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  • Review Article
  • Published:

Heart failure and kidney dysfunction: epidemiology, mechanisms and management

Nature Reviews Nephrology volume 12, pages 610–623 (2016)Cite this article

Subjects

Key Points

  • Heart failure (HF) interacts with kidney disease via numerous pathophysiological pathways in both the acute and chronic setting

  • Mounting data indicate that the complex interplay between the heart and the kidneys involves haemodynamic, (neuro)homonal and cardiovascular disease-associated mechanisms

  • Acceleration of HF or kidney dysfunction is driven by impairment of either the heart or kidneys via mechanisms including induction of inflammation, activation of the cellular immune system, metabolic disorders, anaemia and mineral and bone disorder

  • In an effort to differentiate respective underlying pathologies and to assess acute and/or chronic organ dysfunction over time, five subtypes of cardio-renal syndromes were proposed

  • The absence of a standardized terminology database and the lack of studies specific to cardio-renal syndrome has hampered efforts to develop novel treatments

Abstract

Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid–base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches.

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Figure 1: Overview of key cardio-renal interactions.
Figure 2: Definitions of cardio-renal syndromes.
Figure 3: Haemodynamic mechanisms in cardio-renal interactions.
Figure 4: (Neuro)hormonal mechanisms in cardio-renal interactions.
Figure 5: Cardiovascular disease-associated mechanisms leading to the progression of heart failure, chronic kidney disease (CKD), and/or acute kidney injury (AKI).

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References

  1. Schocken, D. D. et al. Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 117, 2544–2565 (2008).

    PubMed  Google Scholar 

  2. van Riet, E. E. et al. Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review. Eur. J. Heart Fail. 18, 242–252 (2016).

    PubMed  Google Scholar 

  3. Redfield, M. M. et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 289, 194–202 (2003).

    PubMed  Google Scholar 

  4. Bagshaw, S. M. et al. Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol. Dial. Transplant. 25, 1406–1416 (2010).

    PubMed  Google Scholar 

  5. House, A. A. et al. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol. Dial. Transplant. 25, 1416–1420 (2010).

    PubMed  Google Scholar 

  6. Segall, L., Nistor, I. & Covic, A. Heart failure in patients with chronic kidney disease: a systematic integrative review. BioMed Res. Int. 2014, 937398 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Mentz, R. J., O'Connor, C. M. Pathophysiology and clinical evaluation of acute heart failure. Nat. Rev. Cardiol. 13, 28–35 (2016).

    CAS  PubMed  Google Scholar 

  8. Filippatos, G., Farmakis, D. & Parissis, J. Renal dysfunction and heart failure: things are seldom what they seem. Eur. Heart J. 35, 416–418 (2014).

    PubMed  Google Scholar 

  9. Mehta, R. L. et al. Acute Kidney Injury Network. Report of an initiative to improve outcomes in acute kidney injury. Crit. Care 11, R31 (2007).

    PubMed  PubMed Central  Google Scholar 

  10. Damman, K., Tang, W. H., Testani, J. M. & McMurray, J. J. Terminology and definition of changes renal function in heart failure. Eur. Heart J. 35, 3413–3416 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hogg, K., Swedberg, K. & McMurray, J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J. Am. College Cardiol. 43, 317–327 (2004).

    Google Scholar 

  12. McMurray, J. J. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 33, 1787–1847 (2012).

    PubMed  Google Scholar 

  13. Ezekowitz, J. et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J. Am. College Cardiol. 44, 1587–1592 (2004).

    Google Scholar 

  14. Hillege, H. L. et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 113, 671–678 (2006).

    PubMed  Google Scholar 

  15. McAlister, F. A., Ezekowitz, J., Tonelli, M. & Armstrong, P. W. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation 109, 1004–1009 (2004).

    PubMed  Google Scholar 

  16. McClellan, W. M., Langston, R. D. & Presley, R. Medicare patients with cardiovascular disease have a high prevalence of chronic kidney disease and a high rate of progression to end-stage renal disease. J. Am. Soc. Nephrol. 15, 1912–1919 (2004).

    PubMed  Google Scholar 

  17. van Deursen, V. M. et al. Co-morbidities in patients with heart failure: an analysis of the European Heart Failure Pilot Survey. Eur. J. Heart Fail. 16, 103–111 (2014).

    PubMed  Google Scholar 

  18. Morley, J. E., Anker, S. D. & von Haehling, S. Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology-update 2014. J. Cachexia Sarcopenia Muscle 5, 253–259 (2014).

    PubMed  PubMed Central  Google Scholar 

  19. Adams, K. F. et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am. Heart J. 149, 209–216 (2005).

    PubMed  Google Scholar 

  20. Tonelli, M. et al. Chronic kidney disease and mortality risk: a systematic review. J. Am. Soc. Nephrol. 17, 2034–2047 (2006).

    PubMed  Google Scholar 

  21. Sud, M., Tangri, N., Pintilie, M., Levey, A. S. & Naimark, D. Risk of end-stage renal disease and death after cardiovascular events in chronic kidney disease. Circulation 130, 458–465 (2014).

    PubMed  Google Scholar 

  22. Gansevoort, R. T. et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 382, 339–352 (2013).

    PubMed  Google Scholar 

  23. United States Renal Data System. Chronic kidney disease in the adult NHANES population. USRDS annual report data http://www.usrds.org/2009/pdf/V1_01_09.pdf (2009).

