RESUMEN
BACKGROUND: The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear. METHODS: In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation. RESULTS: Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 [95% confidence interval {CI}, 2.14 to 12.64; P<0.001]; 3.46 [95% CI, 1.39 to 8.56; P=0.007]; and 4.12 [95% CI, 1.26 to 13.45; P=0.02], respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 [95% CI, 0.39 to 9.82; P=0.42]; 0.44 [95% CI, 0.05 to 3.72; P=0.45]; and 1.34 [95% CI, 0.20 to 8.82; P=0.76], respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87 ± 0.12 vs. 0.78 ± 0.14 [P=0.05], and 0.86 ± 0.09 vs. 0.78 ± 0.14 [P=0.007], respectively). CONCLUSIONS: The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft. (ClinicalTrials.gov number, NCT01879124 .).
Asunto(s)
Supervivencia de Injerto/fisiología , Trasplante de Riñón/fisiología , Arteria Renal/fisiología , Resistencia Vascular , Adulto , Factores de Edad , Anciano , Biopsia , Velocidad del Flujo Sanguíneo , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/fisiopatología , Humanos , Riñón/irrigación sanguínea , Riñón/patología , Pruebas de Función Renal , Trasplante de Riñón/diagnóstico por imagen , Trasplante de Riñón/patología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pronóstico , Estudios Prospectivos , Flujo Pulsátil , Arteria Renal/diagnóstico por imagen , Ultrasonografía DopplerRESUMEN
Functional catheter problems are a major challenge for peritoneal dialysis (PD) programs. Here we performed a retrospective single-center study of 110 consecutive patients receiving a first PD catheter (swan neck double-cuff Missouri curled catheters, open surgical technique). Using postimplantation X-ray, the following categories were defined: swan neck angle (posterioanterio view (PA): under 45°, 45-90°, over 90°), inclination (angle between intramural part of catheter and horizontal line; lateral view: greater than/equal to 30°, under 30°), and the position of silicone bead relative to spine (PA view: L1-2, L3-4, lower) and catheter tip (PA view: hypogastric, umbilical, subcostal). Covariates included demographics, body size, previous abdominal surgery, and abdominal wall hernias. During a mean follow-up of 36 months, the time to first functional catheter problem was significantly associated with both the swan neck angle and inclination. The need for surgical intervention was significantly associated with inclination only. Technique failure was not associated with any parameter. In multivariate analysis, inclination was the sole variable significantly associated with functional catheter problems (hazard ratio 3.65 [1.98-6.72]) and the need for surgical intervention (hazard ratio 2.86 [1.19-6.88]). Thus, our study defines a set of X-ray variables that predict functional PD catheter problems and can be used for troubleshooting in individual cases as well as for education and internal audit purposes.
Asunto(s)
Obstrucción del Catéter/etiología , Catéteres de Permanencia , Migración de Cuerpo Extraño/etiología , Diálisis Peritoneal/efectos adversos , Diálisis Peritoneal/instrumentación , Radiografía Abdominal , Adulto , Anciano , Bélgica , Diseño de Equipo , Femenino , Migración de Cuerpo Extraño/cirugía , Humanos , Estimación de Kaplan-Meier , Masculino , Auditoría Médica , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Although renal transplantation (Tx) improves the outcome of patients with renal disease, cardiovascular (CV) risk remains high. Recently, it was demonstrated that asymmetric dimethylarginine (ADMA) levels predict CV events and graft survival in renal transplant recipients (RTRs). Little is known about the impact of renal Tx on the plasma levels of ADMA and symmetric dimethylarginine (SDMA). The present study aimed to define the time course of ADMA and SDMA after Tx. METHODS: We prospectively followed 167 incident RTRs with visits at the time of Tx and 3 and 12 months thereafter. At all visits, demographics and relevant biochemistry were recorded and blood was sampled for analysis of ADMA and SDMA (high-performance liquid chromatography). Eighty-four patients had an additional sampling in the immediate postoperative period. In a case-controlled substudy (n = 31), we compared ADMA and SDMA levels between RTRs and chronic kidney disease (CKD) patients, matched for glomerular filtration rate, gender, age, CV history and diabetes. RESULTS: Overall, plasma ADMA and SDMA levels decreased after Tx. The decline of SDMA was more pronounced and paralleled the recovery of renal function. Interestingly, the decline of ADMA was preceded by an increase in the immediate postoperative period. In the case-controlled substudy, SDMA levels were similar, whereas ADMA levels were significantly higher in RTRs compared with the CKD counterparts (P = 0.003). CONCLUSION: ADMA levels follow a biphasic pattern after successful renal Tx with a transient rise in the immediate postoperative period followed by a decline. Levels remain elevated compared with CKD patients, matched for age, gender, diabetes, CV history and renal function.
