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Cellular apoptosis in the cardiorenal axis

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Abstract

Cardiomyocyte apoptosis plays a pivotal role in the pathogenesis of heart failure. It may be induced by different stimuli, and it seems to be perpetuated by oxidative stress and inflammation. In this scenario, heart failure may trigger various cell-mediated and humoral pathways affecting distant organs, such as kidneys, contributing to higher therapeutic costs, morbidity and mortality. The term Cardiorenal Syndromes describes this condition and represents an important model for exploring the pathophysiology of cardiac and renal dysfunction. In this review, we have analyzed the mechanisms of organ interaction and the role of apoptosis in heart–kidney crosstalk, in particular its role in the pathogenesis of the different types of Cardiorenal Syndromes.

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References

  1. Takemura G, Kanoh M, Minatoguchi S, Fujiwara H (2013) Cardiomyocyte apoptosis in the failing heart—a critical review from definition and classification of cell death. Int J Cardiol 167(6):2373–2386. doi:10.1016/j.ijcard.2013.01.163

    Article  PubMed  Google Scholar 

  2. Gustafsson AB, Gottlieb RA (2007) Bcl-2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol 292(1):C45–C51. doi:10.1152/ajpcell.00229.2006

    Article  PubMed  CAS  Google Scholar 

  3. Fisher SA, Langille BL, Srivastava D (2000) Apoptosis during cardiovascular development. Circ Res 87(10):856–864

    Article  PubMed  CAS  Google Scholar 

  4. Wong LS, van der Harst P, de Boer RA, Huzen J, van Gilst WH, van Veldhuisen DJ (2010) Aging, telomeres and heart failure. Heart Fail Rev 15(5):479–486. doi:10.1007/s10741-010-9173-7

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Buja LM, Vela D (2008) Cardiomyocyte death and renewal in the normal and diseased heart. Cardiovasc Pathol 17(6):349–374. doi:10.1016/j.carpath.2008.02.004

    Article  PubMed  CAS  Google Scholar 

  6. Olivetti G, Melissari M, Capasso JM, Anversa P (1991) Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68(6):1560–1568

    Article  PubMed  CAS  Google Scholar 

  7. Fujita T, Ishikawa Y (2011) Apoptosis in heart failure. The role of the beta-adrenergic receptor-mediated signaling pathway and p53-mediated signaling pathway in the apoptosis of cardiomyocytes. Circ J 75(8):1811–1818. doi:10.1253/circj.CJ-11-0025

    Article  PubMed  CAS  Google Scholar 

  8. Dorn GW 2nd (2009) Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res 81(3):465–473. doi:10.1093/cvr/cvn243

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94(4):1621–1628. doi:10.1172/JCI117504

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Itoh G, Tamura J, Suzuki M, Suzuki Y, Ikeda H, Koike M et al (1995) DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gel electrophoresis. Am J Pathol 146(6):1325–1331

    PubMed Central  PubMed  CAS  Google Scholar 

  11. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ et al (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335(16):1182–1189. doi:10.1056/NEJM199610173351603

    Article  PubMed  CAS  Google Scholar 

  12. Narula J, Kolodgie FD, Virmani R (2000) Apoptosis and cardiomyopathy. Curr Opin Cardiol 15(3):183–188

    Article  PubMed  CAS  Google Scholar 

  13. Gill C, Mestril R, Samali A (2002) Losing heart: the role of apoptosis in heart disease—a novel therapeutic target? FASEB J 16(2):135–146. doi:10.1096/fj.01-0629com

    Article  PubMed  CAS  Google Scholar 

  14. Abbate A, Biondi-Zoccai GG, Baldi A (2002) Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodeling. J Cell Physiol 193(2):145–153. doi:10.1002/jcp.10174

    Article  PubMed  CAS  Google Scholar 

  15. Braunwald E (2013) Heart failure. JACC Heart Fail 1(1):1–20. doi:10.1016/j.jchf.2012.10.002

    Article  PubMed  Google Scholar 

  16. Kang PM, Izumo S (2000) Apoptosis and heart failure: a critical review of the literature. Circ Res 86(11):1107–1113

    Article  PubMed  CAS  Google Scholar 

  17. Sabbah HN (2000) Apoptotic cell death in heart failure. Cardiovasc Res 45(3):704–712. doi:10.1002/jcp.10174

    Article  PubMed  CAS  Google Scholar 

  18. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA et al (1997) Apoptosis in the failing human heart. N Engl J Med 336(16):1131–1141. doi:10.1056/NEJM199704173361603

    Article  PubMed  CAS  Google Scholar 

  19. Orogo AM, Gustafsson AB (2013) Cell death in the myocardium: my heart won’t go on. IUBMB Life 65(8):651–656. doi:10.1002/iub.1180

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Norbury CJ, Hickson ID (2001) Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 41:367–401. doi:10.1146/annurev.pharmtox.41.1.367

    Article  PubMed  CAS  Google Scholar 

  21. van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ (2005) Myocyte apoptosis in heart failure. Cardiovasc Res 67(1):21–29. doi:10.1016/j.cardiores.2005.04.012

