RESUMEN
BACKGROUND: The impact of isolated v-lesions on clinical outcome in biopsies with acute cellular rejection (ACR) is unclear. METHODS: Two hundred and sixty-five biopsies showing the highest ACR severity for each patient were recruited and classified into four groups: (i) acute interstitial rejection (AIR) I with minimal tubulointerstitial inflammation (TI), (ii) AIR II with intensive TI, (iii) acute vascular rejection (AVR) I with minimal TI, and (iv) AVR II with intensive TI. RESULTS: The complete reversal rates of AIR I and AIR II groups were marginally higher than AVR I and AVR II groups (p = 0.16). At eight yr of transplantation, the death-censored graft survival (DCGS) rate of AIR I group (93.3%) was significantly higher compared with the AVR I (72.7%) or AVR II (72.9%) group. AVR I group had a similar DCGS rate with AVR II group (72.7% vs. 74.1%), whereas AVR with v1-lesion showed significantly higher graft survival (GS) rate than those with v2-lesion (70.2% vs. 45.5%). The t-lesion of AIR and v-lesion of AVR group were associated with graft loss. CONCLUSION: The extent of TI is non-specifically associated with graft loss in biopsies with AVR; the higher grade v-lesion predicts the lower complete reversal rate and poorer long-term graft survival.
Asunto(s)
Rechazo de Injerto/patología , Trasplante de Riñón , Riñón/patología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Inflamación/patología , Estimación de Kaplan-Meier , Túbulos Renales/patología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: Von Hippel-Lindau protein (VHL) provides the degradation of hypoxia-inducible factor (HIF). Tetracycline-induced, Pax8-rtTA-based knockout of VHL (VHL-KO) affects all renal tubules and periportal hepatocytes and leads to sustained upregulation of HIF. Here, we study the phenotype of VHL-KO in both organs, the time course of changes, and long-term morpho-functional outcome. METHODS: Mice with doxycycline-induced VHL-KO and controls (CON) were followed for up to 9 months. Systemic and tissue parameters were evaluated using clinical chemistry, histology, immunohistochemistry, RT-PCR and in situ hybridisation. RESULTS: At day 3 following VHL-KO, substantial abundance of HIF-1α and -2α was detected in the nuclei of hepatocytes and renal tubular epithelia. Hypoxia, induced by bleeding anaemia, did not further augment HIF signal. Erythropoietin mRNA was detectable in hepatocytes but not in the kidney. Vascular endothelial growth factor mRNA was upregulated in kidney but not in liver. At day 7 following VHL-KO, the renal capillary density was enhanced, reaching its maximum at day 14. Blood haemoglobin increased constantly up to day 28 (23.3 vs. 15.8 g dL(-1) , VHL-KO vs. CON). Thereafter, it was kept within the normal range by weekly blood collections. Pathological changes were absent from kidney and liver 9 months after VHL-KO. CONCLUSIONS: Inducible, Pax8-rtTA-based deletion of VHL leads to organ-specific expression of epithelial HIF and erythropoietin in liver and kidney without causing pathological changes. Uniform, maximal and sustained HIF activation along the renal tubule may serve to study the potential benefits of hypoxia adaptation in experimental renal injury.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Factores de Transcripción Paired Box/genética , Transactivadores/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Capilares/metabolismo , Eritropoyesis , Eritropoyetina/genética , Eritropoyetina/metabolismo , Femenino , Genotipo , Hemoglobinas/metabolismo , Inmunohistoquímica , Hibridación in Situ , Riñón/irrigación sanguínea , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neovascularización Fisiológica , Factor de Transcripción PAX8 , Fenotipo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
Donor-specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody-mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3-4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow-up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log-rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log-rank: p = 0.036). Four of 10 patients with AMR-all in the everolimus group-lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus-based immunosuppression is associated with an increased risk for the development of DSA and AMR.