Asunto(s)
Arginina/análogos & derivados , Biomarcadores/sangre , Trasplante de Riñón , Insuficiencia Renal Crónica/sangre , Adulto , Anciano , Arginina/sangre , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Estudios Prospectivos , Insuficiencia Renal Crónica/cirugía , Factores de Riesgo , Adulto JovenRESUMEN
The effect of baseline histology and individual histologic lesions at the time of transplantation on long-term graft survival has been evaluated using different scoring systems, but the predictive capacity of these systems has not been adequately validated. All kidney recipients transplanted in a single institution between 1991 and 2009 who underwent a baseline kidney allograft biopsy at transplantation were included in this prospective study (N=548). All baseline biopsies were rescored according to the updated Banff classification, and the relationship between the individual histologic lesions and donor demographics was assessed using hierarchical clustering and principal component analysis. Survival analysis was performed using Cox proportional hazards analysis and log-rank testing. Mean follow-up time was 6.7 years after transplantation. Interstitial fibrosis, tubular atrophy, and glomerulosclerosis associated significantly with death-censored graft survival, whereas arteriolar hyalinosis and vascular intimal thickening did not. Notably, donor age correlated significantly with interstitial fibrosis, tubular atrophy, and glomerulosclerosis and associated independently with graft survival. On the basis of these findings, a novel scoring system for prediction of 5-year graft survival was constructed by logistic regression analysis. Although the predictive performance of previously published histologic scoring systems was insufficient to guide kidney allocation in our cohort (receiver operating characteristic area under the curve ≤0.62 for each system), the new system based on histologic data and donor age was satisfactory for prediction of allograft loss (receiver operating characteristic area under the curve = 0.81) and may be valuable in the assessment of kidney quality before transplantation.
Asunto(s)
Supervivencia de Injerto , Trasplante de Riñón , Riñón/patología , Adolescente , Adulto , Anciano , Aloinjertos , Biopsia , Niño , Secciones por Congelación , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de TiempoRESUMEN
Renal transplant recipients have an increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) and aortic calcifications (ACs) are well-known CV risk factors in patients with chronic kidney disease. We aimed to determine the prognostic value of AS and AC in incident renal transplant recipients (RTRs). We conducted a prospective study in 253 single RTR. AC were scored by means of lumbar X-ray. Carotid-femoral pulse wave velocity (PWV) was assessed in a subgroup of 115 patients. AC were present in 61% of patients. After a mean follow-up of 36 months, 32 CV events occurred in the overall group and 13 events in the PWV subgroup. When we accounted for age, gender, and CV history, AC score (HR, hazard ratio 1.09 per 1 unit increase; 95% CI 1.02-1.17) and PWV (HR 1.45 per 1 m/s; 95% CI 1.16-1.8) remained an independent predictor of CV events in Cox-regression analyses. Using receiver operating characteristics, the area under the curve for predicting CV events amounted to 0.80 and 0.72 for sum AC and PWV, respectively. Both AS and AC are strong predictors of future CV events in an incident RTR population. These vascular assessments are readily available and easy to perform, making them ideal tools for further risk stratification. (ClinicalTrials.gov number: NCT00547040).
