Multiple Risk Factor Intervention in Chronic Kidney Disease: Management of Cardiac Disease in Chronic Kidney Disease Patients

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1 Med Clin N Am 89 (2005) Multiple Risk Factor Intervention in Chronic Kidney Disease: Management of Cardiac Disease in Chronic Kidney Disease Patients Bryan M. Curtis, MD, FRCPC a, Adeera Levin, MD, FRCPC b,c, Patrick S. Parfrey, MD, FRCPC a, * a Division of Nephrology and Clinical Epidemiology Unit, Patient Research Centre, Health Sciences Centre, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John s, NF A1B 3V6, Canada b Nephrology Education and Research, St. Paul s Hospital, 1081 Burrard Street, Room 6010A, Vancouver, BC V6Z 1Y6, Canada c Division of Nephrology, Department of Medicine, University of British Columbia, St. Paul s Hospital, Vancouver, BC, Canada This article describes the prevalence of chronic kidney disease (CKD), cardiovascular disease (CVD), and the relationship between CKD and CVD, from both pathophysiologic and epidemiologic perspectives. Also explored are the management of CVD in patients with CKD, and the evidence base that supports the implementation of targeted multiple risk factors for CVD in CKD patients. Burden of illness The burden of illness and costs associated with CKD is a large and growing health care concern. A recent analysis of United States data indicates that end-staged kidney disease (ESKD) leads to more lost lifeyears than prostate cancer in men, and almost as many as breast cancer in black women [1]. The largest contributor to this mortality is cardiac disease [2], and although the mortality rate in elderly patients with kidney disease is Dr. Curtis is a Research Fellow supported by the Kidney Foundation of Canada. * Corresponding author. address: pparfrey@mun.ca (P.S. Parfrey) /05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi: /j.mcna medical.theclinics.com

2 512 CURTIS et al a little greater than in the normal population, the mortality in patients who are 25 to 34 years old is several orders of magnitude higher than in normal individuals of the same age [3]. Similarly, the financial cost of ESKD far exceeds that for prostate or colorectal cancer in men, and breast cancer in black women [1], with the direct cost of caring for a patient on dialysis over $50,000 annually [4,5]. As of 2001, the incidence and prevalence of the ESKD population in the United States was greater than 90,000 and 290,000, respectively, with over 15,000 patients receiving kidney transplants [6]. It is estimated that by 2030 the number of patients with ESKD may reach 2.24 million [6]. Prevalence estimates of CKD are sensitive to the definitions and methods used to identify the disease [7 9] and may be somewhat artificially increased by the impact of within-person measurement error resulting from reliance on a single serum creatinine measurement [9]. Estimates of CKD are also age dependant because CKD was present in about 8% of the Framingham population, but increased to 20% in the elderly [10]. Population studies, such as the National Health and Nutrition Survey III cross-sectional survey of 29,000 persons, revealed that 3% of people over 17 years of age had elevated serum creatinine above the 99th percentile [11]. Furthermore, it is estimated that approximately 8 million people in the United States have kidney disease of stage III or higher [12]. Hypertension, diabetes, and cardiac disease are associated with a higher prevalence of CKD [7,10,11]. Although most patients reach ESKD secondary to chronic progressive disease (in North America largely caused by diabetes and hypertension [6]) there are limited data on the natural history of CKD in unselected populations. Most CKD patients do not progress to ESKD because either the CKD is not progressive [13,14] or they die first, the major contributor of mortality being CVD [10]. CKD imparts cardiac risk through coexisting diseases, such as hypertension, atherosclerosis, diabetes, or hyperlipidemia; through factors associated with CKD including anemia, inflammation, divalent ion abnormalities, and hyperhomocysteinemia; and other putative risk factors, including oxidative stress (Box 1). As CKD deteriorates it is likely that the prevalence and severity of several risk factors change [15,16]. Fortunately, interventions that retard progression of CKD are similar to measures that reduce CVD risk. Cardiac risk factor intervention in the early phases of CKD should not only reduce rate of cardiac death but also slow the progression of kidney disease. In fact, it is currently unknown how much of the growth in ESKD is caused by growth in the prevalence of CKD [17] as opposed to a reduction in mortality resulting from improved CVD management [18]. Recent epidemiologic analyses differ in their conclusions about whether CKD independently contributes to the risk of cardiovascular mortality [19,20], but agree that CKD is a marker of high cardiovascular risk. It is unclear how much of the association between kidney and vascular disease

