RESUMO
BACKGROUND: An early report has shown the clinical benefit of the asymptomatic preoperative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening test, and some clinical guidelines recommended this test. However, the cost-effectiveness of asymptomatic screening was not evaluated. We aimed to investigate the cost-effectiveness of universal preoperative screening of asymptomatic patients for SARS-CoV-2 using polymerase chain reaction (PCR) testing. METHODS: We evaluated the cost-effectiveness of asymptomatic screening using a decision tree model from a payer perspective, assuming that the test-positive rate was 0.07% and the screening cost was 8500 Japanese yen (JPY) (approximately 7601 US dollars [USD]). The input parameter was derived from the available evidence reported in the literature. A willingness-to-pay threshold was set at 5 000 000 JPY/quality-adjusted life-year (QALY). RESULTS: The incremental cost of 1 death averted was 74 469 236 JPY (approximately 566 048 USD) and 291 123 368 JPY/QALY (approximately 2 212 856 USD/QALY), which was above the 5 000 000 JPY/QALY willingness-to-pay threshold. The incremental cost-effectiveness ratio fell below 5 000 000 JPY/QALY only when the test-positive rate exceeded 0.739%. However, when the probability of developing a postoperative pulmonary complication among SARS-CoV-2-positive patients was below 0.22, asymptomatic screening was never cost-effective, regardless of how high the test-positive rate became. CONCLUSIONS: Asymptomatic preoperative universal SARS-CoV-2 PCR screening is not cost-effective in the base case analysis. The cost-effectiveness mainly depends on the test-positive rate, the frequency of postoperative pulmonary complications, and the screening costs; however, no matter how high the test-positive rate, the cost-effectiveness is poor if the probability of developing postoperative pulmonary complications among patients positive for SARS-CoV-2 is sufficiently reduced.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Análise Custo-Benefício , COVID-19/diagnóstico , Reação em Cadeia da Polimerase , Anos de Vida Ajustados por Qualidade de Vida , Teste para COVID-19RESUMO
Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.
Assuntos
COVID-19 , Células B de Memória , Humanos , SARS-CoV-2 , Células T de Memória , Vacina BNT162 , VacinaçãoRESUMO
BACKGROUND: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity. METHODS: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group. RESULTS: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1ß, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group. CONCLUSIONS: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients.
Assuntos
Anticorpos Antivirais , Vacina BNT162 , COVID-19 , Imunidade Humoral , Imunização Secundária , Diálise Renal , Humanos , Masculino , Feminino , COVID-19/imunologia , COVID-19/prevenção & controle , Pessoa de Meia-Idade , Idoso , Anticorpos Antivirais/sangue , Vacina BNT162/imunologia , Citocinas/sangue , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Imunidade Celular , Imunoglobulina G/sangue , Japão , Células B de Memória/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Diálise Peritoneal , População do Leste AsiáticoRESUMO
BACKGROUND: The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment. METHODS: Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats. RESULTS: Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin. CONCLUSIONS: The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.
Assuntos
Sistema Cardiovascular , Inibidores do Transportador 2 de Sódio-Glicose , Ratos , Animais , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Glucose , FibroseRESUMO
BACKGROUND: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown. METHODS: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing. RESULTS: Two genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion. CONCLUSIONS: Common variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.
