RESUMO
This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.
Assuntos
Farmacogenética , População da América do Sul , Tacrolimo , Humanos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genótipo , Rejeição de Enxerto/genética , Imunossupressores/efeitos adversos , América Latina , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Tacrolimo/efeitos adversos , Povos Indígenas , População Branca , População da África SubsaarianaRESUMO
Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14 d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9-58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6-12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4 ng/mL vs. < 6.4 ng/mL: HR 0.4, 95% CI, 0.2-0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4 ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.
Assuntos
Transplante de Fígado , Tacrolimo , Humanos , Criança , Basiliximab/efeitos adversos , Tacrolimo/efeitos adversos , Transplante de Fígado/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Estudos de Viabilidade , Imunossupressores/efeitos adversos , Terapia de Imunossupressão/efeitos adversos , Esteroides/efeitos adversos , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/tratamento farmacológicoRESUMO
BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.
Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Humanos , Everolimo/efeitos adversos , Tacrolimo/efeitos adversos , Sirolimo/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Estudos Prospectivos , Imunossupressores/efeitos adversos , Ácido Micofenólico/efeitos adversos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/prevenção & controle , TransplantadosRESUMO
Evidence supporting a starting dose of 2 g/day of mycophenolate mofetil (MMF) in combination with tacrolimus (TAC) for renal transplantation (RT) is still limited, but maintaining a dose of <2 g could result in worse clinical outcomes in terms of acute rejection (AR). This study aimed to determine the association between AR and infectious and noninfectious complications after RT with a dose of 1.5 g vs 2 g of MMF. A prospective cohort study was performed with a 12-month follow-up of recipients of RT from living donors with low (1.5 g/day) or standard (2 g/day) doses of MMF. The association between adverse effects and complications and doses of MMF was examined using Cox proportional hazard models, and survival free of AR, infectious diseases, and noninfectious complications was evaluated using the Kaplan-Meier test. At the end of the follow-up, the incidence of infectious diseases was 52% versus 50% (P = .71) and AR was 5% versus 5% (P = .86), respectively. The survival rate free of gastrointestinal (GI) complications requiring medical attention was higher in the low-dose group than in the standard-dose dose (88% vs 45%, respectively; P < .001). The use of 1.5 g/day of MMF confers a reduction in GI complications without an increase in infectious diseases or the risk of AR.
Assuntos
Doenças Transmissíveis , Transplante de Rim , Humanos , Tacrolimo/efeitos adversos , Ácido Micofenólico/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , México/epidemiologia , Estudos Prospectivos , Quimioterapia Combinada , Doenças Transmissíveis/etiologia , Hospitais , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/epidemiologia , Sobrevivência de EnxertoRESUMO
INTRODUCTION: Despite significant advancements in immunosuppressive regimens and surgical techniques, the prevalence of adverse events related to immunosuppression remains a major challenge affecting the long-term survival rates of pancreas and kidney allografts. AREAS COVERED: This article presents a comprehensive review of the literature and knowledge (Jan/2012-Feb/2023) concerning glucose metabolism disorders and nephrotoxicity associated with tacrolimus and mammalian target of rapamycin inhibitors (mTORi). Novel signaling pathways potentially implicated in these adverse events are discussed. Furthermore, we extensively examine the findings from clinical trials evaluating the efficacy and safety of tacrolimus, mTORi, and steroid minimization. EXPERT OPINION: Tacrolimus-based regimens continue to be the standard treatment following pancreas transplants. However, prolonged use of tacrolimus and mTORi may lead to hyperglycemia and nephrotoxicity. Understanding and interpreting experimental data, particularly concerning novel signaling pathways beyond calcineurin-NFAT and mTOR pathways, can offer valuable insights for therapeutic interventions to mitigate hyperglycemia and nephrotoxicity. Additionally, critically analyzing clinical trial results can identify opportunities for personalized safety-based approaches to minimize side effects. It is imperative to conduct randomized-controlled studies to assess the impact of mTORi use and steroid-free protocols on pancreatic allograft survival. Such studies will aid in tailoring treatment strategies for improved transplant outcomes.
