Cardiac Function and Cardiovascular Disease in Chronic Kidney Disease

Abstract

Cardiovascular disease is the leading cause of mortality across the spectrum of chronic kidney disease (CKD), with increased risk seen in individuals with reduced glomerular filtration rate (GFR) and in those with even minimally elevated urine albumin excretion. Cardiovascular disease has many manifestations in individuals with CKD, including atherosclerotic and stiff vessels with resultant ischemic heart disease and heart failure and structural changes like left ventricular hypertrophy (LVH) and valvular diseases are common at all CKD stages. The risk of cardiovascular disease outcomes increases as kidney function declines, with the risk of cardiovascular disease death in patients undergoing dialysis 10 to 20 times that of the general population. This chapter focuses largely on individuals with reduced GFR, reviewing the epidemiology, diagnosis, clinical manifestations, and treatment of cardiovascular disease and cardiovascular disease risk in individuals with CKD.

Keywords

cardiovascular disease, chronic kidney disease, cholesterol, myocardial infarction, heart failure, left ventricular hypertrophy, ischemic heart disease, dialysis

Cardiovascular disease is the leading cause of mortality across the spectrum of chronic kidney disease (CKD), with increased risk seen in individuals with reduced glomerular filtration rate (GFR) and in those with even minimally elevated urine albumin excretion. Cardiovascular disease has many manifestations in individuals with CKD, including atherosclerotic and stiff vessels with resultant ischemic heart disease and heart failure and structural changes like left ventricular hypertrophy (LVH) and valvular diseases are common at all CKD stages. The risk of cardiovascular disease outcomes increases as kidney function declines, with the risk of cardiovascular death in patients undergoing dialysis 10 to 20 times that of the general population. This chapter focuses largely on individuals with reduced GFR, acknowledging that albuminuria identifies individuals with CKD and is a very strong predictor of cardiovascular disease risk at all levels of kidney function, including individuals with CKD stages 1 through 3a where metabolic sequelae of reduced GFR are not yet clinically apparent.

Epidemiology of Cardiovascular Disease in Chronic Kidney Disease

Stages 3 to 4 Chronic Kidney Disease

Manifesting with cardiac ischemia, heart failure, and arrhythmia, cardiovascular disease is overwhelmingly the leading cause of morbidity and mortality in individuals with CKD. Among individuals with reduced GFR, there is a progressive increase in the age-standardized incidence of cardiovascular disease events as kidney function declines, such that, compared with an age-standardized baseline rate of 21 cardiovascular events per 1000 person-years in individuals with estimated glomerular filtration rate (eGFR) greater than 60 mL/min per 1.73 m ², rates increase to 37, 113, 218, and 366 events per 1000 person-years among people with eGFR of 45 to 59 (CKD stage 3a), 30 to 44 (CKD stage 3b), 15 to 29 (CKD stage 4), and less than 15 mL/min per 1.73 m ²(CKD stage 5), respectively. Even in analyses that adjust for demographic factors as well as cardiovascular risk factors such as diabetes, hypertension, albuminuria, and dyslipidemia, the risk of cardiovascular death is dramatically increased at lower GFR ( Fig. 55.1 ). The risk relationship between eGFR and cardiovascular disease events is independent of a person having preexisting cardiovascular disease ( Fig. 55.2 ).

Prevalence of cardiovascular disease in people with CKD is similarly high. For example, in population screening programs administered by the National Kidney Foundation, 12% to 20% of individuals with eGFR of 30 to 60 mL/min per 1.73 m ²(stage 3 CKD) state that they have had a previous “heart attack or stroke,” versus 5% to 10% for those with eGFR of 60 mL/min per 1.73 m ²or greater. In analyses adjusted for similar risk factors such as those mentioned earlier, both reduced eGFR and moderately increased albuminuria with preserved eGFR (urine albumin-to-creatinine ratio [UACR] 30 to 300 mg/g, indicating CKD stages 1 to 2) were independently associated with prevalent cardiovascular disease. Likewise, in pooled community cohorts, cardiovascular disease was prevalent in 31.3% of individuals with eGFR between 15 and 60 mL/min per 1.73 m ²(stage 3 to 4 CKD) versus 14.4% with eGFR ≥60 mL/min per 1.73 m ².

