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1.
Diabetes Obes Metab ; 26(7): 2905-2914, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38719436

RESUMO

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.


Assuntos
Bases de Dados Factuais , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Progressão da Doença , Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Masculino , Feminino , Japão/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/complicações , Pessoa de Meia-Idade , Idoso , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia
2.
Clin Exp Nephrol ; 28(5): 440-446, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38340247

RESUMO

BACKGROUND: Patients with chronic kidney disease (CKD) reportedly show dysbiosis, which is the imbalance of gut microbiome. Dysbiosis increases the uremic toxin level in the intestine, and uremic toxins transfer into the blood, causing CKD progression. Sake lees, a traditional Japanese fermented food, may help reduce uremic toxins by altering the gut microbiome. Additionally, D-alanine, which is present in sake lees, may have a renoprotective effect. The present pilot study aims to evaluate the effect of adding sake lees to the standard CKD dietary therapy in reducing blood uremic toxins. METHODS: This pilot study is a single-center, open-label, randomized controlled trial. Twenty-four patients with CKD will be enrolled and allocated 1:1 to the intervention and control groups. The intervention group will receive standard CKD dietary therapy with an additional intake of 50 g of sake lees per day for 8 weeks, whereas the control group will only receive standard CKD dietary therapy. The primary endpoint is the change in serum indoxyl sulfate after 8 weeks. The secondary endpoint is the plasma D-alanine and fecal microbiome changes. CONCLUSION: This pilot study provides insight into the development of a new diet focused on gut microbiome and D-amino acids in patients with CKD. CLINICAL TRIAL REGISTRATION: This protocol was approved by the Clinical Trial Review Board of Kanazawa University Hospital on October 27, 2022 (2022-001 [6139]) and available to the public on the website of the Japan Registry of Clinical Trials on November 22, 2022 (jRCT1040220095).


Assuntos
Microbioma Gastrointestinal , Insuficiência Renal Crônica , Toxinas Urêmicas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Disbiose , Alimentos Fermentados , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Toxinas Urêmicas/sangue
3.
Clin Exp Nephrol ; 28(8): 784-792, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38506982

RESUMO

BACKGROUND: Magnesium deficiency is associated with various health conditions, but its impact on the progression of chronic kidney disease (CKD) remains unclear. This study aimed to investigate the association between serum magnesium levels and prognosis of renal function in CKD patients. METHODS: This is an analysis of the Japan Chronic Kidney Disease Database Ex (J-CKD-DB-Ex), which is a multicenter prospective cohort including CKD patients enrolled from January 1, 2014 to December 31, 2020. We included adult outpatients with CKD stage G3 and G4 at the time of initial magnesium measurement. Patients were classified by magnesium levels as low (<1.7 mg/dl), normal (1.7-2.6 mg/dl), or high (>2.6 mg/dl). The primary outcomes were the composite of an eGFR < 15 ml/min/1.73 m2 or a ≥30% reduction in eGFR from the initial measurement, which was defined as CKD progression. We applied the Kaplan-Meier analysis and Cox regression hazard model to examine the association between magnesium levels and CKD progression. RESULTS: The analysis included 9868 outpatients during the follow-up period. The low magnesium group was significantly more likely to reach CKD progression. Cox regression, adjusting for covariates and using the normal magnesium group as the reference, showed that the hazard ratio for the low magnesium group was 1.20 (1.08-1.34). High magnesium was not significantly associated with poor renal outcomes compared with normal magnesium. CONCLUSION: Based on large real-world data, this study demonstrated that low magnesium levels are associated with poorer renal outcomes.


Assuntos
Progressão da Doença , Taxa de Filtração Glomerular , Magnésio , Insuficiência Renal Crônica , Humanos , Magnésio/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Estudos Prospectivos , Deficiência de Magnésio/sangue , Deficiência de Magnésio/complicações , Japão/epidemiologia , Rim/fisiopatologia
4.
Diabetes Res Clin Pract ; 212: 111682, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677368

