RESUMEN
BACKGROUND: The influence of converting to once daily, extended-release LCP-Tacrolimus (Tac) for those with high tacrolimus variability in kidney transplant recipients (KTRs) is not well-studied. METHODS: Single-center, retrospective cohort study of adult KTRs converted from Tac immediate release to LCP-Tac 1-2 years post-transplant. Primary measures were Tac variability, using the coefficient of variation (CV) and time in therapeutic range (TTR), as well as clinical outcomes (rejection, infections, graft loss, death). RESULTS: A total of 193 KTRs included with a follow-up of 3.2 ± .7 years and 1.3 ± .3 years since LCP-Tac conversion. Mean age was 52 ± 13 years; 70% were African American, 39% were female, 16% living donor and 12% donor after cardiac death (DCD). In the overall cohort, tac CV was 29.5% before conversion, which increased to 33.4% after LCP-Tac (p = .008). In those with Tac CV >30% (n = 86), conversion to LCP-Tac reduced variability (40.6% vs. 35.5%; p = .019) and for those with Tac CV >30% and nonadherence or med errors (n = 16), LCP-Tac conversion substantially reduced Tac CV (43.4% vs. 29.9%; p = .026). TTR significantly improved for those with Tac CV >30% with (52.4% vs. 82.8%; p = .027) or without nonadherence or med errors (64.8% vs. 73.2%; p = .005). CMV, BK, and overall infections were significantly higher prior to LCP-Tac conversion. In the overall cohort, 3% had rejection before conversion and 2% after (p = NS). At end of follow-up, graft and patient survival were 94% and 96%, respectively. CONCLUSIONS: In those with high Tac CV, conversion to LCP-Tac is associated with a significant reduction in variability and improvement in TTR, particularly in those with nonadherence or medication errors.
Asunto(s)
Trasplante de Riñón , Tacrolimus , Adulto , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Tacrolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Estudios Retrospectivos , Receptores de Trasplantes , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiologíaRESUMEN
Achieving therapeutic tacrolimus levels is an essential component of balancing immunosuppression in kidney transplantation. At our institution, the starting tacrolimus dose was reduced from .075 mg/kg BD (higher dose [HD]) to .050 mg/kg BD (lower dose [LD]), to better achieve our target level of 6-10 µg/L in the early posttransplant period. Kidney transplant recipients (KTRs) transplanted 1-year before (HD: n = 64) and after (LD: n = 63) the starting dose reduction were retrospectively compared. Achieved tacrolimus levels were significantly lower in the LD group during the first 14 days posttransplant, but not at day 21 or day 28. A higher proportion of LD KTRs achieved therapeutic levels (day 1-3: 36.1% vs. 18.8%; day 4-7: 50.8% vs. 40.6%, day 8-14: 83.6% vs. 71.7%), while the HD KTRs were more likely to have supratherapeutic levels. Tacrolimus dose was significantly lower on day 5 compared to day 0 in the HD group but similar in the LD group. Rates of delayed graft function, posttransplant diabetes, and treated rejection at 6 months and graft outcomes at 3 years were all similar. Lowering the starting tacrolimus dose increased the proportion of KTRs achieving therapeutic range and minimized dose changes early posttransplant without an impact on clinical outcomes.
Asunto(s)
Trasplante de Riñón , Tacrolimus , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Estudios Retrospectivos , Tacrolimus/uso terapéutico , Receptores de TrasplantesRESUMEN
Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus <6 ng/ml versus >8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.
