Effect of Dry-weight Probing Guided by Lung-Ultrasound on Ambulatory Blood Pressure and Arterial Stiffness in Hemodialysis Patients (LUST Sub-Study)

Patient selection and study preparations Potentially eligible hemodialysis patients, not fitting the exclusion criteria, will provide written informed consent and will be evaluated for the diagnosis of hypertension. If patients are treated with antihypertensive therapy, a brief-wash out from medications period will take place and home BP will be monitored up to a maximum of 4 weeks. During this period BP ≥160/110 mmHg will be a threshold for further medication withdrawal. Hypertension diagnosis will be based on mean BP values ≥135/85 mmHg with home BP monitoring the days after the mid and last dialysis of the week for 2 consecutive weeks using a validated self-inflating automatic oscillometric device (cuff with bladder size encircling at least 80% of arm circumference and covering two thirds of arm length). Every patient will be asked to conduct both morning and evening BP measurements at the level of brachial artery after 5 min of rest and with two measurements per occasion taken 2 min apart according to the European Society of Hypertension 2013 guidelines. The mean of the last measurements would be used. Study period A total number of 70 eligible patients undergoing hemodialysis in the Hemodialysis Unit of the Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Greece and in affiliated Hemodialysis Units in Northern Greece, as well in the Hemodialysis Units of the Department of Nephrology University Clinical Centre Maribor, Slovenia will participate in the study. In all potentially eligible patients full medical history, as well as demographic characteristics and drug treatment will be recorded, followed by a detailed physical examination. Patients that meet the inclusion and exclusion criteria, will be randomized with a ratio of 1:1 into two equal groups consisting of 35 patients. In the intervention group a specific treatment strategy for dry-weight reduction will be applied guided by lung ultrasound, whereas in the control group standard-of-care treatment will be applied guided by conventional clinical criteria. Blood samples for hematological and biochemical laboratory tests will be collected at baseline prior to a mid-week dialysis session; these tests will correspond to the routine monthly laboratory tests of the patients. In the intervention group UF regimen and dry-weight will be guided by the number of pre-dialysis US-B lines measured by lung ultrasound prior to a mid-week dialysis session. In patients who will be included in both the main study (LUST) and the present sub-study (i.e. additional inclusion criteria of LUST study: history of myocardial infarction with or without ST elevation or unstable angina, acute coronary syndrome documented by ECG recordings and cardiac troponins or stable angina pectoris with documented coronary artery disease by prior coronary angiography or ECG or dyspnea class III-IV NYHA), a total number of ≥15 US-B lines indicates moderate to severe lung congestion; UF will be intensified in these patients. They will undergo dry-weight reduction less than 0.2 kg/session (0.6 kg/week) with a maximum UF rate ≤10 ml/kg/h, so that episodes of hemodynamic instability and hypotension are minimized. If needed longer and/or additional dialysis sessions will be applied to a maximum of 5 hours/session or 4 sessions/week. US-B lines measurements will be repeated at least once a week (before and after a mid-week dialysis session) until the treatment goal is achieved (\<15 US-B lines) over a period of 8 weeks. Thereafter, lung ultrasound will be conducted once a month. In patients without pulmonary congestion at pre-dialysis baseline (\<15 US-B lines), no UF intensification will be applied and US-B lines will be measured on a weekly basis. Patients in the intervention group with \<15 US-B lines at baseline who will develop clinical signs of pulmonary congestion and/or ≥15 US-B lines at any time will be treated according to those with lung congestion at baseline. In patients who will be included only in the present sub-study, and are expected to have hypertension with better cardiac function and, possibly, less degree of lung congestion compared to the typical subjects of the main LUST study, UF will be intensified on the basis of a total number of ≥5 US-B lines which indicates mild to moderate lung congestion. These patients will also undergo careful dry-weight reduction less than 0.2 kg/session (0.6 kg/week) with a maximum UF rate ≤10 ml/kg/h, so that episodes of hemodynamic instability and hypotension are minimized. If needed longer and/or additional dialysis sessions will be applied to a maximum of 5 hours/session or 4 sessions/week. US-B lines measurements will be repeated at least once a week (before and after a mid-week dialysis session) until the treatment goal is achieved (\<5 US-B lines) over a period of 8 weeks. Thereafter, lung ultrasound will be conducted once a month. In patients without pulmonary congestion at pre-dialysis baseline (\<5 US-B lines), no UF intensification will be applied and US-B lines will be measured on a weekly basis. Patients in the intervention group with \<5 US-B lines at baseline who will develop clinical signs of pulmonary congestion and/or ≥5 US-B lines at any time will be treated according to those with lung congestion at baseline. Reduction of post-dialysis weight with UF intensification to achieve treatment goal will be pursued for 8 weeks. During this period BP should be maintained in levels \<160/110 mmHg. If BP exceeds these levels, per protocol drug therapy will be initiated. As a first step, carvedilol per os will be administered on a starting dose of 3.125 mg b.i.d. up to a maximum tolerated dose (≤25 mg b.i.d.) until BP levels are \<160/110 mmHg or until patient experiences signs of bradycardia (HR \<60 bpm) or other adverse effects. As a second step of drug therapy, irbesartan will be initiated on a starting dose of 75 mg daily up to maximum tolerated dose (≤300 mg daily) until BP levels are \<160/110 mmHg or any adverse effects are presented. Finally, amlodipine on a starting dose of 5 mg daily up to maximum tolerated dose (≤10 mg daily) will be administered on failure of the two previous steps to achieve BP levels \<160/110 mmHg. If BP is still not controlled at goal, any antihypertensive class can be added according to treating physician's choice. In