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- ItemSomente MetadadadosAdequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients(Lippincott Williams & Wilkins, 2018) Felipe, Claudia [UNIFESP]; Ferreira, Alexandra [UNIFESP]; Bessa, Adrieli [UNIFESP]; Abait, Tamiris [UNIFESP]; Perez, Juliana D. [UNIFESP]; Casarini, Dulce Elena [UNIFESP]; Medina-Pestana, Jose [UNIFESP]; Tedesco, Helio [UNIFESP]Background: This study investigates the adequacy of initial everolimus (EVR) dose, with and without calcineurin inhibitors (CNI), in kidney transplant recipients. Methods: This retrospective cohort analysis involved data from 305 kidney transplant recipients participating in 3 randomized trials receiving reduced dose cyclosporin A (CsA) combined with EVR 0.75 mg BID (CSA/EVR0.75, N = 32) or 1.5 mg BID (CSA/EVR1.5, N = 31), reduced dose tacrolimus (TAC) combined with EVR 1.5 mg BID (TAC(0.05)/EVR1.5, N = 83), standard dose TAC combined with EVR 1.5 mg BID (TAC(0.1)/EVR1.5,N = 93), and EVR 1.5 mg BID (EVR1.5, N = 66) with TAC introduction after day 5. The adequacy of the initial EVR dose, based on EVR whole blood trough between 3 and 8 ng/mL, was compared using first EVR blood concentrations obtained at day 3 after transplantation. Results: Recipient age, proportion of patients with diabetes mellitus, and proportion of grafts from living donors were different among the groups. Dose-corrected EVR concentrations were higher in patients receiving CsA than in those receiving TAC or no calcineurin inhibitors (6.7 +/- 5.9 versus 5.4 +/- 2.2 versus 2.4 +/- 0.8 versus 2.5 +/- 0.9 versus 2.2 +/- 0.7, P = 0.000). No differences were observed comparing dose adjusted EVR concentrations combined with TAC or alone (P = 0.073). The proportion of patients with EVR concentration below <3 ng/mL was lower when EVR was combined with CsA (25 versus 3 versus 43 versus 33 versus 50%, P = 0.000). Later introduction of TAC did not influence EVR concentrations. There were no differences in mean CsA concentrations comparing patients receiving EVR 0.75 or 1.5 mg BID (240 +/- 143 versus 213 +/- 105 ng/mL). On the other hand, mean TAC concentrations were higher according to the initial TAC dose regimen (6.4 +/- 3.9 versus 9.8 +/- 5.9 ng/mL). Conclusions: In de novo kidney transplant recipients, the choice of the initial dose of EVR should consider the type of calcineurin inhibitor to reach target EVR concentration within the first week in a higher proportion of patients, maximizing the efficacy/toxicity profile.