Asunto(s)
Rechazo de Injerto , Tacrolimus , Rechazo de Injerto/etiología , Supervivencia de Injerto , Antígenos HLA/genética , Antígenos HLA-DR , Prueba de Histocompatibilidad , Humanos , Estados UnidosRESUMEN
The novel coronavirus disease 2019 (COVID-19) is a highly infectious and rapidly spreading disease. There are limited published data on the epidemiology and outcomes of COVID-19 infection among organ transplant recipients. After initial flulike symptoms, progression to an inflammatory phase may occur, characterized by cytokine release rapidly leading to respiratory and multiorgan failure. We report the clinical course and management of a liver transplant recipient on hemodialysis, who presented with COVID-19 pneumonia, and despite completing a 5-day course of hydroxychloroquine, later developed marked inflammatory manifestations with rapid improvement after administration of off-label, single-dose tocilizumab. We also highlight the role of lung ultrasonography in early diagnosis of the inflammatory phase of COVID-19. Future investigation of the effects of immunomodulators among transplant recipients with COVID-19 infection will be important.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/complicaciones , Trasplante de Hígado , Neumonía Viral/complicaciones , Diálisis Renal , Receptores de Trasplantes , COVID-19 , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/cirugía , Infecciones por Coronavirus/tratamiento farmacológico , Hepatitis C/complicaciones , Hepatitis C/cirugía , Humanos , Hidroxicloroquina/uso terapéutico , Inflamación , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugía , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/tratamiento farmacológico , Reoperación , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
Tacrolimus (Tac) is an effective anti-rejection agent in kidney transplantation, but its off-target effects make withdrawal desirable. Although studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs unsuccessful Tac removal are unknown. We performed microarray analyses of peripheral blood mononuclear cells (PBMC) RNA from subjects enrolled in the Clinical Trials in Organ Transplantation-09 study in which we randomized stable kidney transplant recipients to Tac withdrawal or maintenance of standard immunosuppression beginning 6 months after transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a downregulatory and proapoptotic gene program enriched within T cells. Functional analyses suggested stronger donor-reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data from a small, but unique, patient cohort support the conclusion that successful Tac withdrawal is not simply due to absence of donor-reactive immunity but rather is associated with an active immunological process.
Asunto(s)
Inmunosupresores , Trasplante de Riñón , Tacrolimus , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Humanos , Inmunosupresores/administración & dosificación , Trasplante de Riñón/efectos adversos , Leucocitos Mononucleares , Ácido Micofenólico/uso terapéutico , Tacrolimus/administración & dosificación , Receptores de TrasplantesRESUMEN
Tacrolimus (Tac) is widely used to prevent rejection and graft loss in solid organ transplantation. A limiting characteristic of Tac is the high intra and interpatient variability associated with its use. Routine therapeutic drug monitoring (TDM) is necessary to facilitate Tac management and to avoid undesirable clinical outcomes. However, whole blood trough concentrations commonly utilized in TDM are not strong predictors of the detrimental clinical outcomes of interest. Recently, researchers have focused on Tac intrapatient variability (Tac IPV) as a novel marker to better assess patient risk. Higher Tac IPV has been associated with a number of mechanisms leading to shortened graft survival. Medication nonadherence (MNA) is considered to be the primary determinant of high Tac IPV and perhaps the most modifiable risk factor. An understanding of the methodology behind Tac IPV is imperative to its recognition as an important prognostic measure and integration into clinical practice. Therapeutic interventions targeting MNA and reducing Tac IPV are crucial to improving long-term graft survival.
Asunto(s)
Trasplante de Riñón , Tacrolimus , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéuticoRESUMEN
The clinical manifestation of COVID-19 can vary from an asymptomatic course to ARDS requiring invasive mechanical ventilation and extracorporeal membrane oxygenation. A kidney transplanted patient infected with SARS CoV-2 infection showed a mild disease despite immune suppression. It is possible that Immunosuppression can "be protective" as the cytokine storm is an important factor in the disease story. Despite the good outcome reported in the present case report, is remains of vital importance the solid organ transplant patients use precautions in order to avoid the infection.
