renal function or CV status.

In the General Population

There are plenty of observations that demonstrate an independent association between diminished GFR or proteinuria and major adverse CV events (MACE) in the general population [17–21].

In a high-quality meta-analysis of general population cohorts including 105,872 participants with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants with urine protein dipstick measurements, followed for 7.9 years, Matsushita et al. concluded that eGFR less than 60 mL/min/1.73 m2 and ACR 1.1 mg/mmol (10 mg/g) or more independently predict all cause and CV mortality risk in the general population. In studies with dipstick measurement of proteinuria, a trace urine-positive dipstick was also associated with increased all-cause and CV mortality independently of the level of kidney function [19].

Go et al. evaluated 1,120,295 subjects for the risk of death, CV events, and hospitalization relative to various levels of GFR over 2.84 years [22]. The adjusted hazard ratio for death was 1.2 with an eGFR of 45–59 mL/min/1.73 m2 (95 % CI, 1.1–1.2), 1.8 with an eGFR of 30–44 mL/min/1.73 m2 (95 % CI, 1.7–1.9), 3.2 with an eGFR of 15–29 mL/min/1.73 m2 (95 % CI, 3.1–3.4), and 5.9 with an estimated GFR of less than 15 mL/min/1.73 m2 (95 % CI, 5.4–6.5). The adjusted hazard ratio for CV events also increased inversely with the estimated GFR: 1.4 (95 % CI, 1.4–1.5), 2.0 (95 % CI, 1.9–2.1), 2.8 (95 % CI, 2.6–2.9), and 3.4 (95 % CI, 3.1–3.8), respectively. This large study demonstrated effectively the inverse association between GFR and rates of CV morbidity and mortality in patients without a prior history of CVD.

Weiner at al. pooled data from community-based trials including the Atherosclerosis Risk in Communities Study, CV Health Study, Framingham Heart Study, and Framingham Offspring Study; 22,634 subjects were followed for 10 years. CKD was defined by a GFR between 15 and 60 mL/min/1.73 m2. A composite of myocardial infarction, fatal coronary heart disease (CHD), stroke, and death was the primary study outcome. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio, 1.19; 95 % CI, 1.07–1.32) [21].

In Patients with CV Risk Factors or Preexistent CVD

A growing number of studies have shown an association between the decrease in GFR and CV events among patients with known risk factors for CVD or preexistent CVD [2, 4, 23–28]. Van der Velde et al. performed a collaborative meta-analysis of ten cohorts with 266,975 patients with a history of hypertension, diabetes, or CV disease. Hazard ratios for CV mortality at eGFRs of 60, 45, and 15 mL/min/1.73 m2 were 1.11, 1.73, and 3.08, respectively, compared to an eGFR of 95 mL/min/1.73 m2, whereas similar findings were noted for all-cause mortality. There was also an association between albuminuria and risk for overall and CV mortality. The authors concluded that decreased eGFR and higher albuminuria are risk factors for all-cause and CV mortality in high-risk populations, independent of each other and of CV risk factors.

Mann et al. performed a post hoc analysis of the Heart Outcomes and Prevention Evaluation (HOPE) study [29]. The HOPE study included individuals with an objective evidence of vascular disease or diabetes combined with another CV risk factor and was designed to test the benefit of add-on ramipril vs. placebo. Nine hundred and eighty subjects with mild renal insufficiency (serum creatinine ≥ 1.4 mg/dL) and 8,307 subjects with normal renal function (serum creatinine < 1.4 mg/dL) were followed for ≈5 years. The cumulative incidence of the primary outcome (composite of CV death, myocardial infarction, or stroke) was significantly higher in individuals with mild renal insufficiency compared to those with normal renal function (P < 0.001).

Perkovic et al. in the Perindopril Protection against Recurrent Stroke Study (PROGRESS) randomly allocated 6,105 participants with cerebrovascular disease to perindopril-based blood pressure-lowering therapy or placebo. Individuals with CKD were at approximately 1.5-fold greater risk of major vascular events, stroke, and CHD, and were more than twice as likely to die (all P ≤ 0.002).

