Chronic renal failure: A cardiovascular risk factor
2005; Elsevier BV; Volume: 68; Linguagem: Inglês
10.1111/j.1523-1755.2005.09906.x
ISSN1523-1755
Autores Tópico(s)Parathyroid Disorders and Treatments
ResumoChronic 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. 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. Chronic renal disease (CRD) has become a considerable health care problem. According to the National Health and Nutrition Examination Survey III study1K/DOQI: Clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Kidney Disease Outcome Quality Initiative.Am J Kidney Dis. 2002; 39: S1-S246Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 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 population2Lindner A. Charra B. Sherrard D.J. Scribner B.H. Accelerated atherosclerosis in prolonged maintenance hemodialysis.N Engl J Med. 1974; 290: 697-701Crossref PubMed Scopus (1464) Google Scholar, 3Parfrey P.S. Foley R.N. 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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 patients5Renal Data System USRDS 2003 Annual report: Atlas of end-stage renal disease in the United States. National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2003Google Scholar. 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 age6Foley R.N. Parfrey P.S. Sarnak M.J. Epidemiology of cardiovascular disease in chronic renal disease.J Am Soc Nephrol. 1998; 9: S16-S23Crossref PubMed Scopus (30) Google Scholar. 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 dilation7Parfrey P.S. Collingwood P. Foley R.N. Bahrle A. Images in Nephrology. Left ventricular disorders detected by mode echocardiography in chronic uraemia.Neprol Dial Transplant. 1996; 11: 1328-1331Crossref PubMed Scopus (41) Google Scholar. 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 risk8Ruilope L.M. Van Veldhuisen D.J. Ritz E. Luscher T.F. Renal function: The Cinderella of cardiovascular risk profile.J Am Coll Cardiol. 2001; 38: 1782-1787Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar,9Ritz E. Minor renal dysfunction: An emerging independent cardiovascular risk factor.Heart. 2003; 89: 963-964Crossref PubMed Scopus (33) Google Scholar. An independent relationship has been found between reduced GF and the risk of death, cardiovascular events, and the need for hospitalization10Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8250) Google Scholar. One population study comparing actuarial survival curves adjusted by terciles of GF found that renal failure is associated with increased cardiovascular mortality11Henry R.A. Kostense P.J. Bos G. et al.Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study.Kidney Int. 2002; 62: 1402-1407Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. 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 anemia12Abramson J.L. Jurkovitz C.T. Vaccarino V. et al.Chronic kidney disease, anemia, and incident stroke in a middle-aged, community-based population: The ARIC Study.Kidney Int. 2003; 64: 610-615Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar. 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 any-cause death, as in the Multiple Risk Factor Intervention Trial13Flack J. Neaton J. Daniels B. Esunge P. Ethnicity and renal disease: lessons from the Multiple Risk Factor Intervention Trial and Treatment of Mild Hypertension Study.Am J Kidney Dis. 1993; 21: 31-40Abstract Full Text PDF PubMed Scopus (103) Google Scholar. 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 events14Hansson L. Zanchetti A. Carruthers S.G. et al.for the HOT study group: Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial.Lancet. 1998; 351: 1755-1762Abstract Full Text Full Text PDF PubMed Scopus (5245) Google Scholar. Because serum creatinine levels and the GF rate do not correlate linearly, the most reliable method for estimating 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 patient15Cockcroft D.W. Gault M.H. Prediction of creatinine clearance from serum creatinine.Nephron. 1976; 16: 31-41Crossref PubMed Scopus (12499) Google Scholar. 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.16Chonabian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JNC 7.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (9729) Google Scholar. 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.Table 1Emerging factors and uremia related factors of cardiovascular risk in CRFAnemiaAlterations in Ca—P metabolismVascular access (increased cardiac output)Chronic volume expansionHyperhomocysteinemiaDyslipidemia, increased lipoprotein AHyperfibrinogenemia, Factor VIIOxidative stressAltered nitric oxide/endothelial balanceInflammationMalnutritionEndothelial dysfunctionCa, calcium; P, phosphorus. Open table in a new tab Ca, calcium; P, phosphorus. 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 function17Mcmahon D.C. Roger S.D. Levin A. For The Slimheart Investigators Group Development, prevention and potential reversal of left ventricular hypertrophy in chronic kidney disease.J Am Soc Nephrol. 2004; 15: 1640-1647Crossref PubMed Scopus (75) Google Scholar. 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 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 dysfunction18London G.M. Cardiovascular disease in chronic renal failure: Pathophysiologic aspects.Semin Dial. 2003; 16: 85-94Crossref PubMed Scopus (241) Google Scholar. There is a known association between normocytic, normochromic anemia, and CRD that becomes more important as GF deteriorates19Eschbach J.W. Adamson J.W. Anemia of end-stage renal disease (ESRD).Kidney Int. 1985; 28: 1Abstract Full Text PDF PubMed Scopus (279) Google Scholar. 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 develop20Cannata J.B. Diaz Lopez J.B. Alteraciones hematológicas en la insuficiencia renal crónica.in: Llach F. Valderrábano F. Insuficiencia Renal Crónica, Diálisis y Trasplante Renal. Norma, Madrid1997: 423-447Google Scholar. 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 failure21Parfrey P.S. Foley R.N. Harnett J.D. et al.Outcome and risk factors for left ventricular disorders in chronic uremia.Nephrol Dial Transplant. 1996; 11: 1277-1285Crossref PubMed Scopus (539) Google Scholar. 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.22Levin A. Thompson C.R. Ethier J. et al.Left ventricular mass index increase in early renal disease: Impact of decline on hemoglobin.Am J Kidney Dis. 1999; 34: 125-134Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar. 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 mortality23Al-Ahmad A. Rand W.M. Manjunath G. et al.Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction.J Am Coll Cardiol. 2001; 38: 955-962Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar. Data from Medicare consider anemia a multiplicative risk factor for mortality in patients with CRD24Collins A.J. Li S. Gilberston D.T. et al.Chronic kidney disease and cardiovascular disease in the Medicare population.Kidney Int. 2003: S24-31Abstract Full Text Full Text PDF Scopus (268) Google Scholar. The hospitalization rate also shows a relationship with the patient's degree of anemia25Holland D.C. Lam M. Predictors of hospitalization and death among predialysis patients: A retrospective cohort study.Neprol Dial Transplant. 2000; 15: 650-658Crossref PubMed Scopus (120) Google Scholar.Table 2Cardiovascular symptoms related to anemia in CRFIncreased cardiac outputLeft ventricular hypertrophyPalpitations and tachycardiaAnginaCongestive heart diseaseMyocardial contractility alterations Open table in a new tab 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 studies22Levin A. Thompson C.R. Ethier J. et al.Left ventricular mass index increase in early renal disease: Impact of decline on hemoglobin.Am J Kidney Dis. 1999; 34: 125-134Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar,26Portoles J. Torralbo A. Martin P. et al.Cardiovascular effects of recombinant human erythropoietin in predialysis patients.Am J Kidney Dis. 1997; 29: 541-548Abstract Full Text PDF PubMed Scopus (210) Google Scholar have demonstrated partial regression of left ventricular hypertrophy after administration of erythropoietin for anemia. Correction of anemia in CRD improves survival27Mocks J. Franke W. Ehmer B. et al.Analysis of safety database for long-term epoetin-beta treatment. A meta-analysis covering 3697 patients.in: Koch K.M. Stein G. Pathogenetic and Therapeutic Aspects of Chronic Renal Failure. Marcel Dekker, New York1997: 163Google Scholar, decreases morbidity and mortality28Morbidity And Mortality Of Renal Dialysis An NIH consensus conference statement. Consensus Development Conference Panel.Ann Intern Med. 1994; 121: 62Crossref PubMed Scopus (206) Google Scholar, and increases the patient's quality of life29Delano B.G. Improvements in quality of life following treatment with r-HuEPO in anemic hemodialysis patients.Am J Kidney Dis. 1989; 14: 14PubMed Google Scholar. Partial correction of anemia in patients with heart failure and CRD improves heart function30Silverberg D.S. Wexler D. Blum M. et al.The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations.J Am Coll Cardiol. 2000; 35: 1737-1744Abstract Full Text Full Text PDF PubMed Scopus (612) Google Scholar. 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 Guidelines31Locatelli F. Aljama P. Barany P. et al.Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure.Neprol Dial Transplant. 2004; 19: 1-44PubMed Google Scholar. 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 literature32Block G.A. Hulbert-Shearon T.E. et al.Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: A national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2013) Google Scholar,33Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1432) Google Scholar. In CRD, vascular calcifications are a consequence of alterations in mineral metabolism34Safar M.E. Blacher J. Pannier B. et al.Central pulse pressure and mortality in end-stage renal disease.Hypertension. 2002; 39: 735-738Crossref PubMed Scopus (665) Google Scholar. 