Abstract
Aims: To present an update on undiagnosed coronary artery disease (CAD) in patients starting hemodialysis at a Japanese hospital, with a focus on CAD prevalence, risk factors, and coronary lesions’ distribution in this population.
Methods: A cross-sectional, retrospective study of patients who began hemodialysis due to end-stage renal disease (ESRD) in a Japanese hospital between January 2009 and December 2023 and underwent coronary computed tomography (CCT) was carried out. Coronary artery disease was screened using CCT immediately after the initiation of hemodialysis and then confirmed by CCT/coronary angiography (CAG). Based on these evaluations, patients were divided into CAD and non-CAD groups, and their demographic and clinical characteristics were compared. Logistic regression analysis was performed to detect factors associated with CAD. Additionally, variations in CAD prevalence and coronary artery calcification scores (CACS) over time were assessed considering 3-year intervals.
Results: Data from 272 patients were included. CAD was observed in nearly half (47%) of them. Lesions were mainly observed in the left anterior descending artery (73%). The prevalence of a coronary artery calcification score of ＞65 notoriously increased from 2012–2014 to 2015–2017 and thereafter stabilized, while the proportion of patients diagnosed with CAD tended to decrease overall. Multiple regression analysis indicated that only a history of smoking, statin use, low albumin levels, and low HDL-C levels were independently and significantly associated with CAD occurrence in these ESRD patients.
Conclusions: Many well-known CAD risk factors in the general population were not predictors of undiagnosed CAD in our target population.
Introduction
During the course of end-stage renal disease (ESRD), cardiovascular disease is the primary cause of death1-3). In patients with CKD, coronary artery disease (CAD) and heart failure are common4). CAD development in these subjects is mainly attributed to the following factors: progression of arteriosclerosis, hypertension impact, dyslipidemia, calcium and phosphorus metabolic abnormalities, and the effects of renal dysfunction itself1). The combination of these factors is thought to lead to a high prevalence of CAD in patients with CKD. Therefore, CAD and CKD are closely related medical conditions, and adequate cardiovascular risk management is critical in patients with CKD1).
The prevalence of CAD has been reported to be approximately 50% in the hemodialysis population aged ＞65 years5). As kidney function declines, the prevalence of coronary artery lesions increases, making the diagnosis and treatment of CAD more difficult6, 7). In advanced CKD, coronary computed tomography (CCT) and coronary angiography (CAG) are not recommended unless CAD symptoms or a CAD history already exists owing to the risk of contrast nephropathy. Currently, no effective prevention method for contrast nephropathy has been established8). In individuals with CKD, additional CKD-specific factors such as uremia, increased sympathetic activity, and CKD-mineral and bone disease are assumed to accelerate the onset and progression of CAD, acting in addition to the conventional CAD risk factors, including smoking, diabetes mellitus (DM), hypertension, and dyslipidemia9, 10).
On the other hand, CKD modifies the clinical presentation and symptoms of CAD so that many individuals with CKD may present as asymptomatic. It has been reported that, compared with those without kidney disease, patients with CKD are more likely to report shortness of breath and less likely to describe chest pain in the event of acute myocardial infarction (AMI)11). Furthermore, a retrospective cohort study, which drew information from The Third National Registry of Myocardial Infarction and the United States Renal Data System databases, revealed that 44% of hemodialysis patients reported having chest pain, compared with 68% of non-hemodialysis patients12). Because early diagnosis of asymptomatic CAD is difficult in advanced CKD, and CAD treatment in this population is particularly challenging, entailing a prognosis extremely poor7), it is very important to recognize this entity and its clinical characteristics at dialysis initiation when CCT and CAG can be performed relatively safely. To our knowledge, there have been no recent reports on coronary artery lesions in hemodialysis patients, yet the management of CKD and CAD has changed in the last decades.
Aim
We performed a retrospective observational study to present an update on undiagnosed coronary artery disease (CAD) in patients initiating hemodialysis at a Japanese hospital, with a focus on CAD prevalence, risk factors, and coronary lesions’ distribution in this population.
Methods
Study Design and Participants
We conducted a retrospective observational study of patients who began maintenance hemodialysis for ESRD between January 2009 and December 2023 at the Showa University Northern Yokohama Hospital (Yokohama, Japan). Only those who underwent CCT at that time—a decision left to the discretion of the physician and generally based on the patient’s overall condition—were included. Patients with a history of CAD, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), peritoneal dialysis (PD) initiation, or transition from PD were excluded. This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The study protocol was approved by the Ethics Committee for Clinical Research at Showa Medical University (approval number: 2023-141-A). Opt-out consent was obtained from all study participants.