With respect to the relationship between albuminuria and CKD in patients with CV risk factors or preexistent CKD, Anavekar et al. [30] in a post hoc analysis of the Irbesartan Diabetic Nephropathy Trial (IDNT) showed that the proportion of patients who exhibited the CV composite endpoint (CV death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization) increased progressively with increasing quartiles of baseline urine ACR. This result was confirmed by a multivariate analysis in which albuminuria was an independent risk factor for CV events with a 1.3-fold increased relative risk for each natural log increase of 1 U in urine ACR. In the IDNT study 1,715 subjects with type-2 diabetes, hypertension, and macroalbuminuria were randomized to irbesartan, amlodipine, or placebo for a mean period of 2.6 years. The patients had mean urine ACR of 1,416.2 mg/g. Moreover, the HOPE study investigators evaluated the risk of CV events associated with baseline microalbuminuria (defined as ACR > 2.0 mg/mmol (equivalent to 17.7 mg/g)). In the overall population, microalbuminuria at baseline approximately doubled the relative risk of the primary composite outcome (myocardial infarction, stroke, or CV death), and this effect was significant in both diabetics (relative risk, 1.97) and nondiabetics (relative risk, 1.61) [31]. Moreover, albuminuria was a continuous risk factor for CV events even below the level of microalbuminuria.

Future CV risk in the general population can be modeled in various ways, one typical approach being the Framingham score (though QRISK and other algorithms may be much superior especially for diverse populations). It has been shown that the Framingham score demonstrates poor overall accuracy in predicting cardiac events in individuals with CKD [32], and this might be due to the increased CV and overall mortality rates in these patients. Modification of the Framingham equations might improve their predictive accuracy, yet new models evaluating CV risk in this population should be developed.

Cardiovascular Risk Factors in CKD: The Role of Dyslipidemia

Evidence that reduced GFR and increased albuminuria independently and continuously predict higher CV event rates in CKD patients with or without preexistent CVD, prompts for the early detection and abrogation of the responsible factors that predispose these patients to the development of CVD. Apart from the traditional CV risk factors that are defined by epidemiological studies such as the Framingham study and are present in the general population, CKD patients also exhibit a variety of non-traditional risk factors that accelerate and aggravate the development of CVD in this population.

Traditional risk factors include smoking, diabetes, hypertension, left ventricular hypertrophy (LVH), older age, and hyperlipidemia. These factors are highly prevalent in the CKD setting [33], and they tend to increase the risk of CVD in early CKD stages [34]. Moreover, metabolic syndrome, a condition characterized by insulin resistance, elevated serum glucose, hypertension, abdominal obesity, and dyslipidemia, might also play a role in the development of CVD. This syndrome is also frequently detected in patients with CKD [35].

Although hypercholesterolemia is one of the most widely recognized CV risk factors in the general population as well as in patients with preexistent CVD [10, 36–39], this association in CKD has been difficult to establish. In fact, some studies have shown that low cholesterol levels associate with increased mortality in dialysis patients [11, 40, 41], whereas another study failed to detect any association between hyperlipidemia and mortality in nondiabetic stage 3–4 CKD patients [42]. However, this reverse epidemiology of lower cholesterol predicting a higher mortality is likely due to cholesterol-lowering effect of malnutrition and systemic inflammation, both present in CKD patients [11, 43]. Furthermore, the presence of numerous non-traditional risk factors in the CKD setting further confounds the association of CKD and CVD, thus increasing the prevalence of CVD even in patients with mild to moderate CKD [44]. These factors include increased oxidative stress, amplified inflammatory status, anemia, abnormalities in mineral-bone metabolism, endothelial dysfunction, and reduced nitric oxide (NO) activity [45–48].

