Atherosclerosis Burden and Therapeutic Challenges Regarding Acute Coronary Syndromes in Chronic Kidney Disease Patients

Abstract

The major cause of death in patients with chronic kidney disease is represented by cardiovascular events. Atherosclerosis is usually initiated by the association of traditional and non-traditional risk factors, and the acute thrombotic complications are more frequent in subjects with reduced glomerular filtration rate. The diagnosis of acute coronary syndromes is challenging due to the increased values of cardiac necrosis enzymes correlated with reduced renal function.

Keywords:acute coronary syndromes, chronic kidney disease, proteinuria.

INTRODUCTION

Chronic kidney disease (CKD) represents a major public health issue. Cardiovascular events are the leading causes of death in patients with CKD. The prevalence of coronary arteries disease (CAD) and heart failure in patients with CKD was 34% in the United States and 25.6% in a Japanese cohort study (1). The association of traditional and non-traditional risk factors specific for chronic kidney disease patients promotes an accelerated atherosclerosis process, thus increasing the incidence of CAD. There is strong evidence that a decreased glomerular filtration rate (eGFR) – below 60 mL/min/1.73 m² – is an independent predictor of cardiovascular mortality even in patients who were not previously at high risk for cardiovascular events (2). This certifies the fact that CKD may be considered a risk factor regarding CAD risk. The ratio between urine albumin and creatinine > 30 mg/g was related to a high cardiovascular risk in subjects with eGFR > 60 mL/min/1.73 m²; thus, albuminuria may be considered a cardiovascular risk factor in the general population (1).

Particularities of the accelerated atherosclerosis process in chronic kidney disease

Atherosclerosis process is an inflammatory disorder and has specific features in chronic kidney disease. The SMART trial illustrated the fact that a decrease in the renal diameters and the elevation 2019; 14(4): 378-383 Maedica A Journal of Clinical Medicine, Volume 14, No. 4, 2019 379 of the creatinine level is usually related to non-obstructive atherosclerosis. Atherogenic triggers include both modifiable and non-modifiable components like advanced age, diabetes mellitus, hypertension, obesity, smoker status and family history of premature cardiovascular disease (2).

There was an important cross-sectional study from our country, which included 3124 subjects aged 18-85 from eight regions (Bucharest, Muntenia, Oltenia, Banat, Crisana, Transilvania, Moldova and Dobrogea), and revealed that the prevalence of cardiovascular risk factors is high in our country and the optimal control are not suitable, explaining also the increasing incidence of cardiovascular disease in the general population (3).

The threshold for development of accelerated atherosclerosis and several complications like acute coronary syndromes, heart failure and cardiovascular mortality is represented by a glomerular filtration rate below 60 mL/min/1.73 m², which corresponds to a serum creatinine of 1.5 mg/dL (4).

Initial cardiovascular change found in patients with CKD is arteriosclerosis described as narrowing of the small arteries and loss of cushioning function. Arteriosclerosis promotes oscillatory patterns of shear stress and a high pulse pressure.

Animal studies revealed that mice with moderate chronic kidney failure express an increase aortic stiffness, leading to left ventricle hypertrophy and diastolic dysfunction. These particularities were related to some adhesion molecules and chronic kidney failure nontraditional factors, excluding other potential causes such as cardiovascular calcification, morphological vascular changes or hypercholesterolemia induced by apolipoprotein E deletion. The study design included two mouse models, apolipoprotein E gene knockout mice and C57 black wild- type mice, divided into four groups based on the presence or absence of chronic kidney disease. The study lot was evaluated using biochemical parameters, echocardiography measurements and histological examination performed after nephrectomy in a specific subgroup. Even if most preexisting trials emphasized that vascular calcification, especially medial calcification is responsible for increased aortic stiffness, the study illustrated that there is not a certain connection between them in the early stages of CKD, so there was no correlation regarding aortic calcification and pulse-wave velocity or the systolic expansion rate of the aorta. The vascular stiffness quantified by the assessment of the aortic pulse wave velocity is augmented once the renal function deteriorates (5).

,,Atherosclerosis” and ,,arteriosclerosis” are distinct vascular lesions (Table 1). Arteriosclerosis expresses the narrowing of the arteries due to the decline of elastin production, while atherosclerosis is determined by cardiovascular factors that promote the lipids peroxidation and appearance of atherosclerotic lesions initially in medium-sized and large arteries.