Data Collection
Information on age, sex, smoking habits, type of primary renal illness, and presence of either DM, hypertension, or dyslipidemia was collected during the initial interviews with each patient. We also gathered data on drug use during the pre-dialytic phase of CKD. Blood pressure was taken with the patient in the supine position. The weight (kg) divided by the square of the height (m) yielded the body mass index (BMI) at the optimal weight. All blood samples were collected at a pre-dialysis time point within 2 weeks of dialysis initiation. Laboratory tests were conducted using standardized clinical laboratory methods.
Evaluation of Coronary Artery Stenosis and Calcification Using CCT and CAG
Coronary artery stenosis and calcium scoring scans were obtained using a multidetector row computed tomography scanner (SOMATOM Definition Flash; Siemens Healthcare, Forchheim, Germany). Patients with CAD were defined as those with at least one stenotic lesion of the coronary artery (≥ 75%) on CCT/CAG. CAG was performed when CCT did not provide conclusive information about the presence/absence of stenotic lesions, and the physician judged there were no significant bleeding risks. The coronary artery calcification score (CACS) was calculated using the Agatston method by board-certified diagnostic radiologists, who were blinded to the participants’ identities, as previously reported13). Additionally, we calculated the proportion of patients with CACS ＞65 at the beginning of hemodialysis; the threshold chosen is based on previous experimental data adjusted for the Japanese population14).
Echocardiographic Assessment
Before being discharged, all patients underwent an echocardiography assessment at a dry weight following a dialysis session or on an intermittent day of hemodialysis. Measurements and calculations of heart morphology were obtained from patient records. These measurements included left ventricular ejection fraction using the biplane-modified Simpson method.
Clinical Outcomes
The primary outcome of this study was the prevalence of CAD. After dividing the patients into two groups, CAD and non-CAD, their clinical and echocardiographic characteristics were compared, and simple and multiple logistic regression was conducted to identify risk factors. Additionally, the distribution of the stenotic lesions as a function of the number of vessels compromised was investigated in the CAD group. Data on therapeutic approaches for coronary disease and diabetes mellitus prevalence were also analyzed.
Statistical Analysis
For continuous variables, data are shown as mean±SD; for categorical variables, data are shown as n (%). A t-test was used to compare continuous variables between the CAD and non-CAD groups. The categorical variables were compared using the χ2 test. Simple and multiple logistic regression models were used to evaluate factors related to CAD; the latter included parameters with P＜0.05 in the univariate analysis. Statistical significance was set at P＜0.05. All statistical analyses were performed using R (version 4.3.2) (R Core Team, Vienna, Austria).
Results
Clinical Characteristics
A total of 677 patients began maintenance hemodialysis at our hospital between January 2009 and December 2023; approximately half of them (355/677) underwent CCT as a screening test for preexisting asymptomatic CAD in the relevant period, at the discretion of the physician in charge of each patient (Fig.1). After excluding 83 subjects, data from 272 participants were further analyzed.
Overall, the mean age was 69±13 years; 70% were male, and 57% had DM (Table 1). The most common underlying disease leading to dialysis was diabetic kidney disease, followed by nephrosclerosis, chronic glomerulonephritis, and autosomal dominant polycystic kidney disease. Based on the results of CCT (or CCT plus CAG), these 272 patients were divided into two groups: CAD (n = 128 [47%]) and non-CAD (n = 144 [53%]).
Table 1.Demographic and clinical characteristics of the included participants
| Characteristics |
All |
CAD |
non-CAD |
| n
|
272 |
128 |
144 |
| Age (years), mean±SD |