Asunto(s)
Aorta/patología , Calcinosis/diagnóstico , Enfermedades Cardiovasculares/diagnóstico , Trasplante de Riñón/métodos , Rigidez Vascular , Adulto , Área Bajo la Curva , Enfermedades Cardiovasculares/complicaciones , Arterias Carótidas/patología , Femenino , Estudios de Seguimiento , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Curva ROC , Insuficiencia Renal/complicaciones , Insuficiencia Renal/terapia , Factores de Riesgo , Resultado del TratamientoRESUMEN
UNLABELLED: Mycophenolate mofetil (MMF) decreases the risk of acute rejection and is associated with improved graft survival in renal transplant recipients. However, MMF-related side effects often necessitate dose reduction, which may expose patients to a higher risk of acute rejection and graft loss. This study's aim was to examine the reasons for MMF dose reduction during the first post-transplant year and its impact on acute rejection, overall and death-censored graft loss. METHODS: Single-center retrospective analysis of 749 renal transplant recipients treated with MMF in their initial maintenance immunosuppressive protocol. RESULTS: In 365 patients (48.7%) a total of 530 MMF dose reductions were done. Reasons for reduction were hematologic toxicity (46.5%), infection (16.1%), gastrointestinal side effects (12.3%), malignancy (2.1%), study protocol (14.6%), and unknown (13.5%). MMF dose reduction as such was not an independent predictor of acute rejection or graft survival, although reductions in ≥ 50% of initial dose were significantly associated with acute rejection. CONCLUSIONS: In this retrospective cohort, by far the most important reason for MMF dose reduction during the first post-transplantation year was hematologic. MMF dose reductions in ≥ 50% increased the risk of acute rejection but did not compromise graft survival.
Asunto(s)
Supervivencia de Injerto , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Adulto , Anciano , Anemia/inducido químicamente , Femenino , Rechazo de Injerto , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/mortalidad , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Pancitopenia/inducido químicamente , Estudios Retrospectivos , Trombocitopenia/inducido químicamenteRESUMEN
BACKGROUND: Serum phosphorus concentrations reflect a dynamic balance between generation, exchanges, and removal. Time-averaged phosphorus concentrations (TAC(phos)) reflect the overall exposure better than single time-point concentrations, especially in dialysis patients treated with an intermittent modality. The present study aimed to determine the daytime rhythm of phosphorus in dialysis patients and to compare the TAC(phos) in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients. METHODS: Serum concentrations of urea nitrogen, creatinine and phosphorus were determined at regular intervals in 10 healthy volunteers (HV), 8 CAPD patients and 10 HD patients. In HV and CAPD patients, blood was sampled at 08:30 (fasting), 09:30, 10:30, 12:30, 16:30, and 08:30 h the next day. In HD patients, blood was sampled before and after the midweek dialysis session and rebound was assessed at regular time-points post-dialysis. TAC(phos) were determined according to the trapezoidal rule. RESULTS: Serum phosphorus levels show a daytime rhythm in CAPD patients, similar to what is observed in HV, with a nadir around 10:30 h and a rise in the afternoon. The magnitude of this daytime fluctuation is limited as compared to the treatment-related fluctuations in HD. These important fluctuations also translate in predialysis serum phosphorus concentrations overestimating the TAC. Remarkably, TAC(phos) were significantly lower in HD as compared to CAPD patients. CONCLUSIONS: Daytime phosphorus rhythm is preserved in CAPD patients. These fluctuations are limited as compared to fluctuations in HD patients. Treatment-related fluctuation should be accounted for when comparing phosphorus exposure between different groups.