the control group follow-up, dry-weight and UF regimen will be guided only by conventional clinical and laboratory criteria. Blood pressure and blood pressure changes over time, pedal edema, presence or absence of dyspnea, body weight gain between dialysis and hemodynamic instability during dialysis session will be some of the clinical criteria that will determine possible post-dialysis weight adjustments in these patients. The use of lung ultrasound to estimate lung congestion will not be allowed in these patients. A threshold of BP 160/110 mmHg will be set for the first 8 weeks of the study. If BP exceeds these levels, per protocol drug therapy will be initiated as mentioned in the intervention group. After 8 weeks of treatment, per protocol drug therapy will be performed in patients from both study groups, aiming at maintaining Home BP levels \<135/85 mmHg. The primary and secondary measurements of the study will be carried in prespecified time-points that are listed below: Study-Point 1: Participants in the study will be asked to come to their dialysis unit 30 min before the start of the first or second dialysis of the week. A Mobil-O-Graph monitor with a cuff of appropriate size will be fitted to and BP will be recorded for 48 hours. The device will be programmed to collect data every 20 minutes, except for 23:00 to 07:00 (data collection every 30 minutes). An ABPM would be considered successful if \>80% of recordings are valid with no more than two non-consecutive day hours (07.00-23.00 hours) with fewer than two valid measurements, and no more than one night hour (23.00-07.00 hours without valid recording, according to standard recommendations for ABPM. Patients with unsuccessful 24-hour ABPM will repeat the measurement a week later. Participants in the study will further come to the echocardiography unit on the first or the second interdialytic day of the week (Tuesday or Thursday for patients on M-W-F schedule and Wednesday or Friday for patients on T-T-S schedule) exactly 24 hours after the scheduled starting time of the previous dialysis session. All study participants will undergo an echocardiography study, as well as US-B lines measurement with lung ultrasound. Body composition would be estimated with the use of Bioelectrical Impedance Analysis. PWV and AIx recordings with the Sphygmocor device would be taken. The results from this echocardiographic study and 48-hour ABPM will be used as the baseline reference.. Following echocardiographic assessment, patients will be randomized in 1:1 ratio in the intervention and control arms with permuted blocks of 4 subjects, using a computer-generated randomization schedule stratified by sex and center. Participants in the study will be asked to come to their dialysis unit one hour earlier than their second (Wednesday or Thursday) or the third (Friday or Saturday) dialysis session of the week is scheduled, following at least a 8-hour fast and without having received their morning medication. The ABPM device will be removed and checked for completeness. Patients with unsuccessful 48-hour ABPM will repeat the measurement and all further evaluations a week later. Body weight will be measured with the use of validated electronic weighting scales. Height will be also evaluated for the BMI calculation. Office blood pressure measurements will be acquired after 5 min of rest (sitting posture) with the use of a validated oscillometric device or standard mercury sphygmomanometer at the level of brachial artery in the contralateral arm of the side where vascular access is located. Venous blood specimens will be collected for routine hematological and biochemical laboratory testing, as mentioned before. A lung ultrasound will be conducted in all study participants in the intervention group using the GE VScan lung ultrasound device, 15 minutes before hemodialysis session initiation. With patient in a lying posture pre-dialysis US-B lines will be measured in both lungs, while the transducer is placed vertically from the second up to the fifth intercostal space consecutively, along the parasternal, the mid-clavear, the anterior axillary and the mid axillary lines. All measurements will be performed in a quiet room with controlled air temperature (approximately 22 ° C) The sum of the US-B lines produces a score (US-B lines score) and UF regimen will be guided accordingly. In patients who will be include in both the main LUST study and the present sub-study with ≥15 US-B lines and in patients who will be included only in this sub-study with ≥5 US-B lines, UF will be intensified and dry-weight will be reduced according to the value of US-B lines score over a period of 8 weeks (Figure 2). Thresholds in dry-weight reduction and UF rates will be applied and if needed longer and/or additional dialysis sessions will be conducted as mentioned before. In the control arm standard-of-care treatment will be applied guided by conventional clinical criteria. Afterwards all study participants from both arms will undergo their scheduled dialysis session. Over the period of the first 8 weeks of the study US-B lines measurements with lung ultrasound will be repeated at least once a week (before and after a mid-week dialysis session) in all patients in the active arm. During this period per protocol drug therapy will be initiated if BP exceeds a threshold of home BP 160/110 mmHg. Study Point 2: Two months (8 weeks) after baseline all patients will be subjected again in the examinations described at Study Point 1 (i.e. 48-hour ABPM, echocardiography, bioimpedance analysis and pulse wave tonometry) exactly in the same manner with regards to the scheduled hemodialysis sessions. If treatment goal is achieved during this post-dialysis US-B lines measurement, lung ultrasounds will be conducted once a month from this point on. Patients in the intervention group who have achieved the treatment goal of post-dialysis US-B lines score at previous evaluations and who will develop clinical signs of pulmonary congestion and/or ≥15 or ≥5 US-B lines according to the patients' stratification at any time will be treated according to those with lung congestion at baseline. A threshold of Home BP \<135/85 mmHg will be set after this point and when needed the same per protocol drug therapy will be performed in patients from both study groups. Study Point 3: One year after their first evaluation all patients will undergo all examinations described in baseline, with a similar order.