69±13 |
70±12 |
68±13 |
| Male sex, n (%)
|
190 (70) |
89 (70) |
101 (70) |
| BMI (kg/m2), mean±SD
|
22.4±4.1 |
22.2±4.2 |
22.5±4.1 |
| Smoking, n (%)
|
65 (25) |
34 (27) |
31 (22) |
| DM, n (%)
|
155 (57) |
80 (63) |
75 (52) |
| Hypertension, n (%)
|
246 (90) |
118(92) |
128 (89) |
| Dyslipidemia, n (%)
|
137 (50) |
80 (63) |
57 (40) |
| Causes of hemodialysis, n (%)
|
|
| Diabetic kidney disease |
134 (49) |
68 (53) |
66 (46) |
| Hypertensive kidney disease |
80 (29) |
35 (27) |
45 (31) |
| Chronic glomerular nephritis |
18 (7) |
5 (4) |
13 (9) |
| Polycystic kidney disease |
8 (3) |
0 (0) |
8 (6) |
| Unknown |
8 (3) |
5 (4) |
3 (2) |
| Others |
24 (9) |
15 (12) |
9 (6) |
| LVEF (%), mean±SD |
56±12 |
55±12 |
57±12 |
| Hemoglobin (g/dL), mean±SD |
9.2±1.5 |
9.2±1.4 |
9.3±1.5 |
| Albumin (g/dL), mean±SD |
3.3±0.6 |
3.2±0.6 |
3.4±0.5 |
| Creatinine (mg/dL), mean±SD |
9.0±3.6 |
8.8±3.8 |
9.2±3.4 |
| eGFR (mL/min/1.73 m2), mean±SD
|
5.4±1.9 |
5.6±2.0 |
5.3±1.8 |
| LDL-C (mg/dL), mean±SD |
92.4±32.6 |
95.2±30.4 |
90.0±34.3 |
| HDL-C (mg/dL), mean±SD |
45.1±16.8 |
41.8±14.5 |
48.2±18.1 |
| Calcium (mg/dL), mean±SD |
8.3±1.0 |
8.3±1.1 |
8.3±1.0 |
| Phosphate (mg/dL), mean±SD |
6.4±2.1 |
6.4±2.3 |
6.5±2.0 |
| CRP (mg/dL), mean±SD |
1.7±4.2 |
2.3±5.2 |
1.3±3.0 |
| ESA, n (%)
|
178 (65) |
81 (63) |
97 (67) |
| RAAS inhibitor, n (%)
|
93 (34) |
45 (35) |
48 (33) |
| Statin, n (%)
|
93 (34) |
52 (41) |
41 (29) |
| Aspirin, n (%)
|
53 (20) |
33 (26) |
20 (14) |
| Antiplatelet, n (%)
|
44 (16) |
27 (21) |
17 (12) |
| Vitamin D, n (%)
|
62 (23) |
28 (22) |
34 (24) |
| Calcium carbonate, n (%)
|
72 (27) |
37 (29) |
35 (24) |
| Phosphate binder, n (%)
|
23 (9) |
11 (9) |
12 (8) |
| Calcimimetics, n (%)
|
2 (1) |
1(1) |
1 (1) |
BMI, body mass index; CAD, coronary artery disease; CRP, C-reactive protein; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESA, erythropoiesis-stimulating agent; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; RAAS, renin-angiotensin-aldosterone system.
The clinical characteristics, hemodynamic/laboratory parameters, and medications received by these groups of patients are shown in Table 1 and Supplementary Table 1. The prevalence of dyslipidemia and a history of cerebrovascular disease were higher in the CAD group than in the non-CAD group (63% and 23% vs. 40% and 10%, respectively, P＜0.01). In the CAD group, aspirin and statins were administered more frequently than in the non-CAD group: 26% and 41% vs. 14% and 29%, respectively (P = 0.02 and P = 0.04). No significant differences between groups in the administration of antihypertensive drugs, including renin-angiotensin-aldosterone system inhibitors, were observed. Diastolic blood pressure was lower in the CAD group than in the non-CAD group. Serum albumin and high-density lipoprotein cholesterol (HDL-C) levels were lower in the CAD group than in the non-CAD group: 3.2±0.6 vs. 3.4±0.5 g/dL (P＜0.01) and 41.8±14.5 vs. 48.2±18.1 mg/dL (P＜0.01), respectively.
Supplementary Table 1.Additional clinical and medication data
|
All |
CAD |
non-CAD |
P-value
|
| Systolic blood pressure (mmHg), mean±SD |
140±23 |
138±22 |
142±24 |
0.13 |
| Diastolic blood pressure (mmHg), mean±SD |
72±13 |
70±11 |
73±14 |
0.03 |
| Heart rate (beats/min), mean±SD |
71±10 |
72±10 |
71±11 |
0.39 |
| Cerebrovascular disease, n (%)
|
44 (16) |
29 (23) |
15 (10) |
0.01 |
| Peripheral artery disease, n (%)
|
37 (15) |
23 (19) |
14 (11) |
0.11 |
| Beta blocker, n (%)
|
85 (31) |
43 (34) |
42 (29) |
0.51 |
| Diuretics, n (%)
|
192 (71) |
90 (70) |
102 (71) |
＞0.99 |
| Ezetimibe, n (%)
|
12 (4) |
6 (5) |
6 (4) |
＞0.99 |
| Alpha blocker, n (%)
|
31 (11) |
17 (13) |
14 (10) |
0.47 |
| Calcium channel blocker, n (%)
|
218 (80) |
104 (81) |
114 (79) |
0.78 |
| Iron, n (%)
|
29 (11) |
11 (9) |
18 (13) |
0.40 |
| Uric acid-lowering therapy, n (%)
|
186 (68) |
84 (66) |
102 (71) |
0.43 |
CAD, coronary artery disease.
Most electrocardiogram/echocardiographic parameters (Supplementary Table 2) and all additional laboratory parameters (Supplementary Table 3) did not differ significantly between groups.
