Published by JGC
  About Us    Contact Us 


Journal of Geriatric Cardiology September 2005 5th issue

Symposium Issue: Review Article:

Atherosclerosis in elderly patients with renal insufficiency
Sandeep S. Soman
Division of Nephrology and Hypertension, Henry Ford Health System, CFP-5, Detroit, MI 48202


Corresponding author ： Sandeep S. Soman, MD
Division of Nephrology and, Hypertension, Henry Ford Health System, CFP-5
Detroit, MI 48202
Phone: 313-916 2992
Fax: 248-237 4926
 Email: ssomanmd@yahoo.com 

Introduction

As people age, cardiovascular structure and function change and this is superimposed on by specific pathophysiologic disease mechanisms. In addition to lipid levels, diabetes, sedentary lifestyle, and genetic factors that are known risks for coronary disease, hypertension, and stroke — the quintessential cardiovascular (CV) diseases related to atherosclerosis within our society — advancing age unequivocally confers the major risk
(Fig. 1). Mortality due to cardiovascular disease is more than any other disease and creates enormous costs for the health care system. The main underlying problem in cardiovascular disease is atherosclerosis, a process that obstructs major arteries with lipid deposits and cell accumulation.1 Decreased kidney function (estimated glomeral filtration rate, GFR, < 70 mL/min/1.73 m2) is an independent risk factor for cardiovascular disease and all-cause mortality in the general population.2


Fig. 1. Interactions between aging, cardiovascular changes and clinically significant vascular disease.

It is estimated that, by the year 2035, nearly one in four individuals will be 65 years of age or older. The Census Bureau estimates that the proportion of individuals aged 65+ years will increase from 12.6% in 2000 to 13.2% in 2010 and to 16.5% in 2020 (35, 40, and 54 million individuals). The prevalence of moderately or severely decreased kidney function in this age group is 20.6% (SE, 1.1%) and is substantial even in the absence of diabetes or hypertension (10.8%; SE, 1.0%). Data from the NHANES III, a study of community-dwelling adults, estimated that 25% of all Americans 70 years of age and older had moderately or severely decreased kidney function.3 (Fig. 2). Physiological implications of many older individuals having less than half the kidney function of young adults are still unknown but are important to determine, given the aging of the population. Dosage adjustment of drugs excreted by the kidneys;greater risk for such complications of CKD as anemia, bone disease, and malnutrition; and increased risk for developing kidney failure all need to be considered in the routine care of older individuals with a decreased GFR.


Fig. 2 Prevalence of decreased kidney function (GFR < 60 mL/min/1.73 m2) in the overall noninstitutionalized US population, as well as by history of diabetes and presence of hypertension: NHANES III, 1988 to 1994. (Reproduced with permission from Coresh, J., et al., Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41: 1-12.)

Epidemiology

Thirteen percent of the U.S. population is currently 65 years or older, and about half of these 25 million people have cardiovascular disease. By the year 2030, 1 in 5 Americans will be older than 65 years, with the subset older than 85 years increasing most prominently in size (Fig. 3).
Cardiovascular disease increases dramatically with aging and is the major cause of mortality and disability in elderly persons; 83% of all cardiovascular deaths in the United States occur in patients older than 65 years of age.
Cardiovascular disease is also a major contributor to the need for hospital, ambulatory, and custodial care. In 1987, two-thirds of the U.S. health care expenditures for cardiac disease (totaling $22.3 billion) was for patients older than age 65.4 Elderly patients are intensive users of emergency medical services and of medical services in general.5 Coronary heart disease is the most prevalent cardiac problem, followed by hypertensive cardiovascular disease, with valvular and pulmonary heart disease other important etiologies (Fig. 3-5).6 Despite these statistics, data is limited regarding cardiovascular disease in the octogenarian and beyond, compromising optimal clinical care for such patients.7 Cardiovascular disease at an elderly age is additionally complicated by its frequent association with multiple other comorbid illnesses.


Fig. 3 Percentage of the world population aged 60 years or older over the last century and projections for the next century (United Nations, 2000a). (Reprinted with permission from McLean, AJ, DG Le Couteur, Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004; 56: 163-84.)


Fig.4. Incidence of coronary heart disease by age and sex. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises. Part I. Aging arteries: A "set-up" for vascular disease. Circulation 2003;107:129-46. (With permission.)

Currently, there are approximately 406,081 patients with end-stage renal disease (ESRD) in the United States.8 This hardly describes the impact of renal disease, because moderate chronic kidney disease (CKD), which is defined as a glomerular filtration rate (GFR) <60 ml/min/1.73m2, is nearly 10 times more prevalent than ESRD. The annual mortality rate for patients with ESRD is approximately 20%, and around fifty percent of these deaths are attributable to cardiovascular disease.9, 10 Cardiovascular events are as much as 50 times more likely to occur in patients with ESRD than in the general population.11,12 In children with ESRD, cardiac death is 100 times more likely than in the general population and accounts for 23% of the mortality rate.13 Patients with CKD undergoing coronary revascularization also have an increased mortality rates.14 Greater degrees of renal dysfunction are associated with a higher mortality rate (risk ratio of death for a creatinine clearance of 70 ml/min, 1.46; for a creatinine clearance of 50 ml/min, 2.25; for a creatinine clearance of 30 ml/min, 3.70; and 8.91 for patients undergoing dialysis). In a prospective cohort study from the Northern New England Cardiovascular Disease Study Group of patients after coronary artery bypass grafting surgery (CABG), the presence of dialysis-dependent CKD was associated with a 4-fold increase in hospital mortality rate compared with patients not undergoing dialysis (12.2% vs 3%; adjusted odds ratio for death of 3.1).15 Thus, these epidemiologic studies demonstrate that CKD is a highly prevalent condition in which varying degrees of CKD are associated with mortality and cardiovascular events and higher mortality after interventions for cardiovascular diseases. Prevention of renal disease and better treatments for cardiovascular disease in patients with established CKD will likely have a significant impact on survival rates.


Fig.5. Incidence of thromboembolic stroke by age and sex. Lakatta, E.G. , D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular disease. Circulation 2003; 107: 139-46.


Fig.6. Incidence of heart failure by age and sex. Lakatta, EG, D Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease. Circulation 2003;107: 346-54.