Asunto(s)
Ciclosporina/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Antígenos HLA/inmunología , Inmunosupresores/uso terapéutico , Isoanticuerpos/efectos adversos , Trasplante de Riñón/inmunología , Sirolimus/análogos & derivados , Adolescente , Adulto , Anciano , Niño , Preescolar , Everolimus , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Supervivencia de Injerto/inmunología , Humanos , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Sirolimus/uso terapéutico , Tasa de Supervivencia , Donantes de Tejidos , Adulto JovenRESUMEN
BACKGROUND: Daptomycin is a novel antibiotic with primarily renal elimination. METHODS: In an open-label, prospective trial, the pharmacokinetics of daptomycin after single (8 mg/kg BW) and multiple intravenous doses (4 mg/kg BW) at steady state were determined in critically ill, dialysis-dependent patients treated with continuous veno-venous hemodialysis (CVVHD). Daptomycin levels were determined by HPLC. Subjects with normal renal function received one dose of 4 mg/kg BW of daptomycin. RESULTS: In the normal controls, daptomycin administration resulted in a mean maximum concentration (Cmax) of 60.7 ± 10.7 mg/l and an area under the time-versus-concentration curve from 0 to 24 h (AUC0-24) of 402 ± 56 mg × h/l. In the CVVHD-treated patients, a loading dose of 8 mg/kg lead to Cmax of 87.5 ± 15.0 mg/l, AUC0-24 of 537 ± 97 mg × h/l and AUC24-48 of 193 ± 69 mg × h/l, respectively. After multiple doses of 4 mg/kg every 48 h, Cmax was 41.8 ± 5.0 mg/l, AUC0-24 302 ± 43 mg × h/l and AUC 24-48 h 102 ± 24 mg × h/l, respectively. Approximately 40% of the daptomycin dose administered was removed by CVVHD. Mean plasma half-lives of daptomycin in patients were 2 - 3 times longer than in healthy controls. CONCLUSIONS: The dosing regimen of 4 mg/kg TBW of daptomycin administered to CVVHD patients every 48 h is inappropriate to achieve effective antimicrobial plasma concentrations of daptomycin in the second half of the dosing interval (24 - 48 h). Doses of ≥ 4 mg/kg TBW administered intravenously every 24 h are necessary in CVVHD patients to assure that plasma daptomycin levels are comparably high to subjects with normal renal function and to avoid underdosing.
Asunto(s)
Antibacterianos/farmacocinética , Enfermedad Crítica , Daptomicina/farmacocinética , Diálisis Renal , Insuficiencia Renal/metabolismo , Anciano , Anciano de 80 o más Años , Daptomicina/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Insuficiencia Renal/terapiaRESUMEN
BACKGROUND: Rejection still has a fundamental impact on patient and graft survivals after renal transplantation. Published studies vary widely in their reporting of biopsy-proven acute rejection (BPAR) and non-BPAR rates. We undertook a systematic search of existing publications for reasons explaining this difference. Additionally, we analyzed our own population, which has a clearly defined biopsy strategy, to further investigate the rate of non-BPAR in routine clinical practice. METHODS: From large, multicenter, randomized, controlled trials investigating immunosuppressive regimens in de novo kidney transplant recipients, we extracted the rates of all reported rejections ("total" rate) versus BPAR. Non-BPAR was defined as the difference between "total" and BPAR. Additional analyses were performed for potential influencing factors, such as year of publication, number, and mean age of patients recruited and impact factor of the journal at the time of publication. We scanned all de novo adult patients undergoing kidney transplantation in our center between 1996 and 2004 for rejection episodes during the first year. RESULTS: The median rate of non-BPAR within the first year in 27 papers was 7% (range, 0%- 16.9%). Similarly, the relative proportion of non-BPAR showed large differences. We could not identify potential influencing factors to explain the large variability. Among our population, 136/365 patients (37.3%) experienced acute rejection episodes, with BPAR diagnosed in 90/365 patients (24.7%), yielding an absolute 12.6% rate of non-BPAR. CONCLUSION: Even centers with a well-defined biopsy strategy show a substantial proportion of non-BPAR episodes. Therefore, complete reporting of both BPAR and non-BPAR is important for the proper interpretation of study results.
