Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). The increased risk of CVD begins during the earlier stages of CKD before the onset of kidney failure. Although patients with CKD have a very high prevalence of traditional CVD risk factors such as diabetes and hypertension, they are also exposed to other nontraditional, uremia-related CVD risk factors such as abnormal calcium-phosphorus metabolism and inflammation. Although some of the burden of CVD in CKD may be due to atherosclerosis, it is apparent that patients with CKD also have a high prevalence of vascular stiffness due to nonatherogenic causes and disorders of left ventricular structure and function. In this chapter, we discuss the epidemiology and pathophysiology of CVD in patients with CKD, with a focus on dialysis patients and nontransplant recipients with stages 3 to 4 CKD. We also discuss the different manifestations of CVD in kidney disease and review diagnostic and therapeutic options.
Keywords
arrhythmia, cardiovascular disease, chronic kidney disease, dyslipidemia, endocarditis, heart failure, ischemic heart isease, myocardial infarction, valve disease, vascular calcification
Outline
Epidemiology, 176
Stage 1 to 2 Chronic Kidney Disease, 176
Stage 3 to 4 Chronic Kidney Disease, 176
Dialysis, 178
Risk Factors, 179
Mechanisms of Cardiovascular Disease Risk in Chronic Kidney Disease, 179
Traditional Cardiovascular Disease Risk Factors, 180
Hypertension and Blood Pressure, 180
Dyslipidemia, 182
Diabetes Mellitus, 184
Left Ventricular Hypertrophy and Cardiomyopathy, 184
Other Traditional Risk Factors, 186
Nontraditional Cardiovascular Disease Risk Factors, 186
Oxidative Stress and Inflammation, 186
Nitric Oxide, Asymmetrical Dimethylarginine, and Endothelial Function, 186
Homocysteine, 187
Chronic Kidney Disease–Mineral Bone Disorder, 187
Other Nontraditional Risk Factors, 188
Cardiovascular Disease Clinical Syndromes, 188
Structural Disease: Percardial and Valvular Conditions, 192
Pericardial Disease, 192
Endocarditis, 192
Mitral Annular Calcification, 192
Aortic Calcification and Stenosis, 192
Arrhythmia and Sudden Cardiac Death, 193
Epidemiology
Stage 1 to 2 Chronic Kidney Disease
Even in the absence of reduced estimated glomerular filtration rate (eGFR), kidney damage, which most often is identified through the presence of albumin in the urine, is associated with a higher prevalence of surrogates of cardiovascular disease (CVD), including left ventricular hypertrophy (LVH) in patients with hypertension, arterial intima media thickening in patients with diabetes, and brain white matter hyperintensity volume in the elderly. Albuminuria, even at high normal levels (10 to 29 mg/g) and moderately elevated levels (30 to 299 mg/g), is an independent, graded risk factor for CVD and all-cause death in the general population, identifying a high-risk population even in the absence of reduced kidney function ( Fig. 12.1 ). This risk association is present regardless of whether an individual has diabetes.
Stage 3 to 4 Chronic Kidney Disease
Reduced kidney function is defined by a glomerular filtration rate (GFR) below 60 mL/min/1.73 m 2 ; stage 3a chronic kidney disease (CKD) refers to a GFR of 45 to 59 and CKD stage 3b to GFR of 30 to 44 mL/min/1.73 m 2 . CVD is common in all stages of CKD, with the high prevalence of CVD in incident dialysis patients suggesting that CVD develops before the onset of kidney failure. Most observational studies have relied on eGFR to define CKD; accordingly, there has been a proliferation of research in the past two decades, since the 2002 publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for CKD, on the association between reduced eGFR, typically defined as below 60 mL/min/1.73 m 2 , and CVD events. The new paradigm stressed in the KDOQI guideline specifically highlighted people with CKD as a high-risk population for CVD with unique issues and risk factors.
Critically, death from CVD among individuals with CKD is far more common than progression to kidney failure, particularly among individuals with earlier stages of kidney disease and those with relatively low levels of albuminuria, highlighting that targeting CVD risk and risk factor reduction is an essential aspect of care of individuals with CKD. Globally, reduced GFR is associated with 4% of deaths worldwide, and more than half of these deaths attributed to CKD were cardiovascular deaths. Several studies also have shown that manifestations of CVD, including LVH, may be seen relatively early in CKD. The 2016 USRDS Annual Data Report, which used Medicare claims data to explore the associations between CKD and CVD in older US adults, notes a prevalence of CVD of 68.8% among older adults with CKD compared with 34.1% among those without CKD ( Fig. 12.2 ). Those with CKD also fared worse when having cardiovascular events. The 2-year survival of patients with acute myocardial infarction (AMI) was 80% among patients without a diagnosis of CKD, compared with 69% for patients with CKD stage 1 to 2, 64% for patients with CKD stage 3, and 53% for patients with CKD stage 4 to 5.
Similarly, among patients with CKD stage 3 to 4 in the Cardiovascular Health Study (CHS, comprising subjects aged 65 years and older), 26% had coronary artery disease, 8% had heart failure, and 55% had hypertension at baseline, whereas among those with eGFR above 60 mL/min/1.73 m 2 , 13% had coronary artery disease, 3% had heart failure, and 36% had hypertension. Similar findings were noted in the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort of individuals aged 45 to 64 years, wherein participants with eGFR below 60 mL/min/1.73 m 2 had a baseline prevalence of coronary artery disease, cerebrovascular disease, and diabetes of 11%, 10%, and 24%, respectively, whereas participants with eGFR above 60 mL/min/1.73 m 2 had a baseline prevalence of coronary artery disease, cerebrovascular disease, and diabetes of 4.1%, 4.4%, and 13%, respectively.