    Article  PubMed  CAS  Google Scholar 

  22. Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267(5203):1456–1462

    Article  PubMed  CAS  Google Scholar 

  23. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26(4):239–257

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Wolf BB, Green DR (1999) Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 274(29):20049–20052

    Article  PubMed  CAS  Google Scholar 

  25. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. doi:10.1080/01926230701320337

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Kaushal GP (2003) Role of caspases in renal tubular epithelial cell injury. Semin Nephrol 23(5):425–431. doi:10.1002/iub.1180

    Article  PubMed  CAS  Google Scholar 

  27. Communal C, Sumandea M, de Tombe P, Narula J, Solaro RJ, Hajjar RJ (2002) Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci USA 99(9):6252–6256. doi:10.1073/pnas.092022999

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  28. Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81(4):505–512. doi:10.1016/j.cardiores.2005.04.012

    Article  PubMed  CAS  Google Scholar 

  29. Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2(4):277–288. doi:10.1038/nrc776

    Article  PubMed  CAS  Google Scholar 

  30. Ashkenazi A, Dixit VM (1999) Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 11(2):255–260

    Article  PubMed  CAS  Google Scholar 

  31. Thorburn A (2004) Death receptor-induced cell killing. Cell Signal 16(2):139–144

    Article  PubMed  CAS  Google Scholar 

  32. Gilles S, Zahler S, Welsch U, Sommerhoff CP, Becker BF (2003) Release of TNF-alpha during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers. Cardiovasc Res 60(3):608–616

    Article  PubMed  CAS  Google Scholar 

  33. Janicki JS, Brower GL, Levick SP (2015) The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling. Methods Mol Biol 1220:121–139. doi:10.1007/978-1-4939-1568-2_8

    Article  PubMed Central  PubMed  Google Scholar 

  34. Niu A, Wang B, Li YP (2015) TNFalpha shedding in mechanically stressed cardiomyocytes is mediated by Src activation of TACE. J Cell Biochem 116(4):559–565. doi:10.1002/jcb.25006

    Article  PubMed  CAS  Google Scholar 

  35. Aoyagi T, Matsui T (2011) The Cardiomyocyte as a source of cytokines in cardiac injury. J Cell Sci Ther 2012(S5):505–512

    Google Scholar 

  36. Dorge H, Schulz R, Belosjorow S, Post H, van de Sand A, Konietzka I et al (2002) Coronary microembolization: the role of TNF-alpha in contractile dysfunction. J Mol Cell Cardiol 34(1):51–62. doi:10.1006/jmcc.2001.1489

    Article  PubMed  CAS  Google Scholar 

  37. Festjens N, van Gurp M, van Loo G, Saelens X, Vandenabeele P (2004) Bcl-2 family members as sentinels of cellular integrity and role of mitochondrial intermembrane space proteins in apoptotic cell death. Acta Haematol 111(1–2):7–27. doi:10.1159/000074483

    Article  PubMed  CAS  Google Scholar 

  38. Sanz AB, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A (2008) Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 19(9):1634–1642. doi:10.1681/ASN.2007121336

    Article  PubMed  CAS  Google Scholar 

  39. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2(9):647–656. doi:10.1038/nrc883

    Article  PubMed  CAS  Google Scholar 

  40. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281(5381):1322–1326

    Article  PubMed  CAS  Google Scholar 

  41. Lane K, Dixon JJ, MacPhee IA, Philips BJ (2013) Renohepatic crosstalk: does acute kidney injury cause liver dysfunction? Nephrol Dial Transplant 28(7):1634–1647. doi:10.1093/ndt/gft091

    Article  PubMed  Google Scholar 

  42. Azimzadeh Jamalkandi S, Azadian E, Masoudi-Nejad A (2014) Human RNAi pathway: crosstalk with organelles and cells. Funct Integr Genom 14(1):31–46. doi:10.1007/s10142-013-0344-1

    Article  CAS  Google Scholar 

  43. Molls RR, Rabb H (2004) Limiting deleterious cross-talk between failing organs. Crit Care Med 32(11):2358–2359

    PubMed  Google Scholar 

  44. Virzi G, Day S, de Cal M, Vescovo G, Ronco C (2014) Heart–kidney crosstalk and role of humoral signaling in critical illness. Crit Care 18(1):201. doi:10.1186/cc13177

    Article  PubMed Central  PubMed  Google Scholar 

  45. Li X, Hassoun HT, Santora R, Rabb H (2009) Organ crosstalk: the role of the kidney. Curr Opin Crit Care 15(6):481–487. doi:10.1097/MCC.0b013e328332f69e

    Article  PubMed  Google Scholar 

  46. Bang C, Antoniades C, Antonopoulos AS, Eriksson U, Franssen C, Hamdani N et al (2015) Intercellular communication lessons in heart failure. Eur J Heart Fail. doi:10.1002/ejhf.399

