Thyroid Status and Death Risk in US Veterans With Chronic Kidney Disease

Abstract

Objective: Given that patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) have a disproportionately higher prevalence of hypothyroidism compared with their non-CKD counterparts, we sought to determine the association between thyroid status, defined by serum thyrotropin (TSH) levels, and mortality among a national cohort of patients with NDD-CKD.

Patients and methods: Among 227,422 US veterans with stage 3 NDD-CKD with 1 or more TSH measurements during the period October 1, 2004, to September 30, 2012, we first examined the association of thyroid status, defined by TSH categories of less than 0.5, 0.5 to 5.0 (euthyroidism), and more than 5.0 mIU/L, with all-cause mortality. We then evaluated 6 granular TSH categories: less than 0.1, 0.1 to less than 0.5, 0.5 to less than 3.0, 3.0 to 5.0, more than 5.0 to 10.0, and more than 10.0 mIU/L. We concurrently examined thyroid status, thyroid-modulating therapy, and mortality in sensitivity analyses.

Results: In expanded case-mix adjusted Cox analyses, compared with euthyroidism, baseline and time-dependent TSH levels of more than 5.0 mIU/L were associated with higher mortality (adjusted hazard ratios [aHRs] [95% CI], 1.19 [1.15-1.24] and 1.23 [1.19-1.28], respectively), as were baseline and time-dependent TSH levels of less than 0.5 mIU/L (aHRs [95% CI], 1.18 [1.15-1.22] and 1.41 [1.37-1.45], respectively). Granular examination of thyroid status showed that incrementally higher TSH levels of 3.0 mIU/L or more were associated with increasingly higher mortality in baseline and time-dependent analyses, and TSH categories of less than 0.5 mIU/L were associated with higher mortality (reference, 0.5-<3.0 mIU/L) in baseline analyses. In time-dependent analyses, untreated and undertreated hypothyroidism and untreated hyperthyroidism were associated with higher mortality (reference, spontaneous euthyroidism), whereas hypothyroidism treated-to-target showed lower mortality.

Conclusion: Among US veterans with NDD-CKD, high-normal TSH (≥3.0 mIU/L) and lower TSH (<0.5 mIU/L) levels were associated with higher death risk. Interventional studies identifying the target TSH range associated with the greatest survival in patients with NDD-CKD are warranted.

Conflict of interest statement

Financial Disclosures:

None of the authors declare conflicts of interest.

Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Association between baseline (Panel A) and time-dependent (Panel B) thyroid status and all-cause mortality

Unadjusted model included serum TSH level. Case-mix model adjusted for covariates in the unadjusted model, as well as age, sex, race, and ethnicity. Expanded case-mix model adjusted for covariates in the case-mix model, as well as diabetes, congestive heart failure, cardiovascular disease, hypertension, hyperlipidemia, and Charlson Comorbidity Index. Expanded case-mix+laboratory model adjusted for covariates in the expanded case-mix model, as well as estimated glomerular filtration rate, serum albumin, hemoglobin, cholesterol, triglycerides, low-density lipoprotein. Expanded case-mix+laboratory+thyroid medication model adjusted for covariates in the expanded case-mix+laboratory model, as well as thyroid hormone supplementation and anti-thyroid medication use.

Figure 2. Association between continuous baseline (Panel A) and time-dependent (Panel B) thyrotropin (TSH) and all-cause mortality

Figures present hazard ratios (short-dashed line) and 95%CI’s (solid lines) for TSH analyzed as a spline with knots at the 33rd and 66th percentiles of observed values (TSH levels 1.4mIU/L and 2.4mIU/L, respectively). A histogram of observed TSH values and a hazard reference ratio of 1 (dashed line) is overlaid. Analyses shown are expanded case-mix adjusted models, which included serum TSH level, age, sex, race, ethnicity, diabetes, congestive heart failure, cardiovascular disease, hypertension, hyperlipidemia, and Charlson Comorbidity Index.

Figure 3. Baseline (Panel A) and time-dependent (Panel B) thyroid status and all-cause mortality across clinically relevant subgroups

P-values for interaction tests presented. Analyses shown are expanded case-mix adjusted models, which included serum TSH level, age, sex, race, ethnicity, diabetes, congestive heart failure, cardiovascular disease, hypertension, hyperlipidemia, and Charlson Comorbidity Index. Abbreviations: eGFR, estimated glomerular filtration rate; CHF, congestive heart failure; CVD, cardiovascular disease; BMI, body mass index.

Figure 4. Baseline (Panels A and B) and time-dependent (Panels C and D) thyroid status, thyroid medications, and all-cause mortality

Analyses shown are expanded case-mix adjusted models, which included serum TSH level, age, sex, race, ethnicity, diabetes, congestive heart failure, cardiovascular disease, hypertension, hyperlipidemia, and Charlson Comorbidity Index.

Figure 4. Baseline (Panels A and B) and time-dependent (Panels C and D) thyroid status, thyroid medications, and all-cause mortality

Analyses shown are expanded case-mix adjusted models, which included serum TSH level, age, sex, race, ethnicity, diabetes, congestive heart failure, cardiovascular disease, hypertension, hyperlipidemia, and Charlson Comorbidity Index.