Reduced GFR is associated with incident CVD in most cohort studies that have evaluated this relationship. The relative strength of this association is similar in high-risk and lower-risk populations, although the absolute risk of CVD events is far greater among those with kidney and CVD risk factors. Of note, risk thresholds for eGFR and albuminuria appear similar regardless of age, sex, or race. Among high-risk populations, the Studies of Left Ventricular Dysfunction (SOLVD) trial included individuals with left ventricular ejection fraction below 35%; participants in SOLVD with CKD had a 40% increased risk of mortality and a 50% to 70% increased risk of death due to heart failure. Similarly, in the Heart Outcomes and Prevention Evaluation (HOPE) trial, patients with CKD had a 40% increased risk of the composite outcome of myocardial infarction (MI), CVD death, and stroke. The largest general population study to date evaluated Kaiser Permanente patients in northern California, who had serum creatinine measured as a part of their clinical care, and noted a strong, graded relationship between eGFR and subsequent CVD outcomes; this was particularly notable below an eGFR of 45 mL/min/1.73 m 2 . Accordingly, the presence of reduced GFR identifies a high-risk population.
Dialysis
Among dialysis patients, CVD is the single leading cause of mortality, accounting for approximately 40% of deaths. The majority of cardiovascular events, approximately 30% of all deaths (and 75% of cardiovascular deaths), are classified as either cardiac arrest or arrhythmia. This high burden of CVD mortality is well illustrated by comparing CVD mortality in the dialysis population with the general population; mortality due to CVD is 5 to 37 times higher in dialysis patients who are 45 years old and older and 140 times higher in dialysis patients between the ages of 20 and 45 than in this age group in the general population ( Fig. 12.3 ).
The high CVD mortality rate in dialysis patients likely reflects both a high prevalence of CVD and a high case fatality rate. Based on data obtained from medical claims, at the time of dialysis initiation 73.6% of hemodialysis and 61.3% of peritoneal dialysis patients have CVD, with 46.2%, 43.8%, and 37.9% of incident hemodialysis patients having atherosclerotic heart disease, congestive heart failure, and peripheral artery disease, respectively ( Fig. 12.4 ). Of note, dialysis patients are exceedingly diagnosed with non-ST elevation MI (NSTEMI) rather than ST elevation MI (STEMI), likely reflecting both the pathophysiology of CVD in this population and increased sensitivity of troponin assays.
Dialysis patients with CVD also have a very high case fatality rate. Seminal data from Herzog and colleagues noted a 60% 1-year mortality and 90% 5-year mortality rate after AMI in 34,189 dialysis patients. More recent data evaluating AMI in 2009 to 2011 are essentially unchanged, with 61% 1-year mortality and 74% 2-year mortality for hemodialysis patients and 69% and 80% 1- and 2-year mortality for peritoneal dialysis patients. In-hospital death among dialysis patients hospitalized for AMI is nearly twice that of nondialysis patients (21.3% vs. 11.7%) ; risk appears highest in the first several months after dialysis initiation.
Risk Factors
CVD risk factors are defined as characteristics, both modifiable and nonmodifiable, that increase the risk of developing CVD. Traditional CVD risk factors were identified in the Framingham Heart Study as conferring increased risk of CVD in the general population; these were later incorporated into prediction equations to aid physicians in identifying individuals at higher risk. Traditional risk factors include older age, male sex, hypertension, diabetes, smoking, and family history of coronary disease ( Table 12.1 ). Traditional CVD risk factors are common in individuals with CKD, as suggested by higher coronary risk scores using the Framingham prediction equations in individuals with reduced kidney function (GFR <60 mL/min/1.73 m 2 ). Nontraditional risk factors include items that were not described in the original Framingham studies; nontraditional risk factors are those risk factors that both increase in prevalence as kidney function declines and have been hypothesized to be CVD risk factors in this population. Nontraditional risk factors may be particular to individuals with kidney disease (such as anemia and abnormalities in mineral metabolism) but also may include factors recognized as important in the general population (such as inflammation and oxidative stress). Of note, the Framingham equations have poor discrimination and calibration in individuals with stage 3 to 4 CKD, perhaps reflecting either greater severity of traditional CVD risk factors that are not accounted for in risk equations or the role of nontraditional risk factors.
| Traditional Risk Factors | Nontraditional Factors |
|---|---|
|
|
Mechanisms of Cardiovascular Disease Risk in Chronic Kidney Disease
There are several reasons why reduced GFR may be an independent risk state for CVD outcomes. These include, but are not limited to, residual confounding from traditional risk factors and insufficient adjustment for nontraditional risk factors. In addition, reduced kidney function may be a marker of the severity of either diagnosed or undiagnosed vascular disease. Finally, patients with CKD may not receive sufficient therapy for their disease, including medications such as aspirin, beta blockers, angiotensin-converting enzyme inhibitors (ACEIs), and diagnostic and therapeutic procedures.
Similarly, there are several reasons why albuminuria may be an independent risk factor for CVD outcomes. Albuminuria, even at high normal levels, may represent kidney disease itself, with an associated risk of subsequent CKD progression and development of elevated and severely elevated albuminuria. Albuminuria likely also represents the kidney manifestation of systemic endothelial disease burden, and it may be associated with systemic inflammatory markers and abnormalities in the coagulation and fibrinolytic systems.
