RESUMO
Tremor is a common side effect of tacrolimus correlated with peak-dose drug concentration. LCPT, a novel, once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ~30% dose reduction vs. immediate-release tacrolimus. In this phase 3b study, kidney transplant recipients (KTR) on a stable dose of tacrolimus and with a reported clinically significant tremor were offered a switch to LCPT. Tremor pre- and seven d post-conversion was evaluated by independent, blinded movement disorder neurologists using the Fahn-Tolosa-Marin (FTM) scale and by an accelerometry device; patients completed the QUEST (quality of life in essential tremor) and the Patient Global Impression of Change. There were 38 patients in the mITT population. A statistically and clinically significant improvement in tremor (FTM score, amplitude as measured by the accelerometry device and QOL [p-values < 0.05]) resulted post-conversion. Change in QUEST was significantly (p = 0.006) correlated (R = 0.44) with change in FTM; 78.9% of patients reported an improvement after switching to LCPT (p < 0.0005). To our knowledge this is the first trial in KTR that utilizes a sophisticated and reproducible measurement of tremor. Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose reduction of immediate-release tacrolimus for patients experiencing tremor.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim , Complicações Pós-Operatórias/induzido quimicamente , Tacrolimo/administração & dosagem , Tremor/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Resultado do Tratamento , Tremor/diagnóstico , Tremor/prevenção & controle , Adulto JovemRESUMO
Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four-yr data on 904 patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non-AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non-AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC-MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non-AA patients. Biopsy-proven acute rejection was higher in AA vs. non-AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non-AA patients. Kidney allograft survival remains lower for AA vs. non-AA recipients even under the current standard of care.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Adulto , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Terapia de Imunossupressão , Falência Renal Crônica/etnologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Prognóstico , Estudos Prospectivos , Fatores de TempoRESUMO
MORE was a four-yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC-MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy-proven acute rejection, graft loss or death to be similar for EC-MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC-MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC-MPS and MMF cohorts during follow-up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC-MPS vs. MMF, without an increase in adverse events.
Assuntos
Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Comprimidos com Revestimento Entérico/administração & dosagem , Tacrolimo/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Prospective data are lacking concerning the effect of reduced mycophenolic acid (MPA) dosing on efficacy and the influence of concomitant tacrolimus exposure. The Mycophenolic Renal Transplant (MORE) Registry is a prospective, observational study of de novo kidney transplant patients receiving MPA therapy under routine management. The effect of MPA dose reduction, interruption, or discontinuation (dose changes) was assessed in 870 tacrolimus-treated patients: 375 (43.1%) reduced tacrolimus (≤ 7 ng/mL at baseline) and 495 (56.9%) standard tacrolimus (>7 ng/mL); enteric-coated mycophenolate sodium 589 (67.7%) and mycophenolate mofetil 281 (32.3%). During baseline to month 1, months 1-3, months 3-6, and months 6-12, 9.3% (78/838), 16.6% (132/794), 20.7% (145/701), and 13.1% (70/535) patients, respectively, required MPA dose changes. These patients experienced an increased risk of biopsy-proven acute rejection at one yr with tacrolimus exposure either included in the model (hazard ratio [HR] 2.60, 95% CI 1.28-5.29, p = 0.008) or excluded (HR 2.58, 95% CI 1.28-5.23, p = 0.008). MPA dose changes were significantly associated with one yr graft failure when tacrolimus exposure was included (HR 2.23; 95% CI 1.01-4.89, p = 0.047) but not when tacrolimus exposure was excluded (HR 2.16; 95% CI 0.99-4.79; p = 0.054). These results suggest that reducing or discontinuing MPA can adversely affect graft outcomes regardless of tacrolimus trough levels.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/administração & dosagem , Nefropatias/cirurgia , Transplante de Rim , Ácido Micofenólico/administração & dosagem , Complicações Pós-Operatórias , Tacrolimo/administração & dosagem , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Feminino , Seguimentos , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sistema de RegistrosRESUMO
BACKGROUND: The association between clinical events and everolimus exposure in patients receiving reduced-exposure calcineurin inhibitor therapy is poorly explored. METHODS: In a pre-planned, descriptive analysis of data from a randomized controlled trial, events were correlated with everolimus trough concentrations in 556 newly transplanted kidney transplant patients receiving everolimus with reduced-exposure cyclosporine (CsA) and steroids. Influence of everolimus exposure on clinical events was stratified according to predefined time-normalized concentrations. RESULTS: The incidence of treated biopsy-proven acute rejection and graft loss at month 12 was highest in patients with everolimus <3 ng/mL (36.4% and 28.6%, respectively, vs. 9.1-15.3% and 0.9-5.0% with higher concentration ranges). A higher mortality rate was observed in patients with an everolimus trough concentration ≥ 12 ng/mL (10.0% vs. 1.7-5.6% with lower concentration ranges). The lowest rates of renal dysfunction (defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and hypertriglyceridemia were generally observed with everolimus trough concentration in the range 3-8 ng/mL and CsA <100 ng/mL. Proteinuria occurred most frequently in patients with very low or very high everolimus trough concentrations. CONCLUSIONS: These results support an exposure-response relationship between clinical events and everolimus trough concentrations in kidney transplant patients receiving reduced-exposure CsA.