- ItemSomente MetadadadosBortezomib in Kidney Transplant: Current Use and Perspectives(Bentham Science Publ Ltd, 2017) Requiao-Moura, Lucio R.; de Sandes-Freitas, Taina V.; Marcelo-Gomes, Gessika [UNIFESP]; Rangel, Erika B.Background: Despite major advances in transplant medicine, antibody-mediated rejection (AMR) continues to have severe clinical implications and adversely affect graft survival. Therefore, the search for alternative drugs to treat AMR is widely pursued. The first-in-class proteasome inhibitor bortezomib (BZ) is a selective inhibitor of the 26S proteasome, which was initially approved for the treatment of malignant plasma cell disorders. Methods: This review encompasses how our understanding of inhibiting proteasome pathway created the basis of BZ research and important milestones accomplished in AMR treatment in the transplant setting. It further discusses at length the results of clinical studies, the tolerability profile, drug-drug interactions and the perspectives of BZ use in desensitization protocols. Results: Proteasome inhibition can downregulate NF-kappa B activity
- ItemSomente MetadadadosCircadian and time-dependent variability in tacrolimus pharmacokinetics(Blackwell Publishing, 2007-04-01) Park, Sung-In; Felipe, Claudia R.; Pinheiro-Machado, Paula G.; Garcia, Riberto; Tedesco-Silva, Helio; Medina-Pestana, Jose O.; Universidade Federal de São Paulo (UNIFESP)Tacrolimus (TAC) is considered a critical dose drug. the purpose of our study was to investigate circadian and time-dependent changes in TAC pharmacokinetics over the first year after kidney transplantation. Pharmacokinetic (PK) studies were performed in 26 recipients of first living donor kidney transplants at day 7 after morning (a.m.) and evening (p.m.) doses of TAC. Additional serial PK studies were carried out in nine patients at month 6 (M6) and month 12 (M12). Blood samples were collected before 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after TAC administration. Demographics, TAC and adjunctive immunosuppressive doses, hematology, and biochemistry were recorded in each PK study. Mean age was 37 years, body mass index 23 kg/m(2), 58% males, and 85% Caucasian. Higher AUC (231.4 vs. 220 ng.h/mL, P = 0.06) and C-max (34.1 +/- 12.6 vs. 24.4 +/- 9.8 ng/mL, P < 0.001), and lower T-max (1.6 +/- 0.8 vs. 2.7 +/- 2.0 h, P = 0.05) values were observed comparing a.m. and p.m. administrations. Comparing D7, M6 and M12, there was a significant increase in dose-normalized AUC (31.4 +/- 22.2 vs. 50.1 +/- 33 vs. 39.2 +/- 24.4 ng.h/mL/mg, P = 0.005), C-max (4.4 +/- 2.4 vs. 7.8 +/- 3.5 vs. 6.0 +/- 3.3 ng/mL/mg, P < 0.001) and T-max (1.6 +/- 1.1 vs. 1.7 +/- 0.4 vs. 1.8 +/- 0.8 h, P = 0.006), respectively. Over the first year the intraindividual variability of dose-normalized AUC, C-max and C-0 were 82%, 72%, and 90%, respectively. No significant changes were observed comparing inter-individual variability of dose-normalized AUC (21%, 24%, 33%), C-max (46%, 45%, 55%), C-0 (49%, 83%, 81%) at D7, M6 and M12, respectively. We observed a good correlation between a.m. and p.m. TAC AUC (r(2) = 0.90) and C-0 (r(2) = 0.88). Tacrolimus pharmacokinetics display circadian variation suggesting a slower and delayed absorption phase at nighttime. Tacrolimus also showed time-dependent PK changes, suggesting an improvement in absorption during the first 6 months. Despite circadian variation we observed good correlations between a.m. and p.m. TAC AUC (r(2) = 0.90) and C-0 (r(2) = 0.88) and between C-0 and total daily TAC exposure (a.m. + p.m. AUC) suggesting that trough-guided therapeutic monitoring is still a reliable and simple strategy to optimize the clinical use of TAC.
