Co-existence of Hypertension and Pre-existing Cardiovascular Disease and Mortality in Patients on Continuous Ambulatory Peritoneal Dialysis

We conducted a retrospective study of 3073 incident Chinese patients on CAPD from ve dialysis centers between January 1, 2005 and December 31, 2018 in a real-world setting. The primary and secondary outcomes were all-cause and CVD mortality. The association between interesting comorbidities and mortality was analyzed using Cox regression models and the Fine and Gray competing risk models.


Introduction
Although renal replacement therapy (RRT) has been signi cantly improved in recent decades, the overall prognosis of end stage renal disease (ESRD) remains poor, with only 11% of peritoneal dialysis patients surviving past 10 years [1]. Cardiovascular disease (CVD) accounts for approximately 50% of deaths in dialysis patients [2]. Dialysis patients have 10 to 30 times of CVD mortality than the general population, even after adjusting for age, gender, and ethnicity [3]. Dialysis patients have a high prevalence of traditional CVD risk factors, such as hypertension (HTN), pre-existing CVD, diabetes mellitus, etc. The presence of HTN affects approximately 70.0% of Chinese patients on continuous ambulatory peritoneal dialysis (CAPD) [4,5]. Elevated, lower or uncontrolled blood pressure (BP) is highly prevalent among dialysis patients and is associated with increased mortality in this population [6][7][8]. Meanwhile, chronic kidney disease (CKD) has been identi ed as an independent risk factor for CVD, resulting in twice as likely to develop CVD compared to the general population [9][10][11]. So, patients may have a higher prevalence of pre-existing CVD, when receiving RRT. Dialysis patients with pre-existing CVD have poorer survival compared to those without pre-existing CVD [12,13]. Interestingly, among CAPD patients, we wonder whether co-existence of HTN and pre-existing CVD has a more harmful effect on mortality than HTN or pre-existing CVD alone, and pre-existing CVD is more strongly associated with mortality than HTN. The objective of this study was to evaluate (1) the association between the co-existence of HTN and preexisting CVD at the start of dialysis and mortality, (2) the association between pre-existing CVD and HTN and mortality in CAPD patients.

Study Design and Population
We conducted a retrospective cohort study of 3073 incident CAPD patients from ve PD centers of three provinces in China, between January 1, 2005, and December 31, 2018. The inclusion criteria were relatively broad, which implies that the patients may be reasonably representative for the CAPD population. On behalf of the real world setting of CAPD, no patient were excluded in this study. The study was approved by the Human Ethics Committee of each research center, consistent with the ethical principles of the Declaration of Helsinki.

Data Collection and De nitions
Data on demographics, comorbid conditions, medications, and laboratory values at the start of CAPD were abstracted from medical records by two trained investigators in each center using uniform and standardized data collection tools: demographic characteristics (age, sex, body mass index, systolic BP, diastolic BP, 24-hour urine volume, current smoking, and current alcohol consumption); comorbidities (diabetes mellitus, pre-existing CVD, HTN, hyperlipidemia); medications (calcium channel blockers, beta blockers, angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors [ACEI/ARBs], diuretics, statins, and aspirin); and laboratory variables (hemoglobin, serum albumin, serum uric acid, estimated glomerular ltration rate [eGFR], cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, high-sensitivity C-reactive protein [hs-CRP]). The diagnosis of HTN was de ned as pre-dialysis systolic BP measurements >150 mmHg or diastolic BP > 85mmHg measured by ambulatory BP monitoring from medical records at the start of dialysis, or the use of antihypertensive medications [6]. The presence of CVD were de ned as coronary heart disease, congestive heart failure, arrhythmias, cerebrovascular disease, or peripheral vascular disease. Current smoking was de ned as at least one cigarette a day, and current alcohol consumption de ned as > 20 grams of ethanol a day [15]. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [16].

Outcomes and Follow-Up
The primary and secondary outcomes were all-cause and CVD mortality, respectively. If the patients died in any hospital, the exact cause of death was available by death certi cates, and if the patients died outside a hospital, experts would meet a consensus on the cause of death, with a comprehensive consideration of recent health conditions provided by family members, and the medical history and descriptions from each dialysis center. Patients who died within three months from transferring to hemodialysis to death were considered to receive failure of CAPD therapy and not to be censored. All participants were conducted CAPD schedules in the light of International Standardized Peritoneal Dialysis Guidelines [17], and clinical nephrologists regularly adjusted the CAPD regimens according to patient's health conditions. All patients were followed up until CAPD cessation, death, the end of 8-year duration, or as of June 30, 2019. Transferring to hemodialysis with survival time of at least three months, renal transplantation, transferring to other centers, loss of follow-up, or still survival with a follow-up period of 8 years were considered to be censored.