Defining CKD

Chronic kidney disease is defined according to the presence or absence of kidney damage and level of kidney function—irrespective of the type of kidney disease (diagnosis). Among individuals with chronic kidney disease, the stages are defined based on the level of kidney function. Identifying the presence and stage of chronic kidney disease in an individual is not a substitute for accurate assessment of the cause of kidney disease, extent of kidney damage, level of kidney function, comorbid conditions, complications of decreased kidney function, or risks for loss of kidney function or cardiovascular disease in that patient. Defining stages of chronic kidney disease requires “categorization” of continuous measures of kidney function, and the “cut-off levels” between stages are inherently arbitrary. Nonetheless, staging of chronic kidney disease will facilitate application of clinical practice guidelines, clinical performance measures and quality improvement efforts to the evaluation, and management of chronic kidney disease (Table.1 ).16
Using serum creatinine level as an indicator of renal function grossly underestimates the prevalence of renal insufficiency. Even the use of equations to measure creatinine clearance may underestimate the prevalence of CKD, especially in the elderly.16,17 (Table.1). The prevalence of CKD is severely underestimated when it is defined on the basis of serum creatinine level instead of creatinine clearance. (Fig. 7).18-20

Small rises in creatinine are linked to poor long-term outcomes

Recently, it has been shown that even mild degrees of kidney disease translates to differences in outcomes after coronary artery disease.21-24 The leading theory is that when renal function declines, the associated abnormal vascular pathobiology accelerates, and hence the progression of CVD events occurs at a higher rate.25


Fig. 7 Percentiles of GFR and Cockcroft-Gault CCr by age plotted on the same graph as data by Davies and Shock on inulin clearance in healthy men. Percentiles are calculated using a fourth-order polynomial weighted quantile regression. The solid line shows a polynomial regression to the inulin data. Dashed lines without symbols show the 5th and 95th percentiles for GFR estimates. (Reproduced with permission from Coresh, J, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003；41: 1-12.

In adults in the Multiple Risk Factor Intervention Trial (MRFIT), even a mild increase in creatinine level was an independent risk factor for coronary heart disease and all-cause mortality.26 Recently, the Heart Outcomes Prevention Evaluation (HOPE) trial investigators demonstrated a 40% increase in the risk of major adverse cardiovascular events associated with mild CKD (creatinine level 1.4–2.3 mg/dL).27 Additionally, a GFR <75 mL/min/1.73 m2 was an independent predictor of mortality in both ST elevation and non-ST–elevation myocardial infarctions.24 (Fig. 9). Greater degrees of CKD are associated with increased adverse outcomes after cardiovascular events, and in elderly patients with mild CKD (creatinine level, 1.5–2.4 mg/dL), the 1-year mortality rate was nearly doubled compared with elderly patients with normal renal function (46% vs 24%).28, 29 Moderate CKD (creatinine level, 2.5–3.9 mg/dL) resulted in an even higher mortality rate of 66%. Thus, CKD is a strong predictor of mortality after a myocardial infarction.

Changes with Aging

Table1. Definition and stages of chronic kidney disease




Fig. 8 Kaplan–Meier Estimates of the Rates of Death at Three Years from Any Cause (Panel A) and of the Cardiovascular Composite End Point (Panel B), According to the Estimated GFR at Baseline. (Reproduced with permission from Anavekar, NS, et al, Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004; 351: 1285-95.)

The presentation of cardiovascular disease in elderly patients is complicated by its superimposition on the physiologic and structural cardiovascular changes of aging, which decreases cardiac functional reserve capacity, limits the performance of physical activity, and lessens the ability to tolerate a variety of stresses, including cardiovascular disease.30 These changes and their possible relationship to atherosclerosis are described in Table 2 and Table 3. These myriad changes require that the cardiovascular manifestations of aging be differentiated from those of disease.31

There is a growing body of evidence that increased large artery thickening and stiffness and endothelial dysfunction in apparently otherwise healthy older persons and the ensuing increase in systolic and pulse pressure, formerly thought to be part of "normal" aging, precede clinical disease and predicts a higher risk for developing clinical atherosclerosis, hypertension, and stroke. There is also evidence of a vicious cycle: altered mechanical properties of the vessel wall influence the development of atherosclerosis, and the latter, via endothelial cell dysfunction and other mechanisms, influences vascular stiffness. Combinations of age associated endothelial dysfunction, intimal medial thickening, arterial stiffening, and arterial pulse pressure widening occurring to varying degrees determine the overall vascular aging profile of a given individual. Additional risk factors — including hypertension, smoking, dyslipidemia, diabetes, diet, kidney disease and heretofore unidentified genetic factors — interact with vascular aging (as described above) to activate an atherosclerotic plaque. According to this view, the development and progression of atherosclerosis in older persons differs from that in younger persons and from that in experimental younger animals because it represents an interaction of atherosclerotic risk factors and their effect to produce atherosclerotic plaque at any age and related to vascular aging. 32,33

Cardiorenal Disease

The modern day, first world epidemics of obesity and hypertension are central drivers of a secondary epidemic of combined chronic kidney disease (CKD) and cardiovascular disease (CVD).34 Approximately half of those with diabetes will develop diabetic nephropathy. Conversely, half of all cases of end-stage renal disease (ESRD) are due to diabetic nephropathy.35 With the graying of America, and cardiovascular care shifting towards the elderly, there is an imperative need to understand why decreasing levels of renal dysfunction act as a major adverse prognostic factor after contrast exposure with or without peripheral or percutaneous coronary intervention (PCI).
A 45–54-year-old dialysis patient has a cardiovascular mortality risk about 65 times higher than the general population.11 A 3-fold increased risk is detectable in patients even with very mild increases in serum creatinine.36 Thus, the risk rises steeply as renal failure progresses. It is useful to start with the final outcome, ESRD, when trying to determine the dynamics of its risk factors. The predicted risk of death from cardiovascular disease in the next 5 years for a 50-year-old smoker with a previous myocardial infarction, a systolic BP of 140 mmHg and serum cholesterol of 190 mg u dl is 5.4%. The predicted risk would be 50% (almost 10 times higher) if the man is on chronic dialysis treatment. This huge difference in risk suggests that, in patients with ESRD, traditional risk factors only partly account for the high cardio-vascular mortality rate. In recent years, substantial progress has been made in identifying risk factors specific to patients with Anemia, extra-cellular volume expansion, inappropriately increased angiotensin II levels, high calcium-phosphate product (Ca P), inflammation,hyperhomocysteinemia, and, perhaps, impaired nitric oxide (NO) synthesis, due to accumulation of NO synthase inhibitors, all contribute to cardiovascular risk in ESRD. Most of these factors affect generation of reactive oxygen species. It appears likely that high oxidative stress plays an important role in mediating adverse effects on the cardiovascular system.

Table 2. Cardiovascular structural remodeling.


Table 3. Cardiovascular functional changes.


Genetic factors, such as gene polymorphisms that regulate homocysteine levels, the renin–-angiotensin system and the endogenous anti-oxidant system itself, are all important also. Furthermore, an absolute or relative deficiency in anti-oxidants such as vitamin C or E, or other endogenous vasoprotectors such as adiponectin, may contribute to vascular damage.37,38

Pathobiology of Atherosclerosis

Atherosclerotic lesions (atheromata) are asymmetric focal thickenings of the innermost layer of the artery, the intima (Fig. 10). These consist of cells, connective-tissue elements, lipids, and debris.39 Blood-borne inflammatory and immune cells and their derivatives constitute an important part of an atheroma, the remainder being vascular endothelial and smooth-muscle cells. The atheroma is usually preceded by a fatty streak, an accumulation of lipid-laden cells beneath the endothelium.40 Most of these cells in the fatty streak are macrophages, together with some T cells.

