RESUMO
Sodium benzoate (SB), a known D-amino acid oxidase (DAO) enzyme inhibitor, has an anti-inflammatory effect, although its role in renal damage has not been explored. 2,8-dihydroxyadenine crystal induced chronic kidney disease, in which TNF-α is involved in the pathogenesis, was established by oral adenine administration in C57BL/6JJcl mice (AdCKD) with or without SB to investigate its renal protective effects. SB significantly attenuated AdCKD by decreasing serum creatinine and urea nitrogen levels, and kidney interstitial fibrosis and tubular atrophy scores. The survival of AdCKD mice improved 2.6-fold by SB administration. SB significantly decreased the number of infiltrating macrophages observed in the positive F4/80 immunohistochemistry area and reduced the expression of macrophage markers and inflammatory genes, including TNF-α, in the kidneys of AdCKD. Human THP-1 cells stimulated with either lipopolysaccharide or TNF-α showed increased expression of inflammatory genes, although this was significantly reduced by SB, confirming the anti-inflammatory effects of SB. SB exhibited renal protective effects in AdCKD in DAO enzyme deficient mice, suggesting that anti-inflammatory effect of SB was independent of DAO enzyme activity. Moreover, binding to motif DNA sequence, protein level, and mRNA level of NF-κB RelB were significantly inhibited by SB in AdCKD kidneys and lipopolysaccharide treated THP-1 cells, respectively. We report that anti-inflammatory property of SB is independent of DAO enzymatic activity and is associated with down regulated NF-κB RelB as well as its downstream inflammatory genes such as TNF-α in AdCKD.
Assuntos
Insuficiência Renal Crônica , Fator de Necrose Tumoral alfa , Humanos , Animais , Camundongos , Camundongos Endogâmicos C57BL , Benzoato de Sódio , Lipopolissacarídeos , Monócitos , NF-kappa B , MacrófagosRESUMO
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
PURPOSE: Remote patient monitoring (RPM) has contributed to improved patient-centered outcomes and prognosis in patients with end-stage renal disease on automated peritoneal dialysis (APD). However, evidence from prospective trials is lacking. METHODS: The participants (n = 15; median age: 65 years; males: 10; peritoneal dialysis vintage: 6.4 ± 3.5 years) randomly received APD therapy using the Kaguya® APD system either with or without the connective use of the cloud-based RPM software Sharesource® for 12 weeks. The primary outcome was patient satisfaction assessed using a modified nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) questionnaire. The secondary outcomes were healthcare resource consumption, the health-related quality of life (HRQOL) subscales assessed with the Kidney Disease Quality of Life-Short Form questionnaire, and clinical laboratory parameters. RESULTS: Significant improvements were observed in the TSQM-9 subscales of Effectiveness (64.4 ± 18.8 vs. 57.8 ± 18.8; P = 0.006) and Convenience (76.3 ± 15.4 vs. 63.3 ± 17.3; P < 0.001) in patients on Sharesource®. Moreover, Sharesource® reduced the total amount of healthcare resource consumption (0.80 ± 1.32 vs. 1.87 ± 2.39 times/12 weeks; P = 0.02) and consultation time during regular monthly visits (813 ± 269 vs. 1024 ± 292 s; P < 0.001). A significant increase in ultrafiltration volume was found associated with more frequent modification of APD prescription in patients with Sharesource®. Sharesource® also improved the HRQOL subscale of General Health and Vitality. CONCLUSION: Sharesource® can improve patient-centered outcomes in patients on APD while reducing the treatment burden for both patients and medical staff. TRIAL REGISTRATION: The study was registered in the Japan Registry of Clinical Trials (jRCT Number: jRCTs032190005).
Assuntos
Falência Renal Crônica , Diálise Peritoneal , Idoso , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Masculino , Monitorização Fisiológica , Satisfação do Paciente , Diálise Peritoneal/efeitos adversos , Estudos Prospectivos , Qualidade de VidaRESUMO
Dysregulation of nicotinamide adenine dinucleotide (NAD +) metabolism contributes to the initiation and progression of age-associated diseases, including chronic kidney disease (CKD). Nicotinamide N-methyltransferase (NNMT), a nicotinamide (NAM) metabolizing enzyme, regulates both NAD + and methionine metabolism. Although NNMT is expressed abundantly in the kidney, its role in CKD and renal fibrosis remains unclear. We generated NNMT-deficient mice and a unilateral ureter obstruction (UUO) model and conducted two clinical studies on human CKD to investigate the role of NNMT in CKD and fibrosis. In UUO, renal NNMT expression and the degraded metabolites of NAM increased, while NAD + and NAD + precursors decreased. NNMT deficiency ameliorated renal fibrosis; mechanistically, it (1) increased the DNA methylation of connective tissue growth factor (CTGF), and (2) improved renal inflammation by increasing renal NAD + and Sirt1 and decreasing NF-κB acetylation. In humans, along with CKD progression, a trend toward a decrease in serum NAD + precursors was observed, while the final NAD + metabolites were accumulated, and the level of eGFR was an independent variable for serum NAM. In addition, NNMT was highly expressed in fibrotic areas of human kidney tissues. In conclusion, increased renal NNMT expression induces NAD + and methionine metabolism perturbation and contributes to renal fibrosis.
Assuntos
NAD , Nicotinamida N-Metiltransferase , Insuficiência Renal Crônica , Obstrução Ureteral , Animais , Feminino , Fibrose , Humanos , Masculino , Metionina , Camundongos , NAD/metabolismo , Niacinamida/metabolismo , Nicotinamida N-Metiltransferase/genética , Nicotinamida N-Metiltransferase/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismoRESUMO
Fabry disease (FD) is an X-linked genetic lysosomal disorder caused by alpha-galactosidase A (GLA) deficiency. Multiple myeloma (MM) predominately affects older adults, which ranks as the second commonest hematological malignancy. Their overlap has rarely been reported. We present a case of the coexistence of FD and MM in a patient. We report the case of a 68-year-old woman who was referred to our hospital for the evaluation of thoracic spine tumor with bone destruction. On admission, her serum creatinine (Cr) level was elevated to 12.70 mg/dL from the baseline value of 0.91 mg/dL. Bone marrow aspiration revealed MM. Renal biopsy showed myeloma cast nephropathy, which was the primary cause of acute kidney injury. Renal pathology also showed podocyte swelling and tubule myeloid bodies in a mosaic pattern compatible with female FD. Consequently, the patient was diagnosed as FD based on the germ line mutation in GLA. The patient was treated with bortezomib and dexamethasone therapy, which significantly improved the renal function. This is the second case demonstrating a potential pathogenic relationship between FD and MM. Since FD is one of the few genetic diseases for which there are therapeutic agents with fewer side effects, diagnostic value of FD is high. If an MM patient has multiple organ abnormalities or any familial history, the physician should suspect FD.
Assuntos
Doença de Fabry , Nefropatias , Mieloma Múltiplo , Idoso , Bortezomib/uso terapêutico , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , Feminino , Humanos , Rim/patologia , Nefropatias/patologia , Masculino , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológicoRESUMO
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.