Association of thyroid functional disease with mortality in a national cohort of incident hemodialysis patients

Connie M Rhee, Steven Kim, Daniel L Gillen, Tolga Oztan, Jiaxi Wang, Rajnish Mehrotra, Sooraj Kuttykrishnan, Danh V Nguyen, Steven M Brunelli, Csaba P Kovesdy, Gregory A Brent, Kamyar Kalantar-Zadeh, Connie M Rhee, Steven Kim, Daniel L Gillen, Tolga Oztan, Jiaxi Wang, Rajnish Mehrotra, Sooraj Kuttykrishnan, Danh V Nguyen, Steven M Brunelli, Csaba P Kovesdy, Gregory A Brent, Kamyar Kalantar-Zadeh

Abstract

Context: Hypothyroidism is a common condition that disproportionately affects hemodialysis patients. In the general population, hypothyroidism is associated with higher mortality, particularly in populations with underlying cardiovascular risk. Despite their heightened cardiovascular mortality, the impact of hypothyroidism on the survival of hemodialysis patients remains uncertain.

Objective: To examine whether hypothyroidism is independently associated with higher mortality in hemodialysis patients.

Design, setting, and patients: Among 8840 incident hemodialysis patients receiving care from a large national dialysis provider from January 2007 to December 2011, we examined the association of hypothyroidism (TSH >5.0 mIU/L) with mortality.

Main outcome measures: Associations between baseline and time-dependent hypothyroidism with all-cause mortality were determined using case-mix adjusted Cox models. In secondary analyses, we examined the impact of low-normal, upper-normal, subclinical range, and overt range TSH levels (TSH ≥ 0.5-3.0, >3.0-5.0, >5.0-10.0, and >10.0 mIU/L, respectively) on mortality risk.

Results: The study population consisted of 1928 (22%) hypothyroid and 6912 (78%) euthyroid patients. Baseline and time-dependent hypothyroidism were associated with higher mortality: adjusted hazard ratios (95% confidence intervals) were 1.47 (1.34-1.61) and 1.62 (1.45-1.80), respectively. Compared to low-normal TSH, upper-normal, subclinical hypothyroid, and overt hypothyroid TSH levels were associated with incrementally higher adjusted death risk in baseline and time-dependent analyses. In time-dependent analyses, the hypothyroidism-mortality association was increasingly stronger across higher body mass index strata.

Conclusions: Hypothyroidism as well as upper-normal TSH levels are associated with higher mortality in hemodialysis patients. Further studies are needed to determine whether restoration of TSH to low-normal levels with thyroid hormone replacement therapy ameliorates adverse outcomes in hemodialysis patients.