The role of oxidative stress and inflammation in the development of CVD in CKD has recently been increasingly supported. In patients with CKD the balance between the production of reactive oxygen species (ROS)/free radicals (FR) and antioxidant defenses is shifted towards amplified oxidative stress. The increase in ROS/FR is caused by numerous factors such as uremic toxins, diabetes mellitus, chronic inflammation, and the dialysis treatments per se [49, 50]. Oxidative stress in uremia can be increased through activation of various ROS-producing enzymatic systems such as the reduced nicotinamide adenine dinucleotide (NAD(P)H) oxidase, xanthine oxidase, uncoupled endothelial NO synthase, and myeloperoxidase (MPO) [51, 52]. Among them, NAD(P)H oxidase seems to be the most important source of oxidative stress in vessels [53], whereas MPO, an enzymatic constituent of neutrophils and macrophages, is also highly expressed in atheromatic lesions [54]. MPO might also play a role in accelerated atherosclerosis in dialysis patients as it has been reported to be released from white blood cells during hemodialysis. Oxidative modification of macromolecules such as lipids, proteins, and nucleic acids results in structural and functional changes and accelerates atherosclerosis. In this regard, elevated plasma levels of oxidized low-density lipoprotein (LDL) have been shown to correlate with CHD [55]. Patients with CKD have increased levels of oxidized LDL [56].

Increased oxidative stress also induces the expression of inflammatory biomarkers. In this regard, both CKD and ESRD are characterized by elevated levels of inflammatory markers such as C-reactive protein (CRP), an acute phase protein reactant, TNF-α, IL-6, fibrinogen, factors VIIc and VIIIc, and the adhesion molecules VCAM-1 and ICAM-1 [57–59]. In the MDRD study elevated levels of CRP [60] were associated with an increased risk of all-cause and CV mortality in stage 3 and 4 CKD patients. Moreover, in dialysis patients increased levels of CRP and IL-6 have been associated with a significant increased risk of sudden cardiac death independently of traditional CVD risk factors [47, 61].

Endothelial dysfunction, which is present in CKD, is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression [62]. Microalbuminuria might be a manifestation of impaired endothelial function [63], thus explaining the link between microalbuminuria and increased CV morbidity and mortality reported in many epidemiology studies (see section on “Association Between CKD and CVD-Epidemiological Data”). Reduced NO production seems to be the main culprit for the endothelial dysfunction observed in CKD [64, 65]. In hemodialysis patients, increased levels of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, have been reported and independently predict overall mortality and CV outcomes [66]. Moreover, in patients with mild to advanced CKD, ADMA level is inversely related to GFR and represents an independent risk factor for progression to ESRD and mortality [67]. ADMA, now considered one of the strongest markers of atherosclerosis [68], is increased under inflammatory conditions and might serve as a link between inflammation and endothelial dysfunction [69]. Finally, the term protein-energy wasting (PEW) has been recently introduced to describe the role of malnutrition, inflammation, and atherosclerosis on the increased mortality observed in patients with ESRD [46, 70].

Yet, it should be noted that the exact pathomechanisms by which these nontraditional risk factors contribute to the development of CVD are still unclear, and various studies report contradictory results. In this regard, although the aforementioned studies demonstrated a positive association between elevated levels of CRP [60] and adverse CV outcomes, no such relationship was detected in the Irbesartan for Diabetic nephropathy trial [71]. Similarly, although coronary artery calcification, which is a frequent finding in CKD patients, has been linked to abnormalities in mineral-bone metabolism [72], studies evaluating the associations between parathyroid hormone, calcium, and phosphorus with coronary artery calcification report conflicting results [73, 74].

Characteristics of Dyslipidemia in CKD

Multiple lipoprotein abnormalities are detected in CKD patients caused by a profound dysregulation in their metabolism (Table 5.3). The primary characteristic of dyslipidemia in CKD is hypertriglyceridemia, with 40–50 % of CKD patients having fasting triglyceride levels greater than 200 mg/dL. Of note, the lipid profile of patients with CKD depends on CKD stage, the presence or not of nephrotic syndrome, and the dialysis modality for ESRD patients [75]. In this regard, apart from the increased triglycerides, in patients with stage 5 CKD total serum cholesterol and LDL are normal or low, whereas high-density lipoprotein (HDL) is decreased [76, 77]. Patients with stage 1–4 CKD might exhibit increased total cholesterol and LDL cholesterol, whereas nephrotic patients are usually characterized by a marked increase in total cholesterol and LDL levels with cholesterol being directly correlated with the degree of albuminuria and indirectly with serum albumin level [78]. Finally, peritoneal dialysis patients are characterized by increased protein losses in the peritoneal fluid effluent, a condition mimicking the nephrotic syndrome [79]. These losses might induce the hepatic production of albumin and lipoproteins, resulting in elevated concentrations of total cholesterol, LDL, and a modified highly atherogenic form of LDL, lipoprotein (a) (Lp(a)) [80, 81]. Moreover, increased insulin levels, which is a consequence of the absorption of glucose from the dialysis fluid, may induce the hepatic synthesis of very low-density lipoprotein (VLDL) and possibly Lp(a) [82].

