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.

Evolving concepts in the pathogenesis of uraemic cardiomyopathy

Abstract

The term uraemic cardiomyopathy refers to the cardiac abnormalities that are seen in patients with chronic kidney disease (CKD). Historically, this term was used to describe a severe cardiomyopathy that was associated with end-stage renal disease and characterized by severe functional abnormalities that could be reversed following renal transplantation. In a modern context, uraemic cardiomyopathy describes the clinical phenotype of cardiac disease that accompanies CKD and is perhaps best characterized as diastolic dysfunction seen in conjunction with left ventricular hypertrophy and fibrosis. A multitude of factors may contribute to the pathogenesis of uraemic cardiomyopathy, and current treatments only modestly improve outcomes. In this Review, we focus on evolving concepts regarding the roles of fibroblast growth factor 23 (FGF23), inflammation and systemic oxidant stress and their interactions with more established mechanisms such as pressure and volume overload resulting from hypertension and anaemia, respectively, activation of the renin–angiotensin and sympathetic nervous systems, activation of the transforming growth factor-β (TGFβ) pathway, abnormal mineral metabolism and increased levels of endogenous cardiotonic steroids.

Key points

  • Patients with chronic kidney disease or end-stage renal disease have an increased risk of cardiovascular disease and mortality.

  • Uraemic cardiomyopathy is characterized by diastolic dysfunction and marked left ventricular hypertrophy with profound ventricular fibrosis.

  • Factors that have been implicated in the development and progression of uraemic cardiomyopathy include haemodynamic overload, alterations in mineral metabolism, insulin resistance, circulating uraemic toxins and endogenous cardiotonic steroids.

  • Oxidative stress seems to have a role in all of the putative molecular pathways that are involved in the pathogenesis of uraemic cardiomyopathy.

  • Treatments that are effective in other cardiomyopathic conditions such as antihypertensive drugs improve clinical outcomes in uraemic cardiomyopathy only modestly at best.

  • The available data suggest that targeting oxidative stress might be a beneficial therapeutic strategy for patients with uraemic cardiomyopathy.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: Molecular mechanisms of haemodynamic overload in uraemic cardiomyopathy.
Fig. 2: The role of mineral and bone disorder in uraemic cardiomyopathy.
Fig. 3: The role of insulin resistance in uraemic cardiomyopathy.
Fig. 4: Endogenous cardiotonic steroids and the Na+/K+-ATPase–Src–ROS amplification loop in uraemic cardiomyopathy.
Fig. 5: Crosstalk between signalling pathways involved in uraemic cardiomyopathy.

References

  1. Collins, A. J., Foley, R. N., Gilbertson, D. T. & Chen, S. C. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int. Suppl. 5, 2–7 (2015).

    Google Scholar 

  2. Silverberg, D., Wexler, D., Blum, M., Schwartz, D. & Iaina, A. The association between congestive heart failure and chronic renal disease. Curr. Opin. Nephrol. Hypertens. 13, 163–170 (2004).

    CAS  PubMed  Google Scholar 

  3. London, G. M., Pannier, B., Marchais, S. J. & Guerin, A. P. Calcification of the aortic valve in the dialyzed patient. J. Am. Soc. Nephrol. 11, 778–783 (2000).

    CAS  PubMed  Google Scholar 

  4. Dad, T. & Weiner, D. E. Stroke and chronic kidney disease: epidemiology, pathogenesis, and management across kidney disease stages. Semin. Nephrol. 35, 311–322 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. Kulkarni, N., Gukathasan, N., Sartori, S. & Baber, U. Chronic kidney disease and atrial fibrillation: a contemporary overview. J. Atr. Fibrillation 5, 448 (2012).

    PubMed  PubMed Central  Google Scholar 

  6. Whitman, I. R., Feldman, H. I. & Deo, R. CKD and sudden cardiac death: epidemiology, mechanisms, and therapeutic approaches. J. Am. Soc. Nephrol. 23, 1929–1939 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Dennis, V. W. Coronary heart disease in patients with chronic kidney disease. J. Am. Soc. Nephrol. 16 (Suppl. 2), 103–106 (2005).

    Google Scholar 

  8. Moe, S. M. & Chen, N. X. Mechanisms of vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 19, 213–216 (2008).

    CAS  PubMed  Google Scholar 

  9. Khan, N. A. et al. Kidney function and mortality among patients with left ventricular systolic dysfunction. J. Am. Soc. Nephrol. 17, 244–253 (2006).

    PubMed  Google Scholar 

  10. Wang, X., Liu, J., Drummond, C. A. & Shapiro, J. I. Sodium potassium adenosine triphosphatase (Na/K-ATPase) as a therapeutic target for uremic cardiomyopathy. Expert Opin. Ther. Targets 21, 531–541 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. London, G. M. et al. Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: follow-up of an interventional study. J. Am. Soc. Nephrol. 12, 2759–2767 (2001).

    CAS  PubMed  Google Scholar 

  12. Middleton, R. J., Parfrey, P. S. & Foley, R. N. Left ventricular hypertrophy in the renal patient. J. Am. Soc. Nephrol. 12, 1079–1084 (2001).

    CAS  PubMed  Google Scholar 

  13. Zoccali, C. et al. Prognostic value of echocardiographic indicators of left ventricular systolic function in asymptomatic dialysis patients. J. Am. Soc. Nephrol. 15, 1029–1037 (2004).

    PubMed  Google Scholar 

  14. Kennedy, D. et al. Effect of chronic renal failure on cardiac contractile function, calcium cycling, and gene expression of proteins important for calcium homeostasis in the rat. J. Am. Soc. Nephrol. 14, 90–97 (2003).

    CAS  PubMed  Google Scholar 

  15. Nagueh, S. F. et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur. Heart J. Cardiovasc. Imaging 17, 1321–1360 (2016).

    PubMed  Google Scholar 

  16. Otsuka, T., Suzuki, M., Yoshikawa, H. & Sugi, K. Left ventricular diastolic dysfunction in the early stage of chronic kidney disease. J. Cardiol. 54, 199–204 (2009).

    PubMed  Google Scholar 

  17. de Almeida, E. A. et al. Diastolic function in several stages of chronic kidney disease in patients with autosomal dominant polycystic kidney disease: a tissue Doppler imaging study. Kidney Blood Press. Res. 30, 234–239 (2007).

    PubMed  Google Scholar 

  18. Diez, J. Mechanisms of cardiac fibrosis in hypertension. J. Clin. Hypertens. 9, 546–550 (2007).

    CAS  Google Scholar 

  19. Lopez, B., Gonzalez, A., Hermida, N., Laviades, C. & Diez, J. Myocardial fibrosis in chronic kidney disease: potential benefits of torasemide. Kidney Int. 74 (Suppl. 111), S19–S23 (2008).

    Google Scholar 

  20. Hung, S. C., Lai, Y. S., Kuo, K. L. & Tarng, D. C. Volume overload and adverse outcomes in chronic kidney disease: clinical observational and animal studies. J. Am. Heart Assoc. 4, e001918 (2015).

    PubMed  PubMed Central  Google Scholar 

  21. Grabner, A. & Faul, C. The role of fibroblast growth factor 23 and Klotho in uremic cardiomyopathy. Curr. Opin. Nephrol. Hypertens. 25, 314–324 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Shinohara, K. et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J. Am. Soc. Nephrol. 13, 1894–1900 (2002).

    PubMed  Google Scholar 

  23. Spoto, B., Pisano, A. & Zoccali, C. Insulin resistance in chronic kidney disease: a systematic review. Am. J. Physiol. Renal Physiol. 311, F1087–F1108 (2016).

    CAS  PubMed  Google Scholar 

  24. Hung, S. C., Kuo, K. L., Wu, C. C. & Tarng, D. C. Indoxyl sulfate: a novel cardiovascular risk factor in chronic kidney disease. J. Am. Heart Assoc. 6, e005022 (2017).

