RESUMO
INTRODUCTION: Aging of the kidney is associated with complex molecular, histological, and functional changes. Although the aging process itself does not induce renal damage, underlying disease such as diabetes mellitus can aggravate kidney injury during aging. Although oxidative stress is considered an important mediator in age-related renal fibrosis, it is unclear how oxidative stress increases during normal and diabetic aging. METHODS: In this study, we investigated molecular changes in the kidney in normal and diabetic aging mice. C57BL/6 mice were studied at 2, 12, and 24 months of age, and leptin receptor-deficient db/db mice were studied at 8, 12, 16, 20, 24, and 38 weeks of age. We measured renal functional parameters, fibrotic and inflammatory markers, and oxidative stress markers at all the above time points. RESULTS: Both nondiabetic and diabetic mice exhibited progressive microalbuminuria during their lifespan. Interestingly, both diabetic aging and normal aging mice showed progressive increases in oxidative stress markers such as plasma and urinary 8-isoprostane, as well as renal lipid hydroperoxide content. In renal tissues, proinflammatory and profibrotic molecules were significantly upregulated in an age-dependent manner. Expression of three NADPH oxidase (Nox) isoforms, namely, Nox1, Nox2, and Nox4, was significantly increased during aging. Compared with normal aging mice, diabetic db/db mice demonstrated more dramatic changes during aging process. CONCLUSIONS: Our findings suggest that NADPH oxidases play an important role in the aging kidney under both normal and diabetic conditions. Targeting of these oxidases might be a new promising therapy to treat issues associated with aging kidneys.
Assuntos
Diabetes Mellitus Experimental , NADPH Oxidases , Camundongos , Animais , NADPH Oxidases/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Camundongos Endogâmicos C57BL , Rim/patologia , Estresse Oxidativo , Envelhecimento , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: The incidence of fractures is much higher in patients with chronic kidney disease, especially those on hemodialysis (HD). Denosumab is known to treat osteoporosis. However, no exact guideline exists for treatment with denosumab in patients, especially those with diabetes. This study analyzed the effect of denosumab in HD patients with or without diabetes. MATERIALS AND METHODS: Dual-energy X-ray absorptiometry was performed in 89 HD patients: 42 were diagnosed with osteoporosis. 33 patients were treated with denosumab. An observational retrospective analysis was conducted in 25 HD patients whose follow-up biomarkers were measured at 6 months after denosumab treatment. FINDINGS: Bone mineral density (BMD) of lumbar spine (LS) and femur neck (FN) were largely improved (+3.40% and 4.96%, respectively) 1 year after the treatment. The T-scores were also improved. Both bone turnover markers were significantly decreased 6 months after treatment; the levels of C-terminal telopeptide (CTX) and bone-specific alkaline phosphatase (bsALP) were decreased by -1.04 ± 1.24 ng/mL (p < 0.001) and -35.72 ± 36.07 IU/L (p < 0.001), respectively. The response was significantly different between the diabetes and non-diabetes group. The increase in LS BMD was significantly lower in the diabetes group than in the non-diabetes group (0.02 ± 0.03 vs. 0.07 ± 0.02, p = 0.02). Decrease in CTX, but not in bsALP, was also lower in the diabetes group compared to the non-diabetes group (-0.58 ± 0.70 vs. -1.55 ± 1.12, p = 0.03). Pretreatment with calcium and calcitriol prevented symptomatic hypocalcemia except in 1 case. CONCLUSION: Denosumab improved bone density and osteoclastic activity in HD patients, with a lower response in patients with diabetes.