  24. Levey, A. S. et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 80, 17–28 (2011).

    PubMed  Google Scholar 

  25. Kottgen, A. et al. Reduced kidney function as a risk factor for incident heart failure: the atherosclerosis risk in communities (ARIC) study. J. Am. Soc. Nephrol. 18, 1307–1315 (2007).

    CAS  PubMed  Google Scholar 

  26. Sud, M., Tangri, N., Pintilie, M., Levey, A. S. & Naimark, D. M. ESRD and death after heart failure in CKD. J. Am. Soc. Nephrol. 26, 715–722 (2015).

    PubMed  Google Scholar 

  27. Tsuruya, K., Eriguchi, M., Yamada, S., Hirakata, H. & Kitazono, T. Cardio-renal syndrome in end-stage kidney disease. Blood Purif. 40, 337–343 (2015).

    CAS  PubMed  Google Scholar 

  28. Johnson, D. W., Craven, A. M. & Isbel, N. M. Modification of cardiovascular risk in hemodialysis patients: an evidence-based review. Hemodial. Int. 11, 1–14 (2007).

    PubMed  Google Scholar 

  29. Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New Engl. J. Med. 351, 1296–1305 (2004).

    CAS  PubMed  Google Scholar 

  30. Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 32 (Suppl. 3), S112–S119 (1998).

    CAS  PubMed  Google Scholar 

  31. Foley, R. N. et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int. 47, 186–192 (1995).

    CAS  PubMed  Google Scholar 

  32. Soucie, J. M. & McClellan, W. M. Early death in dialysis patients: risk factors and impact on incidence and mortality rates. J. Am. Soc. Nephrol. 7, 2169–2175 (1996).

    CAS  PubMed  Google Scholar 

  33. Harnett, J. D. et al. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int. 47, 884–890 (1995).

    CAS  PubMed  Google Scholar 

  34. Wang, A. Y. et al. Heart failure in long-term peritoneal dialysis patients: a 4-year prospective analysis. Clin. J. Am. Soc. Nephrol. 6, 805–812 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Basile, D. P., Anderson, M. D. & Sutton, T. A. Pathophysiology of acute kidney injury. Comprehensive Physiol. 2, 1303–1353 (2012).

    Google Scholar 

  36. Berl, T. & Henrich, W. Kidney-heart interactions: epidemiology, pathogenesis, and treatment. Clin. J. Am. Soc. Nephrol. 1, 8–18 (2006).

    CAS  PubMed  Google Scholar 

  37. Chertow, G. M., Burdick, E., Honour, M., Bonventre, J. V. & Bates, D. W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J. Am. Soc. Nephrol. 16, 3365–3370 (2005).

    PubMed  Google Scholar 

  38. Nash, K., Hafeez, A. & Hou, S. Hospital-acquired renal insufficiency. Am. J. Kidney Dis. 39, 930–936 (2002).

    PubMed  Google Scholar 

  39. Uchino, S. et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294, 813–818 (2005).

    CAS  PubMed  Google Scholar 

  40. Bagshaw, S. M., George, C., Dinu, I. & Bellomo, R. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol. Dial. Transplant. 23, 1203–1210 (2008).

    PubMed  Google Scholar 

  41. Hsu, C. Y. et al. Community-based incidence of acute renal failure. Kidney Int. 72, 208–212 (2007).

    PubMed  PubMed Central  Google Scholar 

  42. Waikar, S. S., Curhan, G. C., Wald, R., McCarthy, E. P. & Chertow, G. M. Declining mortality in patients with acute renal failure, 1988 to 2002. J. Am. Soc. Nephrol. 17, 1143–1150 (2006).

    PubMed  Google Scholar 

  43. Kolhe, N. V., Muirhead, A. W., Wilkes, S. R., Fluck, R. J. & Taal, M. W. The epidemiology of hospitalised acute kidney injury not requiring dialysis in England from 1998 to 2013: retrospective analysis of hospital episode statistics. Int. J. Clin. Practice 70, 330–339 (2016).

    CAS  Google Scholar 

  44. Martensson, J. & Bellomo, R. Sepsis-induced acute kidney injury. Crit. Care Clin. 31, 649–660 (2015).

    PubMed  Google Scholar 

  45. Rossaint, J. & Zarbock, A. Acute kidney injury: definition, diagnosis and epidemiology. Minerva Urol. Nefrol. 68, 49–57 (2015).

    PubMed  Google Scholar 

  46. Damman, K. et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur. Heart J. 35, 455–469 (2014).

    PubMed  Google Scholar 

  47. Davison, B. A. et al. Worsening heart failure following admission for acute heart failure: a pooled analysis of the PROTECT and RELAX-AHF Studies. JACC Heart Fail. 3, 395–403 (2015).

    PubMed  Google Scholar 

  48. Grams, M. E. & Rabb, H. The distant organ effects of acute kidney injury. Kidney Int. 81, 942–948 (2012).

    PubMed  Google Scholar 

  49. Metra, M. et al. Is worsening renal function an ominous prognostic sign in patients with acute heart failure? The role of congestion and its interaction with renal function. Circul. Heart Fail. 5, 54–62 (2012).

    Google Scholar 

  50. 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 

  51. Ronco, C., Haapio, M., House, A. A., Anavekar, N. & Bellomo, R. Cardio-renal syndrome. J. Am. College Cardiol. 52, 1527–1539 (2008).

    Google Scholar 

  52. McCullough, P. A. et al. Pathophysiology of the cardio-renal syndromes: executive summary from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib. Nephrol. 182, 82–98 (2013).

    PubMed  Google Scholar 

  53. Hadjiphilippou, S. & Kon, S. P. Cardio-renal syndrome: review of our current understanding. J. R. Soc. Med. 109, 12–17 (2016).