    PubMed  Google Scholar 

  47. Gill R, Tsung A, Billiar T (2010) Linking oxidative stress to inflammation: toll-like receptors. Free Radic Biol Med 48(9):1121–1132. doi:10.1016/j.freeradbiomed.2010.01.006

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Feltes CM, Van Eyk J, Rabb H (2008) Distant-organ changes after acute kidney injury. Nephron Physiol 109(4):p80–p84. doi:10.1159/000142940

    Article  PubMed  CAS  Google Scholar 

  49. Satoh M, Minami Y, Takahashi Y, Nakamura M (2008) Immune modulation: role of the inflammatory cytokine cascade in the failing human heart. Curr Heart Fail Rep 5(2):69–74

    Article  PubMed  CAS  Google Scholar 

  50. Yndestad A, Damas JK, Oie E, Ueland T, Gullestad L, Aukrust P (2007) Role of inflammation in the progression of heart failure. Curr Cardiol Rep 9(3):236–241

    Article  PubMed  Google Scholar 

  51. Ronco C, House AA, Haapio M (2008) Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med 34(5):957–962. doi:10.1007/s00134-008-1017-8

    Article  PubMed  Google Scholar 

  52. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B (2005) The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 26(1):11–17. doi:10.1093/eurheartj/ehi020

    Article  PubMed  Google Scholar 

  53. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R (2008) Cardiorenal syndrome. J Am Coll Cardiol 52(19):1527–1539. doi:10.1016/j.jacc.2008.07.051

    Article  PubMed  Google Scholar 

  54. Goh CY, Vizzi G, De Cal M, Ronco C (2011) Cardiorenal syndrome: a complex series of combined heart/kidney disorders. Contrib Nephrol 174:33–45. doi:10.1159/000329233

    Article  PubMed  Google Scholar 

  55. McCullough PA, Kellum JA, Haase M, Muller C, Damman K, Murray PT et al (2013) Pathophysiology of the cardiorenal syndromes: executive summary from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 182:82–98. doi:10.1159/000349966

    Article  PubMed  Google Scholar 

  56. Fabbian F, Pala M, De Giorgi A, Scalone A, Molino C, Portaluppi F et al (2011) Clinical features of cardio-renal syndrome in a cohort of consecutive patients admitted to an internal medicine ward. Open Cardiovasc Med J 5:220–225. doi:10.2174/1874192401105010220

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  57. Bagshaw SM, Cruz DN, Aspromonte N, Daliento L, Ronco F, Sheinfeld G et al (2010) Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI consensus conference. Nephrol Dial Transplant 25(5):1406–1416. doi:10.1093/ndt/gfq066

    Article  PubMed  Google Scholar 

  58. Gigante A, Liberatori M, Gasperini ML, Sardo L, Di Mario F, Dorelli B et al (2014) Prevalence and clinical features of patients with the cardiorenal syndrome admitted to an internal medicine ward. Cardiorenal Med 4(2):88–94. doi:10.1159/000362566

    Article  PubMed Central  PubMed  Google Scholar 

  59. Rosner MH, Ronco C, Okusa MD (2012) The role of inflammation in the cardio-renal syndrome: a focus on cytokines and inflammatory mediators. Semin Nephrol 32(1):70–78. doi:10.1016/j.semnephrol.2011.11.010

    Article  PubMed  CAS  Google Scholar 

  60. Virzi GM, de Cal M, Cruz DN, Bolin C, Vescovo G, Ronco C (2012) Type 1 cardiorenal syndrome and its possible pathophysiological mechanisms. Giornale italiano di nefrologia: organo ufficiale della Societa italiana di nefrologia 29(6):690–698

    Google Scholar 

  61. Goh CY, Ronco C (2010) Cardio-renal syndromes. J Ren Care 36(Suppl 1):9–17. doi:10.1111/j.1755-6686.2010.00174.x

    Article  PubMed  Google Scholar 

  62. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM et al (2010) Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 31(6):703–711. doi:10.1093/eurheartj/ehp507

    Article  PubMed Central  PubMed  Google Scholar 

  63. Virzi GM, Torregrossa R, Cruz DN, Chionh CY, de Cal M, Soni SS et al (2012) Cardiorenal Syndrome Type 1 may be immunologically mediated: a pilot evaluation of monocyte apoptosis. Cardiorenal Med 2(1):33–42

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Cruz DN (2013) Cardiorenal syndrome in critical care: the acute cardiorenal and renocardiac syndromes. Adv Chronic Kidney Dis 20(1):56–66. doi:10.1053/j.ackd.2012.10.005

    Article  PubMed  Google Scholar 

  65. Virzi GM, Clementi A, de Cal M, Brocca A, Day S, Pastori S et al (2015) Oxidative stress: dual pathway induction in cardiorenal syndrome type 1 pathogenesis. Oxid Med Cell Longev 2015:391790. doi:10.1155/2015/391790

    Article  PubMed Central  PubMed  Google Scholar 

  66. Pastori S, Virzi GM, Brocca A, de Cal M, Clementi A, Vescovo G et al (2015) Cardiorenal syndrome type 1: a defective regulation of monocyte apoptosis induced by proinflammatory and proapoptotic factors. Cardiorenal Med 5(2):105–115. doi:10.1159/000371898