Most CVD risk factors lead to atherosclerosis, nonatherosclerotic vascular stiffness, cardiomyopathy, or any combination of these three conditions ( Table 12.2 ). Both atherosclerosis, defined as an occlusive disease of the vasculature, and nonatherosclerotic vascular stiffness, a function of nonocclusive remodeling of the vasculature, may manifest as ischemic heart disease (IHD) and heart failure. Some risk factors, including dyslipidemia, primarily predispose the patient to development and progression of atherosclerosis, whereas others, including volume overload and elevated calcium-phosphorus product, may predispose the patient to vascular remodeling. Still other risk factors, including anemia and possibly the presence of arteriovenous fistulas, may predispose the patient to cardiac remodeling, LVH, and cardiomyopathy. Essential to the understanding of CVD in CKD is an understanding of the interplay of these various risk factors. A simplified schematic of this interrelationship directed toward individuals with CKD not requiring kidney replacement therapy is displayed in Fig. 12.5 .
| Types of CVD | Pathology | Surrogates | Clinical Manifestations of CVD |
|---|---|---|---|
| Arterial vascular disease | Atherosclerosis | Inducible ischemia, carotid IMT, cardiac CT (may be less useful than in the GP for atherosclerosis because of medial rather than intimal calcification), ischemia by ECG | IHD (myocardial infarction, angina, sudden cardiac death), cerebrovascular disease, PAD, heart failure |
| Nonatherosclerotic vascular stiffness | Aortic pulse wave velocity, medial vascular calcification, LVH (indirectly), increased pulse pressure | IHD, heart failure | |
| Cardiomyopathy | Concentric LVH as well as LV dilatation with proportional hypertrophy | LVH, systolic dysfunction, and diastolic dysfunction by echocardiogram. LVH by ECG | Heart failure, hypotension, IHD |
Traditional Cardiovascular Disease Risk Factors
Hypertension and Blood Pressure
Hypertension is both a cause and a result of kidney disease. About 70% to 80% of patients with stages 1 to 4 CKD have hypertension, and the prevalence of hypertension increases as GFR declines, such that 80% to 90% of patients starting dialysis are hypertensive.
Chronic Kidney Disease Stage 3 to 4
Blood pressure in stage 3 to 4 CKD has been investigated in more detail than in dialysis patients, although the focus of most studies has been on retarding progression of kidney disease rather than reducing CVD outcomes. Hypertension is highly prevalent in patients with CKD. In adults participating in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004, 80% to 90% of individuals with eGFR below 60 mL/min/1.73 m 2 had hypertension, with hypertension more prevalent at lower eGFR levels, compared with approximately 40% of participants with eGFR of 60 to 90 mL/min/1.73 m 2 and 25% of participants with eGFR of 90 mL/min/1.73 m 2 or higher. In the Modification of Diet in Renal Disease (MDRD) study, hypertension was more commonly seen with CKD due to glomerular disease than tubulointerstitial disease.
Elevated systolic blood pressure is an independent risk factor for CVD outcomes in both diabetic and nondiabetic CKD patients. A secondary analysis of the MDRD study, which included a predominantly nondiabetic population, showed a 35% increased risk of hospitalization for CVD for each 10 mmHg increase in systolic blood pressure, and this increased risk remained significant even after adjusting for other traditional risk factors. However, some of the added CVD risk may be driven by an increased rate of kidney disease progression associated with worse blood pressure control; for example, randomization to a lower blood pressure target in the MDRD study reduced the composite outcome of all-cause mortality and kidney failure 7 years after completion of the randomized intervention ; this was driven by fewer episodes of kidney failure.
Blood pressure is often insufficiently controlled in individuals with CKD. Fig. 12.6 shows the number of blood pressure medications, on average, to achieve targeted blood pressure thresholds in populations with CKD or diabetes, with achievement of a systolic blood pressure below 140 mmHg often requiring 2 or more medications in a clinical trial setting. In the Chronic Renal Insufficiency Cohort (CRIC), approximately 67% of participants had a systolic blood pressure below 140 mmHg, with the majority of participants using at least three antihypertensive medications. Therapies for hypertension are discussed in detail in Chapter 4 , with CKD patients, specifically those with diabetes or albuminuria, prescribed ACEIs and angiotensin receptor blockers (ARBs), often in conjunction with a diuretic.
The Systolic Blood Pressure Intervention Trial (SPRINT) randomized over 9000 individuals without diabetes but with CVD risk factors, including 2646 with eGFR below 60 mL/min/1.73 m 2 , to an intensive systolic blood pressure target of <120 mmHg versus a standard target of <140 mmHg. After median follow-up of 3.3 years, there was a nonstatistically significant lower risk of CVD events and a statistically significant lower risk of death among those randomized to the intensive target without a major difference in serious adverse events between groups. This trial potentially supports a lower blood pressure target for cardiovascular risk reduction in individuals with nondiabetic stage 3 and 4 CKD, although follow-up time was insufficient to draw conclusions regarding kidney disease progression. Blood pressure targets are covered more fully in Chapter 4 .
Dialysis
There is a U-shaped relationship between blood pressure and CVD outcomes in the dialysis population, with higher CVD events and mortality rates at both markedly elevated postdialysis systolic blood pressures (>180 mmHg) and lower blood pressures (<110 mmHg) but no apparent increased risk at systolic blood pressure levels that would be consistent with severe hypertension in the general population. However, higher blood pressures do not appear entirely benign in dialysis patients, either; hypertension is an independent risk factor for IHD, LVH, heart failure, and cerebral hemorrhage. Based on data from the HEMO study, greater visit-to-visit blood pressure variability is associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline systolic blood pressure. Similarly, large cohort data suggest that mortality risk is greatest among dialysis patients who have a >30 mmHg drop in systolic blood pressure during the treatment and among those whose blood pressure increases during dialysis.