    PubMed  PubMed Central  Google Scholar 

  54. Tsuruya, K. & Eriguchi, M. Cardio-renal syndrome in chronic kidney disease. Curr. Opin. Nephrol. Hypertension 24, 154–162 (2015).

    CAS  Google Scholar 

  55. Mall, G., Huther, W., Schneider, J., Lundin, P. & Ritz, E. Diffuse intermyocardiocytic fibrosis in uraemic patients. Nephrol. Dial. Transplant. 5, 39–44 (1990).

    CAS  PubMed  Google Scholar 

  56. Wali, R. K. et al. Effect of kidney transplantation on left ventricular systolic dysfunction and congestive heart failure in patients with end-stage renal disease. J. Am. College Cardiol. 45, 1051–1060 (2005).

    Google Scholar 

  57. Bock, J. S. & Gottlieb, S. S. Cardio-renal syndrome: new perspectives. Circulation 121, 2592–2600 (2010).

    PubMed  Google Scholar 

  58. Waldum, B. & Os, I. The cardio-renal syndrome: what the cardiologist needs to know. Cardiology 126, 175–186 (2013).

    PubMed  Google Scholar 

  59. Graziani, G. et al. Renal dysfunction in acute congestive heart failure: a common problem for cardiologists and nephrologists. Heart Fail. Rev. 19, 699–708 (2014).

    CAS  PubMed  Google Scholar 

  60. Carlstrom, M., Wilcox, C. S. & Arendshorst, W. J. Renal autoregulation in health and disease. Physiol. Rev. 95, 405–511 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Ljungman, S., Laragh, J. H. & Cody, R. J. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 39 (Suppl. 4), 10–21 (1990).

    PubMed  Google Scholar 

  62. Singh, D. K., Winocour, P. & Farrington, K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat. Clin. Practice Nephrol. 4, 216–226 (2008).

    CAS  Google Scholar 

  63. Manotham, K. et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int. 65, 871–880 (2004).

    PubMed  Google Scholar 

  64. Norman, J. T., Clark, I. M. & Garcia, P. L. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 58, 2351–2366 (2000).

    CAS  PubMed  Google Scholar 

  65. Heywood, J. T. et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J. Cardiac Fail. 13, 422–430 (2007).

    Google Scholar 

  66. Nohria, A. et al. Cardio-renal interactions: insights from the ESCAPE trial. J. Am. College Cardiol. 51, 1268–1274 (2008).

    Google Scholar 

  67. Mullens, W. et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J. Am. College Cardiol. 53, 589–596 (2009).

    Google Scholar 

  68. Drazner, M. H., Rame, J. E., Stevenson, L. W. & Dries, D. L. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. New Engl. J. Med. 345, 574–581 (2001).

    CAS  PubMed  Google Scholar 

  69. Maeder, M. T., Holst, D. P. & Kaye, D. M. Tricuspid regurgitation contributes to renal dysfunction in patients with heart failure. J. Cardiac Fail. 14, 824–830 (2008).

    Google Scholar 

  70. Mullens, W. et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J. Am. College Cardiol. 51, 300–306 (2008).

    Google Scholar 

  71. Chen, K. P. et al. Peripheral edema, central venous pressure, and risk of AKI in critical illness. Clin. J. Am. Soc. Nephrol. 11, 602–608 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Damman, K. et al. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J. Am. College Cardiol. 53, 582–588 (2009).

    Google Scholar 

  73. Guyton, A. C. Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol. Rev. 35, 123–129 (1955).

    CAS  PubMed  Google Scholar 

  74. Uemura, K. et al. A novel framework of circulatory equilibrium. Am. J. Physiol. Heart Circulatory Physiol. 286, H2376–2385 (2004).

    CAS  Google Scholar 

  75. Magder, S. Point: the classical Guyton view that mean systemic pressure, right atrial pressure, and venous resistance govern venous return is/is not correct. J. Appl. Physiol. 101, 1523–1525 (2006).

    CAS  PubMed  Google Scholar 

  76. Winton, F. R. The influence of venous pressure on the isolated mammalian kidney. J. Physiol. 72, 49–61 (1931).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Gottschalk, C. W. & Mylle, M. Micropuncture study of pressures in proximal tubules and peritubular capillaries of the rat kidney and their relation to ureteral and renal venous pressures. Am. J. Physiol. 185, 430–439 (1956).

    CAS  PubMed  Google Scholar 

  78. Doty, J. M. et al. Effect of increased renal venous pressure on renal function. J. Trauma 47, 1000–1003 (1999).

    CAS  PubMed  Google Scholar 

  79. Braam, B., Joles, J. A., Danishwar, A. H. & Gaillard, C. A. Cardio-renal syndrome — current understanding and future perspectives. Nat. Rev. Nephrol. 10, 48–55 (2014).

    CAS  PubMed  Google Scholar 

  80. Ronco, C. et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur. Heart J. 31, 703–711 (2010).

    PubMed  Google Scholar 

  81. Damman, K., Voors, A. A., Navis, G., van Veldhuisen, D. J. & Hillege, H. L. The cardio-renal syndrome in heart failure. Prog. Cardiovasc. Dis. 54, 144–153 (2011).

    PubMed  Google Scholar 

  82. Afsar, B. et al. Focus on renal congestion in heart failure. Clin. Kidney J. 9, 39–47 (2016).

    CAS  PubMed  Google Scholar 

  83. Erly, B. et al. Hepatorenal syndrome: a review of pathophysiology and current treatment options. Semin. Intervent. Radiol. 32, 445–454 (2015).