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Virzi GM, de Cal M, Day S, Brocca A, Cruz DN, Castellani C et al (2015) Pro-apoptotic effects of plasma from patients with cardiorenal syndrome on human tubular cells. Am J Nephrol 41(6):474–484. doi:10.1159/000438459

    Article  PubMed  CAS  Google Scholar 

  68. Wrigley BJ, Lip GY, Shantsila E (2011) The role of monocytes and inflammation in the pathophysiology of heart failure. Eur J Heart Fail 13(11):1161–1171. doi:10.1093/eurjhf/hfr122

    Article  PubMed  CAS  Google Scholar 

  69. Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94(12):1543–1553. doi:10.1161/01.RES.0000130526.20854.fa

    Article  PubMed  CAS  Google Scholar 

  70. de Haij S, Daha MR, van Kooten C (2004) Mechanism of steroid action in renal epithelial cells. Kidney Int 65(5):1577–1588. doi:10.1111/j.1523-1755.2004.00553.x

    Article  PubMed  Google Scholar 

  71. Cantaluppi V, Quercia AD, Dellepiane S, Ferrario S, Camussi G, Biancone L (2014) Interaction between systemic inflammation and renal tubular epithelial cells. Nephrol Dial Transplant 29(11):2004–2011. doi:10.1093/ndt/gfu046

    Article  PubMed  Google Scholar 

  72. Havasi A, Borkan SC (2011) Apoptosis and acute kidney injury. Kidney Int 80(1):29–40. doi:10.1038/ki.2011.120

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Cantaluppi V, Dellepiane S, Quercia AD, Ferrario S (2014) Detrimental role of humoral signalling in cardio-renal cross-talk. Crit Care 18(1):404. doi:10.1186/cc13704

    Article  PubMed Central  PubMed  Google Scholar 

  74. Pastori S, Virzì GM, Brocca A, de Cal M, Cantaluppi V, Castellani C et al (2015) Cardiorenal Syndrome Type 1: activation of dual apoptotic pathways. Cardiorenal Med 5:306–315

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Bagshaw SM, Hoste EA, Braam B, Briguori C, Kellum JA, McCullough PA et al (2013) Cardiorenal syndrome type 3: pathophysiologic and epidemiologic considerations. Contrib Nephrol 182:137–157. doi:10.1159/000349971

    Article  PubMed  Google Scholar 

  76. Anker SD, Coats AJ (2002) How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol. 86(2–3):123–130

    Article  PubMed  Google Scholar 

  77. Momii H, Shimokawa H, Oyama J, Cheng XS, Nakamura R, Egashira K et al (1998) Inhibition of adhesion molecules markedly ameliorates cytokine-induced sustained myocardial dysfunction in dogs in vivo. J Mol Cell Cardiol 30(12):2637–2650

    Article  PubMed  CAS  Google Scholar 

  78. Daemen MA, Van’t Veer C, Denecker G, Heemskerk VH, Wolfs TG, Clauss M et al (1999) Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation. J Clin Invest 104(5):541–549

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  79. Kelly KJ (2003) Distant effects of experimental renal ischemia/reperfusion injury. J Am Soc Nephrol 14(6):1549–1558

    Article  PubMed  CAS  Google Scholar 

  80. Kelly KJ, Meehan SM, Colvin RB, Williams WW, Bonventre JV (1999) Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int 56(3):922–931. doi:10.1046/j.1523-1755.1999.00629.x

    Article  PubMed  CAS  Google Scholar 

  81. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL et al (1996) Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest 98(12):2854–2865. doi:10.1172/JCI119114

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  82. Patten M, Kramer E, Bunemann J, Wenck C, Thoenes M, Wieland T et al (2001) Endotoxin and cytokines alter contractile protein expression in cardiac myocytes in vivo. Pflugers Arch 442(6):920–927

    Article  PubMed  CAS  Google Scholar 

  83. Muller-Werdan U, Schumann H, Fuchs R, Reithmann C, Loppnow H, Koch S et al (1997) Tumor necrosis factor alpha (TNF alpha) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity. J Mol Cell Cardiol 29(11):2915–2923. doi:10.1006/jmcc.1997.0526

    Article  PubMed  CAS  Google Scholar 

  84. Chertow GM, Normand SL, Silva LR, McNeil BJ (2000) Survival after acute myocardial infarction in patients with end-stage renal disease: results from the cooperative cardiovascular project. Am J Kidney Dis 35(6):1044–1051

    Article  PubMed  CAS  Google Scholar 

  85. Herzog CA (2002) Dismal long-term survival of dialysis patients after acute myocardial infarction: can we alter the outcome? Nephrol Dial Transplant 17(1):7–10

    Article  PubMed  Google Scholar 

  86. Ronco C, Cruz DN, Ronco F (2009) Cardiorenal syndromes. Curr Opin Crit Care 15(5):384–391. doi:10.1097/MCC.0b013e32832e971b

