ABSTRACT
Introduction
Little is known about the effect of cardiac rehabilitation (CR) on cardiovascular events in patients with advanced chronic kidney disease (CKD).
Methods
We performed a retrospective cohort study in 189 patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 who were referred to our outpatient CR center. They were divided into two groups according to whether they participated in CR or not, and compared for major adverse cardiovascular events (MACEs) incidences.
Results
There were 143 that participated in CR and 46 that did not. The cumulative MACE rates in the participation group were lower than in the non‐participation group (48% vs. 61%, p = 0.015). The hazard ratio for all‐cardiovascular events in the participation group as compared to the non‐participation group after adjusting for confounders was 0.56 (95% CI, 0.35–0.89, p = 0.014).
Conclusion
CR might reduce MACEs in patients with advanced CKD.
Keywords: advanced chronic kidney disease, cardiac rehabilitation, major adverse cardiovascular event
1. Introduction
It is widely known that cardiac rehabilitation (CR) [1], a comprehensive disease management program that includes exercise training at appropriate exercise levels and nutritional and medication guidance, could not only improve the coronary risk factors [2] and exercise capacity [3], but could also reduce cardiovascular events [4] in patients with cardiovascular disease (CVD). In the guidelines of many countries, CR is positioned as a recommended Class I therapy for CVD patients and should be strongly administered [1, 5, 6]. Furthermore, there have been some recent reports, including our study [7], that CR also improves coronary risk factors and exercise capacity in patients with chronic kidney disease (CKD) [8], including those on dialysis. In patients with advanced CKD, we have previously reported that CR improves the coronary risk factors and exercise capacity [9]. Another of our studies reported that CR might also improve kidney function in CKD patients [7]. However, little is known about the effects of CR on cardiovascular events and death in patients with advanced CKD. It is generally known that the worse the kidney function, the more likely it is for the patient to develop cardiovascular events [10]. In addition, cardiac disease is the leading cause of death in patients with end‐stage renal failure, accounting for almost 50% of deaths in patients in the United States [11]. In other words, patients with advanced CKD could be a high‐risk population for cardiovascular events. Therefore, there should be an urgent need to find a treatment that can reduce cardiovascular events in patients with advanced CKD.
To address the knowledge gap in the literature, we aimed to evaluate the effect of CR on cardiovascular events in patients with advanced CKD. In addition, we also investigated the association between participation in CR and the occurrence of cardiovascular events.
2. Materials and Methods
2.1. Study Design and Participants
This is a single‐center retrospective cohort study using data from patients who were admitted to the Tokai University Hachioji Hospital for the evaluation and treatment of CVD and referred to our outpatient CR center from April 2014 to June 2022. Among the CVD patients who were referred to the center, we identified patients with advanced CKD (estimated glomerular filtration rate based on serum creatinine concentration [eGFRcr] of less than 30 mL/min/1.73 m2) [12], including CKD patients with dialysis.
All data were abstracted from the medical records in the hospital. All names and identifiers were removed before any data were analyzed. The patients' medical records were retrospectively reviewed, and the investigational items were collected, including the age, sex, body mass index, underlying cardiovascular diseases (ischemic heart disease, non‐ischemic heart failure, and post‐cardiac surgery), coronary risk factors (smoking, hypertension, diabetes mellitus, and dyslipidemia), current medications (angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers, beta‐blockers, diuretics, and antihyperlipidemic drugs), blood examinations (triglyceride, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, HbA1c, brain natriuretic peptide [BNP], hemoglobin, albumin, C‐reactive protein, serum creatinine concentration [Scr], eGFRcr, estimated glomerular filtration rate based on serum cystatin C [eGFRcys], CKD Grade [G4, G5, and dialysis]), echocardiographic findings (left atrial diameter, left ventricular end‐diastolic diameter, and left ventricular ejection fraction, left ventricular inflow velocity waveform E wave/early mitral annular motion velocity waveform e′ of left ventricular septal dilatation [E/e′]), session attendance (amount of exercise during the CR at the outpatient visit), and percentage of patients who participated in nutritional guidance, medication education, and attending an educational class of cardiopulmonary resuscitation. All values were collected at the outpatient CR referral except for the session attendance, nutritional guidance, medication education, and attending an educational class of cardiopulmonary resuscitation. We divided them into participation and non‐participation groups and used our medical records to extract any major adverse cardiovascular events (MACEs) from them.