    PubMed  PubMed Central  Google Scholar 

  25. Vanholder, R., Schepers, E., Pletinck, A., Nagler, E. V. & Glorieux, G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J. Am. Soc. Nephrol. 25, 1897–1907 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kennedy, D. J., Malhotra, D. & Shapiro, J. I. Molecular insights into uremic cardiomyopathy: cardiotonic steroids and Na/K ATPase signaling. Cell. Mol. Biol. 52, 3–14 (2006).

    CAS  PubMed  Google Scholar 

  27. Alhaj, E. et al. Uremic cardiomyopathy: an underdiagnosed disease. Congest. Heart Fail. 19, E40–E45 (2013).

    PubMed  Google Scholar 

  28. Zoccali, C. et al. Chronic fluid overload and mortality in ESRD. J. Am. Soc. Nephrol. 28, 2491–2497 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ruwhof, C. & van der Laarse, A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc. Res. 47, 23–37 (2000).

    CAS  PubMed  Google Scholar 

  30. Sadoshima, J., Jahn, L., Takahashi, T., Kulik, T. J. & Izumo, S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J. Biol. Chem. 267, 10551–10560 (1992).

    CAS  Google Scholar 

  31. Kira, Y. et al. Effect of long-term cyclic mechanical load on protein synthesis and morphological changes in cultured myocardial cells from neonatal rat. Cardiovasc. Drugs Ther. 8, 251–262 (1994).

    CAS  PubMed  Google Scholar 

  32. Komuro, I. et al. Stretching cardiac myocytes stimulates protooncogene expression. J. Biol. Chem. 265, 3595–3598 (1990).

    CAS  PubMed  Google Scholar 

  33. Cooper, G. t., Kent, R. L., Uboh, C. E., Thompson, E. W. & Marino, T. A. Hemodynamic versus adrenergic control of cat right ventricular hypertrophy. J. Clin. Invest. 75, 1403–1414 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Komuro, I., Kurabayashi, M., Takaku, F. & Yazaki, Y. Expression of cellular oncogenes in the myocardium during the developmental stage and pressure-overloaded hypertrophy of the rat heart. Circ. Res. 62, 1075–1079 (1988).

    CAS  PubMed  Google Scholar 

  35. Sadoshima, J., Xu, Y., Slayter, H. S. & Izumo, S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75, 977–984 (1993).

    CAS  PubMed  Google Scholar 

  36. Tamura, K. et al. Activation of angiotensinogen gene in cardiac myocytes by angiotensin II and mechanical stretch. Am. J. Physiol. 275, R1–R9 (1998).

    CAS  PubMed  Google Scholar 

  37. Malhotra, R., Sadoshima, J. & Brosius, F. C. 3rd & Izumo, S. Mechanical stretch and angiotensin II differentially upregulate the renin-angiotensin system in cardiac myocytes in vitro. Circ. Res. 85, 137–146 (1999).

    CAS  PubMed  Google Scholar 

  38. Rockman, H. A. et al. Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. Proc. Natl Acad. Sci. USA 88, 8277–8281 (1991).

    CAS  PubMed  Google Scholar 

  39. Fiorillo, C. et al. Cardiac volume overload rapidly induces oxidative stress-mediated myocyte apoptosis and hypertrophy. Biochim. Biophys. Acta 1741, 173–182 (2005).

    CAS  PubMed  Google Scholar 

  40. Kennedy, D. J. et al. Partial nephrectomy as a model for uremic cardiomyopathy in the mouse. Am. J. Physiol. Renal Physiol. 294, F450–F454 (2008).

    CAS  PubMed  Google Scholar 

  41. Kennedy, D. J. et al. Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension 47, 488–495 (2006).

    CAS  PubMed  Google Scholar 

  42. Tsujimoto, I. et al. The antioxidant edaravone attenuates pressure overload-induced left ventricular hypertrophy. Hypertension 45, 921–926 (2005).

    CAS  PubMed  Google Scholar 

  43. Hotamisligil, G. S. & Davis, R. J. Cell signaling and stress responses. Cold Spring Harb. Perspect. Biol. 8, a006072 (2016).

    PubMed  PubMed Central  Google Scholar 

  44. Cohen, P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 7, 353–361 (1997).

    CAS  PubMed  Google Scholar 

  45. Dingar, D. et al. Effect of pressure overload-induced hypertrophy on the expression and localization of p38 MAP kinase isoforms in the mouse heart. Cell. Signal. 22, 1634–1644 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ihle, J. N. Cytokine receptor signalling. Nature 377, 591–594 (1995).

    CAS  PubMed  Google Scholar 

  47. Schindler, C. & Darnell, J. E. Jr. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu. Rev. Biochem. 64, 621–651 (1995).

    CAS  PubMed  Google Scholar 

  48. Pan, J. et al. Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circ. Res. 81, 611–617 (1997).

    CAS  PubMed  Google Scholar 

  49. Lambers Heerspink, H. J., de Borst, M. H., Bakker, S. J. & Navis, G. J. Improving the efficacy of RAAS blockade in patients with chronic kidney disease. Nat. Rev. Nephrol. 9, 112–121 (2013).

    PubMed  Google Scholar 

  50. Franssen, C. F. & Navis, G. Chronic kidney disease: RAAS blockade and diastolic heart failure in chronic kidney disease. Nat. Rev. Nephrol. 9, 190–192 (2013).

    CAS  PubMed  Google Scholar 

  51. Hudlicka, O., Brown, M. & Egginton, S. Angiogenesis in skeletal and cardiac muscle. Physiol. Rev. 72, 369–417 (1992).

    CAS  PubMed  Google Scholar 

  52. Kurdi, M. & Booz, G. W. New take on the role of angiotensin II in cardiac hypertrophy and fibrosis. Hypertension 57, 1034–1038 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mehta, P. K. & Griendling, K. K. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am. J. Physiol. Cell Physiol. 292, C82–C97 (2007).

    CAS  PubMed  Google Scholar 

  54. Fernandez-Ruiz, I. Pharmacotherapy: angiotensin II — a new tool in vasodilatory shock. Nat. Rev. Cardiol. 14, 384 (2017).

    CAS  PubMed  Google Scholar 

  55. Taniyama, Y. et al. Role of p38 MAPK and MAPKAPK-2 in angiotensin II-induced Akt activation in vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 287, C494–C499 (2004).

    CAS  PubMed  Google Scholar 

  56. Pellieux, C. et al. Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2. J. Clin. Invest. 108, 1843–1851 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Zablocki, D. & Sadoshima, J. Angiotensin II and oxidative stress in the failing heart. Antioxid. Redox Signal. 19, 1095–1109 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kawada, N., Imai, E., Karber, A., Welch, W. J. & Wilcox, C. S. A mouse model of angiotensin II slow pressor response: role of oxidative stress. J. Am. Soc. Nephrol. 13, 2860–2868 (2002).

    CAS  PubMed  Google Scholar 

  59. Polizio, A. H. et al. Angiotensin II regulates cardiac hypertrophy via oxidative stress but not antioxidant enzyme activities in experimental renovascular hypertension. Hypertens. Res. 31, 325–334 (2008).

    CAS  PubMed  Google Scholar 

  60. Zhao, Q. D. et al. NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFkappaB signaling pathways. Circulation 131, 643–655 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Ferrario, C. M., Chappell, M. C., Dean, R. H. & Iyer, S. N. Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis. J. Am. Soc. Nephrol. 9, 1716–1722 (1998).

    CAS  PubMed  Google Scholar 

  62. Balakumar, P. & Jagadeesh, G. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology. Cell. Signal. 26, 2147–2160 (2014).

    CAS  PubMed  Google Scholar 

  63. Jankowski, V. et al. Angioprotectin: an angiotensin II-like peptide causing vasodilatory effects. FASEB J. 25, 2987–2995 (2011).