Assuntos
Conservadores da Densidade Óssea , Diabetes Mellitus , Biomarcadores , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Remodelação Óssea , Denosumab/efeitos adversos , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Humanos , Diálise Renal , Estudos RetrospectivosRESUMO
Despite that clinical trials have been examining the safety profile of coronavirus disease 2019 (COVID-19) vaccines, there are concerns about long-term side effects as the number of vaccinations increases. Herein, we report a case of new-onset renal-limited anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis after booster vaccination with the mRNA 1273 (Moderna) vaccine. A 72-year-old woman with no specific past history, and who had a normal renal function, developed ANCA-associated vasculitis following heterologous booster with mRNA1273 (Moderna) vaccine. After a kidney biopsy, she was diagnosed with ANCA-associated pauci-immune crescentic glomerulonephritis. Her renal function and constitutional symptoms have been improved with treatment with plasmapheresis, intravenous cyclophosphamide and steroid pulse therapy (intravenous 500 mg of methylprednisolone sodium succinate for 3 days) followed by a reduced steroid regimen.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , COVID-19 , Glomerulonefrite , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/etiologia , Anticorpos Anticitoplasma de Neutrófilos , Feminino , Glomerulonefrite/patologia , Humanos , Vacinação/efeitos adversosRESUMO
AIMS: The long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period. METHODS: The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study. RESULTS: The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00% ± 0.21% and 0.65% ± 0.22% lower at week 52 than at baseline (P < .001 and P = .003), respectively. No significant difference in the change in HbA1c level was found between the 2 groups (P = .148). Trends in fasting plasma glucose, fructosamine and glycated albumin levels in the 2 groups were similar to trends in HbA1c levels. The eGFR of both groups was also significantly lower at week 52 than at baseline, and no significant difference in change in eGFR was found between the 2 groups. In contrast, both drugs had little effect on urinary albumin excretion, although both drugs significantly reduced the urinary type IV collagen level. The overall rates of adverse events were similar between the 2 groups. CONCLUSIONS: Gemigliptin and linagliptin did not differ with respect to safety and efficacy in patients with T2DM and renal impairment. The 2 drugs had similar glucose-lowering effects, and the changes in eGFR and albuminuria were also similar. Additionally, the risk of side effects, including hypoglycaemia, was similar between the 2 groups.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Linagliptina/uso terapêutico , Piperidonas/uso terapêutico , Pirimidinas/uso terapêutico , Insuficiência Renal Crônica/fisiopatologia , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Monitoramento de Medicamentos , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Rim/fisiopatologia , Linagliptina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Piperidonas/efeitos adversos , Pirimidinas/efeitos adversos , Insuficiência Renal Crônica/complicações , Índice de Gravidade de Doença , Compostos de Sulfonilureia/uso terapêuticoRESUMO
The epithelial to mesenchymal transition (EMT), a hallmark of chronic kidney disease, is a key event in the conversion from tubular epithelial cells to myofibroblasts in renal fibrosis. Epstein-Barr virus (EBV) is a γ-herpes oncovirus associated with chronic kidney disease. However, the relationship between EBV and the EMT process in renal tubular epithelial cells is not well understood. Among EBV-latent genes, EBV-encoded latent membrane protein 1 (LMP1) induces EMT by regulating a variety of molecules in EBV-induced oncogenic transformation. In this study, we investigated EBV-encoded LMP1 and EMT process markers in human proximal tubule epithelial cell line HK-2. LMP1 overexpression induces cell morphological changes via the epithelial to mesenchymal process in HK-2 cells, and these changes accelerate cell proliferation, cell motility, and invasion. Furthermore, VSIG4 upregulation by EBV-LMP1 induced LMP1-mediated EMT, cell motility, and invasion. VSIG4 upregulation by LMP1 was regulated at the transcriptional level via the NF-kB signaling axis. These results suggest that EBV-encoded LMP1 regulates EMT through the NF-kB-VSIG4 axis in HK-2 cells, and VSIG4 is a potential target in EBV-induced chronic kidney diseases.