Asunto(s)
Ritmo Circadiano , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Fósforo/sangre , Adulto , Anciano , Anciano de 80 o más Años , Nitrógeno de la Urea Sanguínea , Estudios de Casos y Controles , Creatinina/sangre , Femenino , Humanos , Fallo Renal Crónico/metabolismo , Masculino , Persona de Mediana Edad , Diálisis Peritoneal Ambulatoria Continua , Fósforo/metabolismo , Diálisis RenalRESUMEN
BACKGROUND/AIMS: Sudden death is the major cause of cardiac mortality in dialysis patients, accounting for approximately 60% of cardiovascular deaths. A prolonged QT interval and arterial calcification have been associated with increased cardiovascular morbidity and mortality in different patient populations including patients with chronic kidney disease (CKD). In the present study, we aimed to elucidate the association of vascular calcification with corrected QT interval duration in patients with end-stage renal disease. METHODS: We performed a single-center cross-sectional study in patients referred for renal transplantation. Patients taking QT-prolonging agents or with conduction abnormalities were excluded. Aortic calcifications were scored by means of lumbar X-rays. RESULTS: In the final analysis, 193 patients (118 men, 52 years old) were included. A prolonged QT interval was observed in 26% of the patients. Multivariate analysis showed an independent and direct association between corrected QT duration and the extent of aortic calcifications (p = 0.0004) independent of age, gender, cardiovascular history, electrolytes and parameters of mineral metabolism. CONCLUSIONS: A prolonged QT interval is prevalent in patients with CKD stage 5D. Aortic calcification is associated with a prolonged QT duration, independent of traditional determinants.
Asunto(s)
Electrocardiografía/métodos , Trasplante de Riñón/efectos adversos , Calcificación Vascular/patología , Anciano , Aorta/patología , Estudios Transversales , Electrólitos , Femenino , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Radioinmunoensayo/métodos , Factores Sexuales , Resultado del Tratamiento , Calcificación Vascular/complicacionesRESUMEN
BACKGROUND: The metabolic syndrome (MS) is an important risk factor for graft dysfunction and patient death after renal transplantation. The aim of this sub-analysis of the Symphony study was to assess the progression of the laboratory parameters associated with MS in the first year after transplantation. METHODS: Data collected from the Symphony study were used; 1645 patients were randomized to receive standard-dose cyclosporine (Stand-CsA), low-dose cyclosporine (Low-CsA), tacrolimus (Low-Tac) or sirolimus (Low-SRL), in addition to mycophenolate mofetil (MMF) and corticosteroids. Data were collected for levels and progression over the first year post-transplantation of systolic and diastolic blood pressure, uric acid, triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and fasting glucose levels by treatment arm. RESULTS: The low-SRL group had significantly higher levels of triglycerides and LDL. The two CsA arms were associated with the highest uric acid levels at each time point. There were no significant differences in overall levels or changes in glucose or HDL. Patients in the standard-CsA arm had significantly higher diastolic blood pressure than those in the Low-SRL and Low-Tac arms. Systolic blood pressure was higher in the Low-CsA arm than in the Low-Tac arm. The use of antihypertensive and antidiabetic agents was similar between the treatment arms. In the Low-SRL arm, more patients were treated with lipid-lowering therapy. Mean daily steroid doses were the highest in the Low-SRL arm. CONCLUSIONS: This sub-analysis demonstrates that there is a difference in metabolic parameters between immunosuppressive groups. CsA therapy was associated with the highest values of uric acid and systolic and diastolic blood pressure. Patients on SRL therapy had the worst lipaemic control. A possible effect of Tac on new-onset diabetes could not be excluded.