- ItemSomente MetadadadosCompreendendo a vivência da família no processo de transplante renal de intervivos parentes(Universidade Federal de São Paulo (UNIFESP), 2013-11-27) Cruz, Maria Goreti da Silva da [UNIFESP]; Horta, Ana Lucia de Moraes Horta [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Non-communicable chronic disease rates have increased significantly worldwide and end stage chronic kidney disease (CKD) follows the same trend, even in Brazil. Aspects linked to this disease profoundly affect patient’s family life, particularly when intervivostransplant becomes an immediate issue. Objective:To understand the dynamics of family life when their family members face the need for intervivos transplant. Method:A qualitative approach was the choice for this study of clinical cases. Data were collected between August 2012 and February 2013 in interviews having the guiding question “What is it like coping with kidney transplantation when donor and recipient are members of the same family?” Study participants comprised 4 families with 3 of them having siblings as recipient and donor and one parent and child.The reporting of family members were subject to thematic analysis. Results:The following categories were identified: 1) The impact of the chronic renal disease and dialysis on the family life; 2) The facts and feelings experienced by the family during the different phases of kidney transplantation, comprising 3 subcategories: a) The family getting prepared for the transplant; b) The family coping with hospitalization and getting prepared for hospital discharge: c) The family coping with patient’s condition and needs after transplant; 3) Family interaction with healthcare team over the course of the disease and transplant; 4) The family re-thinking the life of the household urged by CKD and kidney transplant; and 5) The family seeking for support in social networks and metaphysical resourcing as an strategy to cope with problems. Discussion:For the members of the participating families, the fact of having one of their kinship affected by CKD, and another as donor in an intervivoskidney transplant was an unpaired and meaningful experience regarding the perception of disease and healing processes Although the participants were going through post-transplant times when study interviews were carried out, their reporting focused initially on CKDdiagnosis and dialysis treatment going on to kidney transplant, starting with the difficulty in finding a compatible donor, and finishing with the current facts experienced. The failure of a relative’s kidneys spurred changes in personal and familial routine in the attemptto tailor an effective adaptive strategy such as redesigning the role of family members, and to activate resources to cope with new requirements. The lack of information on CKDand the inability to recognize its symptoms allowed the condition to worsen tothe point of a kidney transplant being necessary. Participants reported loss of independence of family members, the end of short-, medium-or long-term personal quests, and fear of death. The donor was viewed as the person who would give the patient his/her life back and bring the family members back to their old routine activities. No fears or feelings regarding organ donation was highlighted. Organ recipient’s report included anguish while waiting for the organ needed, and the ambiguous experience of being close to life and death over the course of his/her treatment. Reporting on the healthcare team, the family members pointed out their attentiveness, and competence in providing specialized medical advice , but failed to recognize them as professionals taking part in a multidisciplinary team. The team of nurse was praised for their nursing care, attentiveness, incentive for adhering to treatment and ability to make patients to share their experiences with other patients. The support network was particularlyimportant to families in all phases of treatment regarding both emotional and material aspects. Religious thinking was present during the whole course of the disease helping the study participants decisive occasions in particular. Final Considerations:The experiences reported by the individuals enrolled in the present study evidence that the family itself should also be the focus of a multidisciplinary assistance
- ItemSomente MetadadadosThe emergence of cytomegalovirus resistance to ganciclovir therapy in kidney transplant recipients(Elsevier B.V., 2006-12-20) Nogueira, Eliana; Ozaki, Kikumi S.; Tomiyama, Helena; Granato, Celso F. H.; Camara, Niels O. S.; Pacheco-Silva, Alvaro; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)Transplant recipients that have not been previously exposed to the cytomegalovirus (CMV) are highly susceptible to viral diseases while under immunosuppression therapy. CMV disease requires prolonged therapy, facilitating the emergence of resistant strains. Persistence of positive antigenemia represents clinical evidence of the presence of resistant strains, although its frequency is unknown. These strains may present amino acid deletions or Substitutions in conserved regions of the UL97 protein, point mutations in the DNA polymerase (UL54), or both. in this study we aimed to analyze the prevalence of mutations associated with ganciclovir resistance in transplant recipients. Fifteen kidney transplant recipients and four kidney-pancreas transplant recipients, with a positive and oscillating CMV viremia detected by sequential antigenemia test, were enrolled. the UL97 gene was amplified by Nested-PCR and enzymatically digested in samples of these patients in order to detect mutations in the most common codons, such as 460 (M460V), 594 (A594V) and 595(L595S/F). the end-product fragments were further sequenced. Nine (47.4%) out of 19 patients presented with mutations in UL97 at codons L595S (55.6%), A594V (11.1%), A595F/A594V (11.1%) and L595S/A594V (22.2%). None presented with Mutation at the M460V codon. Renal transplant patients with oscillation in viral load for more than 2 weeks might have developed viral resistance to anti-drug therapy. Its detection might aid physicians in their clinical plan of tapering the patient's immunosuppression. (c) 2006 Elsevier B.V. All rights reserved.