    CAS  PubMed  Google Scholar 

  64. Lautner, R. Q. et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ. Res. 112, 1104–1111 (2013).

    CAS  PubMed  Google Scholar 

  65. Liu, C. et al. Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats. Amino Acids 50, 1071–1081 (2018).

    CAS  PubMed Central  Google Scholar 

  66. Schlaich, M. P. et al. Sympathetic activation in chronic renal failure. J. Am. Soc. Nephrol. 20, 933–939 (2009).

    PubMed  Google Scholar 

  67. Park, J. Cardiovascular risk in chronic kidney disease: role of the sympathetic nervous system. Cardiol. Res. Pract. 2012, 319432 (2012).

    PubMed  PubMed Central  Google Scholar 

  68. Fisher, J. P., Young, C. N. & Fadel, P. J. Central sympathetic overactivity: maladies and mechanisms. Auton. Neurosci. 148, 5–15 (2009).

    PubMed  PubMed Central  Google Scholar 

  69. Zoccali, C. et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 105, 1354–1359 (2002).

    CAS  PubMed  Google Scholar 

  70. Grassi, G., Seravalle, G., Dell’Oro, R. & Mancia, G. Sympathetic mechanisms, organ damage, and antihypertensive treatment. Curr. Hypertens. Rep. 13, 303–308 (2011).

    CAS  PubMed  Google Scholar 

  71. Chalothorn, D. et al. Differential cardiovascular regulatory activities of the alpha 1B- and alpha 1D-adrenoceptor subtypes. J. Pharmacol. Exp. Ther. 305, 1045–1053 (2003).

    CAS  PubMed  Google Scholar 

  72. Xu, Q. et al. Myocardial oxidative stress contributes to transgenic beta(2)-adrenoceptor activation-induced cardiomyopathy and heart failure. Br. J. Pharmacol. 162, 1012–1028 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cohn, J. N. et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N. Engl. J. Med. 311, 819–823 (1984).

    CAS  PubMed  Google Scholar 

  74. Elias, A. N., Vaziri, N. D. & Maksy, M. Plasma norepinephrine, epinephrine, and dopamine levels in end-stage renal disease. Effect of hemodialysis. Arch. Intern. Med. 145, 1013–1015 (1985).

    CAS  PubMed  Google Scholar 

  75. Patel, M. B. et al. Altered function and structure of the heart in dogs with chronic elevation in plasma norepinephrine. Circulation 84, 2091–2100 (1991).

    CAS  PubMed  Google Scholar 

  76. Barki-Harrington, L., Perrino, C. & Rockman, H. A. Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc. Res. 63, 391–402 (2004).

    CAS  PubMed  Google Scholar 

  77. Vidal, M., Wieland, T., Lohse, M. J. & Lorenz, K. beta-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gbetagamma/Erk-dependent pathway. Cardiovasc. Res. 96, 255–264 (2012).

    CAS  PubMed  Google Scholar 

  78. Moniri, N. H. & Daaka, Y. Agonist-stimulated reactive oxygen species formation regulates beta2-adrenergic receptor signal transduction. Biochem. Pharmacol. 74, 64–73 (2007).

    CAS  PubMed  Google Scholar 

  79. Bovo, E., Lipsius, S. L. & Zima, A. V. Reactive oxygen species contribute to the development of arrhythmogenic Ca(2)(+) waves during beta-adrenergic receptor stimulation in rabbit cardiomyocytes. J. Physiol. 590, 3291–3304 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Villarreal, F. J. & Dillmann, W. H. Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen. Am. J. Physiol. 262, H1861–H1866 (1992).

    CAS  PubMed  Google Scholar 

  81. Lee, A. A., Dillmann, W. H., McCulloch, A. D. & Villarreal, F. J. Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J. Mol. Cell. Cardiol. 27, 2347–2357 (1995).

    CAS  PubMed  Google Scholar 

  82. Murakami, K., Takemura, T., Hino, S. & Yoshioka, K. Urinary transforming growth factor-beta in patients with glomerular diseases. Pediatr. Nephrol. 11, 334–336 (1997).

    CAS  PubMed  Google Scholar 

  83. Bottinger, E. P. & Bitzer, M. TGF-beta signaling in renal disease. J. Am. Soc. Nephrol. 13, 2600–2610 (2002).

    PubMed  Google Scholar 

  84. Dobaczewski, M., Chen, W. & Frangogiannis, N. G. Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J. Mol. Cell. Cardiol. 51, 600–606 (2011).

    CAS  PubMed  Google Scholar 

  85. Kuwahara, F. et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation 106, 130–135 (2002).

    CAS  PubMed  Google Scholar 

  86. Saito, K. et al. Iron chelation and a free radical scavenger suppress angiotensin II-induced upregulation of TGF-beta1 in the heart. Am. J. Physiol. Heart Circ. Physiol. 288, H1836–H1843 (2005).

    CAS  PubMed  Google Scholar 

  87. Elkareh, J. et al. Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. Hypertension 49, 215–224 (2007).

    CAS  PubMed  Google Scholar 

  88. de Albuquerque Suassuna, P. G., Sanders-Pinheiro, H. & de Paula, R. B. Uremic cardiomyopathy: a new piece in the chronic kidney disease-mineral and bone disorder puzzle. Front. Med. 5, 206 (2018).

    Google Scholar 

  89. London, G. M. et al. Uremic cardiomyopathy: an inadequate left ventricular hypertrophy. Kidney Int. 31, 973–980 (1987).

    CAS  PubMed  Google Scholar 

  90. Goodman, W. G. The consequences of uncontrolled secondary hyperparathyroidism and its treatment in chronic kidney disease. Semin. Dial. 17, 209–216 (2004).

    PubMed  Google Scholar 

  91. Andersson, P., Rydberg, E. & Willenheimer, R. Primary hyperparathyroidism and heart disease—a review. Eur. Heart J. 25, 1776–1787 (2004).

    CAS  PubMed  Google Scholar 

  92. Rostand, S. G. & Drueke, T. B. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int. 56, 383–392 (1999).

    CAS  PubMed  Google Scholar 

  93. Lishmanov, A., Dorairajan, S., Pak, Y., Chaudhary, K. & Chockalingam, A. Elevated serum parathyroid hormone is a cardiovascular risk factor in moderate chronic kidney disease. Int. Urol. Nephrol. 44, 541–547 (2012).

    CAS  PubMed  Google Scholar 

  94. Silver, J. & Naveh-Many, T. FGF-23 and secondary hyperparathyroidism in chronic kidney disease. Nat. Rev. Nephrol. 9, 641–649 (2013).

    CAS  PubMed  Google Scholar 

  95. Krajisnik, T. et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J. Endocrinol. 195, 125–131 (2007).

    CAS  PubMed  Google Scholar 

  96. Schluter, K. D. & Piper, H. M. Cardiovascular actions of parathyroid hormone and parathyroid hormone-related peptide. Cardiovasc. Res. 37, 34–41 (1998).

    CAS  PubMed  Google Scholar 

  97. Urena, P. et al. Parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acids are widely distributed in rat tissues. Endocrinology 133, 617–623 (1993).

    CAS  PubMed  Google Scholar 

  98. Smogorzewski, M., Zayed, M., Zhang, Y. B., Roe, J. & Massry, S. G. Parathyroid hormone increases cytosolic calcium concentration in adult rat cardiac myocytes. Am. J. Physiol. 264, H1998–H2006 (1993).

    CAS  PubMed  Google Scholar 

  99. Yao, L. et al. Parathyroid hormone and the risk of incident hypertension: the Atherosclerosis Risk in Communities study. J. Hypertens. 34, 196–203 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Craver, L. et al. Mineral metabolism parameters throughout chronic kidney disease stages 1-5—achievement of K/DOQI target ranges. Nephrol. Dial. Transplant. 22, 1171–1176 (2007).

    CAS  PubMed  Google Scholar 

  101. Hruska, K. A., Mathew, S., Lund, R., Qiu, P. & Pratt, R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 74, 148–157 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Slinin, Y., Foley, R. N. & Collins, A. J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J. Am. Soc. Nephrol. 16, 1788–1793 (2005).