Asunto(s)
Inmunosupresores/administración & dosificación , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Síndrome Metabólico/etiología , Inmunología del Trasplante , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Análisis Químico de la Sangre , Determinación de la Presión Sanguínea , Índice de Masa Corporal , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Hiperlipidemias/diagnóstico , Hiperlipidemias/epidemiología , Fallo Renal Crónico/diagnóstico , Trasplante de Riñón/inmunología , Trasplante de Riñón/métodos , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/análogos & derivados , Pronóstico , Valores de Referencia , Medición de Riesgo , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversosRESUMEN
BACKGROUND: Both poor residual renal function (RRF) and high fibroblast growth factor 23 (FGF-23) levels are associated with arterial stiffness, left ventricular hypertrophy and increased (cardiovascular) mortality. Whether FGF-23 and RRF are interrelated is unknown. METHODS: We performed a prospective observational cohort study in 35 peritoneal dialysis (PD) patients with evaluation at 1, 6, 12 and 24 months after start of PD. In addition, the role of RRF was assessed in a cross-sectional observational cohort study including 68 prevalent haemodialysis patients. RESULTS: RRF significantly declined over time in PD patients. This decline was parallelled by a significant increase of both serum phosphorus and FGF-23 levels. In the prevalent dialysis cohort, RRF was found to be inversely associated with serum FGF-23 levels, independent of dialysis vintage, dialytic creatinine clearance, estimates of dietary phosphate intake (i.e. normalized protein nitrogen appearance), active vitamin D therapy and serum phosphorus and calcium levels. RRF, serum phosphorus and calcium levels and active vitamin D therapy explain 69% of the variation in FGF-23. The 38 anuric patients had higher FGF-23 levels but similar serum phosphorus levels. CONCLUSIONS: We demonstrate an important association between RRF and FGF-23, independent of classical determinants. This favours the hypothesis that the ailing kidney directly contributes to the raised FGF-23 levels. Whether FGF-23 is associated with poor outcomes independent of RRF, or vice versa, remains to be clarified.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Enfermedades Renales/terapia , Riñón/fisiopatología , Diálisis Peritoneal , Diálisis Renal , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Enfermedad Crónica , Estudios de Cohortes , Estudios Transversales , Progresión de la Enfermedad , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/fisiopatología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de TiempoRESUMEN
BACKGROUND: The calcimimetic cinacalcet is approved for treating secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Biochemical profiles and clinical outcomes in patients discontinuing cinacalcet at the time of transplantation are scarce. METHODS: We performed a prospective observational cohort study, including 303 incident renal transplant recipients, of whom 21 were on cinacalcet treatment at the time of transplantation. Parameters of mineral metabolism and incidence of parathyroidectomy and nephrocalcinosis in patients discontinuing cinacalcet at the time of transplantation patients ("cinacalcet +") were compared to cinacalcet-naïve patients ("cinacalcet -"). Mean follow-up was 35.6 ± 15.8 months. RESULTS: At the time of transplantation, parameters of mineral metabolism were similar in both groups. Conversely, at month 3, serum ionized calcium (p = 0.0007), calcitriol (p = 0.02), biointact parathyroid hormone (p = 0.06) levels and urinary fractional excretion of phosphorus (p = 0.06) were higher, while serum phosphorus levels (p = 0.06) were lower in "cinacalcet +." Analysis based on matching at the time of initiation showed that the course of post-transplant mineral metabolism in cinacalcet-treated patients (median treatment period 12.5 months) vs. cinacalcet-naïve patients was identical. "Cinacalcet +" patients are characterized by a high-incidence proportion of both post-transplant nephrocalcinosis (45% at month 3) and parathyroidectomy (28.6%). No difference in renal function was observed between "cinacalcet +" and "cinacalcet-" patients. CONCLUSION: Cinacalcet does not affect the course of secondary hyperparathyroidism in patients awaiting kidney transplantation. Biochemical profiles and a high parathyroidectomy rate suggest rebound hyperparathyroidism in renal transplant recipients discontinuing cinacalcet at the time of transplantation, which may be related to the short exposure time specific to this population. Risk/benefit studies are urgently required to define the role of continued calcimimetic treatment in renal transplant recipients and to determine the optimal treatment of secondary hyperparathyroidism in patients listed for transplantation.
