REVIEW URRENT C OPINION
Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease Vasil Peev, Ali Nayer, and Gabriel Contreras
Purpose of review Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients. Recent findings Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia. Summary In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation. Keywords cardiovascular disease, chronic kidney disease, dyslipidemia, inflammation, malnutrition
INTRODUCTION Patients with chronic kidney disease (CKD) have a much higher prevalence of cardiovascular disease (CVD) with higher mortality than non-CKD patients [1]. Additionally, patients with CKD develop CVD at a much early age [2]. In CKD patients, dyslipidemia, a traditional risk factor for CVD, accounts significantly to the pathogenesis and risk of CVD during the early stages of CKD [3]; however, malnutrition and inflammation, nontraditional risk factors for CVD, modify the risk relationship of dyslipidemia with CVD during late stages of CKD. Malnutrition and inflammation are very prevalent in CKD with an important role in CVD [4]. The epidemiology and pathogenesis of CVD in CKD is complex with multiple risk factors interacting together. In this article, we will review the epidemiology and pathogenesis of dyslipidemia, malnutrition and inflammation determining CVD in CKD. Evidence from interventional trials of hepatic hydroxymethyl www.co-lipidology.com
glutaryl-CoA reductase inhibitors (statins) in CKD will also be discussed.
DYSLIPIDEMIA Dyslipidemias are defined as a constellation of an abnormal amount of lipids in the blood. In CKD patients, dyslipidemias are characterized by either elevated or reduced lipid levels. The prevalence of total cholesterol of more than 240 mg/dl is particularly high in approximately 90% of nephrotic CKD nondialysis patients. Likewise, elevated LDL University of Miami Miller School of Medicine, Miami, Florida, USA Correspondence to Gabriel Contreras, MD, MPH, Division of Nephrology, University of Miami Miller School of Medicine, 1120 NW 14th street, Suite 817, Miami, FL 33136, USA. Tel: +1 305 243 3583; e-mail: [email protected] Curr Opin Lipidol 2014, 25:54–60 DOI:10.1097/MOL.0000000000000045 Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Li pids malnutrition, inflammation in kidney disease Peev et al.
KEY POINTS In CKD nondialysis patients, hypercholesterolemia increased the risk for the development of CVD events. Cholesterol lowering therapy demonstrates a significant benefit reducing the risk for CVD events in CKD nondialysis patients. In end-stage renal disease (ESRD) patients, the relationship between cholesterol levels and CVD and allcause mortality are paradoxical and attributable to the confounding effect of malnutrition and inflammation. In ESRD patients, cholesterol-lowering therapy does reduce the risk of CVD events and all-cause mortality.
cholesterol of more than 130 mg/dl is commonly seen in approximately 85% of nephrotic CKD nondialysis patients [5]. Elevated triglycerides of more than 200 mg/dl and reduced HDL cholesterol of less than 35 mg/dl are also common across most groups of CKD patients [5]. In CKD nondialysis patients particularly with nephrotic syndrome, the total cholesterol and LDLcholesterol levels are directly related to the degree of proteinuria and inversely related to the degree of plasma oncotic pressure [6]. Higher proteinuria and lower serum oncotic pressure correlate strongly with increased synthesis of apoprotein beta the principle protein contained in LDL-cholesterol. CKD nondialysis patients with nephrotic syndrome also have decreased activity of both total and tissue bound lipoprotein lipase enzymes whose primarily role is the catabolism of triglycerides, thereby resulting in elevated triglyceride levels in these patients [7]. Patients across all spectrum of CKD have reduced synthetic rates of apoprotein A-I and HDL-cholesterol that correlate with the decline of the glomerular filtration rate. This results in decreased extraction of cholesterol from the vascular system and low content of cholesterol in all HDL fractions promoting the development of atherosclerosis [8]. Interestingly, patients with moderate CKD and ESRD commonly have reduced total cholesterol levels [5]. In the African American Study of Kidney Disease and Hypertension (AASK) [9] that enrolled CKD nondialysis patients with a glomerular filtration rate between 20 and 65 ml/min/1.73 m2, 54% of the patients not using statins at baseline had total cholesterol levels less than 200 mg/dl. In the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) [10], patients had a much higher prevalence of 64% of reduced total cholesterol level. In patients with moderate CKD and ESRD, reduced total cholesterol is a recognized biomarker of
malnutrition and inflammation [11]. Mechanisms of malnutrition and inflammation modifying dyslipidemia risk for CVD in late CKD stages have been a subject of high interest in the past decade and are reviewed in the following sections.
