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Renal Mechanisms and Heart Failure

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Hypertension and Heart Failure

Part of the book series: Updates in Hypertension and Cardiovascular Protection ((UHCP))

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Abstract

Chronic kidney disease is an established cardiovascular risk factor, and renal dysfunction is one of the most important independent risk factors for poor outcomes and all-cause mortality in patients with heart failure. The mechanisms by which the onset of acute heart failure or acutely decompensated chronic heart failure leads to worsening renal function are multiple and complex, being different in acute versus chronic heart failure. In opposite way, multiple mechanisms are involved in deterioration of heart function in patients with impaired renal function. Cardiac and renal diseases commonly present in the same patient have been associated with increased cost of care, complications, and mortality. Importantly, worsening renal function and chronic kidney disease are the most important causes of “therapeutic nihilism” in HF patients.

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References

  1. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52(19):1527–39.

    PubMed  Google Scholar 

  2. Kalra PR, Kalra PA. Cardiorenal syndrome: epidemiology, pathogenesis, and outcomes. Dialog Cardiovasc Med. 2011;16:251–63.

    Google Scholar 

  3. Hillege H, Girbes A, de Kam P, Boomsma F, de Zeeuw D, Charlesworth A, Hampton J, van Veldhuisen D. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102:203–10.

    CAS  PubMed  Google Scholar 

  4. Adams K Jr, Fonarow G, Emerman C, LeJemtel T, Costanzo M, Abraham W, Berkowitz R, Galvao M, Horton D, For the ADHERE Scientific Advisory Committee and Investigators. 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. 2005;149:209–16.

    PubMed  Google Scholar 

  5. McAlister F, Ezekowtiz J, Tonelli M, Armstrong P. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation. 2003;109:1004–9.

    Google Scholar 

  6. Herzog C, Muster H, Li S, Collins A. Impact of congestive heart failure, chronic kidney disease, and anemia on survival in the Medicare population. J Card Fail. 2004;10:467–72.

    PubMed  Google Scholar 

  7. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow G, et al. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol. 2008;51:1268–74.

    PubMed  Google Scholar 

  8. Mullens W, Abrahams Z, Francis G, Sokos G, Taylor D, Starling R, Young J, Tang W. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53:589–96.

    PubMed  PubMed Central  Google Scholar 

  9. Cowie M, Komajda M, Murray-Thomas T, Underwood J, Ticho B, POSH Investigators. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH). Eur Heart J. 2006;27:1216–22.

    PubMed  Google Scholar 

  10. Ljungman S, Laragh J, Cody R. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs. 1990;39(Suppl 4):10–21. discussion 22-4.

    PubMed  Google Scholar 

  11. Harman P, Kron I, McLachlan H, et al. Elevated intra-abdominal pressure and renal function. Ann Surg. 1982;196:594–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Mullens W, Abrahams Z, Francis G, et al. Prompt reduction in intra-abdominal pressure following large-volume mechanical fluid removal improves renal insufficiency in refractory decompensated heart failure. J Card Fail. 2008;14:508–14.

    PubMed  Google Scholar 

  13. Goldsmith S, Francis G, Cowley A Jr, Levine T, Cohn J. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol. 1983;1:1385–90.

    CAS  PubMed  Google Scholar 

  14. Funaya H, Kitakaze M, Node K, Minamino T, Komamura K, Hori M. Plasma adenosine levels increase in patients with chronic heart failure. Circulation. 1997;95:1363–5.

    CAS  PubMed  Google Scholar 

  15. Cicoira LZ, Rossi A, et al. Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. Am Coll Cardiol. 2001;37:1808–12.

    CAS  Google Scholar 

  16. de Boer RA, Voors A, Muntendam P, van Gilst W, van Veldhuisen D. Galectin-3: a novel mediator of heart failure development and progression. Eur J Heart Fail. 2009;11:811–7.

    Google Scholar 

  17. Palmer B. Pathogenesis of ascites and renal salt retention in cirrhosis. J Investig Med. 1999;47:183–202.

    CAS  PubMed  Google Scholar 

  18. Virzì G, Clementi A, de Cal M, et al. Oxidative stress: dual pathway induction in cardiorenal syndrome type 1 pathogenesis. Oxidative Med Cell Longev. 2015;2015:391790.

    Google Scholar 

  19. Colombo P, Ganda A, Lin J, et al. Inflammatory activation: cardiac, renal, and cardio-renal interactions in patients with the cardiorenal syndrome. Heart Fail Rev. 2012;17:177–90.

