Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Nonthyroidal illness and the cardiorenal syndrome

Nature Reviews Nephrology volume 9, pages 599–609 (2013)Cite this article

Subjects

Abstract

The cardiorenal syndrome represents a final common pathway for renal and congestive heart failure and heralds a poor prognosis. Factors that link the failing heart and the failing kidneys—the so-called cardiorenal connectors—are, therefore, of clinical and therapeutic interest. Alterations in the levels and function of thyroid hormones that fit the spectrum of nonthyroidal illnesses could be considered to be cardiorenal connectors as both renal failure and heart failure progress with the development of nonthyroidal illness. In addition, circumstantial evidence suggests that nonthyroidal illness can induce deterioration in the function of the heart and the kidneys via multiple pathways. As a consequence, these reciprocal associations could result in a vicious cycle of deterioration that likely contributes to increased mortality. In this Review, we describe the evidence for a pathophysiological role of nonthyroidal illness in the cardiorenal syndrome. We also discuss the available data from studies that have investigated the efficacy of thyroid hormone replacement therapy in patients with renal failure and the rationale for interventional trials to examine the effects of normalization of the thyroid hormone profile in patients with renal failure and congestive heart failure.

Key Points

  • Cardiac disease and renal disease are frequently accompanied by nonthyroidal illness (that is, alterations in thyroid hormones in the absence of hypothalamic–pituitary–thyroidal disease)

  • General factors (such as inflammation and nutritional deficiencies) and pathophysiological factors that are specific to cardiac and renal disease contribute to the development of nonthyroidal illness

  • The presence of nonthyroidal illness is associated with an increased risk of cardiovascular death in patients with cardiac and/or renal disease

  • Nonthyroidal illness can result in deterioration of cardiovascular and renal function via several pathways

  • The genesis of nonthyroidal illness in cardiac and renal failure as well as its deleterious effects on both organ systems suggest that nonthyroidal illness acts as a cardiorenal connector in the cardiorenal syndrome

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Nonthyroidal illness as a cardiorenal connector.
Figure 2: Thyroid hormone levels in nonthyroidal illness.
Figure 3: Direct effects of T3 on the cardiomyocyte.

Similar content being viewed by others

References

  1. Ronco, C. Cardio-renal syndromes: from foggy bottoms to sunny hills. Heart Fail. Rev. 16, 509–517 (2011).

    Article  PubMed  Google Scholar 

  2. Smith, G. L. et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J. Am. Coll. Cardiol. 47, 1987–1996 (2006).

    Article  PubMed  Google Scholar 

  3. Bongartz, L. G. et al. The severe cardiorenal syndrome: 'Guyton revisited'. Eur. Heart J. 26, 11–17 (2005).

    Article  PubMed  Google Scholar 

  4. Hamilton, M. A. Prevalence and clinical implications of abnormal thyroid hormone metabolism in advanced heart failure. Ann. Thorac. Surg. 56, S48–S52 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Zoccali, C. et al. Low triiodothyronine: a new facet of inflammation in end-stage renal disease. J. Am. Soc. Nephrol. 16, 2789–2795 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Spratt, D. I. et al. Physiological effects of nonthyroidal illness syndrome in patients after cardiac surgery. Am. J. Physiol. Endocrinol. Metab. 293, E310–E315 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Iervasi, G. et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch. Intern. Med. 167, 1526–1532 (2007).

    Article  PubMed  Google Scholar 

  8. Gerdes, A. M. & Iervasi, G. Thyroid replacement therapy and heart failure. Circulation 122, 385–393 (2010).

    Article  PubMed  Google Scholar 

  9. Zoccali, C. et al. Low triiodothyronine and survival in end-stage renal disease. Kidney Int. 70, 523–528 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Carrero, J. J. et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J. Intern. Med. 262, 690–701 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Meuwese, C. L. 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. 7, 131–138 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Warner, M. H. & Beckett, G. J. Mechanisms behind the non-thyroidal illness syndrome: an update. J. Endocrinol. 205, 1–13 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Peeters, R. P. et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J. Clin. Endocrinol. Metab. 88, 3202–3211 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Docter, R., Krenning, E. P., de Jong, M. & Hennemann, G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin. Endocrinol. (Oxf.) 39, 499–518 (1993).