MALNUTRITION AND INFLAMMATION In recent years, a considerable attention has been centered in the epidemiology and pathogenesis of malnutrition and inflammation in CVD. In CKD patients, the prevalence of malnutrition and inflammation is much higher, ranging between 31 and 77%, than in the general population of less than 10%. There are many measurable biomarkers of malnutrition and inflammation recommended in CKD patients [11]. In the AASK [9] of CKD nondialysis patients, the prevalence of malnutrition and inflammation was 31%, defined as a BMI lower than 23 kg/m2 or a high sensitivity C reactive protein (hs-CRP) of more than 10 mg/l. Similarly, in another observational study of CKD nondialysis patients from the Veterans Affairs health system [12], the prevalence of malnutrition and inflammation was 37%, defined as a serum albumin 3.7 g/dl or less lymphocyte count 22% or less or white blood cell count more than 7500/mm3. In the CHOICE study [10] of CKD dialysis patients, the prevalence of malnutrition and inflammation was 77%, defined as a serum albumin less than 3.6 g/dl, hs-CRP at least 10 mg/l or interleukin-6 (IL-6) at least 3.09 pg/ml. Malnutrition and inflammation are particularly common in CKD dialysis patients. Several lines of evidence demonstrate that there are CKD-related and CKD-unrelated causes of malnutrition and inflammation (Fig. 1) [13–23]. CKD causes of malnutrition and inflammation include among others uremic syndrome, use of nonsterile dialysate, use of bioincompatible membranes during hemodialysis and vascular access infections. CKD-unrelated causes of malnutrition and inflammation include the presence of congestive heart failure, tobacco smoking, insulin resistance, elevated fat mass and hypertension. All of these CKDrelated and CKD-unrelated causes of malnutrition and inflammation are accompanied by increased cytokine production, including tumor necrosis factor-alpha, interferon-gamma, IL-1 and IL-6 that reduce the appetite, the intake of calories and proteins, thereby leading to muscle wasting, weight loss, decreased serum albumin, lymphopenia and low cholesterol levels. In CKD dialysis patients [23], reduced cholesterol levels correlate with increased IL-1 and tumor necrosis factor-alpha, underscoring the significance of malnutrition and inflammation
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
55
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism
FIGURE 1. CKD, chronic kidney disease; hs-CRP, highsensitivity C-reactive protein. Several lines of evidence demonstrate that there are CKD related and unrelated causes of malnutrition-inflammation in CKD.
in the dyslipidemia of late stages of CKD. Studies demonstrate that inflammatory cytokines also disrupt cholesterol-mediated LDL receptor feedback regulation [24], permitting intracellular accumulation of unmodified LDL and foam cell formation, a wellknown predecessor of advanced atherosclerosis.
RISK RELATIONSHIPS OF CHOLESTEROL WITH CARDIOVASCULAR DISEASE AND MORTALITY ARE MODIFIED BY MALNUTRITION AND INFLAMMATION IN CHRONIC KIDNEY DISEASE In studies of the general population, the risk relationship of total cholesterol level with CVD mortality is direct, strong and progressive without the evidence of a threshold [25–27]. In moderate CKD and ESRD populations [28–32], the relationship of serum cholesterol level with CVD events and all-cause mortality is inconsistent and often paradoxical. These findings were underscored in a recent observational study [33 ] involving 836 060 participants with and without CKD from the Alberta kidney disease network. In this study, investigators examined the relation between LDL-cholesterol and hospitalization for myocardial infarction in strata defined by estimated glomerular filtration rate. Although higher levels of LDL-cholesterol were associated with higher risk for all strata, the excess risk associated with markedly elevated LDL-cholesterol was the largest for participants with baseline estimated glomerular filtration rate at least 90 ml/min per 1.73 m2 (normal control group) and the lowest for participants with estimated glomerular filtration rate between 15 and 59.9 ml/min per 1.73 m2 (CKD stage 3 group). Specifically, the adjusted hazard ratios (95% confidence intervals, &
56
www.co-lipidology.com