Asunto(s)
Rechazo de Injerto , Trasplante de Riñón , Biopsia , HumanosRESUMEN
BACKGROUND: Transgenic overexpression of human endothelin-2 in rats was used to characterize the contribution of endothelin to diabetic cardiomyopathy. MATERIALS AND METHODS: Diabetes mellitus was induced by streptozotocin in transgenic rats and transgene-negative controls. Nondiabetic animals were included as well to form a 4-group study design. Heart morphological and molecular alterations were analysed following 6 months of hyperglycaemia. RESULTS: Plasma endothelin concentrations were significantly higher in both transgenic groups than in wild-type groups (nondiabetic: 3.5 +/- 0.4 vs. 2.1 +/- 0.2, P < 0.05; diabetic: 4.5 +/- 0.4 vs. 2.5 +/- 0.4 fmol mL(-1), P < 0.01). Diabetes induced cardiac hypertrophy in both wild-type and transgenic rats and showed the highest myocardial interstitial tissue volume density in diabetic transgenic rats (1.5 +/- 0.07%) as compared with nondiabetic transgenic (1.1 +/- 0.03%), nondiabetic wild-type (0.8 +/- 0.01%) and diabetic wild-type rats (1.1 +/- 0.03%; P < 0.01 for all comparisons). A similar pattern with the most severe changes in the enothelin-2 transgenic, diabetic animals was observed for hypertrophy of the large coronary arteries and the small intramyocardial arterioles respectively. Cardiac mRNA expression of endothelin-1, endothelin receptors type A and B were altered in some degree by diabetes or transgenic overexpression of endothelin-2, but not in a uniform manner. Blood pressure did not differ between any of the four groups. CONCLUSIONS: Overexpression of the human endothelin-2 gene in rats aggravates diabetic cardiomyopathy by more severe coronary and intramyocardial vessel hypertrophy and myocardial interstitial fibrosis. This transgenic intervention provides further and independent support for a detrimental, blood pressure-independent role of endothelins in diabetic cardiac changes.
Asunto(s)
Cardiomiopatías/metabolismo , Diabetes Mellitus Experimental/complicaciones , Endotelina-2/metabolismo , Animales , Arteriolas/patología , Presión Sanguínea , Cardiomiopatías/etiología , Vasos Coronarios/fisiopatología , Complicaciones de la Diabetes , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelina-2/genética , Hipertrofia , Miocardio/patología , ARN Mensajero/metabolismo , Ratas , Ratas Transgénicas/metabolismo , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Estreptozocina/efectos adversosRESUMEN
We addressed the effect of post-transplant lymphoproliferative disorder (PTLD) treatment with rituximab monotherapy or CHOP-based chemotherapy (+/- rituximab) after upfront immunosuppression reduction (IR) on renal graft function in a longitudinal analysis of 58 renal transplant recipients with PTLD and 610 renal transplant controls. Changes in the estimated glomerular filtration rate over time were calculated from a total of 6933 creatinine measurements over a period of >1 year using a linear mixed model with random and fixed effects. Renal graft function significantly improved with treatment of PTLD, especially in the chemotherapy subgroup. Patients treated with IR+chemotherapy +/- rituximab had a noninferior graft function compared with untreated controls suggesting that the negative impact of IR on the renal graft function can be fully compensated by the immunosuppressive effect of CHOP. The immunosuppressive effect of single agent rituximab may partially compensate the negative impact of IR on the graft function. Thus, it is possible to reduce immunosuppression when using chemotherapy to treat PTLD.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia de Injerto , Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Trastornos Linfoproliferativos/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Trastornos Linfoproliferativos/etiología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Factores de Riesgo , Rituximab , Vincristina/administración & dosificaciónRESUMEN
Multiple myeloma (MM) is a malignancy with excessive production of monoclonal proteins. At disease presentation 30% of MM patients have significant renal impairment which may progress to renal failure requiring dialysis. Besides chemotherapy extracorporeal elimination procedures such as plasma exchange have been applied as adjuvant strategies to eliminate free light chains from circulating blood, however the efficacy was poor with older techniques. We report about a highly efficient method to eliminate serum free light chain (sFLC) using a newly designed protein leaking membrane in patients suffering from sFLC induced acute renal failure. The protein leaking membrane (HCO 1100) is characterized by increased pore size facilitating elimination of middle molecules such as sFLC kappa (22.5 kD). The HCO 1100 membrane was applied in a hemodialysis and hemodiafiltration mode and compared to standard procedures (high flux hemodialysis, hemodiafiltration and plasma exchange). Hemodiafiltration with the protein leaking membrane HCO 1100 was superior to all other extracorporeal replacement strategies in eliminating sFLC-kappa from circulating blood. A median blood reduction rate of 40.8% (range 13.9%-66.4%) was achieved during hemodiafiltration. The corresponding peak clearance rate was 25 ml/min. Importantly, the poorest elimination rate was achieved by plasma exchange followed by standard high flux hemodialysis. Extracorporeal elimination strategies with the protein leaking membrane HCO 1100 may be a promising adjuvant treatment strategy for patients with sFLC nephropathy requiring dialysis. Hemodiafiltration and to lesser extend also hemodialysis with the HCO 1100 hemofilter are able to eliminate substantial amounts of sFLC kappa in MM patients.
