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Imaging Sodium and Lymphatics in Lymphedema

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University of Virginia

Status

Active, not recruiting

Conditions

Lymphedema, Secondary
Lymphedema of Leg
Lymphedema Related Fibrosis

Treatments

Procedure: Complete decongestive therapy
Other: Standard imaging protocol

Study type

Observational

Funder types

Other
NIH

Identifiers

NCT05242900
302403
1R01HL155523-01 (U.S. NIH Grant/Contract)
202424

Details and patient eligibility

About

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.

Full 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.

Enrollment

75 estimated patients

Sex

Female

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

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

Trial design

75 participants in 3 patient groups

At-risk for lymphedema
Description:
Participants at-risk for leg lymphedema
Treatment:
Other: Standard imaging protocol
With lymphedema
Description:
Participants with leg lymphedema
Treatment:
Other: Standard imaging protocol
With lymphedema undergoing complete decongestive therapy (CDT)
Description:
Participants with leg lymphedema undergoing routine complete decongestive therapy (CDT)
Treatment:
Other: Standard imaging protocol
Procedure: Complete decongestive therapy

Trial contacts and locations

1

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Central trial contact

Study coordinator

Data sourced from clinicaltrials.gov

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