RESUMO
An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis in uremic patients, yet its dysfunction poses a significant clinical challenge. Venous stenosis, primarily caused by venous neointimal hyperplasia, is a key factor in the failure of vascular access. During vascular access dysfunction, endothelial cells (ECs) transform mechanical stimuli into intracellular signals and interact with vascular smooth muscle cells. Tanshinone IIA, an important compound derived from Salvia miltiorrhiza, has been widely used to treat cardiovascular diseases. However, its role in modulating ECs under uremic conditions remains incompletely understood. In this research, ECs were exposed to sodium tanshinone IIA sulfonate (STS) and subjected to shear stress and uremic conditions. The results indicate that STS can reduce the suppressive effects on the expression of NF-κB p65, JNK and Collagen I in uremia-induced ECs. Moreover, the downregulation of NF-κB p65, JNK and Collagen I can be enhanced through the inhibition of ERK1/2 and the upregulation of Caveolin-1. These findings suggest that tanshinone IIA may improve EC function under uremic conditions by targeting the Caveolin-1/ERK1/2 pathway, presenting tanshinone IIA as a potential therapeutic agent against AVF immaturity caused by EC dysfunction.
Assuntos
Abietanos , Caveolina 1 , Uremia , Uremia/metabolismo , Uremia/tratamento farmacológico , Uremia/patologia , Humanos , Abietanos/farmacologia , Abietanos/uso terapêutico , Caveolina 1/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Fator de Transcrição RelA/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , FenantrenosRESUMO
BACKGROUND & AIMS: Turmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. METHODS: This longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500 mg of Curcuma longa extract, with 98.42 % total curcuminoids) or placebo (three capsules of 500 mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: Twenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. CONCLUSION: Curcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT04413266.
Assuntos
Curcumina , Diálise Peritoneal , Insuficiência Renal Crônica , Uremia , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Leucócitos Mononucleares/metabolismo , Método Simples-Cego , Inflamação , Estresse Oxidativo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Diarileptanoides/farmacologia , Diarileptanoides/uso terapêutico , Suplementos Nutricionais , Uremia/tratamento farmacológicoRESUMO
INTRODUCTION: Chronic kidney disease (CKD) is a global health problem with increasing incidence which is closely associated with cardiac dysfunction. In CKD, uremic toxins accumulate as kidney function declines. Additionally, high salt intake is a growing health issue worldwide which can exacerbate kidney disease. In this study, we investigated the effect of reducing plasma levels of protein-bound uremic toxins in a rat model of CKD, challenged with high salt intake and compared the effects to those of conventional treatment using an angiotensin-converting enzyme inhibitor (ACEI). METHODS: In rats, the right kidney and 2/3 of the left kidney were surgically removed (5/6 nephrectomy). Animals were fed a normal-salt diet and randomized to either no treatment (control) or chronic treatment with either the oral absorbent AST-120 to reduce plasma levels of protein-bound uremic toxins or the ACEI enalapril to inhibit angiotensin II signaling for 5 weeks. Following treatment, kidney function was measured before and after a week of high salt intake. Cardiac output and markers of oxidative stress were measured at the end of the study period. RESULTS: Treatment with AST-120 resulted in decreased levels of the uremic toxin indoxyl sulfate, improved cardiac output (mL/min: AST-120 44.9 ± 5.4 compared to control 26.6 ± 2.0; p < 0.05), and decreased urinary oxidative stress. ACEI reduced oxidative stress in kidney tissue and improved the glomerular filtration rate in response to high salt intake (mL/min: ACEI 1.5 ± 0.1; compared to control 1.1 ± 0.1; p < 0.05). Both interventions improved intrarenal oxygen availability (mm Hg: AST-120 42.8 ± 0.8; ACEI 43.2 ± 1.9; compared to control 33.4 ± 1.3; p < 0.05). CONCLUSION: AST-120 administered to reduce plasma levels of uremic toxins, such as indoxyl sulfate, has potential beneficial effects on both cardiac and kidney function. Targeting uremic toxins and angiotensin II signaling simultaneously could be an efficient strategy to target both cardiac and kidney dysfunction in CKD, to further slow progression of disease in patients with CKD.
