RESUMEN
Immunosuppressive therapy aims to protect transplanted organs from host responses. Individuals have unique repertoires of responses to foreign antigens and toxic reactions to immunosuppressants; the former determining the type or intensity of rejection reactions and the latter influencing the severity of iatrogenic effects. Because existing agents target molecules that are widely distributed in tissues, new strategies must selectively block lymphoid cells only, disrupt alloresponses but not innate immune responses, interact synergistically with other agents, facilitate the homeostatic process that naturally leads to graft acceptance and ideally only interrupt donor-specific responses. Approaches presently under investigation aim to alter cell trafficking, or selectively deviate the maturation of antigen-presenting cells or inhibit lymphocyte-activation cascades - events that are crucial to rejection responses.
Asunto(s)
Terapia de Inmunosupresión/métodos , Trasplante de Órganos/métodos , Inmunología del Trasplante , Animales , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/inmunología , Humanos , Inmunosupresores/farmacologíaRESUMEN
INTRODUCTION: Recombinant P-selectin glycoprotein ligand IgG fusion protein, rPSGL-Ig (YSPSL), a fusion protein of human P-selectin ligand and IgG1-Fc, blocks leukocyte adhesion and protects against ischemia reperfusion injury (IRI) in animal models. PATIENTS AND METHODS: This randomized 15-center, double-blind, 59-patient Ph2a study assessed YSPSL's safety in recipients of deceased-donor kidney allografts and its potential efficacy in improving early graft function. Two doses and two dosing modalities were evaluated. RESULTS: No drug-specific toxicities or increased adverse event rates were noted. Two YSPSL-treated patients died of causes determined as unrelated to study drug. YSPSL did not reduce the incidence of dialysis within the first week post-transplant (41% in treated vs. 20% in placebo patients). Renal function endpoints scored at post-operative days 1 & 2 were also not impacted by YSPSL. However, at day 5, the fraction of patients with serum creatinine above 6 mg/dL was lower in the YSPSL vs. placebo group (26% vs. 55%, p = 0.043). Large variations in the dialysis-delayed graft function (DGF) rates were observed between centers, independently of treatment assignment, indicating subjectivity of this endpoint. CONCLUSION: In this first Ph2a study in kidney transplantation, YSPSL was safe but did not impact the dialysis-DGF rate. Further studies with more objective efficacy endpoints are required to define the impact of YSPSL on early renal allograft function.
Asunto(s)
Rechazo de Injerto/prevención & control , Trasplante de Riñón , Glicoproteínas de Membrana/metabolismo , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Estudios de Cohortes , Creatinina/sangre , Método Doble Ciego , Femenino , Humanos , Inmunosupresores , Pruebas de Función Renal , Masculino , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Daño por Reperfusión/prevención & control , Donantes de Tejidos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: We sought to examine repeat versus primary renal transplantations using sirolimus-based regimens. METHODS: We compared 98 repeat versus 200 matched primary recipients treated de novo with sirolimus plus cyclosporine. Every repeat case received polyclonal antibody induction and continuous steroids. Outcomes were evaluated over a mean five-year follow-up by univariate and multivariate techniques. Kaplan-Meier plots were analyzed with using log-rank statistics with significance at P < or = 0.05. RESULTS: Significant differences in demographic features included greater panel reactive antibody (PRA), younger age, fewer HLA-mismatches and more pre-emptive repeat versus primary grafts. Neither graft and patient survivals, nor incidences of biopsy-proven acute rejection (BPAR), chronic vasculopathy or tubular atrophy/interstitial fibrosis among biopsies performed for cause were significantly different at 1 and 5 years. Younger recipients, better HLA matches and absence of diabetes promoted repeat graft survival; whereas older age, longer cold ischemia time and BPAR reduced primary transplant outcomes. Renal function was similar at 1, 3, 12, 24, 48 and 60 months. CONCLUSION: At 5 years this sirolimus regimen achieved similar efficacy for repeat versus primary transplantations.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Sirolimus/uso terapéutico , Adulto , Femenino , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Trasplante de Riñón/inmunología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Reoperación , Trasplante Homólogo , Resultado del TratamientoRESUMEN
All immunosuppressive medications require a learning curve that enables clinicians to improve the therapeutic index of agents. Mammalian target of rapamycin (mTOR) inhibitors are potentially a less nephrotoxic form of immunosuppression than calcineurin inhibitors (CNIs) that has been used in kidney transplant recipients for more than two decades. This drug class has a novel immunosuppressive action, probably mediated in part through inhibition of growth receptor signaling mechanisms. In addition, it has a unique drug toxicity, which is partially dose-related. This medication class also possesses antiproliferative activity, which may be useful in-post-transplant patients with increased atherosclerotic and malignancy risks. mTOR inhibitors have been utilized for de novo immunosuppression with CNIs, corticosteroids, and antimetabolites. mTOR inhibitors also have been used as CNI-sparing agents both early and late post-transplant. Much debate remains over how to best utilize mTOR inhibition in kidney transplantation.
