RESUMEN
Performance evaluation of new dialysis membranes is primarily performed in vitro, which can lead to differences in clinical results. Currently, data on dialysis membrane performance and safety are available only for haemodialysis patients. Herein, we aimed to establish an in vivo animal model of dialysis that could be extrapolated to humans. We created a bilateral nephrectomy pig model of renal failure, which placed a double-lumen catheter with the hub exposed dorsally. Haemodialysis was performed in the same manner as in humans, during which clinically relevant physiologic data were evaluated. Next, to evaluate the utility of this model, the biocompatibility of two kinds of membranes coated with or without vitamin E used in haemodiafiltration therapy were compared. Haemodialysis treatment was successfully performed in nephrectomized pigs under the same dialysis conditions (4 h per session, every other day, for 2 weeks). In accordance with human clinical data, regular dialysis alleviated renal failure in pigs. The vitamin E-coated membrane showed a significant reduction rate of advanced oxidation protein products during dialysis than non-coated membrane. In conclusion, this model mimics the pathophysiology and dialysis condition of patients undergoing haemodialysis. This dialysis treatment model of renal failure will be useful for evaluating the performance and safety of dialysis membranes.
Asunto(s)
Modelos Animales de Enfermedad , Membranas Artificiales , Diálisis Renal , Animales , Diálisis Renal/instrumentación , Porcinos , Vitamina E , Ensayo de Materiales , Materiales Biocompatibles Revestidos , Nefrectomía , Hemodiafiltración/instrumentación , Hemodiafiltración/métodosRESUMEN
The development of biocompatible membranes, aiming to limit the inflammatory response, oxidative stress, and coagulability during hemodialysis, has been an important step in reducing dialysis-related adverse outcomes. This includes a reduction in the risk of clotting of the extracorporeal circuit, thus enabling hemodialysis with a reduced dose or even without systemic anticoagulant drugs in patients with an increased bleeding risk. In this article, we summarize the in vitro research and clinical evidence on the antithrombotic properties of vitamin E- and heparin-coated membranes.
Asunto(s)
Anticoagulantes , Coagulación Sanguínea , Heparina , Membranas Artificiales , Diálisis Renal , Vitamina E , Humanos , Diálisis Renal/métodos , Heparina/uso terapéutico , Anticoagulantes/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Vitamina E/uso terapéutico , Materiales Biocompatibles RevestidosRESUMEN
The use of vitamin E-bonded cellulose membrane dialyzers has been reported to cause a decrease in oxidative lipid marker levels (Nakai et al., Ther Apher Dial 14:505-540, 1; Nakai et al., J Jpn Soc Dial Ther 45:1-47, 2; Mashiba et al., Arterioscler Thromb Vasc Biol 21:1801-1808, 3). However, few studies have identified this effect with vitamin E-bonded polysulfone membranes, and no studies report the same effect on alpha (1) antitrypsin-LDL complex, a new oxidative lipid marker. This prompted us to examine the influence of use of VPS-HA vitamin E-bonded polysulfone high-flux membrane dialyzers on this new oxidative lipid marker. The subjects were 17 patients who had been dialyzed with VPS-HA for 12 months. The subjects' baseline characteristics were as follows. Their average age was 65.6 ± 13.1 years, comprising 8 males and 9 females; hemodialysis vintage was 83.8 ± 85.4 months. Eight had chronic glomerular nephropathy and five had diabetic nephropathy. The primary outcome was defined as alpha (1) antitrypsin-LDL complex level after 12 months, as a post-study using VPS-HA. Secondary outcomes included triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol levels. The data were analyzed pre-study and after 3, 6, 9 and 12 months for alpha (1) antitrypsin-LDL complex, and pre-study and post-study for the other indicators. Twelve months after switching to VPS-HA, alpha (1) antitrypsin-LDL complex, total cholesterol and LDL cholesterol had significantly decreased. Triglycerides and HDL cholesterol had not significantly changed. Hemodialysis therapy with VPS-HA was shown to decrease alpha (1) antitrypsin-LDL complex, an index of oxidative stress, and also to decrease some lipid markers.