This study conformed to the principals set forth in the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) at Tokai University. All patients provided informed consent.
2.2. Primary Outcomes
The primary endpoint of this study was the occurrence of MACE. MACEs in this study were defined as all‐cause death, heart failure hospitalizations, coronary or peripheral artery revascularizations, or cerebrovascular disease. We collected all the MACE information from our medical records, and the observation period for the patient was from the reservation date referred to our outpatient CR center to the date we could verify the presence or absence and details of the event in our medical records.
2.3. Outpatient Cardiac Rehabilitation Program
The CR program is an outpatient comprehensive program including exercise training, nutritional guidance, medication education, and attending an educational class of cardiopulmonary resuscitation according to the Guidelines for Rehabilitation in Patients with Cardiovascular Disease [13]. For the supervised exercise training, the physiotherapists instructed the patients in the most appropriate aerobic exercises, including walking or bicycle ergometer exercise for 20 min and resistance training for 20 min/lesson in the rehabilitation room. The intensity of the aerobic exercise was determined individually at the heart rate during the anaerobic threshold level obtained by a symptom‐limited cardiopulmonary exercise test or at a level from 11 to 13 of the 6 to 20 scale training rating (original Borg Rating of Perceived Exertion Scale [14, 15]). The patients were also instructed to do aerobic exercise at the prescribed heart rate or resistance training for 30–60 min, 3–7 times a week at home. Nutritional guidance was provided individually or in groups to those who requested it, regardless of whether they participated in CR. Medication education and an educational class of cardiopulmonary resuscitation were provided in groups to those who participated in CR and requested it.
2.4. Statistical Analysis
Data are presented as the mean ± SD, median (quartiles) or number (%). We used a non‐paired t‐test for comparisons of continuous variables and a chi‐square test for comparisons of categorical variables between the two groups. First, the event‐free survival calculated by the Kaplan–Meier method was compared between the two groups using log‐rank statistics. Next, the effect on the MACE occurrence, as measured by a hazard ratio for the participation group as compared to the non‐participation group, was estimated with the use of a Cox regression analysis. Then, we added the confounding factors: age, sex, patient comorbidities (angina pectoris, myocardial infarction, and silent myocardial ischemia), and BNP [16] at the CR referral to adjust this analysis.
All tests were assessed at a level of significance of a p value of < 0.05. The statistical analyses were performed using SPSS, version 16 software (SPSS Inc.).
3. Results
3.1. Characteristics of the Study Patients
The baseline characteristics of the study population are shown in Table 1. We were able to enroll 189 patients that met the enrollment criteria. Of the enrolled patients, there were 143 patients that participated in the CR (participation group, 76%) and 46 did not (non‐participation group, 24%) (Figure 1). The reasons for no CR participation are described in Table 2.
TABLE 1.
The baseline characteristics of 189 patients with an eGFRcr of less than 30 mL/min/1.73 m2 referred to our outpatient CR center.