Asunto(s)
Lesión Renal Aguda/terapia , Hemodiafiltración/métodos , Cadenas kappa de Inmunoglobulina/sangre , Mieloma Múltiple/terapia , Lesión Renal Aguda/etiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicacionesRESUMEN
BACKGROUND: The Genius dialysis system is increasingly used as an intermittent hemodialysis device in the setting of acute renal failure. Slow extended hemodialysis is preferred in the case of critical ill patients. In this study we established a safe and feasible citrate anticoagulation protocol for slow extended hemodialysis (SLED) with the Genius system. METHODS: We compared six anticoagulation protocols using SLED in 34 critically ill patients with acute renal failure. One group (A) received only citrate anticoagulation. Four groups (B - D) were treated with citrate and different additional systemic anticoagulation. Patients in the last group (F) were anticoagulated with heparin and were free of citrate anticoagulation. The total number of treatments was 103. A 4% sodium citrate solution was infused into the arterial line of the dialysis device for citrate anticoagulation. The dialysis solution contained one mmol/L of calcium. No additional calcium supplementation was done. We monitored electrolyte, acid-base and cardiovascular status prospectively. RESULTS: Hemodialysis was well tolerated hemodynamically. Electrolytes remained stable throughout hemodialysis in all groups. The decrease in ionized and total calcium was within the expected, clinically acceptable range. Bicarbonate and pH levels increased during dialysis, especially if citrate was used. CONCLUSIONS: Slow extended Genius hemodialysis with citrate is well tolerated and offers a safe and effective alternative to systemic anticoagulation.
Asunto(s)
Lesión Renal Aguda/terapia , Anticoagulantes/uso terapéutico , Ácido Cítrico/uso terapéutico , Soluciones para Hemodiálisis , Diálisis Renal/métodos , Anciano , Estudios de Factibilidad , Femenino , Fondaparinux , Soluciones para Hemodiálisis/química , Soluciones para Hemodiálisis/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Polisacáridos/uso terapéutico , Diálisis Renal/instrumentación , Resultado del TratamientoRESUMEN
BACKGROUND: The use of trisodium-citrate for regional anticoagulation of the extracorporal circuit during renal replacement therapy (RRT) has received increased interest, particularly in critically ill patients with increased risk of bleeding. Continuous renal replacement therapies are the most extensively investigated and used procedures in this regard. However, when patients recover from critical illness, RRT is often switched to intermittent procedures. In this prospective study, we investigated the efficacy and safety of citrate anticoagulation during intermittent hemodialysis (IHD) performed with a standard roller blood pump device. METHODS: We treated 11 critically ill patients with acute renal failure. These patients received a total of 31 intermittent IHD treatments. The targeted IHD treatment time was 6 h (4.5 l/h treatment dose). For anticoagulation, a 4% trisodium-citrate solution was continuously infused into the arterial line of the extracorporeal circuit. A calcium-free, lactate-based dialysis solution was used in all treatment procedures. Calcium was continuously substituted via a separate central line. Electrolyte and acid-base changes as well as the cardiovascular hemodynamics were analyzed. RESULTS: All patients achieved the targeted filter life time. Filter clotting did not occur. Electrolytes and acid base values were well-maintained throughout the study period. Particularly metabolic derangements were not observed. All treatments were hemodynamically well-tolerated. CONCLUSIONS: Intermittent hemodialysis with citrate anticoagulation can be safely applied in critically ill patients at high risk of bleeding.