Assuntos
Estudo de Associação Genômica Ampla , Rim , Creatinina , Humanos , Polimorfismo de Nucleotídeo Único , Isomerases de Dissulfetos de Proteínas/genética , Uromodulina/genéticaRESUMO
BACKGROUND: Critical coronavirus disease 2019 (COVID-19) has a high fatality rate, especially in hemodialysis (HD) patients, with this poor prognosis being caused by systemic hyperinflammation; cytokine storms. Steroid pulse therapy or tocilizumab (TCZ) have insufficient inhibitory effects against cytokine storms in critical cases. This study evaluated the clinical effects and safety of combining steroid pulse therapy and TCZ. METHODS: From September 2020 to May 2021, 201 patients with COVID-19 were admitted to our hospital. Before February 2021, patients with an oxygen demand exceeding 8 L/min were intubated and treated with standard therapy (dexamethasone and antiviral therapy). After February 2021, patients underwent high-flow nasal cannula oxygen therapy and were treated with TCZ (8 mg/kg) and methylprednisolone (mPSL) (500 mg/day [≤ 75 kg], 1000 mg/day [> 75 kg]) for 3 days. We compared background characteristics, laboratory findings, and prognosis between non-HD and HD patients and between patients who received and did not receive TCZ and mPSL pulse therapy. RESULTS: Among non-HD patients, the TCZ + mPSL pulse group had significantly higher survival rates and lower secondary infection rates (p < 0.05), than the standard therapy group. All HD patients in the standard therapy group with oxygen demand exceeding 8 L/min died. Contrastingly, all patients in the TCZ + mPSL pulse group survived, with their oxygen demand decreasing to 0-1 L/min within 3 weeks post-administration. CONCLUSION: TCZ combined with mPSL pulse therapy improved the survival rate without significant adverse events in critical HD and non-HD patients with COVID-19 by strongly suppressing systemic hyperinflammation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Tratamento Farmacológico da COVID-19 , Síndrome da Liberação de Citocina/prevenção & controle , Glucocorticoides/administração & dosagem , Nefropatias/terapia , Metilprednisolona/administração & dosagem , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/mortalidade , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Quimioterapia Combinada , Feminino , Glucocorticoides/efeitos adversos , Humanos , Nefropatias/diagnóstico , Nefropatias/imunologia , Nefropatias/mortalidade , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Pulsoterapia , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The mortality rate of Coronavirus disease 2019 (COVID-19) is extremely high in hemodialysis patients (HDP). These patients also develop lower antibody titers after vaccination. Therefore, factors associated with antibody titers and vaccine efficacy in HDP with breakthrough infection need to be investigated. METHODS: We measured anti-S1 antibody titers in HDP (n = 104) and controls (n = 35), evaluating the influence of background on HDP by multivariable regression analysis. We classified 26 HDP patients admitted with COVID-19 into the unvaccinated (n = 15) and breakthrough infection group (n = 11), performing between-group comparisons of laboratory findings and prognosis. Vaccinated COVID-19 patients were classified into HDP and non-HDP controls, and compared the relationship between antibody titer and severity, and the prognosis of breakthrough infection. RESULTS: The antibody titer was significantly lower in the HDP group than in the control group. Among HDP, age and smoking history were significantly independent factors associated with antibody titer. The breakthrough infection group had significantly better laboratory findings (KL-6 and LDH), severity, and hospitalization period than the unvaccinated group even if antibody titers were lower than the known threshold for neutralization (p < 0.05). There was no significant difference in prognosis between the HDP and non-HDP with breakthrough infection. Severity of COVID-19 tended to be higher with lower antibody titer in non-HDP, but not in HDP. CONCLUSION: Vaccines improved the severity of COVID-19 and hospitalization period of breakthrough infection in HDP, although HDP, especially in elderly smokers had lower antibody titers than control. There was no significant association between antibody titer and severity in HDP.
Assuntos
COVID-19 , SARS-CoV-2 , Idoso , Anticorpos Antivirais , Vacina BNT162 , Vacinas contra COVID-19 , Humanos , Prognóstico , Diálise RenalRESUMO
BACKGROUND: Ceftazidime encephalopathy is reported to be caused by the repeated administration of ceftazidime in patients with renal impairment because of the high serum concentration of ceftazidime. Ceftazidime encephalopathy has been considered to be caused by the elevation of the cerebrospinal fluid (CSF) concentration. However, as no reports have measured CSF concentrations, the relationship with ceftazidime encephalopathy and CSF concentration has not been clarified. CASE PRESENTATION: Case 1: An 80-year-old Japanese man under a combination therapy with peritoneal dialysis and hemodialysis, who had been treated for a cellulitis with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was only under 0.1 µg/mL. Case 2: An 88-year-old Japanese man with chronic kidney disease, who had been treated for a urinary tract infection with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was within the therapeutic range. However, his serum and CSF concentration of quinolinic acid was markedly increased. CONCLUSIONS: Patients with renal failure are more likely to develop ceftazidime encephalopathy. We need to pay attention to the dosage of ceftazidime and to the appearance of neurological symptoms. Ceftazidime encephalopathy was considered to be caused by the high CSF concentration, but it could be caused by quinolinic acid as neurotoxic substance.
