A Randomized Controlled Trial of Thyroid Hormone Supplementation in Hemodialysis Patients

Hypothyroidism, defined by elevated thyrotropin (TSH) levels, is a common endocrine complication in chronic kidney disease patients, and prior evidence shows that higher TSH levels, even within the normal laboratory range, are strongly associated with impaired quality of life and cardiovascular disease in this population. Levothyroxine is one of the most frequently prescribed medications in chronic kidney disease, yet its efficacy and safety in these patients have not been well-studied. Hence, this study will investigate 1) whether levothyroxine improves patient-centered (e.g., health-related quality of life, physical performance, strength) and 2) cardiovascular (e.g., coronary artery calcification, endothelial function, systolic function) outcomes in dialysis patients, and 3) if thyroid hormone replacement exerts classic metabolic effects (i.e., changes in body fat and resting energy expenditure) in this population.

Data spanning over three decades show that hypothyroidism is highly prevalent in the chronic kidney disease (CKD) population, affecting 25% of those receiving dialysis therapy. In the general population hypothyroidism, defined by elevated thyrotropin (TSH) levels, has been associated with impaired health-related quality of life (HRQOL) and cardiovascular (CV) morbidity and mortality, but until recently there was a paucity of data regarding its prognostic implications in CKD. Our research has been the first to show a link between high-normal TSH levels and worse HRQOL Short Form 36 scores in dialysis patients, particularly among subscales centered on physical health (e.g., physical function, energy/fatigue). Our studies have also advanced the field by showing that elevated TSH levels even within the "normal" range (\>3.0mIU/L) are associated with heightened risk of CV disease and death across multiple dialysis cohorts. However, there remains considerable controversy as to 1) whether thyroid dysfunction is causally associated with adverse patient-centered and CV outcomes, and 2) if elevated TSH levels represent thyroid functional disease vs. non-thyroidal illness in CKD. While levothyroxine is one of the most commonly prescribed medications in CKD, little is known about its efficacy in this population.

To address these knowledge gaps, we propose to conduct a randomized double-blind placebo-controlled trial among 336 hemodialysis patients with high-normal or subclinical hypothyroid range serum TSH levels to determine the effects of 24 weeks (i.e., 6 months) of levothyroxine vs. placebo on 1) HRQOL Short Form 36 (SF36) Physical Component Score and 2) coronary artery calcifcation (CAC) progression (co-primary endpoints).

As secondary endpoints, we will also examine 1) HRQOL measured by the ThyPRO survey, 2) physical performance, 3) endothelial function, 4) vascular calcification inhibitor levels, and 5) total body fat percentage. In a sub-study of 108 hemodialysis patients, we will also examine exploratory secondary endpoints of 1) muscle strength, 2) systolic function, and 3) resting energy expenditure.

Eligibility Criteria:
Inclusion Criteria:

* Age 18-75 years old
* Received hemodialysis at least four weeks
* Have two consecutive thyrotropin (TSH) levels \>3.0-10.0mIU/L during the screening period
* Have normal free thyroxine (FT4) levels
* Have ability to provide written informed consent

Exclusion Criteria:

* Active treatment with thyroid hormone supplementation or anti-thyroid medications
* Active receipt of dialysis
* Prior kidney transplantation
* Life expectancy less than six months
* Active malignancy or prior thyroid malignancy
* Active pregnancy or planning a pregnancy
* Active coronary ischemia or atrial fibrillation (evaluated by EKG)
* Active congestive heart failure exacerbation
* Osteoporosis
* Weight in excess of 450 lbs.
* Hyperthyroidism as determined by TSH \<0.5mIU/L during the screening period, anti-thyroid medication use, or hyperthyroidism diagnosis