Assuntos
Insuficiência Renal Crônica , Uremia , Animais , Ratos , Angiotensina II , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Débito Cardíaco , Indicã/farmacologia , Rim , Insuficiência Renal Crônica/tratamento farmacológico , Cloreto de Sódio na Dieta , Uremia/tratamento farmacológico , Toxinas UrêmicasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Cardiorenal syndrome type 4 (CRS type 4), with high rates of morbidity and mortality, has become a social and economic problem worldwide over the last few decades. Zhen-Wu decoction, a traditional medicine used in East Asia, has been widely used in the treatment of cardiovascular disease and kidney disease, and has shown potential therapeutic effects for the clinical treatment of CRS type 4. However, the underlying mechanism has not been extensively explored. AIM OF THE STUDY: The purpose of this study was to investigate the effect and underlying mechanism of Zhen-Wu decoction on uremic cardiomyopathy, offering a potential target for clinical treatment of CRS type 4. MATERIALS AND METHODS: Five/six nephrectomized mice were utilized for experiments in vivo. The cardioprotective effects of Zhen-Wu decoction were evaluated by echocardiography and tissue staining. RNA-Seq data were used to investigate the potential pharmacological mechanism. The prediction of targets and active components was based on our previous strategy. Subsequently, the protective effect of the selected compound was verified in experiments in vitro. RESULTS: Zhen-Wu decoction alleviated cardiac dysfunction and endothelial injury in 5/6 nephrectomized mice, and the mechanism may involve the inflammatory process and oxidative stress. The activation of the Nrf2 signaling pathway was predicted to be a potential target of Zhen-Wu decoction in protecting endothelial cells. Through our machine learning strategy, we found that lactiflorin as an ingredient in Zhen-Wu decoction, alleviates IS-induced endothelial cell injury by blocking Keap1 and activating Nrf2. CONCLUSIONS: The present study demonstrated that Zhen-Wu decoction and lactiflorin could protect endothelial cells against oxidative stress in mice after nephrectomy by activating the Nrf2 signaling pathway.
Assuntos
Medicamentos de Ervas Chinesas , Uremia , Animais , Simulação por Computador , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Células Endoteliais/metabolismo , Glicosídeos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Monoterpenos , Fator 2 Relacionado a NF-E2/metabolismo , Uremia/tratamento farmacológicoRESUMO
INTRODUCTION: Uremia could accelerate atherosclerosis (AS) formation involving Treg/Th17 imbalance. Losartan regulates the imbalance between regulatory T cells (Treg cells) and T helper 17 cells (Th17 cells). However, their interactions in uremia accelerated AS (UAAS) remained poorly understood. METHODS: UAAS mice model was established, and after losartan and VO-OHpic (VO, phosphatase and tensin homolog [PTEN] inhibitor) injection, biological indexes, and inflammatory cytokines (transforming growth factor-ß1, TGF-ß1; interleukin-10 [IL-10]; IL-17 and IL-6) levels were determined using enzyme-linked immunosorbent assay. Pathological changes on aorta were observed using hematoxylin-eosin staining. Percentages of Treg cells (CD4+CD25+Foxp3+) and Th17 cells (CD4+IL-17+) in total CD4+ T cells were determined using flow cytometry. PTEN expressions were measured using Western blot, quantitative real-time polymerase chain reaction, and immunohistochemistry staining as needed. RESULTS: After UAAS mice model construction, biological indexes (urea, cholesterol, and triglycerides) levels were increased, and aortic atherosclerotic plaque was formed. In UAAS mice, in total CD4+ T cells, Treg cells percentage was decreased yet Th17 cells percentage was increased, and TGF-ß1 and IL-10 levels were downregulated yet IL-17 and IL-6 levels were upregulated. An opposite effect was found after losartan treatment. PTEN was downregulated in UAAS mice, and suppressing PTEN reversed the alleviating effects of losartan in UAAS mice. CONCLUSION: Losartan attenuated UAAS in mice by regulating Treg/Th17 cells balance via mediating PTEN/PI3K/Akt pathway, providing possible therapeutic method for UAAS in clinical practice.