    Article  CAS  Google Scholar 

  15. Boelen, A., Kwakkel, J. & Fliers, E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr. Rev. 32, 670–693 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Feingold, K. et al. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am. J. Physiol. Endocrinol. Metab. 286, E201–E207 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Feingold, K. R. et al. LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney. J. Lipid Res. 49, 2179–2187 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Squire, C. R. Methods for the investigation of thyroid function. Methods Mol. Biol. 324, 91–108 (2006).

    CAS  PubMed  Google Scholar 

  19. Song, S. H. et al. The prevalence of low triiodothyronine according to the stage of chronic kidney disease in subjects with a normal thyroid-stimulating hormone. Nephrol. Dial. Transplant. 24, 1534–1538 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Kaptein, E. M. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr. Rev. 17, 45–63 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Kaptein, E. M. et al. The thyroid in end-stage renal disease. Medicine (Baltimore) 67, 187–197 (1988).

    Article  CAS  Google Scholar 

  22. Yonemura, K. et al. Low free thyroxine concentrations and deficient nocturnal surge of thyroid-stimulating hormone in haemodialysed patients compared with undialysed patients. Nephrol. Dial. Transplant. 15, 668–672 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Pagliacci, M. C. et al. Thyroid function tests in patients undergoing maintenance dialysis: characterization of the 'low-T4 syndrome' in subjects on regular hemodialysis and continuous ambulatory peritoneal dialysis. Nephron 46, 225–230 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Lo, J. C., Chertow, G. M., Go, A. S. & Hsu, C. Y. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int. 67, 1047–1052 (2005).

    Article  PubMed  Google Scholar 

  25. Ramirez, G., O'Neill, W. Jr, Jubiz, W. & Bloomer, H. A. Thyroid dysfunction in uremia: evidence for thyroid and hypophyseal abnormalities. Ann. Intern. Med. 84, 672–676 (1976).

    Article  CAS  PubMed  Google Scholar 

  26. Chen, W. L., Huang, W. S., Lin, Y. F. & Shieh, S. D. Changes in thyroid hormone metabolism in exertional heat stroke with or without acute renal failure. J. Clin. Endocrinol. Metab. 81, 625–629 (1996).

    CAS  PubMed  Google Scholar 

  27. Iglesias, P. et al. Thyroid function tests in acute kidney injury. J. Nephrol. 26, 164–172 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Witzke, O. et al. Differential T4 degradation pathways in young patients with preterminal and terminal renal failure. Horm. Metab. Res. 39, 355–358 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Meuwese, C. L., Stenvinkel, P., Dekker, F. W. & Carrero, J. J. Monitoring of inflammation in patients on dialysis: forewarned is forearmed. Nat. Rev. Nephrol. 7, 166–176 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Abo-Zenah, H. A., Shoeb, S. A., Sabry, A. A. & Ismail, H. A. Relating circulating thyroid hormone concentrations to serum interleukins-6 and 10 in association with non-thyroidal illnesses including chronic renal insufficiency. BMC Endocr. Disord. 8, 1 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zoccali, C. et al. Low triiodothyronine and cardiomyopathy in patients with end-stage renal disease. J. Hypertens. 24, 2039–2046 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Hermus, R. M. et al. Continuous infusion of interleukin-1β induces a nonthyroidal illness syndrome in the rat. Endocrinology 131, 2139–2146 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Carrero, J. J. et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM). J. Ren. Nutr. 23, 77–90 (2013).

    Article  PubMed  Google Scholar 

  34. Meuwese, C. L., Carrero, J. J. & Stenvinkel, P. Recent insights in inflammation-associated wasting in patients with chronic kidney disease. Contrib. Nephrol. 171, 120–126 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Tomoda, F. et al. Effects of erythropoietin treatment on thyroid dysfunction in hemodialysis patients with renal anemia. Nephron 66, 307–311 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Sato, K. et al. Reversible primary hypothyroidism and elevated serum iodine level in patients with renal dysfunction. Acta Endocrinol. (Copenh.) 126, 253–259 (1992).

    Article  CAS  Google Scholar 

  37. Wiederkehr, M. R., Kalogiros, J. & Krapf, R. Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients. Nephrol. Dial. Transplant. 19, 1190–1197 (2004).