RESUMO

AIMS: It is unclear whether the effect of proteinuria on rapid kidney function decline is equivalent among diabetic kidney disease (DKD), non-DKD with diabetes (NDKD+DM), and nephrosclerosis without diabetes (NS-DM), particularly in advanced chronic kidney disease patients. METHODS: In total, 1038 chronic kidney disease patients who participated in the BRIGHTEN study were included in the present study. A linear mixed effect model was applied to estimate the annual estimated glomerular filtration rate decline in each disease group. RESULTS: The prevalence of rapid decliners (rapid kidney function decline, defined as an eGFR loss of > 5 mL/min/1.73 m2/year) in the DKD group (44.6 %) was significantly higher compared with the NDKD+DM (27.9 %) and NS-DM (27.0 %) groups. By contrast, the prevalence of rapid decliners in different urine total protein to creatinine ratio (UPCR) categories (<0.5, 0.5 to < 1.0, 1.0 to < 3.5, and ≥ 3.5 g/g) were equivalent between the DKD and NS-DM groups. Moreover, the prevalence of a UPCR < 1.0 g/g in rapid decliners of the NS-DM group was more than double than in those of the DKD and NDKD+DM groups. CONCLUSIONS: The risk of rapid kidney function decline in NS-DM patients with low levels of proteinuria may be greater than initially predicted.


Assuntos
Nefropatias Diabéticas , Taxa de Filtração Glomerular , Proteinúria , Insuficiência Renal Crônica , Humanos , Proteinúria/epidemiologia , Proteinúria/fisiopatologia , Masculino , Feminino , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/epidemiologia , Pessoa de Meia-Idade , Taxa de Filtração Glomerular/fisiologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/epidemiologia , Idoso , Progressão da Doença , Adulto , Rim/fisiopatologia , Creatinina/urina , Nefroesclerose/fisiopatologia , Nefroesclerose/epidemiologia , Prevalência
5.
J Clin Neurosci ; 123: 41-46, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38531193

RESUMO

No reports of longitudinal studies on phase angle (PhA) in lumbar spinal stenosis (LSS) exist, and its association with postoperative clinical outcomes is unclear. We longitudinally investigated PhA in patients with LSS preoperatively to 12 months postoperatively and determined the association between PhA and the Japanese Orthopedic Association (JOA) score. This prospective observational study included patients who underwent consecutive surgical treatments for clinically and radiologically defined LSS. Outcome measures including walking speed, Timed Up and Go test (TUG), JOA score, and PhA based on bioelectrical impedance analysis were measured preoperatively and at 3, 6, and 12 months postoperatively. Correlations between PhA and the JOA score and motor function were analyzed. The effect of PhA on JOA scores was evaluated using mixed-effect models for repeated measurements (MMRM). Eighty-nine patients were included at baseline, and 85, 85, and 78 patients were analyzed at 3, 6, and 12 months postoperatively, respectively. PhA was 3.9 ± 0.8 (p = 0.086), 4.0 ± 0.8 (p = 0.644), and 4.1 ± 0.9 (p = 0.791) at 3, 6, and 12 months postoperatively and 4.2 ± 0.8 at baseline. PhA was significantly correlated with the JOA score (p < 0.01) and walking speed and TUG results (p < 0.01) at all assessment points. In the MMRM, PhA was associated with the JOA score at all assessment points. Changes in postoperative JOA scores after lumbar spine surgery are associated with PhA at each assessment time point. PhA may be a useful postoperative clinical indicator after surgery for LSS.


Assuntos
Vértebras Lombares , Estenose Espinal , Humanos , Estenose Espinal/cirurgia , Masculino , Feminino , Idoso , Vértebras Lombares/cirurgia , Vértebras Lombares/diagnóstico por imagem , Estudos Prospectivos , Pessoa de Meia-Idade , Resultado do Tratamento , Período Pós-Operatório , Período Pré-Operatório , Estudos Longitudinais
6.
Cureus ; 16(5): e61273, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38947696

RESUMO

PURPOSE: To increase the number of medical students or residents who want to become surgeons, we must evaluate our program that recruits new young surgeons. METHODS: We planned surgical training programs for medical students and residents that we named the MANGOU (Miyazaki Advanced New General surgery Of University) training project in the Department of Surgery, Miyazaki University, Japan. From January 2016 through December 2022, we asked trainees who attended this training to complete questionnaires to evaluate their interest in surgery, confidence in surgical skills, and training. Scoring of the questionnaire responses was based on a 5-point Likert scale, and we evaluated this training prospectively. RESULTS: Among the 109 trainees participating in this training, 61 answered the questionnaires. Two participants found the training boring, but 59 (96.7%) enjoyed it. All of them answered "Yes" to wanting to participate in the next training. Respective pre- and post-training scores were as follows: confidence in surgical skills, 2.2 ± 1.0 and 3.0 ± 1.0 (p < 0.0001); interest in surgery, 4.2 ± 0.8 and 4.4 ± 0.5 (p = 0.0011); and willingness to become surgeons, 3.9 ± 0.7 and 4.1 ± 0.6 (p = 0.0011). All scores rose after MANGOU training. CONCLUSION: We planned MANGOU surgical wet lab training for medical students and residents that aimed to educate and recruit new surgeons. After joining the MANGOU training, the trainees' anxiety about surgery was reduced, their confidence in performing surgical procedures improved, they showed more interest in surgery, and they increased their motivation to become surgeons.