Assuntos
Encefalopatias , Diálise Peritoneal , Insuficiência Renal , Idoso de 80 Anos ou mais , Ceftazidima/efeitos adversos , Humanos , Masculino , Ácido QuinolínicoRESUMO
A 70-year-old woman, who started on hemodialysis 7 months before for end-stage renal disease due to diabetic nephropathy and was diagnosed with symptomatic multiple myeloma 1 month before, was admitted to our hospital with critical coronavirus disease 2019 and treated with long-term immunosuppressive therapy such as steroids and tocilizumab. During treatment, Bacillus subtilis was detected in the blood cultures. We could not exclude the association of natto (fermented soybeans) with B. subtilis var. natto, which the patient had been eating every day from 8 days after admission. She was prohibited from eating natto and treated with vancomycin. Later, B. subtilis detected in the blood culture was identified as B. subtilis var. natto, which was identical with those contained in the natto that the patient consumed daily using a next-generation sequencer. Gut dysbiosis due to old age, malignant tumor, diabetes mellitus, end-stage renal disease, and intestinal inflammation caused by severe acute respiratory syndrome coronavirus 2 increased intestinal permeability and the risk of bacterial translocation, causing B. subtilis var. natto bacteremia. Therefore, careful consideration might be given to the intake of fermented foods containing live bacteria in patients with severe immunocompromised conditions.
Assuntos
Bacteriemia , Tratamento Farmacológico da COVID-19 , COVID-19 , Falência Renal Crônica , Mieloma Múltiplo , Alimentos de Soja , Idoso , Bacillus subtilis , Bacteriemia/tratamento farmacológico , COVID-19/complicações , Ingestão de Alimentos , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Diálise Renal , Alimentos de Soja/microbiologiaRESUMO
A 60-year-old man presented with dyspnea four days after the second dose of the coronavirus disease (COVID-19) vaccine. Imaging revealed extensive ground-glass opacification. Blood tests were notable for elevated KL-6 levels. Bronchoalveolar lavage fluid analysis showed increased lymphocyte-dominant inflammatory cells and decreased CD4/CD8 ratio. These findings were consistent with the diagnosis of drug-induced interstitial lung disease (DIILD). To the best of our knowledge, this has never been reported in previous literature. Treatment with glucocorticoids relieved his symptoms. This paper highlights that although extremely rare, COVID-19 vaccine could cause DIILD, and early diagnosis and treatment are crucial to improve patient outcomes.
Assuntos
COVID-19 , Doenças Pulmonares Intersticiais , Vacinas contra COVID-19 , Dispneia , Humanos , Pulmão , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Pessoa de Meia-Idade , SARS-CoV-2RESUMO
BACKGROUND: Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. METHODS: CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. RESULTS: IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. CONCLUSIONS: Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.
Assuntos
Bactérias/isolamento & purificação , Disbiose/complicações , Microbioma Gastrointestinal , Resistência à Insulina , Insuficiência Renal Crônica/fisiopatologia , Sarcopenia/etiologia , Uremia/complicações , Animais , Disbiose/microbiologia , Transplante de Microbiota Fecal , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sarcopenia/patologia , Sarcopenia/terapiaRESUMO
Ketone bodies including ß-hydroxybutyrate (ß-OHB) have been shown to protect against ischemic tissue injury when present at low concentrations. We evaluated the impact of ß-OHB on renal ischemia/reperfusion injury (IRI). Mice were treated with a continuous infusion of ß-OHB using an osmotic mini-pump before and after IRI. We also tested the effects of increasing endogenous serum ß-OHB levels by fasting. Renal IRI was attenuated by ß-OHB treatment compared to saline control, with similar results in the fasting condition. ß-OHB treatment reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and increased expression of forkhead transcription factor O3 (FOXO3), an upstream regulator of pyroptosis. Although ß-OHB treatment did not impact markers of apoptosis, it decreased the expression of caspase-1 and proinflammatory cytokines, indicating that ß-OHB blocked pyroptosis. In a human proximal tubular cell line exposed to hypoxia and reoxygenation, ß-OHB reduced cell death in a FOXO3-dependent fashion. Histone acetylation was decreased in kidneys exposed to IRI and in proximal tubular cells exposed to hypoxia and reoxygenation, and this effect was ameliorated by ß-OHB through the inactivation of histone deacetylases. In vitro, ß-OHB treatment restored histone acetylation at the FOXO3 promoter. Consistent with epigenetic molecular effects, the renoprotective effects of ß-OHB were still observed when the continuous infusion was stopped at the time of IRI. Thus, ß-OHB attenuates renal IRI through anti-pyroptotic effects, likely mediated by an epigenetic effect on FOXO3 expression.
Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Proteína Forkhead Box O3/genética , Túbulos Renais/irrigação sanguínea , Piroptose/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Ácido 3-Hidroxibutírico/uso terapêutico , Acetilação/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Infusões Intravenosas , Masculino , Camundongos , Regiões Promotoras Genéticas/genética , Piroptose/genética , Traumatismo por Reperfusão/etiologiaRESUMO
Uromodulin, the most abundant protein in normal urine, is essentially produced by the cells lining the thick ascending limb. There it regulates the activity of the cotransporter NKCC2 and is involved in sodium chloride handling and blood pressure regulation. Conflicting reports suggested that uromodulin may also be expressed in the distal convoluted tubule (DCT) where its role remains unknown. Using microdissection studies combined with fluorescent in situ hybridization and co-immunostaining analyses, we found a significant expression of uromodulin in mouse and human DCT at approximately 10% of thick ascending limb expression levels, but restricted to the early part of the DCT (DCT1). Genetic deletion of Umod in mouse was reflected by a major shift in NCC activity from the DCT1 to the downstream DCT2 segment, paralleled by a compensatory expansion of DCT2. By increasing the distal sodium chloride and calcium ion load with chronic furosemide administration, an intrinsic compensatory defect in the DCT from Umod-/- compared to wild type mice was found manifested as sodium wasting and hypercalciuria. In line, co-expression studies in HEK cells suggested a facilitating role for uromodulin in NCC phosphorylation, possibly via SPAK-OSR1 modulation. These experiments demonstrate a significant expression of uromodulin in the early part of mouse and human DCT. Thus, biosynthesis of uromodulin in the DCT1 is critical for its function, structure and plasticity, suggesting novel links between uromodulin, blood pressure control and risk of kidney stones.
Assuntos
Túbulos Renais Distais/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Uromodulina/biossíntese , Uromodulina/genética , Uromodulina/metabolismo , Animais , Furosemida/farmacologia , Expressão Gênica , Células HEK293 , Humanos , Hipercalciúria/induzido quimicamente , Hipercalciúria/genética , Túbulos Renais Distais/fisiologia , Masculino , Camundongos , Camundongos Knockout , Fosforilação , RNA Mensageiro , Sódio/metabolismo , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Membro 1 da Família 12 de Carreador de Soluto/antagonistas & inibidores , Membro 1 da Família 12 de Carreador de Soluto/genéticaRESUMO
BACKGROUND: Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment. METHOD: Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx + AST) (n = 10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact. RESULTS: The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx + AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx + AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx + AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx + AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects. CONCLUSION: AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.
Assuntos
Carbono/farmacologia , Absorção Intestinal/efeitos dos fármacos , Óxidos/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Nefrectomia , Ratos , Ratos Endogâmicos SHR , TóquioRESUMO
BACKGROUND: The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS: Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS: Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 × 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS: Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.
Assuntos
Intestinos/microbiologia , Lactobacillus/fisiologia , Insuficiência Renal Crônica/prevenção & controle , Animais , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Ratos , Insuficiência Renal Crônica/sangueRESUMO
BACKGROUND: The lipodystrophy-like phenotype has been suggested in early chronic kidney disease (CKD). It includes adipose tissue atrophy, systemic insulin resistance (IR), dyslipidemia and ectopic lipid accumulation. To elucidate its pathogenesis, we investigated the role of two uremic toxins that affect insulin sensitivity: an endogenous nitric oxide synthase inhibitor, and asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS). METHODS: Six-week-old Sprague-Dawley rats were rendered CKD by subtotal nephrectomy (Nx) and compared with sham-operated rats. Cultured 3T3-L1 fibroblasts were differentiated into mature adipocytes with or without ADMA. Transgenic (Tg) mice overexpressing each isoform of ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2 were subject to Nx and their phenotypes were investigated. RESULTS: In Nx rats, IR was evident and insulin stimulation failed to activate insulin signaling in adipose tissues. Adipose tissue weight, adipocyte size and adipocyte differentiation marker expressions decreased as a consequence of IR in Nx. Tissue lipid content in the liver and muscle increased in Nx rats. Tissue levels of ADMA, IS and oxidative stress increased in the adipose tissue of Nx rats. Both DDAH1 and DDAH2 expressions decreased, and a putative IS receptor, aryl hydrocarbon receptor, expression increased in the adipose tissue of Nx rats. ADMA inhibited adipocyte differentiation, triglyceride accumulation and insulin signaling, which were reversed by pretreatment with cGMP. In each type of Tg mice overexpressing DDAH1 or DDAH2, all lipodystrophy-like phenotypes induced by Nx were reversed. CONCLUSIONS: In mild CKD, dysregulation of the ADMA/DDAH pathway in adipose tissue triggers lipodystrophy-like phenotype changes, including ectopic fat depositions.