Asunto(s)
Calcio/metabolismo , Hiperparatiroidismo Secundario/tratamiento farmacológico , Fallo Renal Crónico/metabolismo , Trasplante de Riñón/mortalidad , Minerales/metabolismo , Naftalenos/uso terapéutico , Cinacalcet , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/mortalidad , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Nefrocalcinosis/tratamiento farmacológico , Nefrocalcinosis/etiología , Hormona Paratiroidea/metabolismo , Paratiroidectomía , Pronóstico , Estudios Prospectivos , Diálisis Renal , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: This multicenter phase II study in renal transplantation compared 3 concentration-controlled ranges of FK778 (manitimus) with mycophenolate mofetil (MMF) both given in combination with tacrolimus and corticosteroids. METHODS: 364 patients were randomized to 12-month treatment: high-level FK778 group (H, N=87) received 4 x 600 mg/day (4 days) followed by 120 mg/day; mid-level FK778 group (M, N=92) received 3 x 600 mg/day (3 days) followed by 110 mg/day, low-level FK778 group (L, N=92) received 2 x 600 mg/day (2 days) followed by 100 mg/day, and control group received MMF 1 g/day (MMF, N=93). After week 6, FK778 doses were adjusted to trough ranges of 75-125 µg/mL (H), 50-100 µg/mL (M) and 25-75 µg/mL (L). Tacrolimus and steroids were administered at the same dose in each of the 4 groups. RESULTS: Biopsy proven acute rejection (BPAR) at 24 weeks, the primary study endpoint, was comparable in the L (22.8%) and MMF (17.2%) groups but higher in the H (34.5%) and M (29.3%) groups. BPAR at 12 months was comparable in the L (23.9%) and MMF (19.4%) groups but higher in the H (34.5%) and M (31.5%) groups. Graft and patient survival were lowest in the H group and renal function was poorest in the H and M groups. Premature study withdrawal was highest in the H group. CONCLUSIONS: Efficacy was similar between the low-level FK778 and MMF groups. Increased FK778 exposure was poorly tolerated and did not improve efficacy.
Asunto(s)
Alquinos/administración & dosificación , Inmunosupresores/administración & dosificación , Isoxazoles/administración & dosificación , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Nitrilos/administración & dosificación , Esteroides/administración & dosificación , Tacrolimus/administración & dosificación , Adulto , Alquinos/sangre , Método Doble Ciego , Quimioterapia Combinada , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/sangre , Isoxazoles/sangre , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/sangre , Nitrilos/sangre , Esteroides/sangre , Tacrolimus/sangreRESUMEN
BACKGROUND: The uremic retention solutes indoxyl sulfate and p-cresyl sulfate are linked to cardiovascular disease and overall survival. Dialytic clearances are limited, which is principally attributed to tight protein binding. Extending dialysis duration would be expected to substantially increase protein-bound uremic solute removal. The aim of the current study was to study protein-bound uremic retention solute clearances and kinetics during longer-hours nocturnal hemodialysis. METHODS: In a prospective cohort study of 32 maintenance alternate-night nocturnal hemodialysis patients, we followed serum concentrations, solute removals and solute clearances of p-cresyl sulfate and indoxyl sulfate. Spent dialysate sampling was fractionated to compare solute removals between the first 4 h and next 4 h of nocturnal dialysis. Single-compartment variable volume kinetics were calculated. RESULTS: Dialytic clearances of protein-bound uremic retention solutes are maintained during nocturnal (longer-hours) dialysis. Clearances of indoxyl sulfate exceed those of p-cresyl sulfate, presumably due to less tight protein-binding. Apparent distribution volumes increase substantially during nocturnal dialysis, indicative of multi-compartmental behavior of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. CONCLUSIONS: During nocturnal hemodialysis, serum concentrations of protein-bound solute concentrations are reduced less than predicted. Reduction ratios are not a valid tool to estimate total solute removal of protein-bound uremic retention solutes.
