RESUMO
Clinical trials utilizing regulatory T cell (Treg) therapy in organ transplantation have shown promising results, however, the choice of a standard immunosuppressive regimen is still controversial. Calcineurin inhibitors (CNIs) are one of the most common immunosuppressants for organ transplantation, although they may negatively affect Tregs by inhibiting IL-2 production by conventional T cells. As a strategy to replace IL-2 signaling selectively in Tregs, we have introduced an engineered orthogonal IL-2 (ortho IL-2) cytokine/cytokine receptor (R) pair that specifically binds with each other but does not bind with their wild-type counterparts. Murine Tregs were isolated from recipients and retrovirally transduced with ortho IL-2Rß during ex vivo expansion. Transduced Tregs (ortho Tregs) were transferred into recipient mice in a mixed hematopoietic chimerism model with tacrolimus administration. Ortho IL-2 treatment significantly increased the ortho IL-2Rß(+) Treg population in the presence of tacrolimus without stimulating other T cell subsets. All the mice treated with tacrolimus plus ortho IL-2 achieved heart allograft tolerance, even after tacrolimus cessation, whereas those receiving tacrolimus treatment alone did not. These data demonstrate that Treg therapy can be adopted into a CNI-based regimen by utilizing cytokine receptor engineering.
Assuntos
Inibidores de Calcineurina , Tacrolimo , Camundongos , Animais , Inibidores de Calcineurina/farmacologia , Tacrolimo/uso terapêutico , Linfócitos T Reguladores , Interleucina-2/metabolismo , Receptores de Interleucina-2 , Sobrevivência de Enxerto , Imunossupressores/uso terapêuticoRESUMO
Chronic kidney disease (CKD) after solid organ transplant is a common clinical presentation, affecting 10% to 20% of liver, heart, and lung transplant recipients and accounting for approximately 5% of the kidney transplant waiting list. The causes of CKD are different for different types of transplants and are not all, or even predominantly, due to calcineurin inhibitor toxicity, with significant heterogeneity particularly in liver transplant recipients. Many solid organ transplant recipients with advanced CKD benefit from kidney transplantation but have a higher rate of death while waitlisted and higher mortality after transplant than the general kidney failure population. Recent organ allocation policies and proposals have attempted to address the appropriate identification and prioritization of candidates in need of a kidney transplant, either simultaneous with or after nonkidney transplant. Future research should focus on predictive factors for individuals identified as being at high risk for progression to kidney failure and death and on strategies to preserve kidney function and minimize the CKD burden in this unique patient population.
Assuntos
Transplante de Rim , Transplante de Órgãos , Insuficiência Renal Crônica , Insuficiência Renal , Humanos , Rim , Transplante de Rim/efeitos adversos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/cirurgia , Fatores de RiscoRESUMO
Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity.
Assuntos
Inibidores de Calcineurina , Proteína HMGB1 , Animais , Inibidores de Calcineurina/efeitos adversos , Ciclosporina/efeitos adversos , Metabolismo Energético , Imunossupressores/efeitos adversos , Camundongos , Tacrolimo/toxicidadeRESUMO
Improving long-term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority-based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy-proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence-based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and "real world" CNI- based standard of care, containing subjects with well-documented evidence of immune quiescence at 6 months posttransplant-ideal candidates for delayed CNI substitution. Our analysis indicates an evidence-based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.
Assuntos
Inibidores de Calcineurina , Transplante de Rim , Inibidores de Calcineurina/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêuticoRESUMO
Regulatory T (Treg) cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non-rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pretransplant, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy-proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL-2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first-week peripheral blood Treg frequency correlates with AR after LT under tacrolimus-based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations.
Assuntos
Transplante de Fígado , Tacrolimo , Basiliximab , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Linfócitos T Reguladores , Tacrolimo/uso terapêuticoRESUMO
The coronavirus disease 2019 (COVID-19) pandemic is declared a global health emergency. COVID-19 is triggered by a novel coronavirus: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Baseline characteristics of admitted patients with COVID-19 show that adiposity, diabetes, and hypertension are risk factors for developing severe disease, but so far immunosuppressed patients who are listed as high-risk patients have not been more susceptible to severe COVID-19 than the rest of the population. Multiple clinical trials are currently being conducted, which may identify more drugs that can lower mortality, morbidity, and burden on the society. Several independent studies have convincingly shown that cyclosporine inhibit replication of several different coronaviruses in vitro. The cyclosporine-analog alisporivir has recently been shown to inhibit SARS-CoV-2 in vitro. These findings are intriguing, although there is no clinical evidence for a protective effect to reduce the likelihood of severe COVID-19 or to treat the immune storm or acute respiratory distress syndrome (ARDS) that often causes severe morbidity. Here, we review the putative link between COVID-19 and cyclosporine, while we await more robust clinical data.