Assuntos
Tecido Adiposo/metabolismo , Amidoidrolases/genética , Arginina/análogos & derivados , Regulação da Expressão Gênica , Estresse Oxidativo/genética , RNA/genética , Insuficiência Renal Crônica/genética , Amidoidrolases/biossíntese , Animais , Arginina/biossíntese , Arginina/genética , Western Blotting , Células Cultivadas , Masculino , Camundongos , Camundongos Transgênicos , Nefrectomia/efeitos adversos , Fenótipo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Insuficiência Renal Crônica/metabolismo , Transdução de SinaisRESUMO
In this study, we examined the association between chronic kidney disease (CKD) and insulin resistance. In a patient cohort with nondiabetic stages 2-5 CKD, estimated glomerular filtration rate (eGFR) was negatively correlated and the plasma aldosterone concentration was independently associated with the homeostasis model assessment of insulin resistance. Treatment with the mineralocorticoid receptor blocker spironolactone ameliorated insulin resistance in patients, and impaired glucose tolerance was partially reversed in fifth/sixth nephrectomized rats. In these rats, insulin-induced signal transduction was attenuated, especially in the adipose tissue. In the adipose tissue of nephrectomized rats, nuclear mineralocorticoid receptor expression, expression of the mineralocorticoid receptor target molecule SGK-1, tissue aldosterone content, and expression of the aldosterone-producing enzyme CYP11B2 increased. Mineralocorticoid receptor activation in the adipose tissue was reversed by spironolactone. In the adipose tissue of nephrectomized rats, asymmetric dimethylarginine (ADMA; an uremic substance linking uremia and insulin resistance) increased, the expression of the ADMA-degrading enzymes DDAH1 and DDAH2 decreased, and the oxidative stress increased. All of these changes were reversed by spironolactone. In mature adipocytes, aldosterone downregulated both DDAH1 and DDAH2 expression, and ADMA inhibited the insulin-induced cellular signaling. Thus, activation of mineralocorticoid receptor and resultant ADMA accumulation in adipose tissue has, in part, a relevant role in the development of insulin resistance in CKD.
Assuntos
Aldosterona/metabolismo , Resistência à Insulina , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Insuficiência Renal Crônica/fisiopatologia , Espironolactona/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Idoso , Aldosterona/sangue , Amidoidrolases/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Núcleo Celular/metabolismo , Citocromo P-450 CYP11B2/metabolismo , Feminino , Taxa de Filtração Glomerular , Teste de Tolerância a Glucose , Homeostase/efeitos dos fármacos , Humanos , Proteínas Imediatamente Precoces/metabolismo , Masculino , Pessoa de Meia-Idade , Nefrectomia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Mineralocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Renina/sangue , Transdução de Sinais/efeitos dos fármacos , Espironolactona/uso terapêuticoRESUMO
A 70-year-old immunocompetent male with a history of insomnia presented with pneumonia and bacteremia caused by Bacillus subtilis. The patient took benzodiazepines and regularly consumed alcohol and natto (fermented soybeans). Initial antibiotic treatment was not effective, and bronchoalveolar lavage was performed. Bronchoalveolar lavage fluid (BALF) analysis revealed an increased lymphocytes fraction, and B. subtilis was detected in the BALF. Whole-genome sequencing confirmed the congruence of the genetic sequences between the strain in the blood culture of the patient, BALF, and strain isolated from the consumed natto, confirming B. subtilis subsp. natto as the causative pathogen of pneumonia and bacteremia. Vancomycin followed by levofloxacin and systemic corticosteroid were used to treat the condition. This case highlights community-acquired pneumonia and bacteremia caused by B. subtilis subsp. natto, particularly in individuals who consume natto.