รายงานการลาศึกษาต่อระดับปริญญาเอก เรื่อง cardiorenal syndrome ณ Monash University, Australia (2008-2012) ผศ.พญ.สุรีย์ เลขวรรณวิจิตร 15 May 2012

Cardiorenal syndrome non-dialyzable uraemic toxins? Increased CV morbidity & mortality Anemia Neurohormonal activation Pathologic remodeling Diuretic therapy Diminished blood flow Vasoconstriction hemodynamics Inflammation non-dialyzable uraemic toxins? Indoxyl sulfate (IS) Oxidative stress Potential Deleterious Effects of Diuretics and Cardiorenal Syndrome of HF Diuretic resistance and refractoriness in HF patients are due to a number of factors including avid Na+ and H2O reabsorption in the proximal tubule due to the effects of Ang II and high levels of aldosterone that also contribute (to a lesser extent) to Na+ reabsorption. Loop and thiazide diuretics exert effects on the distal to proximal tubule, where most of the Na+ and H2O has already been reabsorbed. Therefore, loop and thiazide diuretics have less substrate (tubular Na+ and H2O) on which to exert their effects. Renal vasoconstriction mediated by norepinephrine, endothelin-1, and Ang II can lead to decreased GFR, reducing the ability of most diuretics to get to their site of action in renal tubules, thus leading to diuretic resistance. Weber KT. N Engl J Med. 2001;345:1689 Francis GS et al. Ann Intern Med. 1985;103:1 Hypothesis1: Indoxyl sulfate has adverse cardiac effects. Hypothesis2: MI causes renal function and structural changes over time.

Indoxyl sulfate: In vitro study Cardiac fibroblast Cardiac myocyte Collagen synthesis Protein synthesis Why is the effect not dose-dependent? It’s hard to explain but this may be due to its protein-bound property which is normally about 90% bound to albumin in CKD. An average serum albumin level in RF patients is around 3.5 g/dl which is recommended to add in cultured condition by some experts. The condition used in my experiment is 0.5 g/dl BSA, seven times less. This means there is less protein-bound form or more free IS. THP-1 cell: Pro-inflammatory cytokine gene expression

Indoxyl sulfate: In vivo study GI tract Indoxyl sulfate (circulation) urine AST-120 OAT1 and 3

Cardiac Fibrosis Sham STNx+Vehicle STNx+AST-120 0.8X 0.8X 0.8X 6

Renal changes post-MI: In vivo study

In vivo MI–AST120 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 2010;31(14):1771-1779. Krum H, Iyngkaran P, Lekawanvijit S. Pharmacological Management of the Cardiorenal Syndrome in Heart Failure. Current Heart Failure Reports 2009;6:105-111. 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 28th February 2011

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 16- 18 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 pro- inflammatory mRNA 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 59th Annual Scientific Meeting. Perth, Australia; Heart, Lung and Circulation 2011, 20;S61. 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 mRNA expression post-MI in the rat. In: The CSANZ 59th Annual Scientific Meeting. Perth, Australia; Heart, Lung and Circulation 2011, 20;S58. 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 60th Annual Scientific Session and i2 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 44ht 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 58th Annual Scientific Meeting. Adelaide, Australia; Heart, Lung and Circulation 2010, 19;S76-77. 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:S1076. 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 57th Annual Scientific Meeting. Sydney, Australia; Heart, Lung and Circulation 2009, 18(suppl 3);S174. 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):S338. 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 Professor Henry Krum Professor Darren Kelly Dr. Andrew Kompa Dr. Bing Wang Monash University University of Melbourne Prince Doctor Fund Faculty of Medicine Chiang Mai University Thailand