Asunto(s)
Inmunosupresores/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Neoplasias Renales/etiología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Humanos , Terapia de Inmunosupresión , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Renales/complicaciones , Ratones , Modelos Biológicos , Proteínas Serina-Treonina Quinasas/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Serina-Treonina Quinasas TORRESUMEN
BACKGROUND: Because the course of polyoma virus-associated nephropathy (PVAN) has not been evaluated in a large cohort of patients receiving sirolimus (SRL)-based regimens, we have herein presented the incidence, clinical characteristics, and outcomes of 378 renal transplant recipients treated with SRL-based immunosuppression. METHODS: This retrospective single center study evaluated 344 kidney alone (KTX) and 34 simultaneous pancreas-kidney (SPK) transplantations performed between June 2000 and December 2004. RESULTS: At a mean follow-up of 43.3 months, six kidney (1.7%) and three kidney-pancreas (9.0%) transplanted patients displayed biopsy-proven PVAN. The mean time to diagnosis after transplantation was 18.2 months (range: 3.5-31.1 months), with a higher incidence among patients exposed (4.23%) versus not exposed to rabbit antithymocyte globulin (rATG; 0.53%; P=0.019) or SPK (9.0%) versus KTX (1.7%) recipients (odds ratio: 5.43; confidence interval: 1.29-22.8; P=0.038). Despite treatment with cidofovir, reduced immunosuppression and maintenance therapy with no agents other than SRL (C0=10.2+/-2.7 ng/dL) plus modest doses of prednisone (< or =5 mg), five patients (55.5%) experienced renal allograft failure. No rejection episodes were documented during the PVAN treatment and pancreatic function continued to be excellent among the SPK patients. CONCLUSIONS: Patients treated with SRL-based immunosuppression showed an incidence at the lower end of the range described with various other contemporaneous immunosuppressive regimens and with other cohorts not undergoing BK virus polymerase chain reaction surveillance. Exposure to rATG and SPK transplantation represented risk factors for the occurrence of PVAN, which showed a pernicious course despite withdrawal of calcineurin antagonists and/or mycophenolate mofetil.
Asunto(s)
Virus BK , Enfermedades Renales/virología , Trasplante de Riñón , Infecciones por Polyomavirus/complicaciones , Sirolimus/uso terapéutico , Infecciones Tumorales por Virus/complicaciones , Adulto , Animales , Suero Antilinfocítico/efectos adversos , Suero Antilinfocítico/uso terapéutico , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Incidencia , Enfermedades Renales/epidemiología , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/efectos adversos , Conejos , Estudios Retrospectivos , Factores de Riesgo , Trasplante HomólogoRESUMEN
Renal transplantation is the treatment of choice for most patients with end-stage renal disease. However, in spite of continuous progress in surgical techniques and immunosuppressive therapy, a wide variety of vascular and nonvascular complications can arise postoperatively. Vascular complications include transplant renal artery stenosis, arteriovenous fistulas or intrarenal pseudoaneurysms following renal transplant biopsy, extrarenal pseudoaneurysms, and graft thrombosis. Nonvascular complications include urologic complications (eg, ureteral obstruction, urine leak) and perigraft fluid collections (eg, lymphocele, abscess, hematoma, urinoma). These postoperative complications can be diagnosed and managed with minimally invasive techniques; however, an understanding of renal transplant anatomy and the risks of posttransplantation immunosuppressive therapy unique to this patient population is essential to their successful application. In addition, familiarity with the indications for and limitations of these techniques as well as collaboration between the radiologist and the transplantation surgeon are vital for maximizing the chances of renal allograft survival.