CIs) of myocardial infarction associated with LDL-cholesterol of more than 189 compared with 100.4–131 mg/dl were 3.01 (2.46, 3.69), 2.30 (2.00, 2.65) and 2.06 (1.59, 2.67) in participants with estimated glomerular filtration rate at least 90, 89.9–60, and 59.9–15 ml/min per 1.73 m2, respectively. The incidence rate of myocardial infarction in this latter group as a function of LDL-cholesterol levels (LDL-cholesterol of 189 mg/dl) was notably U-shaped (myocardial infarction events of 9.7, 7.8, 7.6, 8.8 and 9.9 per 1000 patient-years) compared with the direct, strong and progressive association for the unequivocally normal control group (myocardial infarction events of 1, 1, 1.4, 2.1 and 3.1 per 1000 patient-years). The association between higher LDL-cholesterol and myocardial infarction was weaker for people with lower baseline estimated glomerular filtration rate, despite higher absolute risk of myocardial infarction. Investigators concluded that increased LDL-cholesterol is less useful as a marker of coronary risk among people with CKD than the general population. It appears that other risk factors are likely more responsible for CVD events in CKD patients. The AASK and CHOICE studies [9,10] recently provided evidence that the paradoxical relationship of cholesterol level with overall mortality and its U-shaped relationship with CVD mortality can be explained by the confounding effect of the commonly present malnutrition and inflammation in moderate and advanced CKD. In the CHOICE study [10] of ESRD patients (Table 1), lower baseline cholesterol levels were associated with greater all-cause mortality in the overall cohort and in the subgroup of 77% of patients with malnutrition and inflammation. By contrast, there was a significant, continuous and positive relationship of higher cholesterol levels with all-cause mortality in the subgroup of 23% of patients without malnutrition and inflammation. In the AASK study [9] of CKD nondialysis patients (Table 2), the risk of CVD events did not vary significantly by cholesterol level in the 31% of patients with malnutrition and inflammation. The association of high cholesterol with CVD events was limited to the 69% of patients without malnutrition and inflammation.
EVIDENCE FROM INTERVENTIONAL TRIALS OF STATIN THERAPY IN CHRONIC KIDNEY DISEASE Statin therapy for elevated cholesterol levels in the general population with and without cardiovascular risk factors reduces the risk of cardiovascular events and is now well established, recommended therapy. However, the precise role of statin therapy for Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Li pids malnutrition, inflammation in kidney disease Peev et al. Table 1. The risk association between baseline total cholesterol levels and all-cause mortality is modified by malnutritioninflammation Total cholesterol
Overall (n ¼ 823) HR (95% CI)
Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease Vasil Peev, Ali Nayer, and Gabriel Contreras
Purpose of review Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients. Recent findings Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia. Summary In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation. Keywords cardiovascular disease, chronic kidney disease, dyslipidemia, inflammation, malnutrition
INTRODUCTION Patients with chronic kidney disease (CKD) have a much higher prevalence of cardiovascular disease (CVD) with higher mortality than non-CKD patients [1]. Additionally, patients with CKD develop CVD at a much early age [2]. In CKD patients, dyslipidemia, a traditional risk factor for CVD, accounts significantly to the pathogenesis and risk of CVD during the early stages of CKD [3]; however, malnutrition and inflammation, nontraditional risk factors for CVD, modify the risk relationship of dyslipidemia with CVD during late stages of CKD. Malnutrition and inflammation are very prevalent in CKD with an important role in CVD [4]. The epidemiology and pathogenesis of CVD in CKD is complex with multiple risk factors interacting together. In this article, we will review the epidemiology and pathogenesis of dyslipidemia, malnutrition and inflammation determining CVD in CKD. Evidence from interventional trials of hepatic hydroxymethyl www.co-lipidology.com
glutaryl-CoA reductase inhibitors (statins) in CKD will also be discussed.
DYSLIPIDEMIA Dyslipidemias are defined as a constellation of an abnormal amount of lipids in the blood. In CKD patients, dyslipidemias are characterized by either elevated or reduced lipid levels. The prevalence of total cholesterol of more than 240 mg/dl is particularly high in approximately 90% of nephrotic CKD nondialysis patients. Likewise, elevated LDL University of Miami Miller School of Medicine, Miami, Florida, USA Correspondence to Gabriel Contreras, MD, MPH, Division of Nephrology, University of Miami Miller School of Medicine, 1120 NW 14th street, Suite 817, Miami, FL 33136, USA. Tel: +1 305 243 3583; e-mail: [email protected] Curr Opin Lipidol 2014, 25:54–60 DOI:10.1097/MOL.0000000000000045 Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Li pids malnutrition, inflammation in kidney disease Peev et al.
