cardiorenal syndrome Monash University Australia 2008 2012 15

���������� cardiorenal syndrome � Monash University, Australia (2008 -2012( ��. ������� 15 May 2012

Cardiorenal syndrome Increased CV morbidity & mortality Pathologic remodeling Diminished blood flow Vasoconstriction Diuretic therapy Neurohormonal activation hemodynamics Oxidative stress Inflammation Neurohormonal activation Anemia non-dialyzable uraemic toxins? Indoxyl sulfate (IS) Hypothesis 1: Indoxyl sulfate has adverse cardiac effects. Hypothesis 2: MI causes renal function and structural changes over time.

Indoxyl sulfate: In vitro study Cardiac fibroblast Cardiac myocyte Collagen synthesis Protein synthesis THP-1 cell: Pro-inflammatory cytokine gene expression

Indoxyl sulfate: In vivo study AST-120 GI tract Indoxyl sulfate (circulation) OAT 1 and 3 urine

Cardiac Fibrosis Sham STNx+Vehicle 0. 8 X STNx+AST-120 0. 8 X

Renal changes post-MI: In vivo study

In vivo MI–AST 120 study Background MI (16 weeks) renal fibrosis

Serum IS Results Heart Kidney

Publications § Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Krum H, Wang B. Does Indoxyl Sulfate, A Uraemic Toxin, Have Direct Effects on Cardiac Fibroblasts & Myocytes? Eur Heart J. 1771 -1779: (14)31; 2010 § Krum H, Iyngkaran P, Lekawanvijit S. Pharmacological Management of the Cardiorenal Syndrome in Heart Failure. Current Heart Failure Reports. 6: 105 -111; 2009 § Lekawanvijit S, Kompa AR, Zhang Y, Wang BH, Kelly DJ, Krum H. 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. 2012 Feb 24. [Epub ahead of print] § Liu S, Lekawanvijit S, Kompa AR, Wang BH, Kelly DJ, Krum H. Cardiorenal Syndrome: Pathophysiology, Preclinical Models, Management and Potential Role of Uraemic Toxins. Clin Exp Pharmacol Physiol. 2011 Oct 20. doi: 10. 1111/j. 1440 -1681. 2011. 05632. x. [Epub ahead of print] § Lekawanvijit S, Kompa A, Manabe M, Kelly DJ, Krum H. Chronic Kidney Disease-Induced Cardiac Fibrosis is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uraemic Toxin, Indoxyl Sulfate. (Under review at PLOS One) Presentation title 28 th February 2011 12

Conference communications § Lekawanvijit S, Kompa A, Wang BH, Nishijima F, Kelly DJ, Krum H. Chronic Kidney Disease-Induced Cardiac Fibrosis is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uraemic Toxin, Indoxyl Sulfate Reducing Circulating Levels of Indoxyl Sulfate, a Non-Dialysable Uremic Toxin, Ameliorates Chronic Kidney Disease-Induced Cardiac Fibrosis. In: The Japanese Circulation Society 1618 March 2012. Fukuoka, Japan. § Lekawanvijit S, Kompa AR, Manabe M, Kelly DJ, Krum H. Reduction of renal fibrosis as well as cardiac pro-fibrotic and proinflammatory m. RNA expression by an oral charcoal adsorbent, AST- , 120 in post-MI rats. In: The American Heart Association Scientific Sessions 12 -16 November 2011. Orlando, Florida, USA. § Lekawanvijit S, Kompa A, Wang BH, Nishijima F, Kelly DJ, Krum H. Chronic Kidney Disease-Induced Cardiac Fibrosis is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uraemic Toxin, Indoxyl Sulfate. In: The ASN Kidney Week, 8 -13 November 2011, Philadelphia, Pennsylvania, USA . § Lekawanvijit S, Kompa AR, Manabe M, Kelly DJ, Krum H. Reducing circulating levels of a non-dialysable uraemic toxin, indoxyl sulfate, ameliorates chronic kidney disease-induced cardiac fibrosis. In: The European Society of Cardiology Congress . 2011 Paris, France; European Heart Journal 2011, 32 (Abstract Supplement): 1002. § Lekawanvijit S, Kompa AR, Manabe M, Wang BH, Kelly DJ, Krum H. Chronic Kidney Disease-Induced Cardiac Fibrosis is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uraemic Toxin, Indoxyl Sulfate. In: The CSANZ 59 th Annual Scientific Meeting. Perth, Australia; Heart, Lung and Circulation 2011, 20; S 61. § Lekawanvijit S, Kompa A, Manabe M, Kelly DJ, Krum H. An oral charcoal adsorbent, AST- , 120 reduces renal fibrosis as well as cardiac pro-fibrotic and pro-inflammatory m. RNA expression post-MI in the rat. In: The CSANZ 59 th Annual Scientific Meeting. Perth, Australia; Heart, Lung and Circulation 2011, 20; S 58. § Lekawanvijit S, Kompa A, Manabe M, Kelly DJ, Krum H. Chronic Kidney Disease-Induced Cardiac Fibrosis is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uraemic Toxin, Indoxyl Sulfate. In: The American College of Cardiology 60 th Annual Scientific Session and i 2 Summit, April 2 -5, 2011, New Orleans, Louisiana, USA; J Am Coll Cardiol 2011; 57: 192.

Conference communications (cont. ) § Lekawanvijit S, Kompa A, Manabe M, Kelly DJ, Krum H. Chronic Kidney Disease-Induced Cardiac Fibrosis is Ameliorated by Reducing Circulating Levels of a Non-Dialysable Uraemic Toxin, Indoxyl Sulfate. In: The 44 ht Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) Annual Scientific Meeting. Melbourne, Australia. 28 November – 1 December, 2010. § Lekawanvijit S, Kompa A, Zhang Y, Wang BH, Kelly DJ, Krum H. Myocardial infarction impairs renal function, induces renal interstitial fibrosis and increases Kim- 1 expression: Implications for the cardiorenal syndrome. In: The CSANZ 58 th Annual Scientific Meeting. Adelaide, Australia; Heart, Lung and Circulation 2010, 19; S 76 -77. § Lekawanvijit S, Kompa A, Zhang Y, Wang BH, Kelly DJ, Krum H. Myocardial infarction impairs renal function, induces renal interstitial fibrosis and increases Kim- 1 expression: Implications for the cardiorenal syndrome. In: The American Heart Association Scientific Sessions 2009. Orlando, Florida, USA; Circulation 2009, 120: S 1076. § Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Krum H, Wang B. Does Indoxyl Sulfate, A Uraemic Toxin, Have Direct Effects on Cardiac Fibroblasts & Myocytes? In: The CSANZ 57 th Annual Scientific Meeting. Sydney, Australia; Heart, Lung and Circulation 2009, 18(suppl 3); S 174. § Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Krum H, Wang B. Does Indoxyl Sulfate, A Uraemic Toxin, Have Direct Effects on Cardiac Fibroblasts & Myocytes? In: The American Heart Association Scientific Sessions . 2008 New Orleans, Louisiana, USA; Circulation 2008, 118(suppl 2): S 338. § Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Krum H, Wang B. Does Indoxyl Sulfate, A Uraemic Toxin, Have Direct Effects on Cardiac Fibroblasts & Myocytes? In: The Alfred Week Research Poster Display. 20 -24 October, 2008.

Acknowledgements Supervisors n n n Professor Henry Krum Professor Darren Kelly Dr. Andrew Kompa Dr. Bing Wang Monash University of Melbourne Prince Doctor Fund Faculty of Medicine Chiang Mai University Thailand