    Article  PubMed  Google Scholar 

  38. Wilber, J. F. & Utiger, R. D. The effect of glucocorticoids on thyrotropin secretion. J. Clin. Invest. 48, 2096–2103 (1969).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wiersinga, W. M. & Touber, J. L. The influence of β-adrenoceptor blocking agents on plasma thyroxine and triiodothyronine. J. Clin. Endocrinol. Metab. 45, 293–298 (1977).

    Article  CAS  PubMed  Google Scholar 

  40. Singh, N., Weisler, S. L. & Hershman, J. M. The acute effect of calcium carbonate on the intestinal absorption of levothyroxine. Thyroid 11, 967–971 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Napolitano, G. et al. Thyroid function and plasma selenium in chronic uremic patients on hemodialysis treatment. Biol. Trace Elem. Res. 55, 221–230 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Carrero, J. J. et al. Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease. Nephrol. Dial. Transplant. 26, 184–190 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Miyashita, K. et al. Regulation of rat liver type 1 iodothyronine deiodinase mRNA levels by testosterone. Mol. Cell Endocrinol. 115, 161–167 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Iervasi, G. et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 107, 708–713 (2003).

    Article  PubMed  Google Scholar 

  45. Psirropoulos, D. et al. Heart failure accompanied by sick euthyroid syndrome and exercise training. Curr. Opin. Cardiol. 17, 266–270 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Opasich, C. et al. Sick euthyroid syndrome in patients with moderate-to-severe chronic heart failure. Eur. Heart J. 17, 1860–1866 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Ascheim, D. D. & Hryniewicz, K. Thyroid hormone metabolism in patients with congestive heart failure: the low triiodothyronine state. Thyroid 12, 511–515 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Hamilton, M. A., Stevenson, L. W., Luu, M. & Walden, J. A. Altered thyroid hormone metabolism in advanced heart failure. J. Am. Coll. Cardiol. 16, 91–95 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Pingitore, A. et al. Early activation of an altered thyroid hormone profile in asymptomatic or mildly symptomatic idiopathic left ventricular dysfunction. J. Card. Fail. 12, 520–526 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Pantos, C. et al. Thyroid hormone is a critical determinant of myocardial performance in patients with heart failure: potential therapeutic implications. Eur. J. Endocrinol. 157, 515–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Shanoudy, H. et al. Early manifestations of “sick euthyroid” syndrome in patients with compensated chronic heart failure. J. Card. Fail. 7, 146–152 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Iltumur, K. et al. Clinical investigation: thyroid function test abnormalities in cardiac arrest associated with acute coronary syndrome. Crit. Care 9, R416–R424 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Karga, H. et al. The role of cytokines and cortisol in the non-thyroidal illness syndrome following acute myocardial infarction. Eur. J. Endocrinol. 142, 236–242 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Wortsman, J., Premachandra, B. N., Chopra, I. J. & Murphy, J. E. Hypothyroxinemia in cardiac arrest. Arch. Intern. Med. 147, 245–248 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Friberg, L., Werner, S., Eggertsen, G. & Ahnve, S. Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch. Intern. Med. 162, 1388–1394 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Ross, R. Atherosclerosis--an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  CAS  Google Scholar 

  57. Torre-Amione, G. et al. Tumor necrosis factor-α and tumor necrosis factor receptors in the failing human heart. Circulation 93, 704–711 (1996).

    Article  CAS  Google Scholar 

  58. Mancini, D. M. et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 85, 1364–1373 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. Adams, K. F. Jr et al. Prospective assessment of the occurrence of anemia in patients with heart failure: results from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) Registry. Am. Heart J. 157, 926–932 (2009).

    Article  PubMed  Google Scholar 

  60. Eskes, S. A. & Wiersinga, W. M. Amiodarone and thyroid. Best Pract. Res. Clin. Endocrinol. Metab. 23, 735–751 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Stockigt, J. R. et al. Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors. J. Clin. Endocrinol. Metab. 60, 1025–1031 (1985).

    Article  CAS  PubMed  Google Scholar 

  62. Simonides, W. S. et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J. Clin. Invest. 118, 975–983 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wassen, F. W. et al. Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure. Endocrinology 143, 2812–2815 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Boelen, A. et al. Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 150, 1984–1990 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Ueta, C. B. et al. Absence of myocardial thyroid hormone inactivating deiodinase results in restrictive cardiomyopathy in mice. Mol. Endocrinol. 26, 809–818 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nomura, S. et al. Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. J. Clin. Invest. 56, 643–652 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. de Jager, D. J. et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 302, 1782–1789 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Katzeff, H. L., Powell, S. R. & Ojamaa, K. Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3 . Am. J. Physiol. 273, E951–E956 (1997).