| Variables | Overall (n = 189) | Participation group (n = 143) | Non‐participation group (n = 46) | p |
|---|---|---|---|---|
| Patient demographics | ||||
| Age, years | 76 (67, 81) | 75 (65, 80) | 78 (70, 83) | 0.079 |
| Men/women | 128 (68%)/61 | 91 (64%)/52 | 37 (80%)/9 | 0.034 |
| Body mass index, kg/m2 | 21.5 (19.4, 24.2) | 21.3 (19.4, 24.1) | 21.7 (19.4, 24.1) | 0.905 |
| Underlying cardiovascular diseases | ||||
| Ischemic heart disease | 119 (63%) | 86 (60%) | 33 (72%) | 0.156 |
| Non‐ischemic heart failure | 41 (22%) | 34 (24%) | 7 (15%) | 0.221 |
| Post‐cardiac surgery | 53 (28%) | 43 (30%) | 10 (22%) | 0.346 |
| Coronary risk factors | ||||
| Smoking (current and ever) | 122 (65%) | 92 (64%) | 30 (65%) | 0.913 |
| Hypertension | 134 (71%) | 105 (73%) | 29 (63%) | 0.177 |
| Diabetes mellitus | 95 (50%) | 75 (52%) | 20 (43%) | 0.290 |
| Dyslipidemia | 95 (50%) | 71 (50%) | 24 (52%) | 0.766 |
| Current medications | ||||
| ACE‐I/ARBs | 73 (39%) | 60 (42%) | 13 (28%) | 0.097 |
| β‐Blockers | 115 (61%) | 93 (65%) | 22 (48%) | 0.038 |
| Diuretics | 90 (48%) | 69 (48%) | 21 (46%) | 0.759 |
| Antihyperlipidemic drugs | 129 (68%) | 95 (66%) | 34 (74%) | 0.343 |
| Blood examinations at the beginning of CR | ||||
| Triglyceride (casual), mg/dL | 119 (87, 158) | 124 (88, 165) | 106 (77, 132) | 0.017 |
| LDL‐Chol, mg/dL | 81 (64, 103) | 87 (67, 107) | 67 (60, 85) | 0.005 |
| HDL‐Chol, mg/dL | 50 (43, 61) | 50 (43, 61) | 48 (44, 57) | 0.484 |
| HbA1c, % | 5.9 (5.6, 6.5) | 5.9 (5.6, 6.4) | 5.9 (5.6, 6.5) | 0.407 |
| BNP, pg/mL | 313 (116, 628) | 268 (106, 607) | 402 (180, 799) | 0.125 |
| Hemoglobin, g/dL | 11.0 (10.1, 12.1) | 11.2 (10.3, 12.2) | 10.8 (10.1, 12.0) | 0.160 |
| Albumin, g/dL | 3.6 (3.4, 3.9) | 3.6 (3.4, 3.9) | 3.7 (3.4, 3.9) | 0.741 |
| C‐reactive protein, mg/dL | 0.250 (0.086, 0.663) | 0.234 (0.077, 0.611) | 0.368 (0.118, 0.773) | 0.520 |
| Scr, mg/dL | 3.01 (1.96, 6.12) | 2.96 (1.95, 6.05) | 3.52 (2.04, 6.61) | 0.886 |
| eGFRcr, mL/min/1.73 m2 | 14.3 (7.1, 24.2) | 14.6 (7.0, 24.9) | 12.2 (7.2, 22.9) | 0.787 |
| eGFRcr excluding HD, mL/min/1.73 m2 | 22.8 (20.0, 27.2) | 22.9 (19.3, 27.4) | 22.8 (21.2, 26.4) | 0.680 |
| eGFRcys, mL/min/1.73 m2 (n = 171) | 15.1 (4.9, 22.7) | 15.1 (5.0, 22.9) | 15.0 (4.6, 21.2) | 0.855 |
| eGFRcys excluding HD, mL/min/1.73 m2 (n = 102) | 21.7 (16.9, 26.4) | 21.9 (17.6, 26.1) | 20.1 (16.2, 26.4) | 0.359 |
| CKD grade | ||||
| G4 | 93 (49%) | 71 (50%) | 22 (48%) | 0.830 |
| G5 | 96 (51%) | 72 (50%) | 24 (52%) | 0.830 |
| Dialysis | 82 (43%) | 61 (43%) | 21 (46%) | 0.721 |
| Echocardiographic findings at the beginning of CR (n = 188) | ||||
| LAD, mm | 45 (40, 49) | 45 (40, 49) | 47 (41, 51) | 0.703 |
| LVDd, mm | 50 (45, 55) | 50 (45, 55) | 51 (46, 56) | 0.452 |
| LVEF, % | 53 (36, 60) | 53 (36, 60) | 54 (41, 59) | 0.561 |
| E/e′ (n = 148) | 14.1 (11.2, 18.5) | 13.9 (11.1, 17.9) | 14.4 (12.3, 19.9) | 0.730 |
| Cardiopulmonary exercise testing at the beginning of CR (n = 109) | ||||
| Peak oxygen uptake | — | 13.0 (11.5, 14.6) | — | |
| Anaerobic threshold | — | 9.9 (8.7, 11.0) | — | |
| Session attendance, times/3 months | — | 5 (3, 8) | — | |
| Nutritional guidance | 125 (66%) | 99 (69%) | 26 (57%) | 0.113 |
| Medication education | — | 65 (45%) | — | |
| Educational class of cardiopulmonary resuscitation | — | 62 (43%) | — | |
Note: Values are presented as median (quartiles) or n (%).