Assuntos
Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Túbulos Renais/metabolismo , NF-kappa B/metabolismo , Receptores de Complemento/genética , Proteínas da Matriz Viral/metabolismo , Animais , Células Cultivadas , Cães , Humanos , Túbulos Renais/citologia , Células Madin Darby de Rim Canino , Receptores de Complemento/metabolismoRESUMO
Patients with chronic kidney disease (CKD) have markedly increased rates of major adverse cardiovascular and cerebrovascular events (MACCEs) and mortality. Therefore, identifying early biomarkers predicting clinical outcomes in patients with CKD is critical. We aimed to determine whether osteoglycin, a basic component of the vascular extracellular matrix, was associated with MACCEs or all-cause mortality, using data from a prospective randomized controlled study, K-STAR (Kremezin STudy Against Renal disease progression in Korea: NCT 00860431). A total of 383 patients (mean age: 56.4 years, men/women = 252/131) with CKD stage 3 to 4 from the original trial were enrolled in the present study. We measured serum osteoglycin level and examined the impact of osteoglycin on clinical outcomes. The mean value of osteoglycin levels was 13.3 ± 9.4 ng/mL (healthy control: 5.3 ± 2.1 ng/mL). In multivariable analysis, lower levels of proteinuria and hemoglobin and higher levels of C-reactive protein were significantly associated with higher osteoglycin levels. Estimated glomerular filtration rate was not related to osteoglycin level. During a mean follow-up period of 56 months, 25 deaths, 61 MACCEs, and 76 composite outcomes (all-cause mortality or MACCEs) occurred. In the non-diabetic group, each 1-ng/mL increase in serum osteoglycin was associated with all-cause mortality and composite outcome (hazard ratio [HR] = 1.058, P = 0.031; HR = 1.041, P = 0.036). However, osteoglycin levels were not associated with mortality, MACCEs, or composite outcome in the diabetic group. Our results indicate that serum osteoglycin is a potential predictor of adverse outcomes in patients with CKD.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/mortalidade , Progressão da Doença , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/mortalidade , Doenças Cardiovasculares/complicações , Transtornos Cerebrovasculares/complicações , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Although dipeptidyl peptidase IV (DPPIV) inhibitors are known to have renoprotective effects, the mechanism underlying these effects has remained elusive. Here we investigated the effects of DA-1229, a novel DPPIV inhibitor, in two animal models of renal injury including db/db mice and the adriamycin nephropathy rodent model of chronic renal disease characterized by podocyte injury. For both models, DA-1229 was administered at 300 mg/kg/day. DPPIV activity in the kidney was significantly higher in diabetic mice compared with their nondiabetic controls. Although DA-1229 did not affect glycemic control or insulin resistance, DA-1229 did improve lipid profiles, albuminuria and renal fibrosis. Moreover, DA-1229 treatment resulted in decreased urinary excretion of nephrin, decreased circulating and kidney DPPIV activity, and decreased macrophage infiltration in the kidney. In adriamycin-treated mice, DPPIV activity in the kidney and urinary nephrin loss were both increased, whereas glucagon-like peptide-1 concentrations were unchanged. Moreover, DA-1229 treatment significantly improved proteinuria, renal fibrosis and inflammation associated with decreased urinary nephrin loss, and kidney DPP4 activity. In cultured podocytes, DA-1229 restored the high glucose/angiotensin II-induced increase of DPPIV activity and preserved the nephrin levels in podocytes. These findings suggest that activation of DPPIV in the kidney has a role in the progression of renal disease, and that DA-1229 may exert its renoprotective effects by preventing podocyte injury.
Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Rim/efeitos dos fármacos , Rim/lesões , Piperazinas/farmacologia , Podócitos/efeitos dos fármacos , Animais , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Mediadores da Inflamação/sangue , Mediadores da Inflamação/urina , Rim/fisiopatologia , Masculino , Proteínas de Membrana/urina , Camundongos , Camundongos Endogâmicos C57BL , Osteopontina/biossíntese , Osteopontina/genética , Podócitos/patologia , Substâncias Protetoras/farmacologiaRESUMO
Genome-wide association studies (GWASs) have identified multiple loci associated with the risk of CKD. Almost all risk variants are localized to the noncoding region of the genome; therefore, the role of these variants in CKD development is largely unknown. We hypothesized that polymorphisms alter transcription factor binding, thereby influencing the expression of nearby genes. Here, we examined the regulation of transcripts in the vicinity of CKD-associated polymorphisms in control and diseased human kidney samples and used systems biology approaches to identify potentially causal genes for prioritization. We interrogated the expression and regulation of 226 transcripts in the vicinity of 44 single nucleotide polymorphisms using RNA sequencing and gene expression arrays from 95 microdissected control and diseased tubule samples and 51 glomerular samples. Gene expression analysis from 41 tubule samples served for external validation. 92 transcripts in the tubule compartment and 34 transcripts in glomeruli showed statistically significant correlation with eGFR. Many novel genes, including ACSM2A/2B, FAM47E, and PLXDC1, were identified. We observed that the expression of multiple genes in the vicinity of any single CKD risk allele correlated with renal function, potentially indicating that genetic variants influence multiple transcripts. Network analysis of GFR-correlating transcripts highlighted two major clusters; a positive correlation with epithelial and vascular functions and an inverse correlation with inflammatory gene cluster. In summary, our functional genomics analysis highlighted novel genes and critical pathways associated with kidney function for future analysis.
Assuntos
Estudo de Associação Genômica Ampla , Insuficiência Renal Crônica/genética , Estudos de Casos e Controles , Humanos , Inflamação/metabolismo , Glomérulos Renais/metabolismo , Polimorfismo Genético , Insuficiência Renal Crônica/metabolismo , Uromodulina/genética , Urotélio/metabolismoRESUMO
It is known that blood pressure variability (BPV) can independently affect target organ damage (TOD), even with normal blood pressure. There have been few studieson chronic kidney disease (CKD) patients. We evaluated the relationship between BPV and TOD in a cross-sectional, multicenter study on hypertensive CKD patients. We evaluated 1,173 patients using 24-hr ambulatory blood pressure monitoring. BPV was defined as the average real variability, with a mean value of the absolute differences between consecutive readings of systolic blood pressure. TOD was defined as left ventricular hypertrophy (LVH) (by the Romhilt-Estes score ≥4 in electrocardiography) and kidney injury (as determined from an estimated glomerular filtration rate [eGFR]<30 mL/min/1.73 m(2) and proteinuria).The mean BPV of the subjects was 15.9±4.63 mmHg. BPV displayed a positive relationship with LVH in a univariate analysis and after adjustment for multi-variables (odds ratio per 1 mmHg increase in BPV: 1.053, P=0.006). In contrast, BPV had no relationship with kidney injury. These data suggest that BPV may be positively associated with LVH in hypertensive CKD patients.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertrofia Ventricular Esquerda/fisiopatologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Adulto , Idoso , Monitorização Ambulatorial da Pressão Arterial , Estudos Transversais , Eletrocardiografia , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/lesões , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteinúria/complicaçõesRESUMO
INTRODUCTION: The widely employed Kidney Donor Profile Index (KDPI) scoring system, designed for assessing deceased donors (DD), plays a pivotal role in predicting graft function post kidney transplantation (KT). Given the dynamic nature of renal function, including serum creatinine (sCr), in managing DDs, it remains uncertain optimal timing to use KDPI for assessing postoperative graft function. METHODS: In this retrospective review, we assessed 246 DDs who were managed within a donor management program from January 2010 to December 2021. We collected sCr values for KDPI scoring at admission, peak, and last measurements before KT. Recipient data included occurrence of slow graft function (SGF), delayed graft function (DGF), and glomerular filtration rate (GFR) at one-year post-transplantation (1 Y). Using Receiver Operating Characteristic (ROC) and Pearson correlation analyses, we explored correlations of KDPI score (admission, peak, last) with graft function (SGF, DGF, GFR 1 Y). RESULTS: The average age of DDs and recipients was 49.78 ± 13.37 and 52.54 ± 10.49 years, respectively, with mean KDPI values at admission, peak, and last measurements of 62.36 ± 25.44, 66.94 ± 24.73, and 63.75 ± 25.80. After transplantation, SGF was observed in 81 recipients (32.9%) and DGF in 32 (13.0%). For SGF, the Area Under the Curve (AUC) from ROC analysis were 0.684 (95% CI, 0.615-0.753; P < .001) at admission, 0.691 (0.623-0.759; P < .001) at peak, and 0.697 (0.630-0.765; P < .001) at the last measurement. In predicting DGF, the corresponding AUC values were 0.746 (0.661-0.831; P < .001) at admission, 0.724 (0.637-0.810; P < .001) at peak, and 0.721 (0.643-0.809; P < .001) at the last. Moreover, KDPI scores at all time points-admission, peak, and last-moderately correlated with GFR 1 Y (Râ¯=â¯-0.426, -0.423, -0.417). CONCLUSION: KDPI measurements at all time points, particularly admission, would be more effective in predicting DGF in DDKT.
