Long-Term Predialysis Systolic Blood Pressure Variability and Intradialytic Cardiac Hemodynamics in Hemodialysis Patients

The association in hemodialysis patients between long-term predialysis blood pressure variability and intradialytic cardiac hemodynamics was assessed prospectively in 1070 patients receiving maintenance hemodialysis for more than 3 months. Predialysis blood pressure variability was assessed over 1-year intervals. Outcomes included factors were intradialytic hypotension and change in rate-pressure product. The nal cohort’s mean age was 59 years, and 57% were males. Greater predialysis systolic blood pressure variability was associated with an increased risk of intradialytic hypotension (adjusted hazard ratio, 1.097; 95% condence intervals 1.055 to 1.140) and change in rate-pressure product (adjusted hazard ratio, 1.213; 95% condence intervals 1.163 to 1.265). Results were similar when blood pressure variability was stratied by baseline systolic blood pressure. Factors associated with higher systolic blood pressure variability were older age, female sex, longer duration of dialysis, and diagnosis of diabetic nephropathy, and lower levels of serum albumin. In conclusion, greater predialysis systolic blood pressure variability among hemodialysis patients was associated with greater intradialytic cardiac hemodynamic instability. Strategies to reduce blood pressure variability might be benecial for hemodialysis patients.


Introduction
Hypertension is reported in greater than 90% of patients receiving long-term hemodialysis and may contribute to morbidity and cardiovascular diseases (CVD) 1 . However, the relationship between blood pressure (BP) and CVD in hemodialysis patients is complex and confounded by many associations 2 .
Fluctuations in BP or BP variability (BPV) is common in hemodialysis patients. Those uctuations entail changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) that occurs before (predialysis), during (intradialytic), or after (post-dialytic) the treatments 3 . BPV can be short-term, midterm, or long-term. Short-term BPV includes beat-to-beat, minute-to-minute, hour-to-hour, and circadian variability over a period of 24 hours; midterm BPV includes variability over a periods of days; long-term BPV includes variability over weeks, months, seasons, and even years 4 .
The goal of this study was to elucidate the role of some readily available clinical and demographic factors in BPV, including predialysis BP and BPV in cardiac hemodynamics 3 . The present study recruited incident hemodialysis patients from 9 centers studied over one year to assess the association of longterm predialysis BPV with intradialytic cardiac hemodynamic instability, including intradialytic hypotension (IDH), and myocardial ischemia.

BPV parameters
The mean VIM SBP that was used for the BPV metric was 15.44±3.85, and mean VIM DBP was 8.69±2.13 (Table 1).

Baseline characteristics
The nal study cohort comprised 1070 in-center maintenance hemodialysis patients at 9 hemodialysis centers that represented 75% of the initial cohort ( Figure 1). Demographic, clinical, and biochemical characteristics are shown in Table 2. Mean age was 59±14 years, and 57% were male, and 14% had a history of smoke. Glomerulonephritis accounted for 56% of the causes of end-stage renal disease (ESRD), with 74% having hypertension and 24% having diabetes mellitus and 14% having a history of a cardiocerebrovascular event. The median dialysis vintage was 52 months, the mean dry weight was 57±12 kg and the ratio of excess predialysis weight at start of hemodialysis to dry weight was 4.37±2.39 %.
BPV and intradialytic cardiac hemodynamic instability Intradialytic hypotension: The incidence of IDH over the 1-year was 26%. The risk of IDH was associated with higher VIM SBP in both the unadjusted and fully adjusted models (Table 3). In the fully adjusted model, each 1 SD increase in the VIM SBP was associated with 9.7% higher risk of IDH (95% con dence interval [95% CI], 5.5% to 14.0%).

Myocardial ischemia:
The changes in rate-pressure product (RPP) during a dialysis session were used to estimate myocardial ischemia and were divided into binary variables based on their median. A higher VIM SBP was associated with an increased risk of great change in RPP in both unadjusted and fully adjusted models (Table 3). In the fully adjusted model, each 1 SD increase in the VIM SBP was associated with 21.3% higher risk of great change in RPP (95% CI, 16.3% to 26.5%).

Sensitivity analyses:
VIM SBP analyzed as tertiles had a similar association with outcomes as the primary analysis (Table S1).
After strati cation by baseline SBP, the magnitude and direction of the association between VIM SBP and outcomes remained similar to the primary analysis in each of the categories, suggesting that the association between VIM SBP and outcomes was not dependent on baseline BP (Table S2).

Predictors of BPV:
The association between predialysis VIM SBP and patient baseline characteristics was shown in Table 4.
After multivariate adjustment, older age, longer dialysis vintage, and a lower serum albumin were associated with higher VIM SBP .