3 CKD MANAGEMENT: CARDIAC DISEASE 513 Box 1. Risk factors associated with cardiac disease Traditional Age Gender Race Smoking Diabetes Body mass index Hypertension Dyslipidemia Left ventricular hypertrophy (LVH) Fibrinogen Uremia-related Anemia Calcium phosphate Electrolyte abnormality Malnutrition Hypoalbuminemia Inflammation C-reactive protein (CRP) Increased oxidant stress Endothelial activation Prothrombotic factors Hyperhomocysteinemia Cytokines Advanced glycation end products Therapy-related Dialysis Modality Transplant Acute rejection Immunosuppressives results from (1) vascular disease causing kidney failure, (2) kidney failure causing vascular disease, or (3) common underlying factors promoting the progression of kidney and CVD. It is likely that each of these mechanisms apply. CVD is already well established by onset of ESKD [18,21]. On starting dialysis the prevalence of cardiomyopathy is very high, as is the presence of symptomatic ischemic heart disease and heart failure. Symptomatic ischemic heart disease was present in 38% and heart failure in 35% of Canadians at first dialysis [22]. Only 16% of new dialysis patients have normal hearts, with concentric LVH present in 41% and systolic failure in 16% [23]. LVH is already evident in 40% of patients with moderate CKD [24] and in 75% of those commencing dialysis [25]. The high prevalence of CVD on starting dialysis suggests that the predialysis phase of CKD is a state of high cardiac risk. In fact, admission rates for congestive heart failure in patients with CKD are seven times greater than in those without the disease [6].

4 514 CURTIS et al Cardiovascular disease: differentiating between ischemic heart disease and cardiomyopathy CVD in CKD may be broadly classified clinically into two disease entities that may overlap and vary from patient to patient: ischemic heart disease and cardiomyopathy [26] (Fig. 1). Ischemic symptoms result from coronary artery disease or nonatherosclerotic ischemic disease. Coronary artery disease predisposes to diastolic dysfunction and to systolic failure. LVH is present nearly always in dilated cardiomyopathy, but also causes diastolic dysfunction in those with or without normal systolic function. In a recent longitudinal study of kidney transplant recipients, a model of CKD, the rate of ischemic cardiac events was similar to that seen in the Framingham study, whereas the rate of heart failure events was substantially higher. This suggests that CKD may not simply be a state of accelerated atherosclerosis, and may be a predominantly cardiomyopathic state [27]. Cardiomyopathy Cardiomyopathy is common in ESKD and its most common symptom is pulmonary edema, a manifestation of pump failure that may result from either systolic or diastolic dysfunction. Diagnosis may be made with echocardiography [23] because the cardiomyopathy may be the consequence of dilated cardiomyopathy with systolic failure or LVH with diastolic dysfunction. Two major types of LVH may occur. The first is concentric LVH with normal chamber volume, arising from left ventricle (LV) pressure overload, such as from hypertension, arteriosclerosis, and aortic stenosis. The second is eccentric LV dilation resulting from LV volume overload. This occurs in response to salt and water overload, anemia, and arteriovenous fistula. Hemodialysis with its associated hemodynamic stresses is the Ischemic Heart Disease Cardiomyopathy Atherosclerotic Non- Atherosclerotic Concentric LVH LV Dilatation Diastolic Dysfunction Systolic Dysfunction Pump Failure Death Fig. 1. The overlap of cardiac disease in CKD patients. LV, left ventricle.

5 CKD MANAGEMENT: CARDIAC DISEASE 515 quintessential model for overload cardiomyopathy, whose end stage is systolic dysfunction. LV growth starts before the initiation of dialysis and its prevalence is inversely related to the level of declining kidney function. Anemia, hypertension, and diabetes mellitus are risk factors for progressive LV growth [28,29]. In kidney transplant recipients there is evidence that systolic dysfunction, LV dilatation, and concentric hypertrophy present while on dialysis improve after transplantation with concomitant improvement in uremic milieu. In renal transplant recipients, however, hypertension is a risk factor for LV growth, de novo heart failure, and de novo ischemic heart disease [27,30]. Anemia additionally predisposes to de novo heart failure, as does hypoalbuminemia [27]. Ischemic heart disease Ischemia presents as myocardial infarction or angina resulting from decreased perfusion of the myocardium. Coronary artery disease is defined as the pressure of critical stenoses of the large coronary vessels, resulting from atherosclerotic plaques. Although symptoms of ischemic heart disease are most often attributable to the presence of critical coronary artery disease, in about one quarter of the hemodialysis population these symptoms may also result from nonatherosclerotic disease, caused by small vessel disease and LVH. The presence of symptomatic ischemic heart disease is not a significant mortality risk factor independent of congestive heart failure [31]. The implication is that the underlying cardiomyopathy predisposing to heart failure is prognostically more important than coronary perfusion disorders. Arterial disease The structure of arteries may be altered by mechanisms other than atherogenesis. Arteriosclerosis is an intramural vascular remodeling with hypertrophy of the media and subintimal fibrosis that occurs in response to hemodynamic overload and hypertension. As a result, noncompliant conduit vessels develop with an increase in vessel stiffness and diameter. If persistent and long-standing, arteriosclerosis may adversely affect left ventricular structure and function by increasing cardiac workload and contribute directly to ischemic symptoms [32]. Treatment strategies related to cardiovascular risk Hypertension About three quarters of CKD patients have hypertension, the prevalence of which increases as glomerular filtration rate declines. Lowering blood

