Imaging Sodium and Lymphatics in Lymphedema
- Conditions
- Lymphedema, SecondaryLymphedema Related FibrosisLymphedema of Leg
- Interventions
- Other: Standard imaging protocolProcedure: Complete decongestive therapy
- Registration Number
- NCT05242900
- Lead Sponsor
- University of Virginia
- Brief Summary
Recent evidence supports lymphatic regulation of tissue sodium handling, however fundamental gaps persist in knowledge regarding the role of lymphatics in human diseases of sodium dysregulation. The goal of this work is to apply novel, noninvasive imaging tools to measure relationships between lymphatic function and tissue sodium in patients with well-characterized lymphedema. Findings are intended to inform mechanisms of lymphatic clearance of tissue sodium, and provide novel imaging biomarkers of lymphedema progression and treatment response.
- Detailed Description
The overall goal of this work is to apply and evaluate novel, noninvasive MRI technologies sensitive to sodium and lymphatic circulation in patients with well-characterized lymphatic disease. The results will clarify mechanisms of lymphatic clearance of tissue sodium, and evaluate novel biomarkers of lymphedema risk, progression, and treatment response. Recent evidence supports that lymphatics regulate interstitial sodium levels. When lymphatic clearance is impaired, hypertonic interstitial sodium results in tissue swelling, skin sodium storage, and poor blood pressure control. When lymphatic clearance is impaired in rodent models of lymphedema, lymph stasis and inflammation ensue, leading to tissue remodeling and fibrosis. These data suggest, but do not confirm, that impaired lymphatic clearance contributes to tissue sodium storage and fibrosis. However, this possibility has not been investigated rigorously owing to a lack of clinically-feasible measurement tools sensitive to sodium and lymphatics in humans. To address these gaps in knowledge, the investigators have developed a noninvasive MR lymphangiography (MRL) approach to quantify lymphatic vasculature in patients with unilateral lymphedema of the upper-extremities. They confirmed lateralized lymph stasis and enlarged lymphatic collector cross-sectional area that reduced following manual lymphatic drainage therapy. In parallel to these studies, the investigators optimized noninvasive sodium 23Na MRI for measurement of tissue sodium content (TSC) in the legs of patients with lymphatic insufficiency due to lipedema. In preliminary data, they demonstrate these methods together for the first time in patients with cancer-related lower-extremity lymphedema (LEL) who display significantly elevated skin TSC compared to controls (24.2±6.8 vs. 14.2±1.8 mmol/L, p\<0.001, effect size Cohen's d=1.2). Evidence of lymphatic impairment on MRL and tissue sodium deposition are differential in patients with increasing disease severity, and modified by lymphatic complete decongestive therapy (CDT), motivating the following hypotheses:
Hypothesis (1): Skin TSC inversely correlates with lymphatic flow velocity; lymphatic flow velocity reduces and TSC increases following LN removal in patients at risk for lymphedema. Hypothesis (2): Skin TSC positively correlates with lymphedema stage; subcutaneous sodium co-localizes with fibrotic tissue in patients with lymphedema and fibrosis. Hypothesis (3): Skin TSC decreases and lymphatic flow velocity increases after CDT in affected limbs with LEL; imaging metrics are reproducible in healthy volunteers. Impact: Results will demonstrate relationships between tissue sodium and lymphatic dysfunction in human disease using noninvasive MRI technologies. This will outline clinically-feasible biomarkers of lymphedema risk, progression, and treatment response which could have significance for future clinical trials that seek to evaluate the impact of emerging lymphatic therapies on tissue sodium storage.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 75
- Biologically Female
- Age range = 18-80 years
- BMI range = 18 to 40 kg/m2
- Primary lymphedema
- Contraindication to 3T MRI
- Pregnant
- Severe claustrophobia
- Inability to provide written, informed consent
- Active infection anywhere in the body, or open wound on the lower-extremities or at locations for measurement
- Subjects who cannot adhere to the experimental protocols for any reason
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description With lymphedema Standard imaging protocol Participants with leg lymphedema At-risk for lymphedema Standard imaging protocol Participants at-risk for leg lymphedema With lymphedema undergoing complete decongestive therapy (CDT) Standard imaging protocol Participants with leg lymphedema undergoing routine complete decongestive therapy (CDT) With lymphedema undergoing complete decongestive therapy (CDT) Complete decongestive therapy Participants with leg lymphedema undergoing routine complete decongestive therapy (CDT)
- Primary Outcome Measures
Name Time Method Number of participants that changed lymphedema severity Baseline to completion of routine course of physical therapy (approximately 6 weeks) Research participants will undergo periodic noninvasive magnetic resonance lymphangiography after clinically-indicated complete decongestive therapy. The study team will measure change in quantified lymphatic stasis in the treated extremities to study effects of lymphatic stimulation on lymphedema severity.
Concentration of tissue sodium content Baseline to completion of routine course of physical therapy (approximately 6 weeks) Research participants will undergo periodic noninvasive sodium MRI after clinically-indicated complete decongestive therapy. The study team will measure change in tissue sodium content (mmol/L) in the treated extremities to study effects of lymphatic stimulation on sodium clearance.
Concentration of tissue sodium content baseline Baseline For participants at-risk or with lymphedema, noninvasive sodium MRI will measure tissue sodium content (mmol/L) in the extremities to study sodium in lymphedema.
Quantification of lymphatic states in extremities at baseline Baseline For participants at-risk or with lymphedema, noninvasive MR lymphangiography will measure quantified lymphatic stasis in the extremities to study lymphatic physiology in lymphedema.
- Secondary Outcome Measures
Name Time Method Baseline skin water Baseline For participants at-risk or with lymphedema, baseline skin water (% water) will be estimated in the extremities to study tissue composition in lymphedema.
Concentration in skin water Baseline and after a routine course of physical therapy (approximately 6 weeks) Research participants will undergo periodic assessment by tissue dielectric probe to estimate skin water (% water) after clinically-indicated complete decongestive therapy. The study team will measure change in skin water (% water) in the treated extremities to study effects of lymphatic stimulation on tissue composition.
Concentration of limb extracellular water at baseline Baseline For participants at-risk or with lymphedema, baseline limb extracellular water (whole-limb resistance, Ohms) will be estimated in the extremities to study tissue composition in lymphedema.
Concentration in limb extracellular water Baseline and after a routine course of physical therapy (approximately 6 weeks) Research participants will undergo periodic assessment by bioimpedance spectroscopy to estimate limb extracellular water (whole-limb resistance, Ohms) after clinically-indicated complete decongestive therapy. The study team will measure change in limb extracellular water (whole-limb resistance, Ohms) in the treated extremities to study effects of lymphatic stimulation on tissue composition.
Baseline skin elasticity Baseline For participants at-risk or with lymphedema, baseline skin elasticity (Newtons of induration) will be estimated in the extremities to study tissue composition in lymphedema.
Change in skin elasticity Baseline and after a routine course of physical therapy (approximately 6 weeks) Research participants will undergo periodic assessment by fibrometer probe to estimate skin elasticity (Newtons of induration) after clinically-indicated complete decongestive therapy. The study team will measure change in skin elasticity (Newtons of induration) in the treated extremities to study effects of lymphatic stimulation on tissue composition.
Trial Locations
- Locations (1)
University of Virginia
🇺🇸Charlottesville, Virginia, United States