RESUMEN
AIM: To examine whether serum ß2-microglobulin (ß2-MG) could improve the prediction performance for kidney failure with replacement therapy (KFRT) among patients with diabetic nephropathy (DN). METHODS: Patients with biopsy-proven DN at Nara Medical University Hospital were included. The exposure of interest was log-transformed serum ß2-MG levels measured at kidney biopsy. The outcome variable was KFRT. Multivariable Cox regression models and competing-risk regression models, with all-cause mortality as a competing event, were performed. Model fit by adding serum ß2-MG levels was calculated using the Akaike information criterion (AIC). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indexes were used to evaluate the improvement of predictive performance for 5-year cumulative incidence of KFRT by serum ß2-MG levels. RESULTS: Among 408 patients, 99 developed KFRT during a median follow-up period of 6.7 years. A higher serum ß2-MG level (1-unit increase in log-transformed serum ß2-MG level) was associated with a higher incidence of KFRT, even after adjustments for previously known clinical and histological risk factors (hazard ratio [95% confidence interval {CI}]: 3.30 [1.57-6.94] and subdistribution hazard ratio [95% CI]: 3.07 [1.55-6.06]). The addition of log-transformed serum ß2-MG level reduced AIC and improved the prediction of KFRT (NRI and IDI: 0.32 [0.09-0.54] and 0.03 [0.01-0.56], respectively). CONCLUSIONS: Among patients with biopsy-proven DN, serum ß2-MG was an independent predictor of KFRT and improved prediction performance. In addition to serum creatinine, serum ß2-MG should probably be measured for DN.
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Diabetes Mellitus , Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/epidemiología , Nefropatías Diabéticas/etiología , Riñón/patología , Factores de Riesgo , Creatinina , Biopsia , Diabetes Mellitus/patologíaRESUMEN
BACKGROUND: Studies on kidney function and histological findings in diabetic nephropathy (DN) with low urinary protein (UP) are few. We examined the differential impact of histological changes on kidney outcomes between non-proteinuric and proteinuric DN. METHODS: Patients diagnosed with DN by renal biopsy during 1981-2014 were divided into non-proteinuric (UP ≤ 0.5 g/day) and proteinuric (UP > 0.5 g/day) DN. The Cox proportional hazard model was used to examine the association of glomerular lesions (GLs) and interstitial fibrosis and tubular atrophy (IFTA) with end-stage kidney disease (ESKD) development after adjusting for relevant confounders. RESULTS: The non-proteinuric and proteinuric DN groups included 197 and 199 patients, respectively. During the 10.7-year median follow-up period, 16 and 83 patients developed ESKD in the non-proteinuric and proteinuric DN groups, respectively. In the multivariable Cox hazard model, hazard ratios (HRs) [95% confidence intervals (CIs)] of GL and IFTA for ESKD in proteinuric DN were 2.94 [1.67-5.36] and 3.82 [2.06-7.53], respectively. Meanwhile, HRs [95% CIs] of GL and IFTA in non-proteinuric DN were < 0.01 [0-2.48] and 4.98 [1.33-18.0], respectively. IFTA was consistently associated with higher incidences of ESKD regardless of proteinuria levels (P for interaction = 0.49). The prognostic impact of GLs on ESKD was significantly decreased as proteinuria levels decreased (P for interaction < 0.01). CONCLUSIONS: IFTA is consistently a useful predictor of kidney prognosis in both non-proteinuric and proteinuric DN, while GLs are a significant predictor of kidney prognosis only in proteinuric DN.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Fallo Renal Crónico , Sistema Urinario , Humanos , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Riñón , Glomérulos Renales/patología , Proteinuria/etiología , Proteinuria/patología , Fallo Renal Crónico/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Estudios RetrospectivosRESUMEN
BACKGROUND: The relationship between kidney function at 3 months after acute kidney injury (AKI) and kidney function prognosis has not been characterized. METHODS: This retrospective cohort study included adults who underwent noncardiac surgery under general anesthesia. Exclusion criteria included obstetric or urological surgery, missing data and preoperative dialysis. Linear mixed-effects models were used to compare estimated glomerular filtration rate (eGFR) slopes in patients with and without AKI. Multivariable Cox proportional hazard models were used to examine the associations of AKI with incident chronic kidney disease (CKD) and decline in eGFR ≥30%. RESULTS: Among 5272 patients, 316 (6.0%) developed AKI. Among 1194 patients with follow-up creatinine values, eGFR was stable or increased in patients with and without AKI at 3 months postoperatively and declined thereafter. eGFR decline after 3 months postoperatively was faster among patients with AKI than among patients without AKI (P = .09). Among 938 patients without CKD-both at baseline and at 3 months postoperatively-226 and 161 developed incident CKD and a decline in eGFR ≥30%, respectively. Despite adjustment for eGFR at 3 months, AKI was associated with incident CKD {hazard ratio [HR] 1.73 [95% confidence interval (CI) 1.06-2.84]} and a decline in eGFR ≥30% [HR 2.41 (95% CI 1.51-3.84)]. CONCLUSIONS: AKI was associated with worse kidney outcomes, regardless of eGFR at 3 months after surgery. Creatinine-based eGFR values at 3 months after AKI might be affected by acute illness-induced loss of muscle mass. Kidney function might be more accurately evaluated much later after surgery or using cystatin C values.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Adulto , Humanos , Estudios de Cohortes , Estudios Retrospectivos , Creatinina , Diálisis Renal , Riñón , Tasa de Filtración Glomerular , Factores de RiesgoRESUMEN
BACKGROUND: Microalbuminuria is associated with mortality, cardiovascular disease, and end-stage kidney disease. The association between trace proteinuria (detected via dipstick test) and kidney outcomes is unclear. METHODS: This nationwide longitudinal study used data from the Japan Specific Health Checkups Study conducted during 2008-2014. The frequency of trace proteinuria (detected via dipstick test) during first two visits was used as an exposure variable (TrUP 0/2, no trace proteinuria; TrUP 1/2, detected once; TrUP 2/2, detected twice), and kidney outcomes were evaluated. The association between the frequency of trace proteinuria and incidence of 1.5-fold increase in serum creatinine levels and overt proteinuria was analyzed using Cox regression analysis. Trajectories of estimated glomerular filtration rate (eGFR) were compared using a mixed-effect model. RESULTS: Among 306,317 participants, 3188 and 17,461 developed a 1.5-fold increase in serum creatinine levels and new-onset overt proteinuria, respectively, during the median follow-up period of 36.2 months. The adjusted hazard ratio (HR) and 95% confidence interval (CI) for 1.5-fold increase in serum creatinine level in the TrUP 1/2 and TrUP 2/2 groups, compared to TrUP 0/2 group, were 1.23 (1.07-1.42) and 1.39 (1.01-1.92), respectively, and the adjusted HR (95% CI) for overt proteinuria were 2.94 (2.83-3.06) and 5.14 (4.80-5.51), respectively. The eGFR decline rates in the TrUP 1/2 and TrUP 2/2 groups were higher than that in the TrUP 0/2 group (p for interaction < 0.001). CONCLUSIONS: Trace proteinuria (detected via dipstick test) was associated with subsequent kidney function decline and overt proteinuria in the general population.
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Riñón , Proteinuria , Humanos , Creatinina , Estudios Longitudinales , Japón/epidemiología , Proteinuria/diagnóstico , Proteinuria/epidemiología , Proteinuria/complicaciones , Tasa de Filtración Glomerular , Factores de RiesgoRESUMEN
BACKGROUND: The effect of isolated hematuria without proteinuria on kidney function decline, and the modification by the severity of proteinuria in general population are not fully elucidated. METHODS: Participants were included in the Japan Specific Health Checkups Study between 2008 and 2014. The exposure of interest was the frequency of dipstick hematuria during the observation. In each proteinuria frequency category (non-, occasional, persistent), hematuria-related decline in the eGFR rate was examined by analysis of covariance (ANCOVA). eGFR decline trajectories were also assessed using mixed-effects models. RESULTS: Among the 552,951 participants, 146,753 (26.5%) had hematuria, and 56,021 (10.1%) and 8,061 (1.5%) had occasional and persistent proteinuria, respectively. During the median follow-up of 3.0 years, annual change in eGFR decline in participants with hematuria was significantly faster than in those without hematuria (mean [95% confidence interval]: - 0.95 [- 0.98 to - 0.92] vs - 0.86 [- 0.87 to - 0.84] mL/min/1.73 m2/year; P < 0.001). In ANCOVA, the hematuria-related annual eGFR decline rate increased as proteinuria frequency categories increased (differences in annual eGFR decline rate between participants with and without hematuria: 0.08 [0.06 to 0.09] in participants with non-proteinuria category, 0.17 [0.15 to 0.18] in occasional proteinuria category, and 0.68 [0.65 to 0.71] mL/min/1.73 m2/year in persistent proteinuria category; P for interaction < 0.001). Similar results were obtained by the linear mixed-effect model. CONCLUSIONS: Proteinuria has a synergistic effect on dipstick hematuria-related decline in kidney function. Among the general population without proteinuria throughout the observational period, the "isolated hematuria"-related eGFR decline was statistically significant but the difference was small.
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Hematuria , Proteinuria , Humanos , Hematuria/diagnóstico , Hematuria/etiología , Japón/epidemiología , Tasa de Filtración Glomerular , Proteinuria/diagnóstico , Proteinuria/etiología , Proteinuria/epidemiología , Riñón , Factores de RiesgoRESUMEN
The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27-hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC-activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.
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Regulación de la Expresión Génica/efectos de los fármacos , Hidroxicolesteroles/farmacología , Riñón/metabolismo , Transportadores de Anión Orgánico/biosíntesis , Proteínas de Transporte de Catión Orgánico/biosíntesis , Receptores de Estrógenos/metabolismo , Humanos , Transportadores de Anión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/genética , Organoides/metabolismo , Receptores de Estrógenos/genéticaRESUMEN
BACKGROUND: The survival rate of chronic dialysis patients in Japan remains the highest worldwide, so there is value in presenting Japan's situation internationally. We examined whether aggregate figures on dialysis patients in the National Database of Health Insurance Claims and Special Health Checkups of Japan (NDB), which contains data on insured procedures of approximately 100 million Japanese residents, complement corresponding figures in the Japanese Society for Dialysis Therapy Renal Data Registry (JRDR). METHODS: Subjects were patients with medical fee points for dialysis recorded in the NDB during 2014-2018. We analyzed annual numbers of dialysis cases, newly initiated dialysis cases- and deaths. RESULTS: Compared with the JRDR, the NDB had about 6-7% fewer dialysis cases but a similar number of newly initiated dialysis cases. In the NDB, the number of deaths was about 6-10% lower, and the number of hemodialysis cases was lower, while that of peritoneal dialysis cases was higher. The cumulative survival rate at dialysis initiation was approximately 6 percentage points lower in the NDB than in the JRDR, indicating that some patients die at dialysis initiation. Cumulative survival rate by age group was roughly the same between the NDB and JRDR in both sexes. CONCLUSION: The use of the NDB enabled us to aggregate data of dialysis patients. With the definition of dialysis patients used in this study, analyses of concomitant medications, comorbidities, surgeries, and therapies will become possible, which will be useful in many future studies.
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Diálisis Renal , Bases de Datos Factuales , Femenino , Humanos , Japón/epidemiología , Masculino , Sistema de Registros , Tasa de SupervivenciaRESUMEN
BACKGROUND: A dose of 0.5-1 mg/kg/day of prednisolone (PSL) is administered for the initial treatment of minimal change disease (MCD). However, little is known about the optimal PSL dose for the initial treatment of MCD. METHODS: We conducted a retrospective multicenter cohort study of treatment-naive adult patients with MCD diagnosed by renal biopsy from 1981 to 2015 in whom PSL monotherapy was performed as the initial treatment. The exposure of interest was an initial median PSL dose of < 0.63 mg/kg/day (Group L) compared to ≥ 0.63 mg/kg/day (Group H). Cumulative remission and relapse after remission were compared between these groups using Cox regression adjusted for baseline characteristics. RESULTS: Ninety-one patients met the inclusion criteria. During a median follow-up of 2.98 years, 87 (95.6%) patients achieved complete remission, and 47.1% relapsed after remission. There was no significant difference in the remission rate between the groups at 4 weeks of follow-up (66.7 vs. 82.6%). The median time to remission in Group L was comparable to that in Group H (17.0 vs. 14.0 days). A multivariable Cox hazard model revealed that the initial PSL dose was not a significant predictor of remission. The cumulative steroid doses at 6 months, 1 year, and 2 years after treatment initiation were significantly lower in Group L than in Group H. CONCLUSION: The initial PSL dose was not associated with time to remission, remission rate, time to relapse, or relapse rate. Therefore, a low initial steroid dose may be sufficient to achieve remission.
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Nefrosis Lipoidea , Prednisolona , Adulto , Estudios de Cohortes , Humanos , Inmunosupresores/uso terapéutico , Nefrosis Lipoidea/diagnóstico , Nefrosis Lipoidea/tratamiento farmacológico , Prednisolona/efectos adversos , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis. Since most patients have a relatively benign renal prognosis, long-term follow-up is required. During such a long course of disease, relapse of IgAN is occasionally observed after upper respiratory tract infection or without any trigger. However, little is known about the impact of relapse on long-term renal outcomes. METHODS: In this retrospective cohort study of biopsy-proven primary IgAN, we analyzed the association of 5-year therapeutic responsiveness (relapse) with the subsequent development of end-stage kidney disease (ESKD) using a 5-year landmark analysis (Cox model) and explored predictors of relapse from histological and clinical data at baseline. RESULTS: Among 563 patients from the exploratory cohort, most relapses (13.7%) occurred within 5 years after treatment. Using 5-year landmark analysis, among 470 patients, 79 developed ESKD during a median follow-up period of 155 months. Even after adjustment for clinicopathological relevant confounders, hazard ratios (95% confidence intervals) in the relapse and non-responder groups compared with the remission group were 2.86 (1.41-5.79) and 2.74 (1.48-5.11), respectively. Among 250 patients who achieved remission within 5 years, proteinuria, eGFR, mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, and crescent, but not interstitial fibrosis/tubular atrophy, were independent predictors of 5-year relapse in multivariable logistic regression analysis, CONCLUSIONS: Both relapsers and non-responders had similarly strong association with ESKD in patients with IgAN. We also confirmed the predictors of relapse 5 years after renal biopsy, which may guide the treatment strategies for patients with IgAN who occasionally relapse after remission.
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Glomerulonefritis por IGA , Fallo Renal Crónico , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Humanos , Riñón/patología , Fallo Renal Crónico/complicaciones , Pronóstico , Recurrencia , Estudios RetrospectivosRESUMEN
INTRODUCTION: Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial. METHODS: A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR). RESULTS: Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups. CONCLUSION: A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Oxadiazoles/uso terapéutico , Proteinuria/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Tetrazoles/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxadiazoles/farmacología , Tetrazoles/farmacologíaRESUMEN
BACKGROUND: Little is known about the association between pre-operative proteinuria and post-operative acute kidney injury (AKI) in noncardiac surgery. METHODS: This is a retrospective cohort study. Adults who underwent noncardiac surgery under general anesthesia from 2007 to 2011 at Nara Medical University Hospital were included. Those with obstetric or urological surgery, missing data for analyses or pre-operative dialysis were excluded. Exposure of interest was pre-operative proteinuria, defined as (+) or more by dipstick test. The outcome variable was post-operative AKI, defined by Kidney Disease: Improving Global Outcomes criteria, within 1 week after surgery. Multivariable logistic regression analyses were performed. RESULTS: Among 5168 subjects, 309 (6.0%) developed AKI. Pre-operative proteinuria was independently associated with post-operative AKI, with an odds ratio (OR) [95% confidence interval (CI)] of 1.80 (1.30-2.51). A sensitivity analysis restricted to elective surgery yielded a similar result. As proteinuria increased, the association with AKI became stronger [OR (95% CI) 1.14 (0.75-1.73), 1.24 (0.79-1.95), 2.75 (1.74-4.35) and 3.95 (1.62-9.62) for urinary protein (+/-), (+), (2+) and (3+), respectively]. Subgroup analyses showed proteinuria was especially associated with post-operative AKI among subjects with renin-angiotensin system inhibitors, other anti-hypertensives, hypoalbuminemia or impaired renal function (P for interaction = 0.05, 0.003, 0.09 or 0.02, respectively). CONCLUSIONS: In noncardiac surgery, pre-operative proteinuria was independently associated with post-operative AKI. Subjects with proteinuria should be managed with caution to avoid AKI peri-operatively.
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Lesión Renal Aguda/etiología , Complicaciones Posoperatorias/etiología , Cuidados Preoperatorios , Proteinuria/fisiopatología , Procedimientos Quirúrgicos Operativos/efectos adversos , Lesión Renal Aguda/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/patología , Estudios Retrospectivos , Factores de Riesgo , UrinálisisRESUMEN
Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant Staphylococcus aureus (MRSA). In contrast, mice overexpressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA and better in vitro killing of MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, P < .0005) in NeuACE neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation and interleukin-1ß release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection.
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Resistencia a la Enfermedad/genética , Inmunidad Innata , Neutrófilos/inmunología , Peptidil-Dipeptidasa A/inmunología , Infecciones Estafilocócicas/inmunología , Superóxidos/inmunología , Animales , Membrana Celular , Trampas Extracelulares/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Klebsiella pneumoniae , Masculino , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Staphylococcus aureus Resistente a Meticilina/inmunología , Ratones , Ratones Noqueados , NADPH Oxidasas/genética , NADPH Oxidasas/inmunología , Neutrófilos/citología , Neutrófilos/trasplante , Peptidil-Dipeptidasa A/deficiencia , Peptidil-Dipeptidasa A/genética , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Pseudomonas aeruginosa , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/inmunología , Transducción de Señal , Infecciones Estafilocócicas/enzimología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/prevención & control , Superóxidos/metabolismoRESUMEN
A-26-year-old man was admitted to our hospital with diffuse abdominal pain, nausea, and vomiting. He had a history of malignant nephrosclerosis, for which he had been receiving peritoneal dialysis (PD) for the past 14 months. His PD effluent was cloudy and turbid (white blood cell count, 10,528/µL; neutrophils 95.2%). A Gram-negative coccobacillus was isolated from peritoneal fluid culture. However, the organism could not be identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) (Vitek MS, bioMérieux), but was identified as Moraxella osloensis by the 16S rRNA gene sequencing. He was successfully treated with intraperitoneal cefazolin therapy for 3 weeks without removing the intra-abdominal catheter. A literature review revealed three previous case reports all of which were diagnosed by MALDI Biotyper (Bruker Daltonics), suggesting that the identification of M. osloensis may vary depending on the type of MALDI-TOF MS system. In conclusion, we experienced a case of M. osloensis infection in a PD patient, which was successfully treated by antibiotic treatment, without removing the PD catheter.
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Antibacterianos/uso terapéutico , Infecciones Relacionadas con Catéteres/diagnóstico , Moraxella/aislamiento & purificación , Infecciones por Moraxellaceae/diagnóstico , Peritonitis/diagnóstico , Adulto , Infecciones Relacionadas con Catéteres/tratamiento farmacológico , Infecciones Relacionadas con Catéteres/microbiología , Catéteres/efectos adversos , Cefazolina/uso terapéutico , ADN Bacteriano/aislamiento & purificación , Humanos , Masculino , Moraxella/genética , Infecciones por Moraxellaceae/tratamiento farmacológico , Infecciones por Moraxellaceae/microbiología , Nefroesclerosis/terapia , Diálisis Peritoneal/efectos adversos , Diálisis Peritoneal/instrumentación , Peritonitis/tratamiento farmacológico , Peritonitis/microbiología , ARN Ribosómico 16S/genética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masas en Tándem , Resultado del TratamientoRESUMEN
BACKGROUND: Recent evidence emphasizes the critical role of inflammation in the development of diabetic nephropathy. Angiotensin-converting enzyme (ACE) plays an active role in regulating the renal inflammatory response associated with diabetes. Studies have also shown that ACE has roles in inflammation and the immune response that are independent of angiotensin II. ACE's two catalytically independent domains, the N- and C-domains, can process a variety of substrates other than angiotensin I. METHODS: To examine the relative contributions of each ACE domain to the sodium retentive state, renal inflammation, and renal injury associated with diabetic kidney disease, we used streptozotocin to induce diabetes in wild-type mice and in genetic mouse models lacking either a functional ACE N-domain (NKO mice) or C-domain (CKO mice). RESULTS: In response to a saline challenge, diabetic NKO mice excreted 32% more urinary sodium compared with diabetic wild-type or CKO mice. Diabetic NKO mice also exhibited 55% less renal epithelial sodium channel cleavage (a marker of channel activity), 55% less renal IL-1ß, 53% less renal TNF-α, and 53% less albuminuria than diabetic wild-type mice. This protective phenotype was not associated with changes in renal angiotensin II levels. Further, we present evidence that the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain-specific substrate that accumulates in the urine of NKO mice, mediates the beneficial effects observed in the NKO. CONCLUSIONS: These data indicate that increasing AcSDKP by blocking the ACE N-domain facilitates sodium excretion and ameliorates diabetic kidney disease independent of intrarenal angiotensin II regulation.
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Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/deficiencia , Sustitución de Aminoácidos , Angiotensina II/metabolismo , Animales , Dominio Catalítico/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/genética , Canales Epiteliales de Sodio/metabolismo , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Natriuresis/genética , Natriuresis/fisiología , Oligopéptidos/antagonistas & inhibidores , Oligopéptidos/metabolismo , Peptidil-Dipeptidasa A/genética , Dominios Proteicos , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.
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Albuminuria/enzimología , Diabetes Mellitus Experimental/enzimología , Nefropatías Diabéticas/enzimología , Túbulos Renales/enzimología , Peptidil-Dipeptidasa A/metabolismo , Albuminuria/genética , Albuminuria/patología , Albuminuria/fisiopatología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/fisiopatología , Células Endoteliales/enzimología , Tasa de Filtración Glomerular , Glomérulos Renales/enzimología , Glomérulos Renales/fisiopatología , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Ratones Noqueados , Peptidil-Dipeptidasa A/deficiencia , Peptidil-Dipeptidasa A/genética , ARN Interferente Pequeño/genética , EstreptozocinaRESUMEN
Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-ß1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.
Asunto(s)
Enfermedades Renales/metabolismo , Riñón/efectos de los fármacos , Linfangiogénesis/efectos de los fármacos , Obstrucción Ureteral/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacología , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Renal parenchymal injury predisposes to salt-sensitive hypertension, but how this occurs is not known. Here we tested whether renal tubular angiotensin converting enzyme (ACE), the main site of kidney ACE expression, is central to the development of salt sensitivity in this setting. Two mouse models were used: it-ACE mice in which ACE expression is selectively eliminated from renal tubular epithelial cells; and ACE 3/9 mice, a compound heterozygous mouse model that makes ACE only in renal tubular epithelium from the ACE 9 allele, and in liver hepatocytes from the ACE 3 allele. Salt sensitivity was induced using a post L-NAME salt challenge. While both wild-type and ACE 3/9 mice developed arterial hypertension following three weeks of high salt administration, it-ACE mice remained normotensive with low levels of renal angiotensin II. These mice displayed increased sodium excretion, lower sodium accumulation, and an exaggerated reduction in distal sodium transporters. Thus, in mice with renal injury induced by L-NAME pretreatment, renal tubular epithelial ACE, and not ACE expression by renal endothelium, lung, brain, or plasma, is essential for renal angiotensin II accumulation and salt-sensitive hypertension.