- ItemSomente MetadadadosFetal hemoglobin in patients with chronic renal disease(Assoc Bras Divulg Cientifica, 1996-08-01) Figueiredo, Maria Stella [UNIFESP]; Kimura, Eliza Yuriko Sugano [UNIFESP]; Bordin, Jose Orlando [UNIFESP]; Kerbauy, José [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)To investigate whether hemoglobin (Hb) synthesis is affected by different treatment protocols used for end-stage renal disease, we analyzed the electrophoretic pattern of hemoglobin in 136 adult patients with chronic renal failure. Forty-seven patients were not in a dialysis program (ND), 29 individuals were on continuous ambulatory peritoneal dialysis (CAPD), 33 patients were on hemodialysis (HD), and 27 subjects had received a kidney transplant (KT). We found 3.6% hemoglobin C, 1.4% hemoglobin S and 3.6% beta-thalassemia minor as reported in other studies of Brazilian patients. In addition, we found increased fetal hemoglobin (Hb F) levels in 7.4% of the patients which contrasts with the reported 0.01% prevalence rate of hereditary persistence of Hb F in Brazil. Seven out of ten patients with elevated Hb F belonged to either the CAPD or the KT group. We postulate that stress erythropoiesis is probably the mechanism responsible for the Hb F increase in these patients. However, properly designed clinical studies are still necessary to clarify these questions.
- ItemSomente MetadadadosThe impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring(Blackwell Munksgaard, 2002-08-01) Felipe, C. R.; Silva, H. T.; Machado, P. G.; Garcia, R.; Moreira, SRD; Pestana, J. O.; Universidade Federal de São Paulo (UNIFESP)The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. We sought to determine the influence of ethnic miscegenation on tacrolimus pharmacokinetics and trough concentrations during the first 6 months after transplantation.Methods: Tacrolimus concentrations were measured in blood samples obtained from 22 transplant recipients during the first week of transplant, within pharmacokinetic profiles, and throughout the first 6 months post-transplant, using the Pro Tac II ELISA method. Pharmacokinetic parameters and between- and within-subject blood concentration variability were compared stratifying the total population in two distinct ethnic groups of white (W) and non-white (NW) patients, according to a stringent criterion.Results: Between-subject variability in dose-adjusted concentrations during dosing interval varied from 38.8 to 69.5%. Compared with W patients, NW patients showed higher variability in blood tacrolimus concentrations during dosing interval (37.40 +/- 5.64 vs. 56.95 +/- 11.49, p < 0.001) and lower drug exposures (AUC: 229.4 +/- 55.5 vs. 66.9 +/- 67.1 ng x h/mL, p=0.036). the correlation coefficients (r(2)) between C-0, C-12 or C-max and AUC were 0.83, 0.91 and 0.5, respectively. An equation derived from early time concentrations (C-0, C-1.5 and C-4) accounted for 94% of the variability observed in AUC. Compared with W patients, a higher proportion of tacrolimus blood determinations during the first week were below 10 νg/mL in NW patients (24% vs. 62%, p=0.028). Tacrolimus absorption increased from week 1-4 (1.1 +/- 0.53 vs. 1.73 +/- 0.97 νg/mL/mg, p < 0.0001) but was still showed high between- (41.6-70.4%) and within-subject (18.2-32.5%) variability, regardless of ethnicity, after stabilization.Conclusion: Non-white patients show higher tacrolimus variability and lower drug exposures after transplantation compared with W patients. Therefore, higher initial tacrolimus doses and intensive monitoring are recommended when administering tacrolimus-based immunosupressive therapy to NW patients of this transplant population.