Asunto(s)
Cresoles/metabolismo , Indicán/metabolismo , Diálisis Renal/normas , Cresoles/análisis , Femenino , Soluciones para Hemodiálisis/química , Humanos , Indicán/análisis , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Unión Proteica , Diálisis Renal/métodos , Ésteres del Ácido Sulfúrico , Factores de TiempoRESUMEN
BACKGROUND: FTY720 (fingolimod), a novel immunomodulator, has demonstrated potential for prevention of acute rejection in combination with cyclosporine. METHODS: This study evaluated FTY720 2.5 mg versus mycophenolate mofetil (MMF) in a combination regimen with standard tacrolimus and corticosteroids in de novo renal transplant recipients for the composite efficacy within 6 months of transplantation. RESULTS: Incidence of treated biopsy-proven acute rejection was 22.9% with FTY720 and 18.5% with MMF. Increased incidence of macular oedema, transient decrease in heart rate and low rate of infections were seen in the FTY720 arm. CONCLUSION: FTY720 combined with tacrolimus and steroids did not show a significant therapeutic advantage over MMF for the prevention of acute rejection in de novo renal transplant recipients.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/terapia , Trasplante de Riñón/efectos adversos , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Tacrolimus/uso terapéutico , Adolescente , Adulto , Anciano , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Femenino , Clorhidrato de Fingolimod , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Pronóstico , Esfingosina/uso terapéutico , Tasa de Supervivencia , Adulto JovenRESUMEN
At the time of renal transplantation, erythropoiesis-stimulating agents and iron supplementation are routinely discontinued in the prospect of recovery of renal function. This recovery, however, is often delayed and suboptimal. In addition, blood loss because of frequent diagnostic phlebotomies may be substantial. Renal transplant recipients may thus be considered at high risk of anemia in the immediate post-transplant period. We performed a single-center observational study, including 391 recipients of a single kidney. Hemoglobin levels and parameters of iron metabolism were monitored during the immediate post-transplant period, i.e., the first 3 months after transplantation. Hemoglobin levels decreased by 3.8 ± 1.5 g/dl to reach a nadir of 9.1 ± 1.2 g/dl at day 7. Transient severe anemia was observed in 91.3% of the patients. Donor age, gender, renal diagnosis of polycystic disease, pretransplant hemoglobin and ferritin level, estimated glomerular filtration rate at month 3, and duration of initial hospitalization were observed to be independently associated with the hemoglobin level at month 3. Transient severe anemia is an almost universal observation in incident renal transplant recipients. Poor graft function, high donor age, and low iron stores are independently associated with low hemoglobin levels at month 3.
Asunto(s)
Anemia/etiología , Trasplante de Riñón/efectos adversos , Adulto , Anciano , Anemia/sangre , Anemia/epidemiología , Anemia/terapia , Bélgica/epidemiología , Darbepoetina alfa , Transfusión de Eritrocitos , Eritropoyetina/administración & dosificación , Eritropoyetina/análogos & derivados , Femenino , Hematínicos/administración & dosificación , Hemoglobinas/metabolismo , Humanos , Hierro/administración & dosificación , Hierro/sangre , Masculino , Persona de Mediana Edad , Riñón Poliquístico Autosómico Dominante/sangre , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/cirugía , Prevalencia , Factores de RiesgoRESUMEN
A highly sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of midazolam and its major metabolites 1'-hydroxymidazolam and 4-hydroxymidazolam in human plasma was developed and validated. Stable isotope-labeled midazolam-D(4) and 1'-hydroxymidazolam-D(4) were used as internal standards. Compounds were extracted from 0.5 mL plasma by liquid-liquid extraction with ethyl acetate-heptane (1:4). Chromatography was achieved using a Sunfire C(18) column. The mobile phase was a gradient with 10 m m formic acid in Milli-Q water and methanol at a flow rate of 0.3 mL/min. Total run time was 10 min. Detection was performed using a tandem mass spectrometer with positive electrospray ionization. Calibration curves were linear over the range of 0.10-50.0 ng/mL for midazolam and 0.025-25.0 ng/mL for both metabolites. For all compounds the lower limit of quantification was 0.10 ng/mL. Imprecision was assessed according to the NCCLS EP5-T guideline and was below 10% for all compounds. Mean recoveries were between 94 and 109% for midazolam and its metabolites. The validated method was successfully applied in a pharmacokinetic study investigating in vivo CYP3A-activity in a large cohort of renal allograft recipients using sub-therapeutic doses of midazolam as a drug-probe.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Midazolam/análogos & derivados , Midazolam/sangre , Espectrometría de Masas en Tándem/métodos , Estabilidad de Medicamentos , Humanos , Trasplante de Riñón , Midazolam/farmacocinética , Dinámicas no Lineales , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.
Asunto(s)
Inmunoconjugados/efectos adversos , Inmunosupresores/efectos adversos , Trasplante de Riñón , Abatacept , Enfermedad Aguda , Adulto , Antígeno B7-2/análisis , Enfermedades Cardiovasculares/etiología , Tasa de Filtración Glomerular , Rechazo de Injerto , Humanos , Inmunoconjugados/inmunología , Inmunoconjugados/farmacocinética , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/mortalidadRESUMEN
BACKGROUND: Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens. METHODS: We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft-Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. RESULTS: The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%). CONCLUSIONS: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764 [ClinicalTrials.gov].).