Asunto(s)
Rechazo de Injerto/etiología , Rechazo de Injerto/cirugía , Enfermedades Renales/etiología , Enfermedades Renales/cirugía , Trasplante de Riñón/efectos adversos , Radiología Intervencionista/métodos , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina , Enfermedades Vasculares/etiología , Enfermedades Vasculares/cirugíaRESUMEN
INTRODUCTION: Lymphocele is a special complication following kidney transplantation. The authors examined the factors associated with an increased occurrence of clinically significant perinephric fluid collections and/or lymphoceles among sirolimus-treated renal transplant recipients. AIM: From the point of view of the lymphocele a comparison was made for the risks and benefits of the conventional and a newer immunosuppressive combination. METHODS: At the University of Texas in Houston in a retrospective study the incidence, predisposing factors, and consequences of these fluid collections among patients treated with sirolimus-cyclosporine-prednisone ( n = 354, Group I) versus cyclosporine-prednisone-azathioprine ( n = 136, Group II) were compared. RESULTS: More Group I patients (135/354; 38.1%) displayed perinephric fluid collections than Group II patients (24/136; 17.6%; p < 0.001). In both subgroups the serum creatinine levels were elevated at the time of diagnosis from a nadir of 179.5 +/- 141.7 to 359.9 +/- 259.6 mmol/l (Group III, sirolimus treated) and from 222.6 +/- 205.9 to 383.7 +/- 255.2 mmol/l (Group IV, sirolimus free). A significantly greater number of patients required treatment for lymphoceles among Group I (15.8%; 56/354) versus Group II recipients (4.4%; 6/136; p < 0.001). Single or repeated percutaneous drainage procedures successfully treated 35 Group I patients versus all 6 Group IV patients ( p = 0.033). No patients in Group II versus 21 patients in Group I underwent surgical procedures ( p < 0.001). A significantly higher rate and higher histologic grade of acute rejection episodes, particularly proximate to the onset of the lymphocele, occurred among Group IV patients, namely 54.2% (13/24) versus 21.4% (29/135) Group III patients ( p < 0.001). Additionally we report the case of a 29-year-old patient who underwent a lymphocele fenestration with omentoplasty 8 years after his transplantation. Despite an Influenza A + Chlamydia pneumonia and acute rejection which was followed by a GI bleeding and stomach resection he fully recovered and is doing well with an excellent kidney function a year after. CONCLUSIONS: Addition of sirolimus to a cyclosporine-prednisone regimen resulted in both a higher incidence and a requirement for more aggressive treatment of perinephric fluid collections and/or lymphoceles with a much lower acute rejection frequency.
Asunto(s)
Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Linfocele/etiología , Adulto , Azatioprina/efectos adversos , Ciclosporina/efectos adversos , Femenino , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/administración & dosificación , Incidencia , Linfocele/inducido químicamente , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Sirolimus/efectos adversosRESUMEN
BACKGROUND: This study aims to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimune response of pancreas-kidney transplant recipients. METHODS: Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. Ten recipients were also enrolled in a study to measure immune responsiveness. Flow PRA determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed during the first posttransplant year. RESULTS: One-year patient, kidney, and pancreas graft survivals were 97%, 94%, and 92%, respectively. There was one death and three graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study (n=10) displayed>80% depression of CD3, CD4, and CD8 (+) cell counts up to 3 months posttransplant. At transplantation 9/10 patients displayed<10% class I and no class II HLA antibody. By 3 months, 7/10 monitored recipients showed a transient elevation in class I HLA antibodies, including 2 patients who expressed>80% Flow PRA. One patient was pretransplant FCXM positive, whereas by 3 months posttransplant 2/10 patients demonstrated a positive FCXM. There were no clinical consequences of the presence of HLA antibody or the positive FCXMs. By 6 months, 7/9 patients demonstrated immunoregulatory suppressor cells. CONCLUSIONS: The absence of acute rejection events was likely due to inhibition of donor-specific immunity by the immunosuppressive regimen. Seventy percent of patients demonstrated an early, non-donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the monitored patients displayed immunoregulatory cells probably contributing to the successful outcomes.