- ItemSomente MetadadadosInfluência de polimorfismos genéticos na farmacocinética de tacrolimo e sirolimo em receptores de transplante renal(Universidade Federal de São Paulo (UNIFESP), 2016-11-30) Tamashiro, Erika Yumi [UNIFESP]; Silva Junior, Helio Tedesco Silva Junior [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introduction: Published studies have shown controversial results about the influence of single nucleotide polymorphisms (SNPs) on the pharmacokinetics of tacrolimus (TAC) and sirolimus (SRL). Objective: This study aimed to evaluate the influence of SNPs in pharmacokinetics of TAC and SRL in stable kidney transplant recipients. Methods: This was a prospective study including 46 stable renal transplant recipients. SRL group consisted of 25 patients receiving TAC, prednisone (PRED) and mycophenolate sodium (MPS) that were converted from TAC to SRL on the 3rd month post-transplant. TAC group consisted of 21 patients that were maintained in treatment with TAC, PRED and MPS. Both groups were genotyped for polymorphisms on CYP3A4, CYP3A5, CYP2C8, ABCB1, ABCC2 and UGT2B7 genes. Results: During 24 months of follow-up, the genetic polymorphisms CYP3A5 rs15524 and ABCB1 rs1045642 showed a significant impact on the pharmacokinetics of SRL; while CYP3A4 rs2242480 and CYP3A5 rs15524 were significant on pharmacokinetics of TAC, at different times after transplantation. The presence of allelic variants of these genes has been associated with different dosescorrected concentrations, which caused constant changes doses of these drugs, for maintenance of blood levels within respective therapeutic ranges. Additionally, the individual effect of each SNP was independent of post-transplantation time, genotype (homozygous or heterozygous) and type of immunosuppression. Conclusion: The presence of certain SNPs resulted in significant pharmacokinetic changes in doses-corrected concentrations of TAC and SRL, due to changes in the metabolism of these drugs. The pre-transplant determination of genotypes associated with therapeutic drug monitoring can be a strategy that increases the effectiveness, because the therapeutic range would be reached earlier, and to decrease the long-term toxicity secondary to drugs.
- ItemSomente MetadadadosNutrition and metabolism in kidney disease(Elsevier B.V., 2006-03-01) Pupim, Lara B. [UNIFESP]; Cuppari, Lilian [UNIFESP]; Ikizier, T. Alp [UNIFESP]; Vanderbilt Univ; Universidade Federal de São Paulo (UNIFESP)
- ItemSomente MetadadadosPrediction of significant liver fibrosis in kidney transplant patients with chronic hepatitis C virus infection: the TX-3 index(Wiley-Blackwell, 2010-06-01) Schiavon, L. L. [UNIFESP]; Carvalho-Filho, R. J. [UNIFESP]; Narciso-Schiavon, J. L. [UNIFESP]; Pinheiro, S. R. [UNIFESP]; Barbosa, D. V. [UNIFESP]; Lanzoni, V. P. [UNIFESP]; Ferraz, M. L. G. [UNIFESP]; Silva, A. E. B. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)HCV infection is highly prevalent among kidney transplant (KT) recipients. the natural history and management of these patients are controversial. We sought to assess the diagnostic value of noninvasive markers of liver fibrosis in KT HCV-infected patients. This cross-sectional study included 102 KT individuals with positive HCV-RNA. Bivariate and multivariate analyses were used to identify variables associated with significant fibrosis (METAVIR >= F2). Significant fibrosis was observed in 20 patients (20%). Time after transplantation, AST level, and platelet count were identified as independent predictors of significant fibrosis. Based on the regression model, a simplified index was devised. the AUROC for the TX-3 model was 0.867 +/- 0.081 (0.909, when adjusted by DANA). Values < 4.0 of TX-3 showed a NPV of 97% and scores > 9.6 exhibited a PPV of 71%. If biopsy indication was restricted to scores in the intermediate range of TX-3, this could have been correctly avoided in 68% of cases. the APRI score provided a correct diagnosis in only 47 individuals (46%) and exhibited lower diagnostic indices for both cutoffs, as compared to the TX-3 index. Comparison of AUROCs showed a trend towards superior diagnostic accuracy for TX-3 over APRI, although the difference between AUROCs did not reach statistical significance (0.867 +/- 0.053 vs 0.762 +/- 0.066, respectively, P = 0.064). in conclusion, significant liver fibrosis can be reliably predicted in KT HCV-infected subjects by simple and widely available parameters. If additional studies confirm our results, this model might obviate the requirement for a liver biopsy in a significant proportion of those patients.