Cardiovascular disease may be subclinical in CKD populations; in Chronic Renal Insufficiency Cohort (CRIC) participants undergoing cardiac computed tomography, there was a graded increased risk of coronary calcification with both lower eGFR and higher levels of albuminuria, even in individuals with no known history of cardiovascular disease, although whether this suggests medial calcification or atheromatous disease is unknown. Similarly, in the elderly, the frequency of advanced atherosclerotic lesions on autopsy specimens increased as eGFR decreased (33.6% for eGFR ≥60 mL/min per 1.73 m ², 41.7% for CKD stage 3a, 52.3% for CKD stage 3b, and 52.8% for CKD stage 4).

LVH is also highly prevalent in CKD stages 3 and 4, likely reflecting pressure and volume overload. In CRIC, the prevalence of LVH assessed by echocardiography was 32% for eGFR above 60 mL/min per 1.73 m ², rising to 48%, 57%, and 75% for eGFR categories 45 to 59, 30 to 44, and less than 30 mL/min per 1.73 m ², respectively. These findings contrast with a prevalence of LVH of less than 20% in older adults in the general population. Both incident and prevalent heart failure are common in people with CKD. Among adult members of a large group-model health maintenance organization in the northwestern United States, 6.0% of individuals with predominantly early stage 3 CKD had a diagnostic code for heart failure versus 1.8% in an age- and sex-matched population, while, in the Atherosclerosis Risk in Communities (ARIC) study, individuals with eGFR less than 60 mL/min per 1.73 m ²at baseline were at twice the risk of incident heart failure hospitalization and death compared with those with eGFR of ≥90 mL/min per 1.73 m ², regardless of the presence of baseline coronary disease.

Other structural heart diseases seen commonly in CKD include aortic valve, mitral valve, and mitral annular calcification. Mitral valve or annular calcification was present in 20% of individuals with reduced kidney function (roughly stage 3 to 4 CKD) in the Framingham Offspring Study. In CRIC, lower eGFR was strongly associated with increased likelihood of mitral annular calcification, with risk increased by 50%, 130%, 226%, and 278% for eGFR categories 50 to 60, 40 to 50, 30 to 40, and less than 30 mL/min per 1.73 m ², respectively, when compared with eGFR ≥60 mL/min per 1.73 m ². The Framingham Heart Study and other studies also have shown an increased prevalence of aortic valve calcification in individuals with CKD, with CRIC demonstrating a “dose-dependent” association between lower eGFR and greater aortic valve calcification that was independent of traditional cardiovascular risk factors.

Stage 5 Chronic Kidney Disease/Dialysis

In patients undergoing dialysis, incident cardiovascular disease is common, with similar cardiovascular mortality rates in a 30-year-old patient undergoing dialysis and an 80-year-old individual from the general population ( Fig. 55.3 ). This likely reflects a high prevalence of cardiovascular disease (~45% of prevalent dialysis patients in the United States in 2014 had known atherosclerotic heart disease and 40% had congestive heart failure) as well as a high case-fatality rate compared with the general population.

The incidence and prevalence of LVH and heart failure are also extremely high among patients undergoing dialysis. More than 30% of participants in the Frequent Hemodialysis Network studies (a group that overall was healthier than the general dialysis population) had LVH at study entry (defined with cardiac magnetic resonance imaging). Based on United States Renal Data System (USRDS) administrative data that rely on billing codes to identify heart failure events, for patients treated with dialysis in 2009 and followed for up to 3 years, incident heart failure rates were 464 events per 1000 patient-years for hemodialysis and 243 per 1000 patient-years for peritoneal dialysis.

Patients undergoing hemodialysis also have a high prevalence of valvular calcification; in one study, 45% of subjects had calcification of the mitral valve, and 34% of subjects had calcification of the aortic valve, compared with expected prevalence of 3% to 5% in the general population. Studies have demonstrated rates of mitral annular calcification ranging from 30% to 50% in patients undergoing hemodialysis.

