Effectiveness of Two Icodextrin Exchanges on Fluid Status and Blood Pressure Control Compared to a Single Icodextrin Exchange

1. Background and Rationale Fluid overload and hypertension are among the most prevalent and clinically significant complications in pediatric patients receiving chronic peritoneal dialysis (PD). In children, extracellular volume expansion contributes to left ventricular hypertrophy, increased arterial stiffness, impaired growth, and heightened cardiovascular morbidity and mortality. These complications are especially burdensome in low- and middle-income countries (LMICs), where limited access to automated PD, hemodialysis facilities, and antihypertensive medications leads to frequent hospitalizations, increased costs, and higher rates of dialysis modality switch.

Icodextrin is a glucose polymer solution used in PD as a glucose-sparing osmotic agent. Unlike glucose-based solutions that rely on crystalloid osmosis and are subject to rapid dissipation of the osmotic gradient, icodextrin provides sustained ultrafiltration (UF) through colloid osmosis. Its absorption via lymphatic pathways leads to more stable osmotic gradients, particularly during long dwell periods. However, pediatric studies show inconsistent results when icodextrin is used once daily in a single long daytime dwell, with some children demonstrating inadequate fluid removal and variable blood pressure (BP) control.

Emerging observational data and small pilot studies suggest that dividing the icodextrin dose into two separate exchanges per day (2-Ico) may improve ultrafiltration efficiency by maintaining a more consistent osmotic gradient throughout the 24-hour cycle. This approach may also reduce fluctuations in intravascular volume, improve BP stability, and enhance patient comfort. To date, however, no randomized controlled trial (RCT) has rigorously assessed the safety, efficacy, and tolerability of two daily icodextrin exchanges in the pediatric population.

This investigator-led multicenter randomized crossover trial addresses this evidence gap and aims to determine whether two daily icodextrin exchanges improve fluid status, BP control, and patient-related outcomes compared with a single daily icodextrin exchange in children on chronic PD. 2. Study Objectives

Primary Objective:

• To determine whether two daily icodextrin exchanges (2-Ico) provide superior ultrafiltration and blood pressure control compared to one daily icodextrin exchange (1-Ico) in children on PD.

Secondary Objectives:

* To evaluate the effect of 2-Ico versus 1-Ico on:

1. Objective measures of fluid status (bioimpedance spectroscopy, interdialytic weight change, ambulatory BP monitoring). 2. Solute clearance parameters, including Kt/V and creatinine clearance. 3. Safety and tolerability, including infection rates, biochemical complications, and episodes of symptomatic hypotension. 4. Patient- and caregiver-reported quality-of-life outcomes, treatment satisfaction, and burden of care.

3\. Study Hypothesis Two daily icodextrin exchanges are safe, feasible, and more effective than a single daily exchange in improving fluid overload and BP control in children receiving chronic PD.

4\. Study Design This is a prospective, multicenter, randomized, open-label, crossover trial. * Population (P): Children aged 5-18 years on CAPD or CCPD for ≥4 weeks with persistent hypertension (mean arterial pressure \>95th percentile on 24-hour ABPM or requiring antihypertensive medication). * Intervention (I): Two icodextrin exchanges per day (2-Ico). * Comparator (C): One icodextrin exchange per day (1-Ico). * Outcomes (O): Primary - change in 24-hour ultrafiltration volume. Secondary - changes in fluid status, BP, solute clearance, safety, and patient-reported outcomes. * Timeframe (T): 12-week participation per patient, including a 4-week run-in and two 4-week randomized intervention phases (crossover design).

Randomization and Crossover:

Participants will be randomized 1:1 to either sequence (1-Ico → 2-Ico or 2-Ico → 1-Ico) following the run-in period. No washout is required, as each phase is of sufficient duration to reflect steady-state physiology.

5\. Intervention Details

Icodextrin Prescription:

* Fill volume: 550 mL/m² body surface area (BSA), based on pediatric optimization studies (Rousso et al., Pediatr Nephrol 2016; doi:10.1007/s00467-016-3398-1). * Minimum dwell time: 7 hours (acceptable range 7-10 hours). * Total daily exposure: one or two exchanges depending on allocation arm.

CAPD Program:

* Standard CAPD: four daily exchanges. * 1-Ico arm: One icodextrin dwell (typically overnight), with three glucose-based dwells. * 2-Ico arm: Two icodextrin dwells (overnight and first daytime dwell), with two glucose-based dwells. * To minimize cost, one icodextrin bag may be aseptically split for two exchanges without patient disconnection. Families will receive structured retraining to reduce infection risk.

CCPD Program:

* Standard CCPD: nocturnal automated glucose-based exchanges followed by a long daytime dwell. * 1-Ico arm: One icodextrin dwell (daytime). * 2-Ico arm: Two icodextrin dwells (one daytime, one post-school dwell, each ≥7 hours).

Adjunct Management:

* Glucose-based PD fluid strength and dwell times may be adjusted by treating physicians according to patient volume status. * Fluid and sodium intake restrictions will remain constant throughout the study. * All changes will be recorded on standardized case report forms. 6. Outcomes

Primary Outcome:

• Mean change in 24-hour ultrafiltration volume between 1-Ico and 2-Ico phases.

Secondary Outcomes:

1. Fluid Status:

1. Bioimpedance spectroscopy (extracellular water/total body water ratio). 2. Interdialytic weight change. 3. Ambulatory BP monitoring (24-hour mean, systolic/diastolic load). 2. Solute Clearance:

1. Weekly Kt/V (urea). 2. Creatinine clearance (mL/min/1.73m²). 3. Safety and Tolerability:

1. Incidence of peritonitis and exit-site infections. 2. Symptomatic hypotension episodes. 3. Electrolyte disturbances (hyponatremia, hypokalemia). 4. Biochemical safety parameters (glucose, serum lipids). 4. Patient- and Caregiver-Reported Outcomes:

1. Quality of life (PedsQL questionnaire). 2. Treatment satisfaction (Likert scale surveys). 3. Caregiver burden (validated caregiver strain index).

7\. Risks and Benefits

Risks:

* Physical: venipuncture discomfort, transient hypotension, peritonitis due to additional bag handling. * Psychological: survey-related stress, inconvenience of post-school exchange. * Data: low risk of confidentiality breach (mitigated by secure data management).

Benefits:

* Direct: Improved fluid control, BP stabilization, and potential reduction in hospitalizations and antihypertensive medication use. * Indirect: Evidence generation to guide PD practice in LMICs, increased global knowledge on icodextrin optimization in pediatric PD.

• To measure caregiver burden [Time frame: 12 weeks]