Plasma Indoxyl Sulfate Levels Research Articles

Plasma indoxyl sulfate levels predict cardiovascular events in patients with mild chronic heart failure

Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome. The present study aimed to elucidate whether the plasma levels of IS can predict the occurrence of cardiovascular events in patients with chronic heart failure (CHF) and investigate which causes of CHF leading to cardiovascular events are highly influenced by plasma IS levels. We measured the plasma IS levels in 165 patients with CHF [valvular disease: 78, dilated cardiomyopathy: 29, hypertrophic cardiomyopathy (HCM): 25 and others: 33] admitted to our hospital in 2012, and we followed up these patients for more than 5 years (the median follow-up period: 5.3 years). We measured the plasma IS level in 165 patients with CHF, and Kaplan–Meier analyses showed that high plasma IS levels (≥ 0.79 µg/mL, the median value) could predict the occurrence of cardiovascular events, i.e., cardiovascular death or rehospitalization due to the worsening of CHF. The sub-analyses showed that the high IS level could predict cardiovascular events in patients with CHF due to HCM and that the plasma IS levels were closely associated with left ventricular (LV) dimension, LV systolic dysfunction, and plasma B-type natriuretic peptide levels, rather than LV diastolic dysfunction. Plasma IS level predicts cardiovascular events in patients with CHF, especially those with HCM along with cardiac dysfunction. Besides, IS may become a proper biomarker to predict cardiovascular events in patients with CHF.

The Difference in the Changes of Indoxyl Sulfate after Catheter Ablation among Atrial Fibrillation Patients with and without Kidney Dysfunction

Indoxyl sulfate (IS), a protein-bound uremic toxin, induces chronic kidney disease (CKD) and atrial fibrillation (AF). Catheter ablation (CA) of AF improves the renal function. However, the transition of uremic toxins is unclear. This study aimed to investigate the transition of the serum IS level in AF patients with and without CKD after CA. A total of 138 consecutive AF patients who underwent CA and maintained sinus rhythm were prospectively enrolled (paroxysmal AF 67.4%). The patients were divided into 4 groups (non-CKD/low-IS:68, non-CKD/high-IS:28, CKD/low-IS:13, and CKD/high-IS:29). The plasma IS levels and estimated glomerular filtration rate (eGFR) were determined before and 1-year after CA. CKD was defined as CKD stage III and a high-IS according to the mean IS (IS ≥ 1.1 μg/ml). CA significantly improved the eGFR in CKD patients (p < 0.001). The serum IS level in the non-CKD/high-IS group was significantly decreased (from 1.7 ± 0.7 to 1.1 ± 0.6 μg/ml, p < 0.001). However, the serum IS level in the CKD/high-IS group did not improve (from 1.9 ± 0.9 to 1.7 ± 0.7 μg/ml, p = 0.22). The change in the IS in the CKD patients significantly differed from that in those without CKD. In the CKD patients, CA did not significantly decrease the IS, a risk factor of CKD, regardless of an improved eGFR.

AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs.

Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective. To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group). In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-β1 expression and increases in AKT phosphorylation. IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.

Zhenwu Decoction delays ventricular hypertrophy in rats with uremic cardiomyopathy

To investigate the inhibitory effect of Zhenwu Decoction on ventricular hypertrophy in rats with uremic cardiomyopathy and explore the mechanism. Cardiocytes isolated from suckling rats were divided into control group and indoxyl sulfate (IS) group, and the protein synthesis was assayed with [3H]- leucine incorporation and cellular protein expressions were detected using Western blotting. Fifty SD rats were randomly divided into sham operation group, model group, and low- and high-dose Zhenwu Decoction treatment groups, and except for those in the sham operation group, all the rats underwent 5/6 nephrectomy. Four weeks after the operation, the rats in low- and high-dose treatment groups were given Zhenwu Decoction via gavage at the dose of 4.5 g/kg and 13.5 g/kg, respectively; the rats in the sham-operated and model groups were given an equal volume of distilled water. After 4 weeks of treatment, serum levels of IS were determined, and cardiac and ventricular mass indexes were measured in the rats; cardiac ultrasound was performed and Western blotting was used to measure the expressions of BNP, p-ERK1/2, p-p38 and p-JNK in the myocardium. Rat cardiomyocytes treated with IS showed significantly enhanced protein synthesis and increased expression levels of BNP, p-erk1/2, and p-p38 as compared with the control cells (P &lt; 0.01), but the expression of p-jnk was comparable between the two groups. In the animal experiment, the rats in the model group showed significantly increased serum creatinine (SCr) and urea nitrogen (BUN) levels, 24-h urine protein (24 hUpro), plasma IS level, left ventricular mass index (LVMI) and whole heart mass index (HMI) compared with those in the sham group (P &lt; 0.01); Both LVESD and LVEDD were significantly reduced and LVAWS, LVAWD, LVPWS and LVPWD were significantly increased in the model rat, which also presented with obvious cardiomyocyte hypertrophy and increased myocardial expressions of BNP, p-ERK1/2, p-p38 and p-jnk (P &lt; 0.01). Compared with the rats in the model group, the rats treated with low-dose and high-dose Zhenwu Decoction had significantly lowered levels of SCr, BUN, 24 hUpro and IS (P &lt; 0.05) and decreased LVMI and HMI; LVESD, LVEDD, LVPWS, LVAWS, and LVAWD were improved more obviously in the high-dose group, and the myocardial expressions of BNP, p-ERK1/2, p-p38 and p-JNK was significantly downregulated after the treatment. Zhenwu Decoctin can reduce plasma IS levels and inhibit ventricular hypertrophy to delay ventricular remodeling in rats with uremic cardiomyopathy.