    CAS  PubMed  Google Scholar 

  69. Sabatino, L. et al. A study of iodothyronine 5′-monodeiodinase activities in normal and pathological tissues in man and their comparison with activities in rat tissues. Life Sci. 68, 191–202 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Bengel, F. M. et al. Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging. J. Clin. Endocrinol. Metab. 85, 1822–1827 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Amidi, M. et al. Effect of the thyroid state on myocardial contractility and ventricular ejection rate in man. Circulation 38, 229–239 (1968).

    Article  CAS  PubMed  Google Scholar 

  72. Klein, I. & Ojamaa, K. Thyroid hormone and the cardiovascular system. N. Engl. J. Med. 344, 501–509 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Danzi, S. & Klein, I. Thyroid hormone-regulated cardiac gene expression and cardiovascular disease. Thyroid 12, 467–472 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Danzi, S., Ojamaa, K. & Klein, I. Triiodothyronine-mediated myosin heavy chain gene transcription in the heart. Am. J. Physiol. Heart Circ. Physiol. 284, H2255–H2262 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Bauab, R. C. et al. Low triiodothyronine (T3) or reverse triiodothyronine (rT3) syndrome modifies gene expression in rats with congestive heart failure. Endocr. Res. 31, 397–405 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Moalic, J. M. et al. β1 adrenergic receptor and Gα s mRNAs in rat heart as a function of mechanical load and thyroxine intoxication. Cardiovasc. Res. 27, 231–237 (1993).

    Article  CAS  PubMed  Google Scholar 

  77. Murray, J. F. & Kelly, J. J. Jr. The relation of thyroidal homone level to epinephrine response: a diagnostic test for hyperthyroidism. Ann. Intern. Med. 51, 309–321 (1959).

    Article  CAS  PubMed  Google Scholar 

  78. Ojamaa, K., Klein, I., Sabet, A. & Steinberg, S. F. Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac β-adrenergic receptor responsiveness. Metabolism 49, 275–279 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Jaroszynski, A. J. et al. Low-T3 syndrome and signal-averaged ECG in haemodialysed patients. Physiol. Res. 54, 521–526 (2005).

    CAS  PubMed  Google Scholar 

  80. Fredlund, B. O. & Olsson, S. B. Long QT interval and ventricular tachycardia of “torsade de pointe” type in hypothyroidism. Acta Med. Scand. 213, 231–235 (1983).

    Article  CAS  PubMed  Google Scholar 

  81. Shojaie, M. & Eshraghian, A. Primary hypothyroidism presenting with torsades de pointes type tachycardia: a case report. Cases J. 1, 298 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Komar, N. N. & Gabrielsen, T. O. Arterial calcification in adult cretins. Am. J. Roentgenol. Radium. Ther. Nucl. Med. 101, 202–203 (1967).

    Article  CAS  PubMed  Google Scholar 

  83. Meuwese, C. L. et al. Nonthyroidal illness: a risk factor for coronary calcification and arterial stiffness in patients undergoing peritoneal dialysis. J. Intern. Med. http://dx.doi.org/10.1111/joim.12107.

  84. Tatar, E. et al. Associations of triiodothyronine levels with carotid atherosclerosis and arterial stiffness in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 6, 2240–2246 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tatar, E. et al. The association between thyroid hormones and arterial stiffness in peritoneal dialysis patients. Int. Urol. Nephrol. 44, 601–606 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Yilmaz, M. I. et al. Low triiodothyronine alters flow-mediated vasodilatation in advanced nondiabetic kidney disease. Am. J. Nephrol. 33, 25–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Malyszko, J., Malyszko, J. S., Pawlak, K. & Mysliwiec, M. Thyroid function, endothelium, and inflammation in hemodialyzed patients: possible relations? J. Ren. Nutr. 17, 30–37 (2007).