Assuntos
Creatinina , Função Retardada do Enxerto , Taxa de Filtração Glomerular , Transplante de Rim , Doadores de Tecidos , Humanos , Pessoa de Meia-Idade , Creatinina/sangue , Estudos Retrospectivos , Feminino , Masculino , Adulto , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/diagnóstico , Fatores de Tempo , Rim/fisiopatologia , Rim/fisiologia , Sobrevivência de Enxerto , Testes de Função RenalRESUMO
BACKGROUND: The target blood pressure (BP) value is unclear for diabetic kidney disease (DKD). Therefore, we aimed to evaluate the effect of strict BP control or 'on treatment' BP on clinical outcomes in patients with DKD. METHODS: A post-hoc analysis of the prespecified secondary outcomes of the FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC) trial, a randomized multicenter double-blind phase III trial. Eligible patients were aged ≥ 19 years with DKD. We assigned 341 participants with DKD to BP control strategy (standard-systolic BP [SBP] < 140 mmHg versus strict-SBP < 130 mmHg). The outcome was the occurrence of cardiovascular events and renal events. Separate analyses were performed to compared the risk of outcome according to achieved average BP levels. RESULTS: A total of 341 participants were included in the analysis. Over a median follow-up of 2.8 years, cardiovascular/renal events were observed in 25 (7.3%) participants. Mean (SD) SBPs in the standard and strict BP control group were 140.2 (11.6) and 140.2 (11.9) mmHg, respectively. The strict BP control group did not show significantly reduced risk of cardiovascular/renal events (HR 1.32; 95% CI 0.60-2.92]). In the post-hoc analyses using achieved BP, achieved average SBP of 130-139 mmHg resulted in reduced risk of cardiovascular/renal events (HR 0.15; 95% CI 0.03-0.67) compared to achieved average SBP ≥ 140 mmHg, whereas further reduction in achieved average SBP < 130 mmHg did not impart additional benefits. CONCLUSION: In patients with DKD, targeting a SBP of less than 130 mmHg, as compared with less than 140 mmHg, did not reduce the rate of a composite of cardiovascular and renal events. Achieved SBP of 130-139 mmHg was associated with a decreased risk for the primary outcome in patients with DKD. TRIAL REGISTRATION: ClinicalTirals.gov Identifier: NCT02620306, registered December 3, 2015. ( https://clinicaltrials.gov/study/NCT02620306 ).
RESUMO
In response to the increase in the prevalence of chronic kidney disease (CKD) in Korea, the growth of patients requiring renal replacement therapy and the subsequent increase in medical costs, the rapid expansion of patients with end-stage kidney disease (ESKD), and the decrease in patients receiving home therapy, including peritoneal dialysis, the Korean Society of Nephrology has proclaimed the new policy, Kidney Health Plan 2033 (KHP 2033). KHP 2033 would serve as a milestone to bridge the current issues to a future solution by directing the prevention and progression of CKD and ESKD, particularly diabetic kidney disease, and increasing the proportion of home therapy, thereby reducing the socioeconomic burden of kidney disease and improving the quality of life. Here, we provide the background for the necessity of KHP 2033, as well as the contents of KHP 2033, and enlighten the Korean Society of Nephrology's future goals. Together with patients, healthcare providers, academic societies, and national policymakers, we need to move forward with goal-oriented drive and leadership to achieve these goals.