In subjects with CKD there is a special characteristic of atherosclerosis consisting in the presence of extended vascular calcifications. Schwartz et al. demonstrated that in patients with end stage renal disease there is an important calcification of the media, in contrast with the control lot that had mostly fibro-atheromatous plaques. Surprisingly, the intimal layer was not involved in the thickness process, but the arterial lumen was more reduced in uremic patients. In fact, there is not a matter of the plaques size but the consistence makes them more prone to develop acute complications (6).

The hypotheses that the elevated level of cholesterol was not the principal element involved in atherosclerosis in CKD was revealed by AURORA and 4D studies. Lowering cholesterol and LDL-cholesterol did not improve the cardiovascular outcome in subjects with chronic hemodialysis. Statin therapy should be initiated in CKD patients before they develop ESRD (end stage renal disease – CKD requiring dialysis) (7).

Traditional and non-traditional risk factors involved in atherosclerosis in subjects with CKD

The uremic-enhanced risk factors such as malnutrition, anemia, calcium and phosphates metabolism disorders, coagulation disorders are influencing the progression of the atherosclerotic plaque. The volume of the myocytes is enlarged in CKD subjects, resulting in a mismatch between myocytes and capillaries and an imbalance between the coronary blood blow offer and demand (8).

There are two different categories of atherosclerotic lesions that may lead to acute coronary syndrome development. The plaque erosion is characterized by an intact fibrous cap and a white non-occlusive thrombus containing platelets. In contrast, the plaque rupture involves a rupture in the fibrous cap and red thrombus formed mostly by fibrin, which will produce the artery occlusion. For the moment, the mechanism responsible for the initiation of both two lesions by CKD is not clearly explained (9).

Diagnosis of acute coronary syndromes in patients with CKD

The decline of renal function interferes with excretion of the cardiac necrosis enzymes represented by troponin I and T. This aspect illustrates the fact that elevated values of these biomarkers are characteristic in patients with CKD and only serial determinations of these compounds may clarify whether there is a certain suspicion of myocardial necrosis or an elevated baseline value of troponins due to renal damage.

Trials revealed that there was a correlation between the cardiac troponins values and the mortality rate, even in patients without symptoms and signs of myocardial infarction. Elevated values of troponin T were detected in patients with deteriorated renal function and normal coronary arteries. The mortality rate in subjects with high concentrations of troponin T was 47% in one trial, compared with 8.4% recorded in patients with cardiac troponin T less than 0.01 ìg/L (10).

Electrocardiography represents another diagnostic tool used in revealing myocardial infarction, but the presence of left ventricular hypertrophy, pathologic Q waves and ST segment depression during hemodialysis sessions, is detected in subjects with chronic kidney disease without signification of myocardial ischemia (11).

Improvements in assay sensitivity lead to the development of new biomarkers such as high sensitive troponin, which are more specific for the diagnosis of the ACS because the decrease of the eGFR will not affect their renal excretion (12).

Besides its role in revealing the presence of myocardial necrosis, high sensitive troponin is correlated with the incidence of heart failure, left ventricular mass and a left ventricular ejection fraction less than 50%. The incidence of heart failure was 52.8 per 100 subjects in the group with a high sensitive troponin value greater than 5 ng/L (12).

The APACE trial suggested important conclusions regarding the diagnosis of acute coronary syndromes in CKD subjects. First of all, using just one value of hs-cTn is not indicated and serial measures should reveal an increasing tendency of the cardiac enzyme. The 1 and 3 hour-diagnosis algorithm regarding high sensitive troponin, which was included in the third universal definition of the myocardial infarction released by the European Society of Cardiology, represents an option for CKD patients (13).

Therapeutic options in acute coronary syndromes and chronic kidney disease

The major phenomena observed in patients with CKD is called ,,renal nihilism” and illustrates the physicians’ predisposition for choosing the conservative treatment of acute coronary syndrome, leading to a underutilization of interventional coronary angioplasty.

Specific features of the dyslipidemia characteristic in patients with impaired renal function consist in increased VLDL (very low density lipoproteins) cholesterol and decreased HDL (high density lipoproteins) cholesterol. In advanced CKD, HDL-cholesterol has an altered function (14).