Abbreviations: ACE‐I, angiotensin‐converting‐enzyme inhibitor; ARB, angiotensin II receptor blocker; BNP, brain natriuretic peptide; CKD, chronic kidney disease; CR, cardiac rehabilitation; E/e′, left ventricular inflow velocity waveform E wave/early mitral annular motion velocity waveform e′ of left ventricular septal dilatation; eGFRcr, estimated glomerular filtration rate based on serum creatinine concentration; eGFRcys, estimated glomerular filtration rate based on serum cystatin C; HD, hemodialysis; HDL‐Chol, high density lipoprotein cholesterol; LAD, left atrial diameter; LDL‐Chol, low density lipoprotein cholesterol; LVDd, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction; Scr, serum creatinine concentration.
FIGURE 1.
Flow diagram of participants in this study. CR, cardiac rehabilitation; eGFRcr, estimated glomerular filtration rate based on serum creatinine concentration.
TABLE 2.
The reasons for no CR participation in the non‐participation group.
| Variables | No‐participation group (n = 46) |
|---|---|
| Poor general condition | 11 (24%) |
| Decompensated heart failure | 3 (7%) |
| Unstable ischemic heart diseases | 2 (4%) |
| Hematologic diseases | 2 (4%) |
| Aortic aneurysm | 1 (2%) |
| Lower extremity ulcer | 1 (2%) |
| Orthopedic disease | 1 (2%) |
| Pleural effusion | 1 (2%) |
| His/her own will | 11 (24%) |
| Underwent rehabilitation programs at other facilities (non‐CR program) | 7 (15%) |
| Long distance from home | 4 (9%) |
| Too busy (dialysis, etc.) | 3 (7%) |
| Too high age | 2 (4%) |
| Unknown | 8 (17%) |
Abbreviation: CR, cardiac rehabilitation.
Overall, the median age was 76 years, and 68% (128/189) were male. The underlying cardiovascular diseases were ischemic heart disease in 119, non‐ischemic heart failure in 41, and post‐cardiac surgery in 53 patients, respectively. The 40 patients had overlapping diagnoses above. More than half of these patients had multiple coronary risk factors. However, the control of the risk factors before the CR was relatively good (within normal range for the serum triglycerides, cholesterol, and HbA1c). The left ventricular systolic function in the participants was preserved. The patients in the participation group attended our CR program a median of 5 times over a 3‐month period. With regard to kidney function, 93 patients (93/189, 49%) were grade G4 (severe grade of CKD), and 96 patients (51/189, 51%) were grade G5 (kidney failure of CKD). Of the 96 patients with CKD G5, 82 were on hemodialysis.
Comparing the two groups, the participation group had more women and higher levels of triglycerides and low‐density lipoprotein cholesterol than the non‐participation group.