6 516 CURTIS et al pressure reduces mortality in those at risk for cardiovascular events, including diabetics [33 36]. Achieving a target blood pressure of less than 130/80 mm Hg in CKD also slows progression of kidney disease [13,33, 37 41] and those with proteinuria greater than 1 g per 24 hours benefit from even lower blood pressure (\ 125/75 mm Hg) [13]. Three or four different medications are often required to reach these goals. Renin angiotensin system interruption Angiotensin-converting enzyme (ACE) inhibitors have been clearly shown to improve symptoms, morbidity, and survival in nonuremic individuals with heart failure [42]. ACE inhibitors reduce cardiovascular morbidity and death in CKD, as in those with normal glomerular filtration rate [43]. The use of ACE inhibition reduces progression of CKD, proteinuria, and regresses LVH [44 47]. The benefit of ACE inhibition is applicable to those with diastolic and systolic dysfunction. ACE inhibitors should also be used to prevent congestive heart failure in asymptomatic patients whose LV ejection fraction is less than 35% [48] and in post myocardial infarction patients with an ejection fraction of 40% or less [49]. Angiotensin receptor blockers also reduce ESKD and may delay death in type 2 diabetics with nephropathy [50,51]. b-blockers b-blockade is indicated for angina [52] and reduces morbidity and mortality in both heart failure [53,54] and post myocardial infarction [55], and seems equally efficacious in patients with CKD [56]. It should be noted that contraindications to their use (reactive airway disease, sinus-node dysfunction, and cardiac conduction abnormalities) occur frequently in CKD patients, especially in the later stages. Aspirin Aspirin prevents atherothrombotic events in patients at high risk of vascular events [57,58] and has a role in primary prevention in diabetics [33,58]. There have been no studies, however, of aspirin for either the primary or secondary treatment of myocardial ischemia in the CKD population. The risk of complications, mainly bleeding, probably increases as kidney function declines and effects of uremia increase. Aspirin use for the primary prevention of coronary artery disease cannot be recommended for patients with CKD per se. For those patients with acute coronary syndromes, myocardial infarction, or other high-risk individuals, the benefits likely outweigh the risks. There are little data regarding the use of clopidogrel in CKD.

7 CKD MANAGEMENT: CARDIAC DISEASE 517 Diabetes management Diabetes in patients with moderate to severe CKD predicts deterioration in cardiovascular states, in patients with and without CVD at baseline [59]. Furthermore, it is an independent risk factor for ischemic heart disease [27,60,61] and for cardiac failure [27] in kidney transplant recipients. Controlling diabetes has beneficial effects for at least early microvascular disease [62,63]. Metformin showed benefit for macrovascular disease in obese type 2 diabetics [64], but is contraindicated in later stages of CKD. Smoking Approximately 25% of CKD patients and over 50% of dialysis and transplant patients have a history of cigarette use [65]. Smoking status is independently associated with cardiac disease, peripheral vascular disease, and mortality. Importantly, smoking is modifiable and cessation reduces cardiovascular risk [66], may slow CKD progression [67 69], and improves quality of life [70], but may require intense intervention for maximal effect [71]. Abnormal calcium and phosphate metabolism Abnormal levels of calcium, phosphate, parathyroid hormone, and vitamin D in CKD may contribute to cardiomyopathy, LVH, LV fibrosis, atherosclerosis, myocardial ischemia, and vascular and cardiac calcification [72]. In prevalent dialysis patients increased phosphate and calcium phosphate product were independent predictors of coronary artery calcification and mortality [73]. Whether this calcification represents calcification of atherosclerotic plaques or a stage associated with arteriosclerosis is not clear. The onset of these metabolic derangements occurs early on in the progression of CKD and should be prevented or managed as they emerge. The efficacy of interventions to normalize serum calcium and phosphate, however, has not been demonstrated in randomized controlled trials with measurement of major clinical event rates. Recently, the National Kidney Foundation published clinical practice guidelines for appropriate surveillance and treatment of bone metabolism and disease [74]. Statin therapy Statin therapy in CKD seems to have a similar efficacy to that in non- CKD patients with CVD [75 77]. The potential role of statin therapy in CVD management independent of lipid lowering is receiving attention. Their proposed properties include endothelial stabilization and antithrombogenic and anti-inflammatory mechanisms that may modify their effectiveness. The CKD population, similar to dialysis patients, is known to have increased markers of inflammation, such as CRP. This inflammatory state is thought to confer an independent increased CVD risk