    Article  PubMed  Google Scholar 

  87. Cruz DN, Schmidt-Ott KM, Vescovo G, House AA, Kellum JA, Ronco C et al (2013) Pathophysiology of cardiorenal syndrome type 2 in stable chronic heart failure: workgroup statements from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 182:117–136. doi:10.1159/000349968

    Article  PubMed  Google Scholar 

  88. Napoli C, Casamassimi A, Crudele V, Infante T, Abbondanza C (2011) Kidney and heart interactions during cardiorenal syndrome: a molecular and clinical pathogenic framework. Future Cardiol 7(4):485–497. doi:10.2217/fca.11.24

    Article  PubMed  CAS  Google Scholar 

  89. Merrill AJ, Morrison JL, Branno ES (1946) Concentration of renin in renal venous blood in patients with chronic heart failure. Am J Med 1(5):468

    Article  PubMed  CAS  Google Scholar 

  90. Ichikawa I, Brenner BM (1984) Glomerular actions of angiotensin II. Am J Med 76(5B):43–49

    Article  PubMed  CAS  Google Scholar 

  91. Kishimoto T, Maekawa M, Abe Y, Yamamoto K (1973) Intrarenal distribution of blood flow and renin release during renal venous pressure elevation. Kidney Int 4(4):259–266

    Article  PubMed  CAS  Google Scholar 

  92. Ross EA (2012) Congestive renal failure: the pathophysiology and treatment of renal venous hypertension. J Card Fail 18(12):930–938. doi:10.1016/j.cardfail.2012.10.010

    Article  PubMed  CAS  Google Scholar 

  93. Verdiani V, Lastrucci V, Nozzoli C (2010) Worsening renal function in patients hospitalized with acute heart failure: risk factors and prognostic significances. Int J Nephrol 2011:785974. doi:10.4061/2011/785974

    PubMed Central  PubMed  Google Scholar 

  94. Whaley-Connell A, Sowers JR (2012) Oxidative stress in the cardiorenal metabolic syndrome. Curr Hypertens Rep 14(4):360–365. doi:10.1007/s11906-012-0279-2

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Entin-Meer M, Ben-Shoshan J, Maysel-Auslender S, Levy R, Goryainov P, Schwartz I et al (2012) Accelerated renal fibrosis in cardiorenal syndrome is associated with long-term increase in urine neutrophil gelatinase-associated lipocalin levels. Am J Nephrol 36(2):190–200. doi:10.1159/000341651

    Article  PubMed  CAS  Google Scholar 

  96. Lekawanvijit S, Kompa AR, Zhang Y, Wang BH, Kelly DJ, Krum H (2012) Myocardial infarction impairs renal function, induces renal interstitial fibrosis, and increases renal KIM-1 expression: implications for cardiorenal syndrome. Am J Physiol Heart Circ Physiol 302(9):H1884–H1893. doi:10.1152/ajpheart.00967.2011

    Article  PubMed  CAS  Google Scholar 

  97. Angelini A, Castellani C, Ravara B, Franzin C, Pozzobon M, Tavano R et al (2011) Stem-cell therapy in an experimental model of pulmonary hypertension and right heart failure: role of paracrine and neurohormonal milieu in the remodeling process. J Heart Lung Transplant 30(11):1281–1293. doi:10.1016/j.healun.2011.07.017

    Article  PubMed  Google Scholar 

  98. DallaLibera L, Ravara B, Angelini A, Rossini K, Sandri M, Thiene G et al (2001) Beneficial effects on skeletal muscle of the angiotensin II type 1 receptor blocker irbesartan in experimental heart failure. Circulation. 103(17):2195–2200

    Article  CAS  Google Scholar 

  99. Castellani C, Vescovo G, Ravara B, Franzin C, Pozzobon M, Tavano R et al (2013) The contribution of stem cell therapy to skeletal muscle remodeling in heart failure. Int J Cardiol 168(3):2014–2021. doi:10.1016/j.ijcard.2013.01.168

    Article  PubMed  Google Scholar 

  100. Vescovo G, Volterrani M, Zennaro R, Sandri M, Ceconi C, Lorusso R et al (2000) Apoptosis in the skeletal muscle of patients with heart failure: investigation of clinical and biochemical changes. Heart 84(4):431–437

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  101. Vescovo G, Ceconi C, Bernocchi P, Ferrari R, Carraro U, Ambrosio GB et al (1998) Skeletal muscle myosin heavy chain expression in rats with monocrotaline-induced cardiac hypertrophy and failure. Relation to blood flow and degree of muscle atrophy. Cardiovasc Res 39(1):233–241

    Article  PubMed  CAS  Google Scholar 

  102. Angelini A, Castellani C, Virzì GM, Fedrigo M, Thiene G, Valente M et al (2016) The role of congestion in Cardiorenal Syndrome Type 2: new pathophysiological insights into an experimental model of heart failure. Cardiorenal Med 6:61–72