    CAS  PubMed  Google Scholar 

  20. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Verbrugge F, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal dysfunction in congestive heart failure. J Am Coll Cardiol. 2013;62:485–95.

    PubMed  Google Scholar 

  22. Kraut E, Chen S, Hubbard N, Erickson K, Wisner D. Tumor necrosis factor depresses myocardial contractility in endotoxemic swine. J Trauma. 1999;46:900–6.

    CAS  PubMed  Google Scholar 

  23. Karayannis G, Triposkiadis F, Skoularigis J, et al. The emerging role of galectin-3 and ST2 in heart failure: practical considerations and pitfalls using novel biomarkers. Curr Heart Fail Rep. 2013;10:441–9.

    CAS  PubMed  Google Scholar 

  24. Sica D, Oren R, Gottwald M, Mills R, Scios 351 Investigators. Natriuretic and neurohormonal responses to nesiritide, furosemide, and combined nesiritide and furosemide in patients with stable systolic dysfunction. Clin Cardiol. 2010;33:330–6.

    PubMed  PubMed Central  Google Scholar 

  25. Forfia P, Lee M, Tunin R, Mahmud M, Champion H, Kass D. Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart. J Am Coll Cardiol. 2007;49:1079–88.

    CAS  PubMed  Google Scholar 

  26. Abe M, Okada K, Maruyama T, Maruyama N, Matsumoto K, Soma M. Relationship between erythropoietin responsiveness, insulin resistance, and malnutrition-inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients with diabetes. Int J Artif Organs. 2011;34:16–25.

    CAS  PubMed  Google Scholar 

  27. Young J, Abraham W, Albert N, Gattis Stough W, Gheorghiade M, Greenberg B, O’Connor C, She L, Sun J, Yancy C, Fonarow G, For the OPTIMIZE-HF Investigators and Coordinators. 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. 2008;101:223–30.

    CAS  PubMed  Google Scholar 

  28. George J, Patal S, Wexler D, Abashidze A, Shmilovich H, Barak T, Sheps D, Keren G. Circulating erythropoietin levels and prognosis in patients with congestive heart failure: comparison with neurohormonal and inflammatory markers. Arch Intern Med. 2005;165:1304–9.

    CAS  PubMed  Google Scholar 

  29. Fonarow G, Stough W, Abraham W, Albert N, Gheorghiade M, Greenberg B, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50:768–77.

    PubMed  Google Scholar 

  30. Borman N, Kalra P, Kalra PR. Acute kidney injury in patients with decompensated heart failure. Br J Hosp Med (Lond). 2010;71(5):269–75.

    Google Scholar 

  31. Riksen N, Hausenloy D, Yellon D. Erythropoietin: ready for prime-time cardioprotection. Trends Pharmacol Sci. 2008;29:258–67.

    CAS  PubMed  Google Scholar 

  32. Palazzuoli A, Silverberg DS, Iovine F, et al. Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome. Am Heart J. 2007;154:645.e9–15.

    Google Scholar 

  33. Parfrey P. Critical appraisal of randomized controlled trials of anemia correction in patients with renal failure. Curr Opin Nephrol Hypertens. 2011;20:177–81.

    PubMed  Google Scholar 

  34. Kato A. Increased hepcidin-25 and erythropoietin responsiveness in patients with cardio-renal anemia syndrome. Futur Cardiol. 2010;6:769–71.

    CAS  Google Scholar 

  35. Ezekowitz J, McAlister F, Armstrong P. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12,065 patients with new onset heart failure. Circulation. 2003;107:223–5.

    PubMed  Google Scholar 

  36. Okonko D, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008;51:103–12.

    CAS  PubMed  Google Scholar 

  37. Anker S, Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–4.

    CAS  PubMed  Google Scholar 

  38. Hillege H, Nitsch D, Pfeffer M, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671–8.

    PubMed  Google Scholar 

  39. Creemers E, Pinto Y. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res. 2011;89:265–72.

    CAS  PubMed  Google Scholar 

  40. Knight E, Glynn R, McIntyre K, Mogun H, Avorn J. Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction (SOLVD). Am Heart J. 1999;138(5 Pt 1):849–55.

    CAS  PubMed  Google Scholar 

  41. Kishimoto T, Maekawa M, Abe Y, Yamamoto K. Intrarenal distribution of blood flow and renin release during renal venous pressure elevation. Kidney Int. 1973;4:259–66.

    CAS  PubMed  Google Scholar 

  42. Merrill A, Morrison J, Branno E. Concentration of renin in renal venous blood in patients with chronic heart failure. Am J Med. 1946;1:468.

