FP369ACF-TEI, a novel uremic toxin absorbent, has superior adsorption profiles and suppresses renal tubular injury induced by uremic toxins

In patients with chronic kidney disease (CKD), adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds with intrinsic biological activities, many of which are too large to be filtered and/or are protein bound. The renal excretion of protein-bound toxins depends largely on active tubular secretion, which shifts the binding and allows for active secretion of the free fraction. To facilitate this process, renal proximal tubule cells are equipped with a range of transporters that co-operate in basolateral uptake and luminal excretion. Many of these transporters have been characterized as mediators of drug disposition, but have recently been recognized for their importance in the proximal renal tubular transport of uremic toxins as well. This also indicates that during uremia, drug disposition may be severely affected as a result of drug–uremic toxin interaction. In addition, CKD patients receive various drugs to treat their complications potentially resulting in drug–drug interactions (DDIs), also for drugs that are non-renally excreted. This review discusses the current knowledge on formation, disposition and removal of protein-bound uremic toxins. Furthermore, implications associated with drug treatment in kidney failure, as well as innovative renal replacement therapies targetting the protein-bound uremic toxins are being discussed. It will become clear that the complex problems associated with uremia warrant a transdisciplinary approach that unites research experts in the area of fundamental biomedical research with their colleagues in clinical nephrology.

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470-P: SIK2 Protects against Renal Tubular Injury by Inhibiting Endoplasmic Reticulum Stress

Diabetes ◽

10.2337/db20-470-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 470-P

Author(s):

XIAOYU LIAO ◽

BINGYAO LIU ◽

HONGTING ZHENG

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Tubular Injury ◽

Renal Tubular

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Aristolochic acid induces renal tubular injury and inhibits expression of bone morphogenetic protein-7 mRNA in renal tissue of rats

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20080514 ◽

2008 ◽

Vol 6 (5) ◽

pp. 502-507 ◽

Cited By ~ 2

Author(s):

HL Wang

Keyword(s):

Bone Morphogenetic Protein ◽

Aristolochic Acid ◽

Renal Tissue ◽

Tubular Injury ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein ◽

Renal Tubular

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Sitagliptin Ameliorates Renal Tubular Injury in Diabetic Kidney Disease via STAT3-Dependent Mitochondrial Homeostasis Through SDF-1α/CXCR4 Pathway

SSRN Electronic Journal ◽

10.2139/ssrn.3495589 ◽

2019 ◽

Author(s):

Qunzi Zhang ◽

Li He ◽

Feng Liu ◽

Jian Guan ◽

Yang Dong ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Tubular Injury ◽

Diabetic Kidney ◽

Mitochondrial Homeostasis ◽

Renal Tubular

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Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization

Toxins ◽

10.3390/toxins13040274 ◽

2021 ◽

Vol 13 (4) ◽

pp. 274

Author(s):

Iwona Filipska ◽

Agata Winiarska ◽

Monika Knysak ◽

Tomasz Stompór

Keyword(s):

Kidney Disease ◽

Gut Microbiota ◽

Mineral Content ◽

Uremic Toxins ◽

World Population ◽

Uremic Toxin ◽

Excess Morbidity ◽

The Media ◽

Cardio Vascular ◽

End Stage

Chronic kidney disease (CKD) affects more than 10% of the world population and leads to excess morbidity and mortality (with cardiovascular disease as a leading cause of death). Vascular calcification (VC) is a phenomenon of disseminated deposition of mineral content within the media layer of arteries preceded by phenotypic changes in vascular smooth muscle cells (VSMC) and/or accumulation of mineral content within the atherosclerotic lesions. Medial VC results in vascular stiffness and significantly contributes to increased cardio-vascular (CV) morbidity, whereas VC of plaques may rather increase their stability. Mineral and bone disorders of CKD (CKD-MBD) contribute to VC, which is further aggravated by accumulation of uremic toxins. Both CKD-MBD and uremic toxin accumulation affect not only patients with advanced CKD (glomerular filtration rate (GFR) less than 15 mL/min./1.72 m2, end-stage kidney disease) but also those on earlier stages of a disease. The key uremic toxins that contribute to VC, i.e., p-cresyl sulphate (PCS), indoxyl sulphate (IS) and trimethylamine-N-oxide (TMAO) originate from bacterial metabolism of gut microbiota. All mentioned toxins promote VC by several mechanisms, including: Transdifferentiation and apoptosis of VSMC, dysfunction of endothelial cells, oxidative stress, interaction with local renin–angiotensin–aldosterone system or miRNA profile modification. Several attractive methods of gut microbiota manipulations have been proposed in order to modify their metabolism and to limit vascular damage (and VC) triggered by uremic toxins. Unfortunately, to date no such method was demonstrated to be effective at the level of “hard” patient-oriented or even clinically relevant surrogate endpoints.