8 518 CURTIS et al by oxidative stress and resultant atherosclerosis [77]. Although statins have been shown to reduce CRP levels in patients with normal kidney function, it is not known whether this translates into clinical benefit independent of lipid reduction. Anemia The role of anemia, and its treatment, is now a focus of congestive heart failure management strategy and investigation in patients without CKD [78]. Much more is known in patients with kidney disease. The combination of CKD and anemia is independently associated with an increased risk of coronary heart disease and stroke in middle-aged patients [79,80] and, in CKD stage III or greater, anemia is associated with LV growth [24]. In kidney transplant recipients, anemia is an independent risk factor for the development of electrocardiographically diagnosed LVH [27] and of symptomatic heart failure [30]. Treating anemia to a hemoglobin of 110 to 120 g/l improves quality of life, decreases hospitalization, and may improve LVH [81 86]. No strong evidence from randomized control trials currently exists to support normalization of anemia with erythropoietin to treat cardiac disease [87 90]. Multiple risk factor intervention The focus of CKD care must broaden to include CVD risk reduction in addition to, or concomitant with, reducing the progression of kidney decline. With increased understanding of kidney disease pathophysiology and CVD within the CKD population, it has become clearer that treatment and care options are increasingly complex. Given the multiplicity of goals of care and the complexity of treatment options, an individual nephrologist is unlikely to be able to manage CKD care alone. Implementing targeted multiple risk factor intervention programs to manage cardiac disease in CKD may well overwhelm the ability of individual nephrologists in the absence of multidisciplinary teams. Publications using United States data [91,92] demonstrate that care of patients with CKD known to nephrologists continues to be suboptimal, and reasons for this must be further explored. Given the complexity of the care, the increasing comorbidity of the patient population, and the accumulating data describing best practices, a team approach with well-defined roles, responsibilities, and objectives seems to be logical and practical. Studies are underway to address these issues. Summary This article describes the relationship between CVD and CKD, the current state of knowledge regarding medical interventions, and underscores

9 CKD MANAGEMENT: CARDIAC DISEASE 519 the importance of attending to both CVD and kidney disease aspects in each individual. The burden of cardiac disease in CKD patients is high with severe LVH, dilated cardiomyopathy, and coronary artery disease occurring frequently. This predisposes to congestive heart failure, angina, myocardial infarction, and death. Multiple risk factors for cardiac disease exist and include hypertension, diabetes, smoking, anemia, abnormal calcium and phosphate metabolism, inflammation, and LVH. The efficacy of risk factor intervention has not been established in these populations, although there is good evidence for good blood pressure control, partial correction of anemia, treatment of dyslipidemia, cessation of tobacco use, correction of divalent abnormalities, and aspirin use. Appropriate use of ACE inhibitors, b-blockers, and statins should be encouraged. References [1] Kiberd BA, Clase CM. Cumulative risk for developing end-stage renal disease in the US population. J Am Soc Nephrol 2002;13: [2] Culleton BF, Larson MG, Wilson PWF, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999;56: [3] Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998;9(12 Suppl):S [4] Goeree R, Manalich J, Grootendorst P, et al. Cost analysis of dialysis treatments for endstage renal disease (ESRD). Clin Invest Med 1995;18: [5] Lee H, Manns B, Taub K, et al. Cost analysis of ongoing care of patients with end-stage renal disease: the impact of dialysis modality and dialysis access. Am J Kidney Dis 2002;40: [6] US Renal Data System. USRDS 2003 annual data report: atlas of end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; [7] Nissenson AR, Periera BJ, Collins AJ, et al. Prevalence and characteristics of individuals with chronic kidney disease in a large health maintenance organization. Am J Kidney Dis 2001;37: [8] Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Survey (NHANES III). J Am Soc Nephrol 2002;13: [9] Hsu C-Y, Chertow GM, Curhan GC. Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 2002;61: [10] Culleton BF, Larson MG, Evans JC, et al. Prevalence and correlates of elevated serum creatinine levels. Arch Intern Med 1999;159: [11] Coresh J, Wei GL, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the Third National Health and Nutrition Examination Survey ( ). Arch Intern Med 2001;161: [12] 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. [13] Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 1994;330: [14] Hunsicker LG, Adler S, Caggiula A, et al. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 1997;51:

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