Supplementary Table 2.Electrocardiogram and ultrasound cardiography data
|
All |
CAD |
non-CAD |
P-value
|
| Atrial fibrillation, n (%)
|
15 (6) |
8 (6) |
7 (5) |
0.81 |
| Heart-rate corrected QT interval (ms), mean±SD |
441±30 |
441±30 |
441±31 |
0.86 |
| RV5 + SV1 (mm), mean±SD |
3.1±1.2 |
3.1±1.1 |
3.1±1.2 |
0.94 |
| ST-T change, n (%)
|
85 (32) |
45 (35) |
40 (28) |
0.24 |
| Abnormal Q-wave, n (%)
|
1 (0.4) |
1 (0.8) |
0 (0.0) |
0.95 |
| T-wave inversion, n (%)
|
220 (82) |
110 (87) |
110 (77) |
0.06 |
| LVDd (mm), mean±SD |
53±7 |
53±7 |
52±8 |
0.45 |
| LVDs (mm), mean±SD |
37±8 |
38±8 |
36±8 |
0.15 |
| Wall thickness (mm), mean±SD |
10.1±1.6 |
10.1±1.5 |
10.1±1.6 |
0.95 |
| E/e’, mean±SD |
15±6 |
16±7 |
14±6 |
0.03 |
| TRPG (mmHg), mean±SD |
24±8 |
25±9 |
24±7 |
0.20 |
| LVMI (g/m2), mean±SD
|
116±32 |
114±28 |
118±35 |
0.52 |
| Inferior vena cava diameter (mm), mean±SD |
14±4 |
13±4 |
14±4 |
0.07 |
CAD, coronary artery disease; E/e’, early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; LVDd, left ventricular end- diastolic diameter; LVDs, left ventricular end-systolic diameter; LVMI, left ventricular mass index; TRPG, tricuspid regurgitant pressure gradient.
Supplementary Table 3. Additional laboratory data
|
All |
CAD |
non-CAD |
P-value
|
| Total protein (g/dL) |
6.3±0.7 |
6.2±0.7 |
6.3±0.8 |
0.13 |
| Blood urea nitrogen (mg/dL) |
89.6±28.9 |
89.8±29.1 |
86.4±28.8 |
0.91 |
| Uric acid (mg/dL) |
7.2±2.2 |
7.4±2.2 |
7.0±2.1 |
0.12 |
| Potassium (mEq/L) |
4.7±0.9 |
4.7±0.9 |
4.8±0.9 |
0.51 |
| Lactate dehydrogenase (mg/dL) |
289±246 |
276±109 |
300±322 |
0.43 |
| Creatine kinase (mg/dL) |
313±660 |
297±402 |
327±830 |
0.71 |
| Triglycerides (mg/dL) |
134±100 |
137±77 |
132±118 |
0.66 |
| Transferrin saturation (%) |
26.6±15.0 |
25.3±14.5 |
27.7±15.4 |
0.19 |
| Ferritin (ng/mL) |
310±1 588 |
234±235 |
378±2 172 |
0.46 |
| Bicarbonate (mmol/L) |
19.3±4.1 |
19.4±4.4 |
19.2±4.0 |
0.69 |
| Intact parathyroid hormone (pg/mL) |
343±226 |
333±240 |
351±214 |
0.51 |
| Urinary protein quality |
2.8±0.8 |
2.8±0.8 |
2.7±0.8 |
0.50 |
| eGFR slope (mL/min/1.732/year)
|
-8.0±6.2 |
-8.5±6.1 |
-7.5±6.2 |
0.29 |
All data express mean±SD. CAD, coronary artery disease; eGFR, estimated glomerular filtration rate.
Coronary artery evaluation was performed using CCT; CACS scores are shown in Table 2. The CAD group had a 3-fold higher total CACS score (1,290±1,652) than the non-CAD group (390±665), P＜0.001. In all coronary segments, a significantly higher calcification degree was observed in the CAD group compared with the non-CAD group. Coronary artery calcification reached the highest values in the right coronary artery (RCA) in the CAD group and the left anterior descending (LAD) artery in the non-CAD group. Coronary artery calcification was least common in the left circumflex (LCx) artery and the left main trunk (LMT) artery in both groups (Table 2).
Table 2.Coronary artery calcification
a
| Artery |
All |
CAD |
non-CAD |
P-value
|
| LAD |
282±412 |
397±419 |
192±385 |
＜0.001 |
| RCA |
336±928 |
635±1 329 |
106±220 |
＜0.001 |
| LCx |
124±224 |
189±250 |
74±188 |
＜0.001 |
| LMT |
42±104 |
74±140 |
17±51 |
＜0.001 |
| Total |
782±1 277 |
1 290±1 652 |
390±665 |
＜0.001 |
aCoronary artery calcification was measured using the Agatston method11). Data are presented as mean±SD. CAD, coronary artery disease; LAD, left anterior descending; LCx, left circumflex; LMT, left main trunk; RCA, right coronary artery.