Asunto(s)
Anticoagulantes/efectos adversos , Ácido Cítrico/efectos adversos , Diálisis Renal/efectos adversos , Equilibrio Ácido-Base/efectos de los fármacos , Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Calcio/metabolismo , Ácido Cítrico/farmacología , Electrólitos , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
PURPOSE: beta2-microglobulin (beta2MG) is pivotal to the pathogenesis of dialysis-related amyloidosis. We compared the effects of high cut-off hemodialysis (HCO-HD) with those of standard high-flux hemodialysis (HF-HD) regarding the concentration and clearance of beta2MG and albumin. DESIGN: We enrolled ten patients with acute renal failure in a double-blind, cross-over, randomized controlled trial. PROCEDURES: Each patient received four hours of HCO-HD (estimated in vivo cutoff 50-60 kDa) and four hours of HF-HD (estimated in vivo cutoff 15-20 kDa) in random order. Statistical methods and outcome measures: As data lacked normal distribution, we used nonparametric statistical analysis. Plasma and dialysate concentrations of beta2MG and albumin were measured at baseline and after four hours of each study treatment. MAIN FINDINGS: We found significantly greater diffusive beta2MG clearances for HCO-HD compared to HF-HD (at the start: 71.8 ml/min vs. 5.1 ml/min; P=0.008 and at the end: 68.8 ml/min vs. 5.7 ml/min; P=0.008). We found a reduction in plasma beta2MG concentrations of -31.6% during HCO-HD compared to an increase by 25.7% during HF-HD; P=0.008. At baseline (HCO-HD: 26.0 g/L vs. HF-HD: 26.5 g/L), and at the end of both treatments, plasma albumin concentrations were comparable (HCO-HD: 25.5 g/L vs. HF-HD: 26.5 g/L; P=0.25). During HCO-HD, albumin clearance was 1.9 ml/min at the start and decreased significantly to 0.8 ml/min at the end; P=0.008. HF-HD had an albumin clearance of 0.01 ml/min. CONCLUSIONS: HCO-HD was more effective in decreasing plasma beta2MG concentrations than standard HF-HD and did not reduce plasma albumin levels. Further studies of HCO-HD in the treatment of dialysis-related beta2MG accumulation appear warranted.
Asunto(s)
Lesión Renal Aguda/terapia , Diálisis Renal , Albúmina Sérica/análisis , Microglobulina beta-2/sangre , Lesión Renal Aguda/sangre , Adulto , Anciano , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Diálisis Renal/métodosRESUMEN
BACKGROUND: The lower limit of exposure to calcineurin inhibitors has not yet been established in de novo renal transplant patients receiving mycophenolic acid therapy with basiliximab. METHODS: A 12-month, multicenter, randomized, open-label trial was carried out in which de novo renal transplant patients received enteric-coated mycophenolate sodium, cyclosporine microemulsion, steroids and basiliximab. Patients were randomized to receive standard-exposure (n = 45) or reduced-exposure (n = 44) cyclosporine, based on differing C2 target ranges, after the first month post-transplant. RESULTS: Cyclosporine exposure gradually increased over the first month and was lower than previously recommended. Mean calculated creatinine clearance (primary end-point) was similar in the standard-exposure and reduced-exposure groups at month 6 (55.3+/-3.2 ml/min and 61.5+/-3.7 ml/min respectively, n.s.). There were 4 deaths but no death-censored graft losses, resulting in 95.5% patient and graft survival at one year in both groups. At 6 and 12 months, the incidence of biopsy-proven acute rejection was 17.8% and 17.8% in the standard-exposure group, and 13.6% and 15.9% in the reduced-exposure group. Adverse events were similar between treatment groups. Exploratory analyses could not identify a lower limit for the optimal CsA exposure range, but results suggested that high exposure at one year was associated with deteriorating renal function. CONCLUSIONS: These results indicate that enteric-coated mycophenolate sodium with reduced-exposure cyclosporine, steroids and basiliximab induction has an excellent therapeutic effect and is safe in de novo kidney transplant recipients. Lower C2 targets than previously recommended, particularly early post-transplant, do not appear to be associated with compromised efficacy.