    CAS  PubMed  Google Scholar 

  103. Shaman, A. M. & Kowalski, S. R. Hyperphosphatemia management in patients with chronic kidney disease. Saudi Pharm. J. 24, 494–505 (2016).

    PubMed  Google Scholar 

  104. Vervloet, M. G. et al. The role of phosphate in kidney disease. Nat. Rev. Nephrol. 13, 27–38 (2017).

    CAS  PubMed  Google Scholar 

  105. Yamazaki-Nakazawa, A. et al. Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats. Clin. Exp. Nephrol. 18, 56–64 (2014).

    CAS  PubMed  Google Scholar 

  106. Rahabi-Layachi, H., Ourouda, R., Boullier, A., Massy, Z. A. & Amant, C. Distinct effects of inorganic phosphate on cell cycle and apoptosis in human vascular smooth muscle cells. J. Cell. Physiol. 230, 347–355 (2015).

    CAS  PubMed  Google Scholar 

  107. Di Marco, G. S. et al. Increased inorganic phosphate induces human endothelial cell apoptosis in vitro. Am. J. Physiol. Renal Physiol. 294, F1381–F1387 (2008).

    PubMed  Google Scholar 

  108. Gupta, D., Brietzke, S., Hayden, M. R., Kurukulasuriya, L. R. & Sowers, J. R. Phosphate metabolism in cardiorenal metabolic disease. Cardiorenal Med. 1, 261–270 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Mehrotra, R. et al. Chronic kidney disease, hypovitaminosis D, and mortality in the United States. Kidney Int. 76, 977–983 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Gluba-Brzozka, A., Franczyk, B., Cialkowska-Rysz, A., Olszewski, R. & Rysz, J. Impact of vitamin D on the cardiovascular system in advanced chronic kidney disease (CKD) and dialysis patients. Nutrients 10, 709 (2018).

    PubMed Central  Google Scholar 

  111. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007).

    CAS  PubMed  Google Scholar 

  112. Jones, G. Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1alpha-hydroxylase in the classical and nonclassical actions of 1alpha, 25-dihydroxyvitamin D(3). Semin. Dial. 20, 316–324 (2007).

    PubMed  Google Scholar 

  113. Nitsa, A. et al. Vitamin D in cardiovascular disease. In Vivo 32, 977–981 (2018).

    PubMed  PubMed Central  Google Scholar 

  114. Wu, J., Garami, M., Cheng, T. & Gardner, D. G. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J. Clin. Invest. 97, 1577–1588 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Li, Y. C. et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J. Clin. Invest. 110, 229–238 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Leifheit-Nestler, M. et al. Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. Nephrol. Dial. Transplant. 32, 1493–1503 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Benet-Pages, A. et al. FGF23 is processed by proprotein convertases but not by PHEX. Bone 35, 455–462 (2004).

    CAS  PubMed  Google Scholar 

  118. Quarles, L. D. Endocrine functions of bone in mineral metabolism regulation. J. Clin. Invest. 118, 3820–3828 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hu, M. C., Shiizaki, K., Kuro-o, M. & Moe, O. W. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu. Rev. Physiol. 75, 503–533 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Leifheit-Nestler, M. & Haffner, D. Paracrine effects of FGF23 on the heart. Front. Endocrinol. 9, 278 (2018).

    Google Scholar 

  121. Tagliabracci, V. S. et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc. Natl Acad. Sci. USA 111, 5520–5525 (2014).

    CAS  PubMed  Google Scholar 

  122. Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone Miner. Res. 19, 429–435 (2004).

    CAS  PubMed  Google Scholar 

  123. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    CAS  PubMed  Google Scholar 

  124. Saito, H. et al. Circulating FGF-23 is regulated by 1alpha, 25-dihydroxyvitamin D3 and phosphorus in vivo. J. Biol. Chem. 280, 2543–2549 (2005).

    CAS  PubMed  Google Scholar 

  125. Ben-Dov, I. Z. et al. The parathyroid is a target organ for FGF23 in rats. J. Clin. Invest. 117, 4003–4008 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Shimada, T. et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113, 561–568 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hasegawa, H. et al. Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int. 78, 975–980 (2010).

    CAS  PubMed  Google Scholar 

  128. Liu, S. et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J. Am. Soc. Nephrol. 17, 1305–1315 (2006).

    CAS  PubMed  Google Scholar 

  129. Lopez, I. et al. Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int. 80, 475–482 (2011).

    CAS  PubMed  Google Scholar 

  130. Rodriguez-Ortiz, M. E. et al. Calcium deficiency reduces circulating levels of FGF23. J. Am. Soc. Nephrol. 23, 1190–1197 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Tsuji, K., Maeda, T., Kawane, T., Matsunuma, A. & Horiuchi, N. Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha, 25-dihydroxyvitamin D3 synthesis in leptin-deficient mice. J. Bone Miner. Res. 25, 1711–1723 (2010).

    CAS  PubMed  Google Scholar 

  132. Gutierrez, O. et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J. Am. Soc. Nephrol. 16, 2205–2215 (2005).

    CAS  PubMed  Google Scholar 

  133. Isakova, T. et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 79, 1370–1378 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Isakova, T. et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J. Am. Soc. Nephrol. 19, 615–623 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Gutierrez, O. M. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119, 2545–2552 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Hsu, H. J. & Wu, M. S. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am. J. Med. Sci. 337, 116–122 (2009).

    PubMed  Google Scholar 

  137. Isakova, T. et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305, 2432–2439 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Gutierrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 359, 584–592 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. 121, 4393–4408 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Seeherunvong, W. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. Pediatr. Nephrol. 27, 2129–2136 (2012).

    PubMed  Google Scholar 

  141. Leifheit-Nestler, M. et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol. Dial. Transplant. 31, 1088–1099 (2016).

    CAS  PubMed  Google Scholar 

  142. Touchberry, C. D. et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am. J. Physiol. Endocrinol. Metab. 304, E863–E873 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Faul, C. Fibroblast growth factor 23 and the heart. Curr. Opin. Nephrol. Hypertens. 21, 369–375 (2012).

    CAS  PubMed  Google Scholar 

  144. Grabner, A. et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 22, 1020–1032 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Grabner, A. et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci. Rep. 7, 1993 (2017).

    PubMed  PubMed Central  Google Scholar 

  146. Moe, S. M. et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial. Circulation 132, 27–39 (2015).

    CAS  PubMed  Google Scholar 

  147. Isakova, T. et al. Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. Pediatr. Nephrol. 28, 2035–2042 (2013).

    PubMed  PubMed Central  Google Scholar 

  148. Nehgme, R., Fahey, J. T., Smith, C. & Carpenter, T. O. Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J. Clin. Endocrinol. Metab. 82, 2450–2454 (1997).

    CAS  PubMed  Google Scholar 

  149. Shalhoub, V. et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J. Clin. Invest. 122, 2543–2553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Pastor-Arroyo, E. M. et al. The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk. Kidney Int. 94, 49–59 (2018).

    CAS  PubMed  Google Scholar 

  151. Chue, C. D. et al. Cardiovascular effects of sevelamer in stage 3 CKD. J. Am. Soc. Nephrol. 24, 842–852 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Richter, B., Haller, J., Haffner, D. & Leifheit-Nestler, M. Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Pflugers Arch. 468, 1621–1635 (2016).

    CAS  PubMed  Google Scholar 

  153. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Ito, S., Fujimori, T., Hayashizaki, Y. & Nabeshima, Y. Identification of a novel mouse membrane-bound family 1 glycosidase-like protein, which carries an atypical active site structure. Biochim. Biophys. Acta 1576, 341–345 (2002).

    CAS  PubMed  Google Scholar 

  155. Ogawa, Y. et al. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl Acad. Sci. USA 104, 7432–7437 (2007).

    CAS  PubMed  Google Scholar 

  156. Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050–2064 (2010).