Asunto(s)
Suero Antilinfocítico/administración & dosificación , Ciclosporina/administración & dosificación , Inmunosupresores/administración & dosificación , Trasplante de Páncreas , Sirolimus/administración & dosificación , Adulto , Infecciones por Citomegalovirus/etiología , Femenino , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Isoanticuerpos/sangre , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/inmunología , Estudios Prospectivos , Subgrupos de Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Phase II trials of FTY720, a novel immunomodulator, have shown promise in preventing rejection with both standard and reduced cyclosporine exposure. This study was designed to confirm those findings. METHODS: This one-year, multicenter, randomized, phase III study in 696 de novo renal transplant patients compared FTY720 5 mg plus reduced-dose cyclosporine (RDC) or FTY720 2.5 mg plus full-dose cyclosporine (FDC) with mycophenolate mofetil (MMF) plus FDC. All patients received concomitant corticosteroid therapy without antibody induction. The primary efficacy composite endpoint was the incidence of first treated biopsy-proven acute rejection (treated BPAR), graft loss, death or premature study discontinuation at month 12. RESULTS: FTY720 2.5 mg plus FDC was demonstrated to be non-inferior to MMF plus FDC as the primary efficacy endpoint (30.8% and 30.6%) was comparable. The FTY720 5 mg plus RDC treatment regimen was discontinued due to an increased incidence of acute rejection episodes (primary endpoint 43.3%). FTY720 was associated with significantly lower creatinine clearance with a mean difference at 12 months between FTY720 2.5 mg plus FDC and MMF plus FDC of 8 ml/min. CONCLUSIONS: While FTY720 2.5 mg plus FDC yielded similar efficacy to MMF plus FDC, the FTY720 5 mg plus RDC did not allow a 50% reduction in cyclosporine exposure. The associated lower creatinine clearance indicated that FTY720 combined with cyclosporine provided no benefit over standard care.
Asunto(s)
Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Adulto , Creatinina/orina , Ciclosporina/administración & dosificación , Quimioterapia Combinada , Femenino , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Glicoles de Propileno/administración & dosificación , Esfingosina/administración & dosificación , Esfingosina/uso terapéuticoRESUMEN
This multicenter, open-label study compared the efficacy, safety, and pharmacokinetic parameters of sirolimus (rapamycin) tablet and liquid formulations for prevention of efficacy failure. A total of 477 renal allograft recipients were randomly assigned (1:1) to receive either tablet or solution formulations of sirolimus for 12 months, plus cyclosporine (CsA) and steroids. Pharmacokinetic parameters were analyzed based on trough concentrations and 24-hour pharmacokinetic profiles. There were no significant differences in efficacy failure at 3 or 12 months between tablet and solution groups. Graft survival, patient survival, rate of first biopsy-confirmed acute rejection, time to and severity of acute rejection, and laboratory parameters were not significantly different between groups. Mean steady-state sirolimus and CsA pharmacokinetic parameters on days 30 and 90 were not significantly different by formulation, except for longer sirolimus t(max) after tablet administration. Multivariate logistic regression analysis indicated that low sirolimus C(min,TN) and more human leukocyte antigen mismatches were predictors of acute rejection. The tablet and solution formulations of sirolimus demonstrated therapeutic equivalence.