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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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A history of uremic toxicity and of the European Uremic Toxin Work Group (EUTox)

Clinical Kidney Journal ◽

10.1093/ckj/sfab011 ◽

2021 ◽

Cited By ~ 1

Author(s):

Raymond Vanholder ◽

Angel Argiles ◽

Joachim Jankowski ◽

Keyword(s):

Work Group ◽

Target Identification ◽

Kidney Injury ◽

Uremic Toxins ◽

Uremic Toxin ◽

Post Translational Modifications ◽

History Of ◽

Advanced Stages ◽

Uremic Syndrome

Abstract The uremic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease (CKD) resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uremic toxins. Here, we describe the historical evolution of the scientific knowledge about uremic toxins and the role played in this process by the European Uremic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uremic toxin goes back to the early 17th century when the existence of what later would appear to be urea was recognized. It cost about two further centuries to better define the role of urea and its link to kidney failure and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when Insights grew exponentially, coincides with the foundation and activity of EUTox. In the final section we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes, and toxin characteristics in acute kidney injury and transplantation.

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

Circulation ◽

10.1161/circ.130.suppl_2.17220 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Miki Imazu ◽

Masanori Asakura ◽

Takuya Hasegawa ◽

Hiroshi Asanuma ◽

Shin Ito ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Chronic Heart Failure ◽

Kidney Disease ◽

Diastolic Dysfunction ◽

Uremic Toxins ◽

Control Group ◽

Blood Levels ◽

Uremic Toxin ◽

Oral Adsorbent

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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An Immunohistochemical Investigation of Renal Phospholipidosis and Toxicity in Rats

International Journal of Toxicology ◽

10.1177/1091581817726040 ◽

2017 ◽

Vol 36 (5) ◽

pp. 386-394 ◽

Cited By ~ 1

Author(s):

Jing Ying Ma ◽

Sandra Snook ◽

Sheryl Garrovillo ◽

Charles Johnson ◽

David La

Keyword(s):

Electron Microscopy ◽

Membrane Protein ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Vehicle Group ◽

Tubular Injury ◽

Histamine H4 Receptor ◽

Outer Stripe ◽

H4 Receptor ◽

Renal Tubular

Immunohistochemical staining for the lysosome-associated membrane protein 2 (LAMP-2) has been proposed previously as an alternative to electron microscopy to identify hepatic phospholipidosis. This study used LAMP-2 immunohistochemistry (IHC) to diagnose phospholipidosis in rats exhibiting renal tubular injury. Rats were administered toreforant, a histamine H4 receptor antagonist by oral gavage at a dose of 3, 10, or 100 mg/kg/d for 6 months. Hematoxylin and eosin staining revealed renal tubular epithelial cell vacuolation, hypertrophy, degeneration, and luminal dilation in the 100 mg/kg/d group animals. Renal tubular injury was confirmed using kidney injury marker 1 (KIM-1) IHC. The involvement of phosopholipidosis in the renal injury was investigated by LAMP-2. Adipophilin IHC was included to differentiate phospholipidosis from lipidosis. Increased LAMP-2 staining was observed in the 100 mg/kg/d group animals when compared to vehicle group animals. Lysosome-associated membrane protein-2 staining was most prominent in the outer stripe of the outer medulla where KIM-1 staining was also most prominent. By contrast, adipophilin staining was not increased. Phospholipidosis was also confirmed by electron microscopy. These data support the use of LAMP-2 IHC as a diagnostic tool and suggest an association between phospholipidosis and the renal tubular injury caused by toreforant.

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