    CAS  PubMed  Google Scholar 

  43. Al-Ahmad A, Rand W, Manjunath G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:955–62.

    CAS  PubMed  Google Scholar 

  44. Khan N, Ma I, Thompson C, et al. Kidney function and mortality among patients with left ventricular systolic dysfunction. J Am Soc Nephrol. 2006;17:244–53.

    PubMed  Google Scholar 

  45. Weiner D, Krassilnikova M, Hocine T, et al. CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study. BMC Nephrol. 2009;10:26–37.

    PubMed  PubMed Central  Google Scholar 

  46. Testani J, Chen J, McCauley B, et al. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122:265–72.

    PubMed  PubMed Central  Google Scholar 

  47. Bongartz L, Cramer M, Doevendans P, Joles J, Braam B. The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J. 2005;26:11–7.

    PubMed  Google Scholar 

  48. Edmunds N, Lal H, Woodward B. Effects of tumour necrosis factor-α on left ventricular function in the rat isolated perfused heart: possible mechanisms for a decline in cardiac function. Br J Pharmacol. 1999;126:189–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Nishiyama J, Kobayashi S, Ishida A, et al. Up-regulation of galectin-3 in acute renal failure of the rat. Am J Pathol. 2000;157:815–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ma X, Lefer D, Lefer A, Rothlein R. Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion. Circulation. 1992;86:937–46.

    CAS  PubMed  Google Scholar 

  51. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol. 1997;29:859–70.

    CAS  PubMed  Google Scholar 

  52. Nimmo A, Than N, Orchard C, Whitaker E. The effect of acidosis on β-adrenergic receptors in ferret cardiac muscle. Exp Physiol. 1993;78:95–103.

    CAS  PubMed  Google Scholar 

  53. De Deyn P, vanholder R, D’Hooge R. Nitric oxide in uremia: effects of several potentially toxic guanidino compounds. Kidney Int. 2003;84:25–8.

    Google Scholar 

  54. Olgaard K, Lewin E, Silver J. Calcimimetics, vitamin D and ADVANCE in the management of CKD-MBD. Nephrol Dial Transplant. 2011;26:1117–9.

    CAS  PubMed  Google Scholar 

  55. Shamseddin M, Parfrey P. Sudden cardiac death in chronic kidney disease: epidemiology and prevention. Nat Rev Nephrol. 2011;7:145–54.

    PubMed  Google Scholar 

  56. Testani J, McCauley B, Chen J, Shumski M, Shannon R. Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions. Cardiology. 2010;116:206–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Iwanaga Y, Miyazaki S. Heart failure, chronic kidney disease, and biomarkers—an integrated viewpoint. Circ J. 2010;74:1274–82.

    CAS  PubMed  Google Scholar 

  58. Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int. 2007;71:967–70.

    CAS  PubMed  Google Scholar 

  59. McMurray M, Trivax J, McCullough P. Serum cystatin C, renal filtration function, and left ventricular remodeling. Circ Heart Fail. 2009;2:86–9.

    PubMed  Google Scholar 

  60. Vaidya V, Ramirez V, Ichimura T, Bobadilla N, Bonventre J. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol. 2006;290:517–29.

    Google Scholar 

  61. Wellwood J, Ellis B, Price R, Hammond K, Thompson A, Jones N. Urinary N-acetyl- beta-D-glucosaminidase activities in patients with renal disease. Br Med J. 1975;3(5980):408–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang M, Tan J, Wang Y, Meldrum K, Dinarello C, Meldrum D. IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction. Proc Natl Acad Sci U S A. 2009;106:17499–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Noiri E, Doi K, Negishi K, et al. Urinary fatty acid-binding protein 1: an early predictive biomarker of kidney injury. Am J Physiol Renal Physiol. 2009;296:F669–79.

    CAS  PubMed  Google Scholar 

  64. McMahon B, Murray P. Urinary liver fatty acid-binding protein: another novel biomarker of acute kidney injury. Kidney Int. 2010;77:657–9.

    CAS  PubMed  Google Scholar 

  65. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006;97:1759–64.

    CAS  PubMed  Google Scholar 

  66. Palermo M, Armanini D, Shackleton CH, Sorba G, Cossu M, Roitman E, Scaroni C, Delitala G. Furosemide and 11 beta-hydroxysteroid dehydrogenase activity in man. Exp Clin Endocrinol Diabetes. 2002;110:272–6.

