Guruprasad Manjunath, MD; Andrew S. Levey, MD; Mark J. Sarnak, MD

From the Division of Nephrology, Department of Medicine, New England Medical Center, Boston, MA

Abstract: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease. The prevalence of cardiovascular disease is high among patients starting dialysis therapy, indicating that cardiovascular disease begins when the glomerular filtration rate declines—the stage preceding end-stage renal disease. Left ventricular hypertrophy is one of the major risk factors for cardiovascular disease morbidity and mortality in end-stage renal disease and has an extremely high prevalence in chronic kidney disease. Hypertension and anemia are two of the major modifiable risk factors for the development of left ventricular hypertrophy. Treatment of hypertension, particularly with the use of angiotensin-converting enzyme inhibitors, and anemia management with recombinant human erythropoietin, may result in regression of left ventricular hypertrophy and thereby prevent some of its complications. (CVR&R. 2001;22:337-342-348)

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease, a condition that can be divided into three stages: renal injury, often manifested by microalbuminuria; decreased kidney function, defined as a reduction in the glomerular filtration rate (GFR) to below normal (<90 ml/min); and end-stage renal disease (ESRD), defined as a life-threatening reduction in the GFR (<15 ml/min), in which survival requires dialysis or transplantation. This review focuses on CVD in patients with a decreased GFR and those treated with dialysis, and, in particular, emphasizes the epidemiology and potential treatment of left ventricular hypertrophy (LVH). We will not discuss patients with microalbuminuria or renal transplant recipients, although they are both high-risk groups for CVD morbidity and mortality.1-4

Epidemiology of CVD in Chronic Kidney Disease

End-Stage Renal Disease. According to the 1998 United States Renal Data System (USRDS) Annual Report, there are approximately 350,000 patients with ESRD in the U.S. CVD is the primary cause of mortality in patients with ESRD, accounting for approximately 20,000 deaths annually.5 CVD mortality is approximately 10-30 times higher in dialysis patients than in the general population, even after stratification for ethnicity, gender, and the presence of diabetes. After stratification for age, CVD mortality remains approximately 500-fold higher in younger individuals on dialysis and approximately five-fold higher in elderly dialysis patients.6

Cardiovascular morbidity is also extremely high in patients with ESRD. The prevalence of coronary artery disease (CAD), LVH, and congestive heart failure (CHF) in the ESRD population is approximately 40%, 75%, and 40%, respectively. Among individuals of similar age in the general population, the corresponding prevalence figures are 5%-12%, 20%, and 5%.6-10

The prevalence of CVD is also high in patients who have just reached ESRD. Data from the U.S. Renal Data System Dialysis Morbidity and Mortality Study (Wave 2) showed that as many as 40% of incident hemodialysis patients had a history of CAD and CHF, whereas 36% and 31% of peritoneal dialysis patients had CAD and CHF, respectively.9 Foley and colleagues10 demonstrated that approximately 75% of incident dialysis patients (defined as those who had recently begun dialysis therapy) had echocardiographic evidence of LVH. Such data indicate that CVD begins during the stage when the GFR declines and imply that efforts to decrease the burden of CVD in ESRD need to be initiated during earlier stages of chronic kidney disease.11

Decreased GFR. The population of patients with decreased GFR is much larger than either the incident or prevalent ESRD population. Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that there are approximately 6.2 million and 2.5 million people in the U.S. with serum creatine levels of at least 1.5 and 1.7, respectively.12 Because only approximately 87,000 patients reach ESRD each year,13 a large fraction of patients with a decreased GFR will die before they develop ESRD.

Unfortunately, there are very few data on CAD risk factors and outcomes in patients with a decreased GFR. Very few of these patients have been included in long-term observational studies of CAD, and most studies of CAD risk factor interventions have excluded them. Consequently, it remains unknown whether well documented risk factors (i.e., older age, male gender, LVH, lower levels of high-density lipoprotein cholesterol, high total cholesterol, high blood pressure, smoking, and diabetes), as defined in the Framingham Study, are applicable to patients with chronic kidney disease, and whether they adequately explain the increased risk of CAD in this population.

We focused our attention on LVH because of its extremely high prevalence in chronic kidney disease and its major impact on CVD morbidity and mortality. Furthermore, there are methods to prevent progression and induce regression of LVH. We acknowledge at the outset that although regression of LVH has been shown to result in decreased CVD events in the general population,14,15 there have been no studies designed to assess the impact of regression of LVH on CVD events in patients with chronic kidney disease.

Left Ventricular Hypertrophy

End-Stage Renal Disease. The prevalence of LVH in incident dialysis patients is high. In the Canadian Prospective Cohort Study10 of 433 ESRD patients, 74% had LVH at baseline, 35% had left ventricular (LV) dilatation, and 15% had systolic dysfunction. Of those with LVH, 44% had concentric LVH (LVH with normal LV volume) and 30% had eccentric LVH (LVH with LV dilatation).