Based on CCT results, 90/272 participants (33%) underwent CAG, and 127/272 (47%) were confirmed to have coronary stenosis. Participants in the CAD group had an average of 1.7 coronary stenotic lesions. The lesions were mainly found in the LAD artery (73% of CAD patients), followed by the RCA and the LCx; much less frequently, lesions were in the LMT arteries (Table 3).
Table 3. Distribution of coronary artery disease
| Artery |
Participants, n (%) a
|
| LAD |
94 (73) |
| RCA |
63 (49) |
| LCx |
56 (44) |
| LMT |
5 (4) |
aPatients with CAD. LAD, left anterior descending; LCx, left circumflex; LMT, left main trunk; RCA, right coronary artery.
Most patients diagnosed with CAD underwent optimal medical therapy (OMT) or percutaneous coronary intervention (PCI): 59 subjects (46%) each; only 7% received coronary artery bypass grafting (Fig.2). PCI tended to be the treatment of choice among patients with DM.
To further explore the relationship between the number of diseased vessels and other variables, patients were grouped according to this outcome (Fig.2 and Supplementary Table 4). As the number of diseased vessels increased, so did the proportion of patients with DM among those undergoing PCI or CABG. Approximately 50% of total patients with CAD had one-vessel disease (1DV); none of them underwent CABG (Fig.2). In this subset of patients, CAD was more common in the LAD, and PCI was frequently performed in the LAD and RCA, whereas all patients with diseased LCx received OMT exclusively (Supplementary Table 4). In patients with two-vessel disease (2DV), PCI was most frequently performed if LAD was compromised.
Supplementary Table 4.Details of coronary artery disease presentation and medical management
|
1VD (64 patients) |
|
LAD
n = 42 (66%) [22]
|
RCA
n = 16 (25%) [9]
|
LCx
n = 6 (9%) [3]
|
| OMT |
21 (50%) [8] |
6 (38%) [3] |
6 (100%) [3] |
| PCI |
21 (50%) [14] |
10 (63%) [6] |
— |
| CABG |
— |
— |
— |
|
2VD (37 patients) |
|
LAD + RCA
n = 415 (41%) [10]
|
LAD + LCx
n = 413 (35%) [8]
|
RCA + LCx
n = 9 (24%) [7]
|
| OMT |
6 (40%) [2] |
4 (31%) [2] |
6 (67%) [5] |
| PCI |
7 (47%) [6] |
8 (62%) [6] |
2 (22%) [2] |
| CABG |
2 (13%) [2] |
1 (8%) [0] |
1 (11%) [0] |
CABG, coronary artery bypass graft; CAD, coronary artery disease; LAD, left anterior descending; LCx, left circumflex; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCA, right coronary artery; 1VD, one-vessel disease; 2VD, two-vessel disease. Numbers in italics between square brackets indicate the number of patients with diabetes mellitus.
We investigated the changes in the prevalence of CAD and CACS over time through 3-year intervals (Table 4). The proportion of patients with a history of CAD did not change significantly over time, ranging from 13 to 18%. The CACS demonstrated an increasing trend over time, with the most pronounced increase between the second and the third 3-year interval. The proportion of patients with a CACS of ＞65 also increased with time, with a 2-fold increase from the second to the third 3-year interval and stabilizing thereafter at about 50%. Despite this, the proportion of patients diagnosed with CAD tended to decrease over time.
Table 4. Time course of coronary artery disease and coronary artery calcification
|
2009–2011 |
2012–2014 |
2015–2017 |
2018–2020 |
2021–2023 |
| Total, n
|
19 |
68 |
73 |
86 |
108 |
| History of CAD, n (%)
|
3 (16) |
10 (15) |
13 (18) |
11 (13) |
17 (16) |
| Diagnosis of CAD, n (%)
|
9 (47) |
31 (46) |
19 (26) |
34 (40) |
35 (32) |
| CACS, median (IQR) |
– |
182 (841) |
331 (1 087) |
286 (985) |
413 (1 096) |
| CACS of ＞65, n (%)
|
– |
18 (26) |
36 (49) |
46 (53) |
54 (50) |
CAD, coronary artery disease; CACS, coronary artery calcification score; IQR, interquartile range.