Assuntos
Ciclosporina/administração & dosagem , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Sirolimo/análogos & derivados , Adulto , Ciclosporina/efeitos adversos , Ciclosporina/farmacocinética , Ciclosporina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos , Quimioterapia Combinada , Everolimo , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/epidemiologia , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Sirolimo/uso terapêutico , Análise de Sobrevida , Resultado do TratamentoRESUMO
Lai and colleagues demonstrate that pretreatment with N,N-dimethylsphingosine (DMS), a naturally occurring sphingosine derivative, provides renoprotection in ischemia/reperfusion injury. This DMS-induced renoprotection was abolished by the administration of agents that suppress regulatory T cells (Tregs) or by anti-CTLA-4 or anti-CD45 monoclonal antibodies, suggesting that Tregs played a critical role. The finding that Tregs are recruited to the kidney via DMS points to the exciting potential of new approaches to harnessing Tregs for therapeutic purposes.
Assuntos
Injúria Renal Aguda/prevenção & controle , Quimiotaxia de Leucócito/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Isquemia/tratamento farmacológico , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Esfingosina/análogos & derivados , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Masculino , Esfingosina/farmacologiaRESUMO
BACKGROUND: Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking. METHODS: Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg). RESULTS: The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p=0.02]; month 12, 47.3% vs. 39.4% [p=0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose>2000 mg (p=0.029) vs. 2000 mg. CONCLUSIONS: These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Nefropatias/cirurgia , Transplante de Rim , Ácido Micofenólico/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Tacrolimo/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Segurança , Resultado do TratamentoRESUMO
As part of the Spare-the-Nephron trial, we evaluated the combination mycophenolate mofetil (MMF) and sirolimus (SRL) as a calcineurin inhibitor (CNI)-free regimen for the preservation of renal function in renal allograft recipients. This 2-year, open-label, multicenter trial randomized 299 patients of which 151 were maintained on MMF and a CNI, 148 on MMF plus SRL (n=120, tacrolimus; n=31, cyclosporine). Baseline characteristics including measured (iothalamate) glomerular filtration rate (GFR) were similar between groups. After 1 year, the mean percentage change from baseline in the primary end point of measured GFR was significantly higher in the MMF/SRL group compared with the MMF/CNI group. After 2 years, the change was indistinguishable. Calculated creatinine clearance and GFR were significantly greater with MMF/SRL at 2 years within which biopsy-proven acute rejection (BPAR) occurred in 14 MMF/SRL-treated patients (3 graft losses) and in 17 receiving the MMF/CNI (6 graft losses). Significantly, no patients receiving MMF/SRL but five treated with MMF/CNI died. Thus, compared with MMF/CNI treatment, a 2-year regimen of MMF/SRL resulted in similar measures of renal function but with fewer deaths and a trend to less BPAR and graft loss.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Ácido Micofenólico/análogos & derivados , Néfrons/efeitos dos fármacos , Sirolimo/administração & dosagem , Adolescente , Adulto , Idoso , Inibidores de Calcineurina , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Néfrons/fisiopatologia , Estudos Prospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
In response to recently published KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the care of kidney transplant recipients (KTRs), the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) organized a working group of transplant nephrologists and surgeons to review these guidelines and comment on their relevance and applicability for US KTRs. The following commentaries on the KDIGO guidelines represent the consensus of our work group. The KDIGO transplant guidelines concentrated on aspects of transplant care most important to this population in the posttransplant period, such as immunosuppression, infection, malignancy, and cardiovascular care. Our KDOQI work group concurred with many of the KDIGO recommendations except in some important areas related to immunosuppression, in which decisions in the United States are largely made by transplant centers and are dependent in part on the specific patient population served. Most, but not all, KDIGO guidelines are relevant to US patients. However, implementation of many may remain a major challenge because of issues of limitation in resources needed to assist in the tasks of educating, counseling, and implementing and maintaining lifestyle changes. Although very few of the guidelines are based on evidence that is strong enough to justify their being used as the basis of policy or performance measures, they offer an excellent road map to navigate the complex care of KTRs.
