Imaging Sodium and Lymphatics in Lymphedema

Lymphedema of Leg Clinical Trial

Official title:

Imaging Sodium and Lymphatics in Lymphedema

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05242900
• Other study ID #: 202424
• Secondary ID: 1R01HL155523-01
• Status: Recruiting
• Start date: October 10, 2021
• Est. completion date: December 2025

Study information

• Verified date: June 2023
• Source: Vanderbilt University Medical Center
• Contact: Study coordinator
• Phone: 615-875-9935
• Email: salt[@]vumc.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Gender: Female
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Biologically Female
• Age range = 18-80 years
• BMI range = 18 to 40 kg/m2

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Fibrosis
• Lymphedema
• Lymphedema of Leg
• Lymphedema, Secondary

Intervention

Procedure:
• Complete decongestive therapy
The investigators will identify participants undergoing clinically-indicated interventions that they are already receiving for their routine clinical management (complete decongestive physical therapy). They will make no evaluation of the efficacy of these procedures, but rather will test fundamental hypotheses regarding lymphatic clearance of tissue sodium.

Other:
• Standard imaging protocol
The standard imaging protocol entails noninvasive magnetic resonance imaging techniques including sodium and lymphatic angiography.

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Concentration of tissue sodium content	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.	Baseline to completion of routine course of physical therapy (approximately 6 weeks)
Primary	Number of participants that changed lymphedema severity	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.	Baseline to completion of routine course of physical therapy (approximately 6 weeks)
Primary	Concentration of tissue sodium content 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.	Baseline
Primary	Quantification of lymphatic states in extremities at 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.	Baseline
Secondary	Concentration in limb extracellular water	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 and after a routine course of physical therapy (approximately 6 weeks)
Secondary	Concentration in skin water	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.	Baseline and after a routine course of physical therapy (approximately 6 weeks)
Secondary	Change in skin elasticity	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.	Baseline and after a routine course of physical therapy (approximately 6 weeks)
Secondary	Concentration of limb extracellular water at 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.	Baseline
Secondary	Baseline skin water	For participants at-risk or with lymphedema, baseline skin water (% water) will be estimated in the extremities to study tissue composition in lymphedema.	Baseline
Secondary	Baseline skin elasticity	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.	Baseline