Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis

Study Overview
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Brief Summary
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Hypothesis: Patients starting peritoneal dialysis with a glucose-based regimen have high sympathetic activity in response to an increase in leptin and insulin. Converting patients from a regimen of only glucose containing dialysate to a regimen with non-glucose-based solution, icodextrin, will reduce the insulin and leptin levels and will reverse dialysis-induced increases in sympathetic activity.

Detailed Description
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Cardiovascular mortality remains higher among patients treated with peritoneal dialysis as compared to patients treated with hemodialysis. Sympathetic hyperactivity is considered a significant emerging risk factor for cardiovascular mortality among patients with ESRD (End-Stage Renal Disease). Sympathetic activity, via its hemodynamic effects and trophic effects, and in interaction with RAAS (Renin Angiotensin Aldosterone System), does play a major role in cardiac and vascular remodelling, development of LVH and vascular hypertrophy, as well as progression to CHF. Glucose-based dialysate induces hyperinsulinemia and hyperleptinemia. We propose that hyperleptinemia induced by glucose-based peritoneal solution is a significant contributing factor to sympathetic hyperactivity in ESRD patients treated with PD, and could be prevented by non-glucose-based PD solution such as icodextrin-based. Adult patients with ESRD starting PD as their first renal replacement therapy modality will be studied. Patients will be recruited 1-3 weeks prior to starting PD treatment. At baseline, specific studies for microneurography (MSNA), fasting plasma insulin, leptin, catecholamines and brain natriuretic peptide (BNP) will be performed. EKG will be recorded and digitized for further assessment of heart rate variability using power spectral analysis. Extracellular fluid volume status will be assessed by bioelectrical impedance. Central vascular volume will be assessed from inferior vena cava (IVC) by heart ultrasound. Consequently 24-h ambulatory blood pressure monitoring(ABPM)and a 24-h urine collection for urea clearance and creatinine clearance will be done. All participants into the study will receive a PD treatment for 6 weeks with standard glucose-based PD solution Dianeal. The specific studies are repeated at 6 weeks.Then, patients will be randomized to one of the two groups (arms). One group will continue with Dianeal PD solution for another 12 weeks. The other group will receive Dianeal during the day and Extraneal, icodextrin or non-glucose based solution, during the night only, for the next 12 weeks. The specific studies are repeated at 12 weeks after randomization (18 weeks of PD treatment).

Official Title
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Effects of Non-Glucose-Based Peritoneal Dialysis Solution EXTRANEAL on Changes in Leptin Levels and Sympathetic Activity Induced by Conventional Glucose-Based Dialysate DIANEAL in Patients on Peritoneal Dialysis

Conditions
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End-stage Renal Disease (ESRD), Kidney Disease

