Atherosclerotic Diseases in Chronic Kidney Disease

Authors: Toshiaki Nakano

Abstract

Patients with chronic kidney disease (CKD) have a high incidence of atherosclerotic diseases, such as ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. To prevent the incidence of atherosclerotic cardiovascular disease in patients with CKD, the pathology of arteriosclerosis should be determined. Vascular calcification is a characteristic of arteriosclerosis in patients with CKD. Recent studies have reported that coronary artery calcification is associated with acute coronary syndromes. CKD is frequently associated with heart failure. Furthermore, recent evidence suggests that coronary artery calcification affects asymptomatic myocardial ischemia. Hyperphosphatemia and calciprotein particles may be involved in the pathology of vascular calcification. Controlling the progression of vascular calcification and classical atherosclerotic risk factors is important to prevent the occurrence of atherosclerotic diseases in CKD.

I. Introduction

The number of patients with chronic kidney disease (CKD) has been increasing along with an increase in lifestyle-related diseases and the population^ 1 , 2) ^. Patients with CKD appear to have a higher incidence of cardiovascular complications than a population with a normal kidney function. Therefore, lipid-lowering therapies such as statins have been considered to prevent the development of atherosclerotic cardiovascular disease (ASCVD)^ 3) ^. The fact that the effect of lipid-lowering therapy using statins in reducing atherosclerotic cardiovascular events diminishes as CKD progresses to end-stage renal failure suggests that the pathology of atherosclerosis in patients with CKD may be altered^ 4 , 5) ^.

In recent years, evidence has suggested that vascular calcification affects plaque rupture and calcified nodules and exacerbates the development of acute coronary syndrome^ 6) ^. In addition, coronary artery calcification may cause microcirculatory disturbances in the heart^ 7) ^. This review summarizes the epidemiological and pathological characteristics of ASCVD associated with CKD.

II. Epidemiology of Cardiovascular disease in patients with CKD

In a large cohort study, the incidence of cardiovascular disease was 36.6 times higher in a population with a low estimated glomerular filtration rate (eGFR) of 15 ml/min/1.73 m^2^ than in a population with a normal kidney function^ 8) ^. In addition, the incidence of cardiovascular disease was 3.4 times higher after multivariate adjusting for risk factors than that in a population with a normal kidney function. A cohort study of the general Japanese population similarly reported that CKD is an independent risk factor for the development of cardiovascular disease^ 9) ^. Several other reports have shown that CKD and proteinuria are independent risk factors for the development of cardiovascular disease and death^ 10

^.

Common risk factors for CKD and cardiovascular diseases, such as hypertension, diabetes, and dyslipidemia, increase the risk of cardiovascular complications in CKD patients ** ( Fig.1 ) **. In the Suita Study, a multivariate adjusted analysis (adjusted for age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) showed that the incidence of coronary artery disease was 1.34 times higher in CKD stage 3 and 4.01 times higher in CKD stages 4 and 5 than in the general population^ 13) ^. Therefore, the risk of developing coronary artery disease due to CKD remains even after multivariate adjusting for the classical risk factors for atherosclerosis. This finding may be explained by the fact that CKD has various risk factors for cardiovascular disease, such as abnormal calcium and phosphorus metabolism, anemia, accumulation of urea toxins, oxidative stress, chronic inflammation, endothelial dysfunction, increased renin–angiotensin system (RAS) activity, and an increased sympathetic nerve function^ 14

^ ** ( Table 1 , Fig.1 ) **.

Patients on dialysis have a higher incidence of ASCVD than the general population^ 17) ^. Lipid-lowering therapy with statins has been used for patients with CKD. In a clinical trial, a post hoc analysis of pre-dialysis CKD patients showed that statins were effective^ 3) ^. However, statins alone failed to prevent cardiovascular events in patients undergoing dialysis^ 4 , 5) ^. Therefore, risk factors for atherosclerotic diseases other than dyslipidemia may be involved in patients undergoing dialysis.

