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

2. 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.

3. 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

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

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

8. Renal changes post-MI: In vivo study

10. In vivo MI–AST120 study
Background
MI (16 weeks) renal fibrosis

11. Serum IS
Results
Heart Kidney

12. 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):
Krum H, Iyngkaran P, Lekawanvijit S. Pharmacological Management of the Cardiorenal Syndrome in Heart Failure. Current Heart Failure Reports 2009;6:
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 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 Oct 20. doi: /j 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

13. 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 March 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 November 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 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.

14. 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 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 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 October, 2008.

15. 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