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.
Highlights
Reductions in serum levels of the nondialysable uremic toxin, indoxyl sulfate, by the oral adsorbent, AST-120, reduces the pathological cardiac fibrosis associated with chronic kidney disease
This amelioration of cardiac fibrosis with AST-120 occurred in the absence of any change in blood pressure
[19] Increased risk of sudden cardiac death (SCD) is associated with many factors such as cardiac structural changes or the so-called uremic cardiomyopathy, large volume and rapid electrolyte shifts during dialysis and derangements in autonomic function
Summary
Chronic kidney disease (CKD) is a major contributor to cardiovascular (CV) mortality which is responsible for 40–50% of all deaths in such patients. [1] Death from cardiac causes is greater in dialyzed uremic patients by a factor of approximately 10–30 compared to the rates in the respective background population. [2].Studies on cardiac pathology in CKD have previously demonstrated typical structural changes, ‘‘uremic cardiomyopathy’’, comprising fibrosis, hypertrophy and a reduction in capillary supply per unit volume of cardiac tissue. [3] Renal fibrosis is a key characteristic finding in progressive CKD, irrespective of the nature of the initial renal insult.A variety of mechanisms contributing to uremic cardiomyopathy have been proposed such as neurohormonal activation that of the renin-angiotensin-aldosterone and sympathetic nervous systems, [4,5] hemodynamic alterations (especially hypertension), [6] anemia, [6,7] pro-inflammatory cytokine activation, [8] and oxidative stress. [9] Treatments targeting these pathways have demonstrated beneficial effects on these structural and functional changes as well as major clinical outcomes. [10,11,12,13].An important pathophysiological finding generally overlooked as being contributory to cardiac dysfunction in CKD is the accumulation of uremic toxins which are normally excreted by the healthy kidney. Chronic kidney disease (CKD) is a major contributor to cardiovascular (CV) mortality which is responsible for 40–50% of all deaths in such patients. [1] Death from cardiac causes is greater in dialyzed uremic patients by a factor of approximately 10–30 compared to the rates in the respective background population. [9] Treatments targeting these pathways have demonstrated beneficial effects on these structural and functional changes as well as major clinical outcomes. An important pathophysiological finding generally overlooked as being contributory to cardiac dysfunction in CKD is the accumulation of uremic toxins which are normally excreted by the healthy kidney. [16] Treatment with an IS-reducing agent, AST-120, has been shown to reverse kidney fibrosis and delay CKD progression by adsorbing indole (the IS precursor) in the gut. IS is an intestinal bacterial metabolite derived from dietary tryptophan, [14] approximately 90% of circulating IS is albumin-bound. [15] A pro-fibrotic effect of IS on the kidney has been reported and found to be associated with CKD progression. [16] Treatment with an IS-reducing agent, AST-120, has been shown to reverse kidney fibrosis and delay CKD progression by adsorbing indole (the IS precursor) in the gut. [16,17]
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