Figures

Figure 1.
Figure 1.
Algorithm for the study cohort creation.
Figure 2.
Figure 2.
The association between baseline and time-dependent hypothyroidism and all-cause mortality (reference group: euthyroidism). Model 1 is adjusted for entry calendar quarter. Model 2 is adjusted for covariates in model 1, plus age, sex, race/ethnicity, cause of ESRD, vascular access, dialysis vintage, BMI, diabetes, CHF, cerebrovascular disease, MI, other cardiac disease, hypertension, and PVD. Model 3 is adjusted for covariates in model 2, plus serum creatinine, albumin, ferritin, iron saturation, TIBC, bicarbonate, hemoglobin, calcium, phosphate, PTH, spKt/V, cholesterol, weekly ESA dose, and cumulative quarterly iv iron dose. Error bars represent 95% CIs.
Figure 3.
Figure 3.
The association between baseline (A) and time-dependent (B) TSH categories and all-cause mortality (reference group: low-normal TSH). Thyroid functional status is categorized as low-normal, upper-normal, subclinical range, and overt range TSH levels (TSH ≥0.5–3.0, >3.0–5.0, >5.0–10.0, and >10.0 mIU/L, respectively). Model 1 is adjusted for entry calendar quarter. Model 2 is adjusted for covariates in model 1, plus age, sex, race/ethnicity, cause of ESRD, vascular access, dialysis vintage, BMI, diabetes, CHF, cerebrovascular disease, MI, other cardiac disease, hypertension, and PVD. Model 3 is adjusted for covariates in model 2, plus serum creatinine, albumin, ferritin, iron saturation, TIBC, bicarbonate, hemoglobin, calcium, phosphate, PTH, spKt/V, cholesterol, weekly ESA dose, and cumulative quarterly iv iron dose. Error bars represent 95% CIs.
Figure 4.
Figure 4.
The association between baseline (A) and time-dependent (B) TSH deciles and all-cause mortality. Analyses were adjusted for covariates in model 2: entry calendar quarter, age, sex, race/ethnicity, cause of ESRD, vascular access, dialysis vintage, BMI, diabetes, CHF, cerebrovascular disease, MI, other cardiac disease, hypertension, and PVD. Error bars represent 95% CIs.
Figure 5.
Figure 5.
Subgroup analyses of the association between baseline and time-dependent hypothyroidism and all-cause mortality (reference group: euthyroidism). Analyses were adjusted for covariates in model 2: entry calendar quarter, age, sex, race/ethnicity, cause of ESRD, vascular access, dialysis vintage, BMI, diabetes, CHF, cerebrovascular disease, MI, other cardiac disease, hypertension, and PVD. Error bars represent 95% CIs.

