Background
Chronic kidney disease (CKD) eventually progresses to end-stage renal disease, and is also associated with cardiovascular disease (CVD) events and mortality. CKD is an independent risk factor for CVD [
1], and many reports have indicated that CKD is associated with the onset of CVD events, including coronary heart disease (CHD), heart failure, cerebrovascular disease, and death [
2‐
7]. The Kidney Disease: Improving Global Outcomes CKD Work Group 2011 clinical practice guideline indicated that as the estimated glomerular filtration rate (eGFR) declines or urinary protein increases, the incidence of CVD-related death increases [
8].
Studies have shown that hypertension, dyslipidemia, activation of the renin-angiotensin system, chronic inflammation, oxidative stress, insulin resistance, poor vitamin D status, and increase in uremic toxins such as indoxyl sulfate, asymmetric dimethylarginine, and fibroblast growth factor 23 are associated with the pathogenesis of CVD in patients with CKD [
9‐
15]. eGFR decline may exacerbate the effects of the above-described factors. Moreover, dialysis initiation increases the risk of CVD because of intradialytic hypotension due to ultrafiltration, acidosis, or mineral metabolism disorders.
Several reports previously indicated that CVD leads to poor outcomes in limited to pre-dialysis or maintenance dialysis patients [
3,
16‐
18]. There are few previous studies describing the prognosis of dialysis patients whose baseline was set at the time dialysis was initiated. Therefore, we examined whether the incidence of heart disease events differed between CKD patients with and without a history of CHD at dialysis initiation. In this study, we defined heart disease events and mortality and all-cause mortality as outcomes. We compared the outcomes by using propensity score (PS)-matching.
Methods
Subjects
The subjects were patients in whom dialysis had recently been initiated at the 17 centers that participated in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) between October 2011 and September 2013 [
19]. Patients who were withdrawn from dialysis while hospitalized, died while hospitalized, or did not agree to be registered were excluded. The multicenter prospective study cohort included 1,524 patients who were at least 20 years old, had CKD, and provided written informed consent. We excluded 9 patients whose outcomes were unknown, as determined by a survey conducted at the end of March 2015. Thus, we enrolled 1,515 subjects in the study. The dataset analyzed in the present study is presented in the Additional file
1.
Patient characteristics and data at the time dialysis was initiated (baseline)
The baseline was defined as the time at which dialysis was initiated. Body mass index (BMI) was measured at the first dialysis session. Diabetes was defined as a fasting blood glucose level ≥ 126 mg/dL, random blood glucose level ≥ 200 mg/dL, HbA1c (National Glycohemoglobin Standardization Program) level ≥ 6.5%, use of insulin, or use of oral hypoglycemic agents. Medication use referred to the drugs taken at the time of dialysis initiation. Tests were performed using blood samples taken before the first dialysis session. Blood pressure was also measured before the first dialysis session. The following were considered to be heart failure symptoms and findings: (1) dyspnea or orthopnea with hypoxemia; (2) pulmonary congestion or pleural effusion seen on plain chest radiography; and (3) physical findings related to volume excess, such as edema, weight gain, or jugular venous distension.
Definition of coronary heart disease
We classified patients into 2 groups by history of CHD (i.e., a CHD group and a non-CHD group. A diagnosis of CHD was based on information taken from the medical records. History of CHD was defined as a history of percutaneous coronary artery intervention (PCI) or coronary artery bypass graft (CABG), ischemic change seen on electrocardiogram with symptoms including chest pain on exertion, or positive findings on stress myocardial scintigraphy.
Survey of events associated with heart disease and survival prognosis
Events associated with heart disease and survival prognosis as of March 31, 2015 were determined by surveying medical records. For patients who were transferred to other institutions, information was obtained by mailing out survey forms.
Outcomes
The study outcomes included: (1) heart disease events, including onset of acute coronary syndrome, PCI, CABG, hospitalization due to heart failure, or cardiogenic sudden death; (2) mortality due to heart disease; and (3) all-cause mortality.
Statistical processing
The Easy R program was used for statistical processing [
20]. Patient characteristics and baseline data were compared for the two groups using the t-test for continuous variables and Fisher’s exact test for nominal variables. Heart disease events and mortality and all-cause mortality were compared using the log-rank test for Kaplan-Meier curves for the two groups. The PS, which we calculated using logistic regression models, represented the probability that a patient would be assigned to a group with or without a history of CHD. Using a PS-matching procedure, the 2 groups were similarly distributed, indicating that the differences in covariates between the groups were minimized. Moreover, heart disease events and mortality and all-cause mortality were compared for PS-matched patients. Factors contributing to the onset of heart disease events were examined using univariate Cox proportional hazards regression analysis. In addition to a history of CHD, age, gender, and factors that were significant in the univariate analysis (i.e., diabetes mellitus [DM], BMI, eGFR, serum creatinine, high-density lipoprotein [HDL] cholesterol, and use of β-blockers, antiplatelet agents, or statins) served as explanatory variables for the stepwise multivariate Cox proportional hazards analysis. Continuous variables were expressed as the mean and standard deviation, and categorical variables were presented as percentages.
P-values less than 5% were considered statistically significant.
Discussion
In this study, we enrolled patients in whom dialysis was initiated and who were followed thereafter. We confirmed that a history of CHD at the initiation of dialysis was associated with a higher incidence of heart disease events and mortality during dialysis. In addition, the same results were obtained when using PS-matching. We surmised that myocardial remodeling had occurred in these patients. Therefore, disturbed cardiac function can be exacerbated by dialysis initiation, and many factors can arise from dialysis therapy, such as intra-dialysis hypotension due to ultrafiltration. In accordance with the considerations above, the CHD group had poorer prognosis.
