RESUMEN
Blood pressure control with renin-angiotensin system (RAS) blockade has remained the gold standard for treating patients with proteinuric chronic kidney disease (CKD) up to date. Nevertheless, RAS blockade slows but does not halt the progression of kidney disease, thus highlighting the need to search for additional therapeutic approaches. The nonselective phosphodiesterase (PDE) inhibitor pentoxifylline (PTX) is an old drug that exhibits prominent anti-inflammatory, anti-proliferative and anti-fibrotic activities both in vitro and in vivo. Studies in human subjects have shown that PTX monotherapy decreases urinary protein excretion, and add-on therapy of PTX to background RAS blockade additively reduces proteinuria in patients with CKD of various etiology. More recent studies find that PTX combined with RAS blockade delays the decline of glomerular filtration rate in diabetic patients with mild to moderate CKD, and reduces the risk of end-stage renal disease in diabetic and non-diabetic patients in late stage of CKD with high proteinuria levels. In this review, we update the clinical trial results of PTX as monotherapy, or in conjunction or in comparison with RAS blockade on patients with proteinuria and CKD, and propose a mechanistic scheme explaining the renoprotective activities of this drug.
Asunto(s)
Progresión de la Enfermedad , Fallo Renal Crónico/prevención & control , Inhibidores de Fosfodiesterasa/uso terapéutico , Fallo Renal Crónico/etiología , Pentoxifilina/uso terapéutico , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/farmacología , Proteinuria/tratamiento farmacológico , Proteinuria/fisiopatología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/orinaRESUMEN
Fibrosis of the peritoneal cavity remains a serious, life-threatening problem in the treatment of kidney failure with peritoneal dialysis. The mechanism of fibrosis remains unclear partly because the fibrogenic cells have not been identified with certainty. Recent studies have proposed mesothelial cells to be an important source of myofibroblasts through the epithelial-mesenchymal transition; however, confirmatory studies in vivo are lacking. Here, we show by inducible genetic fate mapping that type I collagen-producing submesothelial fibroblasts are specific progenitors of α-smooth muscle actin-positive myofibroblasts that accumulate progressively in models of peritoneal fibrosis induced by sodium hypochlorite, hyperglycemic dialysis solutions, or TGF-ß1. Similar genetic mapping of Wilms' tumor-1-positive mesothelial cells indicated that peritoneal membrane disruption is repaired and replaced by surviving mesothelial cells in peritoneal injury, and not by submesothelial fibroblasts. Although primary cultures of mesothelial cells or submesothelial fibroblasts each expressed α-smooth muscle actin under the influence of TGF-ß1, only submesothelial fibroblasts expressed α-smooth muscle actin after induction of peritoneal fibrosis in mice. Furthermore, pharmacologic inhibition of the PDGF receptor, which is expressed by submesothelial fibroblasts but not mesothelial cells, attenuated the peritoneal fibrosis but not the remesothelialization induced by hypochlorite. Thus, our data identify distinctive fates for injured mesothelial cells and submesothelial fibroblasts during peritoneal injury and fibrosis.
Asunto(s)
Epitelio/patología , Fibroblastos/metabolismo , Peritoneo/patología , Animales , Linaje de la Célula , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Células Epiteliales/metabolismo , Fibrosis/patología , Genes Reporteros , Marcadores Genéticos/genética , Proteínas Fluorescentes Verdes/metabolismo , Ácido Hipocloroso/química , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibrosis Peritoneal/patología , Tamoxifeno/química , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
In adults, membranous nephropathy (MN) is a major cause of nephrotic syndrome. However, the etiology of approximately 75% of MN cases is idiopathic. Secondary causes of MN are autoimmune diseases, infection, drugs, and malignancy. The pathogenesis of MN involves formation of immune complex in subepithelial sites, but the definite mechanism is still unknown. There are three hypotheses about the formation of immune complex, including preformed immune complex, in situ immune-complex formation, and autoantibody against podocyte membrane antigen. The formation of immune complex initiates complement activation, which subsequently leads to glomerular damage. Recently, the antiphospholipase A2 receptor antibody was found to be associated with idiopathic MN. This finding may be useful in the diagnosis and prognosis of MN. The current treatment includes best supportive care, which consists of the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, lipid-lowering agents, and optimal control of blood pressure. Immunosuppressive agents should be used for patients who suffer from refractory proteinuria or complications associated with nephrotic syndrome. Existing evidence supports the use of a combination of steroid and alkylating agents. This article reviews the epidemiology, pathogenesis, diagnosis, and the treatment of MN.