LVH is an independent risk factor for mortality. Silberberg and colleagues16 noted an adjusted relative risk of 2.9 for all-cause mortality in the uppermost quintile compared with the lowermost quintile of LV mass index in 91 ESRD patients, and a similar trend toward increased cardiac mortality. The Canadian Prospective Cohort Study also showed that the LV mass index was independently associated with cardiac mortality after 2 years and that systolic dysfunction is a more important risk factor than LV dilatation, which, in turn, is a greater risk factor than LVH.17,18

LVH is also a significant risk factor for morbidity. In the Canadian Prospective Cohort Study, 44% of patients had concentric LVH at baseline, and these patients had a three-fold adjusted relative risk for CHF, compared to those without LVH; the median time to development of CHF was 38 months.18 The Canadian data also demonstrate that an increase in LV mass index is significantly associated with development of cardiac failure at 12 months (hazard ratio, 1.3) relative to a normal LV mass index.19

Independent predictors of LVH in the Canadian cohort included high systolic blood pressure and female gender. Every 10-mm Hg increase in mean arterial pressure was independently associated with an increased risk of development of LVH (odds ratio, 1.48).20 Independent predictors of an increase in the LV mass index included anemia and the presence of diabetes mellitus.

Decreased GFR. The prevalence of LVH is inversely related to the level of renal function. In one study,8 the prevalence of LVH, as measured by echocardiography, was 45%, 31%, and 27% in patients with creatinine clearance of less than 25, 25-50, and >50 ml/min, respectively. These figures contrast sharply with the <20% prevalence of LVH in similar-aged patients in the general population.7 Older age, lower levels of hemoglobin, increased systolic blood pressure, and lower creatinine clearance were significant independent risk factors for LVH.

In a subsequent study by the same investigators,21 318 patients with a decreased GFR were followed for 12 months for the development of LVH and for identification of risk factors that predicted LV growth. The incidence of de novo LVH was 10.6%, and 25% of the total group showed LV growth. Baseline LV mass index, decrease in hemoglobin, and increased systolic blood pressure were the primary predictors of LV growth.

As in ESRD, the two major modifiable risk factors for LVH in patients with decreased GFR are hypertension and anemia, and we will therefore focus on them.

Hypertension

End-Stage Renal Disease. The prevalence of hypertension in incident dialysis patients ranges from 70%-80%.22 Extracellular volume expansion is a major contributor to hypertension, but essential hypertension, activation of the renin-angiotensin axis, and activation of the sympathetic nervous system also play important roles. Observational data have confirmed that hypertension is associated with an increased risk for LVH, CHF, and CAD in patients with ESRD.20,25

Decreased GFR. There is also a high prevalence of hypertension in patients with a decreased GFR. Of those enrolled in the baseline portion of the Modification of Diet in Renal Disease (MDRD) Study,24 a randomized, controlled trial of the effect of protein restriction and strict blood pressure control on the progression of kidney disease, 83% were noted to have a history of hypertension. Predictors of hypertension in cross-sectional analysis, in decreasing order of importance, included a lower GFR, a higher body mass index, African American ethnicity, older age, and male gender.

Anemia

Anemia-Induced LVH. Anemia results in LVH through several mechanisms. The primary mechanism is a hypoxia-induced increase in cardiac output mediated through increased preload due to an increase in venous return. This, in turn, is due to a decrease in hematocrit and blood viscosity, as well as an increase in sympathetic venoconstriction. Anemia also results in diminished arterial resistance and afterload, purportedly due to recruitment of new vessels by formation of collaterals and arteriovenous shunts secondary to hypoxia-generated metabolites, as well as to endothelial cell-mediated activities. Increased preload, decreased afterload, and  hypoxia-induced tachycardia all lead to increased LV end-diastolic volume and high stroke volume, increasing cardiac work and resulting in LVH.25 In an otherwise healthy patient, such effects are adaptive and reversible, but in the presence of comorbidity, such as  hypertension, diabetes mellitus, or renal failure, the structural changes are less reversible and often lead to maladaptive hypertrophy.

Anemia in ESRD and Decreased GFR. The etiology of anemia in patients with renal disease is often multifactorial, although lack of erythropoietin is usually the primary cause.

The prevalence of anemia is inversely related to the level of renal function. An analysis of NHANES II data suggests that approximately 2.8%-36% of patients with a decreased GFR (serum creatinine of 2-8 mg/dL) have anemia, as defined by a hematocrit of <30%.26 The prevalence of anemia is substantially increased in the ESRD population. In their analysis of data from 131,484 incident dialysis patients, Obrador et al.27 found that 51% had a hematocrit of <28%.

Treatment and Prevention of LVH

Treatment of Hypertension in the General Population. Many classes of antihypertensive medications can induce regression of LVH, most by lowering blood pressure, but some via additional mechanisms. Angiotensin-converting enzyme (ACE) inhibitors may have added benefit, as suggested by meta-analyses comparing various antihypertensive agents in terms of their ability to induce regression of LVH.28,29 ACE inhibitors were the most effective in reducing LVH, followed, in decreasing order of efficacy, by calcium channel blockers, diuretics, and β blockers.