The factors possibly associated with CAD were initially examined using simple logistic regression. As shown in Table 5, in the univariate analysis, significant associations between the presence of CAD and the following factors (odds ratio [95% confidence interval]) were found: history of smoking (1.820 [1.097–3.020]), P = 0.02; diastolic blood pressure (0.978 [0.959–0.998]), P = 0.029; statin use (1.719 [1.037–2.849]), P = 0.036; albumin (0.472 [0.300–0.742]), P = 0.001), HDL-C (0.974 [0.957–0.990]), P = 0.002; and T-wave inversion in the electrocardiogram (1.941 [1.021–3.689]), P = 0.043. In the multiple regression analysis conducted subsequently, only a history of smoking (2.14 [1.13–4.06]), P = 0.02; statin use (1.84 (1.01–3.36]), P = 0.04; low albumin levels (0.55 [0.32–0.96]), P = 0.03; and low HDL-C levels (0.97 [0.96–0.99]), P = 0.01 were independently and significantly associated with CAD.
Table 5. Logistic regression analysis of factors associated with coronary artery disease prevalence in patients with end-stage renal disease initiating hemodialysis
|
Univariate analysis |
Model 1 a
|
Model 2 b
|
| OR |
95% CI |
P-value
|
OR |
95% CI |
P-value
|
OR |
95% CI |
P-value
|
| Age |
1.01 |
0.99–1.03 |
0.21 |
1.05 |
0.99–1.04 |
0.19 |
1.01 |
0.98–1.04 |
0.47 |
| Male sex |
1.03 |
0.61–1.73 |
0.91 |
0.99 |
0.57–1.7 |
0.96 |
1.18 |
0.58–2.37 |
0.65 |
| BMI |
0.98 |
0.93–1.04 |
0.59 |
1 |
0.93–1.06 |
0.87 |
0.96 |
0.89–1.04 |
0.29 |
| Smoking history |
1.82 |
1.10–3.02 |
0.02 |
– |
– |
– |
2.14 |
1.13–4.06 |
0.02 |
| DM |
1.53 |
0.94–2.49 |
0.08 |
1.63 |
0.99–2.68 |
0.05 |
1.18 |
0.66–2.13 |
0.57 |
| Hypertension |
1.48 |
0.64–3.38 |
0.36 |
– |
– |
– |
1.39 |
0.54–3.57 |
0.50 |
| Systolic blood pressure |
0.99 |
0.98–1.00 |
0.13 |
– |
– |
– |
1 |
0.98–1.01 |
0.57 |
| Diastolic blood pressure |
0.98 |
0.96–1.00 |
0.03 |
– |
– |
– |
0.99 |
0.96–1.02 |
0.37 |
| RAAS inhibitor |
1.08 |
0.66–1.79 |
0.75 |
– |
– |
– |
1.07 |
0.58–1.97 |
0.83 |
| Statins |
1.72 |
1.04–2.85 |
0.04 |
– |
– |
– |
1.84 |
1.01–3.36 |
0.04 |
| Hemoglobin |
0.98 |
0.83–1.15 |
0.78 |
– |
– |
– |
– |
– |
– |
| Albumin |
0.47 |
0.30–0.74 |
0.001 |
– |
– |
– |
0.55 |
0.32–0.96 |
0.03 |
| Corrected calcium |
1.02 |
0.81–1.29 |
0.89 |
– |
– |
– |
0.92 |
0.69–1.24 |
0.60 |
| Phosphate |
0.97 |
0.87–1.09 |
0.64 |
– |
– |
– |
0.94 |
0.81–1.09 |
0.41 |
| CRP |
1.06 |
1.00–1.14 |
0.06 |
– |
– |
– |
1.03 |
0.96–1.11 |
0.36 |
| LDL-C |
1.01 |
1.00–1.01 |
0.20 |
– |
– |
– |
1.01 |
1–1.02 |
0.06 |
| HDL-C |
0.97 |
0.96–0.99 |
0.002 |
– |
– |
– |
0.97 |
0.96–0.99 |
0.01 |
| Intact parathyroid hormone |
1 |
1.00–1.00 |
0.50 |
– |
– |
– |
– |
– |
– |
| Urinary protein quality |
1.11 |
0.82–1.49 |
0.50 |
– |
– |
– |
– |
– |
– |
| T-wave inversion |
1.94 |
1.02–3.69 |
0.04 |
– |
– |
– |
– |
– |
– |
| LVEF |
0.98 |
0.96–1.00 |
0.09 |
– |
– |
– |
– |
– |
– |
| LVMI |
1 |
1.00–1.01 |
0.39 |
– |
– |
– |
– |
– |
– |
| Inferior vena cava |
0.94 |
0.88–1.01 |
0.07 |
– |
– |
– |
– |
– |
– |
| eGFR slope |
0.97 |
0.93–1.02 |
0.29 |
– |
– |
– |
– |
– |
– |
a Multiple logistic regression analysis, including age, sex, BMI, and DM; b Multiple logistic regression analysis, including Model 1 + smoking history, hypertension, systolic blood pressure, diastolic blood pressure, RAAS inhibitor, statins, albumin, corrected calcium, phosphate, CRP, LDL- C, and HDL-C.
BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HDL- C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; OR, odds ratio; RAAS, renin-angiotensin-aldosterone-system.
Discussion
In this retrospective, single-center, observational study, we aimed to know the prevalence of undiagnosed CAD among asymptomatic patients beginning hemodialysis due to CKD and to understand the epidemiology of this condition over time in our hospital. This assessment focused on Japanese patients who initiated hemodialysis from 2009 to 2023 and relied on data from 272 subjects. We found that 47% of these patients fulfilled the definition of CAD according to CCT/CAG evaluations. CAD was more prevalent in the LAD artery (73%) than in the other coronary arteries. In our study, the proportion of patients with CACS ＞65 increased over time, while the proportion of patients diagnosed with CAD tended to decrease. It is possible that the widespread prescription of statins in persons at increased risk of CAD (such as CKD patients) has been highly successful in the prevention of cholesterol plaque formation, but, at the same time, it may have increased coronary calcification, as reported before in connection with the so-called and controversial “coronary plaque calcium “paradox”15, 16).
Previous studies have shown that in patients with CKD, advanced atherosclerotic lesions are already present at dialysis initiation. In a study published in 1997, Joki et al.17) reported a prevalence of CAD of 62.5% in asymptomatic patients who underwent CAG at the initiation of hemodialysis, a value greater than that found in this analysis. Contrasting with our findings, additionally, most patients in that cohort (73%) had multivessel disease, and the average number of stenotic lesions per patient was about two-fold higher (3.3), suggesting that the overall medical management of CKD in Japan may have improved during the last decades so that the cardiac health of these subjects deteriorates at a slower rate. In a study published in 2005, Ohtake et al.18) reported a prevalence of coronary artery stenosis evaluated through CAG of 53.3% in a small cohort of asymptomatic patients who initiated dialysis between January 2002 and December 2003 in Shonan Kamakura General Hospital. In this study, we calculated an overall prevalence slightly lower for the entire period (47%) but notably lower for the 2021–2023 subperiod (32%).
The management of CAD in individuals with CKD is challenging because of the burden of comorbidities and potential adverse effects during treatment7). Other uremia-related cardiovascular risk factors, such as inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism, usually exist in these subjects, in addition to the presence of typical CAD risk factors (DM, hypertension)9, 10). It was reported that patients with asymptomatic coronary artery lesions have a high incidence of adverse events after dialysis initiation19).
The early diagnosis of asymptomatic coronary artery stenosis in this population is crucial to prevent cardiovascular events and death. When a dialysis patient develops AMI, the prognosis is extremely poor, and the rate of cardiovascular death increases over time from the first year after onset20). Based on these considerations, CCT should ideally be performed in any patient with ESRD initiating hemodialysis unless contraindicated. Among the reasons for which CAD commonly presents asymptomatically in CKD patients, the presence of anemia, reduced vasodilator reserve, microvascular disease, and autonomic dysfunction secondary to uremia and DM have been cited21). Therefore, dialysis patients need to be considered a high-risk group for CAD, and the active screening of them for CAD is highly recommended.
Coronary artery calcification helps medical practitioners make decisions on primary prevention22). This condition is prevalent among patients with CKD and poor prognosis23). Higher serum calcification-propensity was linked to more severe coronary artery calcification and progression in patients with CKD stages 2–4 24). Inflammation and calcium and phosphate metabolic disorders may contribute to the advancement of coronary artery calcification in CKD25).
According to baseline data from the ISCHEMIA trial, which enrolled more than 8,500 subjects with stable ischemic heart disease, coronary artery lesions mainly occur in the LAD artery (87%)26). This was ascribed to the following interconnected events: 1) the LAD artery supplies most of the heart, for which the blood flow is high; 2) LAD is a relatively long segment and passes through a complicated route, contributing to larger blood flow; and 3) the flow inside LAD is turbulent, so there is an increased burden on the blood vessel wall.
A cross-sectional investigation conducted at a Saitama Sekishinkai Hospital found that LAD was the most affected segment in stage 1 CKD (57% of patients), followed by RCA (26%), but the prevalence of RCA lesions rose considerably as CKD worsened so that it reached 31%, 38%, and 59% in CKD 3, 4, and 5, respectively, overpassing LAD prevalence in stage 5 27). Differences in shear-stress forces due to variations in the shape and size of the arteries affected by calcification and metabolic disturbances might explain these findings28).
We found that the proportion of patients with coronary artery calcification tended to increase over time; however, the proportion of those having coronary stenosis at the time of initiating hemodialysis tended to decrease. This last finding is in line with the results published by Iwasaki
et al.29).
in 2014, who reported that the prevalence of undetected CAD has notoriously declined from 69% in 1993 to 25% in 2010 in patients with ESRD. Those authors indicated that advancements in the treatment of CKD may have reduced the incidence of coronary atherosclerosis29). On the other hand, a global analysis of the evolution of heart disease across the 20th century indicates that primary and secondary prophylaxis became central factors in the decline of acute myocardial infarction (AMI) and sudden cardiac death rates from the mid-1960s30).
