Risk factors and antihypertensive medications for mortality in elderly hospitalized hemodialysis patients: a multicenter retrospective study in China

Background Elderly Hemodialysis patients are increasing yearly. Antihypertensive medications are commonly prescribed to hemodialysis patients but the optimal regimens to prevent morbidity andmortality are unknown. The goal of our study was to compare the association of routinely prescribed antihypertensive regimens with outcomes and analyze the risk factors in elderly hemodialysis patients. Methods This study was a retrospective cohort study based on data from adult hemodialysis patients ( ≥ 18 years old) admitted to 15 hospitals in China between 1 January 2009 and 31 December 2011. The characteristics of elderly hemodialysis patients ( ≥ 60 years old) were analyzed. Antihypertensive drugs into the following regimens: β-blockers, calcium channel blockers, renin–angiotensin system (RAS) blocking drugs and α-blockers. Logistic regression analysis was used to explore the risk factors for death adjusting for clinical and laboratory values and antihypertensive medications. Results A total of 7135 patients on maintenance hemodialysis including 2738 elderly patients were enrolled in this study. The mean levels of hemoglobin, albumin, blood calcium, phosphorus and parathyroid hormone (PTH) in elderly group were lower than the younger group. We compared the characteristics of 2492 survived elderly maintenance hemodialysis patients and 246 patients who died.Aging (OR = 1.59, 95% CI: 1.13-2.24), central venous catheter (OR = 1.62, 95% CI: 1.53-1.72) and Charlson comorbidities index>3(OR=1.97,95% CI: 1.49-2.60)were independently risk factors of mortality in elderly maintenance hemodialysis patients. High levels of hemoglobin (OR=0.76, 95%CI: 0.73-0.79), albumin (OR=0.87, 95%CI: 0.77-0.98), uric acid(OR=0.90,95%CI: 0.84-0.96)and those taking angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) (OR=0.77, 95%CI:


Background
With development of hemodialysis technology and aging of population, patients who need renal replacement therapy are increasing and getting older [1][2]. There are many prognostic factors impacting dialysis patients' mortality, such as: patient-related and therapy-related factors. Age, malnutrition and comorbidities are mainly patient-related factors. Antihypertensive drugs, serum uric acid leveland vascular access typeare, at least partly, therapy-related factors [3].
Hypertension is common and contributes to adverse outcomes in patients undergoing dialysis. Antihypertensive drugs are prescribed to hemodialysis patients commonly but the contribution to life span are unclear.The bene ts of RAS blocking drugs are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, con icting evidence from trials and concerns about hyperkalemia limit RAS blocking drugs use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers [4][5].This study was to investigate the association of different kinds of antihypertensive drugs with mortality in Chinese elderly hemodialysis patients.

Methods
Patients A multicenter, retrospective cohort of maintenance hemodialysis (MHD) patients (aged ≥18 years old) in 15 tertiary hospitals in Chinafrom 1 January 2009 to 31 December 2011 was recruited.The inclusion criteria were as follows: de nite diagnosis of stage of chronic kidney disease 5 stage and undergoing hemodialysis treatment for more than 3 consecutive months. Patients with acute kidney injury, received a kidney transplant or undergone nephrectomy were excluded. The Medical Ethics Committee of the Chinese PLA General Hospital approved the study protocol and waived patient consent.

Demographic and Clinical Data
Finally included in the study were 7135 patients, who were divided into 3 groups according to age: 4397 patients aged less than 60 years; 1808 elderly patients between 60 and 75; and 930 very elderly patients aged over 75. 2738 elderly MHD patients including 2492 survived patients and 246 patients who died. The following information: name, age, gender, hospital number, primary diseases of renal failure, cause of admission, discharge diagnosis, vascular access type and the cause of death were collected from electronic medical records and laboratory databases. Laboratory indicators consisted of albumin, hemoglobin, calcium, phosphorus and PTH levels.Types of vascular access for hemodialysis were divided into two different groups: the CVC group, which included both tunneled and non-tunneled catheters, and the AV group, which included AVF and AVG. The Charlson comorbidity index (CCI) score was calculated for each patients according to their comorbidity pro le [6]. We classi ed antihypertensive drugs into the following regimens: β-blockers, calcium channel blockers, renin-angiotensin system blocking drugs and α-blockers.
Statistical Analysis SPSS software (version 22.0) was applied to Statistical analysis. Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as n(%).One-way ANOVA or the Kruskal-Wallis test was used for continuous variables. The χ2 test was used for categorical variables. Logistic regression analysis was used to explore the risk factors for death in the elderly MHD patients. All tests were two-sided tests and a P value < 0.05 was considered statistically signi cant.