Asunto(s)
Fallo Renal Crónico/terapia , Lípidos/sangre , Membranas Artificiales , Diálisis Renal/instrumentación , Vitamina E/farmacología , Adulto , Anciano , Biomarcadores/sangre , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Estadísticas no Paramétricas , alfa 1-Antitripsina/sangreRESUMEN
Hemodialysis techniques for small animals have not been established because no small dialysis apparatus has been available. We recently developed a small-size dialyzer and established an appropriate blood purification system for small animals. To confirm the appropriate dialysate flow rate, bovine blood was dialyzed for 60 min at a fixed blood flow rate of 1.0 mL/min and variable dialysate flow rates. Blood urea nitrogen and creatinine levels decreased significantly at a dialysate flow rate of 5 mL/min (from 13.7 ± 0.2 to 10.3 ± 1.2 mg/dL and 1.07 ± 0.15 to 0.61 ± 0.12 mg/dL, respectively, P < 0.05). To determine the appropriate in vivo conditions, extracorporeal circulation was performed in anesthetized male Sprague-Dawley rats at a dialysate flow rate of 0.0 mL/min, for 240 min, and at variable blood flow rates. Extracorporeal circulation was successful at a blood flow rate of 1.0 mL/min, but not 1.5 mL/min. To establish in vivo hemodialysis conditions, we used the animal model of end stage renal failure. Sprague-Dawley rats were fed a 0.75% adenine-containing diet for 3 weeks, after which they received hemodialysis for 120 min at a dialysate and blood flow rate of 5.0 and 1.0 mL/min, respectively. There were no significant changes in systolic blood pressure or heart rate during dialysis. Thus, this blood purification system can be safely used for small animals at a dialysate flow rate of 5.0 mL/min and a blood flow rate of 1.0 mL/min. This system provides a basis for further research on hemodialysis therapy.
Asunto(s)
Circulación Extracorporea/métodos , Fallo Renal Crónico/terapia , Membranas Artificiales , Diálisis Renal/métodos , Animales , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Nitrógeno de la Urea Sanguínea , Bovinos , Creatinina/sangre , Modelos Animales de Enfermedad , Frecuencia Cardíaca , Fallo Renal Crónico/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Diálisis Renal/instrumentaciónRESUMEN
Currently, there are no detailed reports on the effects of vitamin E-bonded polysulfone (PS) membrane dialyzers on intradialytic hypotension (IDH) in diabetic hemodialysis (HD) patients. This study was designed to evaluate changes in intradialytic systolic blood pressure (SBP) using "VPS-HA" vitamin E-bonded super high-flux PS membrane dialyzers. The subjects were 62 diabetic HD patients whose intradialytic SBP fell by more than 20%. Group A comprised patients who required vasopressors to be able to continue treatment or who had to discontinue therapy due to their lowest intradialytic SBP being observed at 210 min (28 patients). Group B comprised patients who showed no symptoms and required no vasopressors but showed a gradual reduction in blood pressure, with the lowest intradialytic SBP seen at the end of dialysis (34 patients). The primary outcome was defined as the lowest intradialytic SBP after 3 months using VPS-HA. Secondary outcomes included changes in the following: lowest intradialytic diastolic blood pressure, pulse pressure, pulse rate, plasma nitric oxide and peroxynitrite, serum albumin, and hemoglobin A1c. Group A's lowest intradialytic SBP had significantly improved at 3 months (128.0 ± 25.1 mm Hg vs. 117.1 ± 29.2 mm Hg; P = 0.017). Group B's lowest intradialytic SBP had significantly improved at 1 month (134.4 ± 13.2 mm Hg vs. 121.5 ± 25.8 mm Hg; P = 0.047) and 3 months (139.1 ± 20.9 mm Hg vs. 121.5 ± 25.8 mm Hg; P = 0.011). We conclude that VPS-HA may improve IDH in diabetic HD patients.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Nefropatías Diabéticas/terapia , Hipotensión/tratamiento farmacológico , Diálisis Renal/métodos , Vitamina E/uso terapéutico , Anciano , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/complicaciones , Femenino , Humanos , Hipotensión/sangre , Hipotensión/complicaciones , Masculino , Persona de Mediana Edad , Óxido Nítrico/sangre , Ácido Peroxinitroso/sangre , Polímeros/química , Albúmina Sérica/análisis , Sulfonas/química , Vasoconstrictores/uso terapéutico , Vitamina E/químicaRESUMEN
The fundamental concept for the selection of high-performance membrane is based on solute removal capability and biocompatibility. From this principle, the selection guidelines for high-performance membrane are recommended as follows: (1) The currently available products do not provide coverage of the necessary 'balance between solute removal and biocompatibility' in a single dialyzer for all the dialysis patients. Therefore, it is advisable to choose a high-performance membrane taking into consideration the balance between the solute removal capacity necessary for the patient and the severity of complications that is considered a surrogate marker for biocompatibility. (2) There is an increasing demand in dialysis therapy for new biocompatibility indices such as 'reducing blood pressure variability during dialysis', 'decreasing oxidative stress' and 'delaying the onset or progression of complications'. High-performance membranes developed to address these needs include the ethylene-co-vinyl alcohol copolymer (EVAL) (R) membrane, cellulose triacetate, polymethylmethacrylate, vitamin E-coated polysulfone (PS) membrane, and PS membrane hemodiafiltration filter.