7.
Acta Neuropathol Commun ; 12(1): 122, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164793

RESUMO

Gliomas, particularly glioblastomas (GBMs), pose significant challenges due to their aggressiveness and poor prognosis. Early detection through biomarkers is critical for improving outcomes. This study aimed to identify novel biomarkers for gliomas, particularly GBMs, using chiral amino acid profiling. We used chiral amino acid analysis to measure amino acid L- and D-isomer levels in resected tissues (tumor and non-tumor), blood, and urine from 33 patients with primary gliomas and 24 healthy volunteers. The levels of D-amino acid oxidase (DAO), a D-amino acid-degrading enzyme, were evaluated to investigate the D-amino acid metabolism in brain tissue. The GBM mouse model was created by transplanting GBM cells into the brain to confirm whether gliomas affect blood and urine chiral amino acid profiles. We also assessed whether D-amino acids produced by GBM cells are involved in cell proliferation. D-asparagine (D-Asn) levels were higher and DAO expression was lower in glioma than in non-glioma tissues. Blood and urinary D-Asn levels were lower in patients with GBM than in healthy volunteers (p < 0.001), increasing after GBM removal (p < 0.05). Urinary D-Asn levels differentiated between healthy volunteers and patients with GBM (area under the curve: 0.93, sensitivity: 0.88, specificity: 0.92). GBM mouse model validated the decrease of urinary D-Asn in GBM. GBM cells used D-Asn for cell proliferation. Gliomas induce alterations in chiral amino acid profiles, affecting blood and urine levels. Urinary D-Asn emerges as a promising diagnostic biomarker for gliomas, reflecting tumor presence and severity.


Assuntos
Asparagina , Neoplasias Encefálicas , D-Aminoácido Oxidase , Glioblastoma , Humanos , Glioblastoma/metabolismo , Glioblastoma/urina , Glioblastoma/patologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/urina , Neoplasias Encefálicas/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Asparagina/urina , Asparagina/metabolismo , Adulto , D-Aminoácido Oxidase/metabolismo , D-Aminoácido Oxidase/genética , Camundongos , Idoso , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Proliferação de Células
8.
Intern Med ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38719599

RESUMO

A 78-year-old man with atherosclerosis was diagnosed with hepatocellular carcinoma by transfemoral angiography of the celiac and superior mesenteric arteries (SMA). After surgery, a serum examination revealed progressive renal failure with eosinophilia, leading to end-stage kidney disease, in addition to active gastric ulcers and pancreatitis. Cyanosis in the bilateral toes showed a cholesterol crystal embolism (CCE) in a skin biopsy. Autopsy revealed that CCE involved the arterioles of multiple organs, and its distribution was anatomically consistent with the vascular territories of the celiac artery and SMA. CCE should therefore be considered in patients presenting with multiple types of tissue damage in the vascular territories after angiography.

9.
Kidney Int Rep ; 9(2): 347-355, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38344715

RESUMO

Introduction: Autoantibodies to erythropoietin receptor (anti-EPOR antibodies) have been identified in patients with various kidney diseases. However, data in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) is limited. We assessed the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population. Methods: The CREDENCE randomized patients with T2D and CKD to canagliflozin or placebo. Serum anti-EPOR antibodies, the exposure of interest, were measured using enzyme-linked immunosorbent assay. The primary outcome was doubling of serum creatinine, end-stage kidney disease, or death from kidney or cardiovascular (CV) causes. Secondary outcomes included CV and all-cause mortality. Multivariable Cox-regression models estimated associations between anti-EPOR antibodies and outcomes. The effects of canagliflozin on hemoglobin and hematocrit, stratified by the presence of anti-EPOR antibodies were assessed with a repeated measures mixed effects model. Results: Of 2600 participants with available biosamples, 191 (7.3%) were positive for anti-EPOR antibodies. Higher baseline anti-EPOR antibodies were associated with increased risk of primary outcome (hazard ratio [HR] per 1-SD increase = 1.12, 95% confidence interval [CI] = 1.01-1.24, P = 0.04), with CV death (HR = 1.27, 95% CI = 1.08-1.48, P < 0.01) and all-cause mortality (HR = 1.26, 95% CI = 1.11-1.43, P < 0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0 g/l (95% CI = 6.2-7.9) and 2.4% (2.2-2.7), respectively. These effects were consistent across patients with and without anti-EPOR antibodies (P-interaction = 0.24 and 0.36, respectively). Conclusion: In patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and CV outcome, as well as CV and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies.