Asunto(s)
Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Premedicación , Sirolimus/uso terapéutico , Administración Oral , Adulto , Química Farmacéutica , Ciclosporina/farmacocinética , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacocinética , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Soluciones Farmacéuticas , Sirolimus/administración & dosificación , Sirolimus/farmacocinética , Comprimidos , Equivalencia Terapéutica , Resultado del TratamientoRESUMEN
BACKGROUND: Immunosuppressive drug therapy has been identified as one etiological factor in the increased incidence of and deaths from malignancies in renal transplant recipients. In animal models, calcineurin inhibitors have a positive growth effect, whereas target-of-rapamycin (TOR) inhibitors have a negative growth effect on malignant cells. METHODS: A multivariate analysis of posttransplant malignancies in 33,249 deceased donor primary solitary renal recipients reported by 264 kidney transplant programs to the Organ Procurement and Transplantation Network database from July 1, 1996 to December 31, 2001 was performed. Data were censored at 963 days to allow comparable follow-up time among drug treatment groups. The incidence and relative risks of any de novo malignancy (skin and solid) and for non-skin solid malignancies in patients receiving TOR inhibitors compared to patients receiving calcineurin inhibitors were the primary endpoints. RESULTS: The incidence rates of patients with any de novo posttransplant malignancy were 0.60% with sirolimus/everolimus alone, 0.60% with sirolimus/everolimus + cyclosporine/tacrolimus, and 1.81% with cyclosporine/tacrolimus (P<0.0001); the rates with a de novo solid tumor were 0%, 0.47%, and 1.00%, respectively. In the Cox regression model the relative risk associated with sirolimus/everolimus immunosuppression for any de novo cancer was 0.39 (95% CI: 0.24-0.64; P=0.0002) and for de novo solid cancer was 0.44 (0.24-0.82; P=0.0092). Other significant risk factors were male sex, adult age group, white race, and history of a malignancy. CONCLUSIONS: Maintenance immunosuppression with the TOR inhibitor drugs, sirolimus and everolimus, is associated with a significantly reduced risk of developing any posttransplant de novo malignancy and non-skin solid malignancy.
Asunto(s)
Inmunosupresores/uso terapéutico , Trasplante de Riñón , Neoplasias/prevención & control , Proteínas Quinasas/efectos de los fármacos , Everolimus , Humanos , Terapia de Inmunosupresión/efectos adversos , Incidencia , Neoplasias/epidemiología , Neoplasias/etiología , Medición de Riesgo , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TORRESUMEN
BACKGROUND: This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. METHODS: Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. RESULTS: Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 micromol/L or greater with everolimus and 7 micromol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). CONCLUSIONS: As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin-inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.
Asunto(s)
Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Sirolimus/análogos & derivados , Adolescente , Adulto , Anciano , Quimioterapia Combinada , Everolimus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Seguridad , Sirolimus/uso terapéutico , Donantes de Tejidos/estadística & datos numéricosRESUMEN
BACKGROUND: FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to lymph nodes. This is the first study to evaluate the efficacy and safety of FTY720 in de novo renal transplantation. METHODS: This phase 2a, multicenter, open-label, dose-finding study compared FTY720 (0.25, 0.5, 1.0, or 2.5 mg) with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids. Patients (n=208) received FTY720 (n=167) or MMF (n=41) for 3 months followed by a 3-month follow-up. RESULTS: The incidence of biopsy-confirmed acute rejection at month 3 was 23.3%, 34.9%, 17.5%, and 9.8%, respectively, with FTY720 at doses of 0.25, 0.5, 1.0, and 2.5 mg, versus 17.1% with MMF. The incidence for the composite endpoint (biopsy-confirmed acute rejection, graft loss, or death) was lowest with FTY720 at a dose of 2.5 mg at month 3 (14.6%) compared with FTY720 at doses of 0.25 mg (25.6%), 0.5 mg (34.9%), and 1.0 mg (17.5%), and MMF (19.5%). Safety was comparable between FTY720 and MMF group. The main difference in tolerability was a mild and transient reduction in heart rate. A decrease in peripheral lymphocytes occurred in patients receiving FTY720, as expected from the mode of action, and this was reversible after treatment cessation. CONCLUSIONS: FTY720 at 2.5 mg was found to be as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation. FTY720 was well tolerated and not associated with the side effects commonly observed with immunosuppressant therapies.
Asunto(s)
Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Glicoles de Propileno/uso terapéutico , Adolescente , Adulto , Anciano , Biopsia , Relación Dosis-Respuesta a Droga , Clorhidrato de Fingolimod , Rechazo de Injerto/epidemiología , Rechazo de Injerto/patología , Humanos , Inmunosupresores/sangre , Inmunosupresores/uso terapéutico , Inmunosupresores/toxicidad , Infecciones/epidemiología , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Complicaciones Posoperatorias/clasificación , Complicaciones Posoperatorias/epidemiología , Glicoles de Propileno/sangre , Glicoles de Propileno/toxicidad , Seguridad , Esfingosina/análogos & derivados , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects. METHODS: We examined the neoplasms among 1008 renal transplant recipients treated at a single center with sirolimus-cyclosporine +/- prednisone. RESULTS: Clinical and laboratory data, including 62.3+/-26.1 months follow-up (range 27.1-131), revealed 36 tumors in 35 patients (3.6%) presenting at 32.5+/-29.8 months. The 2.4% incidence of skin tumors, the most common neoplasms, was 1.58-fold greater than the general U.S. population. In addition to a 0.4% incidence of posttransplant lymphoproliferative disorders (PTLD) and a 0.2% incidence of renal cell carcinomas, we observed single cases of breast, bladder, endometrial, lung, and brain neoplasms as well as leukemia. The mean trough drug concentrations at the time of diagnosis in affected recipients were within our putative target ranges. In addition to eleven graft losses due to death with a functioning kidney, two were related to chronic rejection following reduced immunosuppression, and one, therapeutic nephrectomy for PTLD. Five of twelve deaths were caused by malignancies; four others among 1008 patients over the entire follow-up were attributed to cardiovascular events; one, to respiratory failure; and two, at distant locations to unknown causes. CONCLUSIONS: The sirolimus-cyclosporine +/- prednisone combination appears likely to be associated with a reduced incidence of tumors.
Asunto(s)
Ciclosporina/efectos adversos , Trasplante de Riñón , Neoplasias/epidemiología , Sirolimus/efectos adversos , Adolescente , Adulto , Anciano , Ciclosporina/administración & dosificación , Ciclosporina/farmacología , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias/etiología , Neoplasias/inmunología , Neoplasias/patología , Factores de Riesgo , Sirolimus/administración & dosificación , Sirolimus/farmacología , Resultado del TratamientoRESUMEN
AIM: The immunosuppressive agents have a broad spectrum of adverse effects. In the absence of selective and specific drugs the decrease incidence and severity of side effects can be achieved by the combination of synergistic drugs only. Without wise selection and use of the combination of the potent immunosuppressive agents for the immunosuppressive maintenance therapy better results cannot be achieved without or fewer toxicities particularly in high-risk patients who lose their grafts prematurely. Therefore, a good combination will allow not only to reduce individual immunosuppressive drug induced toxicities but will also allow to achieve better graft and patient survival. MATERIAL AND METHODS: To assess the 6-year impact of a sirolimus-based regimen with, modest exposures to cyclosporine among three ethnic groups with different rejection risk, the authors performed a retrospective analysis of 470 renal transplant recipients who were treated contemporaneously: Group 1, high risk African Americans (n = 122); Group 2, moderate risk Hispanics (n = 132); Group 3, mild risk Caucasians (n = 216). Multivariate models were used to compare the outcomes in Group 1 with those of the other two groups. RESULTS: The cumulative incidence of acute rejection episodes over the entire follow-up period was similar among the groups: Group 1, 22.0%, Group 2, 24.2% and Group 3, 23.0%. Although there were no significant differences in overall or individual infection rates, Group 1 and 2 recipients displayed a significantly lower incidence of diarrhea at all times during follow-up compared with Group 3. All recipients showed similar rates of lymphocele formation. However, Group 1 displayed a reduced incidence and decreased severity of hypertriglyceridemia than Group 2 or Group 3 (89.3% vs. 97.2% vs. 93.2%), a similar incidence of hypercholesteremia (94.3% vs. 97.2% vs. 98.5%) was observed. The occurrence of post-transplant diabetes mellitus was greater in Group 1. than Group 3. but similar to Group 2. CONCLUSIONS: A concentration-controlled sirolimus-cyclosporine-prednisone regimen (with steroid withdrawal by 3 months) reduced the incidence of acute rejection episodes and increased 6-year graft survivals among high-risk African Americans to rates similar to other ethnic groups without an augmented toxicity profile.
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Ciclosporina/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Sirolimus/uso terapéutico , Enfermedad Aguda , Adulto , Negro o Afroamericano/estadística & datos numéricos , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Incidencia , Infecciones/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Sirolimus/administración & dosificación , Sirolimus/sangre , Texas/epidemiología , Resultado del Tratamiento , Población Blanca/estadística & datos numéricosAsunto(s)
Infecciones por Coronavirus , Pandemias , Neumonía Viral , Obtención de Tejidos y Órganos , Betacoronavirus , COVID-19 , Humanos , Italia , SARS-CoV-2RESUMEN
Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug-defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients-is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients. Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval. In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly. Because of the critical-dose nature of most of the recent generation of immunosuppressive agents, therapeutic drug monitoring is becoming increasingly important in the selection of doses and treatment regimens.