    Article  CAS  Google Scholar 

  103. Tanaka M, Yoshida H, Furuhashi M, Togashi N, Koyama M, Yamamoto S et al (2011) Deterioration of renal function by chronic heart failure is associated with congestion and oxidative stress in the tubulointerstitium. Intern Med 50(23):2877–2887

    Article  PubMed  CAS  Google Scholar 

  104. Anand IS, Bishu K, Rector TS, Ishani A, Kuskowski MA, Cohn JN (2009) 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 120(16):1577–1584. doi:10.1161/CIRCULATIONAHA.109.853648

    Article  PubMed  CAS  Google Scholar 

  105. Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B, Michelson EL et al (2009) Albuminuria in chronic heart failure: prevalence and prognostic importance. Lancet 374(9689):543–550. doi:10.1016/S0140-6736(09)61378-7

    Article  PubMed  CAS  Google Scholar 

  106. Wali RK, Iyengar M, Beck GJ, Chartyan DM, Chonchol M, Lukas MA et al (2011) Efficacy and safety of carvedilol in treatment of heart failure with chronic kidney disease: a meta-analysis of randomized trials. Circ Heart Fail 4(1):18–26. doi:10.1161/CIRCHEARTFAILURE.109.932558

    Article  PubMed  CAS  Google Scholar 

  107. Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B et al (2012) Influence of baseline and worsening renal function on efficacy of spironolactone in patients with severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol 60(20):2082–2089. doi:10.1016/j.jacc.2012.07.048

    Article  PubMed  CAS  Google Scholar 

  108. Rossignol P, Cleland JG, Bhandari S, Tala S, Gustafsson F, Fay R et al (2012) Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the eplerenone post-acute myocardial infarction heart failure efficacy and survival study. Circulation 125(2):271–279. doi:10.1161/CIRCULATIONAHA.111.028282

    Article  PubMed  CAS  Google Scholar 

  109. Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS et al (2004) Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109(13):1594–1602. doi:10.1161/01.CIR.0000124490.27666.B2

    Article  PubMed  CAS  Google Scholar 

  110. Virzi GM, Corradi V, Panagiotou A, Gastaldon F, Cruz DN, de Cal M et al (2010) ADPKD: prototype of Cardiorenal Syndrome Type 4. Int J Nephrol 2011:490795. doi:10.4061/2011/490795

    PubMed Central  PubMed  Google Scholar 

  111. Clementi A, Virzi GM, Goh CY, Cruz DN, Granata A, Vescovo G et al (2013) Cardiorenal syndrome type 4: a review. Cardiorenal Med 3(1):63–70. doi:10.1159/000350397

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  112. Clementi A, Virzi GM, Brocca A, de Cal M, Vescovo G, Granata A et al (2013) Cardiorenal syndrome Type 4: management. Blood Purif 36(3–4):200–209. doi:10.1159/000356369

    Article  PubMed  Google Scholar 

  113. Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P (2011) Vascular incompetence in dialysis patients—protein-bound uremic toxins and endothelial dysfunction. Semin Dial 24(3):327–337. doi:10.1111/j.1525-139X.2011.00925.x

    Article  PubMed  Google Scholar 

  114. Lekawanvijit S, Kompa AR, Wang BH, Kelly DJ, Krum H (2012) Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res 111(11):1470–1483. doi:10.1161/CIRCRESAHA.112.278457

    Article  PubMed  CAS  Google Scholar 

  115. Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ et al (2011) p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant 26(3):938–947. doi:10.1093/ndt/gfq580

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  116. Tumlin JA, Costanzo MR, Chawla LS, Herzog CA, Kellum JA, McCullough PA et al (2013) Cardiorenal syndrome type 4: insights on clinical presentation and pathophysiology from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 182:158–173. doi:10.1159/000349972

    Article  PubMed  Google Scholar 

  117. Sibal L, Agarwal SC, Home PD, Boger RH (2010) The Role of Asymmetric Dimethylarginine (ADMA) in endothelial dysfunction and cardiovascular disease. Curr Cardiol Rev. 6(2):82–90. doi:10.2174/157340310791162659

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  118. Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Wang BH, Krum H (2010) Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J 31(14):1771–1779. doi:10.1093/eurheartj/ehp574

    Article  PubMed  CAS  Google Scholar 

  119. Lekawanvijit S, Kumfu S, Wang BH, Manabe M, Nishijima F, Kelly DJ et al (2013) The uremic toxin adsorbent AST-120 abrogates cardiorenal injury following myocardial infarction. PLoS One 8(12):e83687. doi:10.1371/journal.pone.0083687

    Article  PubMed Central  PubMed  Google Scholar 

  120. Ronco C, Bowry S, Tetta C (2006) Dialysis patients and cardiovascular problems: can technology help solve the complex equation? Blood Purif 24(1):39–45. doi:10.1159/000089435

    Article  PubMed  Google Scholar 

  121. Bowry SK, Kuchinke-Kiehn U, Ronco C (2005) The cardiovascular burden of the dialysis patient: the impact of dialysis technology. Contrib Nephrol 149:230–239. doi:10.1159/000085685