III. Frequency of Coronary Artery Disease and Coronary Artery Calcification in Patients with CKD

Ischemic heart disease is a relatively frequent complication in CKD patients. According to the Japanese Society for Dialysis Therapy, myocardial infarction accounted for 3.3% of the causes of death among patients on dialysis in Japan in 2022, which was lower than that in previous years^ 18) ^. Deaths directly caused by myocardial infarction have been decreasing owing to the increased use of RAS system inhibitors and statins, therapeutic interventions for renal anemia, and early screening for cardiac diseases. However, regarding a history of ischemic heart disease in predialysis patients with CKD, recent reports from Japan showed a prevalence of 13.4% in the CKD-JAC Study and 10.8% in the Fukuoka Kidney disease Registry Study^ 19 , 20) ^. This finding indicates that ischemic heart disease is a frequent complication of chronic kidney disease. A study of myocardial scintigraphy to screen for ischemic heart disease before the induction of dialysis was performed in Japan^ 21) ^. This study reported that 22% of the patients with end-stage renal failure had ischemic heart disease, and the frequency of complications remained high. An autopsy study showed that advanced atherosclerotic lesions in the coronary arteries increased with CKD stage progression^ 22) ^ ** ( Fig.2 ) **. Therefore, the prevention of ischemic heart disease remains an important issue in patients with CKD.

A study that evaluated coronary artery calcification in patients with CKD who underwent chest computed tomography reported that a higher degree of vascular calcification in the coronary arteries was associated with a poorer survival rate^ 23) ^. Vascular calcification can occur in the intima and the tunica media. Calcification in the tunica media is called Mönckeberg medial calcific sclerosis and is characteristic of patients with CKD and diabetes, often being found in muscular arteries of the upper and lower extremities and pelvic arteries^ 24) ^. However, calcification in the intima often occurs with atherosclerosis and has been reported to be associated with a poorer prognosis than medial calcification^ 25) ^. Although the frequency of medial and intimal calcification in the coronary arteries of patients with CKD is unclear, calcification in the intima of coronary arteries is reported to occur with atherosclerosis in patients with CKD^ 22 , 26) ^. The frequency of vascular calcification in the coronary arteries was reported in autopsy cases in the Hisayama Study^ 2 , 22) ^. In the present study, patients with CKD and an eGFR ＜30 mL/min/1.73 m^2^ had a 4.7-fold increased risk of coronary artery calcification compared with the general population with an eGFR ≥ 60 mL/min/1.73 m^ 2 22) ^. Therefore, patients with CKD have an increased frequency of coronary artery calcification, which may be associated with coronary artery disease.

IV. Pathogenesis of Acute Coronary Syndrome with Coronary Calcification

Acute coronary syndrome is mainly caused by plaque rupture, plaque erosion, and calcified nodules. The most common cause of acute coronary syndrome is plaque rupture, in which rupture of the atheroma results in thrombus formation in the coronary artery. Plaque erosion, in which a thrombus forms on the intimal surface of the plaque, occludes the coronary artery^ 27) ^. Risk factors for plaque rupture include a large lipid core, thin fibrous capsule, high inflammatory cell infiltrates, high levels of angiogenesis, enlarged necrotic core, and positive remodeling^ 28) ^. Recently, coronary calcification was reported to be associated with plaque rupture^ 29) ^. It is difficult to determine whether or not calcification in the intima of coronary arteries directly affects plaque rupture. However, in a previous study, optical coherence tomography during coronary angiography to evaluate the responsible lesion showed that coronary arteries with plaque rupture had spotty calcification in the intima^ 30) ^. This finding suggests that microcalcifications and fragmented calcifications in the intima may be risk factors for plaque ruptures.

Thin-cap fibroatheroma and ruptured plaques with a thin fibrous capsule, which are at high risk of rupture, are often associated with microcalcifications (between 0.5 and 15 µm) and fragmented calcifications (＜3 mm) in the intima^ 27 , 29) ^. Sheet calcification (＞3 mm) is frequently observed in healed plaque ruptures and fibrocalcific plaques and may be associated with stable plaques with a low risk of rupture^ 27 , 29) ^. An autopsy study showed that vascular calcification was associated with intraplaque hemorrhage, which is a risk factor for plaque destabilization^ 31) ^ ** ( Fig.3 ) **. Macrophage infiltration is also associated with the risk of intraplaque hemorrhage and vascular calcification^ 31) ^. These findings suggest that vascular calcification increases the frequency of ASCVD events in patients with advanced atherosclerotic lesions.