Assuntos
Tratamento Farmacológico da COVID-19 , Ciclosporina/uso terapêutico , Hospedeiro Imunocomprometido , Pandemias , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/imunologia , Humanos , Imunossupressores/uso terapêuticoRESUMO
Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim , Tacrolimo/administração & dosagem , Adulto , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/provisão & distribuição , Tacrolimo/provisão & distribuição , TransplantadosRESUMO
Activation, differentiation, and expansion of alloreactive CD8+ T cells, the dominant effectors that mediate murine heart allograft rejection, requires allorecognition, costimulation, and cytokine-initiated signals. While previous work showed that alloreactive CD4+ T cell immunity entails immune cell-produced and locally activated complement, whether and how C3a receptor 1 (C3aR1) signaling impacts transplant outcomes and the mechanisms linking C3aR1 to alloreactive CD8+ T cell activation/expansion remain unclear. Herein we show that recipient C3aR1 deficiency or pharmacological C3aR1 blockade synergizes with tacrolimus to significantly prolong allograft survival versus tacrolimus-treated controls (median survival time 21 vs. 14 days, P < .05). Recipient C3aR1-deficiency reduced the frequencies of posttransplant, donor-reactive CD8+ T cells twofold. Reciprocal adoptive transfers of naive WT or C3ar1-/- CD8+ T cells into syngeneic WT or C3ar1-/- allograft recipients showed that T cell-expressed C3aR1 induces CD8+ T proliferation, mTOR activation and transcription factor T-bet expression. Host C3aR1 indirectly facilitates alloreactive CD8+ T cell proliferation/expansion by amplifying antigen presenting cell costimulatory molecule expression and innate cytokine production. In addition to expanding mechanistic insight, our findings identify C3aR1 as a testable therapeutic target for future studies aimed at improving human transplant outcomes.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Transplante de Coração , Receptores de Complemento/deficiência , Transferência Adotiva , Aloenxertos , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Citocinas/biossíntese , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/administração & dosagem , Isoantígenos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Transdução de Sinais/imunologia , Tacrolimo/administração & dosagemRESUMO
Calcineurin inhibitor immunosuppressive drugs induce changes such as arteriolar hyalinosis (ah) in kidney transplants, raising the possibility that molecular changes in biopsies related to histologic ah can provide information about drug exposure. We hypothesized that molecular changes associated with less-than-expected hyalinosis might highlight a subpopulation of patients with under-immunosuppression/nonadherence at intermediate times of biopsy posttransplant (TxBx). Using gene expression data from 562 indication biopsies, we developed a molecular classifier for predicting the expected ah lesions (Mah ) at a particular TxBx. Mah -scores increased linearly with log(TxBx), but some biopsies had lower scores than expected for TxBx. The deviation of individual Mah -scores below the predicted regression line of Mah -scores vs TxBx is defined as "low hyalinosis index." Low hyalinosis indices were frequent in biopsies between 3 months and 3 years posttransplant, particularly among biopsies lacking histologic hyalinosis (ah0), and were associated with T cell-mediated rejection and a subset of recent-onset antibody-mediated rejection without glomerular double contours. In patients with medical records available for review, low hyalinosis indices were frequently associated with physician-recorded concerns about nonadherence (suspected or proven). We conclude that the Mah classifier and hyalinosis index identify indication biopsies with rejection for which the possibility of patient nonadherence should be considered.
Assuntos
Arteríolas/patologia , Rejeição de Enxerto/etiologia , Hialina/metabolismo , Síndrome da Fibromatose Hialina/fisiopatologia , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/farmacologia , Transplante de Rim/efeitos adversos , Arteríolas/metabolismo , Taxa de Filtração Glomerular , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Complicações Pós-Operatórias , Prognóstico , Fatores de RiscoRESUMO
The surgical risk of transplanted patients is high, and the modified gastrointestinal anatomy after bariatric surgery (BS) may lead to pharmacokinetic alterations in the absorption of immunosuppressive drugs. Data on outcomes of BS and the safety and feasibility of maintaining immunosuppression and graft safety among solid organ transplanted patients are scarce. In the current study, weight loss, improvement in comorbidities, and changes in dosage and trough levels of immunosuppression drugs before and after BS were analyzed for all transplanted patients who underwent laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric bypass (LRYGB) in our institution between November 2011 and January 2017. Thirty-four patients (13 females, 21 males, average age 53 years) were included in the study. A successful weight loss (>50% excess weight loss in 28 of them [82%]) was recorded at the last follow-up. Comorbidities improved significantly. Immunosuppressive stability increased from 39% to 47% among all patients. The tacrolimus blood trough levels declined slightly, but remained within therapeutic range. These data suggest that LSG and LRYGB ensure good immunosuppressive maintenance together with significant weight loss and improvement in comorbidities without serious graft rejection or dysfunction. The surgical risk is higher than in the regular BS population.
Assuntos
Cirurgia Bariátrica/estatística & dados numéricos , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Terapia de Imunossupressão , Obesidade Mórbida/cirurgia , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Comorbidade , Feminino , Seguimentos , Derivação Gástrica , Rejeição de Enxerto/etiologia , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Redução de PesoRESUMO
Calcineurin inhibitor toxicity (CNT) is a frequent occurrence in transplanted renal grafts and autochthone kidneys from patients undergoing long-term treatment with calcineurin inhibitors, notably cyclosporin A (CsA) and tacrolimus. Here, we show an indispensable role of the tumor necrosis factor superfamily (TNFS) molecule TNF-related weak inducer of apoptosis (TWEAK) (TNFSF12) in the pathogenesis of acute CNT lesions in mice. A deficiency in TWEAK resulted in limited tubulotoxicity after CsA exposure, which correlated with diminished expression of inflammatory cytokines and reduced intraparenchymal infiltration with immune cells. We further identified tubular epithelial cells of the kidney as major targets of CsA activity and found that Fn14 (tumor necrosis factor receptor superfamily 12A), the receptor for TWEAK, is a highly CsA-inducible gene in these cells. Correlating with this, CsA pretreatment sensitized tubular epithelial cells specifically to the pro-inflammatory activities of recombinant TWEAK in vitro. Moreover, injection of rTWEAK alone into mice induced moderate disease similar to CsA, and rTWEAK combined with CsA resulted in synergistic nephrotoxicity. These findings support the importance of tubular epithelial cells as cellular targets of CsA toxicity and introduce TWEAK as a critical contributor to CNT pathogenesis.
Assuntos
Inibidores de Calcineurina/efeitos adversos , Citocina TWEAK/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Túbulos Renais/patologia , Receptor de TWEAK/metabolismo , Animais , Células Cultivadas , Citocina TWEAK/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de TWEAK/genéticaRESUMO
Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.
Assuntos
Everolimo/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Neoplasias Cutâneas/prevenção & controle , Austrália/epidemiologia , Ciclosporina/administração & dosagem , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Complicações Pós-Operatórias , Prognóstico , Fatores de Risco , Sirolimo/administração & dosagem , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/epidemiologia , TransplantadosRESUMO
Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short-term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long-term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus-based and 197 to tacrolimus-based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline-adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m2 in the tacrolimus group (P = .50). Biopsy-proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus-based therapy, sirolimus-based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.
Assuntos
Alemtuzumab/farmacologia , Inibidores de Calcineurina/efeitos adversos , Imunossupressores/efeitos adversos , Nefropatias/induzido quimicamente , Transplante Homólogo/efeitos adversos , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.
Assuntos
Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Pele/efeitos adversos , Tacrolimo/farmacologia , Fatores Etários , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Citocinas/metabolismo , Rejeição de Enxerto/etiologia , Humanos , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBARESUMO
In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.
Assuntos
Everolimo/uso terapêutico , Fibrose/tratamento farmacológico , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Prednisolona/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Feminino , Fibrose/etiologia , Rejeição de Enxerto/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , DesmameRESUMO
SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.
Assuntos
Everolimo/farmacologia , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Transplante de Fígado/efeitos adversos , Ácido Micofenólico/farmacologia , Tacrolimo/farmacologia , Feminino , Seguimentos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.
Assuntos
Everolimo/farmacologia , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/farmacologia , Transplante de Rim/efeitos adversos , Tacrolimo/farmacologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Fatores de RiscoRESUMO
ß Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma ß cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 µM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in ß cells, possibly by sharing common pathways of ß cell dysfunction. TAC-induced ß cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Imunossupressores/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Tacrolimo/farmacologia , Animais , Calcineurina/farmacologia , Ciclosporina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fatores de Transcrição NFATC/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Obesidade/fisiopatologia , Ratos , Ratos Zucker , Magreza/fisiopatologiaRESUMO
BACKGROUND: In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. STUDY DESIGN: 36-month follow-up of the intention-to-treat population. SETTING & PARTICIPANTS: CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2). INTERVENTIONS: At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). OUTCOMES: Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. MEASUREMENTS: Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. RESULTS: Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). LIMITATIONS: Exploratory post hoc analysis with a small sample size. CONCLUSIONS: Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.