Asunto(s)
Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/terapia , Glomerulonefritis por IGA/complicaciones , Fallo Renal Crónico/complicaciones , Trasplante de Riñón , Neumonía Viral/complicaciones , Neumonía Viral/terapia , Betacoronavirus , COVID-19 , Ceftriaxona/administración & dosificación , Citocinas/metabolismo , Glomerulonefritis por IGA/cirugía , Humanos , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Pandemias , SARS-CoV-2 , Tacrolimus/administración & dosificación , Resultado del TratamientoRESUMEN
Approximately 33.6% of nondiabetic solid organ transplant recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus-induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus-treated mouse model, with reduction in taxonomic abundance of butyrate-producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus-induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad-spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through the regulation of glucose-regulating hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin, in serum. The butyrate-G-protein-coupled receptor 43-GLP-1 pathway in the intestinal crypts may be involved in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate-associated GLP-1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.
Asunto(s)
Microbioma Gastrointestinal , Hiperglucemia , Animales , Ácido Butírico , Péptido 1 Similar al Glucagón , Hiperglucemia/inducido químicamente , Hiperglucemia/tratamiento farmacológico , Ratones , Tacrolimus/efectos adversosRESUMEN
The SARS-CoV-2 infection can be seen as a single disease, but it also affects patients with relevant comorbidities who may have an increased risk of a severe course of infection. In this report, we present a 77-year-old patient with a heart transplant receiving relevant immunosuppressive therapy who tested positive for SARS-CoV-2 after several days of dyspnea, dry cough, and light general symptoms. Computed tomography confirmed interstitial pneumonia. The patient received antiviral therapy with hydroxychloroquine and showed no further deterioration of the clinical state. After 12 days of hospitalization, the patient was released; he was SARS-CoV-2 negative and completely asymptomatic.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Trasplante de Corazón , Inmunosupresores/administración & dosificación , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Anciano , Betacoronavirus , COVID-19 , Insuficiencia Cardíaca/cirugía , Hospitalización , Humanos , Hidroxicloroquina/administración & dosificación , Terapia de Inmunosupresión , Masculino , Pandemias , Radiografía Torácica , Riesgo , SARS-CoV-2 , Tomografía Computarizada por Rayos X , Tratamiento Farmacológico de COVID-19RESUMEN
In a phase 2 multicenter open-label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)-based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low-dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time, the rate of biopsy-proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.
Asunto(s)
Trasplante de Riñón , Trasplante de Páncreas , Inhibidores de la Calcineurina , Rechazo de Injerto/etiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Ácido Micofenólico , Páncreas , Estudios Prospectivos , HumanosRESUMEN
Tacrolimus (TAC), the mainstay of maintenance immunosuppressive agents, plays a crucial role in new-onset diabetes after transplant (NODAT). Previous studies investigating the diabetogenic effects of TAC have focused on the ß cells of islets. In this study, we found that TAC contributed to NODAT through directly affecting hepatic metabolic homeostasis. In mice, TAC-induced hypoglycemia rather than hyperglycemia during starvation via suppressing gluconeogenetic genes, suggesting the limitation of fasting blood glucose in the diagnosis of NODAT. In addition, TAC caused hepatic insulin resistance and triglyceride accumulation through insulin receptor substrate (IRS)2/AKT and sterol regulatory element binding protein (SREBP1) signaling, respectively. Furthermore, we found a pivotal role of CREB-regulated transcription coactivator 2 (CRTC2) in TAC-induced metabolic disorders. The restoration of hepatic CRTC2 alleviated the metabolic disorders through its downstream molecules (eg, PCK1, IRS2, and SREBP1). Consistent with the findings from bench, low CRTC2 expression in graft hepatocytes was an independent risk factor for NODAT (odds ratio = 2.692, P = .023, n = 135). Integrating grafts' CRTC2 score into the clinical model could significantly increase the predictive capacity (areas under the receiver operating characteristic curve: 0.71 vs 0.79, P = .048). Taken together, in addition to its impact on pancreatic cells, TAC induces "hematogenous diabetes" via CRTC2 signaling. Liver-targeted management may be of help to prevent or heal TAC-associated diabetes.