Assuntos
Aterosclerose , Uremia , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Modelos Animais de Doenças , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Interleucina-6/metabolismo , Losartan/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T Reguladores , Células Th17/metabolismo , Células Th17/patologia , Fator de Crescimento Transformador beta1/metabolismo , Uremia/tratamento farmacológico , Uremia/metabolismoRESUMO
Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.
Assuntos
Lesões Encefálicas , Encéfalo , Ácidos Graxos Ômega-3/farmacologia , Transdução de Sinais/efeitos dos fármacos , Uremia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Linhagem Celular , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Uremia/tratamento farmacológico , Uremia/metabolismo , Uremia/patologiaRESUMO
Uremic pruritus is a distressful complication of chronic kidney disease and results in impaired quality of life and higher mortality rates. Intravenous sodium thiosulfate has been reported to alleviate pruritus in hemodialysis patients. We performed a systematic review and meta-analysis to estimate the efficacy of intravenous sodium thiosulfate in patients with uremic pruritus. A systematic search of electronic databases up to June 2021 was conducted for randomized controlled trials that evaluated the clinical effects of sodium thiosulfate in the management of patients with uremic pruritus. Two reviewers selected eligible articles and evaluated the risk of bias; the results of pruritus assessment and uremic pruritus-related laboratory parameters in selected studies were analyzed. There are four trials published between 2018 and 2021, which include 222 participants. The sodium thiosulfate group displayed significant decrease in the pruritus score (standardized mean difference = -3.52, 95% confidence interval = -5.63 to -1.41, p = 0.001), without a significant increase in the adverse effects (risk ratio = 2.44, 95% confidence interval = 0.37 to 15.99, p = 0.35) compared to the control group. Administration of sodium thiosulfate is found to be a safe and efficacious complementary therapy in improving uremic pruritus in patients with chronic kidney disease.
Assuntos
Antioxidantes/efeitos adversos , Prurido/tratamento farmacológico , Tiossulfatos/efeitos adversos , Uremia/tratamento farmacológico , Vasodilatadores/efeitos adversos , Antioxidantes/farmacologia , Humanos , Prurido/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiossulfatos/farmacologia , Uremia/complicações , Vasodilatadores/farmacologiaRESUMO
Medial vascular calcification has emerged as a key factor contributing to cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular smooth muscle cells (VSMCs) with osteogenic transdifferentiation play a role in vascular calcification. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors reduce reactive oxygen species (ROS) production and calcified-medium-induced calcification of VSMCs. This study investigates the effects of dextromethorphan (DXM), an NADPH oxidase inhibitor, on vascular calcification. We used in vitro and in vivo studies to evaluate the effect of DXM on artery changes in the presence of hyperphosphatemia. The anti-vascular calcification effect of DXM was tested in adenine-fed Wistar rats. High-phosphate medium induced ROS production and calcification of VSMCs. DXM significantly attenuated the increase in ROS production, the decrease in ATP, and mitochondria membrane potential during the calcified-medium-induced VSMC calcification process (p < 0.05). The protective effect of DXM in calcified-medium-induced VSMC calcification was not further increased by NADPH oxidase inhibitors, indicating that NADPH oxidase mediates the effect of DXM. Furthermore, DXM decreased aortic calcification in Wistar rats with CKD. Our results suggest that treatment with DXM can attenuate vascular oxidative stress and ameliorate vascular calcification.
