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<0.05, 1.91 ± 0.16 to 1.67 ± 0.12 mg/dl; p<0.05, 352 ± 57 to 244 ± 49 pg/ml; p<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<0.05, 18.0 ± 2.0 to 11.8 ± 1.0; p<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.

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Faculty Opinions recommendation of A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726323261.793520125 ◽

2016 ◽

Author(s):

Luis Ruilope ◽

Enrique Morales

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Chronic Kidney Disease ◽

Chronic Heart Failure ◽

Kidney Disease ◽

Randomized Controlled Study ◽

Controlled Study ◽

Randomized Controlled

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Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

International Journal of Molecular Sciences ◽

10.3390/ijms22126270 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6270

Author(s):

Chia-Ter Chao ◽

Shih-Hua Lin

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Uremic Toxins ◽

Heme Oxygenase 1 ◽

Signal Pathways ◽

Uremic Toxin ◽

Nuclear Factor ◽

Cognitive Frailty ◽

Renal Function Decline

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

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Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): a randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease

European Journal of Heart Failure ◽

10.1002/ejhf.218 ◽

2015 ◽

Vol 17 (2) ◽

pp. 224-232 ◽

Cited By ~ 54

Author(s):

Bertram Pitt ◽

Stefan D. Anker ◽

Michael Böhm ◽

Mihai Gheorghiade ◽

Lars Køber ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Chronic Heart Failure ◽

Kidney Disease ◽

Receptor Antagonist ◽

Mineralocorticoid Receptor ◽

Randomized Study ◽

Mineralocorticoid Receptor Antagonist

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P4735Xanthine oxidase activation in chronic heart failure patients with concomitant chronic kidney disease

European Heart Journal ◽

10.1093/eurheartj/ehy563.p4735 ◽

2018 ◽

Vol 39 (suppl_1) ◽

Author(s):

M Kolomiiets ◽

A Bilchenko

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Chronic Heart Failure ◽

Kidney Disease ◽

Heart Failure Patients

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MO448MICRORNAS IMPLICATED IN CHRONIC KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab090.0010 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Laurent Metzinger

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Clinical Outcomes ◽

Molecular Mechanisms ◽

Neointimal Hyperplasia ◽

Uremic Toxins ◽

University Hospital ◽

Transcriptional Level ◽

Uremic Toxin ◽

Ckd Stage

Abstract Background and Aims The gene program is controlled at the post-transcriptional level by the action of small non-coding RNAs known as microRNAs (miRNAs), short, single-stranded molecules that control mRNA stability or translational repression via base pairing with regions in the 3' untranslated region of their target mRNAs. Recently, considerable progress has been made to elucidate the roles of miRNAs in vascular pathogenesis and develop the use of miRNAs as biomarkers, and innovative drugs. We demonstrated during the last decade that miRNAs miR-126 and miR-223 are implicated in the course of chronic kidney disease (CKD) and cardiovascular damage. miR-223 expression is enhanced in vascular smooth muscle cells (VSMCs) subjected to an uremic toxin and also in aortas of a murine model of CKD. As restenosis is a common complication of angioplasty, in which neointimal hyperplasia results from migration of VSMCs into the vessel lumen we measured the effect of miR-223 modulation on restenosis in a rat model of carotid artery after balloon injury. We over-expressed and inhibited miR-223 expression using adenoviral vectors, coding a pre-miR-223 sequence or a sponge sequence, used to trap endogenous microRNA, respectively. We demonstrated that inhibiting miR-223 function significantly reduced neointimal hyperplasia by almost half in carotids. Thus down-regulating miR-223 could be a potential therapeutic approach to prevent restenosis after angioplasty. We also correlated miR-126 and miR-223 expression with clinical outcomes in a large cohort of CKD patients, in collaboration with the University Hospital of Ghent (Belgium) and Ambroise Paré Hospital, France. We evaluated both miRNA’s link with all-cause mortality and cardiovascular and renal events over a 6-year follow-up period. The serum levels of miR-126 and miR-223 were decreased as CKD stage advanced, and patients with higher levels of miR-126 and miR-223 had a higher survival rate. Similar results were observed for cardiovascular and renal events. In conclusion, CKD is associated with a decrease in circulating miR-126 and miR-223 levels in CKD patients. We will also present links between several uremic toxin concentrations and miRNA concentration in the patients of this cohort. Finally, anemia is a common feature of CKD that is associated with cardiovascular disease and poor clinical outcomes. A mixture of uremic toxins accumulates in the blood of CKD patients during the course of the disease, and there is good evidence that they modulate erythropoiesis, explaining at least partly anemia. The exact molecular mechanisms implicated are however poorly understood, although recent progresses have been made to identify key components in the CKD process. We will present results on the effect of uremic toxins on erythropoiesis, having an impact on cell metabolism during this process. Taken together, our findings could be of interest to both researchers and clinicians working in the field since they might shed new light on the molecular mechanisms involved in the CKD process. MicroRNAs implicated in Chronic Kidney Disease Pr. Laurent Metzinger, UR-UPJV 4666 HEMATIM, CURS, Université de Picardie Jules Verne, CHU Amiens Sud, Avenue René Laënnec, Salouel, F-80054, Amiens, France. Tel: (+33) 22 82 53 56, Email: [email protected]

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