3.2. Changes in CVD Risks, Echocardiographic Findings, and Renal Function After CR
Changes in CVD risks, echocardiographic findings, and renal function after CR are shown in Table 3. HDL‐Chol was significantly increased in both groups. Hemoglobin improved in the participation group but not in the non‐participation group. eGFRcys also improved in the participation group. Note that eGFRcys was measured in very few cases in the non‐participation group before and after CR, so it is not included in Table 3. The echocardiographic findings showed no significant changes before and after CR in both groups.
TABLE 3.
The changes in the biomarkers and echocardiographic findings between the beginning and end of the CR.
| Overall | Participation group | Non‐participation group | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Before CR | After CR | p | Before CR | After CR | p | Before CR | After CR | p | |
| Biomarkers | |||||||||
| Triglyceride (casual), mg/dL | 130 ± 63 | 125 ± 64 | 0.149 | 136 ± 65 | 132 ± 67 | 0.357 | 111 ± 49 | 97 ± 40 | 0.049 |
| LDL‐Chol, mg/dL | 85 ± 28 | 85 ± 27 | 0.562 | 88 ± 28 | 87 ± 27 | 0.296 | 75 ± 25 | 76 ± 23 | 0.501 |
| HDL‐Chol, mg/dL | 52 ± 15 | 56 ± 17 | < 0.001 | 52 ± 15 | 57 ± 18 | < 0.001 | 51 ± 13 | 54 ± 12 | 0.012 |
| HbA1c, % | 6.1 ± 0.9 | 6.2 ± 1.0 | 0.221 | 6.2 ± 0.9 | 6.2 ± 1.0 | 0.387 | 6.0 ± 0.7 | 6.2 ± 0.8 | 0.296 |
| BNP, pg/mL | 588 ± 1024 | 490 ± 764 | 0.166 | 523 ± 846 | 490 ± 808 | 0.699 | 790 ± 1424 | 488 ± 559 | 0.130 |
| Hemoglobin, g/dL | 11.2 ± 1.7 | 11.7 ± 1.6 | 0.002 | 11.3 ± 1.6 | 11.7 ± 1.6 | 0.006 | 10.9 ± 2.0 | 11.5 ± 1.7 | 0.127 |
| eGFRcr excluding HD, mL/min/1.73 m2 | 22.4 ± 5.5 | 23.5 ± 8.6 | 0.029 | 22.6 ± 5.5 | 23.8 ± 9.0 | 0.051 | 22.0 ± 5.6 | 22.4 ± 6.9 | 0.321 |
| eGFRcys excluding HD, mL/min/1.73 m2 (n = 84) | — | — | — | 22.7 ± 7.7 | 26.5 ± 11.5 | 0.001 | — | — | — |
| Echocardiographic findings | |||||||||
| LVDd, mm | 51 ± 8 | 51 ± 8 | 0.383 | 51 ± 8 | 50 ± 8 | 0.518 | 52 ± 8 | 51 ± 10 | 0.554 |
| LVEF, % | 48 ± 14 | 49 ± 14 | 0.274 | 48 ± 14 | 49 ± 14 | 0.086 | 49 ± 12 | 48 ± 14 | 0.487 |
| E/e′ (n = 108) | 15.7 ± 7.1 | 14.9 ± 7.3 | 0.066 | 15.6 ± 7.1 | 15.3 ± 7.7 | 0.236 | 16.1 ± 7.2 | 13.0 ± 4.6 | 0.104 |
Note: Data are presented as mean ± SD.
Abbreviations: BNP, brain natriuretic peptide; CR, cardiac rehabilitation; E/e′, left ventricular inflow velocity waveform E wave/early mitral annular motion velocity waveform e′ of left ventricular septal dilatation; eGFRcr, estimated glomerular filtration rate based on serum creatinine concentration; eGFRcys, estimated glomerular filtration rate based on serum cystatin C; HD, hemodialysis; HDL‐Chol, high‐density lipoprotein cholesterol; LDL‐Chol, low‐density lipoprotein cholesterol; LVDd, left ventricular end‐diastolic diameter; LVEF, left ventricular ejection fraction.