Recently, calcified nodules protruding into the lumen of coronary arteries have been shown to cause thrombosis^ 6) ^. Necrotic cores in fibroatheroma may become extensively calcified (sheet calcification) over time, forming fibrocalcific plaques. Mechanical stress on diffuse calcified arteries is thought to destroy plate calcification, forming calcified nodules by aggregation of a necrotic core and calcification ** ( Fig.4 ) **. Calcified nodules are often observed in patients with CKD, and balloon intervention often does not provide sufficient dilation for stenotic lesions around calcified nodules in the coronary arteries. Even when stenotic lesions are dilated, calcified nodules may reappear in the stent, causing thrombosis and restenosis.

Therefore, calcification in coronary arteries is a risk factor for plaque rupture, and the formation of calcified nodules can lead to thrombus formation in the lumen, resulting in acute coronary syndrome.

V. Heart Failure Associated with CKD

CKD is frequently associated with left ventricular hypertrophy, especially afferent left ventricular hypertrophy^ 32 , 33) ^. This condition may be due to the fact that hypertension is more frequently complicated by impaired sodium excretion with a decreased kidney function than a normal kidney function, resulting in an increased frequency of left ventricular hypertrophy. In a recent autopsy study, left ventricular wall thickening increased as CKD progressed, and considerable left ventricular wall thickening was observed even after adjusting for risk factors such as hypertension and diabetes mellitus^ 34) ^. Furthermore, an evaluation of myocardial fibrosis showed expansion of fibrosis in myocardial tissue with the progression of the CKD stage. Myocardial wall thickening was also shown to be accompanied by swelling of myocytes, suggesting that local RAS is activated in myocytes^ 35) ^. Myocardial fibrosis may also indicate the presence of peripheral circulatory disturbances within the myocardium. CKD pathogenesis is accompanied by abnormal calcium and phosphorus metabolism, which is associated with an increased frequency of calcification in the vascular intima and medial lesions. Such calcification of the vessel wall contributes to increased arterial stiffness and left ventricular hypertrophy^ 36) ^. In addition, peripheral myocardial tissue has a high risk of ischemia owing to increased vascular stiffness with calcification, leading to fibrosis and an increased risk of heart failure. Therefore, CKD may predispose patients to left ventricular hypertrophy and myocardial fibrosis.

VI. Coronary Microcirculatory Dysfunction and Coronary Artery Calcification

In recent years, there has been widespread implementation of emergency coronary angiography for acute coronary syndrome, with the development of diagnostic techniques using highly sensitive troponin. This has led to the proposal of a new concept of myocardial infarction without nonobstructive coronary arteries (MINOCA) and ischemia with nonobstructive coronary artery disease (INOCA)^ 37) ^. MINOCA occurs not only in patients with heart failure or atrial fibrillation but also in patients with cerebrovascular disease, peripheral arterial disease, and CKD^ 38) ^. The main causes of INOCA are coronary spasms and microvascular dysfunction. Coronary microvascular dysfunction frequently occurs in the hearts of patients with CKD^ 39) ^.

One study evaluated asymptomatic myocardial ischemia in patients on hemodialysis without a history of ischemic heart disease using fatty acid metabolic scintigraphy^ 40) ^. Fatty acid metabolism is frequently impaired in the presence of myocardial ischemia in patients on hemodialysis, which suggests that asymptomatic myocardial ischemia (i.e. INOCA) is more common in the hearts of patients on dialysis than the general population. Furthermore, studies that measured coronary flow reserve (CFR) reported that CFR was lower in patients with CKD than in those without CKD^ 39) ^. Patients with CKD have an impaired vascular endothelial function, which may contribute to a reduced CFR. Another study reported an inverse correlation between the degree of coronary artery calcification and CFR^ 7) ^. These findings suggest that the frequency of coronary microvascular dysfunction is high in CKD patients. In addition, coronary microvascular dysfunction may be caused by impaired vasodilation due to impaired vascular endothelial function and increased vascular resistance due to vascular calcification. Therefore, vascular calcification may also affect myocardial circulatory disturbances.