    CAS  PubMed  Google Scholar 

  67. Tang WH, Mullens W. Cardiorenal syndrome in decompensated heart failure. Heart. 2010;96:255–60.

    PubMed  Google Scholar 

  68. Felker G, Lee K, Bull D, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797–805.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. De Vecchis R, Baldi C. Cardiorenal syndrome type 2: from diagnosis to optimal management. Ther Clin Risk Manag. 2014;10:949–61.

    PubMed  PubMed Central  Google Scholar 

  70. Ronco C, Cruz D, Noland B. Neutrophil gelatinase-associated lipocalin curve and neutrophil gelatinase-associated lipocalin extended-range assay: a new biomarker approach in the early diagnosis of acute kidney injury and cardio-renal syndrome. Semin Nephrol. 2012;32:121–8.

    CAS  PubMed  Google Scholar 

  71. Opdam H, Wan L, Bellomo R. A pilot assessment of the FloTrac cardiac output monitoring system. Intensive Care Med. 2007;33:344–9.

    PubMed  Google Scholar 

  72. Wilcox C, Guzman N, Mitch W, et al. Na+, K+, and BP homeostasis in man during furosemide: effects of prazosin and captopril. Kidney Int. 1987;31:135–41.

    CAS  PubMed  Google Scholar 

  73. Shah S, Anjum S, Littler W. Use of diuretics in cardiovascular diseases: (1) heart failure. Postgrad Med J. 2004;80:201–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ronco C, Ricci Z, Brendolan A, Bellomo R, Bedogni F. Ultrafiltration in patients with hypervolemia and congestive heart failure. Blood Purif. 2004;22:150–63.

    CAS  PubMed  Google Scholar 

  75. McCullough P. Cardiorenal risk: an important clinical intersection. Rev Cardiovasc Med. 2002;3:71–6.

    PubMed  Google Scholar 

  76. Wright R, Reeder G, Herzog C, Albright R, Williams B, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med. 2002;137:563–70.

    PubMed  Google Scholar 

  77. Beattie J, Soman S, Sandberg K, et al. Determinants of mortality after myocardial infarction in patients with advanced renal dysfunction. Am J Kidney Dis. 2001;37:1191–200.

    CAS  PubMed  Google Scholar 

  78. Suki W, Zabaneh R, Cangiano J, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int. 2007;1130–7(127):72.

    Google Scholar 

  79. Garside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation. Health Technol Assess. 2007;11:iii. xi, xiii, 1–167.

    PubMed  Google Scholar 

  80. Neuhofer W, Pittrow D. Role of endothelin and endothelin receptor antagonists in renal disease. Eur J Clin Investig. 2006;36(Suppl 3):78–88.

    CAS  Google Scholar 

  81. Ahmed A, Love T, Sui X, et al. Effects of angiotensin-converting enzyme inhibitors systolic heart failure patients with chronic kidney disease. J Card Fail. 2006;12:499–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Anand I, Bishu K, Rector T, et al. Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure. Circulation. 2009;120:1577–84.

    CAS  PubMed  Google Scholar 

  83. Ko D, Juurlink D, Mamdani M, et al. Appropriateness of spironolactone prescribing in heart failure patients: a population-based study. J Card Fail. 2006;12:205–10.

    CAS  PubMed  Google Scholar 

  84. Cioffi G, Tarantini L, Pulignano G, et al. Prevalence, predictors and prognostic value of acute impairment in renal function during intensive unloading therapy in a community population hospitalized for decompensated heart failure. J Cardiovasc Med (Hagerstown). 2007;8:419–27.

    Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology, Hypertension, Dialysis and Transplantation, School of Medicine University od Zagreb, University Hospital Centre Zagreb, Zagreb, Croatia

    Bojan Jelaković, Vedran Premužić & Ana Jelaković

  2. Cardiology Clinic, School of Medicine University of Zagreb, University Hospital Centre Zagreb, Zagreb, Croatia

    Davor Miličić

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  1. Bojan Jelaković
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  1. Carol Davila University of Medicine and Pharmacy Bucharest and Cardiology Department, Emergency Clinical Hospital, Bucharest, Romania

    Maria Dorobantu

  2. University of Milano-Bicocca, Milano, Italy

    Giuseppe Mancia  & Guido Grassi  & 

  3. Department of Pharmacology, Toxicology and Clinical Psychopharmacology Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

    Victor Voicu

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Jelaković, B., Premužić, V., Jelaković, A., Miličić, D. (2019). Renal Mechanisms and Heart Failure. In: Dorobantu, M., Mancia, G., Grassi, G., Voicu, V. (eds) Hypertension and Heart Failure. Updates in Hypertension and Cardiovascular Protection. Springer, Cham. https://doi.org/10.1007/978-3-319-93320-7_7

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