- ItemSomente MetadadadosProlonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation(Wiley-Blackwell, 2012-03-01) Solini, Samantha; Aiello, Sistiana; Cassis, Paola; Scudeletti, Pierangela; Azzollini, Nadia; Mister, Marilena; Rocchetta, Federica; Abbate, Mauro; Pereira, Rafael Luiz [UNIFESP]; Noris, Marina; Mario Negri Inst Pharmacol Res; Ctr Anna Maria Astori; Universidade Federal de São Paulo (UNIFESP)One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation. Prolonged CI was associated with anticipation of proteinuria onset and graft function deterioration (ischemia: 90d; no ischemia: 150d), more severe tubular atrophy, interstitial fibrosis, and glomerulosclerosis, and increased mortality rate (180d survival, ischemia: 0%; no ischemia: 67%). in ischemic allografts, T and B cells were detected very early and were organized in inflammatory clusters. Higher expression of BAFF-R and TACI within the ischemic allografts indicates that B cells are mature and activated. As a consequence of B cell activity, anti-donor antibodies, glomerular C4d and IgG deposition, important features of chronic humoral rejection, appeared earlier in ischemic than in non-ischemic allograft recipients. Thus, prolonged CI time plays a main role in CAI development by triggering acceleration of cellular and humoral reactions of chronic rejection. Limiting CI time should be considered as a main target in kidney transplantation.
- ItemSomente MetadadadosSafety profile comparing azathioprine and mycophenolate in kidney transplant recipients receiving tacrolimus and corticosteroids(Wiley-Blackwell, 2013-08-01) Cristelli, M. P. [UNIFESP]; Tedesco-Silva, H. [UNIFESP]; Medina-Pestana, J. O. [UNIFESP]; Franco, M. F. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Background. Debate is increasing on whether mycophenolic acid (MPA) provides survival benefits comparable to azathioprine (AZA) after renal transplantation.Methods. This retrospective cohort study compared safety and efficacy of AZA (n = 662) vs. MPA (n = 267) in low- immunologicrisk kidney transplant recipients (KTR) receiving tacrolimus (TAC) and steroids between 1998 and 2007. Primary outcomes were treatment discontinuation and infection. Secondary endpoints included survival free from biopsy- proven acute rejection, graft loss, death, and renal function.Results. the 5- year survival free of treatment discontinuation was higher in the MPA compared to the AZA group (74.1% vs. 60.3%, P < 0.001). MPA was discontinued exclusively because of adverse events (16.4%), while AZA was discontinued primarily for lack of efficacy (21.2%). in univariable analysis, MPA was associated with higher incidence of total (561.5 vs. 667.5 episodes/1000 person- year, P < 0.001), bacterial (167 vs. 158 episodes/1000 person- years, P = 0.001), and viral infections (83.2 vs. 100.4 episodes/1000 personyears, P = 0.001), but this association was not confirmed in multivariable analysis. Over 29% of viral infections in the AZA group occurred after conversion to MPA. A high incidence of tuberculosis was observed (2.9 episodes/1000 person- years) with a higher incidence (but not a statistically significant difference) in the AZA group. No significant differences were found in patient survival (90% vs. 89%, P = 0.78) or graft survival (81% vs. 77.7%, P = 0.08), but infection accounted for > 50% of all deaths.Conclusion. the type of antimetabolite, AZA or MPA, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that AZA is still a viable option for low- risk KTR receiving TAC and steroids.