Lipid-lowering therapy has a different impact in these patients depending of the CKD stage. The Heart Protection Study, ASCOT-LLA trial and Pravastatin Pooling Project outlined the fact that therapy with simvastatin, atorvastatin and pravastatin, strongly reduces the MACE (major adverse cardiac events) in patients with early CKD. CARD analyses reflected that using atorvastatin reduced the incidence of MACE by 42%, with a decline of 64% in stroke for subjects with type 2 diabetes and CKD stage 3 (15).

The 4D study outlines that 20 mg of atorvastatin in patients with impaired kidney function reduced the LDL-cholesterol with 40%, but the impact on cardiovascular mortality, myocardial infarction and nonfatal stroke was not statistically important (15).

Aurora study reflected that using 10 mg of rosuvastatin in dialyzed patients decreased the LDL cholesterol and C reactive protein, but had a modest effect in primary endpoint composite of only 4% (15).

These conclusions were predictable because LDL cholesterol levels are normal in CKD subjects and statins therapy works only for those patients with increased values. The HMG-CoA (b-Hydroxy b-methylglutaryl-CoA) reductase activity is down-regulated in chronic kidney failure (14).

The Sharp trial had a different perspective and a significant reduction in cardiovascular death was suggested by dividing the patients into two groups depending on the dialyzed status, so the risk decline was of 20% in non-dialyzed subjects and 9% in the dialyzed group (15).

Lipid lowering treatment may have reno-protective effects and it was demonstrated that they reduce albuminuria and proteinuria (15).

The Evidence-based Clinical Practice Guidelines for treatment of CDK 2009 recommends an LDL-cholesterol target of 130 mg/dL in subjects with impaired renal function and values below 100 mg/dL are more indicated if it is possible. In dialyzed patients, LDL-cholesterol should be maintained below 130 mg/dL in primary prevention and less than 100 mg/dL in secondary prevention. Also, non-HDL recommendations include values below 150 mg/dL and 130 mg/dL, respectively (15).

European Society of Cardiology (ESC) and European Atherosclerosis Society have different opinions regarding the LDL-cholesterol target. The achievable value for LDL is below 1.8 mmol/L, 70 mg/dL, respectively (15).

Indications for management of coronary artery disease including the superiority of myocardial revascularization over optimal treatment are still in discussion because the subjects with chronic kidney disease are usually excluded from the clinical trials, so strong evidences are lacking. Also, revascularization guidelines included evidences from the general population, the CKD subjects were underrepresented and the randomized trials regarding the outcome of the patients who benefited of myocardial revascularization are lacking.

COURAGE (Optimal Medical Therapy with or without PCI for Stable Coronary Disease) and Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trials reflected that PCI and CABG did not show a significant superiority over optimal medical treatment in all-cause mortality in patients with myocardial infarction. COURAGE excluded the subjects with CKD and Bari 2D encountered only 16 patients with glomerular filtration rate below 30 mL/min/1.73 m² (16, 17).

The accepted conclusion is that DES (drug-eluting stents) are indicated in CKD patients over BMS (bare-metal stents). In addition, for CAD involving less than three coronary arteries, the results of PCI compared with CABG are similar, but in cases with more than three vessels the surgical myocardial revascularization is more suitable (18).

One trial which included real-world, unselected subjects, and evaluated the in-hospital and one year outcomes in 642 patients with CKD who benefited of PCI. The major finding is that kidney function represents an independent predictor regarding the evaluation of ischemic and bleeding events in patients with decreased eGFR and DES (19).

The Syntax study reunited 1800 patients who underwent either PCI with first-generation paclitaxel- eluting stent or CABG (20). Follow-up consisted in a five years period and revealed the incidence of the MACE, including all-cause mortality, myocardial infarction and the necessity to repeat the revascularization procedure (21).

On the short term there were no significant results between PCI versus CABG regarding the primary composite: MACE (6.3% versus 4.0%), all-cause death (2.5% versus 0.7%) and repeated revascularization (1.9% versus 1.3%) (21).

After five years, the analysis reflected that, in subjects with CKD, MACE had a higher incidence in PCI (42.1%) versus CABG (31.5%) groups, whereas the reported death/myocardial infarction/ stroke was 31.9% in the PCI group and 25.5% in the CABG group. This aspect outlines that outcomes on the long term are superior for CABG, especially for diabetic subjects with a complex three vessels or left main involvement (21).