KEY POINTS In CKD nondialysis patients, hypercholesterolemia increased the risk for the development of CVD events. Cholesterol lowering therapy demonstrates a significant benefit reducing the risk for CVD events in CKD nondialysis patients. In end-stage renal disease (ESRD) patients, the relationship between cholesterol levels and CVD and allcause mortality are paradoxical and attributable to the confounding effect of malnutrition and inflammation. In ESRD patients, cholesterol-lowering therapy does reduce the risk of CVD events and all-cause mortality.
cholesterol of more than 130 mg/dl is commonly seen in approximately 85% of nephrotic CKD nondialysis patients [5]. Elevated triglycerides of more than 200 mg/dl and reduced HDL cholesterol of less than 35 mg/dl are also common across most groups of CKD patients [5]. In CKD nondialysis patients particularly with nephrotic syndrome, the total cholesterol and LDLcholesterol levels are directly related to the degree of proteinuria and inversely related to the degree of plasma oncotic pressure [6]. Higher proteinuria and lower serum oncotic pressure correlate strongly with increased synthesis of apoprotein beta the principle protein contained in LDL-cholesterol. CKD nondialysis patients with nephrotic syndrome also have decreased activity of both total and tissue bound lipoprotein lipase enzymes whose primarily role is the catabolism of triglycerides, thereby resulting in elevated triglyceride levels in these patients [7]. Patients across all spectrum of CKD have reduced synthetic rates of apoprotein A-I and HDL-cholesterol that correlate with the decline of the glomerular filtration rate. This results in decreased extraction of cholesterol from the vascular system and low content of cholesterol in all HDL fractions promoting the development of atherosclerosis [8]. Interestingly, patients with moderate CKD and ESRD commonly have reduced total cholesterol levels [5]. In the African American Study of Kidney Disease and Hypertension (AASK) [9] that enrolled CKD nondialysis patients with a glomerular filtration rate between 20 and 65 ml/min/1.73 m2, 54% of the patients not using statins at baseline had total cholesterol levels less than 200 mg/dl. In the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) [10], patients had a much higher prevalence of 64% of reduced total cholesterol level. In patients with moderate CKD and ESRD, reduced total cholesterol is a recognized biomarker of
malnutrition and inflammation [11]. Mechanisms of malnutrition and inflammation modifying dyslipidemia risk for CVD in late CKD stages have been a subject of high interest in the past decade and are reviewed in the following sections.
MALNUTRITION AND INFLAMMATION In recent years, a considerable attention has been centered in the epidemiology and pathogenesis of malnutrition and inflammation in CVD. In CKD patients, the prevalence of malnutrition and inflammation is much higher, ranging between 31 and 77%, than in the general population of less than 10%. There are many measurable biomarkers of malnutrition and inflammation recommended in CKD patients [11]. In the AASK [9] of CKD nondialysis patients, the prevalence of malnutrition and inflammation was 31%, defined as a BMI lower than 23 kg/m2 or a high sensitivity C reactive protein (hs-CRP) of more than 10 mg/l. Similarly, in another observational study of CKD nondialysis patients from the Veterans Affairs health system [12], the prevalence of malnutrition and inflammation was 37%, defined as a serum albumin 3.7 g/dl or less lymphocyte count 22% or less or white blood cell count more than 7500/mm3. In the CHOICE study [10] of CKD dialysis patients, the prevalence of malnutrition and inflammation was 77%, defined as a serum albumin less than 3.6 g/dl, hs-CRP at least 10 mg/l or interleukin-6 (IL-6) at least 3.09 pg/ml. Malnutrition and inflammation are particularly common in CKD dialysis patients. Several lines of evidence demonstrate that there are CKD-related and CKD-unrelated causes of malnutrition and inflammation (Fig. 1) [13–23]. CKD causes of malnutrition and inflammation include among others uremic syndrome, use of nonsterile dialysate, use of bioincompatible membranes during hemodialysis and vascular access infections. CKD-unrelated causes of malnutrition and inflammation include the presence of congestive heart failure, tobacco smoking, insulin resistance, elevated fat mass and hypertension. All of these CKDrelated and CKD-unrelated causes of malnutrition and inflammation are accompanied by increased cytokine production, including tumor necrosis factor-alpha, interferon-gamma, IL-1 and IL-6 that reduce the appetite, the intake of calories and proteins, thereby leading to muscle wasting, weight loss, decreased serum albumin, lymphopenia and low cholesterol levels. In CKD dialysis patients [23], reduced cholesterol levels correlate with increased IL-1 and tumor necrosis factor-alpha, underscoring the significance of malnutrition and inflammation
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
55
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nutrition and metabolism
FIGURE 1. CKD, chronic kidney disease; hs-CRP, highsensitivity C-reactive protein. Several lines of evidence demonstrate that there are CKD related and unrelated causes of malnutrition-inflammation in CKD.
in the dyslipidemia of late stages of CKD. Studies demonstrate that inflammatory cytokines also disrupt cholesterol-mediated LDL receptor feedback regulation [24], permitting intracellular accumulation of unmodified LDL and foam cell formation, a wellknown predecessor of advanced atherosclerosis.