Additional analyses:
Higher predialysis VIM DBP was associated with an increased risk of IDH in both unadjusted and fully adjusted models. In the fully adjusted model, each 1 SD increase in the BPV was associated with 10.0% higher risk of IDH (95% CI, 2.9% to 17.6%) and with an increased risk of great change in RPP. In the fully adjusted model, each 1 SD increase in the BPV was associated with 15.4% higher risk of great change in RPP (95% CI, 8.1% to 23.2%) (Table S3).

Discussion
Predialysis SBP is most commonly selected to diagnose and manage BP in hemodialysis patients 3 . SBP is the major determinant of pulse pressure, since both dependent quite strongly on inelasticity of major conduit vessels and pulse wave velocity. Therefore, predialysis systolic BPV was selected to assess the association between predialysis BPV and intradialytic cardiac hemodynamic instability. The results from this prospective study of 1070 incident in-center hemodialysis patients demonstrated that higher predialysis systolic BPV was independently associated with an increased risk of IDH and myocardial ischemia during hemodialysis sessions. This association persisted across all baseline SBP categories and after adjustment for a number of potential confounding factors. Thus, the predialysis systolic BPV emerges as a potentially modi able risk factor for cardiac hemodynamic instability in hemodialysis patients. Greater predialysis diastolic BPV was found to be independently associated with an increased risk of intradialytic cardiac hemodynamic instability, including IDH, and myocardial ischemia.
IDH and myocardial ischemia are frequent complications of hemodialysis 5 . IDH may result from a failure to tolerate ultra ltration leading to an imbalance between central hypovolemia and re ex-mediated hemodynamic responses 6 , and is clearly associated with adverse outcomes [7][8][9] , and all-cause mortality 7 . Current guidelines recommended to address IDH include regular assessment of dry weight; control of inter-dialytic weight gain by dietary uid and salt restriction; optimization of ultra ltration and dialysate composition; use of a cool dialysate; careful assessment of dosing and timing of antihypertensive drugs; prolonged dialysis time and increased dialysis frequency 10 . However, even with aplenty management, some patients remain prone to IDH. The nding that a higher predialysis systolic BPV was associated with an increased risk of IDH suggests that maintaining a stable predialysis BP may reduce the incidence of IDH.
Previous studies have demonstrated that the RPP highly correlates with invasive measurement of myocardial oxygen consumption, and it is used as an index of myocardial workload and oxygen demand to predict cardiac function, morbidity and mortality 11,12 . Cardiovascular reactivity to acute stress is mediated via the activation of the sympathetic nervous system and hypothalamus-pituitary-adrenal axis, leading to increase in heart rate, blood pressure, vasoconstriction, and vagal withdrawal 13 . A greater hemodynamic response to acute stress including an exaggerated increase in blood pressure or heart rate was associated with incident hypertension and a higher mortality rate 14 . In the present study, the RPP change during hemodialysis was assessed to evaluate the hemodynamic response. A higher predialysis systolic BPV was signi cantly associated with the risk of a greater change in RPP. Thus, strategies to reduce uctuations in predialysis BP might be considered to decrease cardiac hemodynamic stability during hemodialysis.
The BPV is one compelling putative risk factor to explain the strikingly high rate of CVD in hemodialysis patients 15 . Indeed, BPV is signi cantly associated with CVD and mortality in these patients 1,16 . Their BPV may have unique determinant including volume and osmolar shifts, and impaired counter-regulatory responses 17 . Additionally, BPV in hemodialysis patients may entail vascular remodeling, overactivation of the sympathetic nervous system and loss of compliance of conduit vessels with increases in arterial pulse wave velocity 18 . Patients receiving hemodialysis can experience IDH, or myocardial ischemia, both of which increase risk of mortality 19 . Our data extend the retrospective report on 11291 incident hemodialysis patients treated at 210 dialysis clinics in the United States that a greater predialysis systolic BPV was a risk factor for all-cause mortality, cardiovascular mortality, and cardiovascular events 3 . A recent retrospective analysis also con rmed above ndings 20 . The present study has found, for the rst time, that higher predialysis systolic BPV was signi cantly associated with an increased risk of intradialytic cardiac hemodynamic instability, including IDH and a greater change in RPP. The BPV metric was an indicator of BPV independently of mean level of BP 21 . The association between predialysis systolic BPV and cardiac hemodynamic instability remained signi cant after strati cation by baseline SBP category. Therefore, a goal of management of hemodialysis patients to contast their very high CVD mortality might be to maintain cardiac hemodynamic stability.