    PubMed  PubMed Central  Google Scholar 

  157. Barker, S. L. et al. The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody. Nephrol. Dial. Transplant. 30, 223–233 (2015).

    CAS  PubMed  Google Scholar 

  158. Leone, F. et al. Soluble Klotho levels in adult renal transplant recipients are modulated by recombinant human erythropoietin. J. Nephrol. 27, 577–585 (2014).

    CAS  PubMed  Google Scholar 

  159. Ritter, C. S., Zhang, S., Delmez, J., Finch, J. L. & Slatopolsky, E. Differential expression and regulation of Klotho by paricalcitol in the kidney, parathyroid, and aorta of uremic rats. Kidney Int. 87, 1141–1152 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Lau, W. L. et al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 82, 1261–1270 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Moreno, J. A. et al. The inflammatory cytokines TWEAK and TNFalpha reduce renal klotho expression through NFkappaB. J. Am. Soc. Nephrol. 22, 1315–1325 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Zhu, H., Gao, Y., Zhu, S., Cui, Q. & Du, J. Klotho improves cardiac function by suppressing reactive oxygen species (ROS) mediated apoptosis by modulating MAPKs/Nrf2 signaling in doxorubicin-induced cardiotoxicity. Med. Sci. Monit. 23, 5283–5293 (2017).

    PubMed  PubMed Central  Google Scholar 

  163. Mitani, H. et al. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension 39, 838–843 (2002).

    CAS  PubMed  Google Scholar 

  164. Hu, M. C. et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J. Am. Soc. Nephrol. 26, 1290–1302 (2015).

    CAS  PubMed  Google Scholar 

  165. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    CAS  PubMed  Google Scholar 

  166. Corsetti, G. et al. Decreased expression of Klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease. J. Geriatr. Cardiol. 13, 701–711 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Couzin, J. Boosting gene extends mouse life span. Science 309, 1310–1311 (2005).

    CAS  PubMed  Google Scholar 

  169. Yamamoto, M. et al. Regulation of oxidative stress by the anti-aging hormone klotho. J. Biol. Chem. 280, 38029–38034 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Shiraki-Iida, T. et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 424, 6–10 (1998).

    CAS  PubMed  Google Scholar 

  171. Matsumura, Y. et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem. Biophys. Res. Commun. 242, 626–630 (1998).

    CAS  PubMed  Google Scholar 

  172. Lindberg, K. et al. The kidney is the principal organ mediating klotho effects. J. Am. Soc. Nephrol. 25, 2169–2175 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Maekawa, Y. et al. Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway. Geriatr. Gerontol. Int. 11, 510–516 (2011).

    PubMed  Google Scholar 

  174. Hui, H. et al. Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice. Oncotarget 8, 15663–15676 (2017).

    PubMed  PubMed Central  Google Scholar 

  175. Shimamura, Y. et al. Serum levels of soluble secreted alpha-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin. Exp. Nephrol. 16, 722–729 (2012).

    CAS  PubMed  Google Scholar 

  176. Yang, K. et al. Klotho protects against indoxyl sulphate-induced myocardial hypertrophy. J. Am. Soc. Nephrol. 26, 2434–2446 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Xie, J. et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nat. Commun. 3, 1238 (2012).

    PubMed  PubMed Central  Google Scholar 

  178. Song, S. & Si, L. Y. Klotho ameliorated isoproterenol-induced pathological changes in cardiomyocytes via the regulation of oxidative stress. Life Sci. 135, 118–123 (2015).

    CAS  PubMed  Google Scholar 

  179. Kuwahara, K. et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116, 3114–3126 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Wang, Y., Kuro-o, M. & Sun, Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell 11, 410–417 (2012).

    PubMed  PubMed Central  Google Scholar 

  181. Fliser, D. et al. Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int. 53, 1343–1347 (1998).

    CAS  PubMed  Google Scholar 

  182. DeFronzo, R. A. et al. Insulin resistance in uremia. J. Clin. Invest. 67, 563–568 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Feneberg, R., Schaefer, F. & Veldhuis, J. D. Neuroendocrine adaptations in renal disease. Pediatr. Nephrol. 18, 492–497 (2003).

    PubMed  Google Scholar 

  184. Walker, B. G., Phear, D. N., Martin, F. I. & Baird, C. W. Inhibition of insulin by acidosis. Lancet 2, 964–965 (1963).

    CAS  PubMed  Google Scholar 

  185. Hotamisligil, G. S. et al. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271, 665–668 (1996).

    CAS  PubMed  Google Scholar 

  186. Khedr, E. et al. Effect of recombinant human erythropoietin on insulin resistance in hemodialysis patients. Hemodial. Int. 13, 340–346 (2009).

    PubMed  Google Scholar 

  187. Vaziri, N. D. et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 83, 308–315 (2013).

    PubMed  Google Scholar 

  188. Levin, A. et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 71, 31–38 (2007).

    CAS  PubMed  Google Scholar 

  189. Koppe, L. et al. Urea impairs beta cell glycolysis and insulin secretion in chronic kidney disease. J. Clin. Invest. 126, 3598–3612 (2016).

    PubMed  PubMed Central  Google Scholar 

  190. Koppe, L. et al. p-Cresyl sulfate promotes insulin resistance associated with CKD. J. Am. Soc. Nephrol. 24, 88–99 (2013).

    CAS  PubMed  Google Scholar 

  191. Xu, H. et al. Clinical correlates of insulin sensitivity and its association with mortality among men with CKD stages 3 and 4. Clin. J. Am. Soc. Nephrol. 9, 690–697 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Li, Y., Zhang, L., Gu, Y., Hao, C. & Zhu, T. Insulin resistance as a predictor of cardiovascular disease in patients on peritoneal dialysis. Perit. Dial. Int. 33, 411–418 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Cusi, K. et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J. Clin. Invest. 105, 311–320 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Aroor, A. R., Mandavia, C. H. & Sowers, J. R. Insulin resistance and heart failure: molecular mechanisms. Heart Fail. Clin. 8, 609–617 (2012).

    PubMed  PubMed Central  Google Scholar 

  195. Boucher, J., Kleinridders, A. & Kahn, C. R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol. 6, a009191 (2014).

    PubMed  PubMed Central  Google Scholar 

  196. Matsui, T. & Rosenzweig, A. Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J. Mol. Cell. Cardiol. 38, 63–71 (2005).

    CAS  PubMed  Google Scholar 

  197. Manning, B. D. & Toker, A. AKT/PKB signaling: navigating the network. Cell 169, 381–405 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Alessi, D. R. et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15, 6541–6551 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Semple, D., Smith, K., Bhandari, S. & Seymour, A. M. Uremic cardiomyopathy and insulin resistance: a critical role for Akt? J. Am. Soc. Nephrol. 22, 207–215 (2011).

    CAS  PubMed  Google Scholar 

  200. McMullen, J. R. et al. Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc. Natl Acad. Sci. USA 100, 12355–12360 (2003).

    CAS  PubMed  Google Scholar 

  201. Samuelsson, A. M. et al. Hyperinsulinemia: effect on cardiac mass/function, angiotensin II receptor expression, and insulin signaling pathways. Am. J. Physiol. Heart Circ. Physiol. 291, H787–H796 (2006).

    CAS  PubMed  Google Scholar 

  202. Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F. & Birnbaum, M. J. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349–38352 (2001).

    CAS  PubMed  Google Scholar 

  203. DeBosch, B. et al. Akt1 is required for physiological cardiac growth. Circulation 113, 2097–2104 (2006).

    CAS  PubMed  Google Scholar 

  204. Li, Y. et al. Molecular signaling mediated by angiotensin II type 1A receptor blockade leading to attenuation of renal dysfunction-associated heart failure. J. Card Fail. 13, 155–162 (2007).