Fig. 10 Schematic representation of the atheromatous plaque of an artery. (reproduced with permission from Bendtzen and downloaded from site /IIR/14atheroScl/+Ath.htm on 6-12-05

Fatty streaks are prevalent in young people, never cause symptoms, and may progress to atheromata or eventually disappear. The lesions of atherosclerosis occur principally in large and medium-sized elastic and muscular arteries and can lead to ischemia of the heart, brain, or extremities, resulting in infarction.
In the center of an atheroma, foam cells and extracellular lipid droplets form a core region, which is surrounded by a cap of smooth-muscle cells and a collagen-rich matrix. T cells, macrophages, and mast cells infiltrate the lesion and are particularly abundant in the shoulder region where the atheroma grows.39, 41 Many of the immune cells exhibit signs of activation and produce inflammatory cytokines.42-44


Fig. 11. A :Activating effect of LDL infiltration on inflammation in the artery. B: Role of macrophage in the） inflammation of the artery. (Adapted from Hansson, GK, Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352: 1685-95.)

The processes leading to the development of atherosclerotic lesions are not entirely clear. At least two hypotheses address the initiation of the disease: `’response to injury’ and `’response to retention’. The former is well supported by a large body of experimental evidence 45-47 Atherosclerosis is now generally considered an inflammatory disease ―- inflammation being the cause of both initiation and progression of the lesion.45, 46 Injury to endothelium may be the important event that begins the atherosclerotic process. This injury could be due to elevated blood cholesterol levels, hypertension or other factors such as local infections or, smoking. Several types of lipid particles can contribute to the formation of fatty streaks, including cholesterol rich low density lipoprotein particles (LDLs) and triglyceride rich VLDL and remnant particles. Retained lipoproteins tend to get oxidized and become pro-inflammatory and induce further oxidative stress in the surrounding vascular cells (below) leading to recruitment monocyte-macrophages into the subendothelial space and intima and migration of advential smooth muscle cells to intima and their subsequent proliferation within the intima. (Figures 11, 12)


Fig. 12 .A: Effects of T- cell activation on plaque inflammation. B: The cytokine cascade. (Adapted from Hansson, GK, Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352: 1685-95.)

Atherosclerotic lesions are considered advanced when associated with accumulations of lipid, cells (macrophages and smooth muscle cells), and certain matrix components such as collagens and chondroitin sulfate proteoglycans. Proliferation of smooth muscle cells initially may be advantageous since it will generate a fibrous cap to stabilize the lesions. However unregulated proliferation of smooth muscle cells leads to complications as shown in animal models of atherosclerosis and balloon angioplasty-induced restenosis. Lesions considered advanced by their histology may not necessarily narrow the arterial lumen or produce clinical manifestations. This may be due to the fact that these areas covered by a monolayer of endothelial cells or certain matrix components such as heparan sulfate proteoglycans that provide an anti-thrombotic surface over the plaque.48,49 Loss of endothelium or heparan sulfate proteoglycans may uncover sub-endothelial collagen providing a pro-thrombotic surface that promotes platelet adhesion and activation.50 Thrombosis is a major contributor to complication of atherosclerosis. There are two major causes of coronary thrombosis: plaque rupture and endothelial erosion. Plaque rupture, which is detectable in 60 to 70 percent of cases, is dangerous because it exposes prothrombotic material from the core of the plaque — phospholipids, tissue factor, and platelet-adhesive matrix molecules — to the blood.51 Ruptures preferentially occur where the fibrous cap is thin and partly destroyed. At these sites, activated immune cells, which are abundant, produce numerous inflammatory molecules and proteolytic enzymes that weakens the cap and activates cells in the core, transforming the stable plaque into a vulnerable, unstable structure that can rupture, induce a thrombus, and elicit an acute coronary syndrome. Myocardial infarction occurs when the atheromatous process prevents blood flow through the coronary artery.
Thus, in summary, at least three key processes contribute to the complications of atherosclerosis inflammation, cell proliferation and thrombosis (Fig. 13). While cytokines and oxidative stress contribute to inflammation, mitogens and degradation of specific matrix components may contribute to unregulated smooth muscle cell proliferation and thrombosis.
It is now evident that the activation of plaque rather than stenosis precipitates coronary ischemia and infarction.52, 53

Atherosclerosis in patients with kidney disease

The etiology of cardiovascular disease in CKD is complex and may result from an increased prevalence of classic cardiovascular risk factors and factors unique to uremia or dialysis (Table 3).54, 55 As approximately 40% of patients undergoing dialysis have diabetes mellitus as their stated etiology for ESRD and 25% of patients undergoing dialysis have hypertension as their stated etiology for ESRD, patients with CKD have a higher prevalence of the cardiovascular risk factor compared with the general population. 8 CKD may also have an added effect with classic cardiovascular risk factors such as diabetes mellitus.


Fig. 13 . Role of inflammation, smooth muscle cell proliferation and thrombosis in atherosclerosis lesion development and complications. Endothelial injury and lipid (LDL) accumulation may initiate the atherogenic process (1). Subsequent induction of inflammatory cytokines results in recruitment of monocyte macrophages to the vessel. Following uptake of modified LDL macrophages become foam cells. Activated macrophages and foam cells produce mitogens that induce migration of advential smooth muscle cells into intima and proliferation of these migrated cells in the intima. Further loss of endothelium or specific components of extracellular matrix such as heparan sulfate proteoglycans may expose collagen-matrix for thrombotic events (2). Occluded arteries can be opened by balloon angioplasty and stenting (3). These vessels, which loose endothelium during the angioplasty and stenting procedure, can be re-occluded through restenosis (4).

In the Bypass Angioplasty Revascularization Trial,during the 7 year follow-up, the survival rate was highest in patients who had neither CKD or diabetes mellitus (88%) and decreased with either (CKD:61%; diabetes:72%). 55 However, when both conditions were present, the survival rate was only 33%. The increased presence of classic cardiovascular risk factors does not fully account for the marked increased risk of cardiovascular events seen in patients with CKD. This may be related to potential unique mechanisms of accelerated atherogenesis in CKD, which may relate to dialysis or to the uremic state itself. These are discussed below. (See Table 4)

Table 4. Risk factors for atherogenesis associated with kidney disease


CKD may be a unique cardiovascular risk factor. Atherosclerosis in CKD is associated with some distinctive histologic features of degenerative changes within the media of the coronary arteries, calcification and proteoglycan accumulation, and a lack of lipid accumulation.56 In animal models, uremia enhances atherogenesis.56, 57 Moreover, in children undergoing dialysis, coronary artery disease develops proportionally to the duration of dialysis.58 The uremic state itself can be associated with specific additional risk factors (volume overload, calcium-phosphorus abnormalities, increased oxidative stress, hypercatabolism, undefined uremic toxins) which may contribute to the development and progression of atherosclerosis. A chronic inflammatory state and the accumulation of metabolic products such as AGE and ADMA certainly play a major role. Chronic inflammation may be related to concomitant diseases such as diabetes mellitus, recurrent infections and the effects of chronic dialytic therapy. Pro-inflammatory cytokine levels (IL-6, CRP, IL-1, TNF-, MCP-1) are increased in predialysis and dialysis patients.59-62 However, the levels of these cytokines and acute phase proteins rise significantly when patients are treated by HD. 60, 63 Extracorporeal circulation of blood during HD may act as a repeated stimulus for an inflammatory response, mainly due to: 1) exposure of circulating mononuclear cells to the dialysis membrane, 2) exposure of circulating blood to lipopolysaccharide on the dialysate site of the membrane, 3) membrane bio-incompatibility,, 4) back-filtration of bacteria-derived contaminants , 5) type of vascular access , or 6) unrecognized infections.64-70
These findings suggest that non-traditional risk factors for CVD may be especially applicable in the ESRD population and in patients with CKD and are likely to be significant contributors to CVD progression. When ESRD is treated with renal transplantation, the risk of future cardiovascular events decreases despite the baseline high-risk population. Thus, kidney disease itself may have a direct role in atherogenesis and subsequent cardiovascular events. In addition to it’s direct role in affecting atherogenesis, kidney disease also worsens/alters other known traditional and non- traditional risk factors for atherosclerosis. Some of these are discussed below.