Table 5.3 Features of lipid fractions and the enzymes implicated in their metabolism in CKD
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It should be noted that in CKD, apart from lipoproteins assessed in every day clinical practice, a variety of not routinely measured highly atherogenic lipoprotein fragments accumulate. These include chylomicron remnants, VLDL remnants or intermediate-density lipoproteins (IDL), oxidized LDL, small dense-LDL (sd-LDL), and Lp(a) [75]. The former two are products of chylomicron and VLDL metabolism whose clearance is impaired in CKD. These lipoproteins are prone to oxidization, a process that further increases their atherogenic potential. In fact, Shoji et al. showed that among LDL, HDL, VLDL, IDL, and Lp(a), IDL was the lipoprotein fraction more closely associated with aortic sclerosis in hemodialysis patients [83]. Moreover, chylomicron remnants potentiated endothelium-dependent arterial contraction [84], whereas oxidized VLDL remnants significantly enhanced macrophage cholesterol ester accumulation compared to either VLDL remnants, or oxidized LDL in experimental models of atherosclerosis [85]. It is well known that most clinical trials evaluating the role of lipid-lowering treatments in CKD patients do not assess these lipoprotein fractions, and this might be an explanation for the reported negative results.

In CKD there is an impairment in the distribution of LDL subclasses favoring the predominance of sd-LDL particles [86, 87] (see Table 5.3). These electronegative particles penetrate the endothelial barrier easier than large LDL particles and interact with electropositive intimal proteoglycans [88]. This interaction prolongs their retention in the arterial wall, thus rendering them more susceptible to oxidization by ROS. Indeed, sd-LDL particles appear to be more atherogenic than larger LDL fragments [89, 90]. The effect of the routinely administered lipid-lowering agents, statins on sd-LDL in CKD patients, remains unclear. Of note, a recent study reported that statins decrease sd-LDL in peritoneal dialysis patients but not in hemodialysis patients [91]. Apart from oxidization, under the uremic milieu, LDL also undergoes protein carbamylation. This process has been reported to increase the atherogenic potential of LDL through multiple mechanisms, including the proliferation of smooth muscle cells [92].

Elevated plasma levels of Lp(a) have been detected in patients with CKD [93] (see Table 5.3). Moreover, Lp(a) is now recognized as a risk factor for CV morbidity and mortality in hemodialysis patients [94, 95]. Lp(a) is a modified form of LDL emerging from the covalent binding of apolipoprotein(a) to apolipoprotein B through disulfide linkage [96]. In the general population, elevated serum Lp(a), has been recognized as a risk factor for CVD, whereas the association between Lp(a) and CHD risk seem to be continuous [97, 98]. Lp(a) excess is frequently detected in patients with premature CHD [99], and its levels are also associated with cerebrovascular disease, especially in men [100]. Because of its structural similarity to plasminogen, it has been proposed that Lp(a) may promote thrombogenesis by inhibiting fibrinolysis [101]. Moreover, Lp(a) is capable of binding to macrophage receptors, thus promoting foam cell formation and accelerating atherosclerosis [102]. Lp(a) also enhances LDL susceptibility to oxidization [55] and promotes monocyte attachment to vascular endothelial cells by increasing endothelial ICAM-1 expression [103]. Serum Lp(a) levels are genetically determined and are mostly due to polymorphisms at the apo(a) gene (LPA gene) [104]. These polymorphisms account for a variety of sizes of apo(a) isoforms. An inverse association of the size of apo(a) isoforms and Lp(a) levels has been detected (i.e., subjects with low molecular weight isoforms have higher levels of Lp(a)) [104, 105]. Intriguingly, in dialysis patients, small apo(a) isoform size but not Lp(a) level has been identified as an independent predictor of total and CV mortality [106, 107]. There are no clinical trials evaluating the effects of therapeutic regimes targeting the reduction of Lp(a) on CV morbidity and mortality in the general population or in patients with CKD.