Assuntos
Diabetes Insípido/diagnóstico , Oligo-Hidrâmnio/diagnóstico , Adulto , Antidiuréticos/uso terapêutico , Cesárea , Desamino Arginina Vasopressina/uso terapêutico , Diagnóstico Tardio , Diabetes Insípido/complicações , Diabetes Insípido/tratamento farmacológico , Feminino , Humanos , Oligo-Hidrâmnio/etiologia , Poliúria/etiologia , Período Pós-Parto , GravidezRESUMO
Metabolic syndrome (MS) is a risk factor for the development and progression of chronic kidney disease (CKD). However, it is unclear whether decreased renal function affects MS. Through a longitudinal study, we investigated the effect of estimated glomerular filtration rate (eGFR) changes on MS in participants with an eGFR above 60 mL/min/1.73 m2. A cross-sectional (n = 7107) and a 14-year longitudinal study (n = 3869) were conducted to evaluate the association between MS and eGFR changes from the Korean Genome and Epidemiology Study data. The participants were categorized by their eGFR levels (60-75, 75-90, and 90-105 versus ≥ 105 mL/min/1.73 m2). In a cross-sectional analysis, the MS prevalence was significantly increased with a decline in the eGFR in a fully adjusted model. The odds ratio of individuals with an eGFR of 60-75 mL/min/1.73 m2 was observed to be the highest (2.894; 95% confidence interval (CI), 1.984-4.223). In the longitudinal analysis, incident MS significantly increased with an eGFR decline in all the models, with the highest hazard ratio in the lowest eGFR group (1.803; 95% CI, 1.286-2.526). In joint interaction analysis, all covariates showed a significant joint effect with an eGFR decline on the incident MS. MS incidents are associated with eGFR changes in the general population without CKD.
RESUMO
Dye eye disease (DED) is a common ocular disorder in patients with diabetes. It has been reported that APX-115A, a pan-nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase inhibitor, has an apoptosis-inducing effect on Epstein-Barr virus-infected retinal epithelial cells, but its effects in DED are poorly understood. Therefore, a rat model of diabetes was used in the present study to investigate whether APX-115A has an impact on DED in diabetic rats. A diabetic model was established in male Sprague Dawley rats via the intraperitoneal injection of streptozotocin. The eyeballs of the rats were treated with a solution containing APX-115A or a saline control. Tear secretion was measured with the phenol red thread tear test, and the morphology of the eyeball and lacrimal gland tissues was determined using hematoxylin and eosin staining. In addition, localization of NAPDH oxidase 2 (NOX2) in the eyeball and lacrimal gland tissues was detected by immunohistochemistry. The APX-115A treatment had no effect on body weight, blood glucose level or the size of the lacrimal glands. However, morphological changes, namely intracellular vacuoles and acinar atrophy, were observed in the lacrimal glands of the diabetic rats, and APX-115A treatment attenuated these changes. Immunohistochemistry revealed that NOX2 expression was decreased in the lacrimal glands of the diabetic rats, and APX-115A treatment did not attenuate the reduction in NOX2. The corneas of the diabetic rats treated with APX-115A exhibited no change in thickness but had lower NOX2 expression levels compared with those of the control diabetic rats. APX-115A also increased tear secretion and ameliorated the histological changes associated with diabetes. Furthermore, the NOX2 expression levels in the corneas of the diabetic rats treated with APX-115A were restored to the levels observed in normal rats. These findings suggest that APX-115A has potential as a therapeutic agent for DED.