Assuntos
Hiperglicemia , Transplante de Pâncreas , Humanos , Tacrolimo/efeitos adversos , Transplante de Pâncreas/efeitos adversos , Transplante de Pâncreas/métodos , Imunossupressores/efeitos adversos , Sirolimo/efeitos adversos , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/tratamento farmacológico , Inibidores de CalcineurinaRESUMO
BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.
INTRODUCCIÓN: La ototoxicidad corresponde a un efecto secundario a agentes terapéuticos que se manifiesta como hipoacusia sensorioneural bilateral simétrica de frecuencias agudas. Se postulan posibles efectos ototóxicos de los inmunosupresores inhibidores de la calcineurina, pero hasta la fecha es aún incierto. El objetivo de este estudio fue evaluar los cambios audiológicos en pacientes trasplantados en tratamiento inmunosupresor con inhibidores de calcineurina. MATERIAL Y MÉTODO: Cohorte prospectiva. Se incluyeron pacientes adultos sometidos a trasplante hepático o renal tratados con inhibidores de calcineurina. Se realizó una evaluación otorrinolaringo-lógica pre-trasplante con audiometría tonal, emisiones otoacústicas por producto de distorsión y cuestionario Tinnitus Handicap Inventory. Se realizó una evaluación audiológica de seguimiento uno, tres y seis meses después del trasplante. Se compararon los umbrales auditivos antes y después del inicio del tratamiento inmunosupresor y se correlacionaron con las concentraciones plasmáticas de IC. RESULTADOS: Se incluyeron 17 pacientes, 59% hombres, con una mediana de edad de 54,7 años. La mediana de seguimiento fue 5,8 meses. Se observaron cambios en el promedio tonal puro en dos pacientes, los cuales no seguían un patrón audiométrico sugerente de ototoxicidad. Todos los pacientes recibieron Tacrolimus dentro del rango terapéutico durante el seguimiento. Tres pacientes diferentes excedieron el rango esperado una vez sin embargo, se corrigieron rápidamente y no se correlacionaron con cambios auditivos, puntaje de tinnitus o emisiones otoacústicas. DISCUSIÓN: Impresiona que Tacrolimus no se asocia a hipoacusia cuando los niveles están en rango terapéutico durante un período de seguimiento de seis meses post trasplante.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Audiometria de Tons Puros , Transplante de Rim , Transplante de Fígado , Inibidores de Calcineurina/efeitos adversos , Ototoxicidade , Imunossupressores/efeitos adversos , Fatores de Tempo , Estudos Prospectivos , Seguimentos , Tacrolimo/efeitos adversos , Perda Auditiva Neurossensorial/induzido quimicamenteRESUMO
TACROLIMUS, a mainstay of immunosuppression after orthotopic heart transplantation (OHT), is associated with a broad range of side effects. Vasoconstriction caused by tacrolimus has been proposed as a mechanism underlying common side effects such as hypertension and renal injury. Neurologic side effects attributed to tacrolimus include headaches, posterior reversible encephalopathy syndrome (PRES), or reversible cerebral vasospasm syndrome (RCVS). Six case reports have been published describing RCVS in the setting of tacrolimus administration after OHT. The authors report a case of perfusion-dependent focal neurologic deficits attributed to tacrolimus-induced RCVS in an OHT recipient.
Assuntos
Transplante de Coração , Síndrome da Leucoencefalopatia Posterior , Vasoespasmo Intracraniano , Humanos , Tacrolimo/efeitos adversos , Vasoespasmo Intracraniano/induzido quimicamente , Vasoespasmo Intracraniano/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Estado Terminal , Perfusão/efeitos adversos , Transplante de Coração/efeitos adversosRESUMO
BACKGROUND: Losing-salt tubulopathies, such as Bartter syndrome, are rare and usually inherited due to mutations of tubular reabsorption channels of the nephrons. Despite its scarcity, some cases of acquired losing-salt tubulopathies have been described. In this case report, we discuss the main aspects of Bartter syndrome and present a rare pediatric case of probable tacrolimusinduced Bartter-like syndrome in a renal transplanted boy. CASE PRESENTATION: A ten-year-old male patient with end-stage renal disease due to endo and extra capillary glomerulonephritis was submitted to renal transplantation from a deceased donor. The post-operatory evolution was satisfactory with normalization of serum creatinine levels, mild hypertension, and the absence of metabolic disorders. The immunosuppression protocol included tacrolimus (0.3 mg/kg/day), mycophenolate (455 mg/m2/day) and prednisone (0.5 mg/kg/day). Two months later, the patient was hospitalized due to vomiting, dehydration, intense hypokalemia (1.3 mEq/L), hyponatremia (125 mEq/L), and hypochloremia (84 mmol/L). During hospitalization, he evolved with polydipsia (3000 mL/day) and polyuria (120-160 mL/m2/h) associated with major elevation of urinary potassium excretion, hypercalciuria, mild metabolic alkalosis, hyperfiltration, and proteinuria. The tacrolimus dose was reduced under the suspicion of tubular dysfunction, leading to a better metabolic profile. However, the patient developed a Banff IIb graft rejection, which required pulse therapy and elevation of tacrolimus and mycophenolate doses. Recovery of renal function parameters occurred, but the metabolic disorders worsened following tacrolimus dose elevation. The patient required chronic potassium, chloride, and sodium replacement. CONCLUSION: After administering immunosuppressive medications, physicians should be aware of the possibility of Bartter-like or other losing-salt tubulopathies syndromes that can affect metabolic homeostasis. The suspicion must always be considered in the case of a transplanted patient who presents dehydration and hydroelectrolytic disorders right after the commencement of nephrotoxic immunosuppressive drugs, including tacrolimus and cyclosporine.
Assuntos
Síndrome de Bartter , Transplante de Rim , Masculino , Criança , Humanos , Síndrome de Bartter/induzido quimicamente , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/complicações , Tacrolimo/efeitos adversos , Transplante de Rim/efeitos adversos , Desidratação/complicações , Desidratação/tratamento farmacológico , Imunossupressores/efeitos adversos , Potássio/uso terapêuticoRESUMO
BACKGROUND: Ototoxicity is a side effect of drugs and medications that usually leads to bilateral and symmetric sensorineural hearing loss that commonly affects the high-frequency range initially, with or preceded by tinnitus. Possible ototoxic side effects of calcineurin inhibitor immunosuppressants have been suggested, but this remains unclear. Therefore, this study aims to evaluate audiological changes in patients undergoing transplantation receiving immunosuppressive treatment with calcineurin inhibitors. METHODS: Prospective cohort study. Adult patients undergoing liver or kidney transplantation treated with calcineurin inhibitors were included. Pure-tone audiometry, distortion product otoacoustic emissions, and the Tinnitus Handicap Inventory questionnaire were completed at baseline, one, three, and six months after transplantation. Hearing thresholds were compared and correlated with plasma concentrations of calcineurin inhibitors. RESULTS: Seventeen patients were included, 59% males, with a median age of 54.7 years (29-68 years). Twelve patients underwent liver transplantation, four underwent kidney transplantation, and one patient underwent both. The medianfollow-up was 5.8 months (4-8 months). Significant pure-tone average shifts were observed in two patients. Both cases presented fluctuations in their hearing levels, which were not bilateral or symmetrical and affected the higher frequencies. All patients received tacrolimus within the therapeutic range during the follow-up period. Three different patients exceeded the expected range once; however, they were rapidly corrected and did not correlate with any changes in hearing. CONCLUSIONS: It appears that tacrolimus does not cause hearing loss when levels are within the therapeutic range for a follow-up period of six months post-transplantation.
Assuntos
Audiometria de Tons Puros , Inibidores de Calcineurina , Imunossupressores , Transplante de Rim , Transplante de Fígado , Ototoxicidade , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Inibidores de Calcineurina/efeitos adversos , Imunossupressores/efeitos adversos , Estudos Prospectivos , Idoso , Seguimentos , Tacrolimo/efeitos adversos , Perda Auditiva Neurossensorial/induzido quimicamente , Fatores de TempoRESUMO
BACKGROUND: The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking. METHODS: This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101). RESULTS: There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103). CONCLUSIONS: In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.