Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate.

Abstract

Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a uremic toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal-nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n=13) or no treatment (vehicle, n=17) for 12 weeks. Sham operated rats (n=12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A' waves] and a decrease of E/A and E'/A' ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF-β, CTGF) and hypertrophic (ANP, β-MHC and α-skeletal muscle actin) markers, as well as TGF-β and phosphorylated NF-κB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120=227 ± 11 vs vehicle  =224 ± 8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-β and phosphorylated NF-κB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner.

• Authors: Suree Lekawanvijit, Andrew R Kompa, Minako Manabe, Bing H Wang, Robyn G Langham, Fuyuhiko Nishijima, Darren J Kelly, Henry Krum
• Journal: PloS one (PLoS One) Vol. 7 Issue 7 Pg. e41281 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22829936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oxides
• Carbon
• AST 120
• Indican

Topics

• Animals
• Carbon (therapeutic use)
• Cardiomyopathies (blood, drug therapy, etiology)
• Fibrosis (blood, drug therapy, etiology)
• Indican (blood)
• Male
• Oxides (therapeutic use)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Renal Insufficiency, Chronic (blood, complications)