RESUMO
Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept.
Assuntos
Abatacepte , Inibidores de Calcineurina , Imunossupressores , Transplante de Rim , Torque teno virus , Carga Viral , Humanos , Transplante de Rim/efeitos adversos , Abatacepte/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Inibidores de Calcineurina/administração & dosagem , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Torque teno virus/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Adulto , Infecções por Vírus de DNA/tratamento farmacológico , Infecções por Vírus de DNA/virologia , Idoso , Transplantados , Rejeição de Enxerto/prevenção & controleRESUMO
Over the last 7 decades, kidney transplantation has evolved from an experiment between identical twins to becoming the gold standard treatment for end-stage kidney disease. To date, mycophenolate and calcineurin inhibitors, with or without prednisone, continue to constitute the backbone of modern maintenance immunosuppression. Despite major strides in improving acute rejection, long-term outcomes remain suboptimal with current regimens. Alternatives to calcineurin inhibitors such as belatacept and mammalian targets of rapamycin inhibitors exist; however, their wider-scale adoption remains relatively delayed due to concerns about increased rejection rates. In addition to continuing the investigation of steroid and calcineurin inhibitor sparing protocols, it is time to identify measurable surrogates for meaningful long-term graft survival. iBOX, a dynamic risk-prediction tool that predicts long-term death-censored graft failure could be a potential surrogate end point for future immunosuppression clinical trials. In this review, we summarize the landmark studies supporting current immunosuppression protocols and briefly discuss challenges and future directions.
Assuntos
Rejeição de Enxerto , Imunossupressores , Transplante de Rim , Humanos , Imunossupressores/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/imunologia , Terapia de Imunossupressão/métodos , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Falência Renal Crônica/cirurgia , Falência Renal Crônica/imunologia , Ácido Micofenólico/uso terapêutico , Inibidores de Calcineurina/uso terapêuticoRESUMO
Topical therapy remains a critical component in the management of immunemediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroidfree therapeutic alternatives. Despite their potential for skinselective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrierbased delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential antiinflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hardtoformulate' macromolecules in the context of psoriasis and atopic dermatitis.
Assuntos
Inibidores de Calcineurina , Inibidores de MTOR , Humanos , Inibidores de Calcineurina/uso terapêutico , Animais , Inibidores de MTOR/uso terapêutico , Administração Tópica , Nanotecnologia/métodos , Dermatite Atópica/tratamento farmacológico , Nanopartículas/química , Tacrolimo/uso terapêutico , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Sirolimo/uso terapêutico , Sirolimo/farmacologia , Sistemas de Liberação de Medicamentos/métodosRESUMO
Alzheimer's disease (AD) is the most common age-associated neurodegenerative disorder, characterized by progressive cognitive decline, memory impairment, and structural brain changes, primarily involving Aß plaques and neurofibrillary tangles of hyperphosphorylated tau protein. Recent research highlights the significance of smaller Aß and Tau oligomeric aggregates (AßO and TauO, respectively) in synaptic dysfunction and disease progression. Calcineurin (CaN), a key calcium/calmodulin-dependent player in regulating synaptic function in the central nervous system (CNS) is implicated in mediating detrimental effects of AßO on synapses and memory function in AD. This study aims to investigate the specific impact of CaN on both exogenous and endogenous TauO through the acute and chronic inhibition of CaN. We previously demonstrated the protective effect against AD of the immunosuppressant CaN inhibitor, FK506, but its influence on TauO remains unclear. In this study, we explored the short-term effects of acute CaN inhibition on TauO phosphorylation and TauO-induced memory deficits and synaptic dysfunction. Mice received FK506 post-TauO intracerebroventricular injection and TauO levels and phosphorylation were assessed, examining their impact on CaN and GSK-3ß. The study investigated FK506 preventive/reversal effects on TauO-induced clustering of CaN and GSK-3ß. Memory and synaptic function in TauO-injected mice were evaluated with/without FK506. Chronic FK506 treatment in 3xTgAD mice explored its influence on CaN, Aß, and Tau levels. This study underscores the significant influence of CaN inhibition on TauO and associated AD pathology, suggesting therapeutic potential in targeting CaN for addressing various aspects of AD onset and progression. These findings provide valuable insights for potential interventions in AD, emphasizing the need for further exploration of CaN-targeted strategies.
