Portal de Periódicos da CAPES

Cardiovascular risk factors in chronic kidney disease

2005; Elsevier BV; Volume: 68; Issue: 4 Linguagem: Inglês

10.1111/j.1523-1755.2005.00551.x

1523-1755

Vandana Menon, Ambreen Gul, Mark J. Sarnak,

Renal and Vascular Pathologies

Cardiovascular disease is the primary cause of morbidity and premature mortality in chronic kidney disease. While it is well established that patients with kidney failure (chronic kidney disease stage 5) are at high risk of cardiovascular disease morbidity and mortality1.Foley 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, patients with earlier stages of chronic kidney disease also experience a high rate of fatal and nonfatal cardiovascular events2.Manjunath G. Tighiouart H. Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar. Recent guidelines and position statements have therefore defined chronic kidney disease as a cardiovascular risk equivalent, and patients in all stages of chronic kidney disease are considered in the “highest risk group” for development of cardiovascular disease3.Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2675) Google Scholar. We propose that patients with chronic kidney disease are at increased risk for cardiovascular disease for several reasons Figure 1: (1) chronic kidney disease is associated with increased prevalence of traditional and nontraditional cardiovascular disease risk factors; (2) chronic kidney disease is an independent risk factor for cardiovascular disease; (3) many cardiovascular disease risk factors are also risk factors for progression of chronic kidney disease; and (4) the presence of cardiovascular disease may be a risk factor for chronic kidney disease. The interrelationship between cardiovascular and chronic kidney disease, with each contributing to the pathogenesis of the other, leads to a cycle of cardiovascular and kidney disease progression. In the current review we focus on chronic kidney disease stages 1 to 4 and (1) present evidence suggesting that markers of chronic kidney disease, including reduced glomerular filtration rate (GFR) and microalbuminuria, are independent risk factors for cardiovascular disease, (2) describe the spectrum of cardiovascular disease in chronic kidney disease, and (3) discuss the role of traditional and nontraditional risk factors in the development of the different forms of cardiovascular disease. We do not describe management strategies as this is discussed in an accompanying review. An abundance of recent data has demonstrated an association between reduced kidney function and cardiovascular disease morbidity and mortality that persists after adjustment for traditional cardiovascular disease risk factors2.Manjunath G. Tighiouart H. Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar,4.Go 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 (8252) Google Scholar. Possible explanations for this association include that reduced GFR (1) is associated with an increased level of non-traditional risk factors that are frequently not adjusted for in analyses, (2) may be a marker of the severity of diagnosed vascular disease or of undiagnosed vascular disease, (3) may be a measure of residual confounding from traditional risk factors, for example, the severity of hypertension, and (4) patients with reduced GFR may not receive the benefits of optimal therapies such as aspirin, beta blockers, angiotensin-converting enzyme (ACE) inhibitors. Prospective studies have established that albumin excretion, at levels well below the current cutoffs used to define microalbuminuria, is an independent predictor of cardiovascular disease outcomes5.Wachtell K. Ibsen H. Olsen M.H. et al.Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE Study.Ann Intern Med. 2003; 139: 901-906Crossref PubMed Scopus (466) Google Scholar. Potential reasons for these findings include the following: (1) microalbuminuria may be a marker of generalized endothelial dysfunction and vascular permeability, (2) microalbuminuria may be associated with other traditional and nontraditional cardiovascular disease risk factors, and (3) microalbuminuria may be a precursor for the development of early or incipient kidney disease. In support of the last hypothesis, studies have demonstrated that microalbuminuria is associated with an increased risk for development of albuminuria, an accepted marker of kidney disease6.Mann J.F. Gerstein H.C. Yi Q.L. et al.Development of renal disease in people at high cardiovascular risk: Results of the HOPE randomized study.J Am Soc Nephrol. 