    PubMed  PubMed Central  Google Scholar 

  84. Verbrugge, F. H. et al. Abdominal contributions to cardio-renal dysfunction in congestive heart failure. J. Am. College Cardiol. 62, 485–495 (2013).

    Google Scholar 

  85. Volpe, M., Carnovali, M. & Mastromarino, V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin. Sci. 130, 57–77 (2016).

    CAS  PubMed  Google Scholar 

  86. Ruiz-Ortega, M. et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int. Suppl. 82, S12–S22 (2002).

    CAS  Google Scholar 

  87. Sharma, U. C. et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation 110, 3121–3128 (2004).

    CAS  PubMed  Google Scholar 

  88. de Boer, R. A. et al. Galectin-3 in heart failure with preserved ejection fraction. Eur. J. Heart Fail. 15, 1095–1101 (2013).

    CAS  PubMed  Google Scholar 

  89. AbouEzzeddine, O.F. et al. Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in diastolic heart failure). JACC Heart Fail. 3, 245–252 (2015).

    PubMed  PubMed Central  Google Scholar 

  90. Shenker, Y., Sider, R. S., Ostafin, E. A. & Grekin, R. J. Plasma levels of immunoreactive atrial natriuretic factor in healthy subjects and in patients with edema. J. Clin. Invest. 76, 1684–1687 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Trimarco, B. et al. Blunted sympathetic response to cardiopulmonary receptor unloading in hypertensive patients with left ventricular hypertrophy. A possible compensatory role of atrial natriuretic factor. Circulation 80, 883–892 (1989).

    CAS  PubMed  Google Scholar 

  92. Volpe, M. et al. Carotid baroreceptor unloading decreases plasma atrial natriuretic factor in hypertensive patients. J. Hypertension 4, S519–S522 (1986).

    CAS  Google Scholar 

  93. von Haehling, S. et al. Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in predicting survival in patients with chronic heart failure. J. Am. College Cardiol. 50, 1973–1980 (2007).

    CAS  Google Scholar 

  94. Gegenhuber, A. et al. Midregional pro-A-type natriuretic peptide measurements for diagnosis of acute destabilized heart failure in short-of-breath patients: comparison with B-type natriuretic peptide (BNP) and amino-terminal proBNP. Clin. Chem. 52, 827–831 (2006).

    CAS  PubMed  Google Scholar 

  95. Moertl, D. et al. Comparison of midregional pro-atrial and B-type natriuretic peptides in chronic heart failure: influencing factors, detection of left ventricular systolic dysfunction, and prediction of death. J. Am. College Cardiol. 53, 1783–1790 (2009).

    CAS  Google Scholar 

  96. Voors, A. A. et al. C-terminal provasopressin (copeptin) is a strong prognostic marker in patients with heart failure after an acute myocardial infarction: results from the OPTIMAAL study. Eur. Heart J. 30, 1187–1194 (2009).

    CAS  PubMed  Google Scholar 

  97. Farmakis, D., Filippatos, G., Kremastinos, D. T. & Gheorghiade, M. Vasopressin and vasopressin antagonists in heart failure and hyponatremia. Curr. Heart Fail. Rep. 5, 91–96 (2008).

    CAS  PubMed  Google Scholar 

  98. Grassi, G. et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension 57, 846–851 (2011).

    CAS  PubMed  Google Scholar 

  99. 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 

  100. Dibona, G. F., Jones, S. Y. & Sawin, L. L. Reflex influences on renal nerve activity characteristics in nephrosis and heart failure. J. Am. Soc. Nephrol. 8, 1232–1239 (1997).

    CAS  PubMed  Google Scholar 

  101. DiBona, G. F. & Kopp, U. C. Neural control of renal function. Physiol. Rev. 77, 75–197 (1997).

    CAS  PubMed  Google Scholar 

  102. Ramchandra, R. & Barrett, C. J. Regulation of the renal sympathetic nerves in heart failure. Frontiers Physiol. 6, 238 (2015).

    Google Scholar 

  103. Krum, H. et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373, 1275–1281 (2009).

    PubMed  Google Scholar 

  104. Schepers, E. et al. Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 2374–2383 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Bongartz, L. G. et al. Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R815–R823 (2010).

    CAS  PubMed  Google Scholar 

  106. Bongartz, L. G. et al. Subtotal nephrectomy plus coronary ligation leads to more pronounced damage in both organs than either nephrectomy or coronary ligation. Am. J. Physiol. Heart Circulatory Physiol. 302, H845–H854

    CAS  PubMed  Google Scholar 

  107. Voors, A. A. et al. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the selective adenosine A1 receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function). J. Am. College Cardiol. 57, 1899–1907 (2011).

    CAS  Google Scholar 

  108. Kato, S. et al. Aspects of immune dysfunction in end-stage renal disease. Clin. J. Am. Soc. Nephrol. 3, 1526–1533 (2008).

    PubMed  PubMed Central  Google Scholar 

  109. Machowska, A., Carrero, J. J., Lindholm, B. & Stenvinkel, P. Therapeutics targeting persistent inflammation in chronic kidney disease. Translat. Res. 167, 204–213 (2016).

    CAS  Google Scholar 

  110. von Haehling, S. et al. Leukocyte redistribution: effects of beta blockers in patients with chronic heart failure. PLoS ONE 4, e6411 (2009).