Asunto(s)
Presión Arterial , Hipertensión/enzimología , Túbulos Renales/enzimología , NG-Nitroarginina Metil Éster , Peptidil-Dipeptidasa A/metabolismo , Sistema Renina-Angiotensina , Cloruro de Sodio Dietético , Angiotensina II/metabolismo , Animales , Modelos Animales de Enfermedad , Canales Epiteliales de Sodio/metabolismo , Regulación Enzimológica de la Expresión Génica , Hipertensión/inducido químicamente , Hipertensión/genética , Hipertensión/fisiopatología , Túbulos Renales/fisiopatología , Hígado/enzimología , Ratones Transgénicos , Natriuresis , Peptidil-Dipeptidasa A/deficiencia , Peptidil-Dipeptidasa A/genética , Eliminación Renal , Sistema Renina-Angiotensina/genética , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Cardiothoracic ratio by chest radiography is commonly used to assess volume status. Little is known about the relationships between cardiothoracic ratio and the incidence of clinical outcomes in patients undergoing hemodialysis (HD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,436 participants in the Q-Cohort Study 18 years or older who underwent maintenance HD in Japan. PREDICTOR: Cardiothoracic ratio. OUTCOMES & MEASUREMENTS: All-cause mortality and cardiovascular disease (CVD) events. RESULTS: During a 4-year follow-up period, 564 (16.4%) patients died of any cause and 590 (17.2%) developed CVD events. From baseline cardiothoracic ratios, participants were categorized into sex-specific quartiles because cardiothoracic ratio distribution differed by sex. The 4-year event-free survival rate, in terms of all-cause mortality and CVD events, was significantly lower with higher cardiothoracic ratios. Compared to the lowest cardiothoracic ratio (quartile 1), multivariable-adjusted HRs for all-cause mortality were 0.89 (95% CI, 0.66-1.20), 1.41 (1.08-1.86), and 1.52 (1.17-2.00) in patients from quartiles 2, 3, and 4, respectively. Similarly, in comparison to quartile 1, multivariable-adjusted HRs for CVD events were 1.00 (95% CI, 0.77-1.31), 1.18 (0.92-1.53), and 1.37 (1.07-1.76) in patients from quartiles 2, 3, and 4, respectively. Furthermore, the combination of higher cardiothoracic ratio and normohypotension (systolic blood pressure < 140mmHg and diastolic blood pressure < 90mmHg) was associated with higher risk for CVD events. LIMITATIONS: Single measurement of all variables, potentially less-heterogeneous patient population, and limited ascertainment of cardiac parameters and the outcomes. CONCLUSIONS: Higher cardiothoracic ratio is associated with higher risk for both all-cause mortality and CVD events in patients undergoing HD.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Corazón/anatomía & histología , Diálisis Renal/mortalidad , Caja Torácica/anatomía & histología , Anciano , Enfermedades Cardiovasculares/etiología , Causas de Muerte , Estudios de Cohortes , Femenino , Corazón/diagnóstico por imagen , Humanos , Japón , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Estudios Prospectivos , Radiografía Torácica , Diálisis Renal/efectos adversos , Caja Torácica/diagnóstico por imagen , Medición de RiesgoRESUMEN
BACKGROUND: Lymphangiogenesis occurs in diseased native kidneys and kidney allografts, and correlates with histological injury; however, the clinical significance of lymphatic vessels in kidney allografts is unclear. METHODS: This study retrospectively reviewed 63 kidney transplant patients who underwent protocol biopsies. Lymphatic vessels were identified by immunohistochemical staining for podoplanin, and were classified according to their location as perivascular or interstitial lymphatic vessels. The associations between perivascular lymphatic density and kidney allograft function and pathological findings were analyzed. RESULTS: There were no significant differences in perivascular lymphatic densities in kidney allograft biopsy specimens obtained at 0 h, 3 months and 12 months. The groups with higher perivascular lymphatic density showed a lower proportion of progression of interstitial fibrosis/tubular atrophy grade from 3 to 12 months (P for trend = 0.039). Perivascular lymphatic density was significantly associated with annual decline of estimated glomerular filtration rate after 12 months (r = -0.31, P = 0.017), even after adjusting for multiple confounders (standardized ß = -0.30, P = 0.019). CONCLUSIONS: High perivascular lymphatic density is associated with favourable kidney allograft function. The perivascular lymphatic network may be involved in inhibition of allograft fibrosis and stabilization of graft function.