Limited Effect of Intravenously Administered Indoxyl Sulfate, a Uremic Toxin, on the Hepatic Transport of Pravastatin in Normal Rats

Indoxyl sulfate (IS) is a typical uremic toxin that extensively accumulates in the plasma of patients with seriously impaired renal function. This study seeks to clarify whether IS exerts a potent modulating effect on the hepatic transport of pravastatin, which is a substrate of both organic anion transporting peptides (OATPs) and multidrug resistance-associated protein (Mrp) 2 in rats. When IS is administered intravenously to the normal rats at a dose of 120 μmol/kg; plasma IS levels are approximately 600 μM after 2 min and 100 μM after 120 min. In rats with acute renal failure (ARF) induced by cisplatin, the area under the curve (AUC) was more than 2.5-fold greater compared with that in the normal rats, indicating that IS accumulates in ARF rats. Intravenously administered pravastatin almost disappeared from the plasma by 60 min post-administration and approximately 55% of dose was excreted in the bile within 60 min. This result suggested that pravastatin was efficiently taken up from the sinusoid into hepatocytes via rat OATPs on the sinusoidal membrane and preferentially transported in the bile mediated by Mrp2 on the canalicular membrane. IS administered intravenously at a dose of 120 μmol/kg caused neither an increase in plasma pravastatin levels nor a decrease in its biliary excretion. In conclusion, the present results demonstrate that single intravenous administration of IS does not interfere with the hepatic transport of pravastatin directly in vivo, which is at variance with the results of previous in vitro studies.

A Pathophysiological Role of Plasma Indoxyl Sulfate in Patients with Heart Failure

Summary Background One of uremic toxins, indoxyl sulfate (IS), is associated with cardiovascular events. This study aimed to measure the plasma IS levels in patients with and without chronic heart failure (CHF). Methods We measured plasma IS levels in 49 patients with CHF and an estimated glomerular filtration rate (eGFR) of 40–60 ml/min/1.73 m 2 from our institute. These were compared with 31 healthy subjects without CHF (a control), but with comparable eGFR levels, from our resident cohort study. We also test the effect of AST-120 (the oral adsorbent) in 16 CHF patients. Results The plasma IS levels in 49 CHF patients increased (1.38 ± 0.84 (SD) vs 0.12 ± 0.07 μg/ml (a control), p Conclusions Plasma IS levels increased in patients with CHF along with cardiac systolic dysfunction compared with those in healthy subjects, and AST-120 improved cardiac dysfunction in patients with CHF. Oral adsorbents may represent a novel treatment for CHF.

Correlations between Plasma Levels of Anionic Uremic Toxins and Clinical Parameters in Hemodialysis Patients.

When the kidney is seriously impaired, various uremic toxins (UTs) accumulate in the body, often exerting unfavorable effects on physiological functions and drug pharmacokinetics. To prevent this, it is important to determine plasma UT levels accurately in chronic kidney disease patients. Although attempts to predict plasma UT levels using biomarkers have been made, the correlation between UT levels and the markers is not yet fully understood. In this study, we assessed the correlations among plasma levels of indoxyl sulfate (IS), indoleacetic acid (IA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) in 20 hemodialysis patients and evaluated the relationship between the plasma levels of UTs and clinical parameters, such as serum creatinine (Scr), blood urea nitrogen, and estimated glomerular filtration rate (eGFR), with special focus on IS. There were no correlations among the plasma levels of the three UTs before and immediately after hemodialysis. However, a significant correlation was observed between plasma IS levels and Scr before hemodialysis (r=0.643, p=0.002), with the correlation becoming much stronger when using the data obtained immediately after hemodialysis (r=0.744, p<0.001). Further, plasma IS levels showed a significant negative correlation with eGFR (r=-0.558, p=0.011). However, no correlations were observed for IA or CMPF. The results obtained from this study suggest that plasma IS levels can be predicted from Scr values, although the precise mechanism behind the correlation remains to be clarified.