Intradialytic hypotension is a relatively common occurrence during hemodialysis and may also be an independent marker for CVD outcomes, perhaps representing the inability of the heart or blood vessels to compensate appropriately for reduced blood volume or, alternatively, representing heart failure itself in the absence of overt volume overload. In dialysis patients, where myocardial fibrosis and myocyte-capillary mismatch are common, abrupt decreases in perfusion may further cardiac damage and predispose to arrhythmia or the progression of myocardial fibrosis. Hypotension, both chronic and intradialytic, may also identify high-risk dialysis patients. First, hypotension may be a reflection of the severity of other comorbid conditions, including heart failure, cardiomyopathy, and generalized malnutrition; and, second, low blood pressure may predispose dialysis patients to intradialytic hypotension, which may lead to ischemic events and myocardial stunning.
Unfortunately, in the absence of clinical trials delineating blood pressure targets in this population, there is no evidence supporting any blood pressure target or even the best means to achieve a specific blood pressure target, although ultrafiltration to dry weight is generally considered the initial treatment of hypertension. Recent emphasis on volume status and maintaining dialysis patients as close to euvolemia as possible stresses the potential cardiovascular benefits of this approach.
Dyslipidemia
Dyslipidemia is common in all stages of CKD ( Table 12.3 ), although the nature of dyslipidemia can be highly variable. As CKD progresses and kidney failure develops, levels of low-density lipoprotein (LDL) cholesterol that previously were high often normalize, perhaps reflecting worse malnutrition, inflammation, and cachexia. Treatment may differ between CKD stage 3 to 4 and dialysis, with studies suggesting cardiovascular benefits of statins in individuals not treated with dialysis.
| Total Cholesterol | LDL Cholesterol | HDL Cholesterol | Triglycerides | Lp(a) | |
|---|---|---|---|---|---|
| CKD Stages 1 to 4 | |||||
| With nephrotic syndrome | ↑↑ | ↑↑ | ↓ | ↑↑ | ↑↑ |
| Without nephrotic syndrome | ↑ or ↔ | ↑ or ↔ | ↓ or ↔ | ↑ | ↑ |
| CKD Stage 5 | |||||
| Hemodialysis | ↓ or ↔ | ↓ | ↓ | ↑ or ↔ | ↑ |
| Peritoneal dialysis | ↑ | ↑ | ↓ | ↑↑ | ↑↑ |
Chronic Kidney Disease Stage 3 to 4
Earlier stages of CKD are often associated with diabetes, hypertension, CVD, and obesity—conditions that are frequently accompanied by dyslipidemia. In addition, the presence of nephrotic-range proteinuria can also exacerbate dyslipidemia. Among interventions for primary and secondary prevention of CVD in individuals with CKD, lipid-lowering therapies are among the best studied. The Study of Heart and Renal Protection (SHARP), which randomized 9270 individuals with CKD, including 6247 not treated with dialysis, demonstrated a significant benefit associated with simvastatin/ezetimibe use for primary prevention of CVD events in individuals with CKD stage 3b to 5 not receiving dialysis, albeit with no effect on all-cause mortality ( Table 12.4 ). Based on this result, as well as studies conducted in the general population that included individuals with CKD stage 3 and 4, the 2013 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD recommended statin or statin/ezetimibe treatment for all adults 50 years old or older with CKD stage 3a to 5 (nondialysis) and for all younger adults with CKD with diabetes, known coronary disease or stroke, or high CVD risk. The KDIGO workgroup stressed a “fire-and-forget” approach to statin use in CKD rather than treating to a specific LDL-cholesterol target. For secondary prevention of CVD, data on treatment of dyslipidemia in individuals with CKD stage 3 to 4 are largely derived from post hoc analyses of clinical trials in the general population and generally show similar benefits to those seen in the general population. In general, these patients should receive statin therapy.
| Study | Intervention | Population | Median Follow-Up | Primary Outcome | Risk of Primary Outcome | Risk of All-Cause Mortality |
|---|---|---|---|---|---|---|
| 4D | Atorvastatin 20 mg daily (vs. placebo) | 1255 participants Age 18–80 y Type 2 diabetes Hemodialysis for less than 2 y LDL 80–190 mg/dL | 4.0 y | Composite of death from cardiac causes, a fatal stroke, nonfatal MI, or nonfatal stroke | HR = 0.92 (0.77–1.10) | RR = 0.93 (0.79–1.08) |
| AURORA | Rosuvastatin 10 mg daily (vs. placebo) | 2776 participants Age 50–80 y Hemofiltration or hemodialysis for more than 3 mo | 3.8 y | Composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke | HR = 0.96 (0.84–1.11) | HR = 0.96 (0.86–1.07) |
| ALERT | Fluvastatin 40 mg daily with dose increase permitted (vs. placebo) | 2102 participants Age 30–75 y More than 6 mo from transplant Stable kidney graft function No recent MI Total cholesterol 155–348 mg/dL | 5.4 y | Major adverse cardiac event, defined as cardiac death, nonfatal MI, or coronary revascularization procedure | RR = 0.83 (0.64–1.06) | RR = 1.02 (0.81–1.30) |
| SHARP | Simvastatin 20 mg daily + ezetimibe 10 mg daily (vs. placebo) | 9270 participants Age 40+ y No previous MI or coronary revascularization Creatinine more than 1.7 mg/dL (men) or more than 1.5 mg/dL (women) | 4.9 y | Composite of coronary death, b nonfatal MI, ischemic stroke, or any revascularization procedure | RR = 0.83 (0.74–0.94) | RR = 1.02 (0.94–1.11) |
| Subgroups within SHARP c | Nondialysis (n = 6247) | Not reported | As above | RR = 0.78 (0.67–0.91) | Not reported | |
| Hemodialysis (n = 2527) | RR = 0.95 (0.78–1.15) | |||||
| Peritoneal dialysis ( n = 496) | RR = 0.70 (0.46–1.08) |
a In 4D, death from cardiac causes comprised fatal myocardial infarction (death within 28 days after a myocardial infarction), sudden death, death due to congestive heart failure, death due to coronary heart disease during or within 28 days after an intervention, and all other deaths ascribed to coronary heart disease. Patients who died unexpectedly and had hyperkalemia before the start of the three most recent sessions of hemodialysis were considered to have had sudden death from cardiac causes.
