title: Emerging therapies for heart failure: renal mechanisms and effects.
abstract: Improved understanding of the pathophysiology of salt and water homeostasis has provided a foundation for explaining the renal mechanisms of emerging therapies for heart failure, as well as why renal function might potentially be improved or harmed. These aspects are reviewed in this article for a number of newer therapies including adenosine, endothelin, and vasopressin receptor antagonists, as well as extracorporeal ultrafiltration. An appreciation of the complexity and sometimes opposing pathways of these approaches may explain their limited efficacy in early trials, in which there has not been a substantial improvement in patient or renal outcomes. In that there is often a balance between beneficial and maladaptive receptor actions and neurohumoral responses, this physiologic approach also provides insight into the rationale for combining therapies. Multi-agent strategies may thus maximize their effectiveness while minimizing adverse effects and tolerance. In this paper, the theoretical impact of the emerging agents based on their mechanism of action and pathophysiology of the disease is initially addressed. Then, the available clinical evidence for each class of drugs is reviewed with special emphasis on their effect on kidney-related parameters. Finally, a general overview of the complexity of the interpretation of trials is offered along with a number of potential explanations for the observed results.
authors.affiliation: Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, 1600 SW Archer Road, Box 100224, Gainesville, FL 32610-0224, USA. amir.kazory@medicine.ufl.edu
authors.forename: Amir
authors.initials: A
authors.lastname: Kazory
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ross
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000627:therapeutic use; D065092:Antidiuretic Hormone Receptor Antagonists; D059347:Cardio-Renal Syndrome / Q000150:complications / Q000503:physiopathology*; D002986:Clinical Trials as Topic; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000150:complications / Q000628:therapy*; D006801:Humans
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D065092:Antidiuretic Hormone Receptor Antagonists; D065128:Endothelin Receptor Antagonists
references.citation: J Card Fail. 2008 Feb;14(1):1-5
references.pmid: 18226766
references.citation: Am J Cardiol. 2003 Jan 15;91(2):245-8
references.pmid: 12521645
references.citation: J Am Coll Cardiol. 2005 Dec 6;46(11):2043-6
references.pmid: 16325039
references.citation: Eur J Heart Fail. 2001 Aug;3(4):457-61
references.pmid: 11511432
references.citation: J Am Coll Cardiol. 2009 Feb 17;53(7):589-596
references.pmid: 19215833
references.citation: J Am Coll Cardiol. 2003 Jan 15;41(2):204-10
references.pmid: 12535809
references.citation: J Am Coll Cardiol. 2000 Jan;35(1):56-9
references.pmid: 10636259
references.citation: Lancet. 1988 May 7;1(8593):1033-5
references.pmid: 2896877
references.citation: J Card Fail. 2007 Oct;13(8):609-17
references.pmid: 17923351
references.citation: J Card Fail. 2006 Jun;12(5):349-52
references.pmid: 16762797
references.citation: Congest Heart Fail. 2009 Jul-Aug;15(4):210-1
references.pmid: 19627301
references.citation: Eur Heart J. 1997 Feb;18(2):254-8
references.pmid: 9043842
references.citation: N Engl J Med. 2005 Jul 14;353(2):113-6
references.pmid: 16014879
references.citation: N Engl J Med. 2001 Aug 23;345(8):574-81
references.pmid: 11529211
references.citation: J Am Coll Cardiol. 2007 Feb 13;49(6):675-83
references.pmid: 17291932
references.citation: J Am Coll Cardiol. 2003 May 7;41(9):1452-7
references.pmid: 12742280
references.citation: J Am Coll Cardiol. 2005 Dec 6;46(11):2047-51
references.pmid: 16325040
references.citation: Am Heart J. 2001 Aug;142(2):340-9
references.pmid: 11479476
references.citation: Biochem Biophys Res Commun. 1988 Sep 30;155(3):1244-7
references.pmid: 3052444
references.citation: J Card Fail. 2006 Dec;12(9):707-14
references.pmid: 17174232