Asunto(s)
Materiales Biocompatibles/normas , Membranas Artificiales , Diálisis Renal/instrumentación , Difusión , Humanos , Ensayo de Materiales , Peso Molecular , Selección de Paciente , Permeabilidad , Albúmina Sérica/metabolismo , Solubilidad , Uremia/metabolismo , Uremia/terapiaRESUMEN
BACKGROUND: Intradialytic hypotension (IDH) is a common clinical trait in hemodialysis (HD) which is caused by poor biocompatibility of the dialyzer membrane. Aiming to improve IDH, vitamin E-bonded polysulfone dialyzer (VPS-H) was evaluated in a pilot study. METHODS: Eight IDH patients on standard HD were switched from their conventional high-flux dialyzers to VPS-H, and intradialytic blood pressure (BP) was monitored regularly for 10 months. RESULTS: The results showed that hypotension of systolic BP (SBP), diastolic BP (DBP) and pulse pressure (PP) during the session were improved after changing the dialyzer. Notably, almost all the values recorded from 120 minutes into the session until the end of the treatment in the period between the second and tenth month after treatment were significantly different from the corresponding baseline values. Moreover, after 8 to 10 months, the SBP prior to a dialysis session was significantly reduced compared with baseline values. On the other hand, the pulse rate showed no difference throughout the study period. CONCLUSIONS: This study provides early evidence of the beneficial role that vitamin E-bonded dialyzers may have in preventing IDH. Larger controlled trials are needed to confirm this original finding.
Asunto(s)
Antioxidantes/uso terapéutico , Hipotensión/prevención & control , Polímeros/química , Diálisis Renal/instrumentación , Sulfonas/química , Vitamina E/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Materiales Biocompatibles/química , Femenino , Humanos , Hipotensión/etiología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Diálisis Renal/efectos adversosRESUMEN
BACKGROUND/AIMS: Hemodialysis (HD) therapy may lead to functional changes in patient leukocytes. For example, the upregulation of inflammatory cytokines, such as IL-1beta and TNFalpha, has been well characterized. However, these findings do not explain the entire response of leukocytes in HD. In this study, we carried out a comprehensive gene expression analysis in leukocytes treated with various dialysis membranes using DNA microarrays. The identified gene has the potential to be a new marker for testing dialysis membrane biocompatibility. METHODS: Gene expression profiles were compared between a group of leukocytes treated with various dialysis membranes and an untreated group by using DNA microarray analysis. Expression was confirmed by quantitative RT-PCR. The expression of the gene product (leukocyte surface protein) was examined in 20 chronic HD patients by flow cytometry. RESULTS: In addition to the inflammatory cytokines, the urokinase plasminogen activator receptor (uPAR or CD87) gene was induced in leukocytes treated with each dialysis membrane. The extent of induction depended on the membrane's material composition. The expression of the uPAR (CD87) protein on leukocytes was markedly increased in patients undergoing dialysis therapy. The magnitude of uPAR (CD87) protein expression was correlated with clinical findings, i.e., the degree of leukopenia and the expression of adhesion molecules. CONCLUSIONS: The gene and protein expression of uPAR (CD87) depended on the dialysis membrane material and correlated closely with clinical findings. These results suggest that uPAR has the potential to serve as a marker not only for clinical use but also for the development of new dialysis membranes.
Asunto(s)
Biomarcadores/química , Perfilación de la Expresión Génica , Membranas Artificiales , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Receptores de Superficie Celular , Diálisis Renal/métodos , Adulto , Anciano , Anciano de 80 o más Años , Materiales Biocompatibles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Hematopoietic stem-cell-directed gene transfer has achieved limited success in transducing clinically relevant levels of target cells. The expansion of gene-modified cells is one way to circumvent the problem of inefficient transduction with current vectors. To this end, we have developed 'selective amplifier genes' (SAGs) that encode chimeric proteins that are a fusion of granulocyte colony-stimulating factor receptor and the steroid-binding domain. Prototype SAGs conferred estrogen-responsive growth on murine hematopoietic progenitors. METHODS: We constructed a retroviral vector coexpressing an SAG for 4-hydroxytamoxifen (Tm)-specific proliferation and the enhanced green fluorescent protein (EGFP). Murine bone marrow cells were transduced with this vector and transplanted into myeloablated mice. Subsequently, recipients were challenged with Tm, and EGFP(+) cells were enumerated. RESULTS: The challenge induced a significant increase in EGFP(+) leukocytes (21 +/- 4% to 27 +/- 5%), while EGFP(+) cells decreased in untreated animals (21 +/- 5% to 10 +/- 3%). Three months later, bone marrow cells were transplanted from the unchallenged mice to secondary hosts. Again the administration of Tm resulted in an increase of EGFP(+) cells (16 +/- 4% to 35 +/- 3%), contrasting to a decrease in controls (22 +/- 4% to 12 +/- 4%), and the difference was significant for more than 3 months. A detailed study of lineage showed a preferential expansion of EGFP(+) cells in granulocytes and monocytes following Tm administration. CONCLUSIONS: Long-term repopulating cells were transduced with the SAG, and the transduced granulocyte/monocyte precursors were most likely to be expandable in vivo upon Tm stimulation.