Распространение значительного стеноза коронарной артерии и связи с каротидной максимальной токсикоманией в асимптоматических пациентах с умеренной хронической почечной болезнью: один-центральный, перспективный, межсекторальный анализ.

Introduction

Coronary artery disease is a frequently identified complication in individuals with chronic kidney disease (CKD) and is recognized as the principal cause of mortality among this population. 1 The extent of coronary artery stenosis shows a direct relationship with adverse cardiac outcomes, including sudden cardiac death, myocardial infarction, and unstable angina. 2 Therefore, timely identification and management of coronary artery stenosis are essential to reduce the risk of cardiovascular death and acute coronary syndrome. 3

Coronary computed tomography (CT) angiography has been widely used as an imaging modality for diagnosing coronary artery stenosis. 4 A recent study using coronary CT angiography reported that coronary artery stenosis (≥ 50%) was present in nearly 10% of asymptomatic patients with early CKD (stage G1–3a). 5 However, in patients with advanced CKD, coronary CT angiography is frequently not performed because of concerns about the risk of adverse effects, especially contrast-induced nephropathy. 4

Coronary magnetic resonance (MR) angiography is a non-invasive imaging modality for diagnosing coronary artery disease that can provide coronary artery images without contrast agents. 6 Recent studies reported that coronary MR angiography had comparable diagnostic accuracy for detecting coronary artery stenosis, compared with coronary CT angiography. 6 , 7 However, reports that have examined the prevalence of coronary artery stenosis in patients with advanced-stage CKD are scarce. Therefore, we performed the present study to clarify the prevalence and associated factors of significant coronary artery stenosis (≥ 50%) evaluated by coronary MR angiography in asymptomatic patients with moderate-to-severe CKD (stage G3–5). Furthermore, we evaluated the usefulness of carotid maximum intima-media thickness (IMT), a validated surrogate marker for atherosclerosis, with regard to predicting significant coronary artery stenosis in these patients.

Methods

Ethical Approval and Informed Consent

This study was approved by the Institutional Review Board of Saitama Medical Center (S22-058) and performed in accordance with the ethical principles of the Declaration of Helsinki. All participants provided written informed consent prior to their inclusion in the study.

Patients

The inclusion criteria were: (i) age ≥ 20 years and (ii) estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 (CKD stage G3–5). The exclusion criteria were: (i) history of coronary artery disease, (ii) renal replacement therapies, including renal transplantation, hemodialysis, and peritoneal dialysis, (iii) unwilling or unable to provide informed consent, and (iv) contraindications to MR imaging (eg, claustrophobia, pacemakers, and metallic implants).

Study Design

This was a prospective, cross-sectional study performed between 2022 and 2024 at Saitama Medical Center. The presence and severity of coronary artery stenosis was evaluated by coronary MR angiography. Carotid maximum-IMT has been demonstrated to be a useful surrogate marker of coronary artery stenosis in previous studies; 8–12 therefore, it was also evaluated by carotid ultrasonography in this study. Demographical and clinical laboratory data were collected at the time of coronary MR angiography. Factors which were associated with the presence of significant coronary artery stenosis (≥ 50%) were explored by multivariable logistic regression analysis. The diagnostic accuracy of carotid maximum-IMT for detecting significant coronary artery stenosis was explored by receiver operating characteristic (ROC) curve analysis.

Evaluation of Coronary Artery Stenosis by Coronary MR Angiography

Unenhanced whole-heart coronary MR angiography was performed with a 3.0 Tesla MR scanner (Ingenia CX; Philips Healthcare, Amsterdam, The Netherlands) using a 32-channel dStream (Phillips Healthcare) torso coil, at Saitama Central Clinic (an affiliated hospital of Saitama Medical Center). Anatomical images were acquired using a whole-heart three-dimensional T1-weighted turbo field echo sequence (repetition time/echo time: 4.4/2.0 ms) with an acquisition voxel size of 1.43×1.42 × 1.5 mm and reconstruction voxel size of 0.74×0.74 × 0.75 mm. Nitroglycerine oral spray (0.3 mg) was administered before coronary MR angiography. Whole-heart coronary MR angiography images were explored using workstation (Virtual Place Arata; AZE, Ltd., Tokyo, Japan). Segments measuring < 1.5 mm in diameter were excluded from the analysis. Each coronary MR angiography image was evaluated by two experienced radiologists. The severity of coronary artery stenosis was determined visually and categorized as no stenosis, < 50% stenosis, ≥ 50% stenosis, and occlusion ( Figure 1 ), on the basis of previous reports. 13 , 14 In accordance with previous reports, 14 , 15 ≥ 50% stenosis was defined as significant stenosis. Patients exhibiting at least one coronary artery stenotic lesion of ≥ 50% were classified as having significant coronary artery stenosis.