    Article  PubMed  Google Scholar 

  88. Ojamaa, K., Klemperer, J. D. & Klein, I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid 6, 505–512 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. Mizuno, I. et al. Upregulation of the klotho gene expression by thyroid hormone and during adipose differentiation in 3T3-L1 adipocytes. Life Sci. 68, 2917–2923 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Sato, Y. et al. Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification. Circ. Res. 97, 550–557 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Bommer, C. et al. D-thyroxine reduces lipoprotein(a) serum concentration in dialysis patients. J. Am. Soc. Nephrol. 9, 90–96 (1998).

    CAS  PubMed  Google Scholar 

  92. Passino, C. et al. Prognostic value of combined measurement of brain natriuretic peptide and triiodothyronine in heart failure. J. Card. Fail. 15, 35–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Montenegro, J. et al. Changes in renal function in primary hypothyroidism. Am. J. Kidney Dis. 27, 195–198 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Kreisman, S. H. & Hennessey, J. V. Consistent reversible elevations of serum creatinine levels in severe hypothyroidism. Arch. Intern. Med. 159, 79–82 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Shin, D. H. et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 97, 2732–2740 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Shin, D. H. et al. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism. Thyroid 23, 654–661 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kimmel, M., Braun, N. & Alscher, M. D. Influence of thyroid function on different kidney function tests. Kidney Blood Press. Res. 35, 9–17 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Villabona, C. et al. Blood volumes and renal function in overt and subclinical primary hypothyroidism. Am. J. Med. Sci. 318, 277–280 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Hlad, C. J. Jr & Bricker, N. S. Renal function and I131 clearance in hyperthyroidism and myxedema. J. Clin. Endocrinol. Metab. 14, 1539–1550 (1954).

    Article  CAS  PubMed  Google Scholar 

  100. Karanikas, G. et al. Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy. Am. J. Nephrol. 24, 41–45 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Gillum, D. M., Falk, S. A., Hammond, W. S. & Conger, J. D. Glomerular dynamics in the hypothyroid rat and the role of the renin-angiotensin system. Am. J. Physiol. 253, F170–F179 (1987).

    CAS  PubMed  Google Scholar 

  102. Allon, M., Harrow, A., Pasque, C. B. & Rodriguez, M. Renal sodium and water handling in hypothyroid patients: the role of renal insufficiency. J. Am. Soc. Nephrol. 1, 205–210 (1990).

    CAS  PubMed  Google Scholar 

  103. Vargas, F. et al. Vascular and renal function in experimental thyroid disorders. Eur. J. Endocrinol. 154, 197–212 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Moreno, J. M. et al. Role of endothelium-derived relaxing factors in the renal response to vasoactive agents in hypothyroid rats. Am. J. Physiol. Endocrinol. Metab. 285, E182–E188 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Miell, J. P. et al. Effects of hypothyroidism and hyperthyroidism on insulin-like growth factors (IGFs) and growth hormone and IGF-binding proteins. J. Clin. Endocrinol. Metab. 76, 950–955 (1993).

    CAS  PubMed  Google Scholar 

  106. Davis, R. G., Madsen, K. M., Fregly, M. J. & Tisher, C. C. Kidney structure in hypothyroidism. Am. J. Pathol. 113, 41–49 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Salomon, M. I. et al. Renal lesions in hypothyroidism: a study based on kidney biopsies. Metabolism 16, 846–852 (1967).

    Article  CAS  PubMed  Google Scholar 

  108. Mariani, L. H. & Berns, J. S. The renal manifestations of thyroid disease. J. Am. Soc. Nephrol. 23, 22–26 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. McDonough, A. A. et al. Thyroid hormone coordinately regulates Na+-K+-ATPase α and β-subunit mRNA levels in kidney. Am. J. Physiol. 254, C323–C329 (1988).

    Article  CAS  PubMed  Google Scholar 

  110. Cadnapaphornchai, M. A. et al. Urinary concentrating defect in hypothyroid rats: role of sodium, potassium, 2-chloride co-transporter, and aquaporins. J. Am. Soc. Nephrol. 14, 566–574 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Chou, K. M. et al. Correlation of clinical changes with regard to thyroxine replacement therapy in hypothyroid patients—focusing on the change of renal function. Kidney Blood Press. Res. 34, 365–372 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Reinhardt, W. et al. Triiodothyronine (T3) reflects renal graft function after renal transplantation. Clin. Endocrinol. (Oxf.) 46, 563–569 (1997).