    PubMed  PubMed Central  Google Scholar 

  111. Stenvinkel, P., Heimburger, O., Lindholm, B., Kaysen, G.A. & Bergstrom, J. Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA syndrome). Nephrol. Dial. Transplant. 15, 953–960 (2000).

    CAS  PubMed  Google Scholar 

  112. Silverberg, D. S., Wexler, D., Blum, M. & Iaina, A. The cardio renal anemia syndrome: correcting anemia in patients with resistant congestive heart failure can improve both cardiac and renal function and reduce hospitalizations. Clin. Nephrol. 60 (Suppl. 1), S93–S102 (2003).

    PubMed  Google Scholar 

  113. Silverberg, D. S. et al. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol. Dial. Transplant. 18, 141–146 (2003).

    CAS  PubMed  Google Scholar 

  114. Kidney disease: improving global outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. 113, S1–S130 (2009).

  115. Mangner, N. et al. Skeletal muscle alterations in chronic heart failure: differential effects on quadriceps and diaphragm. J. Cachexia Sarcopenia Muscle 6, 381–390 (2015).

    PubMed  PubMed Central  Google Scholar 

  116. Josiak, K., Jankowska, E. A., Piepoli, M. F., Banasiak, W. & Ponikowski, P. Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormones. J. Cachexia, Sarcopenia Muscle 5, 287–296 (2014).

    Google Scholar 

  117. von Haehling, S., Schefold, J. C., Lainscak, M., Doehner, W. & Anker, S. D. Inflammatory biomarkers in heart failure revisited: much more than innocent bystanders. Heart Fail. Clin. 5, 549–560 (2009).

    PubMed  Google Scholar 

  118. Colombo, P. C. et al. Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardio-renal syndrome. Heart Fail. Rev. 17, 177–190 (2012).

    CAS  PubMed  Google Scholar 

  119. Stenvinkel, P. & Larsson, T. E. Chronic kidney disease. a clinical model of premature aging. Am. J. Kidney Diseases 62, 339–351 (2013).

    Google Scholar 

  120. Kooman, J. P., Kotanko, P., Schols, A. M., Shiels, P. G. & Stenvinkel, P. Chronic kidney disease and premature ageing. Nat. Rev. Nephrol. 10, 732–742 (2014).

    CAS  PubMed  Google Scholar 

  121. Schefold, J. P. et al. Increased Indoleamine 2,3-Dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol. Dial. Transplant. 24, 1901–1908 (2009).

    CAS  PubMed  Google Scholar 

  122. Kitai, T., Kirsop, J. & Tang, W. H. Exploring the Microbiome in Heart Failure. Curr. Heart Fail. Rep. 13, 103–109 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Barreto, D. V. et al. Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease. Kidney Int. 77, 550–556 (2010).

    CAS  PubMed  Google Scholar 

  124. Ismahil, M. A. et al. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circul. Res. 114, 266–282 (2014).

    CAS  Google Scholar 

  125. Hoffmann, J. et al. Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients. Circul. Res. 116, 87–98 (2015).

    CAS  Google Scholar 

  126. von Haehling, S. The wasting continuum in heart failure: from sarcopenia to cachexia. Proc. Nutr. Soc. 74, 367–377 (2015).

    PubMed  Google Scholar 

  127. Ebner, N., Elsner, S., Springer, J. & von Haehling, S. Molecular mechanisms and treatment targets of muscle wasting and cachexia in heart failure: an overview. Curr. Opin. Supportive Palliative Care 8, 15–24 (2014).

    PubMed  Google Scholar 

  128. Ebner, N. et al. Mechanism and novel therapeutic approaches to wasting in chronic disease. Maturitas 75, 199–206 (2013).

    CAS  PubMed  Google Scholar 

  129. von Haehling, S., Lainscak, M., Springer, J. & Anker, S. D. Cardiac cachexia: a systematic overview. Pharmacol. Ther. 121, 227–252 (2009).

    CAS  PubMed  Google Scholar 

  130. von Haehling, S., Steinbeck, L., Doehner, W., Springer, J. & Anker, S. D. Muscle wasting in heart failure: an overview. Int. J. Biochem. Cell Biol. 45, 2257–2265 (2013).

    CAS  PubMed  Google Scholar 

  131. Pecoits-Filho, R., Lindholm, B. & Stenvinkel, P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome — the heart of the matter. Nephrol. Dial. Transpl. 17 (Suppl. 11), 28–31 (2002).

    CAS  Google Scholar 

  132. Griendling, K. K., Minieri, C. A., Ollerenshaw, J. D. & Alexander, R. W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circul. Res. 74, 1141–1148 (1994).

    CAS  Google Scholar 

  133. Heymes, C. et al. Increased myocardial NADPH oxidase activity in human heart failure. J. Am. College Cardiol. 41, 2164–2171 (2003).

    CAS  Google Scholar 

  134. Vaziri, N. D., Dicus, M., Ho, N. D., Boroujerdi-Rad, L. & Sindhu, R. K. Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency. Kidney Int. 63, 179–185 (2003).

    CAS  PubMed  Google Scholar 

  135. Munzel, T., Gori, T. & Keaney, J. F. Jr., Maack, C. & Daiber, A. Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications. Eur. Heart J. 36, 2555–2564 (2015).

    PubMed  Google Scholar 

  136. Ratcliffe, P. J. From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway. Blood Purif. 20, 445–450 (2002).

    CAS  PubMed  Google Scholar 

  137. Pschowski, R. et al. Effects of dialysis modality on blood loss, bleeding complications and transfusion requirements in critically ill patients with dialysis-dependent acute renal failure. Anaesth. Intensive Care 43, 764–770 (2015).

