Chronic renal failure: A cardiovascular risk factor

Transcription

1 Kidney International, Vol. 68, Supplement 99 (2005), pp. S25 S29 Chronic renal failure: A cardiovascular risk factor JOAN FORT Servicio de Nefrología, Hospital General Universitario Vall d Hebron, Universidad Autónoma, Barcelona, Spain Chronic renal failure: A cardiovascular risk factor. The risk of developing cardiovascular disease is greatly increased in patients undergoing renal replacement therapy and, notably, morbidity and mortality due to therapy is much higher in these patients than in the general population. Minimal alterations in renal function, as evidenced by reduced glomerular filtration rate and the presence of albuminuria, have been described as potent cardiovascular risk factors. The classic risk factors only partly explain this difference; hence, we must admit the existence of known and emerging factors associated with increased cardiovascular risk in patients with renal disease. This article provides a review of these factors. It describes the role of hyperphosphoremia and elevated calcium-phosphorous product in the formation of cardiovascular calcifications, the contribution of anemia to left ventricular hypertrophy, and the consequences of accelerated atherogenesis with oxidative stress and a microinflammatory state resulting from endothelial dysfunction. Hyperhomocysteinemia, increased sympathetic nervous system activity, lipoprotein alterations with elevated lipoprotein A, and increases in the concentrations of asymmetrical dimethyl-arginine are other examples of the changes described in this population. Patients with renal disease should be considered to be at high risk for developing cardiovascular disease and candidates for implementation of secondary prevention strategies. It is for this reason that early identification of renal failure, which remains hidden in many cases, is of prime importance. EPIDEMIOLOGIC STUDIES PROVIDING EVIDENCE THAT CHRONIC RENAL DISEASE IS ACARDIOVASCULAR RISK FACTOR Chronic renal disease (CRD) has become a considerable health care problem. According to the National Health and Nutrition Examination Survey III study [1], CRD affects 8.3 million individuals over 20 years of age in the United States, that is, 4.6% of the total population. CRD is a major risk factor for developing end-stage renal disease and cardiovascular disease, and for premature mortality. Since the 1970s, it has been known that patients with advanced CRD undergoing dialysis die from cardiovascular causes at a younger age than the normal population [2 4]. In the majority of registries of patients undergoing renal Keywords: chronic renal disease, cardiovascular risk, morbi-mortality. C 2005 by the International Society of Nephrology replacement therapy (United States, Europe, and Japan), approximately 50% of the deaths have a cardiovascular cause [5]. The dialysis population in the United States has a 10- to 20-fold higher risk of death due to cardiovascular complications than the general population after adjusting for age, race, and sex, and the relative risk with respect to the general population is much higher in younger patients [5]. The risk of cardiac mortality in patients under 45 years of age is 100 times higher than the general population, with differences decreasing with advancing age [6]. Studies on cardiovascular pathology at the start of dialysis have demonstrated that only 16% of the patients present with a normal electrocardiogram. The majority show lesions ranging from left ventricular hypertrophy, the most common finding, to systolic dysfunction and left ventricular dilation [7]. In addition, minimum alterations in renal function, as reflected by changes in glomerular filtration (GF) or the presence of microalbuminuria, are related with increased cardiovascular risk [8, 9]. An independent relationship has been found between reduced GF and the risk of death, cardiovascular events, and the need for hospitalization [10]. One population study comparing actuarial survival curves adjusted by terciles of GF found that renal failure is associated with increased cardiovascular mortality [11]. The Atherosclerosis Risk in Communities Study assessed morbidity and mortality due to stroke/cerebrovascular accident as related to the presence of renal failure. Patients with renal disease have a high risk of stroke, regardless of other predictive factors of cerebrovascular disease, with particularly marked risk in patients with renal disease and anemia [12]. The majority of clinical trials on pharmacologic treatment for hypertension have analyzed the relationship between decreased renal function and cardiovascular morbidity and death as well as anycause death, as in the Multiple Risk Factor Intervention Trial [13]. In the Hypertension Optimal Treatment study, designed to assess the effect of blood pressure control on morbidity and mortality, the presence of renal failure was associated with an elevated relative risk of vascular events [14]. Because serum creatinine levels and the GF rate do not correlate linearly, the most reliable method for estimating S-25

