Clinical trial NCT05242900: Imaging Sodium and Lymphatics in Lymphedema
Official title: Imaging Sodium and Lymphatics in Lymphedema
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Lymphedema of Leg
Lymphedema, Secondary
Lymphedema Related Fibrosis
Keywords: MRI
sodium
lymphedema
adipose tissue
fibrosis
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Vanderbilt University Medical Center
First posted: 2022-02-16
Enrollment: 75
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The investigators will recruit adults who are at-risk for lower-extremity lymphedema (n=30) or who have lower-extremity secondary lymphedema (n=45).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Concentration of tissue sodium content
timeFrame: Baseline to completion of routine course of physical therapy (approximately 6 weeks)
measure: Number of participants that changed lymphedema severity
timeFrame: Baseline to completion of routine course of physical therapy (approximately 6 weeks)
measure: Concentration of tissue sodium content baseline
timeFrame: Baseline
measure: Quantification of lymphatic states in extremities at baseline
timeFrame: Baseline
Secondary outcomes:
measure: Concentration in limb extracellular water
timeFrame: Baseline and after a routine course of physical therapy (approximately 6 weeks)
measure: Concentration in skin water
timeFrame: Baseline and after a routine course of physical therapy (approximately 6 weeks)
measure: Change in skin elasticity
timeFrame: Baseline and after a routine course of physical therapy (approximately 6 weeks)
measure: Concentration of limb extracellular water at baseline
timeFrame: Baseline
measure: Baseline skin water
timeFrame: Baseline
measure: Baseline skin elasticity
timeFrame: Baseline
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Virginia
name: Rachelle Crescenzi, PhD
role: PRINCIPAL_INVESTIGATOR
References: