RESUMEN
Podocytes are highly differentiated cells and critical elements for the filtration barrier of the kidney. Loss of their foot process (FP) architecture (FP effacement) results in urinary protein loss. Here we show a novel role for the neutral amino acid glutamine in structural and functional regulation of the kidney filtration barrier. Metabolic flux analysis of cultured podocytes using genetic, toxic, and immunologic injury models identified increased glutamine utilization pathways. We show that glutamine uptake is increased in diseased podocytes to couple nutrient support to increased demand during the disease state of FP effacement. This feature can be utilized to transport increased amounts of glutamine into damaged podocytes. The availability of glutamine determines the regulation of podocyte intracellular pH (pHi). Podocyte alkalinization reduces cytosolic cathepsin L protease activity and protects the podocyte cytoskeleton. Podocyte glutamine supplementation reduces proteinuria in LPS-treated mice, whereas acidification increases glomerular injury. In summary, our data provide a metabolic opportunity to combat urinary protein loss through modulation of podocyte amino acid utilization and pHi.
Asunto(s)
Podocitos/metabolismo , Proteinuria/metabolismo , Animales , Transporte Biológico Activo/genética , Transporte Biológico Activo/inmunología , Células Cultivadas , Citoesqueleto/genética , Citoesqueleto/inmunología , Citoesqueleto/metabolismo , Citoesqueleto/patología , Concentración de Iones de Hidrógeno , Ratones , Ratones Noqueados , Podocitos/inmunología , Podocitos/patología , Proteinuria/genética , Proteinuria/inmunología , Proteinuria/patologíaRESUMEN
The cyclin-dependent kinase inhibitor p21 plays important roles in chronic renal disorders; however, its roles in response to acute renal stress are unclear. Here we evaluated p21 in acute kidney injury and ischemic preconditioning using wild-type and p21 knockout mice that underwent renal ischemia followed by reperfusion. The decline in renal function and histological changes were worse in the knockout than in wild-type mice. Ischemia/reperfusion increased p21 expression in the kidney of wild-type mice compared with sham surgery, suggesting p21 may confer tolerance to ischemia/reperfusion injury. We next tested whether p21 is associated with the protective effect of ischemic preconditioning, an established method to reduce ischemia/reperfusion injury. Ischemic preconditioning attenuated ischemia/reperfusion injury in wild-type but not p21-knockout mice. This preconditioning decreased the number of proliferating tubular cells before but increased them at 24 h after ischemia/reperfusion in the kidneys of wild-type mice. In p21-knockout mice, ischemic preconditioning did not change the number of proliferating cells before but decreased them after ischemia/reperfusion. Ischemic preconditioning increased renal p21 expression and the number of cells in the G1 phase of the cell cycle before ischemia/reperfusion compared with sham surgery. Thus, renal p21 is essential for the beneficial effects of renal ischemic preconditioning. Transient cell cycle arrest induced by ischemic preconditioning by a p21-dependent pathway seems to be important for subsequent tubular cell proliferation after ischemia/reperfusion.
Asunto(s)
Lesión Renal Aguda/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Precondicionamiento Isquémico , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/prevención & control , Animales , Puntos de Control del Ciclo Celular , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/prevención & controlRESUMEN
INTRODUCTION: Latent mesangial immunoglobulin A (IgA) deposition in the donated kidney has been investigated in the context of kidney transplantation. However, few studies have examined the impact of mesangial expansion accompanied with IgA deposition. Therefore, we investigated the effects of latent IgA deposition and mesangial expansion on transplant prognosis following living-donor kidney transplantation. METHODS: We retrospectively analyzed 68 consecutive adult living-donor kidney transplantations performed at Kagawa University Hospital. Biopsies were performed at pre-implantation and at one year after transplantation. RESULTS: Twenty kidneys exhibited latent IgA deposition in pre-implantation biopsies, including 14 with mesangial expansion. Latent IgA deposition was not associated with renal function or donor urinalysis after donation, irrespective of mesangial expansion. Latent IgA deposition was not significantly associated with graft survival rate, allograft function, abnormal urinalysis, or the recurrence of IgA nephropathy, irrespective of mesangial expansion. At one year after transplantation, IgA deposition had disappeared in 14/20 allografts. Estimated glomerular function rate >40 mL/min/1.73 m(2) was significantly associated with the disappearance of IgA deposition. CONCLUSIONS: The present study showed that latent IgA deposition from the donor kidney, irrespective of mesangial expansion, does not affect transplant prognosis following living-donor kidney transplantation.
Asunto(s)
Mesangio Glomerular/patología , Glomerulonefritis por IGA/patología , Trasplante de Riñón , Adulto , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/terapia , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality. METHODS: We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography. RESULTS: The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself. CONCLUSION: Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.
Asunto(s)
Inmunosupresores/farmacocinética , Trasplante de Riñón , Diálisis Peritoneal/efectos adversos , Tacrolimus/farmacocinética , Desequilibrio Hidroelectrolítico/metabolismo , Administración Oral , Adulto , Peso Corporal , Cálculo de Dosificación de Drogas , Monitoreo de Drogas , Femenino , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Absorción Intestinal , Donadores Vivos , Masculino , Persona de Mediana Edad , Diálisis Renal/efectos adversos , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Tacrolimus/sangre , Resultado del Tratamiento , Desequilibrio Hidroelectrolítico/sangre , Desequilibrio Hidroelectrolítico/etiologíaRESUMEN
BACKGROUND: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient's kidney function (allograft function) later in life. METHODS: We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. RESULTS: Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. CONCLUSIONS: The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.
Asunto(s)
Arteriosclerosis/patología , Supervivencia de Injerto/fisiología , Enfermedades Renales/patología , Trasplante de Riñón , Riñón/patología , Anciano , Arteriosclerosis/fisiopatología , Biopsia , Femenino , Humanos , Riñón/irrigación sanguínea , Riñón/fisiología , Enfermedades Renales/fisiopatología , Enfermedades Renales/cirugía , Donadores Vivos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Arteria Renal/patología , Arteria Renal/fisiopatología , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Túnica Íntima/patología , Túnica Íntima/fisiopatologíaRESUMEN
Intrarenal renin-angiotensin system (RAS) plays an important role for the pathogenesis of renal injuries. Experimental studies have demonstrated that angiotensinogen levels in renal tissues reflect the activity of intrarenal RAS. However, dynamics of urinary angiotensinogen have not been investigated in detail. Therefore, we examined the preservation conditions of the measured values of urinary angiotensinogen concentrations and an ultradian rhythm of urinary angiotensinogen excretion in humans. Urine samples were collected from 24 healthy volunteers. The urinary concentrations of angiotensinogen were measured by using ELISA. Two different urine preservation conditions were examined. One cycle of freeze-and-thaw did not change the measured values of urinary angiotensinogen concentrations. Moreover, to keep urine samples at room temperature for 12 hours did not change the measured values of urinary angiotensinogen concentrations. Thus, preservation conditions do not change the measured values of urinary angiotensinogen concentrations. Regarding an ultradian rhythm, blood pressure and the urinary concentrations of angiotensinogen were measured at 09:00, 13:00, and 16:00. The averaged levels of blood pressure were similar over the time. The average of urinary angiotensinogen/creatinine (Cr) ratios was 8.73 ± 1.15 ng/mg Cr at 09:00, 9.53 ± 1.58 ng/mg Cr at 13:00, and 8.58 ± 1.26 ng/mg Cr at 16:00. The urinary angiotensinogen excretion in healthy volunteers does not have an ultradian change during the daytime (P = 0.482). This may be another indication that the intrarenal RAS is independent of the systemic RAS. We have to pay attention to these findings in handling urine samples for measurements of angiotensinogen.
Asunto(s)
Angiotensinógeno/orina , Sistema Renina-Angiotensina/fisiología , Manejo de Especímenes/métodos , Urinálisis/métodos , Ciclos de Actividad/fisiología , Presión Sanguínea , Creatinina/orina , Ensayo de Inmunoadsorción Enzimática , Humanos , TemperaturaRESUMEN
BACKGROUND: Peripheral arterial disease (PAD) is a major complication of haemodialysis (HD), especially in patients with diabetes mellitus. Although previous reports have indicated that low-density lipoprotein apheresis (LDL-A) improves arteriosclerosis in PAD patients, the mechanism by which LDL-A affects PAD is still unclear. In this study, we tested the hypothesis that LDL-A attenuates reactive oxygen species (ROS) production in HD patients with PAD. METHODS: Twenty HD patients with PAD were investigated in this study. Clinical effects were evaluated by thermography and angiography. Oxidative stress in serum was evaluated by thiobarbituric acid reactive substances (TBARS) and expression of p22phox mRNA. RESULTS: Ischaemic symptoms due to PAD were gradually improved in 13 patients (65%) after LDL-A. One session of LDL-A removed approximately 75% of LDL from serum. Some patients exhibited dramatic improvement of severe symptoms of PAD such as skin ulcers after serial performance of LDL-A. The levels of LDL cholesterol, malondialdehyde-modified LDL, high-sensitivity C-reactive protein, vascular endothelial growth factor, international normalized ratio of pro-thrombin time and bradykinin were decreased after a single session of LDL-A, although there were no additional changes after 10 sessions of LDL-A. The levels of fibrinogen and p22phox mRNA were decreased by a single session of LDL-A, and these decreases continued over the entire period of treatment. TBARS was decreased after a course of LDL-A. CONCLUSIONS: LDL-A improved ischaemic symptoms in HD patients with PAD by reducing ROS production in leucocytes. We conclude that LDL-A is an effective therapy for patients with HD complicated by PAD.
Asunto(s)
Eliminación de Componentes Sanguíneos , Leucocitos/enzimología , Lipoproteínas LDL , NADPH Oxidasas/genética , Enfermedades Vasculares Periféricas/metabolismo , Enfermedades Vasculares Periféricas/terapia , Especies Reactivas de Oxígeno/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/sangreRESUMEN
BACKGROUND: Peritoneal mesothelial cells play an important role in peritoneal dialysis and are often exposed to dialysis fluid containing high glucose levels. Loss of peritoneal function is a major complication associated with long-term peritoneal dialysis. In this study, we hypothesized that high glucose levels induce apoptosis, and that insulin attenuates this apoptosis in peritoneal mesothelial cells. To clarify this hypothesis, we examined the effects of insulin on the phosphatidylinositol 3-kinase/Akt signaling pathway and apoptosis in rat peritoneal mesothelial cells. METHODS: Phosphorylated insulin receptor and Akt were detected by western blot analysis. Apoptosis was evaluated by measuring caspase 3 activity and by TUNNEL staining. RESULTS: Insulin (100 nmol/L) increased tyrosine phosphorylation of insulin receptor in peritoneal mesothelial cells. Furthermore, insulin (1-100 nmol/L) dose-dependently stimulated Akt phosphorylation. Treatment with the phosphatidylinositol 3-kinase inhibitors wortmannin (100 nmol/L) and LY294002 (10 micromol/L) attenuated insulin-induced Akt phosphorylation, indicating that insulin phosphorylates Akt via a phosphatidylinositol 3-kinase-dependent pathway. Insulin attenuated caspase 3 activity and decreased the number of TUNNEL-positive cells. The phosphatidylinositol 3-kinase inhibitors and overexpression of a dominant-negative mutant of Akt inhibited the effect of insulin on apoptosis. CONCLUSIONS: The present data indicate that insulin attenuates high glucose-induced apoptosis via the phosphatidylinositol 3-kinase/Akt signaling pathway in peritoneal mesothelial cells. Therefore, the insulin signaling pathway may play a protective role in peritoneal function.
Asunto(s)
Apoptosis/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Glucosa/farmacología , Hipoglucemiantes/farmacología , Insulina/farmacología , Peritoneo/efectos de los fármacos , Androstadienos/farmacología , Animales , Técnicas de Cultivo de Célula , Cromonas/farmacología , Células Epiteliales/patología , Masculino , Morfolinas/farmacología , Peritoneo/patología , Fosfatidilinositol 3-Quinasas/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/fisiología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , WortmaninaRESUMEN
BACKGROUND: Tonsillectomy and steroid pulse (TSP) therapy was proposed as a curative treatment for IgA nephropathy by Hotta et al. (Am J Kidney Dis 38:736-742, 2001) based on data that about 50% of patients achieved clinical remission (CR) of urinary abnormalities. MATERIALS AND METHODS: As a primary survey, we sent a questionnaire and letter to 848 hospitals in Japan, each of which employed a Fellow of the Japanese Society of Nephrology between October and December of 2006, in order to gather information about the prevalence and efficacy of TSP therapy for patients with IgA nephropathy. As a secondary survey, we collected data from both low- and high-CR-rate groups to determine which factors predicted resistance to TSP therapy. RESULTS: A total of 2,746 patients received TSP therapy between 2000 and 2006. The CR rates, calculated by measuring urinary criteria 6 and 12 months after TSP therapy, were 32.0% (347/1,085) and 45.6% (452/991), respectively. Analysis of the 30 hospitals in which TSP therapy had been performed on at least ten patients revealed that the CR rates varied from below 10% to 100%. A secondary survey of ten hospitals revealed that, after correction of the CR rate from each hospital, patients could be categorized into three groups: those with a low CR rate (122 patients in four hospitals), a middle CR rate (78 patients in four hospitals), and a high CR rate (103 patients in two hospitals). The CR rate of all patients (N = 303) was 54.1%. A comparison of patient data between the low- and high-CR-rate groups showed a significant difference in age at onset (years; P = 0.05), amount of proteinuria (g/day; P = 0.02), total protein (g/dl; P = 0.02), pathological grade (P = 0.009), and prognostic score as described by Wakai et al. [Nephrol Dial Transplant 21:2800-2808, 2006, (P = 0.04)]. Univariate analysis revealed that there was a significant difference between non-CR and CR subgroups in duration from diagnosis until TSP therapy (6.9 +/- 6.8 versus 5.3 +/- 5.2 years; P = 0.02), amount of proteinuria (1.5 +/- 1.6 versus 0.8 +/- 0.8 g/day; P < 0.0001), serum creatinine (0.99 +/- 0.40 versus 0.87 +/- 0.34 mg/dl; P = 0.006), pathological grade (P = 0.0006), and Wakai et al.'s prognostic score (37.4 +/- 17.8 versus 28.1 +/- 15.1; P < 0.0001). A multivariate logistic analysis demonstrated that resistance to TSP therapy depends on age at onset, amount of proteinuria, hematuria grade, and pathological grade, and a score predicting resistance to TSP therapy could be derived by the formula: [(-0.0330) x (age) + (0.4772) x log (amount of proteinuria) - (0.0273) x (hematuria grade: 0, 1, 2, and 3) + (0.7604) x (pathological grade: 1, 2, 3, and 4) - 0.1894]. A receiver operating characteristic (ROC) curve showed that patients with a resistance score of greater than -0.02 easily resist TSP therapy (sensitivity 69%, specificity 75%, positive likelihood ratio 2.76). CONCLUSION: TSP therapy shows promise as a treatment that can bring about CR of urinary abnormalities, but unfortunately the average CR rate is about 50% at 1 year after treatment. Predictive factors for resistance to TSP therapy are age at onset, amount of proteinuria, hematuria grade, and pathological grade. The present study suggests that patients with either early-stage or mild to moderate IgA nephropathy easily achieve CR following TSP therapy, whereas patients with late-stage or severe disease are prone to TSP therapy resistance.
Asunto(s)
Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/cirugía , Esteroides , Tonsilectomía , Adolescente , Adulto , Terapia Combinada , Recolección de Datos , Femenino , Glomerulonefritis por IGA/patología , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Curva ROC , Inducción de Remisión , Esteroides/administración & dosificación , Esteroides/uso terapéutico , Encuestas y Cuestionarios , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Mechanical forces and angiotensin II influence the structure and function of vascular cells, and play an important role in reactive oxygen species production. In this study, we examined the effects of mechanical stretch and angiotensin II on the expression of p22-phox and Nox-1, essential membrane components of NADPH oxidase, and superoxide production in rat vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: Neither a stretch force nor angiotensin II alone altered p22-phox and Nox-1 expression in VSMCs. Combined stimulation markedly increased p22-phox and Nox-1 mRNA, however, which was associated with increased NADPH oxidase activity, superoxide production and total 8-iso-prostaglandin F2alpha concentration. The increases in p22-phox mRNA levels induced by a stretch force in combination with angiotensin II were prevented by treatment with an angiotensin type I (AT1) receptor antagonist, RNH-6270 (100 nmol/l). Protein expression of the AT1 receptor was upregulated by a stretch force. CONCLUSIONS: These data indicate that mechanical stretch and angiotensin II synergistically increase NADPH oxidase expression in VSMCs, and suggest that part of this mechanism is mediated through an upregulation of the AT1 receptor induced by mechanical stretch. The combined effects of mechanical strain and angiotensin II might promote vascular damage through the production of superoxide in a hypertensive state.
Asunto(s)
Angiotensina II/fisiología , Miocitos del Músculo Liso/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Superóxidos/metabolismo , Animales , Aorta Torácica/citología , Aorta Torácica/metabolismo , Aorta Torácica/fisiología , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiología , Miocitos del Músculo Liso/fisiología , NADPH Oxidasa 1 , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismo , Estrés MecánicoRESUMEN
BACKGROUND: High-normal albuminuria (HNA) is an independent predictor of cardiovascular risk in the general population. Although hypertensive donor (HTD) candidates with HNA were considered acceptable donors by the Amsterdam Forum 2004, the transplant prognosis of HTDs with HNA has not been determined. Therefore, we investigated the transplant prognosis of HTDs with HNA. METHODS: We retrospectively analyzed 52 adult living-donor kidney transplants performed at Kagawa University Hospital. HNA was defined as albuminuria of 15 to 30 mg/g Cr. Changes in kidney function of donors and recipients were assessed up to 2 years after transplantation. RESULTS: Overall, 38 donors were normotensive and 14 were hypertensive. Nine of 14 HTDs exhibited HNA before donation. More HTDs with HNA had arteriosclerotic vasculopathy or glomerulosclerosis than did normotensive donors (NTDs). Hypertension and the degree of albuminuria did not affect the donors' posttransplantation kidney function. The risk of discompensatory changes in kidney function after donation was significantly higher in HTDs with HNA than in NTDs (odds ratio, 10.5; 95% confidence interval, 1.51-72.9; P=0.02). In multivariate analysis, the coexistence of hypertension and HNA was not significantly associated with discompensatory changes after donation (adjusted odds ratio, 6.04; 95% confidence interval, 0.19-192; P=0.31). Recipients of HTDs with HNA had similar allograft survival rates but lower allograft function compared with recipients of NTDs. CONCLUSIONS: Although further studies are needed to confirm our results, the short-term prognosis of living-donor kidney transplantation was similar between HTDs with HNA and NTDs.
Asunto(s)
Albuminuria/etiología , Selección de Donante , Hipertensión/complicaciones , Trasplante de Riñón/métodos , Donadores Vivos , Adulto , Anciano , Albuminuria/diagnóstico , Albuminuria/fisiopatología , Presión Sanguínea , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Japón , Trasplante de Riñón/efectos adversos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/fisiopatología , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU. METHODS: Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups. RESULTS: The FX group showed significantly greater decreases in serum uric acid (-2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96-10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m(2) versus 47±19 mL/min/1.73 m(2)), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m(2) versus -0.2±6.9 mL/min/1.73 m(2) per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%). CONCLUSION: Treatment with febuxostat sufficiently lowered uric acid levels without severe adverse effects in stable kidney transplant recipients with PTHU.
Asunto(s)
Supresores de la Gota/uso terapéutico , Hiperuricemia/tratamiento farmacológico , Trasplante de Riñón , Tiazoles/uso terapéutico , Xantina Oxidasa/antagonistas & inhibidores , Adulto , Anciano , Febuxostat , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Estudios Retrospectivos , Tiazoles/efectos adversos , Ácido Úrico/sangreAsunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Diálisis Peritoneal , Adolescente , Humanos , Inmunosupresores/administración & dosificación , Túbulos Renales/metabolismo , Donadores Vivos , Masculino , Atención Perioperativa , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: To clarify the role of angiotensin II (Ang II) in insulin-induced arteriosclerosis, we examined the effects of Ang II on insulin-induced mitogen-activated protein (MAP) kinase activation and cellular hypertrophy in rat vascular smooth muscle cells (VSMCs). METHODS: Phosphorylated MAP kinases were detected with western blot analysis. Cellular hypertrophy and glucose uptake were evaluated from incorporation of [(3)H]-labeled-leucine and -deoxy-D-glucose, respectively. Cell sizes were measured by Coulter counter. RESULTS: While Ang II (100 nmol/l, 18 h) augmented cellular hypertrophy by insulin (10 nmol/l, 24 h), insulin alone did not affect hypertrophy without Ang II pretreatment. Insulin increased p38MAP kinase and c-Jun N-terminal kinase (JNK) phosphorylation; in the presence of Ang II, p38MAP kinase, and JNK were further activated by insulin. Treatment of a p38MAP kinase inhibitor, SB203580 (10 µmol/l), and a JNK inhibitor, SP600125 (20 µmol/l), abrogated the [(3)H]-leucine incorporation by insulin in the presence of Ang II. Both the Ang II receptor blocker, RNH-6270 (100 nmol/l), and an antioxidant, ebselen (40 µmol/l), inhibited vascular cell hypertrophy. Specific depletion of insulin receptor substrate-1 with small interfering RNA increased [(3)H]-leucine incorporation by insulin (10 nmol/l, 24 h); pretreatment with Ang II attenuated insulin (10 nmol/l, 30 min)-induced glucose uptake. CONCLUSIONS: Ang II attenuates insulin-stimulated glucose uptake and enhances vascular cell hypertrophy via oxidative stress- and MAP kinase-mediated pathways in VSMCs. Ang II may also cause insulin signaling to diverge from glucose metabolism into vascular remodeling, affecting insulin-induced arteriosclerosis in hypertension.
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Angiotensina II/farmacología , Glucosa/metabolismo , Insulina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Tamaño de la Célula/efectos de los fármacos , Células Cultivadas , Hipertrofia , Proteínas Sustrato del Receptor de Insulina/fisiología , Resistencia a la Insulina , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Fosforilación , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Clinical reports indicate that patients with primary aldosteronism commonly have impaired glucose tolerance; however, the relationship between aldosterone and insulin signaling pathway has not been clarified. In this study, we examined the effects of aldosterone treatment on insulin receptor substrate-1 expression and insulin signaling pathway including Akt phosphorylation and glucose uptake in rat vascular smooth muscle cells. Insulin receptor substrate-1 protein expression and Akt phosphorylation were determined by Western blot analysis with anti-insulin receptor substrate-1 and phosphorylated-Akt antibodies, respectively. Glucose metabolism was evaluated using (3)H-labeled 2-deoxy-d-glucose uptake. Aldosterone (1-100 nmol/L) dose-dependently decreased insulin receptor substrate-1 protein expression with a peak at 18 hours (n=4). Aldosterone-induced degradation of insulin receptor substrate-1 was markedly attenuated by treatment with the selective mineralocorticoid receptor antagonist eplerenone (10 micromol/L; n=4). Furthermore, degradation was blocked by the Src inhibitor PP1 (20 micromol/L; n=4). Treatment with antioxidants, N-acetylcysteine (10 mmol/L), or ebselen (40 micromol/L) also attenuated aldosterone-induced insulin receptor substrate-1 degradation (n=4). In addition, proteasome inhibitor MG132 (1 micromol/L) prevented insulin receptor substrate-1 degradation (n=4). Aldosterone treatment abolished insulin-induced Akt phosphorylation (100 nmol/L; 5 minutes; n=4). Furthermore, aldosterone pretreatment decreased insulin-stimulated (100 nmol/L; 60 minutes; n=4) glucose uptake by 50%, which was reversed by eplerenone (10 micromol/L; n=4). These data indicate that aldosterone decreases insulin receptor substrate-1 expression via Src and reactive oxygen species stimulation by proteasome-dependent degradation in vascular smooth muscle cells; thus, aldosterone may be involved in the pathogenesis of vascular insulin resistance via oxidative stress.
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Aldosterona/fisiología , Regulación hacia Abajo , Insulina/fisiología , Músculo Liso Vascular/metabolismo , Fosfoproteínas/metabolismo , Transducción de Señal/fisiología , Angiotensina II/farmacología , Animales , Células Cultivadas , Proteínas Sustrato del Receptor de Insulina , Resistencia a la Insulina/fisiología , Músculo Liso Vascular/citología , Proteína Oncogénica v-akt/metabolismo , Fosfoproteínas/genética , Fosforilación , Complejo de la Endopetidasa Proteasomal/fisiología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Familia-src Quinasas/fisiologíaAsunto(s)
Hipertensión Renovascular/tratamiento farmacológico , Riñón/efectos de los fármacos , Receptores de Superficie Celular/antagonistas & inhibidores , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , Animales , Femenino , Humanos , Hipertensión Renovascular/fisiopatología , Riñón/fisiopatología , Ratones , Ratas , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Resultado del Tratamiento , Receptor de ProreninaRESUMEN
Recent studies have indicated that derangement of peritubular capillary (PTC) circulation with consequent tubulointerstitial hypoxia plays a pivotal role in the pathogenesis of renal injury. The present study was performed to determine whether azelnidipine, a new dihydropyridine calcium channel blocker, attenuates angiotensin II (AngII)-induced peritubular ischemia in anesthetized rats. The superficial PTCs were visualized directly using an intravital fluorescence videomicroscope system, and the PTC blood flow was evaluated by analyzing the velocity of fluorescein isothiocyanate-labeled erythrocytes. Intravenous infusion of AngII (50 ng/kg/min, 10 min) significantly increased mean arterial pressure (MAP) and renal vascular resistance (RVR) (by 35 +/- 3% and 110 +/- 32%, respectively), and decreased total renal blood flow (RBF) and PTC erythrocyte velocity (by -34 +/- 4 and -37 +/- 1%, respectively). Treatment with azelnidipine (5 microg/kg/min i.v., 10 min) had no effect on basal MAP, RBF, RVR, or PTC erythrocyte velocity. However, azelnidipine markedly attenuated the AngII-induced increases in MAP (7 +/- 3%) and RVR (40 +/- 4%) and decreases in RBF (-24 +/- 1%) and PTC erythrocyte velocity (-22 +/- 1%). Similar attenuation in the AngII-induced responses of MAP, RBF, RVR, and PTC erythrocyte velocity were observed in rats treated with a higher dose of azelnidipine (20 microg/kg/min i.v., 10 min), which significantly decreased basal MAP and RVR and increased RBF and PTC erythrocyte velocity. These data suggest that calcium channel blockade attenuates AngII-induced peritubular ischemia, which may be involved in its beneficial effects on renal injury.
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Angiotensina II/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Isquemia/tratamiento farmacológico , Túbulos Renales/irrigación sanguínea , Adenosina Trifosfato/análisis , Animales , Ácido Azetidinocarboxílico/análogos & derivados , Ácido Azetidinocarboxílico/farmacología , Presión Sanguínea/efectos de los fármacos , Dihidropiridinas/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacosRESUMEN
BACKGROUND: Leptin has been shown to function as an inhibitor of appetite and energy expenditure accelerator. However, it was recently reported that leptin has other important functions as a fibrogenetic factor and a novel, independent risk factor for coronary heart disease. The present study aimed to assess the blood concentration of leptin in acute uraemic rats by using various peritoneal dialysis (PD) solutions. METHODS: To induce acute renal failure, the bilateral renal arteries were ligated via a mid-abdominal incision 1 h before starting PD. Rats were divided into four groups: 13.6 g/L glucose-containing dialysate (group L); 38.6 g/L glucose-containing dialysate (group H); 13.6 g/L glucose and 25 g/L mannitol-containing dialysate with equal osmotic pressure to the dialysate of group H (group M); and renal failure without PD (group F). The concentrations of glucose, urea nitrogen (UN), leptin and insulin were measured at 0, 2 and 4 h after starting PD. RESULTS: We observed significant blood UN suppression in all dialysed groups. Blood glucose was significantly higher in rats treated with the high glucose solution than in those treated with the low glucose solution. Insulin and leptin significantly increased in the high glucose solution group. There was a strong correlation between the blood glucose and insulin levels. We also found a strong correlation between the percentage changes in blood glucose and leptin. The relationship between the percentage changes in insulin and leptin were weak but significant. CONCLUSION: The high glucose PD solution resulted in increased circulating levels of leptin, glucose, and insulin, suggesting that these changes are linked with PD performed with glucose-based dialysis fluid.
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Lesión Renal Aguda/sangre , Solución Hipertónica de Glucosa/farmacología , Soluciones para Hemodiálisis/farmacología , Leptina/sangre , Diálisis Peritoneal , Uremia/sangre , Lesión Renal Aguda/complicaciones , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Uremia/etiologíaRESUMEN
We have recently shown that systemic administration of a superoxide dismutase mimetic, tempol, resulted in decreases in mean arterial pressure and heart rate along with a reduction in renal sympathetic nerve activity (RSNA). It has also been shown that these parameters are significantly increased by systemic administration of a superoxide dismutase inhibitor, diethyldithio-carbamic (DETC), indicating a potential role of reactive oxygen species in the regulation of RSNA. In this study, we examined the effects of local administrations of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) and DETC on RSNA in anesthetized rats. Either tempol or DETC was directly administered onto the renal sympathetic nerves located between the electrode and ganglion. Local application of tempol (10 microL, 0.17 to 1.7 mol/L, n=6) resulted in dose-dependent decreases in integrated RSNA (by -81+/-6% at 1.7 mol/L) without alterations in mean arterial pressure and heart rate. In contrast, DETC (10 microL, 0.17 to 1.7 mol/L, n=6) increased RSNA dose-dependently. The responses of RSNA to tempol and DETC were significantly greater in spontaneously hypertensive rats than in normotensive rats (n=6, respectively). Local application of sodium nitroprusside (1 mmol/L) or N(G)-nitro-L-arginine methyl ester (0.11 mol/L) altered neither basal RSNA nor tempol-induced reductions in RSNA (n=6 and 5, respectively). A voltage-gated potassium channel blocker, 4-aminopyridine (0.1 mol/L), significantly decreased basal RSNA (by -81+/-1%) and completely prevented DETC-induced increases in RSNA (n=5). These results suggest that reactive oxygen species play a role in the regulation of peripheral sympathetic nerve activity, and that at least part of this mechanism is mediated through voltage-gated potassium channels.