    CAS  PubMed  Google Scholar 

  205. Haq, S. et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103, 670–677 (2001).

    CAS  PubMed  Google Scholar 

  206. Shiojima, I. et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J. Clin. Invest. 115, 2108–2118 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Maillet, M., van Berlo, J. H. & Molkentin, J. D. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat. Rev. Mol. Cell Biol. 14, 38–48 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Amann, K. et al. Reduced capillary density in the myocardium of uremic rats—a stereological study. Kidney Int. 42, 1079–1085 (1992).

    CAS  PubMed  Google Scholar 

  209. Amann, K., Breitbach, M., Ritz, E. & Mall, G. Myocyte/capillary mismatch in the heart of uremic patients. J. Am. Soc. Nephrol. 9, 1018–1022 (1998).

    CAS  PubMed  Google Scholar 

  210. Siedlecki, A. M., Jin, X. & Muslin, A. J. Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. Kidney Int. 75, 800–808 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Matsui, T. et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 277, 22896–22901 (2002).

    CAS  PubMed  Google Scholar 

  212. Kataria, A., Trasande, L. & Trachtman, H. The effects of environmental chemicals on renal function. Nat Rev. Nephrol. 11, 610–625 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Thomas, S. S., Zhang, L. & Mitch, W. E. Molecular mechanisms of insulin resistance in chronic kidney disease. Kidney Int. 88, 1233–1239 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Borazan, A. & Binici, D. N. Relationship between insulin resistance and inflamation markers in hemodialysis patients. Ren. Fail. 32, 198–202 (2010).

    CAS  PubMed  Google Scholar 

  215. Kursat, S. et al. Relationship of insulin resistance in chronic haemodialysis patients with inflammatory indicators, malnutrition, echocardiographic parameters and 24 hour ambulatory blood pressure monitoring. Scand. J. Urol. Nephrol. 44, 257–264 (2010).

    CAS  PubMed  Google Scholar 

  216. Martins, C. et al. Insulin resistance is associated with circulating fibrinogen levels in nondiabetic patients receiving peritoneal dialysis. J. Ren. Nutr. 17, 132–137 (2007).

    PubMed  Google Scholar 

  217. Campa, C. C., Ciraolo, E., Ghigo, A., Germena, G. & Hirsch, E. Crossroads of PI3K and Rac pathways. Small GTPases 6, 71–80 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Trirogoff, M. L., Shintani, A., Himmelfarb, J. & Ikizler, T. A. Body mass index and fat mass are the primary correlates of insulin resistance in nondiabetic stage 3–4 chronic kidney disease patients. Am. J. Clin. Nutr. 86, 1642–1648 (2007).

    CAS  PubMed  Google Scholar 

  219. Mahadev, K. et al. The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol. Cell. Biol. 24, 1844–1854 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Morino, K., Petersen, K. F. & Shulman, G. I. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55 (Suppl. 2), 9–15 (2006).

    Google Scholar 

  221. Fujii, H., Goto, S. & Fukagawa, M. Role of uremic toxins for kidney, cardiovascular, and bone dysfunction. Toxins 10, 202 (2018).

    PubMed Central  Google Scholar 

  222. Dobre, M., Meyer, T. W. & Hostetter, T. H. Searching for uremic toxins. Clin. J. Am. Soc. Nephrol. 8, 322–327 (2013).

    CAS  PubMed  Google Scholar 

  223. Neirynck, N. et al. An update on uremic toxins. Int. Urol. Nephrol. 45, 139–150 (2013).

    CAS  PubMed  Google Scholar 

  224. Koppe, L. & Fouque, D. Microbiota and prebiotics modulation of uremic toxin generation. Panminerva Med. 59, 173–187 (2017).

    PubMed  Google Scholar 

  225. Vanholder, R. et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 63, 1934–1943 (2003).

    CAS  PubMed  Google Scholar 

  226. Duranton, F. et al. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 23, 1258–1270 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Zoccali, C. et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358, 2113–2117 (2001).

    CAS  PubMed  Google Scholar 

  228. Tumur, Z. & Niwa, T. Indoxyl sulfate inhibits nitric oxide production and cell viability by inducing oxidative stress in vascular endothelial cells. Am. J. Nephrol. 29, 551–557 (2009).

    CAS  PubMed  Google Scholar 

  229. Huang, C. Y. et al. Effects of pamidronate and calcitriol on the set point of the parathyroid gland in postmenopausal hemodialysis patients with secondary hyperparathyroidism. Nephron Clin. Pract. 122, 93–101 (2012).

    CAS  PubMed  Google Scholar 

  230. Fujii, H. et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol. Dial. Transplant. 24, 2089–2095 (2009).

    CAS  PubMed  Google Scholar 

  231. Sibal, L., Agarwal, S. C., Home, P. D. & Boger, R. H. The role of asymmetric dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr. Cardiol. Rev. 6, 82–90 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Zoccali, C. et al. Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients. Kidney Int. 62, 339–345 (2002).

    CAS  PubMed  Google Scholar 

  233. Elesber, A. A. et al. Coronary endothelial dysfunction is associated with erectile dysfunction and elevated asymmetric dimethylarginine in patients with early atherosclerosis. Eur. Heart J. 27, 824–831 (2006).

    CAS  PubMed  Google Scholar 

  234. Wu, I. W. et al. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol. Dial. Transplant. 26, 938–947 (2011).

    CAS  PubMed  Google Scholar 

  235. Barreto, F. C. et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 1551–1558 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Cao, X. S. et al. Association of indoxyl sulfate with heart failure among patients on hemodialysis. Clin. J. Am. Soc. Nephrol. 10, 111–119 (2015).

    CAS  PubMed  Google Scholar 

  237. Wu, C. C. et al. Serum indoxyl sulfate associates with postangioplasty thrombosis of dialysis grafts. J. Am. Soc. Nephrol. 27, 1254–1264 (2016).

    CAS  PubMed  Google Scholar 

  238. Yang, K. et al. Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway. Toxicol. Lett. 234, 110–119 (2015).

    CAS  PubMed  Google Scholar 

  239. Lekawanvijit, S. et al. Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLOS ONE 7, e41281 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Stockler-Pinto, M. B., Fouque, D., Soulage, C. O., Croze, M. & Mafra, D. Indoxyl sulfate and p-cresyl sulfate in chronic kidney disease. Could these toxins modulate the antioxidant Nrf2-Keap1 pathway? J. Ren. Nutr. 24, 286–291 (2014).

    CAS  PubMed  Google Scholar 

  241. Bolati, D., Shimizu, H., Yisireyili, M., Nishijima, F. & Niwa, T. Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-kappaB. BMC Nephrol. 14, 56 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Chin, L. H. et al. The regulation of NLRP3 inflammasome expression during the development of cardiac contractile dysfunction in chronic kidney disease. Oncotarget 8, 113303–113317 (2017).

    PubMed  PubMed Central  Google Scholar 

  243. Vilaysane, A. et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J. Am. Soc. Nephrol. 21, 1732–1744 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Muteliefu, G., Enomoto, A. & Niwa, T. Indoxyl sulfate promotes proliferation of human aortic smooth muscle cells by inducing oxidative stress. J. Ren. Nutr. 19, 29–32 (2009).

    CAS  PubMed  Google Scholar 

  245. Yamamoto, H. et al. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int. 69, 1780–1785 (2006).

    CAS  PubMed  Google Scholar 

  246. Bartlett, D. E. et al. Uremic toxins activates Na/K-ATPase oxidant amplification loop causing phenotypic changes in adipocytes in in vitro models. Int. J. Mol. Sci. 19, E2685 (2018).

    PubMed  Google Scholar 

  247. Zhao, L. et al. Deletion of interleukin-6 attenuates pressure overload-induced left ventricular hypertrophy and dysfunction. Circ. Res. 118, 1918–1929 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Sriramula, S. & Francis, J. Tumor necrosis factor-alpha is essential for angiotensin II-induced ventricular remodeling: role for oxidative stress. PLOS ONE 10, e0138372 (2015).