Assuntos
Dextrometorfano/farmacologia , Músculo Liso Vascular , Miócitos de Músculo Liso , Estresse Oxidativo/efeitos dos fármacos , Uremia , Calcificação Vascular , Animais , Linhagem Celular , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Ratos , Ratos Endogâmicos WKY , Uremia/tratamento farmacológico , Uremia/metabolismo , Uremia/patologia , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/metabolismo , Calcificação Vascular/patologiaRESUMO
Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (ß3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the ß3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, ß3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the ß3-AR.
Assuntos
Acetanilidas/farmacologia , Cardiomiopatias/tratamento farmacológico , Losartan/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Insuficiência Renal Crônica/complicações , Tiazóis/farmacologia , Uremia/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Masculino , Nefrectomia/efeitos adversos , Óxido Nítrico Sintase Tipo III/genética , Ratos , Ratos Wistar , Uremia/etiologia , Uremia/metabolismo , Uremia/patologiaRESUMO
Chronic kidney disease (CKD) is characterized by the retention of a myriad of solutes termed uraemic (or uremic) toxins, which inflict damage to several organs, including the cardiovascular system. Uraemic toxins can induce hallmarks of cardiovascular disease (CVD), such as atherothrombosis, heart failure, dysrhythmias, vessel calcification and dysregulated angiogenesis. CVD is an important driver of mortality in patients with CKD; however, reliance on conventional approaches to managing CVD risk is insufficient in these patients, underscoring a need to target risk factors that are specific to CKD. Mounting evidence suggests that targeting uraemic toxins and/or pathways induced by uraemic toxins, including tryptophan metabolites and trimethylamine N-oxide (TMAO), can lower the risk of CVD in patients with CKD. Although tangible therapies resulting from our growing knowledge of uraemic toxicity are yet to materialize, a number of pharmacological and non-pharmacological approaches have the potential to abrogate the effects of uraemic toxins, for example, by decreasing the production of uraemic toxins, by modifying metabolic pathways induced by uraemic toxins such as those controlled by aryl hydrocarbon receptor signalling and by augmenting the clearance of uraemic toxins.
Assuntos
Doenças Cardiovasculares/etiologia , Insuficiência Renal Crônica/complicações , Uremia/complicações , Animais , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , Humanos , Uremia/tratamento farmacológico , Uremia/prevenção & controleRESUMO
Chronic kidney disease (CKD) is associated with a high incidence of fractures. However, the pathophysiology of this disease is not fully understood, and limited therapeutic interventions are available. This study aimed to determine the impact of type 1 angiotensin II receptor blockade (AT-1RB) on preventing CKD-related fragility fractures and elucidate its pharmacological mechanisms. AT-1RB use was associated with a lower risk of hospitalization due to fractures in 3276 patients undergoing maintenance hemodialysis. In nephrectomized rats, administration of olmesartan suppressed osteocyte apoptosis, skeletal pentosidine accumulation, and apatite disorientation, and partially inhibited the progression of the bone elastic mechanical properties, while the bone mass was unchanged. Olmesartan suppressed angiotensin II-dependent oxidation stress and apoptosis in primary cultured osteocytes in vitro. In conclusion, angiotensin II-dependent intraskeletal oxidation stress deteriorated the bone elastic mechanical properties by promoting osteocyte apoptosis and pentosidine accumulation. Thus, AT-1RB contributes to the underlying pathogenesis of abnormal bone quality in the setting of CKD, possibly by oxidative stress. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Insuficiência Renal Crônica , Uremia , Animais , Densidade Óssea , Osso e Ossos , Humanos , Ratos , Receptores de Angiotensina , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Uremia/complicações , Uremia/tratamento farmacológicoAssuntos
Hepatite C Crônica , Transplante de Fígado , Uremia , Adulto , Ácidos Aminoisobutíricos , Antivirais/uso terapêutico , Benzimidazóis , Ciclopropanos , Combinação de Medicamentos , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Doadores Vivos , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas , Sulfonamidas , Tacrolimo/efeitos adversos , Uremia/tratamento farmacológicoRESUMO
Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The "gastrointestinal decontamination" through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.