    Article  PubMed  Google Scholar 

  122. House AA, Ronco C (2007) Cardiovascular risk in hemodialysis patients: a mechanistic approach. Int J Artif Organs 30(11):1020–1027

    PubMed  CAS  Google Scholar 

  123. Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG et al (2011) Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 80(6):572–586. doi:10.1038/ki.2011.223

    Article  PubMed  Google Scholar 

  124. Mall G, Huther W, Schneider J, Lundin P, Ritz E (1990) Diffuse intermyocardiocytic fibrosis in uraemic patients. Nephrol Dial Transplant 5(1):39–44

    Article  PubMed  CAS  Google Scholar 

  125. Dou L, Bertrand E, Cerini C, Faure V, Sampol J, Vanholder R et al (2004) The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int 65(2):442–451. doi:10.1111/j.1523-1755.2004.00399.x

    Article  PubMed  CAS  Google Scholar 

  126. Dou L, Cerini C, Brunet P, Guilianelli C, Moal V, Grau G et al (2002) P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines. Kidney Int 62(6):1999–2009. doi:10.1046/j.1523-1755.2002.t01-1-00651.x

    Article  PubMed  CAS  Google Scholar 

  127. Cerini C, Dou L, Anfosso F, Sabatier F, Moal V, Glorieux G et al (2004) P-cresol, a uremic retention solute, alters the endothelial barrier function in vitro. Thromb Haemost 92(1):140–150. doi:10.1267/THRO04010140

    PubMed  CAS  Google Scholar 

  128. Brocca A, Virzi GM, de Cal M, Cantaluppi V, Ronco C (2013) Cytotoxic effects of p-cresol in renal epithelial tubular cells. Blood Purif 36(3–4):219–225. doi:10.1159/000356370

    Article  PubMed  Google Scholar 

  129. Peng YS, Ding HC, Lin YT, Syu JP, Chen Y, Wang SM (2012) Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. Toxicology 302(1):11–17. doi:10.1016/j.tox.2012.07.004

    Article  PubMed  CAS  Google Scholar 

  130. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339(8793):572–575

    Article  PubMed  CAS  Google Scholar 

  131. Pandey NR, Benkirane K, Amiri F, Schiffrin EL (2007) Effects of PPAR-gamma knock-down and hyperglycemia on insulin signaling in vascular smooth muscle cells from hypertensive rats. J Cardiovasc Pharmacol 49(6):346–354. doi:10.1097/FJC.0b013e31804654d7

    Article  PubMed  CAS  Google Scholar 

  132. Liu Y, Liu X, Chen J, Zhang K, Huang F, Wang JF et al (2015) Apocynin attenuates cardiac injury in Type 4 Cardiorenal Syndrome via suppressing cardiac fibroblast growth factor-2 with oxidative stress inhibition. J Am Heart Assoc. doi:10.1161/JAHA.114.001598

    Google Scholar 

  133. Soni SS, Ronco C, Pophale R, Bhansali AS, Nagarik AP, Barnela SR et al (2012) Cardio-renal syndrome type 5: epidemiology, pathophysiology, and treatment. Semin Nephrol 32(1):49–56. doi:10.1016/j.semnephrol.2011.11.007

    Article  PubMed  CAS  Google Scholar 

  134. Mehta RL, Rabb H, Shaw AD, Singbartl K, Ronco C, McCullough PA et al (2013) Cardiorenal syndrome type 5: clinical presentation, pathophysiology and management strategies from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 182:174–194. doi:10.1159/000349970

    Article  PubMed  Google Scholar 

  135. Srisawat N, Hoste EE, Kellum JA (2010) Modern classification of acute kidney injury. Blood Purif 29(3):300–307. doi:10.1159/000280099

    Article  PubMed  Google Scholar 

  136. Chelazzi C, Villa G, De Gaudio AR (2011) Cardiorenal syndromes and sepsis. Int J Nephrol. 2011:652967. doi:10.4061/2011/652967

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  137. Ichinose F, Buys ES, Neilan TG, Furutani EM, Morgan JG, Jassal DS et al (2007) Cardiomyocyte-specific overexpression of nitric oxide synthase 3 prevents myocardial dysfunction in murine models of septic shock. Circ Res 100(1):130–139. doi:10.1161/01.RES.0000253888.09574.7a

    Article  PubMed  CAS  Google Scholar 

  138. Larche J, Lancel S, Hassoun SM, Favory R, Decoster B, Marchetti P et al (2006) Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 48(2):377–385. doi:10.1016/j.jacc.2006.02.069

    Article  PubMed  CAS  Google Scholar 

  139. Zanotti-Cavazzoni SL, Hollenberg SM (2009) Cardiac dysfunction in severe sepsis and septic shock. Curr Opin Crit Care 15(5):392–397. doi:10.1097/MCC.0b013e3283307a4e

    Article  PubMed  Google Scholar 

  140. Tavernier B, Li JM, El-Omar MM, Lanone S, Yang ZK, Trayer IP et al (2001) Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J 15(2):294–296. doi:10.1096/fj.00-0433fje

