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1.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360574

RESUMO

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), three major gasotransmitters, are involved in pleiotropic biofunctions. Research on their roles in hypertension and kidney disease has greatly expanded recently. The developing kidney can be programmed by various adverse in utero conditions by so-called renal programming, giving rise to hypertension and kidney disease in adulthood. Accordingly, early gasotransmitter-based interventions may have therapeutic potential to revoke programming processes, subsequently preventing hypertension and kidney disease of developmental origins. In this review, we describe the current knowledge of NO, CO, and H2S implicated in pregnancy, including in physiological and pathophysiological processes, highlighting their key roles in hypertension and kidney disease. We summarize current evidence of gasotransmitter-based interventions for prevention of hypertension and kidney disease in animal models. Continued study is required to assess the interplay among the gasotransmitters NO, CO, and H2S and renal programming, as well as a greater focus on further clinical translation.


Assuntos
Gasotransmissores/uso terapêutico , Hipertensão/prevenção & controle , Nefropatias/prevenção & controle , Animais , Humanos
2.
Cochrane Database Syst Rev ; 7: CD013662, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236703

RESUMO

BACKGROUND: An abdominal aortic aneurysm (AAA) is an abnormal dilation in the diameter of the abdominal aorta of 50% or more of the normal diameter or greater than 3 cm in total. The risk of rupture increases with the diameter of the aneurysm, particularly above a diameter of approximately 5.5 cm. Perioperative and postoperative morbidity is common following elective repair in people with AAA. Prehabilitation or preoperative exercise is the process of enhancing an individual's functional capacity before surgery to improve postoperative outcomes. Studies have evaluated exercise interventions for people waiting for AAA repair, but the results of these studies are conflicting. OBJECTIVES: To assess the effects of exercise programmes on perioperative and postoperative morbidity and mortality associated with elective abdominal aortic aneurysm repair. SEARCH METHODS: We searched the Cochrane Vascular Specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Physiotherapy Evidence Database (PEDro) databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 6 July 2020. We also examined the included study reports' bibliographies to identify other relevant articles. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) examining exercise interventions compared with usual care (no exercise; participants maintained normal physical activity) for people waiting for AAA repair. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed the included studies, extracted data and resolved disagreements by discussion. We assessed the methodological quality of studies using the Cochrane risk of bias tool and collected results related to the outcomes of interest: post-AAA repair mortality; perioperative and postoperative complications; length of intensive care unit (ICU) stay; length of hospital stay; number of days on a ventilator; change in aneurysm size pre- and post-exercise; and quality of life. We used GRADE to evaluate certainty of the evidence. For dichotomous outcomes, we calculated the risk ratio (RR) with the corresponding 95% confidence interval (CI). MAIN RESULTS: This review identified four RCTs with a total of 232 participants with clinically diagnosed AAA deemed suitable for elective intervention, comparing prehabilitation exercise therapy with usual care (no exercise). The prehabilitation exercise therapy was supervised and hospital-based in three of the four included trials, and in the remaining trial the first session was supervised in hospital, but subsequent sessions were completed unsupervised in the participants' homes. The dose and schedule of the prehabilitation exercise therapy varied across the trials with three to six sessions per week and a duration of one hour per session for a period of one to six weeks. The types of exercise therapy included circuit training, moderate-intensity continuous exercise and high-intensity interval training. All trials were at a high risk of bias. The certainty of the evidence for each of our outcomes was low to very low. We downgraded the certainty of the evidence because of risk of bias and imprecision (small sample sizes). Overall, we are uncertain whether prehabilitation exercise compared to usual care (no exercise) reduces the occurrence of 30-day (or longer if reported) mortality post-AAA repair (RR 1.33, 95% CI 0.31 to 5.77; 3 trials, 192 participants; very low-certainty evidence). Compared to usual care (no exercise), prehabilitation exercise may decrease the occurrence of cardiac complications (RR 0.36, 95% CI 0.14 to 0.92; 1 trial, 124 participants; low-certainty evidence) and the occurrence of renal complications (RR 0.31, 95% CI 0.11 to 0.88; 1 trial, 124 participants; low-certainty evidence). We are uncertain whether prehabilitation exercise, compared to usual care (no exercise), decreases the occurrence of pulmonary complications (RR 0.49, 95% 0.26 to 0.92; 2 trials, 144 participants; very low-certainty evidence), decreases the need for re-intervention (RR 1.29, 95% 0.33 to 4.96; 2 trials, 144 participants; very low-certainty evidence) or decreases postoperative bleeding (RR 0.57, 95% CI 0.18 to 1.80; 1 trial, 124 participants; very low-certainty evidence). There was little or no difference between the exercise and usual care (no exercise) groups in length of ICU stay, length of hospital stay and quality of life. None of the studies reported data for the number of days on a ventilator and change in aneurysm size pre- and post-exercise outcomes. AUTHORS' CONCLUSIONS: Due to very low-certainty evidence, we are uncertain whether prehabilitation exercise therapy reduces 30-day mortality, pulmonary complications, need for re-intervention or postoperative bleeding. Prehabilitation exercise therapy might slightly reduce cardiac and renal complications compared with usual care (no exercise). More RCTs of high methodological quality, with large sample sizes and long-term follow-up, are needed. Important questions should include the type and cost-effectiveness of exercise programmes, the minimum number of sessions and programme duration needed to effect clinically important benefits, and which groups of participants and types of repair benefit most.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Cirúrgicos Eletivos , Condicionamento Físico Humano/métodos , Exercício Pré-Operatório , Aneurisma da Aorta Abdominal/mortalidade , Viés , Exercícios em Circuitos , Cardiopatias/epidemiologia , Cardiopatias/prevenção & controle , Treinamento Intervalado de Alta Intensidade , Humanos , Nefropatias/epidemiologia , Nefropatias/prevenção & controle , Pneumopatias/epidemiologia , Pneumopatias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Reoperação , Fatores de Tempo
3.
Int J Mol Sci ; 22(11)2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34204029

RESUMO

Acute kidney injury (AKI) is a global health challenge of vast proportions, as approx. 13.3% of people worldwide are affected annually. The pathophysiology of AKI is very complex, but its main causes are sepsis, ischemia, and nephrotoxicity. Nephrotoxicity is mainly associated with the use of drugs. Drug-induced AKI accounts for 19-26% of all hospitalized cases. Drug-induced nephrotoxicity develops according to one of the three mechanisms: (1) proximal tubular injury and acute tubular necrosis (ATN) (a dose-dependent mechanism), where the cause is related to apical contact with drugs or their metabolites, the transport of drugs and their metabolites from the apical surface, and the secretion of drugs from the basolateral surface into the tubular lumen; (2) tubular obstruction by crystals or casts containing drugs and their metabolites (a dose-dependent mechanism); (3) interstitial nephritis induced by drugs and their metabolites (a dose-independent mechanism). In this article, the mechanisms of the individual types of injury will be described. Specific groups of drugs will be linked to specific injuries. Additionally, the risk factors for the development of AKI and the methods for preventing and/or treating the condition will be discussed.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Nefropatias/prevenção & controle , Rim/patologia , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Nefropatias/tratamento farmacológico , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Metaboloma
4.
Toxicol Appl Pharmacol ; 425: 115601, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081941

RESUMO

Obesity is recognized as a risk for the development of chronic kidney disease. Excessive fat accumulation in obesity is associated with the overproduction of reactive oxygen species with the underproduction of antioxidant mechanisms generating oxidative stress together with chronic low-grade inflammation which subsequently leads to the development of several obesity-related complications. It has been suggested that the abnormal lipid accumulation can induce endoplasmic reticulum (ER) stress and cellular apoptosis in several tissue types. Agomelatine is a relatively new antidepressant which is a synthetic agonist of melatonin. Previous study reported the antioxidant and anti-inflammatory effects of agomelatine. In this study, we investigated the therapeutic effects of agomelatine in obesity-related renal injury. Male Wistar rats were fed with normal diet or high-fat diet (HF) for 16 weeks. After that, vehicle or agomelatine or vildagliptin was orally administered to HF rats for 4 weeks. Our results indicated that HF rats demonstrated insulin resistance which was accompanied by an impairment of renal function and renal organic anion transporter 3 (Oat3) function as well as renal oxidative stress, ER stress, and apoptosis. Interestingly, agomelatine treatment not only improved the metabolic parameters, renal function and renal Oat3 function but also attenuated renal oxidative stress, ER stress and subsequent apoptosis. Therefore, agomelatine exerted renoprotective effects in obese insulin-resistant condition. These results suggested that agomelatine could be used as a drug to improve metabolic disturbance and prevent kidney dysfunction in obese condition.


Assuntos
Acetamidas/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nefropatias/etiologia , Obesidade/complicações , Animais , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Nefropatias/prevenção & controle , Masculino , Obesidade/induzido quimicamente , Distribuição Aleatória , Ratos , Ratos Wistar
5.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
6.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
7.
Expert Rev Clin Pharmacol ; 14(9): 1113-1131, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34015235

RESUMO

Introduction: The emergence of antimicrobial resistance in Gram-negative bacteria is a concerning challenge for health systems. The polymyxins, including colistin, are one of the limited available options these pathogens management. Nephrotoxicity, beside neurotoxicity is the major dose-limiting adverse reaction of polymyxins, with an up to 60% prevalence. As oxidative stress, inflammatory pathways and apoptosis are considered as the main mechanisms of colistin-induced kidney damage, various studies have evaluated antioxidant and/or antiapoptotic compounds for its prevention. In this article, we reviewed animal and human studies on these probable preventive measures.Area covered: PubMed, Scopus, and google scholar databases were searched using several combination of 'colistin', 'polymyxin E', 'CMS', 'Colistimethate sodium', 'nephrotoxicity', 'kidney injury', 'kidney damage', 'renal injury', 'renal damage', 'nephroprotectants', 'renoprotective', 'nephroprotective', and 'prevention'. All eligible articles including animal and human studies up to the end of 2020 were included.Expert opinion: Most of available studies are in vivo researches on anti-oxidant and anti-apoptotic agents like NAC, vitamin C and E, silymarin, and curcumin which mostly showed promising findings. However, limited human studies on NAC and vitamin C did not demonstrate considerable efficacy. So, before proposing these compounds, further well-designed randomized clinical trials are necessary.


Assuntos
Antibacterianos/efeitos adversos , Colistina/efeitos adversos , Nefropatias/induzido quimicamente , Animais , Antibacterianos/administração & dosagem , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Colistina/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Nefropatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos
9.
BMJ Open ; 11(4): e043436, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33945499

RESUMO

OBJECTIVES: To summarise current evidence on the use of pentoxifylline (PTX) to prevent contrast-induced nephropathy (CIN). METHODS: The PubMed, Embase and CENTRAL databases were searched for randomised controlled trials including patients with and without PTX undergoing contrast media exposure. We analysed the incidence of CIN and serum creatinine changes before and after contrast media exposure. All statistical analyses were conducted with Review Manager V.5.3. RESULTS: We finally enrolled in seven randomised controlled trials with a total of 1484 patients in this analysis. All of seven included studies were performed in patients undergoing angioplasty or stenting. The overall rates of CIN were 8.8% and 10.4% in the PTX groups and control groups, respectively. However, no significant reduction in the CIN rate was observed in the patients treated with PTX compared with the control groups (OR 0.81, 95% CI 0.57 to 1.13, I2=0, p=0.21). All studies reported no hospital mortality and the new requirement for dialysis during the trials. CONCLUSION: Perioperative administration of PTX to patients undergoing angioplasty did not significantly reduce the development of CIN but showed some weak tendency of lower serum creatinine increase. Based on the available trials, the evidence does not support the administration of PTX for the prevention of CIN. More trials with larger sample sizes are needed to evaluate the role of PTX in CIN prevention.


Assuntos
Nefropatias , Pentoxifilina , Meios de Contraste/efeitos adversos , Angiografia Coronária , Creatinina , Humanos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Pentoxifilina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal
10.
Expert Rev Clin Pharmacol ; 14(8): 1039-1050, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34030558

RESUMO

OBJECTIVES: This study was conducted to evaluate the potential nephroprotective effects of febuxostat, mirtazapine, and their combination against gentamicin-induced nephrotoxicity. METHODS: Induction of nephrotoxicity was achieved via gentamicin injection (100 mg/kg, I.P., for 7 days). Two different doses of mirtazapine (15-30 mg/kg), febuxostat (5-10 mg/kg), and their combination were administered daily for 14 days prior to gentamicin injection and then concomitantly with gentamicin for additional 7 days. Nephrotoxicity was evaluated histopathologically and biochemically. Renal caspase-3, extracellular signal-regulated protein kinase 1/2 (ERK1/2), nuclear factor-kappa-ß (NF-κß), and monocyte chemoattractant protein (MCP-1) were assayed. RESULTS: Febuxostat and mirtazapine significantly (p < 0.05) alleviated biochemical and histopathological alterations that were induced by gentamicin and, for the first time, significantly decreased the renal levels of ERK1/2 and MCP-1. Conclusion: Febuxostat and mirtazapine were found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity. EXPERT OPINION: The utility of nonpurine xanthine oxidase inhibitor, such as febuxostat and mirtazapine are offering a new potential opportunity for the future nephroprotective effects therapy: Febuxostat and mirtazapine are found to have a synergistic impact in reducing gentamicin-induced nephrotoxicity.


Assuntos
Febuxostat/farmacologia , Gentamicinas/toxicidade , Nefropatias/prevenção & controle , Mirtazapina/farmacologia , Animais , Antibacterianos/administração & dosagem , Antibacterianos/toxicidade , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Quimiocina CCL2/metabolismo , Sinergismo Farmacológico , Febuxostat/administração & dosagem , Gentamicinas/administração & dosagem , Supressores da Gota/administração & dosagem , Supressores da Gota/farmacologia , Nefropatias/induzido quimicamente , Masculino , Mirtazapina/administração & dosagem , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ratos
11.
Transplant Proc ; 53(5): 1532-1540, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34020797

RESUMO

BACKGROUND: A traditional narrative review was performed to evaluate clinical studies that have examined the clinical implications, risk factors, and prevention of calcineurin inhibitors (CNIs) nephrotoxicity with stress on a belatacept-based rescue regimen. METHODS: The Cochrane Library, PubMed/MEDLINE, EBSCO (Academic Search Ultimate), ProQuest (Central), and Excerpta Medical databases and Google scholar were searched using the keywords (CNI AND Nephrotoxicity prevention) OR ("Calcineurin inhibitor" AND Nephrotoxicity) OR (Tacrolimus AND Nephrotoxicity) OR (Ciclosporin AND Nephrotoxicity) OR (cyclosporine AND Nephrotoxicity) OR (Belatacept) OR (CNI Conversion) for the period from 1990 to 2020. Fifty-five related articles and reviews were found. CONCLUSION: A better understanding of the mechanisms underlying calcineurin inhibitor nephrotoxicity could help in the individualization of therapy for and prevention of CNI nephrotoxicity. Identification of high-risk patients for CNI nephrotoxicity before renal transplantation enables better use and selection of immunosuppression with reduced adverse effects and, eventually, successful treatment of the kidney recipients. Belatacept conversion is a good and safe option in patients with deteriorating renal function attributed to CNI nephrotoxicity.


Assuntos
Abatacepte/uso terapêutico , Inibidores de Calcineurina/efeitos adversos , Imunossupressores/uso terapêutico , Nefropatias/prevenção & controle , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Ciclosporina/efeitos adversos , Humanos , Imunossupressão/métodos , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamente , Complicações Pós-Operatórias/induzido quimicamente , Tacrolimo/efeitos adversos
13.
BMJ ; 373: n1091, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33975892

RESUMO

CLINICAL QUESTION: What are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes? CURRENT PRACTICE: Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades. SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment. This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications' glucose-lowering potential. RECOMMENDATIONS: The guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes• Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists.• More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists.• Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists.• Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists.• For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1 receptor agonists. HOW THIS GUIDELINE WAS CREATED: An international panel including patients, clinicians, and methodologists created these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel applied an individual patient perspective. THE EVIDENCE: A linked systematic review and network meta-analysis (764 randomised trials included 421 346 participants) of benefits and harms found that SGLT-2 inhibitors and GLP-1 receptor agonists generally reduce overall death, and incidence of myocardial infarctions, and end-stage kidney disease or kidney failure (moderate to high certainty evidence). These medications exert different effects on stroke, hospitalisations for heart failure, and key adverse events in different subgroups. Absolute effects of benefit varied widely based on patients' individual risk (for example, from five fewer deaths in the lowest risk to 48 fewer deaths in the highest risk, for 1000 patients treated over five years). A prognosis review identified 14 eligible risk prediction models, one of which (RECODe) informed most baseline risk estimates in evidence summaries to underpin the risk-stratified recommendations. Concerning patients' values and preferences, the recommendations were supported by evidence from a systematic review of published literature, a patient focus group study, a practical issues summary, and a guideline panel survey. UNDERSTANDING THE RECOMMENDATION: We stratified the recommendations by the levels of risk for CVD and CKD and systematically considered the balance of benefits, harms, other considerations, and practical issues for each risk group. The strong recommendation for SGLT-2 inhibitors in patients with CVD and CKD reflects what the panel considered to be a clear benefit. For all other adults with type 2 diabetes, the weak recommendations reflect what the panel considered to be a finer balance between benefits, harms, and burdens of treatment options. Clinicians using the guideline can identify their patient's individual risk for cardiovascular and kidney outcomes using credible risk calculators such as RECODe. Interactive evidence summaries and decision aids may support well informed treatment choices, including shared decision making.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Transportador 2 de Glucose-Sódio/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Nefropatias/prevenção & controle , Guias de Prática Clínica como Assunto , Medição de Risco
14.
Nutrients ; 13(5)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946347

RESUMO

Diet is a leading causative risk factor for morbidity and mortality worldwide, yet it is rarely considered in the design of preclinical animal studies. Several of the nutritional inadequacies reported in Americans have been shown to be detrimental to kidney health; however, the mechanisms responsible are unclear and have been largely attributed to the development of diabetes or hypertension. Here, we set out to determine whether diet influences the susceptibility to kidney injury in male C57Bl/6 mice. Mice were fed a standard chow diet, a commercially available "Western" diet (WD), or a novel Americanized diet (AD) for 12 weeks prior to the induction of kidney injury using the folic acid nephropathy (FAN) or unilateral renal ischemia reperfusion injury (uIRI) models. In FAN, the mice that were fed the WD and AD had worse histological evidence of tissue injury and greater renal expression of genes associated with nephrotoxicity and monocyte infiltration as compared to mice fed chow. Mice fed the AD developed more severe renal hypertrophy following FAN, and gene expression data suggest the mechanism for FAN differed among the diets. Meanwhile, mice fed the WD had the greatest circulating interleukin-6 concentrations. In uIRI, no difference was observed in renal tissue injury between the diets; however, mice fed the WD and AD displayed evidence of suppressed inflammatory response. Taken together, our data support the hypothesis that diet directly impacts the severity and pathophysiology of kidney disease and is a critical experimental variable that needs to be considered in mechanistic preclinical animal studies.


Assuntos
Dieta Ocidental , Dieta , Ácido Fólico/toxicidade , Nefropatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Animais , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/patologia , Fatores de Risco
15.
Life Sci ; 278: 119600, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984362

RESUMO

Kidney injury is a relatively common complication of the use of aminoglycosides. Inflammation and oxidative stress play a key role in gentamicin (GM) nephrotoxicity. We investigated the protective effect of the melatonergic agonist agomelatine (AGM) on GM nephrotoxicity, emphasizing the involvement of TLR-4 signaling, SIRT1 and PPARγ. Rats received 25 mg/kg AGM for 15 days and 100 mg/kg GM for eight days starting at day 7. Elevated serum creatinine, urea and Kim-1 along with multiple histological alterations in the kidney were observed in GM-intoxicated rats. Malondialdehyde (MDA), TNF-α, IL-1ß, nitric oxide (NO) and myeloperoxidase (MPO) were increased, and GSH, SOD and catalase were decreased in the kidney of GM-intoxicated rats. Treatment with AGM significantly ameliorated the kidney function biomarkers, prevented tissue injury, decreased inflammatory cytokines, MDA, NO and MPO, and boosted antioxidants. In addition, AGM suppressed the expression of TLR-4, NF-κB p65, p38 MAPK, ERK-1, VCAM-1 and iNOS, whereas upregulated SIRT1 and PPARγ in the kidney of GM-intoxicated rats. In conclusion, AGM prevented GM nephrotoxicity in rats by attenuating oxidative injury and inflammation. AGM suppressed TLR-4 signaling, enhanced antioxidants and upregulated SIRT1 and PPARγ in the kidney of GM-induced rats.


Assuntos
Acetamidas/uso terapêutico , Antibacterianos/efeitos adversos , Gentamicinas/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , PPAR gama/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Receptor 4 Toll-Like/metabolismo
16.
FASEB J ; 35(5): e21530, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813752

RESUMO

Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-ß increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Nefropatias/prevenção & controle , Proteínas Circadianas Period/fisiologia , Proteína Gli2 com Dedos de Zinco/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/metabolismo
17.
Pharmacology ; 106(5-6): 332-340, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33849026

RESUMO

INTRODUCTION: The presence of mercury in the environment is a worldwide concern. Inorganic mercury is present in industrial materials, is employed in medical devices, is widely used in batteries, is a component of fluorescent light bulbs, and it has been associated with human poisoning in gold mining areas. The nephrotoxicity induced by inorganic mercury is a relevant health problem mainly in developing countries. The primary mechanism of mercury toxicity is oxidative stress. Trimetazidine (TMZ) is an anti-ischemic drug, which inhibits cellular oxidative stress, eliminates oxygen-free radicals, and improves lipid metabolism. The aim of this study was to evaluate whether the administration of TMZ protects against mercuric chloride (HgCl2) kidney damage. METHODS: Adult male Wistar rats received only HgCl2 (4 mg/kg bw, sc) (Hg group, n = 5) or TMZ (3 mg/kg bw, ip) 30 min before HgCl2 administration (4 mg/kg bw, sc) (TMZHg group, n = 7). Simultaneously, a control group of rats (n = 4) was studied. After 4 days of HgCl2 injection, urinary flow, urea and creatinine (Cr) plasma levels, Cr clearance, urinary glucose, and sodium-dicarboxylate cotransporter 1 (NaDC1) in urine were determined. Lipid peroxidation (MDA) and glutathione (GSH) levels were measured in kidney homogenates. RESULTS: Rats only treated with HgCl2 showed an increase in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, and NaDC1 urinary excretion as compared with the control group and a decrease in Cr clearance. TMZHg group showed a decrease in urea and Cr plasma levels, urinary flow, fractional excretion of water, glucosuria, NaDC1 urinary excretion, and an increase in Cr clearance when compared to the Hg group. Moreover, MDA and GSH levels observed in Hg groups were decreased and increased, respectively, by TMZ pretreatment. CONCLUSION: TMZ exerted a renoprotective action against HgCl2-induced renal injury, which might be mediated by the reduction of oxidative stress. Considering the absence of toxicity of TMZ, its clinical application against oxidative damage due to HgCl2-induced renal injury should be considered. The fact that TMZ is commercially available should simplify and accelerate the translation of the present data "from bench to bedside." In this context, TMZ become an interesting new example of drug repurposing.


Assuntos
Nefropatias/prevenção & controle , Intoxicação por Mercúrio/prevenção & controle , Substâncias Protetoras/farmacologia , Trimetazidina/farmacologia , Animais , Creatinina/sangue , Transportadores de Ácidos Dicarboxílicos/urina , Glutationa/metabolismo , Glicosúria/induzido quimicamente , Glicosúria/prevenção & controle , Nefropatias/induzido quimicamente , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Cloreto de Mercúrio/efeitos adversos , Transportadores de Ânions Orgânicos Dependentes de Sódio/urina , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Ratos Wistar , Cloreto de Sódio/urina , Simportadores/urina , Trimetazidina/uso terapêutico , Ureia/sangue , Micção/efeitos dos fármacos
18.
Clin Biochem ; 93: 104-111, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33861983

RESUMO

A direct link between hypercholesterolemia (HC) and renal pathologies has been established. Statins, the drugs of choice for HC management, have been associated with various side effects and toxicities, including nephropathy and other renal insults. Thus, natural dietary products based-alternative strategies for HC and associated pathologies are being considered. OBJECTIVES: Based on the unique nutritional composition and numerous health benefits of Hempseeds (Cannabis sativa), currently the potential anti-inflammatory and redox modulatory effects of hempseeds lipid extract (HEMP) against HC associated renal damage were evaluated and compared with statins (Simvastatin) in HFD induced experimental model of HC in rats. DESIGN & METHODS: The hempseed lipid fractions (HEMP) were prepared and their ameliorating effects on HFD induced lipid profiles, renal function markers (RFT), histopathological/morphological changes, renal oxidative stress, and inflammation markers were studied and compared with statins (HFD + STATINS). Further, HEMP-mediated modulation of lipid metabolism mediators (APO-B/E) was studied. RESULTS: Not only, HEMP administration improved the lipid profiles and morphological signs of HC, but it also was safe compared to Simvastatin in terms of hepatic and renal function markers. Further, changes in renal histoarchitecture, biochemical markers of oxidative stress, and expression profiles of lipid metabolism and inflammatory pathways (Cox-1/2, PGDS, PGES) revealed that HEMP positively modulating the redox homeostasis activated the resolution pathways against HC associated renal insults. CONCLUSION: The outcomes of the current study indicated HEMP's ameliorative and therapeutic potential against hypercholesterolemia-associated nephropathies and other systemic effects.


Assuntos
Anti-Inflamatórios/farmacologia , Anticolesterolemiantes/farmacologia , Cannabis/química , Sequestradores de Radicais Livres/farmacologia , Hipercolesterolemia/tratamento farmacológico , Nefropatias/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Feminino , Sequestradores de Radicais Livres/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/complicações , Nefropatias/etiologia , Nefropatias/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Ratos Wistar , Sinvastatina/uso terapêutico
19.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801911

RESUMO

Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-ß-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Neoplasias da Mama/tratamento farmacológico , Inflamação/prevenção & controle , Nefropatias/prevenção & controle , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacocinética , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cisplatino , Feminino , Humanos , Inflamação/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Camundongos Nus , Ratos Endogâmicos WKY , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
Nutrients ; 13(5)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922959

RESUMO

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.


Assuntos
Benzamidas/uso terapêutico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/complicações , Nefropatias/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Aldeído Pirúvico/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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