    Article  CAS  Google Scholar 

  113. Junik, R. et al. Function, structure, and volume of thyroid gland following allogenic kidney transplantation. Transplant. Proc. 35, 2224–2226 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Thomas, M. C., Mathew, T. H. & Russ, G. R. Changes in thyroxine requirements in patients with hypothyroidism undergoing renal transplantation. Am. J. Kidney Dis. 39, 354–357 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Rosolowska-Huszcz, D., Kozlowska, L. & Rydzewski, A. Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure. Endocrine 27, 283–288 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Utas, C. et al. Improvement of thyroid hormone profile and thyrotrophin (TSH) surge alterations in hemodialysis patients on erythropoietin treatment. Clin. Nephrol. 55, 471–476 (2001).

    CAS  PubMed  Google Scholar 

  117. Disthabanchong, S. & Treeruttanawanich, A. Oral sodium bicarbonate improves thyroid function in predialysis chronic kidney disease. Am. J. Nephrol. 32, 549–556 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Sutter, P. M. et al. Beneficial effect of thyroxin in the treatment of ischemic acute renal failure. Pediatr. Nephrol. 2, 1–7 (1988).

    Article  CAS  PubMed  Google Scholar 

  119. Siegel, N. J. et al. Beneficial effect of thyroxin on recovery from toxic acute renal failure. Kidney Int. 25, 906–911 (1984).

    Article  CAS  PubMed  Google Scholar 

  120. Michael, U. F., Logan, J. L. & Meeks, L. A. The beneficial effects of thyroxine on nephrotoxic acute renal failure in the rat. J. Am. Soc. Nephrol. 1, 1236–1240 (1991).

    CAS  PubMed  Google Scholar 

  121. Acker, C. G. et al. A trial of thyroxine in acute renal failure. Kidney Int. 57, 293–298 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. De Groot, L. J. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies. Crit. Care Clin. 22, 57–86 (2006).

    Article  PubMed  Google Scholar 

  123. Harris, A. R., Fang, S. L., Vagenakis, A. G. & Braverman, L. E. Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in the rat. Metabolism 27, 1680–1690 (1978).

    Article  CAS  PubMed  Google Scholar 

  124. Escobar-Morreale, H. F., del Rey, F. E., Obregon, M. J. & de Escobar, G. M. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 137, 2490–2502 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Straub, E. Effects of L-thyroxine in acute renal failure. Res. Exp. Med. (Berl.) 168, 81–87 (1976).

    Article  CAS  Google Scholar 

  126. Adamovich, K., Baranyai, Z., Guignard, J. P. & Sulyok, E. Effect of thyroxine administration on renal functions in newborn infants with perinatal asphyxia. Acta Paediatr. Hung. 32, 219–233 (1992).

    CAS  PubMed  Google Scholar 

  127. Lim, V. S., Flanigan, M. J., Zavala, D. C. & Freeman, R. M. Protective adaptation of low serum triiodothyronine in patients with chronic renal failure. Kidney Int. 28, 541–549 (1985).

    Article  CAS  PubMed  Google Scholar 

  128. Lim, V. S., Tsalikian, E. & Flanigan, M. J. Augmentation of protein degradation by L-triiodothyronine in uremia. Metabolism 38, 1210–1215 (1989).

    Article  CAS  PubMed  Google Scholar 

  129. Carter, J. N., Eastman, C. J., Corcoran, J. M. & Lazarus, L. Effects of triiodothyronine administration in patients with chronic renal failure. Aust. N. Z. J. Med. 7, 612–616 (1977).

    Article  CAS  PubMed  Google Scholar 

  130. Acker, C. G. et al. Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN). Am. J. Transplant. 2, 57–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Celikyurt, U. et al. Effect of cardiac resynchronization therapy on thyroid function. Clin. Cardiol. 34, 703–705 (2011).

    Article  PubMed  Google Scholar 

  132. D'Aloia, A. et al. Effect of short-term infusive dobutamine therapy on thyroid hormone profile and hemodynamic parameters in patients with acute worsening heart failure and low-triiodothyronine syndrome. J. Investig. Med. 60, 907–910 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Hamilton, M. A. et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am. J. Cardiol. 81, 443–447 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Pingitore, A. et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J. Clin. Endocrinol. Metab. 93, 1351–1358 (2008).