Assuntos
Inibidores de Calcineurina , Calcineurina , Modelos Animais de Doenças , Hipocampo , Sinapses , Tacrolimo , Proteínas tau , Animais , Proteínas tau/metabolismo , Tacrolimo/farmacologia , Masculino , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Calcineurina/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Inibidores de Calcineurina/farmacologia , Fosforilação/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Glicogênio Sintase Quinase 3 beta/metabolismoRESUMO
INTRODUCTION: Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). METHODS: Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). RESULTS: Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0% vs. 85.5%, p < 0.001) and 24 months (61.0% vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4% vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6% vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9% vs. 18.6%, p = 0.003, OR = 0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406 vs. 813 days, p = 0.001) without an increased risk of complications. CONCLUSIONS: CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications.
Assuntos
Inibidores de Calcineurina , Rejeição de Enxerto , Sobrevivência de Enxerto , Imunossupressores , Transplante de Rim , Humanos , Masculino , Feminino , Transplante de Rim/efeitos adversos , Inibidores de Calcineurina/uso terapêutico , Pessoa de Meia-Idade , Seguimentos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Fatores de Risco , Imunossupressores/uso terapêutico , Prognóstico , Falência Renal Crônica/cirurgia , Adulto , Taxa de Filtração Glomerular , Estudos Retrospectivos , Complicações Pós-Operatórias/prevenção & controle , Testes de Função Renal , Terapia de Imunossupressão/métodosRESUMO
BACKGROUND: Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). METHODS: This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. RESULTS: From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS: Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.
Assuntos
Everolimo , Rejeição de Enxerto , Sobrevivência de Enxerto , Imunossupressores , Transplante de Fígado , Doadores Vivos , Humanos , Feminino , Masculino , Everolimo/uso terapêutico , Everolimo/administração & dosagem , Estudos Retrospectivos , Pessoa de Meia-Idade , Rejeição de Enxerto/etiologia , Imunossupressores/uso terapêutico , Seguimentos , Prognóstico , Fatores de Risco , Complicações Pós-Operatórias , Adulto , Taxa de Filtração Glomerular , Taxa de Sobrevida , Testes de Função Renal , Inibidores de Calcineurina/uso terapêuticoRESUMO
INTRODUCTION: Posterior leukoencephalopathy syndrome (PRES) is a rare neurological disease possibly associated with the use of calcineurin inhibitors like cyclosporine A (CSA). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the outbreak of coronavirus disease 19 (COVID-19) can cause neurological manifestations. We described a case of CSA-related PRES whose diagnosis was difficult due to a concurrent infection with SARS-CoV-2. OBSERVATION: The 16-year-old patient was known to have corticosteroid-resistant nephrotic syndrome secondary to minimal change disease. CSA was introduced, and on the fifth day of treatment, the patient presented with seizures followed by fever. Biological and magnetic resonance imaging data were in favor of SARS-CoV-2 encephalitis. Relief of immunosuppression by discontinuation of CSA was decided and the patient was put on anticonvulsants. After being declared cured of COVID-19, which was without other clinical signs, the CSA was reintroduced but the patient presented with seizures the next day. This allowed the physicians to rectify the diagnosis and relate the seizures to a CSA-related PRES. CONCLUSION: Infection with SARS-CoV-2 could be a differential diagnosis of a PRES related to calcineurin inhibitors.
Assuntos
COVID-19 , Ciclosporina , Síndrome da Leucoencefalopatia Posterior , Humanos , Síndrome da Leucoencefalopatia Posterior/induzido quimicamente , Síndrome da Leucoencefalopatia Posterior/diagnóstico , COVID-19/complicações , COVID-19/diagnóstico , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Diagnóstico Diferencial , Adolescente , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Convulsões/etiologia , Convulsões/diagnóstico , Inibidores de Calcineurina/efeitos adversos , Encefalite Viral/diagnóstico , Encefalite Viral/tratamento farmacológico , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials. METHODS: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator's Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349). FINDINGS: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred. INTERPRETATION: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved. FUNDING: Galderma.
