Study population
The study protocol was approved by the ethics committee of the Fifth Hospital of Sun Yat-Sen University (Guangdong, China) and adhered to the Declaration of Helsinki. Informed consent was obtained from each participant. Consecutive patients were recruited from the Fifth Affiliated Hospital of Sun Yat-Sen University (Guangdong, China) between July of 2017 and Nov of 2019. Patients (14–75 years) with primary glomerular disease proved by renal biopsy or clinic findings after exclusion of secondary renal damage factors, were included. Patients were excluded from the study in case of :1) diabetes mellitus;2) acute changes in the eGFR > 30% in the previous three months; 3) maintenance dialysis or history of kidney transplantation; 4) cardiovascular disorders (unstable angina pectoris, heart failure, life-threatening arrhythmia, atrial fibrillation, stroke and grade III–IV retinopathy); 5) pregnancy; 6) night work or shift-work employment; 6) intolerance to ABPM or invalid ABPM data; 7) inability to communicate and comply with all of the study requirements; Finally, a total of 1178 patients were enrolled in this study (Fig. 1).
Ambulatory and clinic blood pressure monitoring
Patients underwent 24-hour ABPM using a Mobil-O-Graph Monitor (I.E.M. GmbH, Stolberg, Germany),.Appropriate cuff size was chosen based on the arm circumference and directly placed on the non-dominant arm. The monitor was programmed to measure every 15 minutes during the day(7: 00 am to 10༚00 pm), and every 30 minutes during the night ༈10༚00 pm to 7༚00 am༉. Monitoring was performed on a working day. Patients were instructed to maintain their usual but not strenuous level of activity, and to keep motionless at the time of measurement. ABPM data were invalid in cases of: 1) > 30% of measurements were lacking; 2༉>3 hours data were missing;3༉sleep time at night was < 6 or > 12 hours during monitoring.
Clinic BP was measured at the physician’s office with a standard mercury sphygmomanometer after a 5-minute rest in a sitting position. For all patients, sphygmomanometric measurements were recorded by the same physician, who was not aware of the results of ABP recordings. Reported values of clinic BP were the mean of 2 or 3 measurements at 1–2 min intervals, recorded during the 2 days in which the ABPM device was installed and removed.
Cardiac, renal and carotid assessment
Cardiac structure and function were assessed by 2 investigators trained for this purpose before starting the study. Linear measurements of interventricular septal wall thickness (IVSd), end-diastolic left ventricular internal dimension (LVIDd), and posterior wall thickness (PWTd) were obtained from M-mode tracings,using 2-dimensional echocardiography. LVM was calculated using the Duvereux method. The left ventricular mass index (LVMI) was obtained by calculating the ratio of LVM to body surface area.
Concentrations of serum creatinine (Scr) were measured by an enzymatic method traceable to isotope dilution mass spectrometry. The estimated Glomerular Filtration Rate (eGFR) was calculated using 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. Awaking(7: 00 am to 10༚00 pm),bedtime༈10༚00 pm to 7༚00 am༉and 24-hour urine samples were collected to detect excretion levels of urinary albumin, protein, and creatinine. Patients were asked to void their bladders at 7:00 am and 10:00 pm to ensure valid results.
Carotid intima-media thickness (cIMT) was determined by averaging 3 measurements taken on each carotid artery (in anterior, lateral and posterior directions), measuring the distance between the leading edge of the lumen–intima interface, and the leading edge of the collagenous upper layer of the adventitia using high-resolution B mode ultrasonography. Measurements were taken in areas free of obvious atherosclerotic plaques around the level of the carotid bifurcation.
Cardiac structure and function were assessed by 2 investigators trained for this purpose before starting the study. Linear measurements of interventricular septal wall thickness (IVSd), end-diastolic left ventricular internal dimension (LVIDd), and posterior wall thickness (PWTd) were obtained from M-mode tracings,using 2-dimensional echocardiography. LVM was calculated using the Duvereux method. The left ventricular mass index (LVMI) was obtained by calculating the ratio of LVM to body surface area.
Concentrations of serum creatinine (Scr) were measured by an enzymatic method traceable to isotope dilution mass spectrometry. The estimated Glomerular Filtration Rate (eGFR) was calculated using 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. Awaking(7: 00 am to 10༚00 pm),bedtime༈10༚00 pm to 7༚00 am༉and 24-hour urine samples were collected to detect excretion levels of urinary albumin, protein, and creatinine. Patients were asked to void their bladders at 7:00 am and 10:00 pm to ensure valid results.
Carotid intima-media thickness (cIMT) was determined by averaging 3 measurements taken on each carotid artery (in anterior, lateral and posterior directions), measuring the distance between the leading edge of the lumen–intima interface, and the leading edge of the collagenous upper layer of the adventitia using high-resolution B mode ultrasonography. Measurements were taken in areas free of obvious atherosclerotic plaques around the level of the carotid bifurcation.
Collection of other data
Information including age, sex, height, weight, smoking and alcohol consumption status, antihypertensive medication were obtained at the time of the BP measurement. Laboratory data (hemoglobin, albumin, calcium, phosphorus, intact parathyroid hormone, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, uric acid and blood urea nitrogen) were obtained at the initial study visit. Blood samples were taken in the morning and analyzed using a 7180 Biochemistry Autoanalyzer (Hitachi, Tokyo, Japan) with reagents from Roche Diagnostics (Mannheim, Germany).
Definitions
CKD was divided into 5 stages and defined as the presence of kidney damage or decreased renal function (eGFR < 60 mL/min per 1.73 m2) for ≥ 3 months according to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 clinical practice guideline. Clinic hypertension was defined as clinic blood pressure (BP) ≥ 140/ 90 mmHg and ambulatory blood pressure (ABP) was defined as 24-hour BP ≥ 130/80 mmHg. Masked hypertension was defined as a normal clinic BP (≤ 140/90 mm Hg) and an elevated ABP (> 130/80 mm Hg). White coat hypertension was regarded as increased clinic BP (> 140/90 mm Hg) and normal ABP (≤ 130/80 mmHg). Normotension was defined as both clinic BP < 140/ 90 mm Hg and ABP < 130/80 mmHg; Sustained hypertension was regarded as clinic BP ≥ 140/90 mm Hg and ABP ≥ 130/80 mmHg. Nighttime hypertension was defined as nighttime systolic BP (SBP) ≥ 120 mm Hg or/and diastolic BP (DBP) ≥ 70 mmHg. Isolated nighttime hypertension was defined as daytime BP < 135/85 mm Hg and nighttime BP ≥ 120/70 mmHg. Participants with a reduction in SBP of ≥ 10% at night-time compared with daytime were considered to have a “dipper” pattern, and an “extreme dipper pattern” referred to a > 20% reduction at nighttime. A “non-dipper” pattern referred to a < 10% reduction at nighttime and a “reversed dipper pattern” referred to higher SBP at nighttime compared with daytime. Target organ damage (TOD) was defined if it met any of four conditions: 1) left ventricular hypertrophy (LVH), namely LVMI ≥ 125 g/m2 (man) or ≥ 120 g/ m2 (woman) ; 2) eGFR < 60 mL/ min per 1.73 m2; 3) Urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g; 4) cIMT ≥ 0.9 mm or existence of carotid plaque in ultrasonography.
Statistical analysis
Statistical analysis was performed with SPSS 25.0 (IBM Corp., Armonk, NY) and Medcalc 18.9(Broekstraat, Mariakerke, Belgium). Descriptive statistics were mean ± SD for continuous variables or median (25-75th interquartile range) for non-normality variables. Frequency and percentage were used for categorical variables. To analyze the sensitivity and specificity of different BP indexes in relationship to TOD༈LVH,eGFR < 60 ml/min per 1.73 m2༌ACR ≥ 30 mg/g༌cIMT ≥ 0.9 mm or carotid plaque༉, we generated and compared receiver operating characteristic (ROC) curves, including area under the curve (AUC) and their 95% CIs. Considering each TOD may be affected by other important factors, and clinic and ambulatory SBP may have different prognostic value, we established 12 multivariate adjusted logistic regression models in all. Model 1–3༌4–6༌7–9 and 10–12 corresponded with LVH༌eGFR < 60 ml/min per 1.73 m2༌ACR ≥ 30 mg/g༌cIMT ≥ 0.9 mm or carotid plaque, respectively. Model 1 included adjustment for age, sex, BMI, smoking, alcohol consumption status, hemoglobin. albumin, eGFR and ACEI/ARB use. Model 4 included adjustment for age, sex, BMI, smoking, alcohol consumption status. hemoglobin. albumin, ACR, iPTH, uric acid, calcium* phosphate product and ACEI/ARB use. Model 7 included adjustment for age, sex, BMI, smoking, alcohol consumption status, hemoglobin, albumin and uric acid. Model 7 included adjustment for age, sex, BMI, smoking, alcohol consumption status, eGFR, LDL-C and statin use. Model 2,5,8,11 included adjustment for the variables in Model 1,4,7,10 respectively and additional adjustment for clinic SBP when examining 24 h/daytime/nighttime SBP as the independent variable. Model 3,6,9,12 included adjustment for the variables in Model 1,4,7,10 respectively and additional adjustment for nighttime SBP when examining clinic SBP as the independent variable. Probability values were 2-tailed and P < 0.05 was considered statistically significant for all comparisons.