The Uremic Toxin Adsorbent AST-120 Abrogates Cardiorenal Injury Following Myocardial Infarction

Suree Lekawanvijit,Henry Krum,Minako Manabe,Darren J Kelly,Fuyuhiko Nishijima,Andrew R Kompa,Bing H Wang,Sirinart Kumfu,Dinender K Singla

doi:10.1371/journal.pone.0083687

Suree Lekawanvijit, Henry Krum + Show 7 more

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https://doi.org/10.1371/journal.pone.0083687

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Abstract

An accelerated progressive decline in renal function is a frequent accompaniment of myocardial infarction (MI). Indoxyl sulfate (IS), a uremic toxin that accumulates from the early stages of chronic kidney disease (CKD), is contributory to both renal and cardiac fibrosis. IS levels can be reduced by administration of the oral adsorbent AST-120, which has been shown to ameliorate pathological renal and cardiac fibrosis in moderate to severe CKD. However, the cardiorenal effect of AST-120 on less severe renal dysfunction in the post-MI setting has not previously been well studied. MI-induced Sprague-Dawley rats were randomized to receive either AST-120 (MI+AST-120) or were untreated (MI+Vehicle) for 16 weeks. Serum IS levels were measured at baseline, 8 and 16 weeks. Echocardiography and glomerular filtration rate (GFR) were assessed prior to sacrifice. Renal and cardiac tissues were assessed for pathological changes using histological and immunohistochemical methods, Western blot analysis and real-time PCR. Compared with sham, MI+Vehicle animals had a significant reduction in left ventricular ejection fraction (by 42%, p<0.001) and fractional shortening (by 52%, p<0.001) as well as lower GFR (p<0.05) and increased serum IS levels (p<0.05). A significant increase in interstitial fibrosis in the renal cortex was demonstrated in MI+Vehicle animals (p<0.001). Compared with MI+Vehicle, MI+AST-120 animals had increased GFR (by 13.35%, p<0.05) and reduced serum IS (p<0.001), renal interstitial fibrosis (p<0.05), and renal KIM-1, collagen-IV and TIMP-1 expression (p<0.05). Cardiac function did not change with AST-120 treatment, however gene expression of TGF-β1 and TNF-α as well as collagen-I and TIMP-1 protein expression was decreased in the non-infarcted myocardium (p<0.05). In conclusion, reduction of IS attenuates cardio-renal fibrotic processes in the post-MI kidney. KIM-1 appears to be a sensitive renal injury biomarker in this setting and is correlated with serum IS levels.

Highlights

Coexistence of renal and cardiac dysfunction, known as cardiorenal syndrome, has an adverse impact on clinical outcomes following acute myocardial infarction (MI)
We recently demonstrated in an experimental model of MI that worsening renal function occurs early post-MI, may be transient and is strongly related to activation of renal inflammatory-fibrosis pathways which lead to nonreversible functional impairment [6]
The heart weight/body weight (HW/BW) and left ventricular weight/body weight (LV/BW) were significantly greater in both MI groups compared with sham animals (Table 1)

Summary

Introduction

Coexistence of renal and cardiac dysfunction, known as cardiorenal syndrome, has an adverse impact on clinical outcomes following acute myocardial infarction (MI). One third of hospitalized MI patients present with coexisting kidney dysfunction [1] and one fifth develop worsening renal function during hospitalization [2]. These patients are at higher risk for in-hospital death [3,4] and cardiovascular events (hospitalization for congestive heart failure, recurrent MI and stroke) after discharge as well as short- and long-term mortality [2,3,4,5]. Even in post-MI patients with mild renal impairment, which may be transient, 10-year prognosis is still poor [2]. Expression of kidney injury molecule (KIM)-1, a novel biomarker of kidney injury, appears to be a promising biomarker to detect and monitor post-MI renal injury [6]

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