Assuntos
Transplante de Rim , Monitorização Fisiológica/normas , Cuidados Pós-Operatórios/normas , Guias de Prática Clínica como Assunto , Protocolos Clínicos , Creatinina/sangue , Taxa de Filtração Glomerular , Glucocorticoides/administração & dosagem , Humanos , Hospedeiro Imunocomprometido , Terapia de Imunossupressão/normas , Nefropatias/cirurgia , Estilo de Vida , Neoplasias Labiais/epidemiologia , Neoplasias/epidemiologia , Neoplasias Cutâneas/epidemiologia , Transplante Homólogo , Estados UnidosRESUMO
OBJECTIVE: Over the last 3 decades, group treatment researchers have become increasingly knowledgeable of the impact of within-group dependency on analyses of group treatment data and of mutual influence processes that occur within therapy groups. Despite these advancements, there remains a lack of consensus on the magnitude of mutual influence, or group effects, in group treatment research. As such, this study sought to estimate the size of group effects on members' posttreatment outcomes by meta-analyzing the intraclass correlation coefficients (ICCs) in group treatment research. In addition, we tested several moderators of the ICC, including outcome type, outcome reactivity, outcome specificity, group format, treatment length, and group size. METHOD: Using robust variance estimations, we meta-analyzed 169 effect sizes from 37 group treatment studies. RESULTS: Findings indicated an average ICC of 0.06. Group size, group format, treatment length, outcome specificity, and outcome type did not significantly moderate the ICC; however, we did find evidence to suggest that the ICC varies as a function of outcome reactivity, with observer-rated outcome measures resulting in the largest ICC. CONCLUSION: These findings suggest that interdependence in group treatment research is an important concept both theoretically and statistically. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Assuntos
Processos Grupais , Transtornos Mentais/terapia , Psicoterapia de Grupo/métodos , Humanos , Transtornos Mentais/psicologia , Avaliação de Resultados em Cuidados de SaúdeRESUMO
The clinical use of the immunosuppressant calcineurin inhibitor cyclosporine is limited by its nephrotoxicity. This is enhanced when combined with the immunosuppressive mTOR inhibitor sirolimus. Nephrotoxicity of both drugs is not yet fully understood. The goal was to gain more detailed mechanistic insights into the time-dependent effects of cyclosporine and sirolimus on the rat kidney by using a comprehensive approach including metabolic profiling in urine ((1)H NMR spectroscopy), kidney histology, kidney function parameters in plasma, measurement of glomerular filtration rates, the oxidative stress marker 15-F(2t)-isoprostane in urine, and immunosuppressant concentrations in blood and kidney. Male Wistar rats were treated with vehicle (controls), cyclosporine (10/25 mg/kg/day), and/or sirolimus (1 mg/kg/day) by oral gavage once daily for 6 and 28 days. Twenty-eight day treatment led to a decrease of glomerular filtration rates (cyclosporine, -59%; sirolimus, -25%). These were further decreased when both drugs were combined (-86%). Histology revealed tubular damage after treatment with cyclosporine, which was enhanced when sirolimus was added. No other part of the kidney was affected. (1)H NMR spectroscopy analysis of urine (day 6) revealed time-dependent changes of 2-oxoglutarate, citrate, and succinate concentrations. In combination with increased urine isoprostane concentrations, these changes indicated oxidative stress. After 28 days of cyclosporine treatment, urine metabonomics shifted to patterns typical for proximal tubular damage with reduction of Krebs cycle intermediates and trimethylamine-N-oxide concentrations, whereas acetate, lactate, trimethylamine, and glucose concentrations increased. Again, sirolimus enhanced these negative effects. Our results indicate that cyclosporine and/or sirolimus induce damage of the renal tubular system. This is reflected by urine metabolite patterns, which seem to be more sensitive than currently used clinical kidney function markers such as creatinine concentrations in serum. Metabolic profiling in urine may provide the basis for the development of toxicodynamic monitoring strategies for immunosuppressant nephrotoxicity.