Abstract 12381: Ast-120, an Adsorbent of Uremic Toxins Normalized the Cardiac Hypertrophic/pro- Apoptotic And Cardioprotective/anti-apoptotic Signaling in Pacing-induced Heart Failure in Dogs

Background: Renal dysfunction increases the plasma levels of indoxyl sulfate (IS), a uremic toxin excreted from the kidney. Interestingly, IS is reported to directly stimulate both collagen synthesis and cardiomyocyte hypertrophy in vitro via the modulation of ERK and p38-MAPK. However, it is unclear whether the pathophysiology of heart failure (HF) changes such intracellular signaling via the IS-dependent pathways. AST-120 is known to inhibit the uptake of indole and decrease the plasma IS levels. Hypothesis: We tested the hypothesis that the removal of plasma IS by using AST-120 modulates the intracellular signaling for hypertrophy, collagen synthesis and apoptosis of the myocardium in the canine HF model in vivo. Method: A canine HF model was produced by continuous rapid ventricular pacing at 230 bpm for 6 weeks. We treated the canine with oral AST-120 (1g/kg/day) administration between 4th and 6th week following the onset of rapid pacing (HF with AST-120 group, HF without AST-120 group, n=7 in each). We also set a control (Control group, n=7) without pacing for 6 weeks. We extracted the protein from the hearts and analyzed it by Western blotting. Result: AST-120 treatment reduced both plasma IS elevated in the canine HF model. HF without AST-120 group showed the activation of ERK signaling and the deactivation of both Akt and p38-MAPK signaling compared with Control group. The treatment with AST-120 increased the phosphorylation levels of Akt and p38-MAPK, and suppressed the ERK phosphorylation. HF without AST-120 group also showed an increased expression of pro-apoptotic Bax protein, and a decreased expression of anti-apoptotic Bcl-2 protein. The increased Bcl-2/Bax ratio was significantly ameliorated by AST-120 treatment. Conclusion: The decreases in plasma levels of indoxyl sulfate by the treatment with AST-120 1) deactivates the cardiac hypertrophic signaling, 2) activates the cardiac survival and anti-apoptotic signals and 3) suppresses the pro-apoptotic signals in failing heart in vivo. Indoxyl sulfate may become a sensitive and novel biomarker/mediator of heart failure explaining the cardio-renal syndrome that links renal dysfunction to heart failure.

AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress.

Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 ± 0.11 versus 0.21 ± 0.03 mg/dL, P <0.05), which was significantly ameliorated in CKD + AST-120 (0.41 ± 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 ± 17 versus 427 ± 36 m, P <0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 ± 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P)H oxidase activity. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD.

Abstract 17220: Effects of the Oral Adsorbent of AST-120 in Patients with both Chronic Heart Failure and Chronic Kidney Disease

Background: One of uremic toxins, indoxyl sulfate (IS) is related to the progression of chronic kidney disease (CKD) and the worse cardiovascular outcomes. We have previously reported the relationship between IS levels and the severity of chronic heart failure (CHF), but the question arises as to whether the treatment of uremic toxin is beneficial in patients with CHF. This study aimed to elucidate whether the treatment with the oral adsorbent which reduces uremic toxin improved the cardiac function of the patients with CHF. Methods: First of all, we retrospectively enrolled 49 patients with both CHF and stage ≤3 CKD in our institute compared with the healthy subjects without CHF or CKD in the resident cohort study of Arita. Secondly, we retrospectively enrolled 16 CHF outpatients with stage 3-5 CKD. They were treated with and without the oral adsorbent of AST-120 for one year termed as the treatment and control groups, respectively. We underwent both blood test and echocardiography before and after the treatment. Results: First of all, among 49 patients in CHF patients, plasma IS levels increased to 1.38 ± 0.84 μg/ml from the value of 0.08 ± 0.06 μg/ml in Arita-cho as a community-living matched with gender and eGFR of CHF patients. We found both fractional shortening (FS) and E/e’, an index of diastolic function were decreased (25.0 ± 12.7%) and increased (13.7 ± 7.5), respectively in CHF patients compared with the value of FS and E/e’ in Arita-cho (FS: 41.8 ± 8.3%, E/e’: 8.8 ± 2.1). Secondly, in the treatment group, the plasma IS levels and the serum creatinine and brain natriuretic peptide levels decreased (1.40 ± 0.17 to 0.92 ± 0.15 μg/ml; p&lt;0.05, 1.91 ± 0.16 to 1.67 ± 0.12 mg/dl; p&lt;0.05, 352 ± 57 to 244 ± 49 pg/ml; p&lt;0.05, respectively) and both FS and E/e’ were improved following the treatment with AST-120 (28.8 ± 2.8 to 32.9 ± 2.6%; p&lt;0.05, 18.0 ± 2.0 to 11.8 ± 1.0; p&lt;0.05). However, these parameters did not change in the control group. Conclusions: The treatment to decrease the blood levels of uremic toxins improved not only renal dysfunction but cardiac systolic and diastolic dysfunction in patients with chronic heart failure. Oral adsorbents might be a new treatment of heart failure especially with diastolic dysfunction.