3.3. Effect of Cardiac Rehabilitation on Cardiovascular Events in Patients With Advanced Chronic Kidney Disease
Table 4 shows the number of events and cumulative event rates in the two groups in this study. The mean follow‐up period was 1102 ± 679 days. The cumulative all‐MACE rates in the participation group were lower than in the non‐participation group (48% [68/143] vs. 61% [28/46], p = 0.015, Figure 2). The unadjusted hazard ratio for all‐MACEs in the participation group as compared to the non‐participation group was 0.58 (95% CI, 0.37–0.90, p = 0.016). This association remained significant after an adjustment for potential confounders (adjusted hazard ratio, 0.56; 95% CI, 0.35–0.89, p = 0.014, Table 4).
TABLE 4.
The primary outcomes of cardiovascular events.
| Outcome | Number of events | Cumulative event rate (%) | p a | Unadjusted hazard ratio b (95% CI) | p | Adjusted hazard ratio b , c (95% CI) | p | ||
|---|---|---|---|---|---|---|---|---|---|
| Participation group | Non‐participation group | Participation group | Non‐participation group | ||||||
| All‐MACEs | 68 | 28 | 48 | 61 | 0.015 | 0.58 (0.37–0.90) | 0.016 | 0.56 (0.35–0.89) | 0.014 |
| All‐cause death | 30 | 12 | 21 | 26 | 0.027 | 0.47 (0.23–0.93) | 0.030 | 0.43 (0.21–0.88) | 0.022 |
| Heart failure hospitalization | 25 | 12 | 17 | 26 | 0.067 | 0.80 (0.40–1.60) | 0.528 | ||
| Coronary revascularization | 17 | 3 | 12 | 7 | 0.541 | 2.17 (0.64–7.44) | 0.213 | ||
| Peripheral revascularization | 8 | 2 | 6 | 4 | 0.955 | 1.54 (0.33–7.25) | 0.586 | ||
| Cerebrovascular disease | 3 | 3 | 2 | 7 | 0.073 | 0.39 (0.08–1.91) | 0.242 | ||
Abbreviations: BNP, brain natriuretic peptide; MACE, major adverse cardiovascular event.
p values were calculated by the log‐rank statistic.
The hazard ratio is for the participation group as compared to the non‐participation group.
The values shown were adjusted for the age, sex, myocardial infarction, angina pectoris, silent myocardial ischemia, and BNP at the beginning of cardiac rehabilitation.
FIGURE 2.
The Kaplan–Meier event‐free survival curves of all‐MACEs.
Additionally, the cumulative all‐cause death rates in the participation group were also lower than in the non‐participation group (21% [30/143] vs. 26% [12/46], p = 0.027, Figure 3). The unadjusted hazard ratio for the all‐cause deaths in the participation group as compared to the non‐participation group was 0.47 (95% CI, 0.23–0.93, p = 0.030). This association remained significant after an adjustment for potential confounders (adjusted hazard ratio, 0.43; 95% CI, 0.21–0.88, p = 0.022, Table 4). The reasons for the all‐cause death in the enrolled patients are shown in Table 5. The cumulative event rates and hazard ratios for each MACE except all‐cause death are depicted in Table 4 and Supporting Information.
FIGURE 3.
The Kaplan–Meier event‐free survival curves of all‐cause deaths.
TABLE 5.
The causes of death.