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Inmunosupresores/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Oral , Ensayos Clínicos como Asunto , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Humanos , Inmunosupresores/farmacocinéticaRESUMEN
BACKGROUND: In a retrospective study we sought to dissect the factors associated with an increased occurrence of clinically significant perinephric fluid collections and lymphoceles among sirolimus-treated renal transplant recipients. METHODS: We compared the incidence, predisposing factors, and consequences of these fluid collections among patients treated with sirolimus-cyclosporine (CsA)-prednisone (Pred) (n=354, group I) versus CsA-Pred with or without azathioprine (n=136, group II). RESULTS: More group I patients (135/354; 38.1%) displayed perinephric fluid collections (denoted as group III) then group II patients (24/136; 17.6%) (denoted as group IV) (P <0.001). In both subgroups the serum creatinine levels were elevated at the time of diagnosis from a nadir of 2.04+/-1.61 to 4.09+/-2.95 mg/dL (group III) and from 2.53+/-2.34 to 4.36+/-2.90 mg/dL (group IV). A significantly greater number of patients required treatment for lymphoceles among group I (56/354; 15.8%) versus group II recipients (6/136; 4.4%; P<0.001). Single or repeated percutaneous drainage procedures successfully treated 35 group I patients versus all 6 group IV patients (P =0.033). No patients in group II versus 21 patients in group I underwent surgical procedures (P <0.001). A significantly higher rate and higher histologic grade of acute rejection episodes, particularly proximate to the onset of the lymphocele, occurred among group IV patients, namely 54.2% (13/24) versus 21.4% (29/135) group III patients (P <0.001). CONCLUSIONS: Addition of sirolimus to a CsA-Pred regimen resulted in both a higher incidence and a requirement for more aggressive treatment of perinephric fluid collections and lymphoceles.
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Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Linfocele/epidemiología , Adulto , Anciano , Ciclosporina/administración & dosificación , Quimioterapia Combinada , Femenino , Rechazo de Injerto , Humanos , Terapia de Inmunosupresión , Incidencia , Linfocele/terapia , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Retrospectivos , Sirolimus/administración & dosificaciónRESUMEN
BACKGROUND: Deep venous thrombosis (DVT) tends to occur in greater frequency among cyclosporine (CsA)-treated renal-transplant recipients. Because administration of sirolimus may increase the whole-blood concentrations of CsA, we sought to assess the impact of the combination regimen on the incidence, predisposing factors, and consequences of postoperative DVT, transplant renal-vein or artery thrombosis, and pulmonary embolus. METHODS: We retrospectively evaluated two cohorts of renal transplant recipients: CsA/prednisone (Pred)+/-azathioprine (n=136, group A) or sirolimus+CsA+Pred (n=354, group B) using Fisher's exact t and chi-square tests, as well as Kaplan-Meier analyses, odds ratios, and multiple logistic regression methods. RESULTS: The 7 of 136 (5.1%) incidence of thrombotic events in group A was similar to the 20 of 354 (5.6%) incidence in group B (P=0.513; NS) and occurred no more frequently ipsilateral to the transplant. Although the occurrence of an acute-rejection episode was not associated with the DVT diagnosis, all affected patients displayed elevated serum creatinine (Scr) values, which remained slightly higher than baseline following recovery (group A 1.63+/-1.22-1.95+/-0.93 mg/dL; group B 1.70+/-1.11-2.01+/-0.88 mg/dL). Renal biopsies failed to show evidence of intrarenal coagulopathy. No patient lost a graft as a complication of DVT, nor did these events produce other lasting adverse effects. Patients in the sirolimus group showed a strong correlation between the occurrence of DVT and the previous existence of an ipsilateral or contralateral lymphocele. CONCLUSION: Addition of sirolimus to a CsA+Pred regimen does not increase the incidence of postoperative thrombotic events among renal transplant recipients.