References

    1. Bando Y, Ushiogi Y, Okafuji K, Toya D, Tanaka N, Miura S. Non-autoimmune primary hypothyroidism in diabetic and non-diabetic chronic renal dysfunction. Exp Clin Endocrinol Diabetes. 2002;110(8):408–415.
    1. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2008;3(5):1296–1300.
    1. Kaptein EM, Quion-Verde H, Chooljian CJ, et al. The thyroid in end-stage renal disease. Medicine. 1988;67(3):187–197.
    1. Kutlay S, Atli T, Koseogullari O, Nergizoglu G, Duman N, Gullu S. Thyroid disorders in hemodialysis patients in an iodine-deficient community. Artif Organs. 2005;29(4):329–332.
    1. Lin CC, Chen TW, Ng YY, Chou YH, Yang WC. Thyroid dysfunction and nodular goiter in hemodialysis and peritoneal dialysis patients. Perit Dial Int. 1998;18(5):516–521.
    1. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int. 2005;67(3):1047–1052.
    1. Ng YY, Wu SC, Lin HD, et al. Prevalence of clinical and subclinical thyroid disease in a peritoneal dialysis population. Perit Dial Int. 2012;32(1):86–93.
    1. Rhee CM, Alexander EK, Bhan I, Brunelli SM. Hypothyroidism and mortality among dialysis patients. Clin J Am Soc Nephrol. 2013;8(4):593–601.
    1. Shantha GP, Kumar AA, Bhise V, Khanna R, Sivagnanam K, Subramanian KK. Prevalence of subclinical hypothyroidism in patients with end-stage renal disease and the role of serum albumin: a cross-sectional study from south India. Cardiorenal Med. 2011;1(4):255–260.
    1. Targher G, Chonchol M, Zoppini G, et al. Prevalence of thyroid autoimmunity and subclinical hypothyroidism in persons with chronic kidney disease not requiring chronic dialysis. Clin Chem Lab Med. 2009;47(11):1367–1371.
    1. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003;88(6):2438–2444.
    1. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132(4):270–278.
    1. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501–509.
    1. Owen PJ, Sabit R, Lazarus JH. Thyroid disease and vascular function. Thyroid. 2007;17(6):519–524.
    1. Pearce EN. Update in lipid alterations in subclinical hypothyroidism. J Clin Endocrinol Metab. 2012;97(2):326–333.
    1. Gencer B, Collet TH, Virgini V, et al. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012;126(9):1040–1049.
    1. Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365–1374.
    1. Iervasi G, Molinaro S, Landi P, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med. 2007;167(14):1526–1532.
    1. McQuade C, Skugor M, Brennan DM, Hoar B, Stevenson C, Hoogwerf BJ. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a PreCIS database study. Thyroid. 2011;21(8):837–843.
    1. Molinaro S, Iervasi G, Lorenzoni V, et al. Persistence of mortality risk in patients with acute cardiac diseases and mild thyroid dysfunction. Am J Med Sci. 2012;343(1):65–70.
    1. Wheeler DC, Haynes R, Landray MJ, Baigent C. Cardiovascular aspects of kidney disease. In: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu AS, Brenner BM, eds. Brenner and Rector's The Kidney. 9th ed Philadelphia, PA: Elsevier Saunders; 2011:2059–2080.
    1. US Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2013.
    1. Rhee CM, Brent GA, Kovesdy CP, et al. Thyroid functional disease: an under-recognized cardiovascular risk factor in kidney disease patients [published online February 25, 2014]. Nephrol Dial Transplant. doi:.
    1. Ladenson PW. Diagnosis of hypothyroidism. In: Braverman LE, Cooper DS, eds. Werner and Ingbar's The Thyroid. 10th ed Chap 45 Philadelphia, PA: Lippincott Williams and Wilkins; 2013:606–611.
    1. Jonklaas J. Treatment of hypothyroidism. In: Braverman LE, Cooper DS, eds. Werner and Ingbar's The Thyroid. 10th ed Chap 46 Philadelphia, PA: Lippincott Williams and Wilkins; 2013:611–628.
    1. Larsen PR. Thyroid-pituitary interaction: feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med. 1982;306(1):23–32.
    1. Drechsler C, Schneider A, Gutjahr-Lengsfeld L, et al. Thyroid function, cardiovascular events, and mortality in diabetic hemodialysis patients. Am J Kidney Dis. 2014;63(6):988–996.
    1. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3–126.
    1. Baskin HJ, Cobin RH, Duick DS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002; 8(6):457–469.
    1. Surks MI, Boucai L. Age- and race-based serum thyrotropin reference limits. J Clin Endocrinol Metab. 2010;95(2):496–502.
    1. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005;90(9):5483–5488.
    1. Lim VS. Thyroid function in patients with chronic renal failure. Am J Kidney Dis. 2001;38(4 suppl 1):S80–S84.
    1. Little RJ, Rubin DB. Statistical Analysis with Missing Data. Hoboken, NJ: John Wiley and Sons; 2002.
    1. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007;116(15):1725–1735.