Evaluation of Carotid Maximum-IMT by Ultrasonography

Carotid ultrasonography was performed using a 7.5-MHz linear transducer (Aplio TA500; Toshiba, Tokyo, Japan) at Saitama Medical Center. Carotid IMT was assessed as the thickness between the lumen–intima and media–adventitia interfaces visualized on the posterior wall of the artery ( Figure 2A ). Carotid maximum-IMT was defined as the largest thickness detected in the observable segments of the common carotid artery, carotid bulb, and internal carotid artery on both sides ( Figure 2B ). All sonographic scans were performed by sonographic technicians. In the analysis of the relationship between carotid maximum-IMT and the prevalence of significant coronary artery stenosis, carotid maximum-IMT was categorized into the following five grades: ≤ 1.0 mm, 1.1–2.0 mm, 2.1–3.0 mm, 3.1–4.0 mm, and ≥ 4.1 mm, in accordance with previous reports. 11

Laboratory Methods

Blood and urine parameters were evaluated at the Department of Clinical Laboratory, Saitama Medical Center. eGFR was calculated using the equation provided by the Japanese Society of Nephrology. 16 The classification of CKD stages (G1–5) was performed based on the Japanese Society of Nephrology CKD guideline. 17 Hypertension was defined as blood pressure ≥ 140/90 mmHg or the current use of antihypertensive agents in accordance with the Japanese Society of Hypertension Guideline. 18 Diabetes mellitus was defined as serum glycated hemoglobin concentration ≥ 6.5% or the current use of blood glucose-lowering agents or/and insulin in accordance with the Japanese Clinical Practice Guideline for Diabetes. 19 Dyslipidemia was defined as low-density lipoprotein cholesterol ≥ 140 mg/dL, high-density lipoprotein cholesterol < 40 mg/dL, triglyceride ≥ 150 mg/dL, or the current use of lipid-lowering agents according to the Japanese Atherosclerosis Society Guideline. 20 Hyperuricemia was defined as serum uric acid ≥ 7.0 mg/dL or the current use of uric acid-lowering agents.

Statistical Analyses

Statistical analyses were performed using JMP Pro, Version 17 (SAS Institute, Inc., Cary, NC, USA). Continuous variables were expressed as means ± standard deviations for normal distributions and as medians [interquartile ranges] for non-normal distributions. Normal distribution of continuous variables was assessed by Shapiro–Wilk test. Categorical variables were expressed as numbers and percentages. Multivariable logistic regression analysis was used to detect the independent factors associated with the presence of significant coronary artery stenosis. Parameters which were associated significantly with the presence of significant coronary artery stenosis in the univariable logistic regression analysis were included in the multivariable logistic regression analysis. An additional multivariable logistic regression analysis using an automated variable selection method based on the minimum Bayesian Information Criterion was performed to ensure the stability and reproducibility of the multivariable model. The ability of carotid maximum-IMT to predict significant coronary artery stenosis was examined using a ROC curve analysis. The optimal cut-off value, area under the ROC curve (AUC), sensitivity, and specificity were calculated for detecting significant coronary artery stenosis. The optimal cut-off value was determined using Youden’s Index, which maximizes the sum of sensitivity and specificity. The relationship between carotid maximum-IMT category and the prevalence of significant coronary artery stenosis was evaluated using Fisher’s exact test. For all tests, p-values <0.05 were considered statistically significant.

Results

Patient Characteristics

The flow diagram for the participants is shown in Figure 3 . One hundred fifty-six patients with CKD stage G3–5 provided written informed consent and were enrolled in the study. Of these, 22 patients were excluded on the basis of the inclusion and exclusion criteria, and the remaining 134 patients underwent coronary MR angiography. No patients had clinical symptoms suggesting coronary artery disease, such as chest pain and dyspnea. Six patients had insufficient diagnostic image quality due to arrhythmia or inadequate breath-holding. Therefore, 128 patients (men: 68.0%; mean age: 70.3 ± 11.2 years) were included in the analysis ( Figure 3 ). Their mean eGFR was 37.6 ± 12.9 mL/min/1.73 m 2 , and CKD stages were as follows: stage G3a, 43 (33.6%); stage G3b, 42 (32.8%); stage G4, 39 (30.5%); and stage G5, 4 (3.1%). The patients’ characteristics and medications are summarized in Table 1 . Of these, 76 patients (60%) had significant coronary artery stenosis. Among these 76 patients, 26 patients (34%) underwent coronary angiography, and 37 patients (49%) underwent technetium-99m tetrofosmin myocardial perfusion scintigraphy. Of the patients who underwent coronary angiography, 7 (27%) had ≥ 90% coronary artery stenosis; therefore, these patients underwent percutaneous coronary intervention. Of the patients who underwent myocardial scintigraphy, ischemia was confirmed in 15 (40%); thus, these patients received optimal medical therapy.

Factors Associated with Significant Coronary Artery Stenosis

Univariable logistic regression analyses revealed that the presence of significant coronary artery stenosis was associated significantly with age (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.01–1.08; P = 0.005), body mass index (OR: 1.14, 95% CI: 1.03–1.28; P = 0.009), high-density lipoprotein cholesterol (OR: 0.97, 95% CI: 0.95–0.99; P = 0.020), glycated hemoglobin (OR: 2.39, 95% CI: 1.36–4.65; P = 0.001), C-reactive protein (OR: 20.14, 95% CI: 1.63–484.42; P = 0.017), and carotid maximum-IMT (OR: 5.17, 95% CI: 2.79–10.51; P < 0.001) ( Table 2 ). We performed multivariable logistic regression analysis using the variables that showed significant associations with the presence of significant coronary artery stenosis in the univariable logistic regression analyses. Multicollinearity was not observed among these variables (variance inflation factor < 5 for all). This analysis revealed that only carotid maximum-IMT (OR: 4.86, 95% CI: 2.32–11.62; P < 0.001) was associated with the presence of significant coronary artery stenosis. We also performed multivariable logistic regression analysis using the minimum Bayesian Information Criterion method. This additional analysis confirmed that only carotid maximum-IMT (OR: 5.19, 95% CI: 2.68–10.04; P < 0.001) was associated with the presence of significant coronary artery stenosis.

Relationship Between the Degree of Carotid Maximum-IMT and the Prevalence of Significant Coronary Artery Stenosis

Carotid maximum-IMT was identified as a significant factor associated with the presence of significant coronary artery stenosis. Therefore, we evaluated the prevalence of significant coronary artery stenosis in each carotid maximum-IMT category. The degree of carotid maximum-IMT was associated significantly with the prevalence of significant coronary artery stenosis ( P < 0.001) ( Figure 4 ).

Diagnostic Accuracy of Carotid Maximum-IMT for Detecting Significant Coronary Artery Stenosis

The ROC curve for carotid maximum-IMT for detecting significant coronary artery stenosis was significant ( P < 0.001). The AUC of carotid maximum-IMT was 0.788 (95% CI: 0.711–0.866), and the cut-off value with the greatest sensitivity and specificity for carotid maximum-IMT was 1.5 mm (sensitivity, 0.84; specificity, 0.58) ( Figure 5 ).

Diagnostic Accuracy of Carotid Maximum-IMT for Detecting Coronary Artery Stenosis of ≥90% and Myocardial Ischemia

In the patients who underwent coronary angiography, the ROC curve for carotid maximum-IMT for detecting ≥ 90% stenosis was not significant ( P = 0.37) and the AUC of carotid maximum-IMT was 0.617 (95% CI: 0.394–0.839). In the patients who underwent myocardial scintigraphy, the ROC curve for carotid maximum-IMT for detecting myocardial ischemia was not significant ( P = 0.63) and the AUC of carotid maximum-IMT was 0.548 (95% CI: 0.356–0.740).

Discussion

In the present study, we found that the prevalence of significant coronary artery stenosis was high (60%) in patients with moderate-to-severe CKD. We also found that carotid maximum-IMT was the only factor associated with the presence of significant coronary artery stenosis in these patients. Furthermore, the degree of carotid maximum-IMT was positively associated with the prevalence of significant coronary artery stenosis. These results suggest that carotid maximum-IMT could be a surrogate marker for significant coronary artery stenosis in patients with moderate-to-severe CKD.