1. Hyperlipidemia
In patients with CKD, lipids are more atherogenic, even when their levels are not elevated.71 Hypertriglyceridemia is common early in the development of CKD, and may be caused by decreased high-density lipoprotein cholesterol (HDL)-mediated cholesterol clearance and inhibition of lipolysis. 72 Late in the progression of CKD, HDL and plasma lipoprotein lipase activity is decreased and may contribute to hypertriglyceridemia. 72 In patients undergoing dialysis, an unfavorable lipid profile, specifically a low HDL cholesterol level and a high triglyceride concentration, is associated with rapid progression of coronary calcification on serial electron-beam computed tomography. 73 Thus, multiple mechanisms, including insulin-resistance and inhibited activity of lipoprotein lipase, may contribute to hypertriglyceridemia in CKD.
Besides being a risk factor of atherosclerosis, lipid profiles are a lso a marker for malnutrition. A low serum cholesterol concentration or evidence of malnutrition as indicated by other markers is associated with enhanced mortality in patients with CKD.74,75 In patients who are malnourished and have severe CKD but are not yet undergoing dialysis, plasma Lp(a) levels were higher than in patients who were not malnourished. 76 Additionally, a significant direct relationship between CRP and plasma Lp(a) was found, and levels of both CRP and Lp(a) were elevated in patients with moderate to severe malnutrition. These data suggest that inflammation may be more prevalent in patients who are malnourished and may help to explain why in clinical practice, hyperlipidemia does not appear to be significantly associated with CKD. Considerable attention is now being paid to this “malnutrition-inflammation-atherosclerosis” axis.77 The bimodal distribution of cardiovascular events with both low and high cholesterol concentrations may mask the true role of lipid reduction in the development of coronary disease in patients with CKD.
It has recently been shown that apolipoprotein E (APOE) genetic variation predicts chronic kidney disease progression, independent of diabetes, race, lipid, and nonlipid risk factors. Risk is lower for those with the ε 4 allele and may increase with ε2, consistent with previous diabetic nephropathy studies, and the risk is of comparable magnitude but in the opposite direction to the association of APOE with CHD.78

2. Inflammation and oxidative stress

Oxidative stress involves the increased production of oxygen free radicals, which can exhaust endogenous antioxidants and lead to vascular injury. ESRD increases oxidative stress, a key mechanism in the development of endothelial dysfunction and atherosclerosis. Oxygen free radicals activate monocytes and promote inflammation, an integral component to atherosclerotic plaque formation and plaque rupture. 79-81 In patients undergoing dialysis, levels of both F2-isoprostanes, a marker of in-vivo oxidative stress, and CRP are elevated. Increased levels of CRP (>16.8 mg/L) are associated with a mortality rate that is twice as high as that in patients with low levels of CRP.82 Increased oxidative stress impairs nitric oxide bioavailability, which has a critical role in maintaining vascular tone and inhibiting atherosclerosis. CKD is also associated with decreased basal whole body nitric oxide production. 83 Thus, oxidative stress, diminished nitric oxide bioavailability, and inflammation may all contribute to the development of atherosclerosis in patients with CKD.

3. Hyperhomocysteinemia

CKD increases the frequency and severity of hyperhomocysteinemia, which is independently associated with cardiovascular events and mortality.84 Hyperhomocysteinemia has many causes in CKD, including decreased activity of the remethylation cycle, decreased serum folate and B vitamin intake, and decreased renal clearance of homocysteine and cysteine.85 Homocysteine may increase oxidative stress, decrease nitric oxide availability, and produce endothelial dysfunction. 86, 87Hyperhomocysteinemia is also associated with increased levels of Lp(a), an inhibitor of the fibrinolytic system, and enhances platelet adhesion to the vascular wall, and therefore could theoretically be a central factor in the development of coronary artery disease in CKD.88, 89 Although an association between homocysteine levels and cardiovascular events has been proven, particularly in patients with CKD, causality has not yet been established.

4. Fibrinogen

Fibrinogen is a marker for adverse cardiovascular events in patients with stable angina and in patients who have sustained an acute myocardial infarction.90 CKD is associated with elevated levels of fibrinogen.91 Fibrinogen is required for platelet aggregation through its interaction with the glycoprotein IIb/IIIa receptors and can also be cleaved to fibrin, an essential step in blood clot formation. Fibrinogen crosslinks with Lp (a) and is co-localized within atherosclerotic plaques, leading to local degradation of fibrinogen to fibrin and enhancement of local coagulability.92

5. Malnutrition

Malnutrition, which is common in ESRD, is prevalent both in dialysis and predialysis patients and may be associated with increased cardiovascular mortality in HD patients.93, 94 Reduced levels of albumin or prealbumin, usually an indicator of malnutrition, are predictors of all-causes mortality as well as cardiovascular mortality in dialysis patients.95, 96 Hypoalbuminemia may be explained by reduced synthesis, a consequence of the pro-inflammatory state. Many cytokines (especially TNF- and IL-6) also suppress appetite and induce catabolism, leading to a wasting illness that may be indistinguishable from malnutrition.97 Stenvinkel et al showed that malnutrition is closely associated with the prevalence of atherosclerosis (evaluated as the presence of unilateral or bilateral carotid plaques) and the inflammatory response. 98 This interaction between malnutrition and atherosclerosis might be partially explained by the increased inflammatory stimulus in ESRD patients, and these overlapping conditions probably underlie the accelerated progression of CVD in ESRD.99

6. Vascular calcifications

Vascular calcification potentially is a different process in those patients with ESRD compared to those with normal renal function. The calcification in ESRD is thought to occur at two sites in the vessel wall: in the media where it is known as Monckeberg's sclerosis (occurs initially in the media of the vessel, usually at the internal elastic lamina, and is not associated with lipid-laden macrophages and intimal hyperplasia), and in the intima (typically found in large vessel disease and coronary arteries, and associated with lipid-laden macrophages and intimal hyperplasia), where it is invariably associated with atherosclerosis.100 Cell biology studies suggest coronary artery calcification (CAC) is an active process analogous to bone formation, given that several genes expressed by calcifying vascular smooth muscle cells are also expressed by osteoblasts.101, 102 Most analyses so far specifically demonstrate that calcium, phosphorus, CPP, and PTH levels, whether measured in cross-section or longitudinally, are not related to CAC or its progression. While high levels of CAC almost certainly represent significant CAD in patients with ESRD, the attenuation of progression of CAC and its relation, if any, to CAD event reduction is unknown.100

7. Anemia and erythropoietin therapy

Anemia is common in CKD in patients undergoing dialysis and in the period before dialysis. At the time of initiation of hemodialysis, 29% of patients are receiving recombinant erythropoietin therapy.103 Even in patients with mild CKD who have a serum creatinine level <2 mg/dL, 45% of patients had a hematocrit level <36%.104 In patients undergoing dialysis, there are multiple studies demonstrating a strong association between hematocrit level and survival.105-107 In a study of 21,899 patients undergoing dialysis, a hemoglobin level <8 mg/dL was associated with a doubling of the mortality rate.108 The increased mortality rate associated with anemia is primarily caused by cardiovascular causes, which may relate to the association with left ventricular hypertrophy (LVH).109 Treatment of anemia may be a modifiable factor in the high cardiovascular mortality and morbidity rates of patients with CKD.

Treatment of acute and chronic coronary artery disease

Patients with CKD clearly constitute a high-risk group for cardiovascular disease and cardiac death.29 Therefore both primary and secondary prevention of coronary disease is essential in such patients. However, because of certain possible differences in the mechanism of atherosclerotic and thrombotic disease between patients with and patients without CKD, an increased risk of certain therapies in patients with CKD, and a lack of data on therapeutic outcomes in such patients, it is unclear whether treatment strategies for primary and secondary prevention designed for the general population are safe and effective for patients with CKD.

Treatment Strategies:

In addition to treatment of clinical manifestation of atherosclerosis, some effort is now being directed towards prevention and treatment of atherosclerosis, in patients with and without kidney disease. Although LDL lowering, diabetes and blood pressure control help in managing the disease, there is a dire need for direct disease modifiers. Some of the more promising strategies are: 1. Lipid Modulation
1.1. LDL Lowering
Cholesterol-lowering drugs, the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins), can achieve a relatively large reduction of plasma cholesterol. Clinical trials have demonstrated that statins can reduce of cardiovascular-related morbidity and mortality. 110 It is generally assumed that the beneficial effect of statins on coronary events is linked to their hypocholesterolemic properties. However, potential pleiotropic effects are now being understood; hence, effects other than cholesterol reduction may play a role in the anti-atherosclerotic properties of statins.

1.2. Non-LDL Lipid Modulation
Elevation of Plasma HDL
HDL can be atheroprotective in several ways.111,112 HDLs can counteract the effects of LDL by removing cholesterol, by a process termed reverse cholesterol transport, from cells in the arterial intima. HDL has antioxidant properties and inhibits LDL oxidation and oxidized LDL-induced adhesion and migration of monocytes. HDL also modulates endothelial function probably by stimulating endothelial NO production, an important anti-atherogenic molecule.
Moderate HDL elevation (5-30%) can be achieved by niacin, fibrates and some statins. Niacin stimulates the synthesis of apoA-I and apoA-II and is by far the most effective HDL elevator (-30%). Clinical trials of ETC-216 (Esperion), which contains a phospholipid plus recombinant ApoAI Milano, a variant of the naturally occurring apoAI, on patients with acute coronary syndromes showed a 4% but statistically significant reduction in plaque volume. HDL particles are subject to continuous remodeling in plasma.. Two proteins in particular are emerging as pharmacological targets for HDL elevation by targeting this remodeling: ATP-binding cassette Al (ABCA1) and cholesteryl ester transfer protein (CETP).113, 114

1.3 ACAT Inhibitors
Acyl-CoA:cholesterol acyltransferase (ACAT) is involved in cholesterol metabolism in macrophages, liver, intestine, and adrenal cortex and may be involved in the development of atherosclerotic lesions.115 The presence of cholesteryl ester-enriched macrophages (foam cells) is a characteristic finding within atherosclerotic lesions. ACAT plays a pivotal role in foam cell formation converting free cholesterol to esterified cholesterol.
Eflucimibe and Practimibe are ACAT inhibitors under development and undergoing trials at various clinical stages.

2. Inflammation and Atherosclerosis
2.1. Targeting Inflammation/Oxidative Stress - an Attractive Approach for Atherosclerosis
There are at least two such approaches that are in clinical development.
AGI-1067
AGI-1067 is an antioxidant that is closely related to the antioxidant probucol discovered in 1960.
AGI-1067 exhibits greater water solubility and cell permeability compared with probucol, and inhibits inducible VCAM-1 expression in vascular endothelial cells. The nonintervened reference coronary segments of the PCI vessel demonstrated improvements with AGI-1067 in the Canadian Antioxidant Restenosis Trial-1 (CART-1), a double-blind, placebo-controlled, randomized clinical trial of 305 patients; , with evidence supportive of a clinical effect on slowing atherosclerosis progression. This compound is currently in trials for atherosclerosis.
BO-653
BO-653 is a novel antioxidant (2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran, Table 1), related to cc-tocopherol and probucol but with superior antioxidant properties, and is currently being investigated.116, 117

Lp-PLA2 inhibitors
Lipoprotein-associated phospholipase A2 [Lp-PLA2, also known as platelet activating factor (PAF)-acetylhydrolase] is a lipase associated with LDL in human plasma, Lp-PLA2 inhibition is an anti-inflammatory approach considered for atherosclerosis118 It hydrolyzes oxidized phosphatidylcholine (PC) to lyso-PC and oxidized fatty acids. These products are pro-inflammatory and implicated in monocyte recruitment and plaque development. The relevance of Lp-PLA2 to atherosclerosis is a subject of debate, and recent results suggest that the LDL-associated Lp-PLA2 may be proatherogenic and distinct from that of the HDL-associated enzyme. Lp-PLA2 has been shown to be a risk factor for coronary events in both men and women.119 SB480848 is currently in late clinical trials for atherosclerosis.

Antiproliferative/cytotoxic agents for drug eluting stents
Prevention of restenosis after successful angioplasty remains one of the most challenging issues in the treatment of obstructive coronary artery disease. The mechanism of in-stent restenosis consisted purely of neointimal smooth muscle cell proliferation. Several cell cycle regulators are being developed for restenosis. The two lead molecules are rapamycin and paclitaxel. Rapamycin (Sirolimus), an antibiotic and immuno-suppressant, was shown to be a promising therapy for prevention of coronary artery stent restenosis.120, 121 Rapamycin upregulates the cyclin-dependent kinase inhibitor p27kipl, resulting in cell-cycle arrest at the Gl to S transition. The results obtained with rapamycin-eluting stents were dramatic (<5% restenosis) and were not observed with other therapeutic approaches. Paclitaxel, an anticancer agent, is another agent that is currently being developed for restenosis.121 Paclitaxel-eluting stents are now approved in Europe and Canada. Compounds like Sirolimus (e.g., everolimus, Guiudant/Novartis) are being pursued as the next generation stent coating.
Novel approaches for atherosclerosis/restenosis
As outlined above, inflammation, smooth muscle proliferation and thrombosis are the major contributors to the disease process. These processes also contribute to the complications of restenosis and in-stent restenosis. Perlecan, a heparan sulfate proteoglycan present in the extracellular matrices of blood vessels, may inhibit smooth muscle proliferation and thrombosis.50, 122 Animal and human data show that there is a dramatic decrease in the content of heparan sulfate proteoglycans in atherosclerotic lesions.123, 124 Multimodal targeting i.e., inhibition of smooth muscle cell proliferation, inflammation and thrombosis, can be achieved via induction of perlecan. Perlecan-inducing compounds inhibited both atherosclerosis and restenosis in animal models .


Future directions
Recent advances in our understanding of the age-associated alterations in vascular and cardiac structure and function, at both the cellular and molecular levels, and more attention being focused at kidney disease, provide valuable clues that will hopefully assist in directing future efforts to develop effective therapies to prevent, delay, or attenuate the CV changes that accompany aging.
Although CKD is highly prevalent in the United States and significantly contributes to the morbidity and mortality rate, there is still a paucity of clinical data on development of atherosclerosis, medications and outcomes in elderly patients with CKD. Fear of adverse effects and adverse events in this population may be driving the absence of these data.
Questions remain as to whether atherosclerosis and cardiovascular disease in patients with CKD is a fundamentally different process than in other patients. When treating patients with CKD, is it appropriate to follow the guidelines for the treatment of cardiovascular disease derived from large randomized studies in which patients with CKD were excluded? For example, data on the role of hyperlipidemia in the development of atherosclerosis in patients with CKD challenges the role of HMG CoA reductase inhibitors in this population. Unexpected results of clinical trials, including the adverse effect of normalizing the hematocrit level in patients with CKD and the increased beneficial effects of ACE-I on coronary artery disease and congestive heart failure in patients with CKD, demonstrate the need for randomized clinical trials to determine the precise role for various medications in this population.27, 125, 126
Future advances in the prevention and treatment of cardiovascular disease in patients with CKD cannot occur until a more systematic approach is taken to study pharmacokinetics, accurately define the adverse-effect profile in this population, and expand the inclusion criteria of the larger efficacy studies to include these patients or design studies specifically targeting this population. Physicians must move beyond the apathy and frustration generated by treating patients with such a difficult disease process. Only by applying the same high standards of evidence-based medicine that have previously guided the treatment of atherosclerosis in the general population to elderly patients with renal dysfunction can we ever hope to improve the excessive mortality rates in these patients with CKD. Future guidelines and consensus statements are needed to help ensure consistent high-quality evidence-based care for the high-risk population of elderly patients with CKD.