2 S-26 Fort: CRF: A cardiovascular risk factor Anemia Table 1. Emerging factors and uremia related factors of cardiovascular risk in CRF Alterations in Ca P metabolism Vascular access (increased cardiac output) Chronic volume expansion Hyperhomocysteinemia Dyslipidemia, increased lipoprotein A Hyperfibrinogenemia, Factor VII Oxidative stress Altered nitric oxide/endothelial balance Inflammation Malnutrition Endothelial dysfunction Ca, calcium; P, phosphorus. filtration is the use of predictive equations such as the Cockcroft-Gault and Modification of Diet in Renal Disease, which take into account the age, sex, and body mass index of the patient [15]. Several consensus documents, such as the Kidney Disease Outcomes Quality Initiative guidelines from the National Kidney Foundation and the American Heart Association, have underlined the relationship between CRD and cardiovascular risk. In addition, the most recent guidelines on the management and treatment of patients with hypertension have included early manifestations of renal insufficiency among the cardiovascular risk factors. In fact, the Report from the Seventh Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure, published in 2003, includes microalbuminuria and a GF rate of <60 ml/min as two cardiovascular risk factors to take into account and as target organ diseases in hypertension. [16]. UREMIA-RELATED FACTORS THAT CONTRIBUTE TO CARDIOVASCULAR RISK In addition to the classic cardiovascular risk factors such as age, family history of cardiovascular disease, hypertension, diabetes, dyslipidemia, smoking, and a sedentary lifestyle, in patients with CRD there several uremia-related factors and emerging factors to be taken into account, as shown in Table 1. The heart and left ventricular hypertrophy Left ventricular hypertrophy, the most frequent cardiac alteration in CRD patients, develops early and occurs at a rate that is inverse to the level of renal function [17]. The factors leading to this alteration are pressure overload and volume overload. Pressure overload is induced by hypertension and results in concentric left ventricular hypertrophy. Volume overload, which is produced by chronic hypervolemia, anemia, or hyperdynamic circulation, is associated with increased cardiac output and favors the development of eccentric left ventricular hypertrophy. Other factors implicated in the development Table 2. Cardiovascular symptoms related to anemia in CRF Increased cardiac output Left ventricular hypertrophy Palpitations and tachycardia Angina Congestive heart disease Myocardial contractility alterations of this alteration, including anemia, secondary hyperparathroidism, hyperactivity of the sympathetic system, inflammation, and hyperhomocysteinemia, will be discussed later. Left ventricular hypertrophy begins as an adaptive mechanism to accommodate pressure or volume overload, but later it becomes a maladaptive phenomenon leading to diastolic dysfunction [18]. Anemia as a cardiovascular risk factor There is a known association between normocytic, normochromic anemia, and CRD that becomes more important as GF deteriorates [19]. Anemia appears when creatinine clearance is less than or equal to 30 ml/min to 40 ml/min (stages 3 and 4 of CRD), and is more severe in the advanced phases (stage 5 CRD, when the patient is about to start dialysis treatment). In certain diseases, such as diabetes, anemia can appear earlier, and in patients with polycystic renal disease, it may never develop [20]. Anemia is generally well tolerated, because the organism has several compensating mechanisms to maintain tissue oxygenation. However, if it is left unchecked, it will eventually have severe consequences on several organs and systems. Among the physiologic alterations associated with anemia in CRD patients, perhaps the most important are increased cardiac output, cardiomegaly, left ventricular hypertrophy, and congestive heart failure [21]. The cardiovascular symptoms are shown in Table 2. Other alterations such as paleness, intolerance to cold, tiredness, and muscle weakness are attributable to the relative hypoperfusion of the skin and muscle tissue due to redistribution of the circulating volume toward more vital processes. Numerous studies have demonstrated a close relationship between cardiovascular morbidity and mortality and anemia, as well as a relationship between left ventricular hypertrophy and anemia. [22]. In fact, anemia is considered one of the uremia-related factors associated with cardiovascular risk in patients with CRD. According to data from the Study of Left Ventricular Dysfunction, decreased GF and reduced hematocrit have a synergistic impact on mortality [23]. Data from Medicare consider anemia a multiplicative risk factor for mortality in patients with CRD [24]. The hospitalization rate also shows a relationship with the patient s degree of anemia [25].