    PubMed  PubMed Central  Google Scholar 

  249. Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114, 1752–1761 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Ramos, L. F., Shintani, A., Ikizler, T. A. & Himmelfarb, J. Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. J. Am. Soc. Nephrol. 19, 593–599 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Viaene, L. et al. Albumin is the main plasma binding protein for indoxyl sulfate and p-cresyl sulfate. Biopharm. Drug Dispos. 34, 165–175 (2013).

    CAS  PubMed  Google Scholar 

  252. Meijers, B. K. et al. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int. 73, 1174–1180 (2008).

    CAS  PubMed  Google Scholar 

  253. Han, H. et al. p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J. Am. Heart Assoc. 4, e001852 (2015).

    PubMed  PubMed Central  Google Scholar 

  254. Manunta, P. et al. Left ventricular mass, stroke volume, and ouabain-like factor in essential hypertension. Hypertension 34, 450–456 (1999).

    CAS  PubMed  Google Scholar 

  255. Kennedy, D. J. et al. Elevated plasma marinobufagenin, an endogenous cardiotonic steroid, is associated with right ventricular dysfunction and nitrative stress in heart failure. Circ. Heart Fail. 8, 1068–1076 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Komiyama, Y. et al. A novel endogenous digitalis, telocinobufagin, exhibits elevated plasma levels in patients with terminal renal failure. Clin. Biochem. 38, 36–45 (2005).

    CAS  PubMed  Google Scholar 

  257. Bagrov, A. Y. et al. Characterization of a urinary bufodienolide Na+,K+-ATPase inhibitor in patients after acute myocardial infarction. Hypertension 31, 1097–1103 (1998).

    CAS  PubMed  Google Scholar 

  258. Kolmakova, E. V. et al. Endogenous cardiotonic steroids in chronic renal failure. Nephrol. Dial. Transplant. 26, 2912–2919 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Hamlyn, J. M. & Manunta, P. Endogenous cardiotonic steroids in kidney failure: a review and an hypothesis. Adv. Chron. Kidney Dis. 22, 232–244 (2015).

    Google Scholar 

  260. Haller, S. T. et al. Monoclonal antibody against marinobufagenin reverses cardiac fibrosis in rats with chronic renal failure. Am. J. Hypertens. 25, 690–696 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Tian, J. et al. Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing marinobufagenin. Hypertension 54, 1313–1320 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Haller, S. T. et al. Rapamycin attenuates cardiac fibrosis in experimental uremic cardiomyopathy by reducing marinobufagenin levels and inhibiting downstream pro-fibrotic signaling. J. Am. Heart Assoc. 5, e004106 (2016).

    PubMed  PubMed Central  Google Scholar 

  263. Haller, S. T. et al. Passive immunization against marinobufagenin attenuates renal fibrosis and improves renal function in experimental renal disease. Am. J. Hypertens. 27, 603–609 (2014).

    CAS  PubMed  Google Scholar 

  264. Arnon, A., Hamlyn, J. M. & Blaustein, M. P. Ouabain augments Ca(2+) transients in arterial smooth muscle without raising cytosolic Na(+). Am. J. Physiol. Heart Circ. Physiol. 279, H679–H691 (2000).

    CAS  PubMed  Google Scholar 

  265. Skou, J. C. The identification of the sodium pump. Biosci. Rep. 24, 436–451 (2004).

    PubMed  Google Scholar 

  266. Tian, J. et al. Binding of Src to Na+/K+-ATPase forms a functional signaling complex. Mol. Biol. Cell 17, 317–326 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. Haas, M., Wang, H., Tian, J. & Xie, Z. Src-mediated inter-receptor cross-talk between the Na+/K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J. Biol. Chem. 277, 18694–18702 (2002).

    CAS  PubMed  Google Scholar 

  268. Liu, J. et al. Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism. Kidney Int. 66, 227–241 (2004).

    CAS  PubMed  Google Scholar 

  269. Tian, J., Gong, X. & Xie, Z. Signal-transducing function of Na+-K+-ATPase is essential for ouabain’s effect on [Ca2+]i in rat cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 281, H1899–H1907 (2001).

    CAS  PubMed  Google Scholar 

  270. Wansapura, A. N., Lasko, V. M., Lingrel, J. B. & Lorenz, J. N. Mice expressing ouabain-sensitive alpha1-Na, K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 300, H347–H355 (2011).

    CAS  PubMed  Google Scholar 

  271. Drummond, C. A. et al. Reduction of Na/K-ATPase affects cardiac remodeling and increases c-kit cell abundance in partial nephrectomized mice. Am. J. Physiol. Heart Circ. Physiol. 306, H1631–H1643 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Xie, Z. et al. Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. J. Biol. Chem. 274, 19323–19328 (1999).

    CAS  PubMed  Google Scholar 

  273. Liu, J. et al. Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+ concentrations. J. Biol. Chem. 275, 27838–27844 (2000).

    CAS  PubMed  Google Scholar 

  274. Yan, Y. et al. Protein carbonylation of an amino acid residue of the Na/K-ATPase alpha1 subunit determines Na/K-ATPase signaling and sodium transport in renal proximal tubular cells. J. Am. Heart Assoc. 5, e003675 (2016).

    PubMed  PubMed Central  Google Scholar 

  275. Liu, J. et al. Attenuation of Na/K-ATPase mediated oxidant amplification with pNaKtide ameliorates experimental uremic cardiomyopathy. Sci. Rep. 6, 34592 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Yan, Y. et al. Involvement of reactive oxygen species in a feed-forward mechanism of Na/K-ATPase-mediated signaling transduction. J. Biol. Chem. 288, 34249–34258 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Chen, Y. et al. Oxidized LDL-bound CD36 recruits an Na+/K+-ATPase-Lyn complex in macrophages that promotes atherosclerosis. Sci. Signal. 8, ra91 (2015).

    PubMed  PubMed Central  Google Scholar 

  278. Kennedy, D. J. et al. CD36 and Na/K-ATPase-alpha1 form a proinflammatory signaling loop in kidney. Hypertension 61, 216–224 (2013).

    CAS  PubMed  Google Scholar 

  279. Mhatre, K. N. et al. Crosstalk between FGF23- and angiotensin II-mediated Ca(2+) signaling in pathological cardiac hypertrophy. Cell. Mol. Life Sci. 75, 4403–4416 (2018).

    CAS  PubMed  Google Scholar 

  280. Raeisi, S. et al. Effects of angiotensin II receptor blockade on soluble Klotho and oxidative stress in calcineurin inhibitor nephrotoxicity in rats. Iran. J. Kidney Dis. 10, 358–363 (2016).

    PubMed  Google Scholar 

  281. Karalliedde, J., Maltese, G., Hill, B., Viberti, G. & Gnudi, L. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin. J. Am. Soc. Nephrol. 8, 1899–1905 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  282. Shimizu, H. et al. Indoxyl sulfate enhances angiotensin II signaling through upregulation of epidermal growth factor receptor expression in vascular smooth muscle cells. Life Sci. 91, 172–177 (2012).

    CAS  PubMed  Google Scholar 

  283. Lin, C. J. et al. Association of indoxyl sulfate with fibroblast growth factor 23 in patients with advanced chronic kidney disease. Am. J. Med. Sci. 347, 370–376 (2014).

    PubMed  Google Scholar 

  284. Taylor, D., Bhandari, S. & Seymour, A. M. Mitochondrial dysfunction in uremic cardiomyopathy. Am. J. Physiol. Renal Physiol. 308, F579–F587 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Burgoyne, J. R., Mongue-Din, H., Eaton, P. & Shah, A. M. Redox signaling in cardiac physiology and pathology. Circ. Res. 111, 1091–1106 (2012).

    CAS  PubMed  Google Scholar 

  286. Annuk, M., Zilmer, M., Lind, L., Linde, T. & Fellstrom, B. Oxidative stress and endothelial function in chronic renal failure. J. Am. Soc. Nephrol. 12, 2747–2752 (2001).

    CAS  PubMed  Google Scholar 

  287. Ruggenenti, P., Cravedi, P. & Remuzzi, G. Mechanisms and treatment of CKD. J. Am. Soc. Nephrol. 23, 1917–1928 (2012).

    CAS  PubMed  Google Scholar 

  288. Balamuthusamy, S. et al. Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a meta-analysis. Am. Heart J. 155, 791–805 (2008).

    CAS  PubMed  Google Scholar 

  289. Perkovic, V. et al. Chronic kidney disease, cardiovascular events, and the effects of perindopril-based blood pressure lowering: data from the PROGRESS study. J. Am. Soc. Nephrol. 18, 2766–2772 (2007).

    PubMed  Google Scholar 

  290. Mann, J. F., Gerstein, H. C., Pogue, J., Bosch, J. & Yusuf, S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann. Intern. Med. 134, 629–636 (2001).

    CAS  PubMed  Google Scholar 

  291. Zannad, F. et al. Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int. 70, 1318–1324 (2006).

    CAS  PubMed  Google Scholar 

  292. Marquez, D. F., Ruiz-Hurtado, G., Ruilope, L. M. & Segura, J. An update of the blockade of the renin angiotensin aldosterone system in clinical practice. Expert Opin. Pharmacother. 16, 2283–2292 (2015).

    PubMed  Google Scholar 

  293. Juurlink, D. N. et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N. Engl. J. Med. 351, 543–551 (2004).

    CAS  PubMed  Google Scholar 

  294. Frankenfield, D. L. et al. Utilization and costs of cardiovascular disease medications in dialysis patients in Medicare Part D. Am. J. Kidney Dis. 59, 670–681 (2012).

  295. Cice, G. et al. Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J. Am. Coll. Cardiol. 41, 1438–1444 (2003).

    CAS  PubMed  Google Scholar 

  296. Cohen-Solal, A. et al. Efficacy and safety of nebivolol in elderly heart failure patients with impaired renal function: insights from the SENIORS trial. Eur. J. Heart Fail. 11, 872–880 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  297. Badve, S. V. et al. Effects of beta-adrenergic antagonists in patients with chronic kidney disease: a systematic review and meta-analysis. J. Am. Coll. Cardiol. 58, 1152–1161 (2011).

    CAS  PubMed  Google Scholar 

  298. Agarwal, R., Sinha, A. D., Pappas, M. K., Abraham, T. N. & Tegegne, G. G. Hypertension in hemodialysis patients treated with atenolol or lisinopril: a randomized controlled trial. Nephrol. Dial. Transplant. 29, 672–681 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. Kitchlu, A. et al. Beta-blockers and cardiovascular outcomes in dialysis patients: a cohort study in Ontario, Canada. Nephrol. Dial. Transplant. 27, 1591–1598 (2012).

    CAS  PubMed  Google Scholar 

  300. Koizumi, M., Komaba, H., Nakanishi, S., Fujimori, A. & Fukagawa, M. Cinacalcet treatment and serum FGF23 levels in haemodialysis patients with secondary hyperparathyroidism. Nephrol. Dial. Transplant. 27, 784–790 (2012).

    CAS  PubMed  Google Scholar 

  301. Greeviroj, P. et al. Cinacalcet for treatment of chronic kidney disease-mineral and bone disorder: a meta-analysis of randomized controlled trials. Nephron 139, 197–210 (2018).

    CAS  PubMed  Google Scholar 

  302. Brunelli, S. M., Thadhani, R., Ikizler, T. A. & Feldman, H. I. Thiazolidinedione use is associated with better survival in hemodialysis patients with non-insulin dependent diabetes. Kidney Int. 75, 961–968 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. Ramirez, S. P. et al. Rosiglitazone is associated with mortality in chronic hemodialysis patients. J. Am. Soc. Nephrol. 20, 1094–1101 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Hatakeyama, S. et al. Effect of an oral adsorbent, AST-120, on dialysis initiation and survival in patients with chronic kidney disease. Int. J. Nephrol. 2012, 376128 (2012).

    PubMed  PubMed Central  Google Scholar 

  305. Schulman, G. et al. Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J. Am. Soc. Nephrol. 26, 1732–1746 (2015).

    CAS  PubMed  Google Scholar 

  306. Drechsler, C. et al. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 87, 1201–1208 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  307. Drozdz, D. et al. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell. Longev. 2016, 7520231 (2016).

    PubMed  PubMed Central  Google Scholar 

  308. Himmelfarb, J. et al. Provision of antioxidant therapy in hemodialysis (PATH): a randomized clinical trial. J. Am. Soc. Nephrol. 25, 623–633 (2014).

    CAS  PubMed  Google Scholar 

  309. Bolignano, D. et al. Antioxidant agents for delaying diabetic kidney disease progression: a systematic review and meta-analysis. PLOS ONE 12, e0178699 (2017).

    PubMed  PubMed Central  Google Scholar 

  310. Cheitlin, M. D. et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article. J. Am. Soc. Echocardiogr. 16, 1091–1110 (2003).

    PubMed  Google Scholar 

  311. Marwick, T. H. et al. Recommendations on the use of echocardiography in adult hypertension: a report from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE). J. Am. Soc. Echocardiogr. 28, 727–754 (2015).

    PubMed  Google Scholar 

  312. Lang, R. M. et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr. 28, 1–39 (2015).

    PubMed  Google Scholar 

  313. Khouri, S. J., Maly, G. T., Suh, D. D. & Walsh, T. E. A practical approach to the echocardiographic evaluation of diastolic function. J. Am. Soc. Echocardiogr. 17, 290–297 (2004).

    PubMed  Google Scholar 

  314. Sodhi, K. et al. pNaKtide attenuates steatohepatitis and atherosclerosis by blocking Na/K-ATPase/ROS amplification in C57Bl6 and ApoE knockout mice fed a Western diet. Sci. Rep. 7, 193 (2017).

    PubMed  PubMed Central  Google Scholar 

  315. Sodhi, K. et al. pNaKtide inhibits Na/K-ATPase reactive oxygen species amplification and attenuates adipogenesis. Sci. Adv. 1, e1500781 (2015).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors’ work was supported by US National Institutes of Health grants HL109015, HL071556 and HL105649; by the Brickstreet Foundation; and by the Huntington Foundation, Inc.

Reviewer information

Nature Reviews Nephrology thanks C. Faul, J. Jankowski and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information

Authors and Affiliations

Authors

Contributions

Both authors researched the data discussed in this article, discussed the content, wrote the article and reviewed or edited the text before submission.

Corresponding author

Correspondence to Joseph I. Shapiro.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Glossary

Endogenous cardiotonic steroids

A class of steroid hormones with important roles in health and disease. Endogenous cardiotonic steroids such as cardenolide and bufadienolide signal through the Na+/K+-ATPase.

Pressure overload

Refers to the pathological state of cardiac muscle in which it has to contract against excessive pressure.

Volume overload

Refers to the pathological state of the heart in which an abnormally large volume of blood must be pumped.

Hypervolaemia

Also known as fluid overload, hypervolaemia is a pathological condition in which there is too much fluid in the blood. Hypervolaemia is common in the setting of renal failure.

Aortocaval fistula

A surgically created arteriovenous fistula between the abdominal aorta and inferior vena cava, distal to the origin of the renal arteries. Aortocaval fistula is used as an experimental model of volume overload.

Secondary hyperparathyroidism

Refers to excessive secretion of parathyroid hormone by the parathyroid gland in response to low serum calcium level and high phosphorus level in the setting of renal failure.

Inflammasomes

A multiprotein intracellular complex that detects pathogenic microorganisms and activates inflammatory responses via the activation of pro-inflammatory cytokines such as IL-1β and IL-18.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Shapiro, J.I. Evolving concepts in the pathogenesis of uraemic cardiomyopathy. Nat Rev Nephrol 15, 159–175 (2019). https://doi.org/10.1038/s41581-018-0101-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-018-0101-8

This article is cited by

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