Asunto(s)
Inmunosupresores , Tacrolimus , Animales , Glucosa , Homeostasis , Hígado , Ratones , Tacrolimus/efectos adversosRESUMEN
This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [Ctrough ] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target Ctrough 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] -8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit-risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias/tratamiento farmacológico , Estudios de Equivalencia como Asunto , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Humanos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Pronóstico , Factores de Riesgo , Tacrolimus/uso terapéutico , Receptores de TrasplantesRESUMEN
BACKGROUND AND AIMS: This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein. MATERIALS AND METHODS: Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout. RESULTS: The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7). CONCLUSIONS: In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/uso terapéutico , Trasplante de Órganos/efectos adversos , Complicaciones Posoperatorias/tratamiento farmacológico , Tacrolimus/uso terapéutico , Receptores de Trasplantes/estadística & datos numéricos , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.
Asunto(s)
Preparaciones de Acción Retardada , Trasplante de Corazón , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Trasplante de Hígado , Tacrolimus/administración & dosificación , Adolescente , Aloinjertos , Biopsia , Niño , Preescolar , Estudios Cruzados , Femenino , Rechazo de Injerto , Humanos , Masculino , Seguridad del Paciente , Estudios Prospectivos , Receptores de Trasplantes , Resultado del TratamientoRESUMEN
Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10-5 -8.8 × 10-6 ) and one suggestive variant in Asian Americans (P = 5.6 × 10-6 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.
Asunto(s)
Citocromo P-450 CYP3A/genética , Etnicidad/estadística & datos numéricos , Fallo Renal Crónico/metabolismo , Trasplante de Riñón/métodos , Polimorfismo de Nucleótido Simple , Tacrolimus/metabolismo , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/metabolismo , Fallo Renal Crónico/etnología , Fallo Renal Crónico/genética , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tacrolimus/administración & dosificaciónRESUMEN
Cannabidiol (CBD), a major purified nonpsychoactive component of cannabis with anticonvulsant properties, was approved by the U.S. Food and Drug Administration (FDA) in June 2018 as an adjuvant treatment for refractory epilepsy (Epidiolex; GW Pharmaceuticals). CBD is metabolized by cytochrome P450 (CYP)3A4 and CYP2C19 with a growing body of evidence suggesting it is also a potent inhibitor of these pathways. We report for the first time a significant drug-drug interaction between the purified CBD product and tacrolimus. A participant in a CBD clinical trial for epilepsy who was also receiving tacrolimus showed an approximately 3-fold increase in dose-normalized tacrolimus concentrations while receiving 2000-2900 mg/day of CBD. Our report delineates an important concern for the transplant community with the increasing legalization of cannabis and advent of an FDA-approved CBD product. Larger studies are needed to better understand the impact of this drug-drug interaction in solid organ transplant recipients.
Asunto(s)
Cannabidiol/metabolismo , Epilepsia/tratamiento farmacológico , Inmunosupresores/metabolismo , Nefritis Intersticial/tratamiento farmacológico , Tacrolimus/metabolismo , Adulto , Cannabidiol/uso terapéutico , Interacciones Farmacológicas , Epilepsia/complicaciones , Epilepsia/metabolismo , Epilepsia/patología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Nefritis Intersticial/complicaciones , Nefritis Intersticial/metabolismo , Nefritis Intersticial/patología , Pronóstico , Tacrolimus/uso terapéuticoRESUMEN
Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single-center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.
Asunto(s)
Rechazo de Injerto/metabolismo , Supervivencia de Injerto/efectos de los fármacos , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias/etiología , Tacrolimus/metabolismo , Adolescente , Adulto , Niño , Preescolar , Monitoreo de Drogas , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/etiología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/metabolismo , Lactante , Recién Nacido , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/patología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/patología , Pronóstico , Factores de Riesgo , Tacrolimus/administración & dosificación , Adulto JovenRESUMEN
A majority of kidney transplant recipients receive calcineurin inhibitor-based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor-intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor-intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long-term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.
Asunto(s)
Abatacept/uso terapéutico , Inhibidores de la Calcineurina/efectos adversos , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Adulto , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto/inmunología , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Terapia de Inmunosupresión , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.