Asunto(s)
Autoanticuerpos/sangre , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Receptores de Fosfolipasa A2/inmunología , Humanos , Pronóstico , Proteinuria/tratamiento farmacológicoRESUMEN
Emerging data have suggested that acute kidney injury (AKI) is often incompletely repaired and can lead to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. However, the underlying mechanisms linking AKI to CKD remain obscure. The present study aimed to investigate the role of cysteine-rich protein 61 (Cyr61) after unilateral kidney ischemia-reperfusion injury (IRI) in mice. After IRI, increased expression of Cyr61 was detected, predominately in the proximal tubular epithelium. This was confirmed by in vitro experiments, which showed that hypoxia stimulated Cyr61 expression in cultured proximal tubular epithelial cells. The proinflammatory property of Cyr61 was indicated by its ability to upregulate monocyte chemoattractant protein-1 and IL-6. Additionally, we found elevated urinary Cyr61 excretion in patients with AKI. Notably, treatment of mice with an anti-Cyr61 antibody attenuated the upregulation of kidney monocyte chemoattractant protein-1, IL-6, IL-1ß, and macrophage inflammatory protein-2 and reduced the infiltration of F4/80-positive macrophages on days 7 and 14 after IRI. In addition, blockade of Cyr61 reduced the mRNA expression of collagen, transforming growth factor-ß, and plasminogen activator inhibitor-I as well as the degree of collagen fibril accumulation, as evaluated by picrosirius red staining, and levels of α-smooth muscle actin proteins by day 14. Concurrently, in the treated group, peritubular microvascular density was more preserved on day 14. We conclude that Cyr61 blockade inhibits the triad of inflammation, interstitial fibrosis, and capillary rarefaction after severe ischemic AKI. The results of this study expand the knowledge of the mechanisms underlying the AKI-to-CKD transition and suggest that Cyr61 is a potential therapeutic target.
Asunto(s)
Lesión Renal Aguda/complicaciones , Proteína 61 Rica en Cisteína/antagonistas & inhibidores , Riñón/patología , Nefritis/etiología , Nefritis/prevención & control , Daño por Reperfusión/complicaciones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Anticuerpos Antiidiotipos/farmacología , Células Cultivadas , Quimiocina CCL2/metabolismo , Proteína 61 Rica en Cisteína/efectos de los fármacos , Proteína 61 Rica en Cisteína/inmunología , Modelos Animales de Enfermedad , Fibrosis/etiología , Fibrosis/metabolismo , Fibrosis/prevención & control , Hipoxia/metabolismo , Técnicas In Vitro , Interleucina-6/metabolismo , Riñón/metabolismo , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Masculino , Ratones , Ratones Endogámicos ICR , Nefritis/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Serpina E2/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Pericytes have been identified as the major source of precursors of scar-producing myofibroblasts during kidney fibrosis. The underlying mechanisms triggering pericyte-myofibroblast transition are poorly understood. Transforming growth factor ß-1 (TGF-ß1) is well recognized as a pluripotent cytokine that drives organ fibrosis. We investigated the role of TGF-ß1 in inducing profibrotic signaling from epithelial cells to activate pericyte-myofibroblast transition. Increased expression of TGF-ß1 was detected predominantly in injured epithelium after unilateral ureteral obstruction, whereas downstream signaling from the TGF-ß1 receptor increased in both injured epithelium and pericytes. In mice with ureteral obstruction that were treated with the pan anti-TGF-ß antibody (1D11) or TGF-ß receptor type I inhibitor (SB431542), kidney pericyte-myofibroblast transition was blunted. The consequence was marked attenuation of fibrosis. In addition, epithelial cell cycle G2/M arrest and production of profibrotic cytokines were both attenuated. Although TGF-ß1 alone did not trigger pericyte proliferation in vitro, it robustly induced α smooth muscle actin (α-SMA). In cultured kidney epithelial cells, TGF-ß1 stimulated G2/M arrest and production of profibrotic cytokines that had the capacity to stimulate proliferation and transition of pericytes to myofibroblasts. In conclusion, this study identified a novel link between injured epithelium and pericyte-myofibroblast transition through TGF-ß1 during kidney fibrosis.
Asunto(s)
Riñón/patología , Miofibroblastos/fisiología , Pericitos/fisiología , Factor de Crecimiento Transformador beta1/fisiología , Animales , Puntos de Control del Ciclo Celular/fisiología , Diferenciación Celular/fisiología , Células Cultivadas , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Fibrosis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Miofibroblastos/patología , Pericitos/metabolismo , Pericitos/patología , Transducción de Señal/fisiología , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/patología , Obstrucción Ureteral/fisiopatologíaRESUMEN
BACKGROUND/PURPOSE: Several studies have shown the renoprotective effects of pentoxifylline in the treatment of chronic kidney disease (CKD). This study was conducted to examine whether there was an increased benefit of including pentoxifylline with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in the treatment of CKD. METHODS: A single-center retrospective analysis was conducted. A total of 661 Stage 3B-5 CKD patients who received ACEI or ARB treatment were recruited. The patients were divided into the pentoxifylline use group and the no pentoxifylline group. Renal survival analysis of the two groups was compared. Subgroup analysis was performed by dividing the patients into lower [urine protein to creatinine ratio (UPCR)<1 g/g] and higher (UPCR ≥ 1 g/g) proteinuria subgroups. RESULTS: There was no between-groups difference regarding mortality and cardiovascular events. Addition of pentoxifylline showed a better renal outcome (p = 0.03). The protective effect of add-on pentoxifylline was demonstrated in the higher proteinuria subgroup (p = 0.005). In the multivariate Cox regression model, pentoxifylline use also showed a better renal outcome [hazard ratio (HR): 0.705; 95% confidence interval (CI): 0.498-0.997; p = 0.048]. This effect was more prominent in the higher proteinuria subgroup (HR: 0.602; 95% CI: 0.413-0.877; p = 0.008). CONCLUSION: In the advanced stages of CKD, patients treated with a combination of pentoxifylline and ACEI or ARB had a better renal outcome than those treated with ACEI or ARB alone. This effect was more prominent in the higher proteinuria subgroup. More large randomized control trials are needed to provide concrete evidence of the add-on effect of pentoxifylline.
Asunto(s)
Antagonistas de Receptores de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Riñón/efectos de los fármacos , Pentoxifilina/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Insuficiencia Renal Crónica/mortalidad , Estudios RetrospectivosRESUMEN
Microvascular pericytes and perivascular fibroblasts have recently been identified as the source of scar-producing myofibroblasts that appear after injury of the kidney. We show that cross talk between pericytes and endothelial cells concomitantly dictates development of fibrosis and loss of microvasculature after injury. When either platelet-derived growth factor receptor (R)-ß signaling in pericytes or vascular endothelial growth factor (VEGF)R2 signaling in endothelial cells was blocked by circulating soluble receptor ectodomains, both fibrosis and capillary rarefaction were markedly attenuated during progressive kidney injury. Blockade of either receptor-mediated signaling pathway prevented pericyte differentiation and proliferation, but VEGFR2 blockade also attenuated recruitment of inflammatory macrophages throughout disease progression. Whereas injury down-regulated angiogenic VEGF164, the dys-angiogenic isomers VEGF120 and VEGF188 were up-regulated, suggesting that pericyte-myofibroblast differentiation triggers endothelial loss by a switch in secretion of VEGF isomers. These findings link fibrogenesis inextricably with microvascular rarefaction for the first time, add new significance to fibrogenesis, and identify novel therapeutic targets.
Asunto(s)
Endotelio Vascular/patología , Riñón/irrigación sanguínea , Riñón/patología , Microvasos/patología , Pericitos/metabolismo , Transducción de Señal , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Capilares/metabolismo , Capilares/patología , Proliferación Celular , Endotelio Vascular/metabolismo , Fibrosis , Humanos , Inmunidad Innata , Riñón/metabolismo , Ratones , Microvasos/metabolismo , Neovascularización Patológica/complicaciones , Neovascularización Patológica/metabolismo , Pericitos/patología , Isoformas de Proteínas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Because baclofen is eliminated mostly by the kidney, baclofen-related encephalopathy is usually found in patients with renal failure. Therefore, hemodialysis has been suggested for those patients to alleviate symptoms and shorten recovery time. We present a case of baclofen intoxication with normal renal function benefiting from hemodialysis. A 55-year-old man took 420 mg of baclofen and was intubated because of respiratory depression. Hisconsciousness returned 9 hours after hemodialysis was finished, and he was extubated smoothly thereafter. The elimination half-life of baclofen before and during hemodialysis was 15.7 and 3.1 hours, respectively. As patients with baclofen overdose could have prolonged elimination even with normal renal function, hemodialysis would be beneficial to those patients with normal renal function.
Asunto(s)
Baclofeno/envenenamiento , Relajantes Musculares Centrales/envenenamiento , Diálisis Renal , Servicio de Urgencia en Hospital , Humanos , Masculino , Persona de Mediana Edad , Mal Uso de Medicamentos de Venta con RecetaRESUMEN
Pericytes are the major source of scar-producing myofibroblasts following kidney injury; however, the mechanisms of this transition are unclear. To clarify this, we examined Collagen 1 (α1)-green fluorescent protein (GFP) reporter mice (pericytes and myofibroblasts express GFP) following ureteral obstruction or ischemia-reperfusion injury and focused on the role of platelet-derived growth factor (PDGF)-receptor (PDGFR) signaling in these two different injury models. Pericyte proliferation was noted after injury with reactivation of α-smooth muscle actin expression, a marker of the myofibroblast phenotype. PDGF expression increased in injured tubules, endothelium, and macrophages after injury, whereas PDGFR subunits α and ß were expressed exclusively in interstitial GFP-labeled pericytes and myofibroblasts. When PDGFRα or PDGFRß activation was inhibited by receptor-specific antibody following injury, proliferation and differentiation of pericytes decreased. The antibodies also blunted the injury-induced transcription of PDGF, transforming growth factor ß1, and chemokine CCL2. They also reduced macrophage infiltration and fibrosis. Imatinib, a PDGFR tyrosine kinase inhibitor, attenuated pericyte proliferation and kidney fibrosis in both fibrogenic models. Thus, PDGFR signaling is involved in pericyte activation, proliferation, and differentiation into myofibroblasts during progressive kidney injury. Hence, pericytes may be a novel target to prevent kidney fibrosis by means of PDGFR signaling blockade.
Asunto(s)
Fibrosis/etiología , Enfermedades Renales/patología , Miofibroblastos/patología , Pericitos/patología , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Daño por Reperfusión/patología , Obstrucción Ureteral/patología , Animales , Diferenciación Celular , Proliferación Celular , Enfermedades Renales/etiología , Ratones , Transducción de Señal/fisiologíaRESUMEN
Sleep disturbance is common in dialysis patients and is associated with the development of enhanced inflammatory responses. Cognitive-behavioral therapy is effective for sleep disturbance and reduces inflammation experienced by peritoneal dialysis patients; however, this has not been studied in hemodialysis patients. To determine whether alleviation of sleep disturbance in hemodialysis patients also leads to less inflammation, we conducted a randomized controlled interventional study of 72 sleep-disturbed hemodialysis patients. Within this patient cohort, 37 received tri-weekly cognitive-behavioral therapy lasting 6 weeks and the remaining 35, who received sleep hygiene education, served as controls. The adjusted post-trial primary outcome scores of the Pittsburgh Sleep Quality Index, the Fatigue Severity Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory were all significantly improved from baseline by therapy compared with the control group. The post-trial secondary outcomes of high-sensitive C-reactive protein, IL-18, and oxidized low-density lipoprotein levels significantly declined with cognitive-behavioral therapy in comparison with the control group. Thus, our results suggest that cognitive-behavioral therapy is effective for correcting disorganized sleep patterns, and for reducing inflammation and oxidative stress in hemodialysis patients.
Asunto(s)
Terapia Cognitivo-Conductual , Citocinas/sangre , Mediadores de Inflamación/sangre , Inflamación/terapia , Estrés Oxidativo , Diálisis Renal/efectos adversos , Trastornos del Sueño-Vigilia/terapia , Sueño , Anciano , Análisis de Varianza , Biomarcadores/sangre , Regulación hacia Abajo , Femenino , Humanos , Inflamación/etiología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/psicología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/inmunología , Trastornos del Sueño-Vigilia/metabolismo , Trastornos del Sueño-Vigilia/fisiopatología , Trastornos del Sueño-Vigilia/psicología , Encuestas y Cuestionarios , Taiwán , Factores de Tiempo , Resultado del TratamientoRESUMEN
Existing chronic kidney disease (CKD) is among the most potent predictors of postoperative acute kidney injury (AKI). Here we quantified this risk in a multicenter, observational study of 9425 patients who survived to hospital discharge after major surgery. CKD was defined as a baseline estimated glomerular filtration rate <45 ml/min per 1.73 m(2). AKI was stratified according to the maximum simplified RIFLE classification at hospitalization and unresolved AKI defined as a persistent increase in serum creatinine of more than half above the baseline or the need for dialysis at discharge. A Cox proportional hazard model showed that patients with AKI-on-CKD during hospitalization had significantly worse long-term survival over a median follow-up of 4.8 years (hazard ratio, 1.7) [corrected] than patients with AKI but without CKD.The incidence of long-term dialysis was 22.4 and 0.17 per 100 person-years among patients with and without existing CKD, respectively. The adjusted hazard ratio for long-term dialysis in patients with AKI-on-CKD was 19.8 compared to patients who developed AKI without existing CKD. Furthermore, AKI-on-CKD but without kidney recovery at discharge had a worse outcome (hazard ratios of 4.6 and 213, respectively) for mortality and long-term dialysis as compared to patients without CKD or AKI. Thus, in a large cohort of postoperative patients who developed AKI, those with existing CKD were at higher risk for long-term mortality and dialysis after hospital discharge than those without. These outcomes were significantly worse in those with unresolved AKI at discharge.
Asunto(s)
Lesión Renal Aguda , Fallo Renal Crónico , Diálisis Renal/mortalidad , Estudios de Cohortes , Estudios de Seguimiento , Hospitalización , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Observación , Complicaciones Posoperatorias , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
BACKGROUND: Information is limited regarding the outcomes of patients with preexisting chronic kidney disease (CKD) who develop dialysis-requiring acute kidney injury. METHODS: 131 adult patients with advanced CKD who received emergent hemodialysis from January to June in 2002 were recruited and monitored for all-cause mortality and end-stage renal disease until the end of 2007. RESULTS: Among patients investigated, 21 (16%) were successfully withdrawn from acute hemodialysis after an average of 8 sessions of dialysis therapy (range: 1-44). Multivariate analysis revealed that larger kidney size (odds ratio, OR = 1.755, p = 0.018), lower predialysis creatinine (OR = 0.722, p = 0.002), and non-diabetes (OR = 0.271, p = 0.037) were predictors for withdrawal. After 5 years, all patients in the non-withdrawal group remained on chronic dialysis, whereas only 8/21 (38%) patients in the withdrawal group developed end-stage renal disease. Cox's analysis showed that age (hazard ratio, HR = 1.043, p < 0.0001), prerenal azotemia (HR = 1.040, p = 0.002), and adjusted propensity score for assigning to dialysis withdrawal (HR = 6.819, p = 0.008) were associated with mortality. Withdrawal from acute dialysis was not related to long-term mortality (p = 0.34). CONCLUSIONS: Among the advanced CKD patients, predictors of the successful weaning from acute dialysis were non-diabetes, larger kidney size and lower serum creatinine levels. The strategy of removal from emergent dialysis was not related to long-term mortality.
Asunto(s)
Lesión Renal Aguda/patología , Fallo Renal Crónico/patología , Diálisis Renal/métodos , Insuficiencia Renal Crónica/patología , Lesión Renal Aguda/mortalidad , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Evaluación de Resultado en la Atención de Salud , Modelos de Riesgos Proporcionales , Insuficiencia Renal Crónica/mortalidad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Metabolic syndrome (MS) is thought to be a risk marker for cardiovascular diseases in the general population and in patients with chronic kidney disease. This study investigated whether the presence of MS also modifies cardiovascular (CV) outcomes among non-diabetic patients undergoing long-term peritoneal dialysis (PD). METHODS: We enrolled 280 patients from a medical centre in North Taiwan who began PD between January 1999 and December 2005 and followed them until December 2009. MS was defined by the modified National Cholesterol Educational Programme (Adult Treatment Panel III) criteria. All parameters and biochemical data were collected by chart review. Patient outcomes (overall and CV death, fatal or non-fatal CV events) were recorded during the follow-up period. Survival was analysed by the Kaplan-Meier method, and the influence of MS and its components on outcomes were analysed by Cox regression models. RESULTS: The average follow-up period was 49.2 months. Non-diabetic patients with MS had worse outcomes than those without MS or at risk for MS, but better than their diabetic counterparts. By multivariate analysis, MS was independently associated with increased risk for CV death (hazard ratio, HR = 13.27) and fatal or non-fatal CV events (HR = 10.50). Among five MS components, hypertriglyceridaemia, low high-density lipoprotein levels and hyperglycaemia were significant risk factors for adverse CV outcomes. CONCLUSIONS: MS is a potent risk marker for adverse CV outcomes in non-diabetic patients on PD. Timely interventions targeting specific component of this syndrome may be required in this subset of patients.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Síndrome Metabólico/complicaciones , Diálisis Peritoneal , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Sepsis is the leading cause of acute kidney injury (AKI) in critical patients. The optimal timing of initiating renal replacement therapy (RRT) in septic AKI patients remains controversial. The objective of this study is to determine the impact of early or late initiation of RRT, as defined using the simplified RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure) classification (sRIFLE), on hospital mortality among septic AKI patients. METHODS: Patient with sepsis and AKI requiring RRT in surgical intensive care units were enrolled between January 2002 and October 2009. The patients were divided into early (sRIFLE-0 or -Risk) or late (sRIFLE-Injury or -Failure) initiation of RRT by sRIFLE criteria. Cox proportional hazard ratios for in hospital mortality were determined to assess the impact of timing of RRT. RESULTS: Among the 370 patients, 192 (51.9%) underwent early RRT and 259 (70.0%) died during hospitalization. The mortality rate in early and late RRT groups were 70.8% and 69.7% respectively (P > 0.05). Early dialysis did not relate to hospital mortality by Cox proportional hazard model (P > 0.05). Patients with heart failure, male gender, higher admission creatinine, and operation were more likely to be in the late RRT group. Cox proportional hazard model, after adjustment with propensity score including all patients based on the probability of late RRT, showed early dialysis was not related to hospital mortality. Further model matched patients by 1:1 fashion according to each patient's propensity to late RRT showed no differences in hospital mortality according to head-to-head comparison of demographic data (P > 0.05). CONCLUSIONS: Use of sRIFLE classification as a marker poorly predicted the benefits of early or late RRT in the context of septic AKI. In the future, more physiologically meaningful markers with which to determine the optimal timing of RRT initiation should be identified.
Asunto(s)
Lesión Renal Aguda/terapia , Cuidados Críticos/métodos , Indicadores de Salud , Terapia de Reemplazo Renal/métodos , Sepsis/complicaciones , Lesión Renal Aguda/etiología , Lesión Renal Aguda/mortalidad , Anciano , Anciano de 80 o más Años , Femenino , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sepsis/mortalidad , Sepsis/terapia , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: The maintenance of good health-related quality of life (HRQoL) is an important goal for end-stage renal disease (ESRD) patients. Whether hemodialysis (HD) and peritoneal dialysis (PD) have different impacts on HRQoL is a concern shared by both physicians and patients. A comparison study of HRQoL between Taiwanese HD and PD patients was conducted. METHODS: ESRD patients at 14 hospitals or dialysis centers in northern Taiwan were recruited in this cross-sectional study. The Chinese-language version of the 36-item Short Form Health Survey Questionnaire (SF-36, Taiwan Standard Version 1.0) was used to evaluate HRQoL. Ordinal regression analyses were used to explore the independent association between HRQoL scores and dialysis modality. By Bonferroni correction test, a P value of <0.005 was regarded as significant. RESULTS: A total of 866 HD patients and 301 PD patients were included. After adjusting for confounding factors, no difference in HRQoL was found among the entire cohort and the diabetic subgroup. CONCLUSION: This study demonstrated that Taiwanese HD and PD patients had similar HRQoL. The current survey improves our understanding of the association of HRQoL with dialysis modality in Taiwan ESRD population.
Asunto(s)
Pacientes/psicología , Diálisis Peritoneal , Calidad de Vida , Diálisis Renal , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , TaiwánRESUMEN
Peritoneal fibrosis (PF), including simple sclerosis and encapsulating peritoneal sclerosis (EPS), is a serious complication in patients on long-term peritoneal dialysis. Tamoxifen has successfully been used in treating EPS; however, the mechanism of tamoxifen in treating EPS fibrosis disorders remains unclear. This study demonstrates a possible antifibrotic mechanism of tamoxifen. A bleach-induced PF rat model was applied as the in vivo treatment target. Tamoxifen was intraperitoneally injected daily to treat PF. The PF scores and thickness of the submesothelial zone over the liver surface were measured as indicators for the severity of PF. Human peritoneal mesothelial cells (HPMC) were used as an in vitro model to test the antifibrotic effect of tamoxifen. Gene expressions of transforming growth factors-ß (TGF-ß), connective tissue growth factor (CTGF) and collagen were investigated using quantitative polymerase chain reactions. In HPMC, tamoxifen showed paradoxical effects between collagen I and TGF-ß. Tamoxifen also inhibited TGF-ß-induced collagen and CTGF. The possible antifibrotic effect of tamoxifen is through inhibiting CTGF to block collagen synthesis, although it enhances TGF-ß which increases fibrosis. These results provide a possible molecular mechanism for tamoxifen.
Asunto(s)
Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Fibrosis Peritoneal/metabolismo , Tamoxifeno/farmacología , Animales , Antineoplásicos Hormonales/farmacología , Células Cultivadas , Factor de Crecimiento del Tejido Conjuntivo/genética , Matriz Extracelular/metabolismo , Humanos , Masculino , Fibrosis Peritoneal/inducido químicamente , Fibrosis Peritoneal/patología , Ratas , Ratas Wistar , Hipoclorito de Sodio/efectos adversos , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Hyperphosphataemia in end-stage renal disease (ESRD) is a major contributor to the development of cardiovascular disease. It has been proposed that the phosphate binder sevelamer has pleiotropic properties. The aim of this study was to evaluate the effects of sevelamer compared with calcium acetate on serum lipid profiles, uric acid and reactive oxygen species in haemodialysis patients with hyperphosphataemia. METHODS: An 8-week, randomized, open-label, parallel-group study was conducted after a 2-week washout period. A total of 52 patients with ESRD on maintenance haemodialysis were screened for enrolment; 26 patients were randomized to each of the sevelamer and calcium acetate groups. Reactive oxygen species (ROS) production, i.e. superoxide and hydrogen peroxide (H2O2)-related radicals, were detected by chemiluminescence measurement with lucigenin and luminol, respectively. RESULTS: There were no significant differences between treatment groups in changes in serum phosphorus (p=0.378) and adjusted serum calcium levels (p=0.980), but there were more hypercalcaemic events in the calcium acetate group (12.0% vs 3.7%) during treatment. Total serum cholesterol (p<0.001) and low-density lipoprotein (LDL) cholesterol (p<0.001) levels decreased significantly compared with baseline in the sevelamer group. The decreases in total serum cholesterol and LDL cholesterol were correlated with the reductions in serum phosphorus levels during sevelamer treatment (correlation coefficient [r]=0.266 and 0.386, respectively). Serum uric acid decreased significantly in the sevelamer group (p=0.020), and this change was correlated with serum phosphorus changes (r=0.458). Decreases in plasma H2O2-related radicals, the major oxidative stressor in ROS (p<0.001), but not superoxide (p=0.593), were observed after sevelamer treatment. CONCLUSION: The improvements in multiple lipid surrogates, uric acid and ROS seen in this study show that sevelamer is a promising therapy for treatment of hyperphosphataemia in maintenance haemodialysis patients with a high risk of cardiovascular disease.
Asunto(s)
Quelantes/uso terapéutico , Fallo Renal Crónico/tratamiento farmacológico , Poliaminas/uso terapéutico , Adulto , Anciano , Calcio/sangre , Femenino , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Lípidos/sangre , Masculino , Persona de Mediana Edad , Fósforo/sangre , Especies Reactivas de Oxígeno/metabolismo , Diálisis Renal , Sevelamer , Ácido Úrico/sangreRESUMEN
OBJECTIVES: To examine whether urinary excretion of cysteine-rich protein 61 (Cyr61), an acknowledged proinflammatory factor in kidney pathologies, increases in chronic kidney disease (CKD) and is associated with subsequent rapid kidney function decline. DESIGN: An observational cohort study. SETTING: In the nephrology outpatient clinics of a tertiary hospital in Taiwan. PARTICIPANTS: We enrolled 138 adult CKD outpatients (n=12, 32, 18, 18, 29 and 29 in stages 1, 2, 3a, 3b, 4 and 5 CKD, respectively) between February and October 2014 and followed them for 1 year. Their mean age was 60.46±13.16 years, and 51 (37%) of them were women. PRIMARY OUTCOME MEASURES: Urinary Cyr61 levels were measured by ELISA. Rapid kidney function decline was defined as an estimated glomerular filtration rate (eGFR) decline rate ≥ 4 mL/min/1.73 m2/year or developing end-stage renal disease during subsequent 3-month or 1-year follow-up period. Models were adjusted for demographic and clinical variables. RESULTS: The urine Cyr61-to-creatinine ratio (UCyr61CR) increased significantly in patients with stage 4 or 5 CKD. Multivariable linear regression analysis showed that log(UCyr61CR) was positively correlated with log(urine protein-to-creatinine ratio) (p<0.001) but negatively correlated with baseline eGFR (p<0.001) and hypertension (p=0.007). Complete serum creatinine data during the follow-up were available for 112 patients (81.2%). Among them, multivariable logistic regression identified log(UCyr61CR) was independently associated with rapid kidney function decline (adjusted OR 2.29, 95% CI 1.27 to 4.15) during the subsequent 3 months. UCyr61CR improved the discriminative performance of clinical models to predict 3-month rapid kidney function decline. In contrast, log(UCyr61CR) was not associated with rapid eGFR decline during the entire 1-year follow-up. CONCLUSIONS: Elevated urinary Cyr61 excretion is associated with rapid short-term kidney function deterioration in patients with CKD. Measuring urinary Cyr61 excretion is clinically valuable for monitoring disease trajectory and may guide treatment planning.
Asunto(s)
Proteína 61 Rica en Cisteína , Insuficiencia Renal Crónica , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón , Persona de Mediana Edad , Pacientes Ambulatorios , Estudios Prospectivos , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
BACKGROUND: Fetuin A, a predictor of mortality in dialysis patients, is associated with vascular calcification and atherosclerosis in hemodialysis (HD) patients. Whether it predicts arteriovenous (AV) access patency is unknown. This study aimed to investigate the association between fetuin A and AV access patency in HD patients. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 238 prevalent HD patients (127 women and 111 men; mean age, 60 ± 12 years) were followed up for AV access patency for 32 months. PREDICTORS: Tertiles of baseline circulating fetuin A levels, corresponding to 0.15-0.25, 0.26-0.32, and 0.33-0.51 g/L. OUTCOME: The major outcome was loss of unassisted AV access patency, defined as AV access thrombosis or need for intervention. MEASUREMENTS: Fetuin A and other markers of inflammation. RESULTS: 100 patients had loss of AV access patency (42%) on follow-up. Patients in the lowest fetuin A tertile had the worst AV access patency (log-rank test, χ(2) = 8.68; P = 0.01). Using Cox proportional hazards regression with patients in the lowest fetuin A tertile as reference, patients in the intermediate tertile had an HR of 0.49 (95% CI, 0.29-0.82), whereas those in the highest fetuin A tertile had an HR of 0.43 (95% CI, 0.25-0.75) for loss of AV access patency. Similarly, considering patients using AV fistulas or grafts separately, patients in the highest fetuin A tertile had less risk of losing AV access patency than patients in the other tertiles (HR, 0.40 [95% CI, 0.19-0.84] for patients with AV fistulas and HR, 0.25 [95% CI, 0.10-0.65] for patients with AV grafts). LIMITATIONS: Focus on the patency of prevalent rather than new AV access in maintenance hemodialysis patients. CONCLUSIONS: Fetuin A deficiency is associated with a higher risk of loss of AV access patency in either native AV fistulas or AV grafts in HD patients.