Disorders of VLDL and Chylomicron Metabolism in CKD

Hypertriglyceridemia in CKD is a consequence of impaired VLDL and chylomicron metabolism, which leads to diminished triglyceride clearance [108] (Fig. 5.1a, b). VLDL and chylomicrons are triglyceride-rich lipoproteins that deliver lipids to muscle and adipose tissue for energy production and storage, respectively. Nascent VLDL consists of a apoB100 lipoprotein core, to which cholesterol ester, triglycerides, and phospholipids are bound. Similarly, in nascent chylomicrons, these lipid fractions are packed in apo48. Both nascent VLDL and chylomicrons mature by receiving apoE and apoC from HDL-2. Endothelium-bound lipoprotein lipase (LPL) in the capillaries of skeletal muscle and adipose tissue is responsible for the hydrolysis of triglycerides of VLDL and chylomicron and the disposal of fatty acids to the adjacent myocytes and adipocytes. This process leads to the formation of VLDL remnants (IDL) and chylomicron remnants, which are subsequently cleared by the liver via LDL receptor-related protein (LRP) [109]. However, the bulk of IDL is converted to LDL after being enriched in cholesterol esters by cholesterol ester transfer protein (CETP) and then lysed by hepatic lipase. LDL is then removed by LDL receptor in the hepatic cells. Finally, the fraction of VLDL that has not been lysed by LPL is cleared entirely by VLDL receptor in adipocytes and myocytes [110]. Impaired metabolism of VLDL in CKD is characterized by the downregulation of LPL, hepatic lipase, LPR, and VLDL receptor, leading to the accumulation of triglycerides, VLDL, and IDL and the triglyceride enrichment of LDL (see Fig. 5.1a, b and Table 5.3). In CKD an increase in plasma Apolipoprotein C-III (apoCIII), a potent inhibitor of LPL, has been reported [75]. ApoCIII and apo CII are important components of VLDL and chylomicrons, and apoCIII/apoCII ratio determines the ability of these lipoproteins to activate LPL. Moreover, in CKD-increased plasma levels of pre-β-HDL, an inhibitor of LPL has been reported [111]. Regular heparinization that occurs in dialysis patients might also result in the degradation of tissue-bound LPL [75].

Fig. 5.1
figure 1

VLDL (a) and chylomicron (b) metabolism. The asterisk denotes downregulation. See text for details. Adapted from [108]

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Another mechanism involved in the impaired lipoprotein metabolism in CKD setting is the reduced expression and activity of hepatic lipase [112, 113]. As discussed earlier, hepatic lipase is responsible for the removal of almost all of the remaining triglycerides from IDL, a process crucial for its conversion to LDL. Therefore, hepatic lipase downregulation leads to the accumulation of IDL, triglyceride enrichment of LDL, and hypertriglyceridemia. Hepatic lipase as well as LPL activity might be diminished by calcium accumulation within liver and adipose tissue cells caused by secondary hyperparathyroidism, a common complication of CKD. Of note, parathyroidectomy can restore both hepatic lipase and LPL activity and plasma triglyceride levels in experimental animals and humans with CKD [114, 115]. Moreover, verapamil administration to rats with CKD prevented the development of hypertriglyceridemia and the reduction of hepatic lipase and LPL activity by reducing basal levels of cytosolic calcium [112].

CKD has also been reported to downregulate LRP, thus leading to the atherogenic chylomicron remnants and IDL accumulation [116]. The downregulation of VLDL receptors in the skeletal muscle, heart, and adipose tissue has also been reported in experimental animals with CKD, a condition leading to elevated VLDL and triglycerides [115, 117]. Finally, increased triglyceride synthesis might contribute to the hypertriglyceridemia observed in nephrotic patients and peritoneal dialysis patients but not in the remainder CKD population [118]. This is due to the upregulation of Acyl-CoA:diglycerol acyltransferase, an enzyme that catalyzes the conversion of diglyceride to triglyceride [119].