Association between plasma indoxyl sulfate levels and cardiac hypertrophy in patients with heart failure

Purpose: Although indoxyl sulfate (IS), one of a uremic toxin, is suggested be a novel prognostic marker in patients with chronic kidney disease, its clinical characteristics has remained uncertain in patients with heart failure (HF) and preserved renal function (RF). We aimed to determine the clinical characteristics of IS in patients with HF. Methods: We studied 726 participants without overt HF and renal disease from a community-living, and prospectively enrolled 154 consecutive hospitalized acute and chronic heart failure (CHF) patients with preserved RF (eGFR >40 ml/min/1.73 m2) (24 acute HF patients and 130 CHF patients, respectively). We also performed right heart catheterization (RHC) in CHF patients (n = 105). Results: The plasma IS (PIS) levels in patients with CHF were significantly higher than that of healthy population matched with gender and eGFR of HF patients (0.79 [25th to 75th IQR: 0.45-1.19] μg/ml vs. 0.07 [0.04-0.11] μg/ml, respectively, p<0.001) (Figure A.), PIS levels were significantly correlated with right atrial pressure (r = 0.19, p = 0.028) and cardiac output (r = -0.30, p<0.001) in RHC study. Echocardiography revealed that LV mass index in High IS group (≥0.79 μg/ml) was significantly higher than that of Low IS group (<0.79 μg/ml) (Figure B.) in CHF patients. Interestingly, of 24 acute HF patients, PIS levels at discharge were significantly elevated compared with the baseline, as preliminary data (0.67 [0.36-0.90] μg/ml to 0.94 [0.76-1.68] μg/ml, p = 0.005) (Figure C). ![Figure][1] Figure 1 Conclusions: The plasma IS levels were suggested to be related to renal perfusion pressure with the prevalence of cardiac hypertrophy. From the change of IS levels during HF hospitalization, IS might be a novel marker to predict remote renal and cardiac status in patients with heart failure. [1]: pending:yes

Relation of Plasma Indoxyl Sulfate Levels and Estimated Glomerular Filtration Rate to Left Ventricular Diastolic Dysfunction

The prognosis of patients with diastolic heart failure (HF) is as poor as that of patients with systolic HF. Greater chronic kidney disease-associated mortality occurs in patients with left ventricular (LV) diastolic HF than in those with systolic HF. Indoxyl sulfate (IS), a uremic toxin, directly affects cardiac cells adversely in in vitro experiments. We investigated the association of IS, a uremic toxin, and chronic kidney disease with LV diastolic dysfunction in the clinical setting. The present study included 204 consecutive patients with preserved LV systolic function. To evaluate LV function, all patients underwent echocardiography. To measure the plasma IS levels and estimated glomerular filtration rate (eGFR), blood samples were obtained. Of the 204 patients, 75 (37%) had LV diastolic dysfunction. A significantly lower prevalence of LV diastolic dysfunction was present in patients with lower plasma IS levels (≤1.0 μg/ml) than those with greater plasma IS levels (38 [29%] vs 37 [51%], p <0.001). Furthermore, a significantly lower prevalence of LV diastolic dysfunction was present in patients with lower plasma IS levels and preserved eGFR than those with greater plasma IS levels and preserved eGFR, those with lower plasma IS levels and a reduced eGFR, or those with greater plasma IS levels and reduced eGFR (20 [21%] vs 18 [53%], p = 0.001; 20 [21%] vs 18 [46%], p = 0.004; and 20 [21%] vs 19 [56%], p <0.001, respectively). In conclusion, greater plasma IS levels or a reduced eGFR, or both, represent an increased risk of LV diastolic dysfunction.