Assuntos
Descontaminação/métodos , Trato Gastrointestinal/metabolismo , Insuficiência Renal Crônica/metabolismo , Toxinas Biológicas/toxicidade , Uremia/metabolismo , Calcificação Vascular/metabolismo , Ensaios Clínicos como Assunto/métodos , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiopatologia , Humanos , Indicã/farmacologia , Indicã/uso terapêutico , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Uremia/tratamento farmacológico , Uremia/fisiopatologia , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/fisiopatologiaRESUMO
Gabapentin and doxepin are well-known treatments of uremic pruritus in hemodialysis patients but no head-to-head studies were conducted to date. The aim of this trial is to compare the efficacy and the tolerability of gabapentin and doxepin in the treatment of uremic pruritus in hemodialysis patients. A single-blind crossover randomized trial was conducted that included hemodialysis patients with uremic pruritus. Patients were randomized to receive 10 mg doxepin daily or 100 mg gabapentin for 4 weeks and the two groups were treated conversely for another 4 weeks after a 4-week washout period. Eighty-five patients were screened for eligibility. Thirty-one met the inclusion criteria and four were excluded. Sixteen patients agreed and signed the consent and two withdrew from the study. VAS scores at baseline were 6.71 and 6.14, and dropped to 0.57 and 2.35 at week 4 in the gabapentin and doxepin groups, respectively. Mean scores of the 5-Domain Itch Scale (5-D) at baseline were 14.71 and 14.64, and dropped to 5.78 and 7.57 at week 4 in the gabapentin and doxepin groups, respectively. Mean scores of the Dermatology Life Quality Index (DLQI) at baseline were 9.6429 and 8.7857, and dropped to 0.71 and 3.35 at week 4 in the gabapentin and doxepin groups, respectively. Reductions in Visual Analog Scale (VAS), 5-D and DLQI were statistically significant (P < .05). No serious side effects were recorded. Limitations of this study include single-blind design, small number of included cases and lack of placebo control. Gabapentin was more effective than doxepin in decreasing uremic pruritus severity and improving quality of life of these patients.
Assuntos
Doxepina/uso terapêutico , Gabapentina/uso terapêutico , Uremia , Método Duplo-Cego , Doxepina/efeitos adversos , Gabapentina/efeitos adversos , Antagonistas dos Receptores Histamínicos , Humanos , Prurido/diagnóstico , Prurido/tratamento farmacológico , Prurido/etiologia , Qualidade de Vida , Método Simples-Cego , Uremia/complicações , Uremia/diagnóstico , Uremia/tratamento farmacológicoRESUMO
In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake. We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equipped with OAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay. We show that selected ARBs and furosemide significantly reduced fluorescein uptake, with the highest potency for ARBs. This was exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function.