As discussed earlier, CKD is characterized by increased oxidative stress. In this environment chylomicron remnants, IDL, LDL, sd-LDL, and Lp(a) might undergo oxidization. These oxidized lipoproteins can bind to receptors on macrophages and trigger the release of pro-inflammatory cytokines thus amplifying the inflammatory status of CKD. The uptake of these lipoproteins by the scavenger receptors of arterial wall macrophages results in their transformation to foam cells, the hallmark of the atherosclerotic lesion. In this regard, increased scavenger receptor expression has been reported in CKD patients [120]. The formation of foam cells is also a consequence of impaired cholesterol export mechanisms (see section on “Disorders of HDL Metabolism in CKD”). LDL has also been reported to activate the renin–angiotensin system [121], leading to increased angiotensin II levels and the upregulation of the angiotensin type-I (AT1) receptor. Angiotensin II, in turn, acting through AT1 receptor, stimulates NAD(P)H oxidase and other enzymes, augmenting synthesis of the superoxide anion and proinflammatory mediators that result in endothelial dysfunction and atherosclerosis aggravation.

Disorders of HDL Metabolism in CKD

In CKD, impaired functionality and reduced levels of HDL have been reported [75]. Normally, HDL prevents atherosclerosis by various mechanisms [108, 122–125] (Fig. 5.2): (1) inhibits and reverses the oxidization of lipoproteins by its antioxidant enzyme constituents, paraoxonase-1 (PON-1) and glutathione peroxidase (GPX); (2) removes oxidized phospholipids and endotoxins and disposes them to the liver via apoA1 and lecithin:cholesterol acyltransferase (LCAT); (3) improves endothelial function by inhibiting cellular adhesion molecule expression [126] and increasing eNOS production [127]; (4) reduces inflammation by alleviating oxidative stress and inhibiting cellular adhesion molecule expression; (5) transfers surplus cholesterol and phospholipids from the periphery to the liver (reverse cholesterol transport [RCT]); (6) contributes apoC and apoE to nascent VLDL and chylomicrons, thus facilitating their proper metabolism and removal; (7) facilitates the conversion of highly atherogenic oxidization-prone IDL to LDL via CETP-mediated exchange of cholesterol esters for triglycerides (indirect RCT); (8) exerts antithrombotic effects through its constituent platelet-activating factor (PAF) acetylhydrolase, which inactivates PAF, thus preventing platelet activation and thrombus formation.

Fig. 5.2
figure 2

Protective role of HDL against atherosclerosis. Reverse cholesterol pathway. The asterisk denotes downregulation, whereas the plus (+) denotes elevation. See text for details. Adapted from [108]

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RCT is a multiorgan, multistep process via which excess cholesterol is retrieved from lipid-laden macrophages in the peripheral tissue and then is transported to the liver, where it is processed and excreted in bile and intestine [108, 123, 128, 129] (see Fig. 5.2). Oxidized LDL and other atherogenic lipid fractions are internalized by vascular macrophages through scavenger receptors (SRA1 and LOX1). This leads to their transformation into foam cells and the acceleration of atherosclerosis. In RCT nascent (lipid-poor) HDL binds to ATP-binding cassette transporter type A1 (ABCA1) and ABCG1 on the macrophage cell membrane [123, 130]. Then free cholesterol is actively transferred to the surface of HDL where it is rapidly esterified by LCAT and then sequestered in the core of HDL (mature HDL). Of note, albumin has also been shown to play a role in transferring cellular-free cholesterol from peripheral tissues to the circulating nascent HDL via passive transportation [131]. Thereafter, mature HDL moves to the liver, where it binds to the HDL docking receptor SRB-1. SRB-1 facilitates the unloading of HDL’s lipid content (cholesterol esters, triglycerides, and phospholipids) and subsequently HDL is released to the circulation as lipid-poor HDL to repeat the cycle [132].