Intervention / Treatment
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* Other: DIANEAL
* Other: EXTRANEAL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (age 18 years and older) Patients with end-stage renal disease(ESRD)/chronic kidney disease(CKD)stage 5 Exclusion Criteria: Diabetes Mellitus Acute coronary syndrome in the past 6 months Cardiac arrhythmias (2nd and 3rd degree heart block or premature ventricular complexes in Lown classes 4 or 5) Symptoms suggestive of obstructive or central sleep apnea (with a score of > 10 on Epworth sleepiness scale) Patients taking Clonidine Body mass index (BMI) > 34 Patients unable to give consent Pregnant women Patients with leg injury involving nerve damage Patients taking anticoagulant medication Patients with significant bleeding disorder or liver disorder Hemoglobin <1.05 g/dl at the time of initiation of therapy patients with unilateral or bilateral nephrectomy Planned kidney transplant in the next 4 months Life expectancy under 6 months Oliguria (urine output less than 400 ml per day)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DIANEAL<br>One group of patients will start peritoneal dialysis with the glucose-based solution (DIANEAL) for 6 weeks, then will continue with the same type of solution for another 12 weeks. | Other: DIANEAL<br>* Weeks 1 to 6 (6 weeks): CAPD (Continuous Ambulatory Peritoneal Dialysis)patients will receive three 4-6 hour dwells of DIANEAL during the day and one 8-10-hour dwell of DIANEAL during the night CCPD (Continuous Cycler Peritoneal Dialysis)patients will receive one-two 4-6 hour dwells of DIANEAL during the day and three to seven 2-4-hour dwells of DIANEAL during the night Weeks 7 to 18 (12 weeks): *same regimen as weeks 1 to 6, for both CAPD and CCPD patients<br>* Other names: Dextrose-based PD solution;|
| Active Comparator: EXTRANEAL<br>The other group of patients will start peritoneal dialysis with the glucose-based solution (DIANEAL) for 6 weeks, then will continue with DIANEAL solution during the day and the non-glucose-based solution, EXTRANEAL, during the night | Other: EXTRANEAL<br>* Weeks 1 to 6 (6 weeks): CAPD (Continuous Ambulatory Peritoneal Dialysis)patients will receive three 4-6 hour dwells of DIANEAL during the day and one 8-10-hour dwell of DIANEAL during the night CCPD (Continuous Cycler Peritoneal Dialysis)patients will receive one-two 8-12-hour dwells of DIANEAL during the day and three to seven 2-4-hour dwells of DIANEAL during the night Weeks 7 to 18 (12 weeks): CAPD (Continuous Ambulatory Peritoneal Dialysis)patients will receive three 4-6 hour dwells of DIANEAL during the day and one 8-10-hour dwell of EXTRANEAL during the night CCPD (Continuous Cycler Peritoneal Dialysis)patients will receive one-two 8-12-hour dwells of DIANEAL during the day and one 8-12-hour dwell of EXTRANEAL during the night<br>* Other names: Icodextrin-based PD solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in muscle sympathetic nerve activity(MSNA) | Muscle sympathetic nerve activity(MSNA) is measured by microneurography at baseline (before starting peritoneal dialysis) 6 weeks of PD 18 weeks of PD(12 weeks after randomization) MSNA increases on a glucose-based dialysis regimen and may decrease by adding non-glucose-based solution | 6 weeks on PD and 18 weeks on PD | 
| Changes in leptin levels | Plasma leptin increases on a glucose-based peritoneal dialysis regimen and may decrease by adding non-glucose-based solution to the dialysis regimen | 6 weeks on PD and 18 weeks on PD | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in blood pressure as assessed from 24-hour ambulatory blood pressure monitor (ABPM) | Blood pressure will be assessed with 24-hour ABPM at baseline, 6 weeks on PD and 18 weeks after starting peritoneal dilaysis. Summary measures of each day and night period include average systolic and diastolic BP as well as % nocturnal dipping. These summary measures can predict cardiovascular events more accurately than casual BP measures | 6 weeks on PD and 18 weeks on PD | 
| Changes in extracellular volume assessed by bioelectrical impedance (BIA) | Bioelectrical impedance directly measures extracellular fluid volume and total body water. The test is based on the ability to detect differences in the conductive properties of a cell by measuring its resistance (impedance) to electrical current. The technique is reliable for tracking sequential changes in extracellular fluid volume. | 6 weeks on PD and 18 weeks on PD | 
| Changes in heart rate variability | During the microneurography testing, EKG is recorded. Heart rate and heart rate variability(HRV) will be analyzed from EKG data at baseline, 6 weeks and 18 weeks after starting dialysis. | 6 weeks on PD and 18 weeks on PD | 
| Changes in central intravascular volume assessed by cardiac ultrasound | Central intravascular volume will be assessed by measuring inferior vena cava (IVC) diameter during cardiac ultrasound at baseline, 6 weeks and 18 weeks on dialysis treatment | 6 weeks on PD and 18 weeks on PD | 
| Changes in plasma catecholamines levels | *Plasma catecholamines (epinephrine and norepinephrine) increase on a glucose-based peritoneal dialysis regimen and may decrease by adding non-glucose-based solution to the dialysis regimen | 6 weeks on PD and 18 weeks on PD | 
| Changes in BNP (Brain Natriuretic Peptide)levels | *Brain Natriuretic Peptide (BNP)increases on a glucose-based peritoneal dialysis regimen and may decrease by adding non-glucose-based solution to the dialysis regimen | 6 weeks on PD and 18 weeks on PD | 
| Changes in plasma insulin levels | *Plasma insulin increases on a glucose-based peritoneal dialysis regimen and may decrease by adding non-glucose-based solution to the dialysis regimen | 6 weeks on PD and 18 weeks on PD | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peritoneal Dialysis, Dialysis Solutions, Artificial Kidney, Renal Replacement Therapy, Renal Dialysis, Sympathetic Nervous System, Leptin, Icodextrin