    CAS  PubMed  Google Scholar 

  138. Lin, C. L. et al. Increased blood loss from access cannulation site during hemodialysis is associated with anemia and arteriovenous graft use. Ther. Apher. Dial. 18, 51–56 (2014).

    CAS  PubMed  Google Scholar 

  139. Groenveld, H. F. et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J. Am. College Cardiol. 52, 818–827 (2008).

    Google Scholar 

  140. Maggioni, A. P. et al. Anemia in patients with heart failure: prevalence and prognostic role in a controlled trial and in clinical practice. J. Cardiac Fail. 11, 91–98 (2005).

    Google Scholar 

  141. Kawashiro, N. et al. Clinical characteristics and outcome of hospitalized patients with congestive heart failure: results of the HIJC-HF registry. Circul. J. 72, 2015–2020 (2008).

    Google Scholar 

  142. Young, J. B. et al. Relation of low hemoglobin and anemia to morbidity and mortality in patients hospitalized with heart failure (insight from the OPTIMIZE-HF registry). Am. J. Cardiol. 101, 223–230 (2008).

    CAS  PubMed  Google Scholar 

  143. von Haehling, S. et al. Anaemia is an independent predictor of death in patients hospitalized for acute heart failure. Clin. Res. Cardiol. 99, 107–113 (2010).

    PubMed  Google Scholar 

  144. von Haehling, S. et al. Anaemia among patients with heart failure and preserved or reduced ejection fraction: results from the SENIORS study. Eur. J. Heart Fail. 13, 656–663 (2011).

    PubMed  Google Scholar 

  145. van der Meer, P., Groenveld, H. F. & Januzzi, J. L. Jr., van Veldhuisen, D. J. Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart 95, 1309–1314 (2009).

    CAS  PubMed  Google Scholar 

  146. Anker, S. D. et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. New Engl. J. Med. 361, 2436–2448 (2009).

    CAS  PubMed  Google Scholar 

  147. Ponikowski, P. et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiencydagger. Eur. Heart J. 36, 657–668 (2015).

    CAS  PubMed  Google Scholar 

  148. von Haehling, S., Jankowska, E. A., van Veldhuisen, D. J., Ponikowski, P. & Anker, S. D. Iron deficiency and cardiovascular disease. Nat. Rev. Cardiol. 12, 659–669 (2015).

    CAS  PubMed  Google Scholar 

  149. Levin, A. et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am. J. Kidney Dis. 34, 125–134 (1999).

    CAS  PubMed  Google Scholar 

  150. Calvillo, L. et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc. Natl Acad. Sci. USA 100, 4802–4806 (2003).

    CAS  PubMed  Google Scholar 

  151. Charytan, D. M., Fishbane, S., Malyszko, J., McCullough, P. A. & Goldsmith, D. Cardio-renal syndrome and the role of the bone-mineral axis and anemia. Am. J. Kidney Dis. 66, 196–205 (2015).

    PubMed  PubMed Central  Google Scholar 

  152. Kovesdy, C. P. & Quarles, L. D. The role of fibroblast growth factor-23 in cardio-renal syndrome. Nephron Clin. Pract. 123, 194–201 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Achinger, S. G. & Ayus, J. C. Left ventricular hypertrophy: is hyperphosphatemia among dialysis patients a risk factor? J. Am. Soc. Nephrol. 17 S255–S261 (2006).

    CAS  PubMed  Google Scholar 

  154. Fujii, H., Kim, J. I., Abe, T., Umezu, M. & Fukagawa, M. Relationship between parathyroid hormone and cardiac abnormalities in chronic dialysis patients. Internal Med. 46, 1507–1512 (2007).

    Google Scholar 

  155. Scialla, J. J. & Wolf, M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat. Rev. Nephrol. 10, 268–278 (2014).

    CAS  PubMed  Google Scholar 

  156. Rozentryt, P. et al. Higher serum phosphorus is associated with catabolic/anabolic imbalance in heart failure. J. Cachexia Sarcopenia Muscle 6, 325–334 (2015).

    PubMed  PubMed Central  Google Scholar 

  157. 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 

  158. Wang, A. Y. et al. Serum 25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis patients: a 3-y prospective cohort study. Am. J. Clin. Nutr. 87, 1631–1638 (2008).

    CAS  PubMed  Google Scholar 

  159. Panizo, S. et al. Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis. Nephrol. Dial. Transplant. 28, 2735–2744 (2013).

    CAS  PubMed  Google Scholar 

  160. de Zeeuw, D. et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 376, 1543–1551 (2010).

    CAS  PubMed  Google Scholar 

  161. Thadhani, R. et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA 307, 674–684 (2012).

    CAS  PubMed  Google Scholar 

  162. Garg, N. et al. Cardiac resynchronization therapy in CKD: a systematic review. Clin. J. Am. Soc. Nephrol. 8, 1293–1303 (2013).

    PubMed  PubMed Central  Google Scholar 

  163. Kidney disease: improving global outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int. 2, 9–335 (2012).

  164. Gastelurrutia, P. et al. Body mass index, body fat, and nutritional status of patients with heart failure: The PLICA study. Clin. Nutr. 34, 1233–1238 (2015).

    PubMed  Google Scholar 

  165. Khalid, U. et al. Pre-morbid body mass index and mortality after incident heart failure: the ARIC study. J. Am. College Cardiol. 64, 2743–2749 (2014).

    Google Scholar 

  166. Rozentryt, P. et al. The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: a randomized, double-blind pilot study. J. Cachexia Sarcopenia Muscle 1, 35–42 (2010).