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Ciclosporina/uso terapéutico , Inhibidores Enzimáticos/administración & dosificación , Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Ácido Micofenólico/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Basiliximab , Bélgica/epidemiología , Biopsia , Creatinina/sangre , Ciclosporina/administración & dosificación , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Quimioterapia Combinada , Emulsiones , Inhibidores Enzimáticos/uso terapéutico , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Rechazo de Injerto/sangre , Rechazo de Injerto/patología , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Tasa de Supervivencia , Comprimidos Recubiertos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The aim of this single-center crossover substudy was to assess pharmacokinetics and pharmacodynamics [inosine 5'-monophosphate dehydrogenase (IMPDH) activity] of enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) at steady-state conditions. Stable maintenance renal transplant patients on 1 g MMF b.i.d. participating in a double-blind, multicenter study, were randomized to receive EC-MPS (720 mg b.i.d.) or continue receiving MMF (1000 mg b.i.d.) for 12 months. Thereafter, all patients (n = 18) received 720 mg EC-MPS b.i.d. Area under the plasma mycophenolic acid (MPA) concentration-time curve with EC-MPS (57.4 +/- 15.0 microg h/mL) fulfilled bioequivalence criteria (geometric mean 0.98 (90% CI: 0.87-1.11) compared to MMF (58.4 +/- 14.1 microg h/mL). Consistent with the delayed release characteristics of EC-MPS, peak MPA concentration (geometric mean 0.89; 90% CI: 0.70-1.13) occurred approximately 0.5 h later (p < 0.05) and predose MPA levels (geometric mean 2.10; 90% CI: 1.51-2.91) were higher and more variable, not fulfilling bioequivalence criteria. IMPDH activity inversely followed MPA concentrations and was inhibited to a similar degree (approximately 85%) by both formulations. The calculated value for 50% IMPDH inhibition was identical for both drugs. In conclusion, equimolar doses of EC-MPS and MMF produce equivalent MPA exposure, while the delayed release formulation of EC-MPS exhibits more variable predose levels and T(max). Overall, IMPDH activity reflected MPA pharmacokinetics.
Asunto(s)
Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapéutico , Adulto , Índice de Masa Corporal , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , IMP Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Comprimidos RecubiertosRESUMEN
The aim of this study was to assess the effects of 1 g of mycophenolate mofetil (MMF) on T-cell function and inosine monophosphate dehydrogenase (IMPDH) activity among patients undergoing kidney transplantation. Five patients undergoing renal transplantation from a living donor were enrolled in this study. Compared to baseline (before MMF intake), CD25 and CD71 expression were significantly decreased during the first hour following MMF intake. T-cell proliferation and IMPDH activity also decreased dramatically. Thereafter, all biomarker levels increased over time. At 4 hours, CD25 and CD71 levels, as well as IMPDH activity, returned to almost baseline values, whereas T-cell proliferation remained below baseline. Intracytoplasmic IL-2 expression remained unchanged after MMF ingestions. In conclusion, administration of 1 g of MMF was associated with a transient decrease in CD25 expression in addition to a temporary dramatic decrease in both T-cell proliferation and IMPDH activity.