RESUMO
NADPH oxidase (NOX)-derived oxidative stress is an important factor in renal progression, with NOX4 being the predominant NOX in the kidney. Recently, Src homology 3 (SH3) domain-containing YSC84-like 1 (SH3YL1) was reported to be a regulator of NOX4. In this study, we tested whether the SH3YL1 protein could predict 3-year renal outcomes in patients with type 2 diabetes. A total of 131 patients with type 2 diabetes were enrolled in this study. Renal events were defined as a 15% decline in the estimated glomerular filtration rate (eGFR) from the baseline, the initiation of renal replacement therapy, or death during the 3 years. The levels of the urinary SH3YL1-to-creatinine ratio (USCR) were significantly different among the five stages of chronic kidney disease (CKD) and the three groups, based on albuminuria levels. The USCR levels showed a significant negative correlation with eGFR and a positive correlation with the urinary albumin-to-creatinine ratio (UACR). Plasma SH3YL1 levels were significantly correlated with UACR. The highest tertile group of USCR and plasma SH3YL1 had a significantly lower probability of renal event-free survival. Furthermore, the highest tertile group of USCR showed a significant association with the incidence of renal events after full adjustment: adjusted hazard ratio (4.636: 95% confidence interval, 1.416-15.181, p = 0.011). This study suggests that SH3YL1 is a new diagnostic biomarker for renal outcomes in patients with type 2 diabetes.
RESUMO
V-set Ig domain-containing 4 (VSIG4) regulates an inflammatory response and is involved in various diseases. However, the role of VSIG4 in kidney diseases is still unclear. Here, we investigated VSIG4 expression in unilateral ureteral obstruction (UUO), doxorubicin-induced kidney injury mouse, and doxorubicin-induced podocyte injury models. The levels of urinary VSIG4 protein significantly increased in the UUO mice compared with that in the control. The expression of VSIG4 mRNA and protein in the UUO mice was significantly upregulated compared with that in the control. In the doxorubicin-induced kidney injury model, the levels of urinary albumin and VSIG4 for 24 h were significantly higher than those in the control mice. Notably, a significant correlation was observed between urinary levels of VSIG4 and albumin (r = 0.912, p < 0.001). Intrarenal VSIG4 mRNA and protein expression were also significantly higher in the doxorubicin-induced mice than in the control. In cultured podocytes, VSIG4 mRNA and protein expressions were significantly higher in the doxorubicin-treated groups (1.0 and 3.0 µg/mL) than in the controls at 12 and 24 h. In conclusion, VSIG4 expression was upregulated in the UUO and doxorubicin-induced kidney injury models. VSIG4 may be involved in pathogenesis and disease progression in chronic kidney disease models.
RESUMO
OBJECTIVES: A low protein diet (LPD) for chronic kidney disease (CKD) is a core dietary therapy to slow CKD progression. A study showed depressive symptoms are more common in populations with an LPD. In this cross-sectional study, we evaluated depressive symptoms and health-related quality of life (HRQOL) in patients with CKD. METHODS: A total of 571 CKD patients were enrolled in this study. The LPD was defined with dietary protein intake ≤0.8 g/kg/day. We divided the CKD into mild CKD and advanced CKD according to severity, as well as diabetic kidney disease (DKD) and non-DKD according to DM. The logistic regression analysis was performed to evaluate the association between an LPD and depressive symptoms as well as HRQOL in CKD patients and each subgroup. RESULTS: An LPD had significantly higher unadjusted Odds Ratio (OR) (1.81, [95% for Confidence Interval (CI), 1.18-2.76]) and multivariate-adjusted OR (1.80, [1.15-2.81]) for depressive symptoms. Moreover, an LPD showed significantly higher unadjusted OR (2.08, 1.44-3.01]) and multivariate OR (2.04, [1.38-3.02]) for poor HRQOL. In DKD subgroups, an LPD had a significant increase in unadjusted OR (2.00, [1.12-3.57]) and multivariate OR (1.99, [1.01-3.44]) for depressive symptoms. The advanced CKD group also showed that an LPD had significantly higher unadjusted OR (1.97, [1.13-3.42]) and multivariate OR (2.03, [1.12-3.73]) for depressive symptoms. CONCLUSIONS: An LPD for CKD patients was significantly associated with depressive symptoms and poor HRQOL. Subgroup analysis indicated that DKD and advanced CKD are more predisposed to depressive symptoms and poor HRQOL.