In the present study, we found that dry weight, or the ratio of excess weight at hemodialysis start to dry weight, was not signi cantly associated with predialysis BPV. Meanwhile, the adjustment for the dry weight and the ratio of excess weight at hemodialysis start to dry weight in the nally outcomes model did not change the association between BPV and outcomes. In a previous retrospective study on the association between predialysis BPV and outcomes, they observed that achievement of prescribed dry weight was associated with lower predialysis BPV, but the adjustment for achievement of prescribed dry weight in the nally outcomes model did not change the association between BPV and outcomes 3 .
Meanwhile, a randomized clinical trial con rmed that dry weight reduction did not affect BPV levels 22 . It is hypothesized that volume losses that occur with dialysis induce baroreceptor-dependent changed in autonomic function that stabilizes venous return (capacitance vessel constriction) and peripheral constriction (arteriolar constriction) subjects with inelastic conduit vessels cannot adequately sense the uctuations in BP and do not mount an effective -counter-regulatory response 18 . BPV reduction is not always accompanied by BP reduction; whether BPV changes depends largely on modi cation of the responsible pathogenesis, which may be in uenced by speci c but not all antihypertensive interventions.
The predialysis systolic BPV was predicted by older age, and longer duration of dialysis. All of these also predict increased pulse wave velocity and conduit vessel stiffness. Moreover, impaired baroreceptor activation (as in old age) drives the sympathetic nervous system that could contribute to the associated with RPP and cardiac disease 18 . Potentially modi able factor included serum albumin that was associated with predialysis systolic BPV. Low serum albumin was associated with in ammation, arterial stiffness and atherosclerosis 20 . Several studies have reported that malnutrition and in ammation could result in atherosclerosis and enhanced BPV 23,24 . Thus, nutritional intervention might help to reduce BPV. Dietary modi cation, such as folic acid supplementation, might contribute to the reduction of BPV. A clinical trial in primary prevention of stroke among adults with hypertension in China found that supplemental folic acid dramatically reduced stroke in the hypertensive Chinese population where (unlike United States and Europe) food is not forti ed with folate and there may be widespread folate de ciency 25 . This could be exacerbated by loss of B vitamin and folate during dialysis. Moreover, the elevated levels of homocysteine could be reduced by the folic acid supplementation, which could modify stroke in Chinese hypertensive patients 26 . Therefore, dietary intervention might help to reduce the risk of CVD.
Further study will be deserved to explore available pharmacological and non-pharmacological interventions.
This study aimed to minimize confoundering in uence on the measured variables. It is well known that blood pressure uctuates with season changes 27 . Therefore, in this study, we measured a consecutive 12 months of predialysis blood pressure to determine BPV. Predialysis BP was measured when patients took a rest after arriving in waiting room prior to dialysis, which was equivalent to visit-to-visit BP. Therefore, it could re ect the long-term degree of BP control and stability 28 . In this multi-center prospective observational study, we demonstrated that greater predialysis systolic BPV was associated with intradialytic cardiac hemodynamic instability. Thus, both reduction in average BP levels and reduction of uctuations in BP should be emphasized in hemodialysis patients. Interventions aimed at reducing BPV might be bene cial in improving adverse outcomes for hemodialysis patients. There are several limitations to our study. First, we only explored the association between predialysis systolic and diastolic BPV, but not other components of BP, such as mean arterial pressure, intradialytic or postdialysis BP.
Fluctuation in these BP components may be risk factors for poor outcomes and needs additional research. Second, the nal cohort recruited most prevalent hemodialysis patients, not incident hemodialysis patients, whose dialysis history might in uence the adverse outcome. However, after adjusted for dialysis vintage, the association still remains. Third, this is a prospective observational study. The results could only explain the association and provide clues for treatment to reduce blood pressure variability. Further study will be deserved to explore optimal blood pressure management strategy and relevant mechanisms in hemodialysis patients.
In conclusion, greater predialysis systolic BPV was associated with intradialytic cardiac hemodynamic instability in hemodialysis patients. Reducing BPV might be bene cial in improving adverse outcomes for hemodialysis patients.