    Article  CAS  PubMed  Google Scholar 

  135. Iervasi, G. et al. in Proceedings of the 2nd International Congress on Heart Disease—New Trends in Research, Diagnosis and Treatment (ed. Kimchi, A.) 549–553 (Medimond Medical Publications, 2001).

    Google Scholar 

  136. Moruzzi, P. et al. Usefulness of L-thyroxine to improve cardiac and exercise performance in idiopathic dilated cardiomyopathy. Am. J. Cardiol. 73, 374–378 (1994).

    Article  CAS  PubMed  Google Scholar 

  137. Moruzzi, P., Doria, E. & Agostoni, P. G. Medium-term effectiveness of L-thyroxine treatment in idiopathic dilated cardiomyopathy. Am. J. Med. 101, 461–467 (1996).

    Article  CAS  PubMed  Google Scholar 

  138. Malik, F. S. et al. Intravenous thyroid hormone supplementation in heart failure with cardiogenic shock. J. Card. Fail. 5, 31–37 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Goldman, S. et al. DITPA (3, 5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 119, 3093–3100 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Morkin, E. et al. Pilot studies on the use of 3, 5-diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure. Cardiology 97, 218–225 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Talukder, M. A. et al. Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 300, H702–H711 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. The coronary drug project research group. The coronary drug project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. JAMA 220, 996–1008 (1972).

  143. [No authors listed] Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. The Expert Panel. Arch. Intern. Med. 148, 36–69 (1988).

  144. Kaptein, E. M., Sanchez, A., Beale, E. & Chan, L. S. Clinical review: thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J. Clin. Endocrinol. Metab. 95, 4526–4534 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Biondi, B. et al. Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency. Eur. J. Endocrinol. 161, 323–329 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Sawin, C. T. et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N. Engl. J. Med. 331, 1249–1252 (1994).

    Article  CAS  PubMed  Google Scholar 

  147. Rosner, M. H. & Bolton, W. K. The mortality risk associated with higher hemoglobin: is the therapy to blame? Kidney Int. 74, 695–697 (2008).

    Article  CAS  PubMed  Google Scholar 

  148. Baxter, J. D. & Webb, P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat. Rev. Drug Discov. 8, 308–320 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Van den Berghe, G. et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of growth hormone-releasing peptide and thyrotropin-releasing hormone in patients with protracted critical illness. J. Clin. Endocrinol. Metab. 84, 1311–1323 (1999).

    CAS  PubMed  Google Scholar 

  150. Chopra, I. J., Solomon, D. H., Hepner, G. W. & Morgenstein, A. A. Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. Ann. Intern. Med. 90, 905–912 (1979).

    Article  CAS  PubMed  Google Scholar 

  151. Surks, M. I. et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291, 228–238 (2004).

    Article  CAS  Google Scholar 

  152. Monzani, F. et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 89, 2099–2106 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to express their gratitude to J. W. M. Plevier (information specialist at The Walaeus Library, Leiden University Medical Center, Netherlands) for her assistance in the literature search. The authors' work and some of the discussed studies are partially supported by the Westman's foundation, by the Center for Gender Medicine at Karolinska Institutet and by the Swedish Medical Research Council (J. J. Carrero).

Author information

Authors and Affiliations

  1. Department of Clinical Epidemiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, Netherlands

    Christiaan L. Meuwese, Olaf M. Dekkers & Friedo W. Dekker

  2. Division of Renal Medicine, Karolinska Institutet, K56, Karolinska University Hospital Huddinge, Huddinge, 14186, Sweden

    Peter Stenvinkel

  3. Center for Molecular Medicine, Karolinska Institutet, K56, Karolinska University Hospital Huddinge, Huddinge, 14186, Sweden

    Juan J. Carrero

Authors
  1. Christiaan L. Meuwese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olaf M. Dekkers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Stenvinkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Friedo W. Dekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan J. Carrero
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C. L. Meuwese and J. J. Carrero researched the data for the article and wrote the manuscript. All authors made a substantial contribution to discussions of the content and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Christiaan L. Meuwese.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Search criteria for Tables 1 and 2 (DOC 32 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meuwese, C., Dekkers, O., Stenvinkel, P. et al. Nonthyroidal illness and the cardiorenal syndrome. Nat Rev Nephrol 9, 599–609 (2013). https://doi.org/10.1038/nrneph.2013.170

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2013.170

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing