Sixty-four ESRD patients (36 females and 28 males) on CAPD for at least three months, with age ≥18 years and BP higher than 140/90 mm Hg (1 mmHg = 0.133 kPa) after treatment with at least three kinds of antihypertensive drugs in sufficient dosage (maximum dose in the dispensatory) for two weeks were enrolled in this open-label, randomized controlled study. All the patients were clinically stable and free from rheumatic heart disease, congenital cardiopathy, complications with chronic infections and severe liver injury with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) two times higher than the upper limits of normal. Participants were excluded if their BP increased to the level of malignant hypertension, or had cardiac or cerebral events during the observation period, or were unable to follow the trial protocol because of severe adverse effects. The patients performed four 2-liter exchanges a day using the Baxter TwinBag system. Dwell times were generally 4–6 h during the day and 8 h overnight.
Patients were recruited in the Department of Blood Purification of Beijing Chao-Yang Hospital, Capital Medical University in China. The patients were treated with regular antihypertensive drugs, including angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), calcium channel blocker (CCB) and β-receptor blocker or α-receptor blocker.
As a normal control group, age and gender matched, 30 healthy individual (15 females and 15 males) were enrolled for measuring plasma ADMA in this study.
The study was approved by the ethics committee of Beijing Chaoyang Hospital, Capital Medical University, and written informed consent was obtained from each participant.
Participants were randomly assigned by computer-generated random number list to receive either nitrate (nitrate group, n = 32) or non-nitrate medication (non-nitrate group, n = 32) on the basis of primary antihypertensive drugs (including ACEI, ARB, CCB, β-receptor blocker or α-receptor blocker).
The nitrate group was treated with sustained-release isosorbide mononitrate (Imdur; AstraZeneca [Wu Xi] Trading Co. Ltd., Wu Xi, China). The initial dosage was 15 mg daily and the dosage was adjusted once a week to the maximal dosage of 60 mg daily based on BP. The targets for systolic BP (SBP) and diastolic BP (DBP) were 110–139 mm Hg and 70–89 mm Hg (1 mmHg = 0.133 kPa), respectively. The dosage of sustained-release isosorbide mononitrate was reduced or the participants removed in the following circumstances: (a) SBP remained below 110 mm Hg when other kinds of antihypertensive drugs (except ACEI and ARB) were withdrawn; (b) there was a severe adverse effect, which was hard to tolerate, such as headache. The entire duration of treatment was 24 weeks. During the observation period, all patients received other conventional therapy, including correction of anemia (target hemoglobin [Hb] ≥ 110g/L) and maintaining calcium and phosphorus balance.
3.4. Judgement of Medication Frequency
The medication amount was calculated by the defined daily dose (DDD). DDD was the mean daily dose needed in adults to achieve the main goals of treatment [26
]. The medication amount of the antihypertensive drug was defined as the ratio of the daily consumption of a certain drug and the DDD value of the drug. The first choice of antihypertensive drug before recruitment was ACEI and ARB, the second was CCB, β-receptor blocker or α-receptor blocker.
3.5. Blood Pressure Measurements
Blood pressures (SBP and DBP) were measured in the morning, before the second daily fluid drainage of the abdominal cavity, by nursing staff using standard mercury sphygmomanometers on the right arm of seated participants who had rested for at least 5 min; three measurements 2 min apart were averaged.
3.6. Laboratory Investigations
To simulate the actual dialysis condition, all PD patients had a full abdomen at the time of blood sampling. Blood samples for laboratory measurements were drawn from the antecubital vein after the first 2 h of PD exchange with 1.5% dextrose dialysate in an overnight fasting state. Serum was separated immediately by lowspeed centrifugation (4000 rpm for 10 min at 4 °C) and used freshly for analysis by biochemists, who were blinded to classification of subjects as CAPD patients and controls.
Blood cell count, liver and renal function, blood glucose, blood lipid and electrolytes were measured by standard methods in the clinical laboratory.
3.7. ADMA Aassay
ADMA levels were measured using an ELISA kit (Protocol No: 07001, Cardiovasics, Palo Alto, CA, USA). Using a standard curve, the absorbance of the ADMA-antibody horse radish peroxidase complex in the sample was measured at 450 nm. ADMA concentrations of serum samples were determined in μmol/L.
3.8. Left Ventricular Mass Index (LVMI)
Echocardiography was performed to evaluate left ventricular mass index (LVMI) at baseline and after 4, 8, 12 and 24 weeks of treatment. Left ventricular end diastolic dimension (LVDD), interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT) were measured. LVMI was calculated and normalized by height2.7 (LVMI = LVM/height2.7).
3.9. Criterion of Therapeutic Effect on BP and LVH
Full treatment response was defined as BP reaching below 140/90 mmHg, or mean arterial pressure decreasing by ≥15 mm Hg, or mean DBP decreasing by ≥20 mmHg. Partial response was defined as BP not falling below 140/90 mmHg, but the mean arterial pressure decreasing by ≥10 mmHg, or mean DBP decreasing by 10~19 mm Hg, or SBP alone decreasing by ≥30 mmHg. A nonresponse was defined as BP not reaching the above definition or in fact rising. Total response rate was defined as [(full responses + partial responses)/total cases] × 100%.
LVH was defined as LVMI >47 g/m2.7
in female or >50 g/m2.7
in male patients [27
3.10. Data Analysis and Statistics
The SPSS version 13.0 statistics package was employed for the statistical analysis. Measurement data were presented as mean value ± standard deviation (±SD). Comparisons were performed using one-way ANOVA with post hoc analysis (LSD), independent-samples t-test or chi-square test. In addition, covariance analysis, partial correlation analysis and binary logistic regression analysis were performed. A p value < 0.05 was regarded as statistically significant.