Results
The average age of hospitalized hemodialysis patients was 53.0 ± 17.8 years old, male patients accounted for 51.1% (table 1). The top three primary diseases in elderly dialysis patients were diabetic nephropathy, hypertension and glomerulonephritis. The top two reasons for the hospitalization of elderly patients were infection and cardiovascular disease (

Discussion
Many elderly hemodialysis patients suffer from various complications and have to be hospitalized, and even require repeated hospitalizations. The high hospitalization rate not only aggravates the nancial burden and psychological pressure of elderly hemodialysis patients, but also greatly increases the mortality rate [7]. We found that the proportion of secondary kidney diseases such as diabetes and hypertension in elderly hemodialysis patients was high, which is consistent with the results of other studies [8][9]. The incidence of anemia and hypoalbuminemia was high in elderly hemodialysis patients. A study of 78,420 dialysis patients found that hemodialysis patient's hospitalization risk is increased by 67% for every 1 g/dL decrease in albumin and increased by 9% for each 1 g/dL drop in hemoglobin [10]. Therefore, we must pay great attention to the nutritional problems in elderly hemodialysis patients in order to reduce the hospitalization rate and improve the quality of life.
Elderly hemodialysis patients often suffer from decreased bone synthesis and reabsorption, and PTH secretion is inhibited [11]. They have degenerative function of hormone secretion and activity, decrease expression of anti-aging Klotho gene and uremic toxins [12].The intake of phosphorus decreases and hypophosphatemia develops, causing a decrease in PTH levels.The speci c mechanism of low transport bone disease in elderly hemodialysis patients remains to be further explored [13].There is a positive correlation between serum PTH levels and serum albumin, creatinineand total cholesterol concentrations in elderly hemodialysis patients [14]. The main therapeutic goal of low-transplant renal bone disease is to reduce calcium ion and vitamin D load, avoid excessive inhibition of PTH, maintain PTH activity and improve the quality of life of hemodialysis patients [15].
Studies have con rmed that hypophosphatemia can increase the all-cause mortality and infection-related mortality of hemodialysis patients compared with the range of serum phosphorus recommended by the kidney disease outcomes quality initiative (KDOQI) [16][17][18]. Other studies have found that hypophosphatemiaincreases the mortality of hemodialysis patients over 65 years old [19]. Hypophosphatemia was an independent risk factor for infection, especially in elderly dialysis patients [20]. Hypocalcemia is an independent predictive risk factor for left ventricular diastolic dysfunction in chronic kidney disease patients.
Elderly hemodialysis patients have a higher mortality rate, and many factors affect their risk of death.
Patients with more comorbidities had higher hospitalization costs, lower survival rates, and a higher risk of death. Age, CCI, malnutrition, serum uric acid level, and CVC are known factorsassociated with the risk of mortality among hemodialysis patients [21][22][23]. Hur et al discussed that low serum uric acid is associated with higher mortality [24].
The treatment of hypertension in dialysis patients is complex and there is no relevant guide [25][26][27][28]. There are mainly four kinds of antihypertensive drugs commonly used in maintenance hemodialysis patients: RAS blockers, calcium ion antagonists, β-blockers and α-blockers.
RAS blockers are mainly divided into angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists. These drugs have great advantages in dialysis patients due to their low dialysis clearance rate, stable hemodynamics, de nite antihypertensive effect and cardio-cerebral organ protection [29].
The prevalence of microin ammation in hemodialysis patients is an important predictor of cardiovascular disease and death in MHD patients [30]. ARB drugs can directly participate in the regulation of the body's immune system and signi cantly reduce the level of serum in ammation indicators in hemodialysis patients [31][32].
Dialysis patients taking RAS blockers had a reduction in all-cause mortality and cardiovascular mortality compared with beta-blockers [29]. ARBs can reduce the overall mortality and cardiovascular mortality of hemodialysis patients, but the use of ACEI did not nd its impact on mortality. Combination of ACEI and ARB increases the mortality of hemodialysis patients [33][34][35]. However, some studies have found that ARB drugs cannot reduce the risk of cardiovascular events and total mortality in long-term dialysis patients compared with other antihypertensive drugs [36][37]. Therefore, large-scale clinical trials are needed to verify the advantages and disadvantages of ACEI/ARB in dialysis patients.
Although the proportion of calcium ion antagonists used in elderly hemodialysis patients is large, the correlation analysis in this study showed no signi cant effect on the mortality of elderly hemodialysispatients. One study divided 130 dialysis patients into two groups according to whether they used calcium antagonists and found that hemoglobin was low in hemodialysis patients who used calcium antagonists, probably because calcium antagonists attenuate the activity of erythropoietin [38][39][40].
A 10-year follow-up study of long-term hemodialysis patients receiving various antihypertensive drug treatments found that beta-blockers can signi cantly reduce all-cause mortality in hemodialysis patients [41]. A recent study found that hemodialysis patients who used a combination of beta-blockers and reninangiotensin system antagonists had the lowest mortality rates [42].
Although we conducted a large-scale study of the clinical features about the hospitalized elderly hemodialysis patients, there are still some problems and de ciencies: First, this study is a retrospective case data, cross-sectional survey design and there was no follow up and we used logistic regression instead of cox regression. Second, the patient list here is extracted from inpatient data. This makes things very different from an outpatient hemodialysis database study. Inpatients are unwell and hemoglobin, phosphate, calcium, these are naturally deranged while patients are acutely unwell. For example: a lower inpatient hemoglobin would be naturally associated with more acute diseases and possibly longer hospital stay.Third, there was a lack of blood pressure values that could heavily in uence clinicians' antihypertensive prescription decisions. In addition, there is still a lack of data on dialysis. The Medical Ethics Committee of the Chinese PLA General Hospital approved the study protocol and waived patient consent.

Competing interests
The authors declare that they have no competing interests Consent for publication Not applicable.

Funding
Not applicable.

Authors' contributions
Each author contributed to the design of the study and interpretation of the data. YHS, GYC, YFX, JQL and SLconceived and designed the study. YHS and GYCparticipated in the literature searches data analysis and interpretation. YHS drafted the manuscript. GYC an XMC revised the nal manuscript. All authors read and approved the nal manuscript.