References

1. Kannel, WB, Overview of atherosclerosis. Clin Ther 1998; 20 (Suppl B): B2-17.
2. Muntner, P, He J, Hamm L, et al. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002; 13: 745-53
3. Coresh, J, Astor BC, Greene T, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003; 41: 1-12.
4. Riley, G, Lubitz J, Prihoda R, et al. The use and costs of Medicare services by cause of death. Inquiry 1987; 24: 233-44.
5. Gerson, LW, Shvarch, L. Emergency medical service utilization by the elderly. Ann Emerg Med 1982;11:
610-12.
6. Mittelmark, MB, Psaty BM, Rautaharju PM, et al. Prevalence of cardiovascular diseases among older adults. The Cardiovascular Health Study. Am J Epidemiol 1993;137: 311-17.
7. Wenger NK, ed. Cardiovascular Disease in the Octogenarian and Beyond. London: Dunitz, 1999.
Health, N I o. USRDS 2003 Annual Data Report. US Renal Data System, 2003.
8. Anonymous, Excerpts from the United States Renal Data System 1998 annual data report: V. patient mortality and survival. Am J Kidney Dis. Am J Kidney Dis 1999;32(Suppl 1)): S69–80.
9. Locatelli, F, Marcilli D, Conte F, et al. Survival and development of cardiovascular disease by modality of treatment in patients with end-stage renal disease. J Am Soc Nephrol, 2001. 12: 2411-17.
10. Levey, A S, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32: 853-906.
11. Brunner, FP, Selwood NH. Profile of patients on RRT in Europe and death rates due to major causes of death groups. The EDTA Registration Committee. Kidney Int Suppl 1992; 38: S4-15.
12. Parekh RS, Carrol CE, Wolfe RA, et al. Cardiovascular mortality in children and young adults with end-stage kidney disease. J Pediatr, 2002;141:191-97.
13. Best PJ, Lennon R, Ting HH, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39:1113-19.
14. Liu, JY, Berkmeyer NJ, Sanders JH, et al. Risks of morbidity and mortality in dialysis patients undergoing coronary artery bypass surgery. Northern New England Cardiovascular Disease Study Group. Circulation 2000;102: 2973-77.
15. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis, 2002; 39 (2 Suppl 1): S1-266.
16. Shlipak, MG, Sarnak MJ, Katz R, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005; 352: 2049-60.
17. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimated glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130: 461-70.
18. Levey, AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139: 137-47.
19. Levey, AS, Ekardet KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005;67: 2089-100.
20. Herzog CA, Ma JZ, Collins AJ, Long-term outcome of dialysis patients in the United States with coronary revascularization procedures. Kidney Int 1999; 56: 324-32.
21. Herzog, CA. Acute myocardial infarction in patients with end-stage renal disease. Kidney Int Suppl 1999; 71: S130-133.
22. Go, AS,　Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351: 1296-305.
23. Anavekar, NS, Mcmurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351: 1285-95.
24. McCullough, PA. Cardiorenal risk: an important clinical intersection. Rev Cardiovasc Med, 2002; 3: 71-76.
25. Flack, JM, Neaton JD, Danies B, et al. Ethnicity and renal disease: lessons from the Multiple Risk Factor Intervention Trial and the Treatment of Mild Hypertension Study. Am J Kidney Dis 1993; 21(4 Suppl 1): 31-40.
26. Mann JF, Gerstein HC, Pogue G, et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001;134: 629-36.
27. Shlipak, MG, Heidenreich PA, Noguchi H, et al. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 2002;137: 555-62.
28. McCullough PA, Soman SS, Shah SS, et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 2000;36: 679-84.
29. Sollott SJ. Normal aging changes in the cardiovascular system. Cardiol Elderly 1993;1: 349- 58.
30. Corti MC, Salive ME, Guralnik JM. Serum albumin and physical function as predictors of coronary heart disease mortality and incidence in older persons. J Clin Epidemiol 1996;49: 519-26.
31. Spagnoli LG, Bonanno E, Mauriello A, et al. Multicentric inflammation in epicardial coronary arteries of patients dying of acute myocardial infarction. J Am Coll Cardiol 2002; 40:1579-88.
32. Clarkson TB. Nonhuman primate models of atherosclerosis. Lab Anim Sci 1998;48 : 569-72.
33. Lewis CE, Jacobs DR Jr, McCreath H, et al. Weight gain continues in the 1990s: 10-year trends in weight and overweight from the CARDIA study. Coronary Artery Risk Development in Young Adults. Am J Epidemiol 2000;151: 1172-81.
34. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36: 646-61.
35. Schillaci G, Reboldi G, Verdecchia P, High-normal serum creatinine concentration is a predictor of cardiovascular risk in essential hypertension. Arch Intern Med 2001;161: 886-91.
36. Johnson RJ, Herrera-Acosta J, Schreiner GF, et al. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 2002; 346: 913-23.
37. Zoccali C. Cardiorenal risk as a new frontier of nephrology: research needs and areas for intervention. Nephrol Dial Transplant 2002;17 Suppl 11: 50-4.
38. Stary HC, et al., A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995;92 : 1355-74.
39. Stary HC, Chanler AB, Dinsmore RE, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1994; 89: 2462-78.
40. Jonasson L. Holm J, SkaLli O, et al.Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986;6:131-38.
41. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995; 92 : 1084-88.
42. Hansson G K, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989; 135 : 169-75.
43. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 2005;352: 1685-95.
44. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340 : 115-26.
45. Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-74.
46. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 1995; 15 : 551-61.
47. Rosenberg RD, Shworak NW, Liu J, et al. Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? J Clin Invest 1997; 99 : 2062-70.
48. Pillarisetti S, Alexander CW, Saxena U. Atherosclerosis -- new targets and therapeutics. Curr Med Chem Cardiovasc Hematol Agents 2004; 2 : 327-34.
49. Pillarisetti S. Lipoprotein modulation of subendothelial heparan sulfate proteoglycans (perlecan) and atherogenicity. Trends Cardiovasc Med 2000;10: 60-65.
50. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92 : 657-71.
51. Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988; 9: 1317-23.
52. Davies M J. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation 1996; 94 : 2013-20.
53. Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999;10: 1606-15.
54. Marso SP, Ellis SG, Gurm HS, et al. Proteinuria is a key determinant of death in patients with diabetes after isolated coronary artery bypass grafting. Am Heart J 2000;139: 939-44.
55. Tvedegaard E, Falk E, Nielsen M. Uremic arterial disease in rabbits with special reference to the coronary arteries. Acta Pathol Microbiol Immunol Scand [A] 1985; 93: 81-88.
56. Tvedegaard E. Kamstrup O. The effect of chronic renal failure in rabbits on plasma lipids and the concentration of cholesterol, calcium and phosphate in the aortic wall. Proc Eur Dial Transplant Assoc 1980; 17: 240-46.
57. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000;342: 1478-83.
58. Herbelin A, Urena P, Nguyan AT, et al. Elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 1991; 39: 954-60.
59. Pereira BJ, Shipiro L, King AJ, et al. Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 1994; 45: 890-96.
60. Papayianni A, Alexopoulos E, GiamalIs P, et al. Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events. Nephrol Dial Transplant 2002;17: 435-41.
61. Rattazzi M, Puato M, Faggin E, et al., New markers of accelerated atherosclerosis in end-stage renal disease. J Nephrol 2003; 16: 11-20.
62. Cavaillon JM, Poignet JM, fitting C, et al. Serum interleukin-6 in long-term hemodialyzed patients. Nephron 1992; 60: 307-13.
63. Arici M, Walls J. End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int 2001; 59: 407-14.
64. Lonnemann G, Haubitz M, Schindler R. Hemodialysis-associated induction of cytokines. Blood Purif 1990; 8: 214-22. 66.65. Schouten WE, Grooteman MP, van Houte AJ, et al. Effects of dialyser and dialysate on the acute phase reaction in clinical bicarbonate dialysis. Nephrol Dial Transplant 2000; 15: 379-84.
66. Memoli B, Minutolo R, Bisesti V, et al. Changes of serum albumin and C-reactive protein are related to changes of interleukin-6 release by peripheral blood mononuclear cells in hemodialysis patients treated with different membranes. Am J Kidney Dis 2002;39: 266-73.
67. Panichi V, Migliori M, De Piotro S, et al. Plasma C-reactive protein in hemodialysis patients: a cross-sectional, longitudinal clinical survey. Blood Purif 2000; 18: 30-36.
68. Kaysen GA, Stevenson FT, Depner TA. Determinants of albumin concentration in hemodialysis patients. Am J Kidney Dis 1997; 29: 658-68.