Treatment of Hypertension in Chronic Kidney Disease. Although some studies have demonstrated that hypertension is a risk factor for LVH and CVD outcomes in patients with chronic kidney disease,30-33 there are, unfortunately, no large, randomized, controlled trials documenting the benefits of treatment of hypertension LVH, in either ESRD or in patients with reduced GFR. In the following paragraphs we present some of the available data on hypertension treatment and its effect on LVH in patients with chronic kidney disease.

As volume expansion is one of the primary causes of hypertension in ESRD, effective fluid management is essential in the management of hypertension. One small, uncontrolled study34 has, in fact, shown that aggressive fluid removal can improve blood pressure control and decrease LV mass index in ESRD patients.

Antihypertensive medications, and ACE inhibitors in particular, may also be beneficial in patients with ESRD. London et al.35 randomized 24 ESRD patients to an ACE inhibitor (perindopril) vs. a calcium channel blocker (nitrendipine). The LV mass decreased only in patients treated with the ACE inhibitor, despite the fact that pre-, post-, and interdialytic blood pressures were similar in both groups. Canella et al.36 noted similar results in 10 hemodialysis patients treated with the ACE inhibitor enalapril, as compared to eight controls who had similar baseline LV mass indexes. None of the patients was on antihypertensive medication before entering the study. Although there was no significant change in blood pressure in either group, LV mass decreased significantly in the enalapril group.

The data in patients with decreased GFR are limited. Tucker and colleagues37 conducted an observational study of 65 patients with decreased GFR in whom the LV mass index was reduced by blood pressure control. Patients treated with ACE inhibitors showed the greatest reduction in the LV mass index. Conversely, in another observational study, Levin et al.21 found no significant difference in LV growth between patients on ACE inhibitors and patients treated with calcium channel blockers. The authors attributed the lack of difference to a combination of inadequate blood pressure control and decreased hemoglobin levels in patients treated with ACE inhibitors.

Treatment of Anemia in Chronic Kidney Disease. Recombinant human erythropoietin (rHuEPO) is extremely effective for the treatment of anemia in patients with chronic kidney disease. It is administered intravenously or subcutaneously, the intravenous dose being 30%-50% higher than the subcutaneous dose to achieve similar effects. Hemodialysis patients are generally treated intravenously on dialysis days, whereas peritoneal dialysis patients and patients with a decreased GFR are generally treated subcutaneously one to three times a week.

Most,38-40 but not all,41,42 studies of ESRD have suggested that partial correction of anemia with rHuEPO can result in regression of LVH and may prevent LV dilatation in patients with established LVH. A recent controlled trial43 randomized 70 patients with ESRD and LVH to two target hemoglobin levels, 10 and 13.5 g/dL. Baseline and follow-up echocardiograms were obtained at 48 weeks. There was no change in the LV mass index in either group; however, there was a greater tendency toward LV dilatation in the group targeted to the lower hemoglobin level.

Although correction of anemia may result in beneficial cardiac effects prior to the development of symptomatic CVD, overzealous treatment of anemia in hemodialysis patients who have established CAD or CHF is not recommended. A recent randomized, controlled trial44 in which the effects of target hematocrit levels of 30% and 42% were evaluated in patients with documented CAD or CHF revealed a trend toward increased mortality in the group with higher hematocrit values.

The beneficial effects of rHuEPO have yet to be confirmed in controlled studies in patients with a decreased GFR; however, two small studies have suggested that rHuEPO may result in regression of LVH. One study45 showed that either partial or complete correction of anemia in nine predialysis patients resulted in regression of LVH, and the second study46 confirmed this finding in 11 patients, whose mean hematocrit was increased from 26.3% to 34.7%.

Novel erythropoietin-stimulating protein (NESP) (darbepoetin alfa), a hyperglycosylated form of rHuEPO with a half-life three times as long,47 may offer the advantages of less frequent dosing, lower cost, and improved compliance. In studies involving more than 1500 patients, the safety profile of NESP has been shown to be comparable to that of rHuEPO, with no evidence of drug accumulation or antibody formation.48 Studies suggest that that once-a-week, and perhaps biweekly, dosing can maintain hemoglobin concentrations in anemic patients with chronic kidney disease.47 NESP is under consideration for approval by the U.S. Food and Drug Administration.

Conclusions

LVH is one of the major risk factors for CVD mortality and morbidity in chronic kidney disease, and its prevalence is extremely high in these patients. Two of the primary risk factors for development of LVH are hypertension and anemia. Although studies of patients with chronic kidney disease are limited, preliminary evidence suggests that treatment of hypertension, particularly with ACE inhibitors, may induce regression of LVH. Although the evidence is not conclusive, it appears that treatment of anemia with rHuEPO may result in regression of LVH and prevent LV dilatation. However, the target hemoglobin level for prevention or treatment of LVH is not well defined. Additional studies are needed to assess the impact of treatment of LVH on CVD outcomes in patients with chronic kidney disease.

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