CKD is associated with a reduction in serum apoA-I and apoA-II, which are mandatory components of the HDL particle [133, 134]. This mechanism might play a crucial role in the reduction of HDL levels detected in CKD patients. Hypoalbuminemia, which is a result of chronic inflammation, in CKD patients might also contribute to reduced HDL levels [77]. However, the main reason for the impaired HDL cholesterol enrichment and maturation in CKD is LCAT deficiency (see Fig. 5.2 and Table 5.3). LCAT deficiency is a result of decreased production by the liver [135]. LCAT deficiency, apart from preventing the maturation of HDL through the esterification of free cholesterol on its surface, also facilitates HDL degradation by the hepatic endocytic receptor (β-chain of ATP synthase). This receptor has higher affinity for the nascent HDL than the mature one, whereas SRB-1 has higher affinity for mature HDL and, as noted above, facilitates HDL cycle from the liver to peripheral tissues and does not degrade it. Apart from the reduced levels of HDL in CKD, there also seems to exist a decreased affinity to its ABCA-1 macrophage receptors due to its oxidization in the uremic milieu [136, 137]. Accumulating evidence also suggests that HDL under systemic oxidative and inflammatory conditions (as in CKD) might also transform and promote oxidative stress and inflammation [138, 139]. Thus, HDL oxidization might impair the maturation of HDL and RCT in general. As discussed earlier, by inhibiting the formation and increasing the disposal of oxidized lipids, HDL exerts both antioxidant and anti-inflammatory effects. It has been reported that in dialysis patients there is a significant reduction in paraoxonase and GPX [136]. Moreover, the expression of macrophage scavenger receptors SRA1 and LOX1 is upregulated in both experimental models and in patients with CKD, a process that seems to be induced by inflammatory cytokines and oxidized LDL [120, 140]. This, combined with apoA-1 reduction, limits the ability of HDL to prevent or reverse the oxidization of LDL and phospholipids, thus promoting an influx of oxidized LDL in macrophages in the artery wall and facilitating foam cell formation and atherosclerosis. In this context, HDL anti-inflammatory activity has been reported to decrease in the uremic plasma of dialysis patients [141]. Thus, it seems that HDL impaired anti-oxidant and anti-inflammatory properties are both a consequence and a cause of increased oxidative stress and inflammation observed in CKD.

Based on the evidence that HDL level is reduced in CKD patients, the design of treatment strategies targeted to increase HDL levels seems plausible. However, efforts to raise HDL in the clinical setting have unexpectedly resulted in unfavorable CV outcomes. CETP inhibitors are a novel class of compounds that are very effective in increasing plasma HDL [142]. However, despite a meaningful increase of plasma HDL, the administration of the CETP inhibitor torcetrapib was early terminated in patients at high risk of coronary events due to increased CV events and overall mortality [143]. This negative outcome was probably related to an off-target effect indicated by increased arterial blood pressure in the treatment group, although a possible torcetrapib adverse effect could not be ruled out. Moreover, in another RCT, torcetrapib failed to halt the progression of coronary atherosclerosis or improve carotid intimal thickness [144]. These discouragingly negative outcomes might be a result of the accumulation of the highly atherogenic IDL [145]. As discussed earlier, CETP plays a crucial role in the conversion of IDL to LDL by promoting the transfer of cholesterol esters from IDL to LDL in exchange of triglycerides [108]. Therefore, CETP inhibition might result in the accumulation of IDL and the acceleration of atherosclerosis, especially in CKD patients in whom IDL clearance is impaired due to LRP-1 and hepatic lipase deficiency. Moreover, neither low HDL nor high CETP activity was associated with CV events in hemodialysis patients over a 48-month observation period [146], implying that functional changes in HDL might play a more important role in atherosclerosis progression. Thus, in CKD, the absolute increase in HDL levels might not be enough to prevent CVD, as there also exist qualitative changes in the HDL molecule impairing its composition, maturation process, as well as its antioxidant and anti-inflammatory properties [136, 139, 147].

Pathophysiology of CVD in the General Population and in the CKD Setting

Atherosclerosis is a chronic, complex, and progressive inflammatory process of the vascular wall of large and medium-sized arteries. Although the exact pathomechanism of this process remains unclear, dyslipidemia and abnormal immune response to endothelial damage with inflammatory recruitment of monocytes and the formation of foam cells seem to play a central role in the development of the atherosclerotic lesions [148, 149]. The chronic inflammation of the vascular wall results in multifocal plaque development. Furthermore, intraplaque hemorrhage, lipid deposition, proliferation of neovessels, and plaque remodeling all contribute to atherosclerotic plaque formation [149, 150]. Although most plaques remain asymptomatic, some progress to luminal obstruction, whereas a few are vulnerable to thrombosis, leading to acute atherothrombotic events such as acute myocardial infarction and stroke [149, 151].