69. Qureshi AR, Alevstrand A, Dianelsson A, et al. Factors predicting malnutrition in hemodialysis patients: a cross-sectional study. Kidney Int 1998; 53: 773-82.
70. Kimak E, Solski J, Janicka L, et al. Lipid and lipoprotein ratios as risk factors of atherosclerosis in patients with chronic renal insufficiency (CRI). Int Urol Nephrol 1999; 31: 263-67.
71. Arnadottir M, Thysell H, Dellongeville J, et al. Evidence that reduced lipoprotein lipase activity is not a primary pathogenetic factor for hypertriglyceridemia in renal failure. Kidney Int 1995; 48: 779-84.
72. Tamashiro M, Iseki K, Sunagawa O, et al. Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis. Am J Kidney Dis 2001; 38: 64-69.
73. Fleischmann EH, Bower JD, Salahudeen AK. Risk factor paradox in hemodialysis: better nutrition as a partial explanation. Asaio J 2001; 47: 74-81
74. Chertow GM, Johansen KL, Lew N, et al. Vintage, nutritional status, and survival in hemodialysis patients. Kidney Int 2000; 57:1176-81
75. Stenvinkel P, Heimburg O, Tuck CH, et al. Apo(a)-isoform size, nutritional status and inflammatory markers in chronic renal failure. Kidney Int 1998; 53:1336-42.
76. Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome -- the heart of the matter. Nephrol Dial Transplant 2002; 17 Suppl 11: 28-31.
77. Hsu CC, Kao WH, Coresh J, et al. Apolipoprotein E and progression of chronic kidney disease. Jama 2005; 293: 2892-99.
78. Witko-Sarsat V, Friendlander M, Nguyan Khoa T, et al., Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 1998; 161: 2524-32.
79. Al-Saady NM, Leatham EW, Gupta S, et al. Monocyte expression of tissue factor and adhesion molecules: the link with accelerated coronary artery disease in patients with chronic renal failure. Heart 1999; 81: 134-40.
80. Maor I, Kaplan M, Hayak T, et al. Oxidized monocyte-derived macrophages in aortic atherosclerotic lesion from apolipoprotein E-deficient mice and from human carotid artery contain lipid peroxides and oxysterols. Biochem Biophys Res Commun 2000; 269:775-80.
81. Spittle MA, Hoenich NA, Handelman GJ, et al. Oxidative stress and inflammation in hemodialysis patients. Am J Kidney Dis 2001;38:1408-13.
82. Wever R, Boer P, Hijmering M, et al. Nitric oxide production is reduced in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 1999; 19: 1168-72.
83. Moustapha A, Naso A, Nahlawi M, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998; 97: 138-41.
84. van Guldener C, Kulik W, BergaR, et al. Homocysteine and methionine metabolism in ESRD: A stable isotope study. Kidney Int 1999; 56:1064-71.
85. Cordoba-Porras A, Sanchez-Quesada JL, Gangzalez-Sastre F, et al. Susceptibility of plasma low- and high-density lipoproteins to oxidation in patients with severe hyperhomocysteinemia. J Mol Med 1996; 74: 771-76.
86. Hultberg B, Andersson A, Isaksson A. The cell-damaging effects of low amounts of homocysteine and copper ions in human cell line cultures are caused by oxidative stress. Toxicology 1997; 123:33-40.
87. Herrmann W, Quast E, Ellgass A, et al. An increased serum level of free Apo(a) in renal patients is more striking than that of Lp(a) and is influenced by homocysteine. Nephron 2000; 85: 41-49.
88. Dardik R, Varon D, Tamarin R, et al. Homocysteine and oxidized low density lipoprotein enhanced platelet adhesion to endothelial cells under flow conditions: distinct mechanisms of thrombogenic modulation. Thromb Haemost 2000; 83: 338-44.
89. Toss H, Lindahl B, Seigbahn A, et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation 1997; 96: 4204-10.
90. Koch M, Kutkuhn B, TrenkwalderE, et al. Apolipoprotein B, fibrinogen, HDL cholesterol, and apolipoprotein(a) phenotypes predict coronary artery disease in hemodialysis patients. J Am Soc Nephrol 1997. 8: 1889-98.
91. Romanic AM, Arleth AJ, Willette Rn, et al. Factor XIIIa cross-links lipoprotein(a) with fibrinogen and is present in human atherosclerotic lesions. Circ Res 1998;83: 264-69.
92. Kopple JD, Greene T, ChumleaWC, et al. Relationship between nutritional status and the glomerular filtration rate: results from the MDRD study. Kidney Int 2000;57: 1688-703.
93. Keane WF, Collins AJ. Influence of co-morbidity on mortality and morbidity in patients treated with hemodialysis. Am J Kidney Dis 1994; 24: 1010-18.
94. Avram MM, Goldwasser P, Erroa M, et al. Predictors of survival in continuous ambulatory peritoneal dialysis patients: the importance of prealbumin and other nutritional and metabolic markers. Am J Kidney Dis 1994;23: 91-98.
95. Lowrie EG, Lew NL., Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990;15: 458-82.
96. Bologa RM, Levine DM, Parker TS, et al. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis 1998; 32:107-14.
97. Stenvinkel P, Heimburger O, Pautre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999; 55: 1899-911.
98. Stenvinkel P, Heimburger O, Pautrc F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal Failure. Kidney Int 1999; 55: 1899-911.
99. Stenvinkel P. Malnutrition and chronic inflammation as risk factors tor cardiovascular disease in chronic renal failure. Blood Puri r 2001; 19: 143-51.
100. McCnllough PA, Soman S. Cardiovascular calcification in patients with chronic renal failure: are we on target with this risk factor? Kidney IntSuppl2004:90:S18-24.
atherosclerosis. I. Human studies. J ExpPathoJ 1986; 2: 261-73.
102.Tanimura A, McGregor DH, Anderson HC. Calcification in atherosclerosis. II. Animal studies. JExpPathol 1986; 2: 275-97.
103. Obrador GT, Rorbets T, St Perter WL. et al. Trends in anemia at initiation of dialysis in the United States. Kidney Int 2001; 60: 1875-84.
104. Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis 2001 ;38: 803-12.
105. Yang CS, Chen S-W, Chiang C-H, et al. Effects of increasing dialysis dose on serum albumin and mortality in hemodialysis patients. Am J Kidney Dis 1996; 27:380-86.
106. Madore F, Lowrie EG, Brugnara C, et al. Anemia in hemodialysis patients: variables affecting this outcome predictor. J Am Soc Nephrol 1997; 8:1921-29.
107. Mocks J. Cardiovascular mortality in haemodialysis patients treated with epoetin beta - a retrospective study. Nephron 2000; 86: 455-62.
108. Mader SL, Josephson KR, Rubenstein LZ. Low prevalent ..: postural hypotension among community-dwelling elderly. JAMA 1987; 258: 1511-14.
109. Foley RN, Parfray PS, Harriett JD, et al. The impact of anemia on c ard lomy opathy, morbidity, and and mortality in end-staj^c renal disease. Am J Kidney Dis 1996; 28: 53-61.
110. Ganesh SK, Nass CM, Blumenthal R.S. Anti-atherosclerotic effects of statins: lessons from prevention trials. 5 Cardiovasc Risk 2003;10l 155-59."
111. Assmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Annu Rev Med 2003; 54: 321-41.
112. Barter P, Kastelein J, Nunn A, et al. High density lipoproteins (HDLs| and atherosclerosis; the unanswered questions. Atherosclerosis 2O03; 168:195-211.
113. Barter PJ, Brewer HB Jr. Chapman MJ, et al. Cholcstcryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vase Biol 2003; 23: 160-67.
114. Oram JF. HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol. Arterioscler Thromb Vase Biol 2OQ3; 23: 720-27.
115. Llaverias G, Laguna JC, Alegret M. Pharmacology of the ACAT mibe (CI-1011). Cardiovasc Drug Rev 2003; 21: 33-50
116. Tamura K,KatoY, Isnikawa A, et al. Design and synthesis of 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols as a novel series of antiatherogenic airtioxidants. J Med Chem 2003; 46:3083-93.
117. Meng CQ. BO-653. Chugai. Curr Opin Investig Drugs 2O03;4: 342-46.
118. MacpheeCH. Lipoprotein-associated phospholipase A2: a potential new risk factor for coronary artery disease and a therapeutic target. Curr Opin Pharmacol 2001; 1:121-25.
119. Caslake MJ, Packard CJ, Suckling KE, et al. Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease. Atherosclerosis 2000; 150:413-19.
120. De Feyler PJ, Smits PC, Reusing BJ, et al. Sirolimus-eluting coronary stents. J Interv Cardiol 2002; 15: 467-70.
121. Grabe E, Bullesfeld L. Initial experience withpaclitaxel-coated stents. J Interv Cardiol 2002; 15: 471-75.
122. Nugent MA, Nugent HA, Losao RV, et al. Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intirnal hyperplasia. Proc Natl Acad Sci U S A 2000; 97: 6722-27.
123. Engelherg H. Endogenous heparin activity deficiency: the 'missing link' in athcrogenesis? Atherosclerosis 2001; 159: 253-60.
124. Krusc R, McrtenM, Yoshida K, et al. Cholesterol-dependent changes ot" glycosaminoglycan pattern hi human aorta. Basic Res Cardiol 1996; 91:344-52.
125. Bcsarab A, Bolton WK, Browne JK, el al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin- N Engl J Med 199H; 339:584-90.
126. Ryden L, Armstrong PW, Cleland JG, et al. Efficacy and safely of high-dose lisinopril in chronic heart failure patients at higb cardiovascular risk, including those with diabetes mellitus. Result from the ATL.