Statistical Analysis
Variables with missing data before the data analysis were imputed using the missForest method, coping with different types of variables [18]. Incidence was calculated as number of events divided by total valid observational time at risk, scaled to episodes per 1000 years. Variables are presented as mean±standard deviation (SD) or median (interquartile range, IQR) or number (%). Patients were divided into four groups: control group (those without either HTN or pre-existing CVD), HTN group, CVD group, and HTN plus CVD group. Baseline variables were compared by the One-Way ANOVA or Kruskal-Wallis tests according to variable distribution (normality tested with Shapiro-Wilk test) for quantitative variables, and the chisquare test when appropriate for categorical variables among the groups. Multiple Logistic regression was conducted to evaluate the association between baseline variables and the co-existence of HTN and pre-existing CVD at baseline. The following factors were included in multiple Logistic regression: age, sex, body mass index, systolic BP, diastolic BP, current smoking, current alcohol consumption, 24-hour urine volume, diabetes mellitus, hyperlipidemia, hemoglobin, serum albumin, serum uric acid, eGFR, cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, and hs-CRP. Medications were not included in the multiple Logistic regression because of the following reason: medications were usually used in those who had developed comorbidities, but not those comorbidity-free patients. If we enrolled medications into the multiple Logistic regression, the ndings must showed that patients with the usage of medications are at higher risk for the presence of HTN plus and pre-existing CVD compared to those without the usage of medications, which was contradicted with clinical knowledge. Therefore, we did not included the usage of medications in multiple Logistic regression.
We used Kaplan-Meier curves to investigate the difference of cumulative mortality among four groups over the observational period. To analyze the association between comorbidities and mortality, we constructed four Cox proportional hazards regression models adjusted for the following factors: Model 1, unadjusted; model 2, model 1 plus age, sex, body mass index, systolic BP, diastolic BP, current smoking, current alcohol consumption, 24-hour urine volume, diabetes mellitus, and hyperlipidemia; model 3, model 2 plus medications; model 4, model 3 plus hemoglobin, serum albumin, serum uric acid, eGFR, cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, and hs-CRP. In addition, the association between comorbidities and mortality were also analyzed among subgroups of men, women, diabetes mellitus, non-diabetes mellitus, hyperlipidemia, and non-hyperlipidemia. The interaction between HTN and CVD on all-cause and CVD mortality was examined by performing a formal test of interaction.

Sensitivity Analysis
First, for all-cause mortality, hemodialysis or renal transplants were considered competing risks. When using hemodialysis or renal transplants as competing risks, we evaluated comorbidities and all-cause mortality using the Fine and Gray competing risk models, with adjusting for variables in the four Cox proportional hazards regression models. Similarly, for CVD mortality, non-CVD mortality, hemodialysis or renal transplants were considered competing risks. Second, for those adult patients with a short-term period of follow-up, the interesting outcomes may not be completely observed, with under-reporting of the incidence of mortality. For fully observing outcomes, we further analyzed the effect of comorbidities at the start of dialysis on mortality in those adult patients with at least 24-month period of follow-up.
The results of the Cox proportional hazards models and the Fine and Gray models were presented as the hazard ratio (HR) and the 95% con dence interval (CI). Statistical analyses were conducted by GraphPad Software 8.0 (GraphPad Prism Software Inc., San Diego, California) and the R package 3.6.0 (https://www.r-project.org/). The level of signi cance was set as 0.05 for all analyses.

Patient Characteristics and comorbidities
All 3073 incident CAPD patients from ve dialysis centers were included in the present study. All variables with less than 5% missing data were imputed before the data analysis, and there was no missing data for outcomes. Of 3073 with a median age of 49.0 (IQR 39.0-61.0), 1780 (57.9%) were men, 1987 (64.6%) had HTN, 431 (14.1%) had pre-existing CVD, and 567 (18.4%) had diabetes mellitus. All patients were divided into four group: HTN plus CVD group (n=370, 12.0%), CVD group (n=60, 2.0%), HTN (52.6%) group, and the control group (n=1027, 33.4%, Table 1). Compared to the control group, HTN plus CVD group tended to be elderly, with higher body mass index, systolic BP, hemoglobin, and cholesterol, but lower diastolic BP, as well as more likely to be current smoking, diabetes mellitus, hyperlipidemia, taking calcium channel blockers, beta blockers, diuretics, ACEI/ARBs, aspirin, and statins.