We compared the outcomes of the 2 groups using PS-matching. The CHD group had a significantly older age, lower percentage of females, and higher prevalence of DM. The patients in the CHD group were likely to develop these associated events and die of heart disease. Therefore, we used PS-matching to adjust for variables. We confirmed that there was a relationship between history of CHD and outcomes after PS-matching. However, there was no significant difference in the prevalence of heart failure symptoms at dialysis initiation between the 2 groups. We assumed that patients in both groups began dialysis under similar conditions, and that that chronically disturbed cardiac function led to poor outcomes.
Reports of evaluation using the Charlson score for the association between complications or comorbidity before introduction of dialysis, and prognosis after dialysis introduction, have been published sporadically [
21‐
23]. Wu et al. [
23] reported the association of a high Charlson comorbidity index with elevated risk of death among nearly 80,000 patients in Taiwan in whom dialysis was initiated. Ivory et al. [
24] scored complications and analyzed the relationship of this score to prognosis in more than 2,000 patients in Australia and New Zealand who began dialysis. In their study, the prevalence of CHD as a complication was 39% in the surviving group and 64% in the non-surviving group, which are higher than the rates observed in our study. In the analysis of prognosis, the survival rate at 6 months after dialysis introduction was significantly poorer in the CHD-complicated group (HR = 1.72; 95% CI = 1.51–1.96), similar to our findings. Among the reports of studies confined to CHD, Genesh et al. [
25] compared the prognosis in the group receiving hemodialysis treatment with that in the group treated with peritoneal dialysis. They demonstrated that the prognosis after dialysis introduction was poor in patients with a history of CHD, similar to the finding in our study. Patients with a history of CHD accounted for 25.9% of all patients in their study. In our study, the percentage of patients with a history of CHD was only 16.9%, although the mean age was higher in our study than in their study. One factor probably explaining this difference is an ethnic difference. That is, all patients in our study were Japanese, while the percentage of Asians was only 3.7% in the study by Genesh et al. Our study can be characterized by enrollment of only Japanese (i.e., Asian) patients. It is additionally characterized, in comparison to the above-cited studies, by homogeneity of patient background variables (achieved by PS-matching), despite the small sample size. Moreover, in contrast with the above-cited studies in which total deaths were analyzed as the outcome measure, the present study also investigated heart disease events and heart disease-associated death. The results of this study may therefore contain useful information.
A guideline for secondary prevention of myocardial infarction (JCS 2011) recommends the use of antiplatelet agents and statins in patients with CHD [
26]. In this study, the usage rates of antiplatelet agents and statins were 73.8 and 66.4%, respectively. We considered that it is difficult to administer antiplatelet agents in some patients with CKD who have a tendency to bleed. On the other hand, administration of statins might have been interrupted because the serum low-density lipoprotein cholesterol levels decreased below the normal range in some patients. This study showed that the CHD group had lower HDL cholesterol levels, even after PS-matching. In addition, a low serum HDL cholesterol level was associated with a higher incidence of heart disease events. Comprehensive management of hypertension, renal anemia, mineral and bone disorders, and dyslipidemia in early stages of CKD before CHD onset could lead to better prognosis. Therefore, more intensive collaboration between nephrologists and cardiologists will be necessary.
The present study has the following limitations. First, we could question the diagnosis of CHD. Although it has the highest reliability for diagnosis, coronary angiography was not used in all patients in the CHD group. Moreover, there are reports describing coronary artery stenosis in asymptomatic patients in whom dialysis was initiated. The results revealed that over 50% of patients had over 75% coronary artery stenosis [
27,
28]. Hence, we surmised that there might have been patients in the non-CHD group who had CHD. Acute coronary syndrome or increased severity of CHD due to an increased number of stenotic or occluded coronary arteries is associated with mortality. Second, we could not evaluate the severity of CHD. In addition, the intervals between the onset of CHD and dialysis initiation were inconsistent.
Acknowledgments
We acknowledge the support provided by the following investigators and members of the Aichi Cohort study of Prognosis in Patients Newly Initiated Into Dialysis (AICOPP), who participated in this study: Akihito Tanaka, Minako Murata, Hibiki Shinjo, Yasuhiro Otsuka, Asami Takeda (Japanese Red Cross Nagoya Daini Hospital), Hirofumi Tamai (Anjo Kosei Hospital), Tomohiko Naruse (Kasugai Municipal Hospital), Kei Kurata (Tosei General Hospital), Hideto Oishi (Komaki City Hospital), Isao Aoyama (Japanese Community Healthcare Organization Chukyo Hospital), Hiroshi Ogawa (Shinseikai Daiichi Hospital), Hiroko Kushimoto (Chita City Hospital), Hideaki Shimizu (Chubu-Rosai Hospital), Junichiro Yamamoto(Tsushima City Hospital), Hisashi Kurata (Toyota Kosei Hospital), Taishi Yamakawa (Toyohashi Municipal Hospital), Takaaki Yaomura (Nagoya Medical Center), Hirotake Kasuga(Nagoya Kyouritsu Hospital), Shizunori Ichida (Japanese Red Cross Nagoya Daiichi Hospital), Shoichi Maruyama (Nagoya University Graduate School of Medicine), Seiichi Matsuo (Nagoya University Graduate School of Medicine), Noritoshi Kato (Nagoya University Graduate School of Medicine).