Types of Cardiovascular Diseases

Cardiovascular disease in individuals with CKD has a variety of manifestations, chiefly comprising atherosclerosis, arteriosclerosis, and cardiomyopathy/valvular disease ( Table 55.1 ). In most cases, clinically apparent cardiovascular disease reflects the interplay among these manifestations. Although there is no consensus on terminology for arteriopathies, atherosclerosis can be defined as an occlusive disease of the vasculature that occurs because of the deposition of lipid-laden plaques, while arteriosclerosis is a nonocclusive remodeling of the vasculature accompanied by a loss of arterial elasticity. Both of these conditions may manifest with ischemic heart disease and heart failure, and clinical disease often reflects the concurrent presence of both atherosclerotic disease and vascular remodeling. Certain risk factors, including dyslipidemia, primarily predispose an individual to development and progression of atherosclerosis, whereas others, including elevated calcium-phosphorus product, may predispose to vascular stiffness. Volume overload and anemia may primarily predispose an individual to cardiac remodeling and LVH, whereas hypertension, which is common at all stages of CKD, is associated with all of these disease manifestations. Over time, the interplay among these manifestations may yield both segmental perfusion defects due to disease affecting larger coronary arteries and insufficient subendocardial perfusion secondary to cardiac hypertrophy (causing increased demand) and capillary dropout. The end result is myocyte death.

Table 55.1

Types of Cardiac Diseases in Chronic Kidney Disease

Cardiovascular Disease Type	Pathologic or Structural Manifestation	Risk Factors	Indicators/Diagnostic Test	Clinical Sequelae
Arterial Disease	Atherosclerosis: Luminal narrowing of arteries because of plaques	Dyslipidemia Diabetes mellitus Hypertension Other traditional and nontraditional risk factors	Inducible ischemia on nuclear imaging Cardiac catheterization	Myocardial infarction Angina Sudden cardiac death Heart failure
	Arteriosclerosis: Diffuse dilatation and wall hypertrophy of larger arteries with loss of arterial elasticity	Hypertension Volume overload Hyperparathyroidism Hyperphosphatemia Other factors predisposing to medial calcification	Vascular calcification Increased pulse pressure Aortic pulse wave velocity Cardiac computed tomography Other arterial imaging	Myocardial infarction Angina Sudden cardiac death Heart failure LVH
Cardiomyopathy	LV Hypertrophy: Adaptive hypertrophy to compensate for increased cardiac demand	Pressure overload Increased afterload because of hypertension, valvular disease, and arteriosclerosis Volume overload Volume retention because of progressive kidney disease ± anemia	Echocardiography Cardiovascular magnetic resonance imaging	Myocardial infarction Angina Sudden cardiac death Heart failure
	Decreased LV contractility	Ischemic heart disease Hypertension LVH Other traditional and nontraditional risk factors	Echocardiography	Cardiorenal syndrome ^a Sudden cardiac death Heart failure Myocardial infarction Angina
	Impaired LV relaxation	Hypertension Anemia and volume overload Abnormal mineral metabolism Other arteriosclerosis risk factors Other traditional and nontraditional risk factors	Echocardiography	Heart failure Myocardial infarction Angina Sudden cardiac death
Structural Disease	Pericardial effusion	Delayed or insufficient dialysis	Echocardiography	Heart failure Hypotension
	Aortic and mitral valve disease	CKD stages 3 through 5 Abnormal calcium/phosphate/PTH metabolism Aging Dialysis vintage	Echocardiography	Aortic stenosis Endocarditis Heart failure
	Mitral annular calcification	CKD Stages 3 through 5 Abnormal calcium/phosphate/PTH metabolism	Echocardiography Uniform echodense rigid band located near the base of the posterior mitral leaflet	Arrhythmia Embolism Endocarditis Heart failure
	Endocarditis	Valvular disease Chronic venous catheters	Echocardiography	Arrhythmia Heart failure Embolism
Arrhythmia	Atrial fibrillation	Ischemic heart disease Cardiomyopathy	Electrocardiography	Hypotension Embolism
	Ventricular arrhythmia	Ischemic heart disease Cardiomyopathy Electrolyte abnormalities	Electrocardiography Electrophysiology study	Sudden cardiac death