| Variables | Overall (n = 189) | Participation group (n = 143) | Non‐participation group (n = 46) |
|---|---|---|---|
| All‐cause deaths | 42 (22%) | 30 (21%) | 12 (26%) |
| Cardiovascular death | 5 (3%) | 2 (1%) | 3 (6%) |
| Heart failure | 4 (2%) | 1 (1%) | 3 (6%) |
| Acute myocardial infarction | 1 (1%) | 1 (1%) | 0 (0%) |
| Non‐cardiovascular death | 37 (20%) | 28 (20%) | 9 (20%) |
| Infections | 12 (6%) | 9 (6%) | 3 (7%) |
| Malignancy | 4 (2%) | 4 (3%) | 0 (0%) |
| Cerebrovascular diseases | 3 (2%) | 2 (1%) | 1 (2%) |
| Digestive diseases | 2 (1%) | 1 (1%) | 1 (2%) |
| Liver cirrhosis | 1 (1%) | 1 (1%) | 0 (0%) |
| Interstitial pneumonia | 1 (1%) | 1 (1%) | 0 (0%) |
| Unknown | 14 (7%) | 10 (7%) | 4 (9%) |
4. Discussion
The following are the findings of this study in 189 CVD patients with advanced CKD. First, we found that the patients who participated in CR were less likely to develop cardiovascular events than those who did not participate. Second, participation in CR had a significant reduction in the incidence of cardiovascular events.
Many studies have shown that comprehensive CR significantly reduces mortality and hospitalization rates in CVD patients, such as coronary artery disease and heart failure [4, 17]. The results of our study were comparable to those of a recent study that showed the effectiveness of CR in preventing cardiovascular events in CVD patients [18]. Several studies have already given reasons for this prognostic effect of CR. First, by improving physical function and exercise capacity and reducing physical symptoms such as dyspnea and chest pain on exertion, exercise could improve the quality of life and prognosis [13]. Second, CR is important for correcting atherosclerosis risk factors such as hypertension, diabetes mellitus, dyslipidemia, obesity, and smoking cessation [19, 20, 21]. The effect on these risk factors stabilizes coronary atherosclerotic lesions, might prevent plaque destruction, and reduce coronary events [22, 23]. Third, exercise could improve coronary endothelial cell function, resulting in an improved coronary reserve from nitric oxide‐mediated coronary vasodilation, increased endothelial adenosine production, vasodilation, and neovascularization, resulting in an improved prognosis [24, 25]. Furthermore, exercise produces antithrombotic effects such as increased plasma volume, decreased blood viscosity, decreased platelet aggregation capacity, and increased thrombolytic capacity, thus reducing the incidence of arterial embolisms [26].
Many cardiovascular events are caused by accelerated aging of the arteries. This premature aging of the arteries mainly involves the aorta and central capacitive arteries and is characterized by aortic stiffening and loss of the stiffness/impedance gradient between the central and peripheral arteries. These changes have a dual effect. That is, upstream, they affect the heart through left ventricular hypertrophy and a reduced coronary perfusion, and downstream, they affect the renal microcirculation (i.e., reduced glomerular filtration) [27]. This relationship between the heart and the kidneys is known as the cardiorenal syndrome. Cardiac dysfunction results in a decrease in the renal blood flow as well as a decrease in the cardiac output. As a result, to maintain the systemic circulation, the sympathetic nervous system and renin‐angiotensin system are activated, and the activated sympathetic nervous system increases the myocardial contractility and heart rate, constricts the blood vessels, causes sodium and water retention in the kidneys, and induces a congested state. Thus, it is known that the cardiovascular and renal systems are interdependent, with failure of one causing failure of the other [28]. Cardiac and kidney dysfunctions share many of the same causes. Based on the above, it is suggested that CR reduced the MACEs in patients with advanced CKD because the CKD patients, who had similar comorbidities to CVD patients, might have experienced an improved physical function and endothelial function, corrected coronary risk factors, and received an antithrombotic effect. It might be an expected outcome that CR, which is effective in reducing cardiovascular events in CVD patients, could reduce the MACEs in patients with advanced CKD, including those on dialysis.