Intriguingly, the pathogenesis and, consequently, the pathologic findings of arterial lesions in CKD patients differ substantially from patients with preserved renal function with classic atherosclerotic disease. In the latter, arterial lesions consist of lipid-laden atheromatous or fibroatheromatous plaques, whereas in the former, atherosclerotic plaques are rich in calcium deposits and fibrous tissue and exhibit a prominent thickening of the intima and media of the vessel wall, resulting in lumen narrowing [152, 153]. Calcium deposition in CKD may occur in the intima (as in classic atherosclerotic plaques) or in the medial layer, where it increases vascular stiffness as well as in cardiac valves [154]. In fact, coronary artery calcification has been reported to be significantly more frequent in predialysis patients compared with matched control subjects with no renal impairment (40 % vs. 13 %) [155]. The calcium content of atherosclerotic lesions in advanced CKD stages is in some occasions so high that many of these patients’ vessels can be readily delineated on simple plain radiograms. The most devastating demonstration of vascular calcification presented in dialysis patients is calciphylaxis or calcific uremic arteriopathy. This life-threatening condition is characterized by extensive microvascular calcification accompanied by intimal proliferation and thrombosis leading to non-healing skin ulcers, necrosis, secondary infection, and sepsis [156]. Although the exact pathomechanisms contributing to vascular calcification remain unclear, elevated calcium (Ca) × phosphate (P) product facilitating the precipitation of Ca and P along with the induction of calcification promoters and the reduction of calcification inhibitors seem to play a major role in this process [157, 158]. Under these conditions, vascular smooth muscle cells acquire an osteoblast phenotype, thus promoting hydroxyapatite formation in the media resulting in vascular calcification. Vascular calcification promotes vascular stiffening. Aortic stiffening combined with anemia and hypertension, which are common in CKD patients, result in the development of LVH. The combination of LVH and tissue calcification may result in myocardial fibrosis and conduction abnormalities that predispose to potentially lethal arrhythmias [152, 153, 159]. Indeed, arrhythmias or cardiac arrest seem to be more common death causes in CKD patients (they account for approximately 60 % of all cardiac deaths in dialysis patients) than myocardial infarction or stroke, which represent typical atherosclerotic diseases [160].

Conclusion

It is well established that reduced GFR and albuminuria predict CV event rates in a continuous and independent manner. This relation between CVD and CKD, apart from the presence of non-traditional CV risk factors such as oxidative stress and inflammation, which are prominent in CKD, has also been attributed to the substantial variations of lipid abnormalities and dyslipidemia characteristics in CKD. Indeed, hypertriglyceridemia is the hallmark of CKD dyslipidemia, whereas total and LDL cholesterol are normal or low. Moreover, a variety of highly atherogenic lipoprotein fragments, which are minimally affected by classic lipid-lowering treatments, such as chylomicron remnants, IDL, sd-LDL, oxidized LDL, and Lp(α), are present in CKD, further aggravating atherosclerotic lesions. Finally, the pathogenesis of arterial lesions in CKD differs substantially from the pathogenesis of classical atherosclerotic disease. In this regard, calcium-rich atherosclerotic plaques with prominent thickening of the intima and media of the vessel wall are the pathologic hallmarks of CKD atherosclerotic lesions, whereas lipid-laden atheromatous or fibroatheromatous plaques are detected in classic atherosclerotic disease. Therefore, it is not surprising that lipid-lowering strategies alone seem to have no meaningful effect in ameliorating CVD in CKD patients, especially in those with advanced renal failure [161, 162]. Thus, an adequately designed therapeutic regime apart from modifying lipoprotein levels (i.e., by the use of a statin) should also probably include agents that reduce oxidative stress, inflammation, and vascular calcification. Therefore, combined treatments targeted at inhibiting or reversing multilevel pathogenetic mechanisms responsible for CVD in CKD will pave the way for the effective management of dyslipidemia and CVD in this fragile population.