Assuntos
Anticorpos Monoclonais Humanizados , Dermatite Atópica , Prurido , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Prurido/tratamento farmacológico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Post-allogeneic hematopoietic cell transplant (HCT) immunosuppression regimens are given as graft-versus-host disease (GVHD) prophylaxis. Most GVHD prophylaxis regimens are based on calcineurin inhibitors (CNIs). Unfortunately, CNIs are associated with significant associated morbidity, frequently cannot be tolerated, and often need to be discontinued. There is no consensus as to which alternative immunosuppression should be used in cases where CNIs have to be permanently discontinued. Cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocking agents are well tolerated and have been used extensively in patients with autoimmune disease and as post-transplant immunosuppression. There are two CTLA4-Ig agents: belatacept and abatacept. Belatacept is routinely used in adult kidney transplantation to prevent rejection and abatacept has been approved by the Food and Drug Administration (FDA) for GVHD prophylaxis in patients undergoing a matched or one allele-mismatched unrelated allogenic HCT. Herein, we describe a case in which abatacept was given off-label to replace tacrolimus GVHD prophylaxis in a patient with neurotoxicity undergoing haploidentical HCT. This case suggests that CTLA4-Ig blockade may be a good alternative to a CNI in cases where the CNI needs to be discontinued and warrants further investigation.
Assuntos
Inibidores de Calcineurina , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Inibidores de Calcineurina/uso terapêutico , Inibidores de Calcineurina/efeitos adversos , Abatacepte/uso terapêutico , Masculino , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Adulto , FemininoRESUMO
Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.
Assuntos
Inibidores de Calcineurina , Doenças Cardiovasculares , Humanos , Inibidores de Calcineurina/efeitos adversos , Animais , Doenças Cardiovasculares/induzido quimicamente , Imunossupressores/efeitos adversosRESUMO
Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.
Assuntos
Ciclosporina , Modelos Animais de Doenças , Vírus da Hepatite E , Hepatite E , Terapia de Imunossupressão , Imunossupressores , Tacrolimo , Animais , Coelhos , Hepatite E/imunologia , Hepatite E/virologia , Hepatite E/tratamento farmacológico , Vírus da Hepatite E/imunologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Prednisolona/uso terapêutico , Prednisolona/farmacologia , Masculino , Imunidade Inata/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Hepatite Crônica/tratamento farmacológico , Hepatite Crônica/imunologia , Hepatite Crônica/virologia , Doença Crônica , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêuticoRESUMO
Atopic dermatitis (AD) is a chronic, recurring, inflammatory skin condition. Xerosis, pruritus, and rash make the clinical diagnosis. Adequate skin care and regular emollient use are key in management. Topical corticosteroids are the first-line treatment for AD flare-ups. Wet wrap therapy can improve AD severity and extent. Topical calcineurin inhibitors are second-line treatments. Emollient use, topical corticosteroids and calcineurin inhibitors, and bleach baths can help prevent flare-ups. Patients with refractory AD that might require immunomodulatory treatments, such as dupilumab (Dupixent), Janus kinase inhibitors, or phototherapy, should be referred to a dermatologist. Seborrheic dermatitis (SD) is a common, chronic, relapsing, inflammatory condition that involves sebaceous skin areas. Infection with Malassezia species and the inflammatory response to it are the probable etiologies. The clinical diagnosis is made by the presence of hallmark greasy, yellow scales on the scalp or face. Infantile SD most commonly involves the scalp and forehead and typically is self-limited. In infants, application of emollients followed by hair brushing and shampooing may be effective. In infants and children, if the condition does not improve with this treatment, topical ketoconazole shampoo, gel, or lotion is safe and effective. Refractory cases of SD can be managed with topical corticosteroids and calcineurin inhibitors.
Assuntos
Inibidores de Calcineurina , Dermatite Atópica , Dermatite Seborreica , Emolientes , Humanos , Dermatite Seborreica/diagnóstico , Dermatite Seborreica/terapia , Dermatite Seborreica/tratamento farmacológico , Dermatite Atópica/terapia , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Criança , Emolientes/uso terapêutico , Adolescente , Inibidores de Calcineurina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Corticosteroides/uso terapêutico , Pré-Escolar , Lactente , Higiene da Pele/métodos , Administração Cutânea , Anticorpos Monoclonais HumanizadosRESUMO
INTRODUCTION: Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients. METHODS: In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated. RESULTS: Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05). However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/mL (P = .015, .032; respectively). CONCLUSION: Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. DOI: 10.52547/ijkd.7815.