Assuntos
Ciclosporina/toxicidade , Imunossupressores/toxicidade , Rim/efeitos dos fármacos , Sirolimo/toxicidade , Animais , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Rim/anatomia & histologia , Espectroscopia de Ressonância Magnética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Prostaglandinas A/urina , Ratos , Ratos Wistar , Sirolimo/administração & dosagem , Sirolimo/sangue , Fatores de Tempo , UrináliseRESUMO
BACKGROUND: Cyclosporine and/or sirolimus impair recovery of renal transplants. This study examines the changes in urine metabolite profiles as surrogate markers of renal cell metabolism and function after cyclosporine and/or sirolimus treatment employing a rat kidney transplantation model. METHODS: Using inbred Lewis rats, kidneys were transplanted into bilaterally nephrectomized recipients followed by treatment with either CsA (cyclosporine) 10, Rapa (sirolimus) 1, CsA10/Rapa1 or CsA25/Rapa1 mg/kg/day for 7 days. On day 7, urine was analyzed by (1)H-NMR spectroscopy. Blood and kidney tissue drug concentrations, tissue high-energy compounds (including ATP, ADP) and oxidative stress markers (15-F(2t)-isoprostanes) in urine were measured by HPLC mass spectrometry. RESULTS: Changes in urine metabolites followed the order Rapa1 < CsA10 < CsA10/Rapa1 < CsA25/Rapa1. Compared with controls, CsA25/Rapa1 showed the greatest changes (creatinine -36%, succinate -57%, citrate -89%, alpha-ketoglutarate -75%, creatine +498%, trimethylamine +210% and taurine +370%). 15-F(2t)-isoprostane concentrations in urine increased in the combined immunosuppressant-treated animals ([CsA25/Rapa1]: 795 +/- 222, [CsA10/Rapa1]: 475 +/- 233 pg/mg/creatinine) as compared with controls (165 +/- 78 pg/mg creatinine). Rapa concentration in blood and tissues increased in the combined treatment (blood: 31 +/- 8 ng/ml, tissue: 1.3 +/- 0.4 ng/mg) as compared with monotherapy (blood: 14 +/- 8 ng/ml, tissue: 0.35 +/- 0.15 ng/mg). Drug blood concentrations correlated with isoprostane urine concentrations, which correlated negatively with citrate, alpha-ketoglutarate and creatinine concentrations in urine. Only CsA25/Rapa1 significantly reduced high-energy metabolite concentrations in transplant kidney tissue (ATP -55%, ADP -24%). CONCLUSION: Immunosuppressant drugs induce changes in urine metabolite patterns, suggesting that immunosuppressant-induced oxidative stress is an early event in the development of nephrotoxicity. Urine 15-F(2t)-isoprostane concentrations and metabolite profiles may be sensitive markers of immunosuppressant-induced nephrotoxicity.
Assuntos
Ciclosporina/toxicidade , Ciclosporina/urina , Transplante de Rim , Metaboloma/fisiologia , Sirolimo/toxicidade , Sirolimo/urina , Animais , Biomarcadores/urina , Transplante de Rim/métodos , Masculino , Metaboloma/efeitos dos fármacos , Ratos , Ratos Endogâmicos LewRESUMO
Acculturation theories often describe how individuals in the United States adopt and incorporate dominant cultural values, beliefs, and behaviors such as individualism and self-reliance. Theorists tend to perceive dominant cultural values as "accessible to everyone," even though some dominant cultural values, such as preserving White racial status, are reserved for White people. In this article, the authors posit that White supremacist ideology is suffused within dominant cultural values, connecting the array of cultural values into a coherent whole and bearing with it an explicit status for White people and people of color. Consequently, the authors frame acculturation as a continuing process wherein some people of color learn explicitly via racism, microaggressions, and racial trauma about their racial positionality; White racial space; and how they are supposed to accommodate White people's needs, status, and emotions. The authors suggest that acculturation may mean that the person of color learns to avoid racial discourse to minimize eliciting White fragility and distress. Moreover, acculturation allows the person of color to live in proximity to White people because the person of color has become unthreatening and racially innocuous. The authors provide recommendations for research and clinical practice focused on understanding the connections between ideology, racism, microaggressions and ways to create psychological healing. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Assuntos