    PubMed  PubMed Central  Google Scholar 

  167. Witte, K. K. et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur. Heart J. 26, 2238–2244 (2005).

    CAS  PubMed  Google Scholar 

  168. Valentova, M. et al. Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure. Eur. Heart J. 37, 1684–1691 (2016).

    PubMed  Google Scholar 

  169. [No authors listed] Retraction. Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis. Heart 99, 820 (2013).

  170. DiNicolantonio, J. J., Di Pasquale, P., Taylor, R. S. & Hackam, D. G. Low sodium versus normal sodium diets in systolic heart failure: systematic review and meta-analysis. Heart http://dx.doi.org/10.1136/heartjnl-2012-302337 (2013).

  171. Kidney disease: improving global outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int. 2, 337–414 (2012).

  172. McMurray, J. J. et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. New Engl. J. Med. 371, 993–1004 (2014).

    PubMed  Google Scholar 

  173. Eshaghian, S., Horwich, T. B. & Fonarow, G. C. Relation of loop diuretic dose to mortality in advanced heart failure. Am. J. Cardiol. 97, 1759–1764 (2006).

    CAS  PubMed  Google Scholar 

  174. ter Maaten, J. M. et al. Diuretic response in acute heart failure-pathophysiology, evaluation, and therapy. Nat. Rev. Cardiol. 12, 184–192 (2015).

    CAS  PubMed  Google Scholar 

  175. Costanzo, M. R., Fonarow, G. C. & Filippatos, G. S. Ultrafiltration in heart failure with cardio-renal syndrome. New Engl. J. Med. 368, 1158–1159 (2013).

    PubMed  Google Scholar 

  176. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT00577135?term=NCT00577135&rank=1 (2016).

  177. US National Library of Medicine. ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT01921829?term=NCT01921829&rank=1 (2016).

  178. Lala, A. et al. Relief and recurrence of congestion during and after hospitalization for acute heart failure: insights from diuretic optimization strategy evaluation in acute decompensated heart failure (DOSE-AHF) and cardio-renal rescue study in acute decompensated heart failure (CARESS-HF). Circul. Heart Fail. 8, 741–748 (2015).

    Google Scholar 

  179. Yancy, C. W. et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 128, 1810–1852 (2013).

    PubMed  Google Scholar 

  180. Lins, R. L. et al. Intermittent versus continuous renal replacement therapy for acute kidney injury patients admitted to the intensive care unit: results of a randomized clinical trial. Nephrol. Dial. Transplant. 24, 512–518 (2009).

    PubMed  Google Scholar 

  181. Schefold, J.C. et al. The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial. Crit. Care 18, R11 (2014).

    PubMed  PubMed Central  Google Scholar 

  182. Vinsonneau, C. et al. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet 368, 379–385 (2006).

    PubMed  Google Scholar 

  183. Zarbock, A. et al. Randomized Clinical Trial. JAMA 20, 2190–2199 (2016).

    Google Scholar 

  184. Seabra, V. F. et al. Timing of renal replacement therapy initiation in acute renal failure: a meta-analysis. Am. J. Kidney Dis. 52, 272–284 (2008).

    PubMed  Google Scholar 

  185. Kellum, J. A. & Ronco, C. Dialysis: results of RENAL — what is the optimal CRRT target dose? Nat. Rev. Nephrol. 6, 191–192 (2010).

    PubMed  Google Scholar 

  186. Kidney disease: improving global outcomes (KDIGO). KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2, 1–138 (2012).

  187. Lin, T. E., Adams, K. F. Jr. & Patterson, J.H. Potential roles of vaptans in heart failure: experience from clinical trials and considerations for optimizing therapy in target patients. Heart Fail. Clin. 10, 607–620 (2014).

    PubMed  Google Scholar 

  188. Lehrich, R. W., Ortiz-Melo, D. I., Patel, M. B. & Greenberg, A. Role of vaptans in the management of hyponatremia. Am. J. Kidney Dis. 62, 364–376 (2013).

    CAS  PubMed  Google Scholar 

  189. Konstam, M. A. et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 297, 1319–1331 (2007).

    CAS  PubMed  Google Scholar 

  190. Morooka, H. et al. Chronic administration of oral vasopressin type 2 receptor antagonist tolvaptan exerts both myocardial and renal protective effects in rats with hypertensive heart failure. Circul. Heart Fail. 5, 484–492 (2012).

    CAS  Google Scholar 

  191. Cannella, G. et al. Prolonged therapy with ACE inhibitors induces a regression of left ventricular hypertrophy of dialyzed uremic patients independently from hypotensive effects. Am. J. Kidney Dis. 30, 659–664 (1997).

    CAS  PubMed  Google Scholar 

  192. O'Connor, C. M. et al. Effect of nesiritide in patients with acute decompensated heart failure. New Engl. J. Med. 365, 32–43 (2011).

    CAS  PubMed  Google Scholar 

  193. van Deursen, V. M. et al. Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF). Circulation 130, 958–965 (2014).

    CAS  PubMed  Google Scholar 

  194. Singh, A., Laribi, S., Teerlink, J. R. & Mebazaa, A. Agents with vasodilator properties in acute heart failure. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/ehv755 (2013).

  195. Teerlink, J. R. et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 381, 29–39 (2013).

    CAS  PubMed  Google Scholar 

  196. Metra, M. et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J. Am. College Cardiol. 61, 196–206 (2013).

    CAS  Google Scholar 

  197. Nimmo, A. J., Than, N., Orchard, C. H. & Whitaker, E. M. The effect of acidosis on β-adrenergic receptors in ferret cardiac muscle. Exp. Physiol. 78, 95–103 (1993).