RISK RELATIONSHIPS OF CHOLESTEROL WITH CARDIOVASCULAR DISEASE AND MORTALITY ARE MODIFIED BY MALNUTRITION AND INFLAMMATION IN CHRONIC KIDNEY DISEASE In studies of the general population, the risk relationship of total cholesterol level with CVD mortality is direct, strong and progressive without the evidence of a threshold [25–27]. In moderate CKD and ESRD populations [28–32], the relationship of serum cholesterol level with CVD events and all-cause mortality is inconsistent and often paradoxical. These findings were underscored in a recent observational study [33 ] involving 836 060 participants with and without CKD from the Alberta kidney disease network. In this study, investigators examined the relation between LDL-cholesterol and hospitalization for myocardial infarction in strata defined by estimated glomerular filtration rate. Although higher levels of LDL-cholesterol were associated with higher risk for all strata, the excess risk associated with markedly elevated LDL-cholesterol was the largest for participants with baseline estimated glomerular filtration rate at least 90 ml/min per 1.73 m2 (normal control group) and the lowest for participants with estimated glomerular filtration rate between 15 and 59.9 ml/min per 1.73 m2 (CKD stage 3 group). Specifically, the adjusted hazard ratios (95% confidence intervals, &
56
www.co-lipidology.com
CIs) of myocardial infarction associated with LDL-cholesterol of more than 189 compared with 100.4–131 mg/dl were 3.01 (2.46, 3.69), 2.30 (2.00, 2.65) and 2.06 (1.59, 2.67) in participants with estimated glomerular filtration rate at least 90, 89.9–60, and 59.9–15 ml/min per 1.73 m2, respectively. The incidence rate of myocardial infarction in this latter group as a function of LDL-cholesterol levels (LDL-cholesterol of 189 mg/dl) was notably U-shaped (myocardial infarction events of 9.7, 7.8, 7.6, 8.8 and 9.9 per 1000 patient-years) compared with the direct, strong and progressive association for the unequivocally normal control group (myocardial infarction events of 1, 1, 1.4, 2.1 and 3.1 per 1000 patient-years). The association between higher LDL-cholesterol and myocardial infarction was weaker for people with lower baseline estimated glomerular filtration rate, despite higher absolute risk of myocardial infarction. Investigators concluded that increased LDL-cholesterol is less useful as a marker of coronary risk among people with CKD than the general population. It appears that other risk factors are likely more responsible for CVD events in CKD patients. The AASK and CHOICE studies [9,10] recently provided evidence that the paradoxical relationship of cholesterol level with overall mortality and its U-shaped relationship with CVD mortality can be explained by the confounding effect of the commonly present malnutrition and inflammation in moderate and advanced CKD. In the CHOICE study [10] of ESRD patients (Table 1), lower baseline cholesterol levels were associated with greater all-cause mortality in the overall cohort and in the subgroup of 77% of patients with malnutrition and inflammation. By contrast, there was a significant, continuous and positive relationship of higher cholesterol levels with all-cause mortality in the subgroup of 23% of patients without malnutrition and inflammation. In the AASK study [9] of CKD nondialysis patients (Table 2), the risk of CVD events did not vary significantly by cholesterol level in the 31% of patients with malnutrition and inflammation. The association of high cholesterol with CVD events was limited to the 69% of patients without malnutrition and inflammation.
EVIDENCE FROM INTERVENTIONAL TRIALS OF STATIN THERAPY IN CHRONIC KIDNEY DISEASE Statin therapy for elevated cholesterol levels in the general population with and without cardiovascular risk factors reduces the risk of cardiovascular events and is now well established, recommended therapy. However, the precise role of statin therapy for Volume 25 Number 1 February 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Li pids malnutrition, inflammation in kidney disease Peev et al. Table 1. The risk association between baseline total cholesterol levels and all-cause mortality is modified by malnutritioninflammation Total cholesterol
Overall (n ¼ 823) HR (95% CI)