Aculturação , Agressão/psicologia , Racismo/psicologia , Predomínio Social , População Branca/psicologia , Ferimentos e Lesões/psicologia , Humanos , Relações Raciais , Estados UnidosRESUMO
BACKGROUND: Clinical data are lacking concerning concomitant administration of everolimus and tacrolimus in renal transplant recipients. METHODS: In a prospective, multicenter, open-label, exploratory, randomized, 6-month study, 92 de novo renal transplant patients received everolimus, steroids, and basiliximab with low or standard tacrolimus exposure. The primary objective was to compare renal function at 6 months after transplant. RESULTS: Mean 6-month serum creatinine (primary safety variable) was 112+/-31 micromol/L (1.26+/-0.35 mg/dL) and 127+/-50 micromol/L (1.44+/-0.57 mg/dL) in the low and standard tacrolimus groups, respectively, (n.s.); mean estimated GFR (Nankivell) was 75.3+/-16.6 mL/min and 72.5+/-15.2 mL/min (n.s.). Biopsy-proven acute rejection occurred in 13 patients: seven (14%) in the low tacrolimus group and six (14%) in the standard tacrolimus group, n.s. One graft was lost in the standard tacrolimus group. No patients died. CONCLUSIONS: Tacrolimus exposure reduction in the presence of everolimus, steroids and basiliximab induction results in good efficacy in de novo renal transplant recipients with very well-preserved renal function. Additional studies are warranted because between-group comparisons were limited by the relatively small differences in tacrolimus exposure in the 2 arms; trough levels were toward the upper end of the low-exposure ranges and toward the bottom of the standard-exposure ranges.
Assuntos
Falência Renal Crônica/cirurgia , Transplante de Rim/imunologia , Sirolimo/análogos & derivados , Tacrolimo/uso terapêutico , Adulto , Quimioterapia Combinada , Everolimo , Feminino , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/etiologia , Doadores Vivos/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Sirolimo/uso terapêutico , Doadores de Tecidos/estatística & dados numéricosRESUMO
BACKGROUND: The genomic response to adaptation of IMCD3 cells to hypertonicity results in both upregulation and downregulation of a variety of genes. METHOD: The present study was undertaken to assess the metabonomic and proteomic response of IMCD3 cells that have been chronically adapted to hypertonicity (600 and 900 mosm/kg H(2)O) as compared to cells under isotonic conditions. RESULTS: Adaptation of IMCD3 cells to hypertonic conditions resulted in a change of a wide range of organic osmolytes, including sorbitol (+8,291%), betaine (+1,099%), myo-inositol (+669%), taurine (+113%) and glycerophosphorylcholine (+61%). Evaluation of the polyol pathway for sorbitol production revealed a reduction in sorbitol dehydrogenase and an increase in aldose reductase mRNA in adapted cells. Proteome analysis revealed increased expression of six glycolytic proteins, including malic enzyme and pyruvate carboxylase, indicating the activation of the pyruvate shunt and changes in glucose metabolism. This study showed that the observed reduction in cell replication could possibly reflect a redirection of cellular energy from cell growth and replication to maintenance of intracellular ion levels in chronically adapted cells. CONCLUSION: The combined metabonomic and proteomic analysis was shown to be a very helpful tool for the analysis of the effects caused by chronic adaptation to hypertonicity. It made it possible to better evaluate the importance of certain changes that occur in the process of adaptation.