Asunto(s)
IMP Deshidrogenasa/metabolismo , Trasplante de Riñón/fisiología , Ácido Micofenólico/análogos & derivados , Linfocitos T/inmunología , Antígenos CD/efectos de los fármacos , Antígenos CD/genética , Biomarcadores , Humanos , Inmunosupresores/uso terapéutico , Subunidad alfa del Receptor de Interleucina-2/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/genética , Trasplante de Riñón/inmunología , Donadores Vivos , Ácido Micofenólico/uso terapéutico , Receptores de Transferrina/efectos de los fármacos , Receptores de Transferrina/genética , Linfocitos T/efectos de los fármacosRESUMEN
AIM: A 12-month multicenter, double-blind trial in which maintenance renal transplant patients were randomized to remain on mycophenolate mofetil (MMF) or convert to enteric-coated mycophenolate sodium (EC-MPS, myfortic) has demonstrated that conversion from MMF to EC-MPS is safe. Patients completing the study were invited to enter an open-label extension. Upon entry to the extension, patients who had received MMF during the randomized phase were converted to EC-MPS ("newly-exposed EC-MPS" group) and were monitored separately from those who had been randomized to EC-MPS ("long-term EC-MPS" group). The aim of the extension study was to collect long-term safety and efficacy data on EC-MPS, and to confirm the safety of conversion from MMF to EC-MPS in a larger patient population. METHODS: All patients received EC-MPS 720 mg b.i.d. with cyclosporine microemulsion and corticosteroids per local practice. Data derived from the analysis of the first 24 months of the extension phase are presented. RESULTS: Of the 297 patients who completed the core study, 260 (88%) entered the extension; 195 (75%) completed the 24-month extension visit. For on-treatment patients > 95% of the planned daily dose of EC-MPS was administered, and < 13% of patients in both groups had discontinued EC-MPS due to adverse events by 24 months. The overall incidence of adverse events during the extension phase, including infections and hematological abnormalities, was comparable to that seen in the core study, with a similar safety profile in the newly-exposed and long-term EC-MPS groups. There were 3 deaths during the first 24 months of the extension, and 2 graft failures in both the "newly-exposed" and "long-term" EC-MPS groups. CONCLUSIONS: These data demonstrate that long-term use of EC-MPS is effective and has an acceptable tolerability profile in renal transplant patients, and confirm that conversion of maintenance renal transplant patients from MMF to EC-MPS is a safe therapeutic option.
Asunto(s)
Inmunosupresores/administración & dosificación , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/administración & dosificación , Adulto , Ciclosporina/administración & dosificación , Método Doble Ciego , Tolerancia a Medicamentos , Femenino , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Seguridad , Comprimidos Recubiertos , Factores de TiempoRESUMEN
Renal transplantation is by far the best therapeutic option for end-stage kidney disease with respect to quality of life, psychosocial rehabilitation, and even patient survival. Optimal immunosuppressive therapy should provide effective prophylaxis of both acute rejection and chronic allograft dysfunction. Thus immunosuppressive therapy should help to maintain good renal function and could help to prevent premature death of the recipient. With the introduction of new immunosuppressants over the last decade a dramatic reduction of acute rejection rates from approximately 50% to 15-30% could be achieved. However, the search for novel immunosuppressive drugs continues, drugs which not only lead to effective prevention of acute rejection, but also have an impact on chronic allograft dysfunction and prevent further deterioration of this multifactorial process. Based on a short presentation of the "three signal model" of immunoactivation, the most important mechanisms and characteristics of the presently available immunosuppressants are described. Because the immunosuppressive objectives change over time, a phase-dependent adaptation is necessary. At present, most centers in Germany use an immunosuppressive combination therapy, consisting of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus), a glucocorticoid (prednisolone or methylprednisolone), and mycophenolic acid (MPA), which is eventually combined with an antibody (e.g., IL-2R antibody) for induction. In contrast to the clear situation 10 years ago, highly specialized knowledge is required today with respect to mechanism of action, side effects, and potential interactions. This may enable the physician to adopt patient-oriented optimal immunosuppression. In the near future more individualized treatment options will be employed, which are adapted to the characteristics and side effects of the immunosuppressant, as well as to the characteristics of the donor, the recipient, and the transplanted organ such as immunology and ischemia. Another aspect is the reduction or elimination of some immunosuppressants at the earliest possible time. With new diagnostic and genetic markers the relationship between recipient and transplanted organ will be characterized better in the future and therapy will become more individualized. Altogether, these measures as well as optimized supportive therapy will help to further improve the longevity of the transplanted organ.