references.citation: Circulation. 2008 Jan 29;117(4):e25-146
references.pmid: 18086926
references.citation: Eur J Heart Fail. 2008 Feb;10(2):176-87
references.pmid: 18242127
references.citation: J Clin Invest. 1989 Sep;84(3):1032-5
references.pmid: 2547837
references.citation: Lancet. 2004 Jul 24-30;364(9431):347-54
references.pmid: 15276394
references.citation: Heart. 2006 Jun;92(6):798-803
references.pmid: 16339819
references.citation: J Am Soc Nephrol. 1991 Aug;2(2):150-5
references.pmid: 1954327
references.citation: Circulation. 2002 Mar 19;105(11):1348-53
references.pmid: 11901047
references.citation: J Am Coll Cardiol. 2007 Oct 16;50(16):1551-60
references.pmid: 17936154
references.citation: J Am Coll Cardiol. 2008 Nov 4;52(19):1540-5
references.pmid: 19007589
references.citation: Am Heart J. 2010 Apr;159(4):505-7
references.pmid: 20362706
references.citation: Circ Heart Fail. 2009 Nov;2(6):523-31
references.pmid: 19919976
references.citation: Circulation. 1997 Mar 18;95(6):1363-5
references.pmid: 9118500
references.citation: J Am Coll Cardiol. 2007 Aug 14;50(7):600-6
references.pmid: 17692744
references.citation: J Card Fail. 2008 Oct;14(8):631-40
references.pmid: 18926433
references.citation: J Am Coll Cardiol. 2006 Apr 18;47(8):1615-21
references.pmid: 16630999
references.citation: Circulation. 2001 Feb 20;103(7):973-80
references.pmid: 11181472
references.citation: Eur J Heart Fail. 2004 Aug;6(5):601-9
references.pmid: 15302008
references.citation: Circulation. 1990 Nov;82(5):1724-9
references.pmid: 2146040
references.citation: Circ Res. 2003 Oct 17;93(8):759-66
references.pmid: 12970111
references.citation: J Card Fail. 2005 Feb;11(1):12-20
references.pmid: 15704058
references.citation: Heart Fail Rev. 2009 Dec;14(4):243-53
references.pmid: 19876734
references.citation: Chest. 2001 Aug;120(2):460-6
references.pmid: 11502644
references.citation: J Am Coll Cardiol. 2007 Jun 5;49(22):2151-9
references.pmid: 17543634
references.citation: Circulation. 2003 Jun 3;107(21):2690-6
references.pmid: 12742979
references.citation: Hypertension. 2008 Sep;52(3):452-9
references.pmid: 18678788
references.citation: Circulation. 2001 Nov 13;104(20):2417-23
references.pmid: 11705818
references.citation: J Card Fail. 2003 Jun;9(3):227-31
references.pmid: 12815573
references.citation: Circulation. 2002 Nov 19;106(21):2666-72
references.pmid: 12438291
references.citation: J Card Fail. 2008 Aug;14(6):515-20
references.pmid: 18672200
references.citation: JAMA. 2004 Apr 28;291(16):1963-71
references.pmid: 15113814
references.citation: Int J Cardiol. 2010 Aug 6;143(1):1-3
references.pmid: 20207034
references.citation: Am J Cardiol. 2008 Jun 2;101(11A):89E-103E
references.pmid: 18514634
references.citation: J Card Fail. 2008 Oct;14(8):641-7
references.pmid: 18926434
references.citation: Congest Heart Fail. 2008 Nov-Dec;14(6):298-301
references.pmid: 19076851
references.citation: Circulation. 2006 Nov 21;114(21):2240-50
references.pmid: 17088462
references.citation: Eur J Heart Fail. 2008 Feb;10(2):165-9
references.pmid: 18279771
references.citation: N Engl J Med. 1999 Aug 19;341(8):577-85
references.pmid: 10451464
references.citation: JAMA. 2007 Mar 28;297(12):1319-31
references.pmid: 17384437
references.citation: Heart. 2009 Jul;95(13):1047-51
references.pmid: 19261603
references.citation: Br J Pharmacol. 2007 Aug;151(7):1025-32
references.pmid: 17558436
references.citation: Biochem Biophys Res Commun. 1988 Aug 30;155(1):167-72
references.pmid: 2458103
references.citation: Am J Physiol Renal Physiol. 2006 Feb;290(2):F273-8
references.pmid: 16189291
references.citation: Circulation. 2006 Oct 10;114(15):1572-80
references.pmid: 17015793
references.citation: CMAJ. 2007 Mar 13;176(6):S1-44
references.pmid: 17353516
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L685-95
references.pmid: 16214819
references.citation: JAMA. 2007 Nov 7;298(17):2009-19
references.pmid: 17986694
references.citation: Mol Cell Biochem. 2004 Apr;259(1-2):163-8
references.pmid: 15124920
references.citation: J Hypertens. 1998 Aug;16(8):1081-98
references.pmid: 9794709