Assuntos
Metabolismo Energético , Enzimas/metabolismo , Medula Renal/metabolismo , Túbulos Renais Coletores/metabolismo , Proteômica , Adaptação Fisiológica , Aminoácidos/metabolismo , Animais , Western Blotting , Linhagem Celular , Proliferação de Células , Eletroforese em Gel Bidimensional , Enzimas/genética , Glucose/metabolismo , Medula Renal/enzimologia , Medula Renal/ultraestrutura , Túbulos Renais Coletores/enzimologia , Túbulos Renais Coletores/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Ressonância Magnética Nuclear Biomolecular , Pressão Osmótica , Fenótipo , Fosfatos/metabolismo , Polímeros/metabolismo , Proteômica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Solução Salina HipertônicaRESUMO
BACKGROUND: The benefit of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in terms of gastrointestinal symptom burden has been evaluated previously using patient-reported outcomes. However, data are lacking concerning the sustained effect of conversion over time, and the potential impact of concomitant calcineurin inhibitor. METHODS: In this 3-month, prospective, multicenter, longitudinal, open-label trial, MMF-treated renal transplant patients with gastrointestinal symptoms receiving cyclosporine or tacrolimus were converted to equimolar doses of EC-MPS. Change in gastrointestinal symptom burden was evaluated using a validated Gastrointestinal Symptom Rating Scale (GSRS). RESULTS: A significant improvement in GSRS score was observed from baseline (2.61, 95% CI 2.54-2.68) to month 1 (1.87, 95% CI 1.81-1.93) after conversion to EC-MPS and was sustained to month 3 (1.81, 95% CI 1.74-188; both P<0.0001 versus baseline). The mean change in overall GSRS score from baseline to month 1 was -0.74 overall (cyclosporine: -0.73 and tacrolimus: -0.74; all P<0.0001 versus baseline), with a slight further improvement (-0.79) at month 3 (cyclosporine: -0.82 and tacrolimus: -0.78; all P<0.0001 versus baseline). A significant improvement in GSRS subscale scores was also observed in the total population regardless of calcineurin inhibitor at month 1, sustained to month 3 (all P<0.0001 versus baseline). The improvement in GSRS score postconversion was similar in African-American and non-African-American patients, and in diabetic and nondiabetic patients. CONCLUSIONS: This exploratory study in 728 patients demonstrates that following conversion from MMF to EC-MPS, regardless of concomitant calcineurin inhibitor, GSRS is improved and sustained over 3 months.
Assuntos
Trato Gastrointestinal/efeitos dos fármacos , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Adolescente , Adulto , Idoso , Feminino , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/química , Ácido Micofenólico/farmacologia , Sensibilidade e Especificidade , Inquéritos e Questionários , Fatores de TempoRESUMO
BACKGROUND: The benefit of converting renal transplant recipients with gastrointestinal (GI) complaints from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) has not been evaluated using patient-reported outcomes. METHODS: A multicenter, open-label, prospective study was undertaken in MMF-treated renal transplant patients. Patients experiencing GI complaints were converted to equimolar EC-MPS (Cohort A). Patients without GI complaints remained on MMF (Cohort B). At baseline and Visit 2 (4-6 weeks postbaseline), patients completed the Gastrointestinal Symptom Rating Scale (GSRS), Gastrointestinal Quality of Life Index (GIQLI) and Psychological General Well-being Index (PGWBI). At Visit 2, patients and physicians completed the Overall Treatment Effect (OTE) scale for GI symptoms. Additionally, patients completed the OTE for health-related quality of life (HRQoL). Minimal important difference (MID) was calculated for GSRS and GIQLI based on patients' and physicians' OTE evaluation. RESULTS: Of 328 patients enrolled (i.e. the intent-to-treat and safety populations), 278 formed the per-protocol population (Cohort A, n=177; Cohort B, n=101). At baseline, Cohort A had significantly worse scores on all GSRS, GIQLI and PGWBI subscales compared to Cohort B (all P<0.0001). All GSRS, GIQLI and PGWBI subscale scores improved significantly in Cohort A between baseline and Visit 2 (all P<0.0001). Mean improvements in all GSRS subscales and most GIQLI subscores exceeded the calculated MID. GSRS, GIQLI and PGWBI subscales remained stable in Cohort B. CONCLUSION: This first exploratory study indicates that converting patients with mild, moderate or severe GI complaints from MMF to EC-MPS significantly reduces GI-related symptom burden and improves patient functioning and well-being.