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 out35Goodman W.G. London G. On Behalf Of The Vascular Calcification Work Group Vascular calcification in chronic kidney disease.Am J Kidney Dis. 2004; 43: 572-579Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar. 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 patients36Ketteler M. Vermeer C. Wanner C. et al.Novel insights into uremic vascular calcification: Role of matrix Gla protein and alpha-2–Heremans Schmid glycoproteins/fetuin.Blood Purif. 2002; 20: 473-476Crossref PubMed Scopus (48) Google Scholar. 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 calciphylaxis37Ehrlich J.E. Rumberger J.A. Detection and clinical management of cardiovascular calcification in ESRD.Nephrol Dial Transplant. 2004; 33: 306-313Google Scholar. 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 CRD38Converse R.L. Jacobsen T.N. Toto R.D. et al.Sympathetic overactivity in patients with chronic renal failure.N Engl J Med. 1992; 327: 1912-1918Crossref PubMed Scopus (965) Google Scholar,39Koomans H.A. Blankestijn P.J. Joles J.A. Sympathetic hyperactivity in chronic renal failure: A wake-up call.J Am Soc Nephrol. 2004; 15: 524-537Crossref PubMed Scopus (175) Google Scholar. 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 response40Elenkov I.J. Wilder R.L. Chrousos G.P. Vizi E.S. The sympathetic nerve-An integrative interface between two supersystems. The brain and immune system.Pharmacol Rev. 2000; 52: 595-638PubMed Google Scholar. 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 patients41Stenvinkel P. Wanner C. Metzger T. et al.Inflammation and outcome in end-stage renal failure: Does female gender constitute a survival advantage?.Kidney Int. 2002; 62: 1791-1798Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar. 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. Perticone42Perticone F. Maio R. Tripepi G. et al.Endothelial dysfunction and mild renal insufficiency in essential hypertension.Circulation. 2004; 110: 821-825Crossref PubMed Scopus (89) Google Scholar 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 low-density lipoprotein, advanced glycosylation end products, cytokines, homocysteine, and lipoprotein A are responsible for the production of oxygen free radicals, a cause of oxidative stress43Shlipak M.G. Fried L.F. Crump C. et al.Cardiovascular disease risk status in elderly persons with renal insufficiency.Kidney Int. 2002; 62: 997-1003Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar,44Kalousova M. Zima T. Tesar V. et al.Relationship between advanced glycol-oxidation end products, inflammatory markers/acute-phase reactants, and some autoantibodies in chronic hemodialysis patients.Kidney Int. 2003: S62-S64Google Scholar. 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 dialysis45Zoccali C. Mallamaci F. Tripepi G. et al.Fibrinogen mortality and incident cardiovascular complications in end-stage renal failure.J Intern Med. 2003; 254: 132-139Crossref PubMed Scopus (74) Google Scholar, 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 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 malnutrition46Kalantar Z.K. Block G. Humphreys M.H. et al.A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients.J Am Soc Nephrol. 2004; 15: 442-453Crossref PubMed Scopus (157) Google Scholar. Other abnormalities with relevant pathogenic potential must be attributed to alterations in the lipoprotein pattern, with elevated lipoprotein A47Kronenberg F. Kuen E. Ritz E. et al.Lipoprotein (a) serum concentrations and apolipoproteins (a) phenotypes in mild and moderate renal failure.J Am Soc Nephrol. 2000; 11: 105-115PubMed Google Scholar, as well as increased concentrations of oxide-nitric synthetase, and asymmetrical dimethyL-arginine48Ito A. Tsao P.S. Adimoolam S. et al.Novel mechanism for endothelial dysfunction: Dysregulation of dimethylarginine dimethylaminohydrolase.Circulation. 1999; 99: 3092-3095Crossref PubMed Scopus (607) Google Scholar. The metabolic syndrome, characterized by abdominal fat accumulation hypertension, hypertriglyceridemia, low high-density lipoprotein levels, and hyperglycemia49Chen J. Muntner P. Hamm L.L. et al.The metabolic syndrome and chronic kidney disease in U.S. adults.Ann Intern Med. 2004; 140: 167-174Crossref PubMed Scopus (1058) Google Scholar, 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 studies50Schelling J.R. Sedor J.R. The metabolic syndrome as a risk factor for chronic kidney disease: More than a fat chance?.J Am Soc Nephrol. 2004; 15: 2773-2774Crossref PubMed Scopus (33) Google Scholar,51Bagby S.P. Obesity-initiated metabolic syndrome and the kidney: A recipe for chronic kidney disease?.J Am Soc Nephrol. 2004; 15: 2775-2791Crossref PubMed Scopus (214) Google Scholar, 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. 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 m2, 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.
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