Co-existence of HTN plus pre-existing CVD at baseline and Related factors
We analyzed the factors associated with the co-existence of HTN and CVD at baseline using the multiple Logistic regression in the study population (Table 2). When adjusting for body mass index, diastolic BP, 24-hour urine volume, current alcohol consumption, serum albumin, serum uric acid, eGFR, cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, and hs-CRP, we found that age, sex, systolic BP, current smoking, diabetes mellitus, hyperlipidemia, and hemoglobin were independently associated with the co-existence of HTN and pre-existing CVD.
The incidence of all-cause mortality was 55.7/1000 patient-years in the study population, with 27.9/1000 patient-years of CVD mortality incidence ( Table 3). The incidence of all-cause mortality was 131.0, 74.4, 56.1, and 32.2/1000 patient-years, and CVD mortality incidence was 69.6, 34.7, 28.2, and 15.0/1000 patient-years among the HTN plus CVD group, CVD group, HTN group, and control group, respectively.

Comorbidities and Mortality
Survival analysis found that the HTN plus CVD group had poorer cumulative survival (P<0.001) and CVD mortality-free survival (P=0.006) compared to the control group ( Figure 1). The association between comorbidities and mortality was evaluated by the different Cox proportional hazards regression models (Table 4). When comparing to the control group, the HTN plus CVD group, CVD group and HTN group had 3.98 (95% CI 3.07 to 5.17), 2.18 (95%CI 1.27 to 3.74), and 1.83 (95%CI 1.47 to 2.28)-time risk of all-cause morality in the model 4, respectively. The HTN plus CVD group, CVD group and HTN group had 4.68 (95%CI 3.27 to 6.69), 2.11(95%CI 0.96 to 4.63), and 1.87 (95%CI 1.37 to 2.54)-time risk for CVD mortality compared to the control group in the model 4, respectively. Similar trends of the association between comorbidities and mortality were observed among subgroups of men, women, diabetes mellitus, nondiabetes mellitus, hyperlipidemia, and non-hyperlipidemia ( Figure 2). There was no signi cant interaction between HTN and CVD on all-cause and CVD mortality (β=0.010, P=0.973; β=0.058, P=0.892) in the study population.

Sensitivity Analysis
When performing competing risk analyses with hemodialysis or renal transplants as the competing risk factors, the HTN plus CVD group, CVD group and HTN group had 3.00 (95% CI 2.19 to 4.11), 2.