Assuntos
Rejeição de Enxerto , Imunossupressores , Transplante de Rim , Tacrolimo , Humanos , Transplante de Rim/efeitos adversos , Tacrolimo/uso terapêutico , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinética , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Imunossupressores/farmacocinética , Imunossupressores/administração & dosagem , Estudos Retrospectivos , Adulto , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/imunologia , Infecções por Citomegalovirus , Sobrevivência de Enxerto/efeitos dos fármacos , Adesão à Medicação , Infecções por Polyomavirus , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/uso terapêutico , Inibidores de Calcineurina/farmacocinética , ViremiaRESUMO
Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na+ and K+ transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide-sensitive NaCl-cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch-like-3/CUL3 E3 ubiquitin-ligase complex, which is responsible for WNK (with-no-lysin-kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K+ channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial-Na+-channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin-mediated regulation of transepithelial Na+ and K+ transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K+ excretion, and induce hyperkalemia.
Assuntos
Inibidores de Calcineurina , Calcineurina , Hiperpotassemia , Potássio , Hiperpotassemia/metabolismo , Animais , Humanos , Calcineurina/metabolismo , Potássio/metabolismo , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Rim/metabolismo , Rim/efeitos dos fármacosRESUMO
ABSTRACT: Atopic dermatitis (AD), a chronic inflammatory, pruritic skin disorder, is seen primarily in the pediatric population but can be found among all age groups. The symptoms of AD can cause embarrassment in patients and can interrupt daily activities and productivity, potentially resulting in avoidance of social situations. In addition to nonpharmacologic management, mainstay pharmacologic treatments for AD are topical medications including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and topical Janus kinase (JAK) inhibitors. Promising new drugs-oral JAK inhibitors and monoclonal antibodies-have emerged as new treatment options for moderate-to-severe AD.
Assuntos
Dermatite Atópica , Dermatite Atópica/enfermagem , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/terapia , Humanos , Inibidores de Janus Quinases/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Corticosteroides/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Profissionais de EnfermagemRESUMO
INTRODUCTION: Most solid organ transplants originate from donors meeting criteria for death by neurological criteria (DNC). Within the organ donor, physiological responses to brain death increase the risk of ischaemia reperfusion injury and delayed graft function. Donor preconditioning with calcineurin inhibition may reduce this risk. METHODS AND ANALYSIS: We designed a multicentre placebo-controlled pilot randomised trial involving nine organ donation hospitals and all 28 transplant programmes in the Canadian provinces of Ontario and Québec. We planned to enrol 90 DNC donors and their approximately 324 organ recipients, totalling 414 participants. Donors receive an intravenous infusion of either tacrolimus 0.02 mg/kg over 4 hours prior to organ retrieval, or a matching placebo, while monitored in an intensive care unit for any haemodynamic changes during the infusion. Among all study organ recipients, we record measures of graft function for the first 7 days in hospital and we will record graft survival after 1 year. We examine the feasibility of this trial with respect to the proportion of all eligible donors enrolled and the proportion of all eligible transplant recipients consenting to receive a CINERGY organ transplant and to allow the use of their health data for study purposes. We will report these feasibility outcomes as proportions with 95% CIs. We also record any barriers encountered in the launch and in the implementation of this trial with detailed source documentation. ETHICS AND DISSEMINATION: We will disseminate trial results through publications and presentations at participating sites and conferences. This study has been approved by Health Canada (HC6-24-c241083) and by the Research Ethics Boards of all participating sites and in Québec (MP-31-2020-3348) and Clinical Trials Ontario (Project #3309). TRIAL REGISTRATION NUMBER: NCT05148715.