3 Fort: CRF: A cardiovascular risk factor S-27 The availability of erythropoietic stimulating agents in 1986 brought about notable changes in the treatment of anemia. First applied only in dialysis patients, in the decade of the 1990s, erythropoietin use was extended to correct anemia in CRD. Various studies [22, 26] have demonstrated partial regression of left ventricular hypertrophy after administration of erythropoietin for anemia. Correction of anemia in CRD improves survival [27], decreases morbidity and mortality [28], and increases the patient s quality of life [29]. Partial correction of anemia in patients with heart failure and CRD improves heart function [30]. Hence, it can be concluded that anemia plays an essential role in the development of left ventricular hypertrophy and mortality in CRD, and that correction of anemia improves cardiovascular status. Although there is little information regarding the correction of anemia in CRD, preliminary, still unpublished results from the Morbi- Mortality in Chronic Renal Disease study carried out in Spain by the Study Group for Diabetic Nephropathy (Grupo Español de Estudio de la Nefropatía Diabética) have shown that 46% of patients with stages 4 and 5 of CRD have anemia with a notable grade of ferropenia. Nevertheless, nephrologists are increasingly more aware of the need for early correction of anemia in their patients, in accordance with the recommendations of the American Dialysis Outcomes Quality Initiative and recently revised European Best Practice Guidelines [31]. Influence of calcium-phosphorus metabolism on valvular and vascular calcifications Vascular calcifications constitute another frequently occurring cardiovascular risk factor that contributes considerably to the high morbidity and mortality in patients with CRD. Articles implicating hyperphosphatemia as an independent risk factor for mortality are becoming increasingly more frequent in the literature [32, 33]. In CRD, vascular calcifications are a consequence of alterations in mineral metabolism [34]. However, various therapeutic measures commonly used for the management of bone mineral alterations, including elevated doses of oral calcium in phosphorus chelates together with vitamin D metabolites, can contribute to the increase in size of vascular calcifications. Even in the absence of hypercalcemia, a positive total calcium balance, which is a cause of calcifications, cannot be ruled out [35]. There are 2 types of calcifications with different implications. Intimal calcifications develop in 80% to 90% of atherosclerotic plaques that protrude into the vessel lumen, causing ischemia and necrosis. Calcification of the media (Monckeberg sclerosis) occurs diffusely in the tunica media and is common in CRD and diabetic patients. Calcification of the media increases vascular rigidity and decreases compliance. This results in systolic hypertension and increased pulse wave velocity, which contribute to left ventricular hypertrophy and compromised diastolic coronary flow. Arterial rigidity due to calcification of the media is associated with increased mortality. In CRD patients, the relative absence of protective factors seems to be linked with the development of vascular calcifications. A deficit of the glycoprotein, fetuin, a potent inhibitor of calcification, has been found in these patients [36]. Evidence of vascular calcifications should prompt clinicians to review the treatment regimens for osteodystrophy, identify the factors that can exacerbate vascular calcification, and implement measures designed to correct cardiovascular risk factors hypertension, dyslipidemia, hyperphosphatemia, and excess calcium supply to avoid severe complications, such as calciphylaxis [37]. Increased sympathetic nervous system activity: A deleterious effect of CRD on the cardiovascular system Another highly relevant cardiovascular risk factor is increased activity of the sympathetic nervous system. Sympathetic hyperactivity has an important role in CRD-associated hypertension. Renal ischemia, elevated angiotensin II, and suppression of cerebral nitric oxide contribute to stimulate sympathetic activity. Accumulating evidence points to a role of this sympathetic hyperactivity in renal and cardiac injury in patients with CRD [38, 39]. It seems that decreased availability of nitric oxide and increased oxidative stress can sensitize target organs to the deleterious actions of sympathetic hyperactivity. Moreover, the sympathetic system is not only a key regulator of cardiovascular function; it also exercises an important function in the mechanisms controlling the immune and inflammatory response [40]. Oxidative stress and the microinflammatory state caused by uremia Patients with CRD present accelerated atherogenesis and, as a cause or consequence, show oxidative stress and an evident microinflammatory state resulting from endothelial dysfunction, which is present even in the initial phases of CRD. C-reactive protein is a potent marker of atherosclerotic complications, and it is a notable predictor of mortality and cardiovascular events in CRD patients [41]. The causes of the inflammatory state in these can be attributed to reduced clearance of proinflammatory cytokines, the uremic state, oxidative stress, and the presence of associated comorbid conditions such as heart failure, diabetes, inflammatory diseases, and so forth. In hemodialysis patients, repeated exposure to bioincompatible dialysis membranes, the poor bacteriologic quality of the dialysis fluid, and the presence of foreign bodies such as polytetrafluoroethylene prostheses and catheters, together with evident or asymptomatic infection, all contribute to increasing the inflammatory state.