Asunto(s)
Corticoesteroides/uso terapéutico , Inhibidores de la Calcineurina , Inhibidores Enzimáticos/administración & dosificación , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Ácido Micofenólico/análogos & derivados , Tacrolimus/administración & dosificación , Corticoesteroides/administración & dosificación , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Ciclosporina/administración & dosificación , Daclizumab , Diabetes Mellitus/etiología , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunoglobulina G/administración & dosificación , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Infecciones Oportunistas , Prednisona/administración & dosificación , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Insuficiencia del TratamientoRESUMEN
INTRODUCTION: Protein-bound uraemic retention solutes, including p-cresyl sulfate and indoxyl sulfate, contribute substantially to the uraemic syndrome. These and several other uraemic retention solutes originate from intestinal bacterial protein fermentation. We investigated whether the prebiotic oligofructose-enriched inulin reduced serum concentration of p-cresyl sulfate and indoxyl sulfate, through interference with intestinal generation. METHODS: We performed a single centre, non-randomized, open-label phase I/II study in maintenance HD patients with a 4-week, escalating dose regimen of oligofructose-enriched inulin (ORAFTI Synergy 1, Tienen, Belgium) (www.clinicaltrials.gov NCT00695513). Changes in p-cresyl sulfate and indoxyl sulfate serum concentrations as well as changes in p-cresyl sulfate and indoxyl sulfate generation rates were analysed. RESULTS: Compliance with therapy was excellent. p-Cresyl sulfate serum concentrations at 4 weeks were significantly reduced by 20% (intention to treat, P = 0.01; per protocol, P = 0.03). Also p-cresyl sulfate generation rates were reduced (P = 0.007). In contrast, neither indoxyl sulfate generation rates (P = 0.9) nor serum concentrations (P = 0.4) were significantly changed. CONCLUSION: The prebiotic oligofructose-inulin significantly reduced p-cresyl sulfate generation rates and serum concentrations in haemodialysis patients. Whether reduction of p-cresyl sulfate serum concentrations, an independent predictor of cardiovascular disease in HD patients, will result in improved cardiovascular outcomes remains to be proven.
Asunto(s)
Cresoles/sangre , Inulina/uso terapéutico , Fallo Renal Crónico/terapia , Oligosacáridos/uso terapéutico , Prebióticos , Diálisis Renal/métodos , Ésteres del Ácido Sulfúrico/sangre , Administración Oral , Anciano , Femenino , Humanos , Indicán/sangre , Inulina/administración & dosificación , Inulina/efectos adversos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Oligosacáridos/administración & dosificación , Oligosacáridos/efectos adversosRESUMEN
INTRODUCTION: In solid organ transplantation (TX), perceived health status (PHS) is a relevant patient-reported outcome. For patients on TX waiting lists, PHS information is limited. The aim of this study was therefore to compare PHS of heart, liver, lung, and renal TX candidates. METHODS: We used a cross-sectional descriptive design, including consecutive heart, liver, lung and renal TX candidates listed at a university hospital in Belgium. PHS was evaluated using the generic EuroQoL instrument, assessing patients' perceptions of their general PHS, and evaluating the health-related domains of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Data were analyzed using multivariable ordinal logistic regression. RESULTS: The study included 314 TX candidates: 29 heart, 75 liver, 67 lung, and 143 renal. Analyses controlling for possible PHS-impacting variables (age, gender, marital status, education, comorbidities) yielded significantly disparate results between the four candidate groups. Renal candidates reported best PHS, followed by liver candidates, whereas heart and lung candidates, whose score differences were not significant, had worst PHS. CONCLUSION: The EQ-5D seems to be a valuable tool to identify differences in health-related problems in the four different organ candidate groups. The results can be used to create intervention programs focusing on effective clinical management for these patients pre- and post-transplant.