Discussion
In our multi-center study of 3073 incident Chinese CAPD patients, the co-existence of HTN and preexisting CVD at the start of dialysis were more strongly associated with all-cause and CVD mortality compared to either HTN or pre-existing CVD alone. Pre-existing CVD was also more strongly associated with all-cause and CVD mortality than hypertension. Similar trends were observed in the competing risk analysis, subgroups of men, women, diabetes mellitus, non-diabetes mellitus, hyperlipidemia, and nonhyperlipidemia patients, as well as those with at least 24-month period of follow up.
HTN is high prevalent and plays a signi cant role in the mortality of dialysis patients [19]. Previous observational studies over the past decade have con rmed the "U-shaped" or "reverse J-shaped" relationship between BP and mortality of dialysis patients [20][21][22][23]. On the contrary, a direct linear association between systolic BP outside the unit and all-cause mortality was observed (HR 1.26 for each 10mmHg higher systolic BP; 95% CI 1.14 to1.40) [24]. However, the relationship between HTN, as a comorbidity, and mortality of dialysis patients has received little attention. Meanwhile, the prevalence of CVD was 64.5% among patients aged > 65 years with chronic kidney disease, compared to 32.4% among those without CKD. Thus, dialysis patients may have a higher prevalence of pre-existing CVD, when receiving RRT, and have poorer survival. A study of 107,922 dialysis patients from the Unite States evaluated the association between the dialysis modality and mortality, with 26.0% of coronary artery disease of new ESRD patients [12]. The HR of death was signi cantly greater for patients with coronary artery disease compared with those without these conditions at ESRD onset CAD (HR 1.11, 95%CI 1.08 to 1.14). We previously conducted a study of 1068 Chinese CAPD patients, with 30.8% of pre-existing CVD patients. This reported that 7.0% of prior stroke CAPD patients (n=75) had 1.82-time risk of all-cause mortality than those without this condition. However, to best of our knowledge, there has been no study focusing on the association between the co-existence of HTN and pre-existing CVD in dialysis patients. In the present study, we rst reported that the co-existence of HTN and pre-existing CVD were more strongly associated with all-cause and CVD mortality compared to either HTN or pre-existing CVD alone in CAPD patients, with similar ndings from the competing risk analysis. The 64.6% of prevalence of HTN in our study was slightly lower that those in these previous studies, in which the prevalence of HTN was 65.7% and 73.8% in Chinese CAPD patients [4,5]. The 14.1% of prevalence of pre-existing CVD was mildly higher than 10.5% pre-existing CVD in one single study with 740 incident Chinese CAPD patients [5], but signi cantly lower than 30.3% in another single study with 985 incident Chinese CAPD patients [4]. In the study population, we found that when using those without either HTN or pre-existing CVD as a reference, patients with only pre-existing CVD had also more strongly associated with all-cause mortality (HR 2.18 vs. HR 1.83) and CVD mortality (HR 2.11 vs. HR 1.87) than those with only HTN. Among patients with at least 24-month survival time, patients with only pre-existing CVD had also more strongly associated with all-cause mortality (HR 1.73 vs. HR 1.46) and CVD mortality (HR 1.93 vs. HR 1.1.58) than those with only HTN, when comparing to those without either HTN or pre-existing CVD alone. Notably, the 2.18 of HR of pre-existing CVD for all-cause mortality was signi cantly higher than 1.11 of HR in the above-mentioned study with 2-year follow-up period [12], but slightly higher than 1.82 of HR in our previous study [13]. The disparities of these ndings may be due to (1) different ethnicity; (2) different sample size; (3) different follow-up duration.
In the present study, baseline variables were unmatched among groups. Compared to patients with only HTN, those with HTN and pre-existing CVD were more likely to be elderly age, higher percentiles of current smoking, diabetes mellitus, and hyperlipidemia, higher levels of systolic BP, hemoglobin, and cholesterol. Elderly age, current smoking, and diabetes mellitus had an adverse effect on the prognosis of dialysis patients [25][26][27][28]. Patients with HTN and pre-existing CVD had higher percentiles of diabetes mellitus and hyperlipidemia than patients with only HTN, which contributed to higher percentiles of taking medications. Therefore, patients with HTN and pre-existing CVD had higher percentiles of taking calcium channel blockers, beta blockers, diuretics, ACEI/ARBs, aspirin, and statins. In summary, we should cautiously interpret our ndings due to the signi cant difference of baseline variables among the study population.
Strengths of this study included a large sample size, population from ve dialysis centers, and a detailed evaluation and adjustment for all-cause and CVD risk factors of real-world data. Several limitations should be considered. First, this was a retrospective study with potential unaccounted confounding factors and the selection biases. Although after adjusting for baseline variables, we did not draw conclusions about potential causal relationship between comorbidities and mortality. Nonetheless, changes of HRs among the model 2, 3, and 4 were less than 10%, suggesting three models we built were stable and reliable for predicting outcomes [29]. Second, one challenge was the de nition of HTN. The optimal method to diagnose HTN in peritoneal dialysis patients is an area of controversy [30]. A recent study reported that similarly to the general populations, ambulatory BP monitoring is the gold standard method in management of HTN in peritoneal dialysis patients [6]. In our study, diagnosis of HTN mainly based on the BP value measured by the ambulatory BP monitoring from their medical records, or the use of antihypertensive medications. Nonetheless, we did not analyzed the effect of changes of systolic BP and diastolic BP on the mortality in CAPD patients. Lastly, all eligible patients were from China, suggesting our ndings may lack generalization to other ethnic populations.
In conclusion, the co-existence of HTN and pre-existing CVD at the start of CAPD had a more harmful effect on the subsequent risk of all-cause and CVD mortality than either HTN or pre-existing CVD alone, and pre-existing CVD was also more strongly associated with risk of all-cause and CVD mortality than HTN among CAPD patients. Our ndings suggested that a combined assessment of HTN and pre-existing CVD compared with separate assessment of the two comorbidities further improved risk strati cation of CAPD patients at risk of mortality.

Declarations
Ethics approval and consent to participate The study was consistent with the ethical principles of the Declaration of Helsinki and was approved by the Human Ethics Committee of the Second A liated Hospital of Guangzhou Medical University, Zhujiang Hospital of Southern Medical University, Jiujiang No. 1 People's Hospital, A liated Sixth People's Hospital, Shanghai Jiao Tong University, The First A liated Hospital of Zhengzhou University, and the First A liated Hospital of Nanchang University. Written informed consent was obtained from all participants.

Consent for publication
All authors have approved the submitted version. All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
No.
Authors' contributions XY W, contributions to the conception, and drafted the work; XR F, the acquisition of data; FF P, the acquisition of data; YQ W, the acquisition of data; NS W, contributions to the conception and design of the work; Q, Z, analysis and interpretation of data; XJ Z, contributions to the conception and design of the work; XF W, contributions to the conception, design of the work, and revised it. All authors have read and approved the manuscript.    Control group: participants without either HTN or pre-existing CVD.
HTN, hypertension; CVD, cardiovascular disease; BP, blood pressure; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein; HR, hazard ratio; CI, confidence interval. Figure 1 Cumulative survival were lowest in those with both HTN plus pre-existing CVD. Control group: participants without either HTN or pre-existing CVD. HTN, hypertension; CVD, cardiovascular disease.