2003; 14: 641-647Crossref PubMed Scopus (125) Google Scholar. Manifestations of cardiovascular disease in chronic kidney disease can be broadly classified as those affecting the myocardium and those affecting the blood vessels although these pathophysiologic processes are not mutually exclusive and are in fact closely interrelated Figure 2. As described below, clinical manifestations of myocardial and vascular remodeling include left ventricular hypertrophy (LVH), increased pulse pressure, and ischemic heart disease, all of which are independent risk factors for mortality in patients with kidney failure8.Zoccali C. Benedetto F.A. Mallamaci F. et al.Prognostic impact of the indexation of left ventricular mass in patients undergoing dialysis.J Am Soc Nephrol. 2001; 12: 2768-2774PubMed Google Scholar, 9.Klassen P.S. Lowrie E.G. Reddan D.N. et al.Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis.JAMA. 2002; 287: 1548-1555Crossref PubMed Scopus (341) Google Scholar, 1.Comorbid conditions and correlations with mortality risk among 3,399 incident hemodialysis patients.Am J Kidney Dis. 1992; 20: 32-38PubMed Google Scholar. The pressure and volume overload that are inherent to the abnormalities of homeostasis seen in chronic kidney disease lead to structural alterations of the myocardium11.London G.M. Parfrey P.S. Cardiac disease in chronic uremia: pathogenesis.Adv Ren Replace Ther. 1997; 4: 194-211PubMed Google Scholar. These structural changes include ventricular remodeling that may lead to eccentric or concentric LVH, systolic and diastolic dysfunction, and resultant clinical symptoms of heart failure. Abnormalities of myocardial structure are common in chronic kidney disease. The prevalence of LVH was 30% in a cohort of patients with chronic kidney disease stages 3 and 412.Mcmahon L.P. Roger S.D. Levin A. 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. In a large cohort derived from a health maintenance organization, the prevalence of heart failure ranged from 5% to 21% among patients with GFR of 15 to 60 mL/min/1.73 m24.Go 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 (8252) Google Scholar. In a community-based cohort of patients with heart failure, 55% had creatinine clearance 50% stenosis [abstract; Ohtake T et al, J Am Soc Nephrol 9:0765, 2005]. In the population-based Atherosclerosis Risk in Communities (ARIC) Study, the prevalence of symptomatic coronary heart disease was 11% among persons with chronic kidney disease versus 4% in those without kidney disease2.Manjunath G. Tighiouart H. Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar. There was a significant association between arterial stiffness, estimated as pulse wave velocity, and kidney function in a cohort of patients with mean creatinine clearance of 68.5 mL/min/1.73 m215.Mourad J.J. Pannier B. Blacher J. et al.Creatinine clearance, pulse wave velocity, carotid compliance and essential hypertension.Kidney Int. 2001; 59: 1834-1841Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar. The consequences of arteriosclerosis and loss of arterial compliance include increased afterload that in turn causes ventricular hypertrophy thus setting up a cycle of deteriorating myocardial function13.Mcalister F.A. Ezekowitz J. Tonelli M. et al.Renal insufficiency and heart failure: Prognostic and therapeutic implications from a prospective cohort study.Circulation. 2004; 109: 1004-1009Crossref PubMed Scopus (558) Google Scholar. In turn, LVH increases myocardial oxygen demand thus further exacerbating ischemic heart disease. Both traditional and nontraditional risk factors have been implicated in the development of cardiovascular disease in chronic kidney disease. Traditional risk factors are those defined in the Framingham Heart Study and used to predict coronary heart disease outcomes in the general population16.Wilson P.W. D'Agostino R.B. Levy D. et al.Prediction of coronary heart disease using risk factor categories.Circulation. 1998; 97: 1837-1847Crossref PubMed Scopus (7010) Google Scholar. Nontraditional risk factors are uremia-related factors that increase in prevalence as kidney function declines and may contribute to the excess risk of cardiovascular disease seen in chronic kidney disease3.Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2675) Google Scholar Table 1.Table 1Manifestations of cardiovascular disease in chronic kidney disease and associated putative risk factorsPathologyTraditional risk factorsNontraditional risk factorsCardiomyopathyOlder ageAlbuminuriaHypertensionReduced glomerular filtration rateValvular diseaseAnemiaDyslipidemiaInflammationSmokingArteriosclerosisDiabetesExtracellular fluid volume overloadAbnormal calcium/phosphate metabolismAtherosclerosisOlder ageAlbuminuriaMale genderReduced glomerular filtration rateHypertensionAnemiaDiabetesInflammationDyslipidemiaOxidative stressSmokingEndothelial dysfunctionPhysical inactivityHomocysteineLeft ventricular hypertrophyLipoprotein(a)MalnutritionThrombogenic factorsSympathetic activityInsulin resistance/metabolic syndromeArteriosclerosisOlder ageAlbuminuriaMale genderReduced glomerular filtration rateSmokingEndothelial dysfunctionHypertensionAbnormal calcium/phosphate metabolismDiabetesMetabolic syndromeDyslipidemia Open table in a new tab Systolic blood pressure and anemia appear to be important determinants of left ventricular remodeling in patients with kidney disease17.Levin A. Thompson C.R. Ethier J. et al.Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin.Am J Kidney Dis. 1999; 34: 125-134Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar. In addition, several traditional and nontraditional cardiovascular disease factors are implicated in the pathogenesis of LVH in chronic kidney disease. In a cohort of incident dialysis patients from Dialysis Morbidity and Mortality Study (DMMS) Wave 2, age, hypertension, diabetes, smoking, and serum calcium and parathyroid hormone (PTH) levels were correlates of LVH18.Stack A.G. Saran R. Clinical correlates and mortality impact of left ventricular hypertrophy among new ESRD patients in the United States.Am J Kidney Dis. 2002; 40: 1202-1210Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar. Limited data exists on determinants of LVH in patients in the earlier stages of chronic kidney disease. In a nested analysis of data from the Australian Predialysis (SLIMHEART) Study, LVH was a product of both increased chamber size as well as wall thickness11.London G.M. Parfrey P.S. Cardiac disease in chronic uremia: pathogenesis.Adv Ren Replace Ther. 1997; 4: 194-211PubMed Google Scholar. In a cross-sectional study of patients with mean creatinine clearance of 25 mL/min, older age, higher systolic blood pressure, lower hemoglobin, and decreased level of kidney function were independent predictors of LVH19.Levin A. Singer J. Thompson C.R. et al.Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention.Am J Kidney Dis. 1996; 27: 347-354Abstract Full Text PDF PubMed Scopus (616) Google Scholar. Similarly, in the ARIC Study, among African Americans with chronic kidney disease stage 3, lower GFR and lower hemoglobin were associated with LVH20.Astor B.C. Arnett D.K. Brown A. et al.Association of kidney function and hemoglobin with left ventricular morphology among African Americans: The Atherosclerosis Risk in Communities (ARIC) study.Am J Kidney Dis. 2004; 43: 836-845Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar. More recent data suggest that additional nontraditional factors may be implicated in the development of LVH in kidney disease. In a cross-sectional study of hemodialysis patients, coronary artery calcification score and pulse pressure were independent correlates of LVH21.Yildiz A. Memisoglu E. Oflaz H. et al.Atherosclerosis and vascular calcification are independent predictors of left ventricular hypertrophy in chronic haemodialysis patients.Nephrol Dial Transplant. 2005; 20: 760-767Crossref PubMed Scopus (48) Google Scholar. Markers of oxidative stress, discussed later, were also associated with LVH independent of carotid intima media thickness and number of plaques in a cohort of chronic hemodialysis patients22.Zoccali C. Mallamaci F. Asahia K. et al.Pentosidine, carotid atherosclerosis and alterations in left ventricular geometry in hemodialysis patients.J Nephrol. 