Asunto(s)
Refuerzo Inmunológico de Injertos/métodos , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/administración & dosificación , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Quimioterapia Adyuvante/tendencias , Humanos , Inmunosupresores/efectos adversos , Fallo Renal Crónico/complicaciones , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina/tendencias , Resultado del TratamientoRESUMEN
Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5-6 year ALERT study were offered open-label fluvastatin XL 80 mg/day in a 2-year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow-up was 6.7 years. Mean LDL-cholesterol was 98 mg/dL (2.5 mmol/L) at last follow-up compared to a pre-study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63-0.99, p = 0.036), and a 29% reduction in cardiac death or definite non-fatal MI (HR 0.71, 95% CI 0.55-0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL-cholesterol associated with reduced risk of MACE in RTR. The lipid-lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Ácidos Grasos Monoinsaturados/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Indoles/administración & dosificación , Trasplante de Riñón , Adulto , Enfermedades Cardiovasculares/mortalidad , Preparaciones de Acción Retardada , Ácidos Grasos Monoinsaturados/efectos adversos , Femenino , Fluvastatina , Estudios de Seguimiento , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Indoles/efectos adversos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Factores de Riesgo , Resultado del TratamientoAsunto(s)
Fallo Renal Crónico/cirugía , Trasplante de Riñón , Donadores Vivos , Contraindicaciones , Humanos , Fallo Renal Crónico/complicaciones , Trasplante de Riñón/ética , Trasplante de Riñón/métodos , Donadores Vivos/ética , Donadores Vivos/legislación & jurisprudencia , Donadores Vivos/psicología , Factores de RiesgoRESUMEN
Renal transplant recipients (RTR) have shortened life expectancy, primarily due to premature cardiovascular disease (CVD). Traditional CVD risk factors are highly prevalent. In addition, several non-traditional risk factors may contribute to the high risk. The aim of the study was to evaluate the effects of renal dysfunction on mortality and cardiovascular complications in 1052 placebo-treated patients of the Assessment of LEscol in Renal Transplantation (ALERT) trial. Follow-up was 5-6 years and endpoints included cardiac death, non-cardiovascular death, all-cause mortality, major adverse cardiac event (MACE), non-fatal myocardial infarction (MI) and stroke. The effects of serum creatinine at baseline on these endpoints were evaluated. Elevated serum creatinine in RTR was a strong and independent risk factor for MACE, cardiac, non-cardiovascular, and all-cause mortality, but not for stroke or non-fatal MI alone. Serum creatinine was associated with increased mortality and MACE, independent of established CVD risk factors. Graft loss resulted in increased incidences of non-cardiovascular death, all-cause mortality, MACE and non-fatal MI. In conclusion, elevated serum creatinine is a strong risk factor for all-cause, non-cardiovascular and cardiac mortality, and MACE, independent of traditional risk factors, but not for stroke or non-fatal MI alone.
Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Rechazo de Injerto/mortalidad , Enfermedades Renales/mortalidad , Trasplante de Riñón/mortalidad , Causas de Muerte , Creatinina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
INTRODUCTION: Laparoscopic living donor nephrectomy (LDN) offers multiple advantages to the donor. Since 1999 LDN has become the only surgical approach for living kidney donation in our department. To our knowledge a donor health-related quality of life (QoL) has not yet been performed with standardized and validated questionnaires to compare laparoscopic with open nephrectomy. We therefore performed a study with two questionnaires (SF-36/GBB-24) and one set of open questions for all donors in our department. METHODS: Questionnaires were sent out to all donors between 1983 and 2001 with at least a 1-year follow-up. To exclude a bias a maximum response rate was sought; donors who did not answer were recontacted as well as their recipients or their physicians to motivate them for participation. RESULTS: The response rate was (89.8%). Except for less limb pain in the laparoscopy group, no difference could be detected for donors QoL with respect to the surgical method. Willingness to donate again was not affected by the surgical method. Nevertheless if asked again today, most donors want laparoscopic kidney retrieval. CONCLUSIONS: Donors health-related QoL is not affected by the surgical method when queried retrospectively. Nevertheless, most donors today would favor laparoscopy, if they could chose again. How laparoscopy affects a reluctant donor to step forward must be determined in a prospective study.