The development and progression of atherosclerosis is accelerated in patients with CKD. 21 An autopsy study reported that the prevalence of advanced coronary atherosclerotic lesions increased as renal function decreased. 22 An observational study using coronary CT angiography reported that coronary artery stenosis (≥ 50%) was observed in nearly 10% of the patients with early CKD (stage G1–3a). 5 Several studies using coronary angiography showed that coronary artery stenosis (≥ 50%) was noted in 40–45% of the CKD patients at the start of renal replacement therapy. 23 , 24 In the present study, coronary MR angiography revealed that coronary artery stenosis (≥ 50%) was present in 60% of the patients with moderate-to-severe CKD (stage G3–5). These results suggest that the prevalence of coronary artery stenosis is high in CKD patients, and coronary artery stenosis already exists before the initiation of renal replacement therapy.

Carotid maximum-IMT is a validated surrogate marker for atherosclerosis and cardiovascular disease. 25 , 26 Several studies reported that carotid maximum-IMT was associated with the presence of coronary artery stenosis in diabetic patients without renal impairment. 8–11 A recent study showed that increased carotid maximum-IMT was associated with the presence and severity of coronary artery disease in non-diabetic patients without renal impairment. 12 In the present study, the degree of carotid maximum-IMT was positively associated with the prevalence of significant coronary artery stenosis in patients with renal impairment. These findings suggest that carotid maximum-IMT is a useful surrogate marker for significant coronary artery stenosis in patients with and without renal impairment.

In CKD patients, CKD-specific cardiovascular risk factors, such as inflammation and oxidative stress, have been considered responsible for the development and progression of atherosclerosis, as well as classical cardiovascular risk factors, including diabetes mellitus, hypertension, and dyslipidemia. 27 Several studies have investigated factors associated with coronary artery stenosis in CKD patients. One study reported that the presence of proteinuria was associated with coronary artery stenosis in patients with early CKD (stage G1–3a). 5 Another study found that smoking, lower ankle–brachial index, greater carotid IMT, and elevated cardiac troponin levels were associated with coronary artery stenosis in patients with CKD initiating renal replacement therapy. 24 However, in the present study, none of the CKD-specific or classical cardiovascular risk factors were associated with significant coronary artery stenosis. In the univariable analyses, several cardiovascular risk factors, namely age, body mass index, high-density lipoprotein cholesterol, glycated hemoglobin, and C-reactive protein showed significant associations with significant coronary artery stenosis. However, these significant associations were not confirmed in the multivariable analysis, suggesting that these risk factors cancelled each other. The predominant risk factors for coronary artery stenosis might differ in individual patients with moderate-to-severe CKD. Our study results suggest that carotid maximum-IMT may act as a surrogate that integrates multiple underlying risk pathways; however, the study design cannot rule out independent contributions of traditional risk factors because the sample size is relatively modest (128 patients, 76 events). Further larger-scale studies are necessary to clarify the risk factors for coronary artery stenosis in CKD patients.

This study has several advantages. First, we examined the prevalence of coronary artery stenosis in patients with moderate-to-severe CKD. Second, we evaluated the factors associated with significant coronary artery stenosis in these patients. Third, we evaluated the diagnostic accuracy of carotid maximum-IMT for detecting significant coronary artery stenosis. The results of our study might be useful for further studies to investigate the prevalence and associated factors of significant coronary artery stenosis in patients with advanced-stage CKD.

This study has some limitations. First, this study was a cross-sectional design, single-center, observational study, which could have been subject to bias in patient selection. Second, the study population was composed of only a Japanese cohort, which limits the generalizability of our study findings. Third, the gold standard for diagnosing coronary artery stenosis is coronary angiography; however, it could only be performed in a limited proportion of patients (26 of 128 patients, 20.3%) and thus most patients lacked angiographic confirmation, which limits diagnostic certainty in our study cohort. Therefore, additional prospective studies that involve multicenter and multiethnic populations and use coronary angiography are needed to validate our study findings.

In conclusion, the prevalence of significant coronary artery stenosis was high in patients with moderate-to-severe CKD. Carotid maximum-IMT was the primary factor associated with the presence of significant coronary artery stenosis and might be a surrogate marker for significant coronary artery stenosis in these patients.

Acknowledgments

The authors thank all members of the medical staff of Saitama Medical Center and Saitama Central Clinic for their excellent work.

Funding Statement

This study received partial financial support from JSPS KAKENHI (grant number JP24K19151).

Data Sharing Statement

Data underlying the findings of this study can be obtained from the corresponding author upon justified request.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflict of interest in this work.

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Associated Data

Data Availability Statement

Data underlying the findings of this study can be obtained from the corresponding author upon justified request.