Among a large set of clinical and laboratory parameters comparatively examined (CAD vs. non-CAD patients) in this study, only a smoking history, statin use, low albumin levels, and low HDL-C levels were significantly associated with coronary lesions presence. According to different reports, low serum albumin levels are associated with an increased risk of myocardial infarction, CAD, stroke, and poor clinical outcomes in patients with CAD31-35). On the other hand, patients with lower serum albumin levels had a higher prevalence of CKD36).
Nevertheless, the role of HDL-C in CAD is still controversial37-39). HDL-C is said to have pleiotropic effects, including the removal of cholesterol from peripheral tissues (reverse cholesterol transfer), as well as anti-apoptotic and anti-inflammatory effects, and to contribute to vasorelaxation and foam cell reduction40). Lower BMI, lower HDL-C, and higher C-reactive protein (CRP) were significantly associated with undiagnosed CAD in ESRD patients in the study by Iwasaki et al.29), whereas DM and fibrinogen were significant and independent risk factors for CAD in asymptomatic CKD patients starting hemodialysis in another study18). In this cohort, DM was not identified as a significant risk factor, but it strongly influenced CAD medical management decisions. In our logistic regression analysis of a similar population, C-reactive protein (CRP) tended to be an independent risk factor for CAD. Because albumin-to-fibrinogen ratio (AFR) and the C-reactive protein-to-albumin ratio (CAR) are recognized as markers of systemic inflammation41), it is possible to speculate that inflammation may contribute to the onset of CAD in these subjects.
Our results tend to confirm previous reports indicating that standard cardiac risk-prediction methods in patients with ESRD may have limited performance and deserve a critical reexamination42). The effects of typical risk factors such as dyslipidemia, hypertension, and DM appear to be altered by ESRD, becoming less useful in predicting an increased likelihood of sudden death and heart failure, for which new risk models may be needed for ESRD7).
To our knowledge, this is the first long-term retrospective study covering the totality of the previous decade in a Japanese hospital and including a relevant number of ESRD patients examined for asymptomatic CAD at the beginning of hemodialysis. Thus, it constitutes a valuable update on this challenging comorbidity in persons with advanced CKD in our country. We consider this its main strength. Additional strengths are that coronary calcification was also followed over time and that the coronary segments and the number of vessels compromised were determined, along with the number of lesions per patient, thus providing a detailed description of the characteristics of CAD in this population.
Among the limitations of this study, we consider the most relevant that the decision to perform CCT before starting hemodialysis was at the discretion of the physician in charge of each patient. It is possible that the patient’s overall condition and the risk of contrast nephropathy were the determinant factors for which about half of the persons starting hemodialysis at our institution did not undergo a screening CCT. Based on this hypothesis, we recognize that the 272 patients here analyzed probably constitute a biased subset of ESRD patients less deteriorated, for which our results should not be extrapolated to the totality of the ESRD population. Nevertheless, their renal function was impaired enough to be prescribed with hemodialysis sessions, so they are still representative of the target medical condition. As additional limitations of this study, it is worth mentioning that causality relations cannot be established due to its cross-sectional, retrospective nature, its single-center design and sample size, which do not allow generalizations, and that other unconsidered variables may have impacted the results.
Conclusion
CAD and CKD are closely related conditions, and adequate cardiovascular risk management of patients with ESRD initiating hemodialysis is critical. In this 14-year assessment performed in a single hospital and based on data from more than 270 eligible patients who underwent CCT, the prevalence of asymptomatic CAD showed a decreasing trend from the middle of the previous decade, probably due to improved medical management and better access to prophylactic therapies. Interestingly, coronary artery calcification levels tended to increase, and in people with CAD, the right coronary artery was the one showing the greatest calcification degree. Among a large set of well-established CAD predictors examined, only smoking history, statin use, low albumin levels, and low HDL-C levels were significantly associated with the presence of CAD. Multi-center studies involving a higher number of patients are needed to validate these interesting findings and to understand their actual clinical significance.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of Interests
HS received personal fees from Kyowa Kirin Co. Ltd., Mochida Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Toa Eiyo Ltd., Novartis Pharma, Mitsubishi Tanabe Pharma Corp., Astellas Pharma Inc., and Kowa Co. Ltd. KY received personal fees from Kyowa Kirin Co. Ltd. and Novartis Pharma. HO received personal fees from Kyowa Kirin Co. Ltd. and AstraZeneca. All other authors have nothing to disclose.
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