    1. Klein I. Endocrine disorders and cardiovascular disease. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease. 9th ed Chap 86 Philadelphia, PA: Elsevier Saunders; 2011:1829–1843.
    1. Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A, Turpin G. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. J Clin Endocrinol Metab. 2001;86(2):732–737.
    1. Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. 2009;94(1):151–156.
    1. Donati RM, Fletcher JW, Warnecke MA, Gallagher NI. Erythropoiesis in hypothyroidism. Proc Soc Exp Biol Med. 1973;144(1):78–82.
    1. Erdogan M, Kösenli A, Ganidagli S, Kulaksizoglu M. Characteristics of anemia in subclinical and overt hypothyroid patients. Endocr J. 2012;59(3):213–220.
    1. Fein HG, Rivlin RS. Anemia in thyroid diseases. Med Clin North Am. 1975;59(5):1133–1145.
    1. Nassar A, Saqi A, Baloch Z, LiVolsi V. Carcinoma showing thymuslike element of the thyroid. Acta Cytol. 2003;47(2):313–315.
    1. Singh AK. What is causing the mortality in treating the anemia of chronic kidney disease: erythropoietin dose or hemoglobin level? Curr Opin Nephrol Hypertens. 2010;19(5):420–424.
    1. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791–798.
    1. Carrero JJ, Stenvinkel P, Lindholm B. Endocrine aspects of chronic kidney disease. In: Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu AS, Brenner BM, eds. Brenner and Rector's The Kidney. 9th ed Chap 57 Philadelphia, PA: Elsevier Saunders; 2011:2122–2137.
    1. Meuwese CL, Carrero JJ, Cabezas-Rodríguez I, et al. Nonthyroidal illness: a risk factor for coronary calcification and arterial stiffness in patients undergoing peritoneal dialysis? J Intern Med. 2013;274(6):584–593.
    1. Meuwese CL, Dekker FW, Lindholm B, et al. Baseline levels and trimestral variation of triiodothyronine and thyroxine and their association with mortality in maintenance hemodialysis patients. Clin J Am Soc Nephrol. 2012;7(1):131–138.
    1. Tatar E, Kircelli F, Asci G, et al. Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients. Clin J Am Soc Nephrol. 2011;6(9):2240–2246.
    1. Tatar E, Sezis Demirci M, Kircelli F, et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. Int Urol Nephrol. 2012;44(2):601–606.
    1. Yilmaz MI, Sonmez A, Karaman M, et al. Low triiodothyronine alters flow-mediated vasodilatation in advanced nondiabetic kidney disease. Am J Nephrol. 2011;33(1):25–32.
    1. Zoccali C, Benedetto F, Mallamaci F, et al. Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease. J Hypertens. 2006;24(10):2039–2046.
    1. Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P. Low triiodothyronine and survival in end-stage renal disease. Kidney Int. 2006;70(3):523–528.
    1. Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122(9):3035–3043.
    1. Langton JE, Brent GA. Nonthyroidal illness syndrome: evaluation of thyroid function in sick patients. Endocrinol Metab Clin North Am. 2002;31(1):159–172.
    1. Wiersinga WM, Van den Berghe G. Nonthyroidal illness syndrome. In: Braverman LE, Cooper DS, eds. Werner and Ingbar's The Thyroid. 10th ed Chap 11C Philadelphia, PA: Lippincott Williams and Wilkins; 2012:203–216.
    1. Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev. 1996;17(1):45–63.
    1. Mariani LH, Berns JS. The renal manifestations of thyroid disease. J Am Soc Nephrol. 2012;23(1):22–26.
    1. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62(5):1524–1538.
    1. Kalantar-Zadeh K, Ikizler TA, Block G, Avram MM, Kopple JD. Malnutrition-inflammation complex syndrome in dialysis patients: causes and consequences. Am J Kidney Dis. 2003;42(5):864–881.
    1. Kalantar-Zadeh K, Kopple JD. Relative contributions of nutrition and inflammation to clinical outcome in dialysis patients. Am J Kidney Dis. 2001;38(6):1343–1350.
    1. Meuwese CL, Dekkers OM, Stenvinkel P, Dekker FW, Carrero JJ. Nonthyroidal illness and the cardiorenal syndrome. Nat Rev Nephrol. 2013;9(10):599–609.
    1. Dekker FW, de Mutsert R, van Dijk PC, Zoccali C, Jager KJ. Survival analysis: time-dependent effects and time-varying risk factors. Kidney Int. 2008;74(8):994–997.
    1. Van Biesen W, Vanholder R, Debacquer D, De Backer G, Lameire N. Comparison of survival on CAPD and haemodialysis: statistical pitfalls. Nephrol Dial Transplant. 2000;15(3):307–311.
    1. Soldin OP. Measuring serum thyroid-stimulating hormone, thyroid hormones, thyroid-directed antibodies, and transport proteins. In: Braverman LE, Cooper DS, eds. Werner and Ingbar's The Thyroid. 10th ed Chap 13A Philadelphia, PA: Lippincott Williams and Wilkins; 2012:279–296.
    1. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–751.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere