RESUMO
Diabetic nephropathy (DN) is a prevalent diabetic microvascular condition. It is the leading cause of kidney disease in the advanced stages. There is no currently effective treatment available. This research aimed to investigate the curative potentials of exosomes isolated from mesenchymal stem cells affecting DN. This study was performed on 70 male adult albino rats. Adult rats were randomized into seven groups: Group I: Negative control group, Group II: DN group, Group III: Balanites treated group, Group IV: MSCs treated group, Group V: Exosome treated group, Group VI: Balanites + MSCs treated group and Group VII: Balanites + exosome treated group. Following the trial period, blood and renal tissues were subjected to biochemical, gene expression analyses, and histopathological examinations. Results showed that MDA was substantially increased, whereas TAC was significantly decreased in the kidney in the DN group compared to normal health rats. Undesired elevated values of MDA levels and a decrease in TAC were substantially ameliorated in groups co-administered Balanites aegyptiacae with MSCs or exosomes compared to the DN group. A substantial elevation in TNF-α and substantially diminished concentration of IGF-1 were noticed in DN rats compared to normal health rats. Compared to the DN group, the co-administration of Balanites aegyptiacae with MSCs or exosomes substantially improved the undesirable elevated values of TNF-α and IGF-1. Furthermore, in the DN group, the mRNA expression of Vanin-1, Nephrin, and collagen IV was significantly higher than in normal healthy rats. Compared with DN rats, Vanin-1, Nephrin, and collagen IV Upregulation were substantially reduced in groups co-administered Balanites aegyptiacae with MSCs or exosomes. In DN rats, AQP1 expression was significantly lower than in normal healthy rats. Furthermore, the groups co-administered Balanites aegyptiacae with MSCs or exosomes demonstrated a substantial increase in AQP1 mRNA expression compared to DN rats.
Assuntos
Aquaporinas , Diabetes Mellitus , Nefropatias Diabéticas , Exossomos , Células-Tronco Mesenquimais , Ratos , Masculino , Animais , Nefropatias Diabéticas/terapia , Nefropatias Diabéticas/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Exossomos/metabolismo , Exossomos/patologia , Células-Tronco Mesenquimais/metabolismo , Aquaporinas/metabolismo , Colágeno/metabolismo , RNA Mensageiro , Diabetes Mellitus/metabolismoRESUMO
Kidney disease in diabetes mellitus is usually explained by diabetic kidney disease, but other superimposed etiologies occur frequently. The distinction between diabetic kidney disease and non-diabetic kidney disease can only be made by performing kidney biopsy. Our objective was to evaluate the association of diabetic kidney disease, non-diabetic kidney disease, or both with renal replacement therapy initiation. This is a retrospective cohort that included patients with type 2 diabetes mellitus for whom a kidney biopsy was indicated. Subjects were followed-up for 5 years, until renal replacement therapy initiation or were lost to follow up. One hundred and forty-one patients were included, 53 (39%) had diabetic kidney disease, 13 (9%) had non-diabetic kidney disease and 75 (54%) had both. Ninety-four percent of the cohort initiated renal replacement therapy during the 5-year follow-up. Higher degree of fibrosis was associated with a trend towards higher risk of requiring renal replacement therapy. In addition, the combined diabetic kidney disease + non-diabetic kidney disease group was associated with higher need of renal replacement therapy initiation when compared to the diabetic kidney disease group.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Estudos Retrospectivos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Fatores de Risco , Rim , Terapia de Substituição Renal/efeitos adversos , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/terapia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Biópsia , Taxa de Filtração GlomerularRESUMO
Background: In a context where the prevalence of Diabetes Mellitus and Hypertension has increased significantly in recent years, kidney diseases become important for the potential demand for specialized health care and resources required. Objective: To analyze the geographical distribution of Diabetic Nephropathy (DN) and Renal Insufficiency (RI) based on the medical consultations given in first-level units of IMSS during 2019, to identify the medical units with the highest burden of care. Material and methods: Ecological-exploratory study in which indicators were estimated for every thousand persons in relation to medical consultations given by ND and RI according to service time, first-level medical unit (UMF) and representation to analyze the magnitude and geographic distribution at the national level. Results: 45% of medical consultations were by ND and 52.4% by RI. The highest burden per DN was registered in UMF No. 50 Cd. Juarez (Chihuahua) and No. 49 Gabino Barreda (Veracruz Sur), with 1.7 first-time medical consultations and 148.3 subsequent medical consultations per 1,000 persons, respectively. While in UMF No. 40 Manlio Fabio Altamirano and No. 25 Cotaxtla, in Veracruz Norte, the highest burden was for RI, with 4.9 first-time medical consultations and 134.2 subsequent medical consultations per 1000 persons, respectively. Conclusions: The results could contribute to strengthening of medical units where it is necessary and the efficient allocation of resources available to meet the demand for health services of ND and RI in IMSS.
Introducción: en un contexto donde la prevalencia de diabetes mellitus e hipertensión arterial ha aumentado significativamente en años recientes, las enfermedades renales adquieren importancia por la potencial demanda de atención especializada y de recursos en salud que requieren. Objetivo: analizar la distribución geográfica de la nefropatía diabética (ND) y la insuficiencia renal (IR) con base en las consultas otorgadas en unidades de primer nivel del Instituto Mexicano del Seguro Social (IMSS) durante 2019, para identificar las unidades médicas con mayor carga de atención. Material y métodos: estudio ecológico-exploratorio en el que se estimaron indicadores por cada mil derechohabientes en relación a las consultas otorgadas por ND e IR según la ocasión de servicio, la unidad médica familiar (UMF) de primer nivel y la representación. Se utilizó estadística espacial para analizar dichos indicadores. Resultados: el 45% de las consultas otorgadas fue por ND y el 52.4% por IR. La mayor carga por ND se registró en la UMF No. 50 de Cd. Juárez (Chihuahua) y en la No. 49 Gabino Barreda (Veracruz Sur), con 1.7 consultas de primera vez y 148.3 subsecuentes por mil derechohabientes, respectivamente. Mientras que en la UMF No. 40 Manlio Fabio Altamirano y No. 25 Cotaxtla, en Veracruz Norte, la mayor carga fue por IR, con 4.9 consultas de primera vez y 134.2 subsecuentes por mil derechohabientes, respectivamente. Conclusiones: los resultados podrían contribuir al fortalecimiento de las unidades médicas que así lo requieran y en la distribución eficiente de los recursos disponibles para atender la demanda de servicios de salud de ND e IR en el IMSS.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Hipertensão , Insuficiência Renal , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/terapia , Humanos , Hipertensão/epidemiologia , Prevalência , Atenção Primária à Saúde , Insuficiência Renal/diagnóstico , Insuficiência Renal/epidemiologia , Insuficiência Renal/etiologiaRESUMO
In patients with diabetes, it has been suggested that physical exercise may reduce albuminuria and the progression of renal disease. However, the molecular mechanism by which physical exercise protects the kidney in diabetes remains poorly understood. The aim of the present study was to determine the contribution of muscle irisin secretion induced by aerobic physical exercise with the subsequent activation of AMPK for kidney protection under diabetic conditions. Aerobic physical exercise in rats protected the kidney in streptozotocin-induced diabetes. It reduced albuminuria, glomerular hypertrophy, and glomerular expression of collagen IV and fibronectin, as well as markers of kidney inflammation, when compared to sedentary diabetic rats. These effects were associated with elevation in muscle FNDC5/irisin and activity of AMPK in the diabetic kidney. However, the beneficial effects of exercise were lost when the diabetic rats were treated with CycloRGDyK, that in the bone it has been described as an irisin receptor blocker. In cultured human tubular (HK-2) cells, treatment with recombinant irisin counteracted the effect of high glucose in a dose-dependent manner. Irisin, per se, also activated AMPK in HK-2 cells. It is concluded that in diabetes, the renal protective effect of exercise may be mediated by the irisin/AMPK pathway.
Assuntos
Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Exercício Físico , Fibronectinas , Proteínas Quinases Ativadas por AMP/metabolismo , Albuminúria , Animais , Nefropatias Diabéticas/terapia , Fibronectinas/metabolismo , Humanos , Rim/metabolismo , Condicionamento Físico Animal , RatosRESUMO
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) worldwide, contributing to a great burden across a variety of patient-reported and clinical outcomes. New interventions for DKD management have been established in recent years, unleashing a novel paradigm, in which kidney-dedicated trials yield informative and robust data to guide optimal clinical management. After unprecedented results from groundbreaking randomized controlled trials were released, a new scenario of evidence-based recommendations has evolved for the management of diabetic patients with CKD. The current guidelines place great emphasis on multidimensional and interdisciplinary approaches, but the challenges of implementation are just starting and will be pivotal to optimize clinical results and to understand the new threshold for residual risk in DKD. We thereby provide an updated review on recent advances in DKD management based on new guideline recommendations, summarizing recent evidence while projecting the landscape for innovative ongoing initiatives in the field. Specifically, we review current insights on the natural history, epidemiology, pathogenesis, and therapeutics of DKD, mapping the new scientific information into the recently released Kidney Disease - Improving Global Outcomes Guidelines translating results from major novel randomized controlled trials to the clinical practice. Additionally, we approach the landscape of new therapeutics in the field, summarizing ongoing phase IIb and III trials focused on DKD. Finally, reflecting on the past and looking into the future, we highlight unmet needs in the current DKD management based on real-world evidence and offer a nephrologist's perspective into the challenge of fostering continuous improvement on clinical and patient-reported outcomes for individuals living with DKD.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Insuficiência Renal Crônica , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/terapia , Humanos , Rim , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapiaRESUMO
Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.
Assuntos
Autofagia/fisiologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/terapia , Autofagia/efeitos dos fármacos , Complicações do Diabetes/fisiopatologia , Complicações do Diabetes/terapia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Nefropatias Diabéticas/metabolismo , Humanos , Hipoglicemiantes/farmacologiaRESUMO
Diabetic kidney disease (DKD) is a worldwide microvascular complication of type 2 diabetes mellitus (T2DM). From several pathological mechanisms involved in T2DM-DKD, we focused on mitochondria damage induced by hyperglycemia-driven reactive species oxygen (ROS) accumulation and verified whether mesenchymal stem cells (MSCs) anti-oxidative, anti-apoptotic, autophagy modulation, and pro-mitochondria homeostasis therapeutic potential curtailed T2DM-DKD progression. For that purpose, we grew immortalized glomerular mesangial cells (GMCs) in hyper glucose media containing hydrogen peroxide. MSCs prevented these cells from apoptosis-induced cell death, ROS accumulation, and mitochondria membrane potential impairment. Additionally, MSCs recovered GMCs' biogenesis and mitophagy-related gene expression that were downregulated by stress media. In BTBRob/ob mice, a robust model of T2DM-DKD and obesity, MSC therapy (1 × 106 cells, two doses 4-weeks apart, intra-peritoneal route) led to functional and structural kidney improvement in a time-dependent manner. Therefore, MSC-treated animals exhibited lower levels of urinary albumin-to-creatinine ratio, less mesangial expansion, higher number of podocytes, up-regulation of mitochondria-related survival genes, a decrease in autophagy hyper-activation, and a potential decrease in cleaved-caspase 3 expression. Collectively, these novel findings have important implications for the advancement of cell therapy and provide insights into cellular and molecular mechanisms of MSC-based therapy in T2DM-DKD setting.
Assuntos
Nefropatias Diabéticas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Obesidade/terapia , Animais , Antioxidantes , Caspase 3/metabolismo , Sobrevivência Celular , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Peróxido de Hidrogênio/metabolismo , Células Mesangiais/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Estresse Oxidativo , Podócitos/metabolismo , Podócitos/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Background and objective: Diabetic kidney disease (DKD) is the most common microvascular chronic complication of diabetes mellitus. Hyperbaric oxygen (HBO2) therapy will increase the partial pressure of oxygen (PaO2) and may improve cell repair processes, which can lead to better renal function. The objective of this study was to quantify the efficacy of adjuvant HBO2 to increase the glomerular filtration rate and urinary albumin excretion in diabetic patients, as well as determine its effectiveness to modify the clinical course of DKD. Materials and methods: An experimental study was performed on patients with stage 3 and 4 DKD. Twenty sessions of HBO2 or ambient air in a hyperbaric chamber were administered. Estimated glomerular filtration rate, urine albumin:creatinine ratio calculation and clinical stage stratification were made prior to and after HBO2 administration. A descriptive, inferential and clinical efficacy analysis was performed. Results: Urinary albumin/creatinine (UACR) mean values prior to HBO2 were 1452.9 ± 644.3 mg/g and decreased to 876.1 ± 504.0 mg/g at the end of the study (p=0.06). The patients in the control group showed a UACR mean of 2784.5 ± 2128.6 mg/g and 2861.4 ± 2424.2 mg/g at baseline and at the end of the study, respectively (p=0.82). Patients in the experimental/HBO2 group showed an estimated GFR of 27.3 ± 9.5 mL/min /1.73m2 before HBO2, with a 34.4 ± 6.9 mL/min/1.73m2 after treatment (p=0.017); control group eGFR was 30.1 ± 9.2 mL/min/1.73m2, decreasing to 22.2 ± 6.8 mL/min/1.73m2 (p=0.004). Relative risk 0.00, relative risk reduction -100%, absolute risk reduction -71.4%, 95% CI (-104.9% to -38.0%), NNT 1, 95% CI (1 to 3). Conclusions: Management with HBO2 for DKD was associated with decreased excretion urinary albumin, improved GFR and clinical stage of patients in stages 3 and 4 of kidney damage unlike those receiving ambient air..
Assuntos
Nefropatias Diabéticas/terapia , Oxigenoterapia Hiperbárica , Adulto , Idoso , Albuminas/metabolismo , Estudos de Casos e Controles , Creatinina/urina , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Oxigenoterapia Hiperbárica/estatística & dados numéricos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Chronic renal disease patients under chronic dialysis (CRDD) have a multifactorial immunological deterioration with an increased risk of Candida infections. Incidence of Candida infections is increasing. Choice of suitable antifungal agents is limited due to the resistance of some species to several antifungals. Aim of the present study was to identify the distribution and antifungal susceptibility patterns of oral isolated Candida species from infected and colonized patients, as well as to investigate the risk factors for oral infection in patients on dialysis. Cross-sectional study, approved by the institutional bioethics committees was performed in CRDD patients. Demographic, clinic data, and oral mucosa samples were obtained. Infection diagnosis was established clinically and confirmed with exfoliative cytology, each sample was plated on CHROMagar Candida and incubated at 36°C for 2 days. Yeast species were identified by carbohydrate assimilation ID 32C AUX system and the apiweb database. For the antifungal susceptibility test, the M44 A-3 method (CLSI) using fluconazole (FCZ), miconazole (MCZ), nystatin (NYS), and voriconazole (VCZ). Study included 119 participants, the main cause of CRD was nephropathy due to DM2 (58%), and three-fourths of the patients were under hemodialysis. Candida prevalence was 56.3% of 67 colonized or infected patients, 88 isolates were obtained. Principal identified species were C. albicans (51.1%), C. glabrata (25%), and C. tropicalis (14.8%). C. glabrata showed a reduced response to FCZ in 50% of isolates and C. albicans had a reduced response in 16% of the isolates. Antifungal agent with the least efficacious response or with the lowest susceptibility in the isolates of these patients was MCZ, followed by VCZ and FCZ, whereas NYS induced the best antifungal response.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candidíase Bucal/microbiologia , Boca/microbiologia , Insuficiência Renal Crônica/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Candida/classificação , Candidíase Bucal/complicações , Candidíase Bucal/diagnóstico , Candidíase Bucal/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/microbiologia , Nefropatias Diabéticas/terapia , Farmacorresistência Fúngica/efeitos dos fármacos , Feminino , Humanos , Masculino , México/epidemiologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Diálise Renal/estatística & dados numéricos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Adulto JovemRESUMO
AIM: To evaluate the effects of P2X7 receptor blockade on renin-angiotensin system (RAS) in rats with diabetic nephropathy (DN). MAIN METHODS: Wistar rats were unilaterally nephrectomized and received streptozotocin for diabetes mellitus (DM) induction; control animals (CTL) received the drug vehicle. The animals were submitted to P2X7 receptor silencing, forming the group (DM + siRNA). The animals were placed in metabolic cages for data collection and evaluation of renal function; at the end of the protocol, the kidney was removed for analysis of P2X7, renin, angiotensin-converting enzyme (ACE), ACE2, angiotensin, thiobarbituric acid reactive substance levels (TBARS), nitric oxide (NO) and qualitative histological. KEY FINDINGS: The metabolic profile was attenuated in DM + siRNA vs. DM and there was a significant improvement in creatinine, urea and proteinuria levels in the same group. Renin expression was significantly decreased in DM + siRNA vs. DM. ACE and ACE2 were significantly reduced in DM + siRNA vs. DM. TBARS levels were decreased and NO showed an increase in DM + siRNA vs. DM, both significant. All histological alterations were improved in DM + siRNA vs. DM. SIGNIFICANCE: Data have shown that although silencing of the P2X7 receptor did not decrease fasting glucose, it promoted an improvement in the metabolic profile and a significant recovery of renal function, revealing a protective action by the inhibition of this receptor. This effect must have occurred due to the inhibition of RAS and the increase of NO, suggesting that the use of P2X7 receptors inhibitors could be used as adjuvant therapy against DN progression.