VII. Cerebrovascular Complications Associated with CKD

Patients with CKD are at a higher risk of developing cerebrovascular disease than those without CKD. A meta-analysis of CKD and cerebrovascular disease reported a 7% increase in the risk of cerebrovascular disease for every 10 mL/min/1.73 m² decrease in the eGFR^ 41) ^. In addition, the appearance of microalbuminuria was reported to increase the risk of cerebrovascular disease 1.53-fold, while overt albuminuria was reported to increase the risk 1.94-fold^ 41) ^. A decline in the kidney function, albuminuria, and proteinuria in CKD are risk factors for cerebrovascular disease.

The risk of cerebrovascular disease is further increased in patients undergoing dialysis, with a 5.2-fold higher incidence than that in the general population^ 17) ^. Hypertension is the greatest risk factor; however, hyperphosphatemia, which is a characteristic of CKD, is associated with a 2.75-fold increased risk of cerebral hemorrhaging^ 42) ^. Renal anemia has also been reported as a risk factor for cerebrovascular disease^ 43) ^. These findings suggest that CKD pathophysiology contributes to the risk of cerebrovascular disease.

VIII. Treatment of Cardiovascular Disease in Patients on Dialysis

The DOPPS study showed that patients on dialysis have a high mortality rate^ 44) ^. Furthermore, patients on dialysis have a higher incidence of atherosclerotic disease than the general population^ 17) ^. Therefore, managing the risk of cardiovascular disease in patients undergoing dialysis is important. In a Q-cohort study of patients on hemodialysis in Japan, those with a systolic blood pressure ≥ 172 mmHg had a higher incidence rate of cardiovascular events than those with systolic blood pressure between 148 to 159 mmHg^ 45) ^. Regarding dyslipidemia, cardiovascular events were also increased in patients with total cholesterol concentrations ≥ 178 mg/dL^ 46) ^. Therefore, hypertension and dyslipidemia are risk factors for cardiovascular events in patients undergoing dialysis.

Notably, hyperphosphatemia is associated with cerebral hemorrhaging and peripheral arterial disease^ 42 , 47) ^. Hyperphosphatemia may cause endothelial dysfunction, and calciprotein particles (CPPs) induced by hyperphosphatemia may induce inflammation in macrophages and vascular smooth muscle cells, leading to atherosclerosis^ 48) ^ ** ( Fig.4 ) **. In addition, a recently published post hoc analysis of the AURORA study showed that rosuvastatin did not prevent major adverse cardiovascular events in patients on hemodialysis with serum phosphorus concentrations ＞5 mg/dL^ 49) ^. However, rosuvastatin reduced major adverse cardiovascular events in patients with serum phosphorus concentrations ＜5 mg/dL. Therefore, hyperphosphatemia may attenuate the effect of statins on the suppression of cardiovascular diseases in patients undergoing hemodialysis. In addition to interventions for classical risk factors, such as hypertension and dyslipidemia, the management of CKD-mineral and bone disorders is also important in treating cardiovascular disease in patients on hemodialysis.

IX. Conclusion

CKD is associated with several risk factors for atherosclerotic diseases, such as hypertension. CKD is also associated with cardiovascular disease owing to the presence of unique pathologies, such as vascular calcification, renal anemia, accumulation of uremic toxins, endothelial dysfunction, and enhancement of the local RAS. In recent years, evidence has suggested that vascular calcification in coronary arteries directly affects acute coronary syndrome or coronary microvascular dysfunction, which in turn may affect MINOCA and INOCA. Hyperphosphatemia has also been implicated in the development of cerebral hemorrhaging and peripheral arterial disease in patients undergoing hemodialysis. Prevention of atherosclerotic disease in patients with CKD requires management of mineral bone metabolism to prevent vascular calcification, in addition to management of classical risk factors, such as hypertension, diabetes, and dyslipidemia.

Acknowledgements

We thank Ellen Knapp, Ph.D., from Edanz (https://jp.edanz.com/ac) for editing the draft of this manuscript.

Conflict of Interest

The author declares no competing interests.