Assuntos
Túbulos Renais/efeitos dos fármacos , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Medicamentos sob Prescrição/farmacologia , Eliminação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Toxinas Biológicas/sangue , Uremia/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Linhagem Celular , Furosemida/farmacologia , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Medicamentos sob Prescrição/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Uremia/sangue , Uremia/fisiopatologiaRESUMO
The nephrotoxicity of aristolochic acids (AAs), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were well-documented, culminating in tubulointerstitial fibrosis (TIF), advanced chronic kidney disease (CKD) and fatal urothelial cancer. Nonetheless, information regarding the attenuation of AAs-induced nephropathy (AAN) and uremic toxin retention is scarce. Propolis is a versatile natural product, exerting anti-oxidant, anti-cancer and anti-fibrotic properties. We aimed to evaluate nephroprotective effects of propolis extract (PE) in a murine model. AAN was developed to retain circulating PCS and IS using C57BL/6 mice, mimicking human CKD. The kidney sizes/masses, renal function indicators, plasma concentrations of PCS/IS, tissue expressions of TIF, α-SMA, collagen IaI, collagen IV and signaling pathways in transforming growth factor-ß (TGF-ß) family were analyzed among the control, PE, AAN, and AAN-PE groups. PE ameliorated AAN-induced renal atrophy, renal function deterioration, TIF, plasma retention of PCS and IS. PE also suppressed α-SMA expression and deposition of collagen IaI and IV in the fibrotic epithelial-mesenchymal transition. Notably, PE treatment in AAN model inhibited not only SMAD 2/3-dependent pathways but also SMAD-independent JNK/ERK activation in the signaling cascades of TGF-ß family. Through disrupting fibrotic epithelial-mesenchymal transition and TGF-ß signaling transduction pathways, PE improves TIF and thereby facilitates renal excretion of PCS and IS in AAN. In light of multi-faced toxicity of AAs, PE may be capable of developing a new potential drug to treat CKD patients exposed to AAs.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Túbulos Renais/efeitos dos fármacos , Própole/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Uremia/tratamento farmacológico , Animais , Ácidos Aristolóquicos , Cresóis/sangue , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Indicã/sangue , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Ésteres do Ácido Sulfúrico/sangue , Fator de Crescimento Transformador beta/metabolismo , Uremia/induzido quimicamente , Uremia/metabolismo , Uremia/patologiaRESUMO
Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.
Assuntos
Bactérias/efeitos dos fármacos , Toxinas Bacterianas/sangue , Quelantes/efeitos adversos , Colo/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Falência Renal Crônica/tratamento farmacológico , Sevelamer/efeitos adversos , Uremia/tratamento farmacológico , Deficiência de Vitamina K/induzido quimicamente , Adulto , Idoso , Bactérias/metabolismo , Biomarcadores/sangue , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/microbiologia , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Fatores de Risco , Resultado do Tratamento , Uremia/sangue , Uremia/microbiologia , Deficiência de Vitamina K/sangueRESUMO
Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor-23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor-23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end-stage renal disease.
Assuntos
Síndrome Cardiorrenal/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Glucuronidase/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Uremia/tratamento farmacológico , Animais , Síndrome Cardiorrenal/sangue , Síndrome Cardiorrenal/mortalidade , Síndrome Cardiorrenal/fisiopatologia , Cardiomiopatias/sangue , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/sangue , Humanos , Proteínas Klotho , Terapia de Alvo Molecular , Prognóstico , Proteínas Recombinantes/uso terapêutico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Uremia/sangue , Uremia/mortalidade , Uremia/fisiopatologiaRESUMO
Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.
Assuntos
Fosfatos de Inositol/química , Fosfatos de Inositol/farmacologia , Calcificação Vascular/tratamento farmacológico , 6-Fitase/metabolismo , Adenina/efeitos adversos , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Difusão Dinâmica da Luz , Etilenoglicol/química , Humanos , Injeções Subcutâneas , Fosfatos de Inositol/farmacocinética , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Ratos Sprague-Dawley , Uremia/tratamento farmacológico , Uremia/fisiopatologia , Calcificação Vascular/induzido quimicamente , Difração de Raios XRESUMO
In recent years, Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions, including cardiac hypertrophy and uremic cardiomyopathy. Cardiotonic steroids (CTS), specific ligands of Na/K-ATPase, regulate its enzymatic activity (at higher concentrations) and signaling function (at lower concentrations without significantly affecting its enzymatic activity) and increase reactive oxygen species (ROS) generation. On the other hand, an increase in ROS alone also regulates the Na/K-ATPase enzymatic activity and signaling function. We termed this phenomenon the Na/K-ATPase-mediated oxidant-amplification loop, in which oxidative stress regulates both the Na/K-ATPase activity and signaling. Most recently, we also demonstrated that this amplification loop is involved in the development of uremic cardiomyopathy. This review aims to evaluate the redox-sensitive Na/K-ATPase-mediated oxidant amplification loop and uremic cardiomyopathy.