Retrospective data illustrates different hypothesis. For instance, Bangalore and co-authors found that CABG was inferior to PCI regarding short-term mortality, stroke and repeated revascularization (22).

The limits of the Syntax study are represented by the usage of first-generation DES, so new proofs and observations regarding the second-generation DES are required.

ESC guidelines referring to myocardial revascularization released in 2014 have a special recommendation on CKD patients. There is a class II b, level B of evidence, indication favoring CABG over PCI in patients with multivessel CAD, with ischemic symptoms whose surgical risk profile is acceptable and life expectancy is beyond one year. On the other hand, for patients with life expectancy less than one year, who develop symptoms or ischemic signs, PCI represent the treatment of choice (23).

The optimal treatment for chronic kidney disease patients who develop ACS should be carefully weighted, and the overall risk should be identified according to the comorbidities, procedural aspects including mortality risk and longterm outcomes.

Peri-interventional management of anticoagulation in CKD subjects represents another controversy. Unfractionated heparin (UNH), bivalirudin and fractionated heparin (enoxaparin) is considered a viable option and it should be administered considering the ischemic and the bleeding risks (23). Dose adjustments in subjects with eGFR less than 30 mL/min/1.73m² of enoxaparin are indicated (24). A meta-analysis reflected that usage of bivalirudin instead of UNH decrease the bleeding risk, with the inconvenience of increased stents thrombosis events (23). Matrix trials revealed that bivalirudin administration versus UNH did not improve the major outcomes including death, risk of myocardial infarction and stroke, in 7213 subjects diagnosed with ACS (23). A metaanalysis including six trials revealed that bivalirudin was superior over heparin in 6405 subjects with CKD and ACS regarding the 30-days bleeding risk with no demonstrated benefits in reducing the ischemic risk (25).

An observational study including two cohorts revealed that acute kidney injury (AKI), a common complication of the CKD subjects, represents a major short-term adverse event. Surgical myocardial revascularization is correlated with a 1.5 to three-fold higher odds of acute kidney injury incidence compared with PCI. Also, in the Acute Catheterization and Urgent Intervention Strategy about 31.7% of the participants who received CABG developed AKI, in contrast with only 14.2% of the subjects who were in the PCI group and experienced contrast nephropathy, with a p<0.0001 (26).

The rate of AKI has decreased using the interventional strategy due to the third-generation iso-osmolar non-ionic contrast substances, proper hydration and N-acetylcysteine infusions (26).

Another important aspect is that chronic kidney disease patients are exposed to a high bleeding risk, so the balance between the ischemic Atherosclerosis Burden and Therapeutic Challenges Regarding Acute Coronary Syndromes in Chronic Kidney Disease Patients Maedica A Journal of Clinical Medicine, Volume 14, No. 4, 2019 383 and bleeding risk is very fragile. The explication resides in the special reactivity of the platelets in the uremic milieu. These cells become more prone to aggregation due to an intense ADP activity, becoming less responsive to P2Y12 inhibitors like clopidogrel.

CONCLUSIONS

The final idea is that chronic kidney disease represents a CAD risk equivalent. The subjects experience an atherosclerotic process with intense media calcification, so they are prone to develop acute coronary syndromes. A corroboration of both traditional and non-traditional risk factors, specific for uremic patients, accelerates the evolution of the atherosclerosis plaque.

The management of this specific population expresses the improper attitude of the physicians who are not confident in using all therapeutic options, illustrating the therapeutic renal nihilism. An optimal attitude should balance between the ischemic and bleeding risk, the incidence of acute kidney injury and MACE, the mortality risk and finally the long-term prognosis.

Conflict of interests: none declared

Financial support none declared.

TABLE 1.

Differences between atherosclerosis and arteriosclerosis and pathophysiological aspects of the two lesions

FIGURE 1.

Traditional and non-traditional risk factors involved in atherosclerotic process in subjects with CKD disease. There are two particular complications of the accelerated atherosclerosis consisting in the white thrombus, which is mainly formed by platelets and the red thrombus, rich in fibrin. HBP= High blood pressure; CVD= cardiovascular disease.