2001; 14: 293-298PubMed Google Scholar. There are limited data on traditional atherosclerotic cardiovascular disease factors in chronic kidney disease stages 1 to 4. Much of the existing information is extrapolated from studies in the general population. However, this extrapolation for the most part seems reasonable, as there is no a priori reason to assume that these risk relationships will widely differ in patients in the earlier stages of chronic kidney disease. A few studies have confirmed the importance of traditional cardiovascular disease risk factors, such as diabetes, higher total cholesterol, lower high-density lipoprotein (HDL) cholesterol, smoking, and higher systolic blood pressure, in the development of atherosclerotic cardiovascular disease in chronic kidney disease stages 1 to 423.Culleton B.F. Larson M.G. Wilson P.W. et al.Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.Kidney Int. 1999; 56: 2214-2219Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar,24.Muntner P. He J. Astor B.C. et al.Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: Results from the Atherosclerosis Risk in Communities Study.J Am Soc Nephrol. 2005; 16: 529-538Crossref PubMed Scopus (375) Google Scholar. Recent studies have suggested that the Framingham risk equation may be inadequate to attribute risk of coronary heart disease in a person with chronic kidney disease25.Longenecker J.C. Coresh J. Powe N.R. et al.Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: The CHOICE Study.J Am Soc Nephrol. 2002; 13: 1918-1927Crossref PubMed Scopus (508) Google Scholar,26.Sarnak M.J. Coronado B.E. Greene T. et al.Cardiovascular disease risk factors in chronic renal insufficiency.Clin Nephrol. 2002; 57: 327-335Crossref PubMed Scopus (177) Google Scholar, although this remains to be evaluated in large prospective studies. A potential explanation for the Framingham equation being inadequate in chronic kidney disease is the presence of nontraditional factors that are not accounted for by this equation. There are few prospective studies or randomized controlled trials evaluating nontraditional factors as risk factors for the development of cardiovascular disease in chronic kidney disease. Available evidence for some of these risk factors is briefly summarized below. We do not discuss anemia, as this is the topic of an accompanying review. Inflammation appears to play an integral part in the pathogenesis of atherosclerosis. The most widely studied marker of inflammation is C-reactive protein (CRP). CRP may not be merely a marker of inflammation but may in fact mediate several key processes in the development of atherosclerosis including plaque initiation, formation, and rupture. In longitudinal analysis, CRP measured at baseline in the Modification of Diet in Renal Disease (MDRD) Study was an independent predictor of all-cause and cardiovascular disease mortality27.Menon V. Greene T. Wang X. et al.C-reactive protein and serum albumin as predictors of all-cause and cardiovascular mortality in patients with chronic kidney disease.Kidney Int. 2005; 68: 766-772Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar. In the Nurses Health Study, higher levels of CRP, interleukin-6 (IL-6), and tumor necrosis factor (TNF) receptors I and II were associated with increased odds of coronary events in women with creatinine clearance 3.5 mg/dL were independent predictors of all-cause mortality46.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (868) Google Scholar. Patients in all stages of chronic kidney disease are at high risk of cardiovascular disease. We have briefly presented available data from studies exploring the mechanisms underlying this excess risk. We acknowledge that this is not an exhaustive review of all the potential risk factors involved in the development of cardiovascular disease in chronic kidney disease. Rather, we have focused on a few with some degree of evidence available and that are potentially modifiable. It needs to be emphasized that causal relationships are yet to be established for many of the risk factors discussed. The implications of our present state of knowledge is that a high suspicion for cardiovascular disease is warranted and that aggressive treatment of traditional risk factors should be instituted in the earlier stages of chronic kidney disease. Additional basic science research, observational studies, and clinical trials, are, however, urgently needed to understand the pathophysiology of cardiovascular disease and to evaluate potential interventions to reduce the burden of cardiovascular disease in chronic kidney disease stages 1 to 4.