Assuntos
Gastroenteropatias/induzido quimicamente , Nível de Saúde , Transplante de Rim/fisiologia , Ácido Micofenólico/análogos & derivados , Qualidade de Vida , Administração Oral , Adolescente , Adulto , Idoso , Atitude Frente a Saúde , Estudos de Coortes , Feminino , Humanos , Transplante de Rim/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Comprimidos com Revestimento Entérico , Resultado do TratamentoRESUMO
BACKGROUND: Nonadherence with immunosuppressive therapy after renal transplantation is a major clinical concern, but longitudinal data are sparse. Adherence data were recorded during the Mycophenolic Acid Observational REnal Transplant (MORE) study to help inform compliance management decisions. MATERIAL AND METHODS: Prospective data were analyzed from the four-year, observational MORE study of de novo adult renal transplant recipients receiving mycophenolic acid (MPA) as enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at 40 US sites under routine management. Adherence was assessed using the Immunosuppressant Therapy Adherence Scale (ITAS): total score 0-12 (12, adherence; <12, nonadherence). A logistic regression model was used to identify factors associated with nonadherence. RESULTS: In total, 808/946 recipients (85.4%) provided ≥1 ITAS score. Nonadherence was reported by 24.8%, 31.5%, 33.0%, 39.8%, 35.4% and 26.4% at months 3, 6, 12, 24, 36 and 48, respectively. Mean ITAS score was higher with EC-MPS vs. MMF at months 24 (11.3[1.0] vs. 10.9[1.4], p=0.001) and 36 (11.4[1.0] vs. 11.1[11.3], p=0.024). The odds ratio for nonadherence was 1.60 (95% CI 1.17, 2.19; p=0.003) for African Americans vs. non-African Americans. The rate of biopsy-proven acute rejection was 12.7% (51/401) in nonadherent recipients vs. 11.3% (46/406) in adherent recipients (p=0.59); graft loss was 4.7% (19/402) vs. 3.0% (12/406) (p=0.20); death was 1.5% (6/402) vs. 4.7% (19/406) (p=0.013). CONCLUSIONS: Adherence to the immunosuppressive regimen decreases over time, highlighting the need to monitor and encourage adherence even in long-term maintenance kidney transplant patients. Other than African American race, demographic factors may be of limited value in predicting nonadherence.
Assuntos
Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Transplante de Rim/mortalidade , Adesão à Medicação/estatística & dados numéricos , Ácido Micofenólico/análogos & derivados , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Feminino , Rejeição de Enxerto/etnologia , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
Kidney allograft damage resulting from donor-specific anti-HLA antibody (DSA) activity has been identified as a key component of long-term graft attrition. DSA that persists following acute antibody-mediated rejection (AMR) episodes and/or DSA associated with chronic graft dysfunction have been shown to be particularly pathogenic. Despite the significantly negative effects of DSA on graft survival, there are currently no accepted treatment modalities. We have previously reported our experience using a regimen of high-dose (5 mg/kg) intravenous immunoglobulin (IVIG) treatment over 6 months for kidney recipients with detectable DSA either following an acute AMR episode or in association with chronic graft dysfunction. In this manuscript, we report further follow-up on this cohort of patients treated with a single regimen of high-dose IVIG. We show a continued significant lowering effect on DSA present following AMR, particularly class I DSA, while DSA associated with chronic graft dysfunction, particularly class II, remains resistant to the immunomodulatory effects of IVIG.
Assuntos
Rejeição de Enxerto/tratamento farmacológico , Antígenos HLA/imunologia , Histocompatibilidade , Imunoglobulinas Intravenosas/administração & dosagem , Imunossupressores/administração & dosagem , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Doença Aguda , Biomarcadores/sangue , Doença Crônica , Colorado , Monitoramento de Medicamentos , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Masculino , Monitorização Imunológica , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Postkidney transplant donor-specific antibodies (DSA) have been identified as important contributors to graft loss. Few therapeutic options exist and have been met with limited success. We report outcomes in patients with de novo DSA and graft damage treated with a protocol of high-dose intravenous immunoglobulin (IVIG). METHODS: Retrospective analysis of 28 kidney transplant recipients with de novo DSA and graft damage in the form of either chronic graft dysfunction (group 1, n=20) or a recent previous acute antibody-mediated rejection (AMR) episode (group 2, n=8) prescribed a standard regimen of high-dose (5 g/kg) IVIG dosed over 6 months. RESULTS: Mean fluorescence intensity (MFI) of 70 total DSA decreased by 12%at the end of treatment (T1, P=0.14) and by 18%at last follow up (T2, P=0.035) compared with treatment initiation (T0) MFI. The most robust effect was seen in class I DSA (37% decrease at T2 versus T0, P=0.05) and in DSA from patients in group 2 (52% decrease at T2 versus T0, P=0.008). Graft function stabilized in patients in group 2 but continued to decline in those in group 1. CONCLUSION: High-dose IVIG resulted in modest DSA MFI reductions in patients with previous graft damage, with a larger effect occurring in class I DSA in patients with a previous acute AMR. There was no clinical treatment benefit in patients with ongoing chronic graft damage, whereas high-dose IVIG may reduce the risk of chronic graft dysfunction in those with an acute AMR event.