b In SHARP, the original primary outcome included cardiac death, defined as death due to hypertensive heart disease, coronary heart disease, or other heart disease; the analytic plan was modified before data analysis to focus on death due to coronary heart disease rather than cardiac death.
c In SHARP, there was no statistically significant difference in the risk of the primary outcome between dialysis and nondialysis patients ( P = 0.25) or between hemodialysis and peritoneal dialysis patients ( P = 0.21).
Dialysis
In hemodialysis patients, high-density lipoprotein (HDL) cholesterol is typically low, whereas triglycerides are highly variable. Other abnormalities include increased levels of lipoprotein (a); a higher proportion of atherogenic, oxidized LDL cholesterol; and abnormal concentrations of apolipoproteins that comprise the major lipoproteins, although LDL and total cholesterol levels are often low or normal (see Table 12.3 ). In peritoneal dialysis patients, the prevalence of hyperlipidemia, defined by elevated LDL cholesterol or triglyceride levels, is approximately 70%. Peritoneal dialysis patients have a somewhat more atherogenic lipid panel than their hemodialysis counterparts, with increased LDL-C, apolipoprotein B, oxidized LDL cholesterol, triglycerides, and lipoprotein (a) and decreased HDL cholesterol. Thus despite total cholesterol levels that may appear relatively normal in many patients, significant dyslipidemia is highly prevalent in the dialysis population.
Observational studies of dialysis patients have noted “reverse epidemiology” between cholesterol levels and risk of death, such that lower cholesterol levels are associated with a higher death rate. For example, in an analysis of data from more than 12,000 hemodialysis patients predating widespread use of lipid-lowering medications, individuals with low total cholesterol levels (<100 mg/dL) had a more than fourfold increase in risk of death compared with patients whose cholesterol levels were between 200 and 250 mg/dL. Low cholesterol in these studies may be a surrogate for malnutrition and inflammation, suggesting that higher cholesterol levels may actually be associated with increased cardiovascular risk in dialysis patients with preserved nutritional status (e.g., serum albumin) and low levels of inflammatory markers (e.g., C-reactive protein [CRP]).
Clinical trial data have not demonstrated a significant survival benefit with statins in dialysis patients (see Table 12.4 ). Two large, adequately powered clinical trials, the German Diabetes and Dialysis (4D) study, which tested atorvastatin versus placebo in 1255 hemodialysis patients with diabetes, and AURORA, which tested rosuvastatin versus placebo in nearly 3000 hemodialysis patients, including both individuals with and individuals without diabetes, both show no benefit associated with statins in hemodialysis patients. A third trial, SHARP, discussed previously, shows no benefit in the subgroup receiving hemodialysis at trial initiation ; peritoneal dialysis patients remain inadequately studied. Based on these results, KDIGO did not recommend routinely initiating statin therapy in hemodialysis patients, although the guideline suggests continuing statins in those who were receiving them predialysis. In patients with longer life expectancies, such as patients expected to receive a kidney transplant, individualized decision making may be most appropriate, with the KDIGO guideline recommending statin therapy in transplant recipients.
Interestingly, data from the United States and from Australia suggest that the rates of CVD death in dialysis patients continue to decrease, albeit less markedly than improvements in the general population and for reasons that remain uncertain. Although this improvement temporally relates to the marked increase in statin use in at-risk populations, the failure to demonstrate that specific interventions, including statins, significantly reduce the CVD burden in individuals treated with maintenance dialysis most likely reflects the fact that there are numerous competing causes of death in these patients, and that multiple risk factor adjustment, rather than addressing single risk factors, may result in CVD risk reduction.
Diabetes Mellitus
Diabetes is the leading cause of kidney failure in the United States. The annual incidence of end-stage renal disease (ESRD) in the United States is 370 per million, with the incidence of ESRD due to diabetes at 156 per million—for context, the rate of ESRD due to diabetes exceeds the rate of HIV infection (123 per million) and exceeds the incidence rates of both pancreatic cancer (∼127 per million) and leukemia (∼139 per million) in the United States. Diabetes in CKD is extensively discussed in Chapter 3 and will not be reviewed here except to note that it is a powerful risk factor for CVD and mortality in the general population and in all stages of kidney disease.