It might be more important to discuss exercise training for CKD patients than for patients with cardiovascular disease. This is because dialysis patients are lower physical function patients with chronic heart failure [29], and their physical inactivity is associated with an increased incidence of cardiovascular events and mortality [30]. However, recently, there have been emerging reports on the effectiveness of exercise training in CKD patients. Several studies have reported that CKD patients, including those on dialysis, have improved exercise capacity, muscle function, cardiovascular function, walking ability, and quality of life with exercise training [31, 32]. Other studies have reported improvements in coronary risk factors, such as a lower blood pressure and improved lipid profiles, with exercise training for patients with CKD [9, 33]. Additionally, one study suggested that exercise might improve vascular endothelial function in patients with CKD [34]. The above studies are sufficient to support the results of the present study. Furthermore, while there have been reports of high physical activity averting cardiac events in patients on dialysis [32], this is the first study to report that a comprehensive CR program including exercise training and nutritional guidance might reduce cardiovascular events in patients with advanced CKD, including dialysis patients.
In addition, it is important to emphasize that the exercise training in this study, which showed the effectiveness of CR, was in a rehabilitation room, not a dialysis unit. Increasingly, exercise training is being recommended for dialysis patients in many countries [35, 36, 37]. However, while there is little evidence that aerobic exercise during dialysis improves physical function and muscle mass, there is a report that exercise capacity is best improved by supervised exercise training in the rehabilitation room [38]. Based on the above and the results of this study, more favorable effects might be shown by actively implementing exercise training in the rehabilitation room for CKD patients.
The most important finding in this study was that even patients with advanced CKD, including those on dialysis, might be prevented from developing cardiovascular events by cardiac rehabilitation programs that include exercise training. To date, there are still few studies on the effects of CR on cardiovascular events in CKD patients. However, the present findings might facilitate patients with advanced CKD to actively participate in CR programs, as they could benefit from the avoidance of cardiovascular events.
This study had several potential limitations. First, there might have been unmeasured confounding factors (e.g., physical functions such as the duration and intensity of exercise at the patient's home, muscle strength and muscle mass, and the exercise capacity) in the present study because of the nature of the retrospective design. Yet, we adjusted for the clinically relevant and important confounders, and therefore the confounding bias could be minimized. Second, the sample size, especially of patients with advanced CKD who did not participate in CR, was relatively limited. In addition, the enrollment method for this study is limited to patients referred to the outpatient CR center. Therefore, it does not include patients who were not referred to this center (e.g., patients who were transferred to another hospital or who did not request a referral). Therefore, there might be selection bias. Third, as this study is retrospective, we were unable to extract data on changes in tests, physical function, exercise capacity, and physical activity levels after referral to our outpatient CR center for some of the participating group and many of the non‐participating group patients. Lastly, the participation rate of the patients in the outpatient CR in this study was high compared to other facilities in Japan [39]. However, our hospital is a facility certified by the Japanese Association of Cardiac Rehabilitation, and the participation rate is around 70% every year, the same as another excellent facility [40]. Therefore, it might be that the external validity of the results of this study is poor due to the gap in the participation rates. Thus, further studies are needed to validate the current findings.
In conclusion, we found that participation in a comprehensive CR program, including supervised exercise training in a rehabilitation room and nutritional guidance, was found to statistically reduce cardiovascular events, including all‐cause death, in patients with advanced CKD. Our findings would facilitate further prospective randomized controlled trials to evaluate the effect of CR on the development of cardiovascular events, including life expectancy, in CKD patients.
Ethics Statement
The research ethics committee of Tokai University (23R‐194).
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supplementary File 1 The Kaplan–Meier event‐free survival curves of each MACE.
Acknowledgments
The authors express their special gratitude to Mr. John Martin for his linguistic assistance.
Hama T., Kakuta T., Amano K., Ushijima A., Yoshimachi F., and Ikari Y., “Effect of Cardiac Rehabilitation on Cardiovascular Events in Patients With Advanced Chronic Kidney Disease,” Therapeutic Apheresis and Dialysis 29, no. 6 (2025): 856–865, 10.1111/1744-9987.70069.
Funding: The authors received no specific funding for this work.
The paper was presented at the 88th Annual Scientific Meeting of the Japanese Circulation Society, March 8th, 2024, Kobe, Japan.
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary File 1 The Kaplan–Meier event‐free survival curves of each MACE.
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.