Assuntos
Inibidores de Calcineurina , Função Retardada do Enxerto , Transplante de Rim , Doadores de Tecidos , Adulto , Feminino , Humanos , Masculino , Morte Encefálica , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/uso terapêutico , Função Retardada do Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Estudos Multicêntricos como Assunto , Ontário , Projetos Piloto , Quebeque , Ensaios Clínicos Controlados Aleatórios como Assunto , Tacrolimo/uso terapêutico , Tacrolimo/administração & dosagemRESUMO
Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506), are commonly used immunosuppressants for preserving transplanted organs and tissues. However, these drugs can cause severe and persistent pain. GluA2-lacking, calcium-permeable AMPA receptors (CP-AMPARs) are implicated in various neurological disorders, including neuropathic pain. It is unclear whether and how constitutive calcineurin, a Ca2+/calmodulin protein phosphatase, controls synaptic CP-AMPARs. In this study, we found that blocking CP-AMPARs with IEM-1460 markedly reduced the amplitude of AMPAR-EPSCs in excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2), but not in inhibitory neurons expressing vesicular GABA transporter, in the spinal cord of FK506-treated male and female mice. FK506 treatment also caused an inward rectification in the current-voltage relationship of AMPAR-EPSCs specifically in VGluT2 neurons. Intrathecal injection of IEM-1460 rapidly alleviated pain hypersensitivity in FK506-treated mice. Furthermore, FK506 treatment substantially increased physical interaction of α2δ-1 with GluA1 and GluA2 in the spinal cord and reduced GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of spinal cords. Correspondingly, inhibiting α2δ-1 with pregabalin, Cacna2d1 genetic knock-out, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide reversed inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons caused by FK506 treatment. In addition, CK2 inhibition reversed FK506 treatment-induced pain hypersensitivity, α2δ-1 interactions with GluA1 and GluA2, and inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons. Thus, the increased prevalence of synaptic CP-AMPARs in spinal excitatory neurons plays a major role in calcineurin inhibitor-induced pain hypersensitivity. Calcineurin and CK2 antagonistically regulate postsynaptic CP-AMPARs through α2δ-1-mediated GluA1/GluA2 heteromeric assembly in the spinal dorsal horn.
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Calcineurina , Caseína Quinase II , Receptores de AMPA , Medula Espinal , Tacrolimo , Animais , Receptores de AMPA/metabolismo , Camundongos , Calcineurina/metabolismo , Masculino , Feminino , Tacrolimo/farmacologia , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Caseína Quinase II/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/fisiologia , Inibidores de Calcineurina/farmacologia , Fenótipo , Canais de CálcioRESUMO
Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.
Assuntos
Inibidores de Calcineurina , Doença Enxerto-Hospedeiro , Isoantígenos , Células T de Memória , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/patologia , Animais , Camundongos , Isoantígenos/imunologia , Inibidores de Calcineurina/farmacologia , Doença Crônica , Células T de Memória/imunologia , Tacrolimo/farmacologia , Linfócitos T CD4-Positivos/imunologia , Ciclosporina/farmacologia , Feminino , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologiaRESUMO
BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.
Assuntos
Vírus BK , Inibidores de Calcineurina , Imunossupressores , Transplante de Rim , Infecções por Polyomavirus , Serina-Treonina Quinases TOR , Tacrolimo , Viremia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Calcineurina/uso terapêutico , Viremia/tratamento farmacológico , Infecções por Polyomavirus/tratamento farmacológico , Tacrolimo/uso terapêutico , Adulto , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Imunossupressores/uso terapêutico , Carga Viral/efeitos dos fármacos , Resultado do Tratamento , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/virologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Sirolimo/uso terapêutico , República da Coreia , Estudos Retrospectivos , IdosoRESUMO
AIMS: With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors (CNI) on cognitive function and related brain pathology from in vitro, in vivo, and clinical studies. We also summarize the potential mechanisms that underlie the pathways related to CNI-induced cognitive impairment. METHODS: We systematically searched articles in PubMed using keywords 'calcineurin inhibitor*' and 'cognition' to identify related articles, which the final list pertaining to underlying mechanisms of CNI on cognition. RESULTS: Several studies have reported an association between calcineurin and the neuropathology of Alzheimer's disease (AD). AD is the most common neurocognitive disorder associated with amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive impairment. CNI, including tacrolimus and cyclosporin A, are commonly prescribed for patients with transplantation of solid organs such as kidney, liver, or heart, those drugs are currently being used as long-term immunosuppressive therapy. Although preclinical models emphasize the favorable effects of CNI on the restoration of brain pathology due to the impacts of calcineurin on the alleviation of amyloid-beta deposition and tau hyperphosphorylation, or rescuing synaptic and mitochondrial functions, treatment-related neurotoxicity, resulting in cognitive dysfunctions has been observed in clinical settings of patients who received CNI. CONCLUSION: Inconsistent results of CNI on cognition from clinical studies have been observed due to impairment of the blood-brain barrier, neuroinflammation mediated by reactive oxygen species, and alteration in mitochondrial fission, and extended research is required to confirm its promising use in cognitive impairment.