Study Population of Patients
Adult patients (aged ≥18 years) receiving maintenance hemodialysis were recruited from the Fourth A liated Hospital, Zhejiang University School of Medicine and 8 public hospitals in Jinhua city, Zhejiang Province of China (Central Hospital of Jinhua, People's Hospital of Jinhua, Central Hospital of Yiwu, People's Hospital of Yongkang, People's Hospital of Pujiang, Dongyang Hospital of Traditional Chinese Medicine, People's Hospital of Lanxi, and Lanxi Hospital of Traditional Chinese Medicine). Inclusion criteria included: (1) maintenance hemodialysis for more than 3 months prior to August 1, 2018; (2) receiving regular 3-times weekly hemodialysis for 4 hours. Exclusion criteria were: (1) patients who died or received a kidney transplant or were changed to peritoneal dialysis or transferred to a different renal unit during follow-up period; (2) those who could not write informed consent. This study was approved by the Research Ethics Committee of the Fourth A liated Hospital, Zhejiang University School of Medicine (K20190047) and was recorded in the Chinese Clinical Trial Register (ChiCTR2000028945). All methods were performed in accordance with the approved guidelines and relevant regulations. Written informed consent was obtained from all participants.

Study Protocol
The hemodynamic data was collected prospectively for all of the hemodialysis sessions of the participants. At each session, patients were assessed for pre-and post-hemodialysis weight, and predialysis and intradialytic SBP, DBP and heart rate (HR) from August 1, 2018 to July 31, 2019. The BP and HR were measured with patient seated in a chair with feet on the oor and back supported. Measurement were made by trained research assistants with a validated automated oscillometric brachial BP monitor (Omron 907XL; Omron Healthcare, Lake Forest, IL). Predialysis BP and HR were measured after a 10-minute rest period in a chair before dialysis. BP was measured three times consecutively before each dialysis, with a 1-minute interval and the results averaged. Intradialytic BP and HR were measured automatically at 30, 60, 120, 180, and 240 minutes by the dialysis apparatus.
Patients were dialyzed on either Monday-Wednesday-Friday or Tuesday-Thursday-Saturday schedules.
Prescriptions for patient's dry weight and antihypertensive drug were made by the nephrologist during their weekly visits. Dry weight was assessed by cardiopulmonary radiology and clinical symptoms including peripheral edema, pulmonary congestion, intra-and extra-dialytic BP and muscle spasm. Excess predialysis weight was de ned as the difference between predialysis and dry weight.
Cardiac hemodynamic instability during hemodialytic procedure were evaluated by IDH, and myocardial ischemia. A decrease in SBP ≥ 20 mmHg or mean arterial pressure (MAP) ≥ 10 mmHg was required to quantify hypotension and ≥3 episodes hypotension per 10 hemodialysis treatments were required to diagnose IDH 29 . The rate-pressure product (RPP) was calculated as SBP multiplied by HR and the change in RPP as the percentage difference between the maximum value and the minimum value during dialysis session 13 . The change in RPP during hemodialysis procedure was used to assess myocardial ischemia, which could represent the early change in cardiac hemodynamics 30 .

BPV and other measurements
For each BP measurements, the SD was calculated (SD SBP and SD DBP ) with the coe cient of variation (CV, CV SBP and CV DBP ) and the variability independent of the mean (VIM, VIM SBP and VIM DBP ). The CV was SD factored by mean BP values (M SBP and M DBP ), and the VIM by the SD factored by the mean to the power x, which was obtained by tting a curve to the plot of SD against the mean blood pressure level 31 .
The following demographic and clinical data were collected: age, gender, comorbidity (diabetes, hypertension, cardiocerebrovascular events), body mass index (BMI), use of antihypertensive medications, dialysis vintage, and occurrence of their cardiocerebrovascular events include myocardial infarction, angina, coronary heart disease, stroke, heart failure and post-cardiac arrest. The diagnosis of hypertensive nephropathy is based on characteristic clinical features, excluding other renal diseases and eventually on the features of kidney biopsy 32 . The following laboratory parameters were also collected: Kt/V, blood hemoglobin, serum albumin, calcium, phosphate, and parathyroid hormone (PTH). All laboratory values were measured using standardized automated methods. Laboratory values were measured monthly except PTH that was measured quarterly. The averaged or median values during the exposure period served as the baseline data.

Statistical Analysis
The baseline characteristics of all the patients were compared tertiles of BPV to assess factors that were associated independently with BPV at baseline using linear mixed effects models with a random intercept for the clinic to account for clustering of outcomes by providers. The follow factors were also incorporated as explanatory variables: demographic characteristics (age, sex), clinical factors (history of diabetes, hypertension, cardiocerebrovascular events, smoke, and BMI), dialysis-related factors (cause of ESRD, dialysis vintage, Kt/V, dry weight, and the ratio of excess weight at hemodialysis start to dry weight), laboratory measurements (serum albumin, calcium, phosphate, hemoglobin, and PTH), and use of antihypertensive medications. The association of BPV with intradialytic cardiac hemodynamic instability, including IDH and myocardial ischemia was assessed by discrete time proportional hazards models using binary regression. HRs were calculated for each outcome per 1 SD increase in BPV after adjustment for the same a pre-de ned potential confounders. A sensitivity analyses for BPV was undertaken by tertiles to quantify the association of BPV with outcomes after strati cation by categories of SBP at baseline (tertiles of SBP). Statistical signi cance was taken as P<0.05 using two-tailed tests.

Competing interests
The authors declare no competing interests.

Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.     BMI: body mass index; ESRD: end stage renal disease; HD: hemodialysis; HB: hemoglobin; Alb: albumin; PTH: parathyroid hormone; RAS: renin angiotensin system; RPP: rate-pressure product; CI: con dence interval.