    CAS  PubMed  Google Scholar 

  198. Ponikowski, P. et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 27, 2129–200 (2016).

    Google Scholar 

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Authors and Affiliations

  1. Department of Intensive Care Medicine, Inselspital, Bern University Hospital, Freiburgstrasse 18, Bern, 3010, Switzerland

    Joerg C. Schefold

  2. Department of Clinical Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Athens, 12462, Greece

    Gerasimos Filippatos

  3. Department of Cardiology and Pneumology, University of Göttingen Medical School, Robert-Koch-Strasse 40, Göttingen, 37075, Germany

    Gerd Hasenfuss

  4. Department of Cardiology and Pneumology, Innovative Clinical Trials, University of Göttingen Medical School, Robert-Koch-Strasse 40, Göttingen, 37075, Germany

    Stefan D. Anker & Stephan von Haehling

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J.C.S. and S.v.H. wrote the article. All authors contributed to discussion and researching of the content and to review and/or editing of the manuscript before submission.

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Correspondence to Stefan D. Anker.

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Competing interests

The Department of Intensive Care Medicine, Bern University Hospital, Switzerland (J.C.S.) has received research and development and/or consulting contracts from Orion Corporation, Abbott Nutrition International, B. Braun Medical AG, CSEM SA, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Edwards Lifesciences SA, and Nestlé, for which no personal financial gain was received; educational grants from Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; AstraZeneca; B. Braun Medical AG, CSL Behring, Maquet, Novartis, Covidien, Nycomed, Pierre Fabre Pharma (Roba Pharma); Pfizer, Orion Pharma; J.C.S. has received research funding, (travel) grants, or speaker fees from Bayer AG/Schering AG, Eli Lilly, Anagnostics Bionanalysis GmbH/ Cube DX GesmbH, and Nestlé. G.F. is a member of committees of heart failure trials and registries sponsored by Novartis, Servier, Cardiorentis, Medtronic and Vifor. G.H. has consulted for Servier, Impulse Dynamics, Novartis, CircuLite, and DC Devices and received honoraria from CVRx, Impulse Dynamics, AstraZeneca, Bayer, and Orion. S.D.A. has consulted or received honoraria from Vifor, Novartis, Cardiorentis, Brahms, Bayer, Relypsa, ZS Pharma and Stealth Peptides. S.v.H. has received consultant honoraria, travel support, and/or speaker's fees from Vifor, Thermo Fisher Scientific, Respicardia, Sorin, Novartis, Chugai Pharma, AstraZeneca, Pfizer, Professional Dietetics and Solartium Dietetics.

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Glossary

Left ventricular ejection fraction

The fraction of left intra-ventricular volume that is pumped from the left ventricle per contraction or heartbeat.

Renin–angiotensin–aldosterone system

A complex hormone system and a key regulator of salt and water homeostasis in humans. The renin–angiotensin–aldosterone system is considered to be one of the key blood pressure regulating hormonal systems. Activation of this system in heart failure and chronic kidney disease makes it particularly important in cardio-renal syndrome.

Forward failure

Term often used by physicians involved in the care of patients with acute heart failure to describe a clinical situation in which left ventricular output is substantially reduced leading to insufficient end-organ and/or peripheral perfusion and/or pulmonary oedema.

Cardiac index

Cardiac index (units: l per min per m2) is a global index of heart function and a quotient of cardiac output and body surface area. This index is important for the monitoring of heart function in critically ill patients in intensive care units.

Renal congestion

Central venous pressure is typically increased in heart failure and acts as the back pressure to venous return, resulting in diminished efferent renal blood flow and renal venous hypertension. Renal congestion is considered to be the result of right ventricular failure, (neuro)hormonal and sympathetic mechanisms resulting in hypervolaemia, inflammation, and reduced glomerular filtration rate.

Preload

The effective end-diastolic volume that stretches the ventricles of the heart before contraction. Ventricular end diastolic volume and/or pressure is used for assessment of preload; atrial pressure might serve as a surrogate marker.

Starling curve

Cardiac function curve showing the graphical relationship between cardiac output or venous return (y-axis) and end diastolic volume or right atrial pressure (x-axis). Frank Starling's law indicates that cardiac output increases in response to increased end diastolic volume (that is, filling) up to a certain maximum (given that all other influencing factors remain constant).

Increased venous return

Increased venous return can almost always be observed in heart failure and results from early activation of key compensatory mechanisms, including neurohormonal responses and activation of the sympathetic nervous system, resulting in increased circulating volume.

Obesity paradox

Epidemiological data show that obese patients with chronic diseases such as heart failure, coronary artery disease or chronic kidney disease requiring dialysis can have higher survival rates compared to those of non-obese individuals.

Orthodema

Key clinical symptoms at rest for congestion include orthopnoea and peripheral oedema. An orthodema congestion score based on these symptoms was previously used to grade congestion in clinical trials.

Aquaresis

Excretion of (free) water without loss of electrolytes via the renal system. Aquaresis is of particular interested in dilutional hyponatraemia. Vaptans (also referred to as aquaretics) are a new class of drugs used to promote aquaresis.

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Schefold, J., Filippatos, G., Hasenfuss, G. et al. Heart failure and kidney dysfunction: epidemiology, mechanisms and management. Nat Rev Nephrol 12, 610–623 (2016). https://doi.org/10.1038/nrneph.2016.113

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