10.
Kidney Int Rep ; 9(2): 323-333, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38344735

RESUMO

Introduction: Data on longitudinal trajectory of kidney function decline and fluctuation in albuminuria leading to end-stage kidney disease (ESKD) is sparse in patients with type 2 diabetes. Methods: Using data from an observational study of patients with type 2 diabetes and biopsy-confirmed diabetic kidney disease (DKD), generalized additive mixed models (GAMMs) were performed to quantify patterns of longitudinal trajectory of estimated glomerular filtration rate (eGFR) decline to ESKD associated with repeated measures of urine albumin-to-creatinine ratio (ACR). Results: Over a median follow-up period of 3.3 years, 155 of 319 patients progressed to ESKD. Among these patients, 91.6% exhibited a curvilinear pattern in their eGFR trajectory. The median coefficient of variation for ACR, representing the variability in ACR measurements, was 48.9 (interquartile range: 36.9, 68.2). The median compound annual growth rate (CAGR) for ACR, reflecting the variation in ACR progression over time, was 43.6% (interquartile range: 0.0, 102.5); and 84.5% of patients developed nephrotic-range albuminuria, with a majority remaining nephrotic and subsequently progressing to ESKD. There was a positive association between the instantaneous speed of eGFR decline and ACR. Conclusion: The observed curvilinear pattern in eGFR trajectory, high variability in ACR progression over time, and positive correlation between the speed of eGFR decline and ACR highlight the complex dynamics of disease progression and emphasize close monitoring of ACR fluctuation over time in patients with DKD.

11.
J Pharm Health Care Sci ; 10(1): 5, 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38191469

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) systems generally use either liquid chromatography/tandem mass spectrometry (LC-MS/MS) or immunoassay, though both methodologies have disadvantages. In this study, we aimed to evaluate whether a CLAM-LC-MS/MS system, which consists of a sample preparation module directly connected to LC-MS/MS, could be used for clinical TDM work for immunosuppressive drugs in whole blood, which requires a hemolytic process. For this purpose, we prospectively validated this system for clinical measurement of tacrolimus and cyclosporin A in patients' whole blood. The results were also compared with those of commercial immunoassays. METHODS: Whole blood from patients treated with tacrolimus or cyclosporin A at the Department of Nephrology and Departments of Rheumatology, Kanazawa University Hospital, from May 2018 to July 2019 was collected with informed consent, and drug concentrations were measured by CLAM-LC-MS/MS and by chemiluminescence immunoassay (CLIA) for tacrolimus and affinity column-mediated immunoassay (ACMIA) for cyclosporin A. Correlations between the CLAM-LC-MS/MS and immunoassay results were analyzed. RESULTS: Two hundred and twenty-four blood samples from 80 patients were used for tacrolimus measurement, and 76 samples from 21 patients were used for cyclosporin A. Intra- and inter-assay precision values of quality controls were less than 7%. There were significant correlations between CLAM-LC-MS/MS and the immunoassays for tacrolimus and cyclosporin A (Spearman rank correlation coefficients: 0.861, 0.941, P < 0.00001 in each case). The drug concentrations measured by CLAM-LC-MS/MS were about 20% lower than those obtained using the immunoassays. CLAM-LC-MS/MS maintenance requirements did not interfere with clinical operations. Compared to manual pretreatment, automated pretreatment by CLAM showed lower inter-assay precision values and greatly reduced the pretreatment time. CONCLUSIONS: The results obtained by CLAM-LC-MS/MS were highly correlated with those of commercial immunoassay methods. CLAM-LC-MS/MS offers advantages in clinical TDM practice, including simple, automatic pretreatment, low maintenance requirement, and avoidance of interference.