Assuntos
Depressão , Insuficiência Renal Crônica , Humanos , Depressão/epidemiologia , Depressão/etiologia , Dieta com Restrição de Proteínas , Qualidade de Vida , Proteínas Alimentares , Estudos Transversais , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologiaRESUMO
Background: Aging is a risk factor for development of chronic kidney disease and diabetes mellitus with commonly shared features of chronic inflammation and increased oxidative stress. Here, we investigated the effect of pan-Nox-inhibitor, APX-115, on renal function in aging diabetic mice. Methods: Diabetes was induced by intraperitoneal injection of streptozotocin at 50 mg/kg/day for 5 days in 52-week-old C57BL/6J mice. APX-115 was administered by oral gavage at a dose of 60 mg/kg/day for 12 weeks in nondiabetic and diabetic aging mice. Results: APX-115 significantly improved insulin resistance in diabetic aging mice. Urinary level of 8-isoprostane was significantly increased in diabetic aging mice than nondiabetic aging mice, and APX-115 treatment reduced 8-isoprostane level. Urinary albumin and nephrin excretion were significantly higher in diabetic aging mice than nondiabetic aging mice. Although APX-115 did not significantly decrease albuminuria, APX-115 markedly improved mesangial expansion, macrophage infiltration, and expression of fibrosis molecules such as transforming growth factor beta 1 and plasminogen activator inhibitor 1. Interestingly, the expression of all Nox isoforms including Nox1, Nox2, and Nox4 was significantly increased in diabetic aging kidneys, and APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. Furthermore, Klotho expression was significantly decreased in diabetic aging kidneys, and APX-115 restored Klotho level. Conclusion: Our results provide evidence that pan-Nox inhibition may improve systemic insulin resistance and decrease oxidative stress, inflammation, and fibrosis in aging diabetic status and may have potential protective effects on aging diabetic kidney.
RESUMO
Background: Diabetes mellitus is a common and crucial metabolic complication in kidney transplantation. It is necessary to analyze the course of glucose metabolism in patients who already have diabetes after receiving a transplant. In this study, we investigated the changes in glucose metabolism after transplantation, and a detailed analysis was performed on some patients whose glycemic status improved. Methods: The multicenter prospective cohort study was conducted between 1 April 2016 and 31 September 2018. Adult patients (aged 20 to 65 years) who received kidney allografts from living or deceased donors were included. Seventy-four subjects with pre-transplant diabetes were followed up for 1 year after kidney transplantation. Diabetes remission was defined as the results of the oral glucose tolerance test performed one year after transplantation and the presence or absence of diabetes medications. After 1-year post-transplant, 74 recipients were divided into the persistent diabetes group (n = 58) and the remission group (n = 16). Multivariable logistic regression was performed to identify clinical factors associated with diabetes remission. Results: Of 74 recipients, 16 (21.6%) showed diabetes remission after 1-year post-transplant. The homeostatic model assessment for insulin resistance numerically increased in both groups throughout the first year after transplantation and significantly increased in the persistent diabetes group. The insulinogenic index (IGI30) value significantly increased only in the remission group, and the IGI30 value remained low in the persistent diabetes group. In univariate analysis, younger age, newly diagnosed diabetes before transplantation, low baseline hemoglobin A1c, and high baseline IGI30 were significantly associated with remission of diabetes. After multivariate analysis, only newly diagnosed diabetes before transplantation and IGI30 at baseline were associated with remission of diabetes (34.00 [1.192-969.84], P = 0.039, and 17.625 [1.412-220.001], P = 0.026, respectively). Conclusion: In conclusion, some kidney recipients with pre-transplant diabetes have diabetes remission 1 year after transplantation. Our prospective study revealed that preserved insulin secretory function and newly diagnosed diabetes at the time of kidney transplantation were favorable factors for which glucose metabolism did not worsen or improve 1 year after kidney transplantation.