4 S-28 Fort: CRF: A cardiovascular risk factor Perticone [42] has suggested that alterations in the vasodilator response to acetylcholine are associated with a loss of renal function in patients with essential hypertension. This association suggests that endothelial dysfunction would play a slight to moderate role in renal failure in patients with uncomplicated hypertension. Several in vitro studies have demonstrated that modified lowdensity lipoprotein, advanced glycosylation end products, cytokines, homocysteine, and lipoprotein A are responsible for the production of oxygen free radicals, a cause of oxidative stress [43, 44]. Fibrinogen is an acute phase reactant whose levels correlate with inflammation markers in patients with CRD. Although fibrinogen levels are increased in CRD patients under dialysis [45], the results in the literature are controversial regarding its role as a predictor of all-cause and cardiovascular mortality. This may be because fibrinogen, which is closely linked to other cardiovascular risk markers and to inflammation, loses significance when these factors are included in the predictive model. Homocysteine and CRD: A still uncertain relationship Homocysteine is moderately elevated in the initial phases of CRD and increases as GF deteriorates. Data in the literature on the relationship between homocysteine and cardiovascular events are not conclusive, probably because of the coexistence of confounding factors, attributable to inflammation and malnutrition [46]. Other abnormalities with relevant pathogenic potential must be attributed to alterations in the lipoprotein pattern, with elevated lipoprotein A [47], as well as increased concentrations of oxide-nitric synthetase, and asymmetrical dimethyl-arginine [48]. The metabolic syndrome and its relationship with CRD The metabolic syndrome, characterized by abdominal fat accumulation hypertension, hypertriglyceridemia, low high-density lipoprotein levels, and hyperglycemia [49], has been associated with an increased risk of developing diabetes mellitus and cardiovascular disease, as well as a higher risk of death by cardiovascular and other causes. Nevertheless, there is little data in the literature on the relationship between the metabolic syndrome and CRD. Some recent studies [50, 51], however, have suggested that the risk of developing CRD and microalbuminuria progressively increases parallel to the number of components of metabolic syndrome, regardless of age, sex, race, and the presence of other potential risk factors for CRD. CONCLUSION Elevated urinary excretion of albumin or proteins is a risk factor for cardiovascular disease both in diabetic and nondiabetic patients. Poor creatinine clearance and low GF are also risk factors in patients with and without diabetes. Patients with CRD, defined as those with persistent renal injury, such as microalbuminuria or proteinuria, or a GF rate <60 ml/min/1.73 m 2, regardless of the cause, have a higher risk of developing cardiovascular disease, including coronary disease, cerebrovascular disease, peripheral artery disease, and heart failure. Hence, they should be considered patients at high cardiovascular risk requiring secondary prevention strategies. All these pathogenic mechanisms are priority areas of interest for future investigation, considering the epidemiologic demonstration of a progressive increase in CRD, mainly because of increasing detection of occult renal failure. The scientific community of nephrologists and the Spanish Society of Nephrology in our country have initiated studies to determine the prevalence of CRD in the general population. 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