Study Population of Patients
Adult patients (aged ≥18 years) receiving maintenance hemodialysis were recruited from the Fourth Affiliated 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 Affiliated 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.
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 floor 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 defined 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 (SDSBP and SDDBP) with the coefficient of variation (CV, CVSBP and CVDBP) and the variability independent of the mean (VIM, VIMSBP and VIMDBP). The CV was SD factored by mean BP values (MSBP and MDBP), and the VIM by the SD factored by the mean to the power x, which was obtained by fitting 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.
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–defined potential confounders. A sensitivity analyses for BPV was undertaken by tertiles to quantify the association of BPV with outcomes after stratification by categories of SBP at baseline (tertiles of SBP). Statistical significance was taken as P<0.05 using two-tailed tests. Statistical analyses were undertaken by using SPSS Statics 22.0 (IBM, New York).