In dialysis patients, the presence of diabetes is an independent risk factor for IHD, heart failure, and all-cause mortality. Dialysis patients with diabetes also have worse long-term outcomes after coronary interventions than do nondiabetic patients with CKD. Notably, similar to other advanced chronic disease populations, the net benefit of rigid diabetes control is uncertain in the dialysis population because microvascular and macrovascular complications already exist and because of a potentially increased risk of hypoglycemia; however, hyperglycemia may still worsen retinopathy, hasten the loss of residual kidney function, cause or worsen peripheral neuropathy, and increase the risk of infection. Several large, observational studies have examined the association between glycosylated hemoglobin level and outcomes in hemodialysis patients. In an analysis of Fresenius data, there was no relationship between glycosylated hemoglobin level and mortality at 1 year ; similarly, in an analysis of DaVita data, there was no significant increased risk of mortality until glycosylated hemoglobin levels rose above 8%, at which time increased mortality risk was appreciated only after extensive multivariable adjustment for case-mix, nutritional, and inflammatory factors. Notably, this result was driven by cardiovascular mortality and was seen only in individuals with hemoglobin levels stable and 11 g/dL or more. The authors theorized that this relationship was not seen at lower hemoglobin levels due to the effect of atypical red blood cell production and turnover on glycosylated hemoglobin values in hemodialysis patients with variable hemoglobin levels, leading to misclassification of glucose exposure. Reflecting the notable lack of studies in the dialysis population of the relationship between glycemic control and CVD outcomes, currently there are no high-level evidence-based recommendations from KDOQI or KDIGO regarding diabetes management in dialysis patients.
Left Ventricular Hypertrophy and Cardiomyopathy
LVH is highly prevalent in both stages 3 and 4 CKD and dialysis patients and represents a physiological adaptation to a long-term increase in myocardial work requirements. LVH can be considered both a traditional risk factor, reflecting its inclusion in the original Framingham prediction instrument, and a cardiovascular outcome.
Epidemiology
In the Chronic Renal Insufficiency Cohort (CRIC), the prevalence of LVH assessed by echocardiography was 32% for eGFR above 60 mL/min/1.73 m 2 , rising to 48%, 57%, and 75% for eGFR categories, 45 to 59, 30 to 44, and <30 mL/min/1.73 m 2 , respectively. These findings contrast with a prevalence of LVH below 20% in older adults in the general population. Prevalence rates may be as high as 70% in incident dialysis patients, likely reflecting the confluence of risk factors predisposing to pressure and volume overload. Among prevalent dialysis patients, LVH is present in 50% to 75% of patients when assessed by echocardiography. LVH is even seen in the majority of children requiring hemodialysis, a group typically not subject to IHD. As in the general population, LVH is an independent risk factor for adverse CVD outcomes in patients treated with dialysis ; this holds true for both concentric LVH and dilated cardiomyopathy.
Pathogenesis
LVH, which may result from either pressure or volume overload, reflects an initially appropriate adaptation by the heart to these forces ( Table 12.5 , see Fig. 12.5 ). Higher cardiac workload may be a tenet of CKD, reflecting increased volume retention and blood pressure accompanying deteriorating kidney function. As workload rises over time, increased oxygen demands by the hypertrophied left ventricle may ultimately exceed its perfusion, resulting in ischemia and eventual myocyte death. In individuals with late-stage CKD, including those treated with dialysis, this inability to increase cardiac perfusion is a reflection not only of LVH but also the high prevalence of atherosclerosis, vascular stiffness, and myocyte dropout limiting the ability to upregulate supply to compensate for increased demand.
| LVH Risk Factor | Physiology/Etiology | LVH Diagnostic Test | LVH Clinical Sequelae |
|---|---|---|---|
| Pressure overload | Reflects increased afterload due to hypertension, valvular disease (most often the aortic valve), vascular stiffness | Echocardiography Cardiac MRI Electrocardiography | Myocardial infarction Angina Arrhythmia and sudden cardiac death Heart failure |
| Volume overload | Reflects volume retention due to progressive kidney disease +/- anemia |
Pressure overload results from increased cardiac afterload, often due to hypertension, valvular lesions including aortic stenosis, and reduced arterial compliance, at least in part due to medial vascular calcification. Volume overload may be related to anemia, as the heart attempts to compensate for decreased peripheral oxygen delivery. Other causes of volume overload include increased extracellular volume seen in CKD and, possibly, the presence of a high-flow arteriovenous fistula or a very high-flow graft.
Often LVH is initially concentric, representing a uniform increase in wall thickness secondary to pressure overload, classically reported to be due to hypertension or aortic stenosis. The concentric thickening of the left ventricle wall allows for generation of greater intraventricular pressure, effectively overcoming increased afterload. Volume overload may result in eccentric hypertrophy secondary to the addition of new sarcomeres in series, although hypertension is also associated with eccentric hypertrophy. Eccentric hypertrophy is defined by an increased left ventricle (LV) diameter with a proportional increase in LV wall thickness. The pathophysiology associated with both concentric and eccentric hypertrophy can manifest with heart failure with preserved ejection fraction (HFpEF). As left ventricular remodeling progresses, capillary density decreases and subendocardial perfusion is reduced. Myocardial fibrosis may ensue and, with sustained maladaptive forces, myocyte death occurs. In its extremes, the endpoint of this cycle can be dilated cardiomyopathy with eventual reduction in systolic function (see Fig. 12.5 ).
Diagnosis
LVH is readily diagnosed with echocardiography. Cardiac function is best assessed in the euvolemic state, because significant volume depletion and overload both reduce left ventricular inotropy. Accordingly, in dialysis patients, two-dimensional echocardiogram results may be most meaningful on the interdialytic day, whereas three-dimensional echocardiography may be useful to assess LV structure because it avoids the use of geometrical assumptions of LV shape that are required to estimate LV mass and volume that are used for interpreting two-dimensional echocardiograms. Magnetic resonance (MR) imaging may be more precise for assessing LV structure than echocardiography, but this technique is more costly and time consuming, with many patients having possible contraindications to MR. Although screening echocardiography is currently recommended for incident dialysis patients, there is no evidence to date that this results in improvement in clinical outcomes.
Therapy
Given the complexity of its development, LVH and subsequent cardiomyopathy present therapeutic challenges. Potentially modifiable risk factors for LVH (and subsequent heart failure) include hypertension, extracellular volume overload, abnormal mineral metabolism, and possibly anemia and high-flow arteriovenous fistulas. It is notable that in CKD patients there is a paucity of trial data showing a mortality benefit associated with treating many of these LVH risk factors.
Data from several small observational studies and nonrandomized trials have suggested that regression of LVH can be induced by modification of risk factors, including anemia and systolic blood pressure, and strict management of volume using treatment modalities like daily dialysis. This was best described in the Frequent Hemodialysis Network Daily Trial, where frequent in-center hemodialysis was associated with better results in the composite outcome of reduced all-cause mortality and LV mass. In contrast, potentially reflecting effects of erythropoiesis stimulating agents on the vasculature, multiple randomized trials, including studies in both dialysis patients and patients with stage 3 to 4 CKD, have not demonstrated regression of LVH or a decrease in LV mass with near-normalization of hemoglobin.
Current treatment for LVH focuses on afterload reduction and volume management; accordingly, ACEIs or ARBs, often in conjunction with diuretics, are a mainstay of treatment in advanced CKD, whereas among dialysis patients the best results may be obtained with volume control. Other therapy at this time is best directed at modifying the multiple risk factors for LVH to prevent its development, particularly in the nondialysis CKD population.
Other Traditional Risk Factors
Other traditional CVD risk factors include advanced age, male sex, and smoking. Of these, only smoking presents an opportunity for intervention. Although there have been few studies examining specific effects of smoking in dialysis patients, evaluation of United States Renal Data System (USRDS) data showed that smoking was a strong, independent risk factor for incident heart failure, incident peripheral vascular disease, and all-cause mortality. Importantly, dialysis patients who were former smokers were more similar to nonsmokers than current smokers in risk, demonstrating the potential benefit of smoking cessation efforts in dialysis patients.
Nontraditional Cardiovascular Disease Risk Factors
Oxidative Stress and Inflammation
Oxidative stress and inflammation are proposed as unifying factors linking both traditional and other nontraditional risk factors in CKD. Oxidative stress may be defined as an imbalance between prooxidants and antioxidants (oxidant defenses) that leads to tissue damage. Most oxidation occurs in the mitochondria, although phagocytes also induce production of reactive oxygen species (ROS) in a “respiratory burst” designed to defend the body against infection. ROS can oxidize lipids, proteins, carbohydrates, and nucleic acids, which can then be measured as markers of oxidant burden. This system is balanced by a series of antioxidant defenses, some of which work by enzymatically catalyzing reduction of oxidant species (e.g., superoxide dismutase, catalase), whereas others work nonenzymatically by scavenging for oxidants (e.g., glutathione, vitamin C). There is also a complicated interplay between ROS and advanced glycation end-products (AGEs) in CKD, such that ROS may be both a cause and a consequence of AGE formation in individuals with diabetes and with CKD, and AGE accumulation may result in tissue damage and further oxidative and inflammatory stress.
Numerous factors in CKD patients increase oxidant stress, including inflammation, malnutrition (by reducing antioxidant defenses), uremic toxins, and potentially the dialysis procedure itself. Patients with CKD not only have higher levels of oxidant stress; they also have decreased defenses, particularly plasma protein-associated free thiols such as glutathione. This “double hit” makes CKD patients particularly vulnerable to sequelae of oxidant stress.
The lesions of atherosclerosis may represent a sequence of inflammatory processes affecting the vasculature; elevated and modified LDL cholesterol, genetic factors, infectious microorganisms, free radicals caused by cigarette smoking, hypertension, diabetes mellitus, ischemic injury, and combinations of these all predispose patients to progressive endothelial dysfunction. These factors are all common in individuals with CKD. In the general population, inflammation is a reasonably well-established risk marker for CVD, with leukocytosis and CRP both independently associated with adverse cardiovascular outcomes. In dialysis patients, several studies have demonstrated a strong, independent association between inflammation and the risk of adverse CVD outcomes, although controversy exists regarding causality. In stage 3 to 4 CKD, inflammatory markers, including CRP, elevated white blood cell count, and fibrinogen, are associated with adverse cardiovascular outcomes.
At this time, specific strategies to treat oxidant stress and inflammation in CKD have not been adopted, although potential therapies may be forthcoming. For example, statins are associated with a greater beneficial effect on CVD events and mortality than would be expected by changes in the lipid profile alone in the general population ; however, although statins may decrease CRP levels in dialysis patients, there is no evidence of a survival benefit associated with their use.
Numerous studies have investigated the use of antioxidants for cardiovascular protection in the general population, including one large trial that demonstrated no benefit of vitamin E supplementation. However, in dialysis patients, a study of 200 patients with prevalent CVD demonstrated a benefit associated with daily use of 800 international units of vitamin E, whereas a separate study showed a benefit with use of 600 mg of acetylcysteine twice daily. Other investigations have used vitamin E–coated dialyzers and noted a decrease in oxidant stress. Overall these studies remain preliminary and have not been consistently reproduced. Ongoing studies are examining other inflammatory mechanisms, such as a small study evaluating the interleukin (IL)-1 receptor blocker, anakinra, in hemodialysis.
Nitric Oxide, Asymmetrical Dimethylarginine, and Endothelial Function
Adequate nitric oxide production is critical for local vascular regulation and endothelial function. In individuals with CKD, nitric oxide production is reduced, likely reflecting substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of nitric oxide synthase (NOS), most notably asymmetrical dimethylarginine (ADMA). ADMA is a competitive inhibitor of NOS and is chiefly metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citrulline and dimethylamine. In kidney disease, particularly in states of high oxidative stress, DDAH activity is reduced, resulting in higher plasma and tissue levels of ADMA. Accordingly, the relationship among nitric oxide, endothelial function, and kidney disease may be another example of a vicious circle in this patient population, with chronic NOS inhibition causing systemic and glomerular hypertension, proteinuria, and glomerular and tubular injury, with these ultimately resulting in progressively worse kidney function that leads to further reductions in nitric oxide availability. One cross-sectional study explored these relationships, demonstrating an independent association between higher ADMA levels and lower eGFR, between higher ADMA levels and reduced coronary flow reserve, and between lower eGFR and reduced coronary flow reserve, with the highest ADMA levels seen in individuals with both lower eGFR and reduced coronary flow reserve. A second cross-sectional study showed a significant reduction in nitroglycerin-induced endothelium-independent vasodilation in CKD, suggesting that nitric oxide responsiveness also may be impaired in advanced CKD. These observations require further exploration in longitudinal analyses across a broader range of GFR levels.
Higher ADMA levels occur in individuals with earlier stages of CKD, and ADMA levels continue to rise as GFR declines. Higher ADMA levels are associated with more rapid kidney function decline and all-cause mortality in people with kidney disease. Furthermore, ADMA has been independently associated with increased cardiovascular risk in both CKD stage 3 to 4 and dialysis populations. In a post hoc analysis of the MDRD Study, each 0.25 μmol/L higher ADMA was associated with both a 31% higher prevalence of CVD (after adjusting for traditional and nontraditional risk factors) and borderline statistically significant 9% and 19% increases in all-cause mortality and CVD mortality, respectively. Similarly, in a cohort of 225 chronic hemodialysis patients, each 1 μmol/L was associated with a statistically significant 26% increase in all-cause mortality and a 17% increase in incident cardiovascular events. This research has established important groundwork for potentially addressing one aspect of increased cardiovascular risk in CKD. However, there has been no pharmacological intervention to date that reliably reduces ADMA levels in individuals with CKD. Accordingly, cardiovascular risk reduction targeting nitric oxide and ADMA remains an active area of research.
Homocysteine
Homocysteine, a metabolite of the essential amino acid methionine, has been implicated in observational studies in the general population as a risk factor for MI and stroke. Homocysteine levels increase as GFR declines, and hyperhomocysteinemia is much more common in dialysis patients than in the general population. Further, as elevated levels of homocysteine can often be reduced using pharmacological doses of B vitamins, it is an attractive potential nontraditional risk factor. To date, there have been multiple large, randomized trials of homocysteine-lowering therapies that enrolled patients at high risk of CVD outcomes in the general population and in late-stage CKD, dialysis, and kidney transplant populations, which, despite successfully lowering homocysteine levels, have failed to demonstrate a reduction in cardiovascular events. Accordingly, there are no data to suggest a benefit to lowering homocysteine with B vitamins.
Chronic Kidney Disease–Mineral Bone Disorder
Chronic kidney disease–mineral bone disorder (CKD-MBD), discussed more fully in Chapter 10 , is an important nontraditional risk factor for CVD in individuals with stage 3 to 5 CKD. The hypothesis that vascular calcification contributes to CVD burden in CKD is supported by several studies in dialysis patients that show independent associations between coronary artery calcification with mortality and between both peripheral artery intimal and medial calcification with mortality.
Arterial calcification, and, specifically, medial calcification, is far more common in individuals with CKD than in the general population, likely reflecting a complex interrelationship among hyperphosphatemia, secondary hyperparathyroidism, vitamin D deficiency, and other markers of mineral metabolism that, in conjunction, serve to overwhelm natural defenses against calcification ( Table 12.6 ). A model suggesting that vascular calcification occurs in patients with decreased plasma levels of inhibitory proteins, including fetuin-A, osteoprotegerin, and matrix Gla protein, has been extensively tested, but, to date, these proteins have not been consistent markers of calcification. Additional proteins that may affect this interrelationship include fibroblast growth factor 23 (FGF-23), a phosphatonin that decreases renal phosphate reabsorption, and klotho, a protein facilitating the binding of FGF-23 to its receptor.
| Factor | Sources and Regulation | Status in CKD | Hypothesized Role in Vascular Calcification |
|---|---|---|---|
| Precipitants | |||
| Phosphorus | Dietary intake Phosphorus binders Vitamin D Dialysis clearance FGF-23/Klotho Parathyroid hormone | ↑↑↑ | Passive precipitation with calcium Higher intracellular phosphate induces osteogenic behavior of VSMCs |
| Calcium | Parathyroid hormone Dietary intake Calcium-containing medications Dialysate Vitamin D | ↔ | Passive precipitation with phosphorus Higher intracellular calcium induces osteogenic behavior of VSMCs |
| Calcification Inhibitors | |||
| Fetuin A | Negative acute phase reactant | Variable | Inhibits local precipitation of calcium and phosphorus |
| Osteoprotegerin | Modulates osteoclast activation by indirectly preventing RANKL binding | Likely ↑ (but relative deficiency) | Local inhibition of cartilage and vascular calcification |
| Matrix Gla protein | Activated by vitamin K-dependent γ-carboxylation (Warfarin reduces active MGP) | Likely ↑ (but relative deficiency) | Local inhibition of cartilage and vascular calcification |
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