12.
Sci Rep ; 14(1): 11481, 2024 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-38769367

RESUMO

Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to < 15 mL/min/1.73 m2 or a reduction of ≥ 30% in eGFR, confirmed by follow-up tests. Over a median follow-up of 513 days, 838 renal events were observed. High serum potassium levels (> 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels (< 33) correlated with higher event rates. Usage of renin-angiotensin system inhibitors, low serum calcium (< 8.4 mg/dL), and high uric acid levels (> 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0-5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD.


Assuntos
Taxa de Filtração Glomerular , Fidelidade a Diretrizes , Insuficiência Renal Crônica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Sistema de Registros , Insuficiência Renal Crônica/fisiopatologia
13.
Immunohorizons ; 8(1): 1-18, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38169549

RESUMO

Despite treatment advances, acute kidney injury (AKI)-related mortality rates are still high in hospitalized adults, often due to sepsis. Sepsis and AKI could synergistically worsen the outcomes of critically ill patients. TLR4 signaling and mitochondrial antiviral signaling protein (MAVS) signaling are innate immune responses essential in kidney diseases, but their involvement in sepsis-associated AKI (SA-AKI) remains unclear. We studied the role of MAVS in kidney injury related to the TLR4 signaling pathway using a murine LPS-induced AKI model in wild-type and MAVS-knockout mice. We confirmed the importance of M1 macrophage in SA-AKI through in vivo assessment of inflammatory responses. The TLR4 signaling pathway was upregulated in activated bone marrow-derived macrophages, in which MAVS helped maintain the LPS-suppressed TLR4 mRNA level. MAVS regulated redox homeostasis via NADPH oxidase Nox2 and mitochondrial reverse electron transport in macrophages to alleviate the TLR4 signaling response to LPS. Hypoxia-inducible factor 1α (HIF-1α) and AP-1 were key regulators of TLR4 transcription and connected MAVS-dependent reactive oxygen species signaling with the TLR4 pathway. Inhibition of succinate dehydrogenase could partly reduce inflammation in LPS-treated bone marrow-derived macrophages without MAVS. These findings highlight the renoprotective role of MAVS in LPS-induced AKI by regulating reactive oxygen species generation-related genes and maintaining redox balance. Controlling redox homeostasis through MAVS signaling may be a promising therapy for SA-AKI.


Assuntos
Injúria Renal Aguda , Sepse , Humanos , Animais , Camundongos , Lipopolissacarídeos , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Sepse/metabolismo
14.
Curr Dev Nutr ; 8(7): 103787, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39045146

RESUMO

Background: d-alanine administration prevented kidney damage in a murine acute kidney injury model. Further data are needed on the influence of d-alanine on kidney function in humans. Objective: This study investigated the effects of d-alanine intake on amino acid metabolism and kidney function in healthy volunteers. Methods: This multicenter pilot study randomly assigned individuals from the general Japanese population to receive 3 g or 6 g of d-alanine intake per day for 7 d in a 1:1 ratio. The primary endpoint was the mean change in plasma and urine d-alanine levels from baseline to 7 d after intake. The secondary endpoints were mean changes in kidney function and other clinical factors. Safety was assessed by evaluating adverse events and clinical parameters. Results: We randomly assigned 24 participants to the 3-g (n = 12) and 6-g d-alanine (n = 12) groups. The mean baseline estimated glomerular filtration rate (eGFR) was 73 mL/min/1.73 m2. The mean plasma d-alanine concentration increased from baseline by 77.5 ± 34.3 and 192.1 ± 80.9 nmol/mL in the 3-g and 6-g d-alanine groups (both p < 0.0001), respectively, in a dose-dependent manner (between-group difference: 114.6 nmol/mL; 95% CI: 62.1-167.2; P = 0.0002). A similar increase was observed for the urine d-alanine to creatinine ratio. The mean eGFR was elevated by 5.7 ± 8.8 mL/min/1.73 m2 in the 6-g d-alanine group (P = 0.045) but did not significantly change in the 3-g d-alanine group. Nonserious adverse events were reported in 11 participants. Conclusions: d-alanine intake increased plasma and urine d-alanine levels and was well tolerated in participants with normal kidney function. These results will be useful in future trials investigating the effects of d-alanine intake on kidney disease progression in patients with chronic kidney disease.This trial was registered at the UMIN Clinical Trials Registry as UMIN000051466.

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