    PubMed  CAS  Google Scholar 

  141. Ronco C, Piccinni P, Kellum J (2010) Rationale of extracorporeal removal of endotoxin in sepsis: theory, timing and technique. Contrib Nephrol 167:25–34. doi:10.1159/000315916

    Article  PubMed  CAS  Google Scholar 

  142. Wen X, Murugan R, Peng Z, Kellum JA (2010) Pathophysiology of acute kidney injury: a new perspective. Contrib Nephrol 165:39–45. doi:10.1159/000313743

    Article  PubMed  Google Scholar 

  143. Jacobs R, Honore PM, Joannes-Boyau O, Boer W, De Regt J, De Waele E et al (2011) Septic acute kidney injury: the culprit is inflammatory apoptosis rather than ischemic necrosis. Blood Purif 32(4):262–265. doi:10.1159/000330244

    Article  PubMed  CAS  Google Scholar 

  144. Lerolle N, Nochy D, Guerot E, Bruneval P, Fagon JY, Diehl JL et al (2010) Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med 36(3):471–478. doi:10.1007/s00134-009-1723-x

    Article  PubMed  Google Scholar 

  145. Cantaluppi V, Weber V, Lauritano C, Figliolini F, Beltramo S, Biancone L et al (2010) Protective effect of resin adsorption on septic plasma-induced tubular injury. Crit Care 14(1):R4. doi:10.1186/cc8835

    Article  PubMed Central  PubMed  Google Scholar 

  146. Novaes AB Jr, de Uzeda M, Fonseca ME, Feitosa AC (1991) The effect of subinhibitory concentrations of metronidazole and tetracycline on the ultrastructure of periodontopathic bacteria. J Antimicrob Chemother 28(1):151–154

    Article  PubMed  CAS  Google Scholar 

  147. Horton JW, Maass D, White J, Sanders B (2000) Nitric oxide modulation of TNF-alpha-induced cardiac contractile dysfunction is concentration dependent. Am J Physiol Heart Circ Physiol 278(6):H1955–H1965

    PubMed  CAS  Google Scholar 

  148. Francis SE, Holden H, Holt CM, Duff GW (1998) Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol 30(2):215–223. doi:10.1006/jmcc.1997.0592

    Article  PubMed  CAS  Google Scholar 

  149. Oudemans-van Straaten HM (2008) Circulating pro-apoptotic mediators in burn septic acute renal failure. Crit Care 12(2):126. doi:10.1186/cc6798

    Article  PubMed Central  PubMed  Google Scholar 

  150. Jo SK, Lee SY, Han SY, Cha DR, Cho WY, Kim HK et al (2001) Alpha-melanocyte stimulating hormone (MSH) decreases cyclosporine a induced apoptosis in cultured human proximal tubular cells. J Korean Med Sci 16(5):603–609

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  151. Mink SN, Kasian K, Jacobs H, Cheng ZQ, Light RB (2008) N, N′-diacetylchitobiose, an inhibitor of lysozyme, reverses myocardial depression and lessens norepinephrine requirements in Escherichia coli sepsis in dogs. Shock 29(6):681–687. doi:10.1097/shk.0b013e31815816c3

    PubMed  CAS  Google Scholar 

  152. Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101(10):3765–3777. doi:10.1182/blood-2002-06-1887

    Article  PubMed  CAS  Google Scholar 

  153. Boos CJ, Goon PK, Lip GY (2006) The endothelium, inflammation, and coagulation in sepsis. Clin Pharmacol Ther 79(1):20–22. doi:10.1016/j.clpt.2005.10.004

    Article  PubMed  Google Scholar 

  154. Abraham E, Singer M (2007) Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35(10):2408–2416

    Article  PubMed  Google Scholar 

  155. White LE, Chaudhary R, Moore LJ, Moore FA, Hassoun HT (2011) Surgical sepsis and organ crosstalk: the role of the kidney. J Surg Res 167(2):306–315. doi:10.1016/j.jss.2010.11.923

    Article  PubMed Central  PubMed  Google Scholar 

  156. Brocca A, Virzi GM, Pasqualin C, Pastori S, Marcante S, de Cal M et al (2015) Cardiorenal syndrome type 5: in vitro cytotoxicity effects on renal tubular cells and inflammatory profile. Anal Cell Pathol (Amst). 2015:469461. doi:10.1155/2015/469461

    PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology, Dialysis and Transplant, San Bortolo Hospital, Vicenza, Italy

    Grazia Maria Virzì & Claudio Ronco

  2. IRRIV-International Renal Research Institute Vicenza, Vicenza, Italy

    Grazia Maria Virzì, Anna Clementi & Claudio Ronco

  3. Department of Nephrology and Dialysis, San Giovanni Di Dio Hospital, Agrigento, Italy

    Anna Clementi

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  1. Grazia Maria Virzì
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Virzì, G.M., Clementi, A. & Ronco, C. Cellular apoptosis in the cardiorenal axis. Heart Fail Rev 21, 177–189 (2016). https://doi.org/10.1007/s10741-016-9534-y

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