FABIANA AGENA

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  • article 13 Citação(ões) na Scopus
    UPLC-MS/MS assay validation for tacrolimus quantitative determination in peripheral blood T CD4+and B CD19+lymphocytes
    (2018) ROMANO, Paschoalina; FERNANDES, Maria da Luz; EBNER, Persio de Almeida Rezende; OLIVEIRA, Nayara Duarte de; OKUDA, Larissa Mitsue; AGENA, Fabiana; MENDES, Maria Elizabete; SUMITA, Nairo Massakazu; COELHO, Veronica; DAVID-NETO, Elias; GALANTE, Nelson Zocoler
    Monitoring tacrolimus (Tac) exposure in cell matrices enriched with lymphocytes can improve Tac therapeutic drug monitoring (TDM) in solid organ transplant recipients. An UPLC-MS/MS based assay for Tac quantification in peripheral blood T CD4+ and B CD19+ lymphocytes was developed. Peripheral blood mononuclear cells (PBMC) were obtained by density gradient centrifugation and highly purified (purity >90%) T CD4+ and B CD19+ cell suspensions were acquired by magnetic negative selection from whole blood of 6 healthy volunteers. The purity of lymphocyte suspensions was checked by flow cytometry. Tac extraction was performed in a liquid-liquid zinc sulfate, methanol and acetonitrile based medium. Ascomycin was used as internal standard. The equipment used was a Waters (R) Acquity (TM) UPLC system (Waters Corporation, Milford, MA, USA). The chromatographic run was performed on a Waters (R) MassTrak TDM C18 (2.1 x 10 mm) column (Waters Corporation, Milford, MA, USA). at a flow rate of 0.4 mL/min. The instrument was set in electrospray positive ionization mode. The method was validated according to Clinical Laboratory Standard Institute (CLSI) guidelines and showed a high sensitivity and specificity over a range of 0-5.2 ng/mL in PBMC, 0-5.0 ng/mL in T CD4+ Lymphocytes and 0-5.3 ng/mL in B CD19+ lymphocytes. Precision was appropriate with CV of intra-assay quantifications ranging from 4.9 to 7.4%, and of inter-assay quantifications from 7.2 to 13.9%. Limit of detection and quantification were 0.100 and 0.115 ng/mL in PBMC, 0.058 and 0.109 ng/mL in T CD4+ and 0.017 and 0.150 ng/mL in B CD19+ cells. Matrix effect was not significant among all the studied matrices. Samples showed stability for Tac quantification over a period of 90 days either at room temperature or at -30 degrees C storage conditions. The method was applied to clinical samples of 20 kidney transplant recipients. Concentrations ranged from 2.200 to 11.900 ng/mL in whole blood, from 0.005 to 0.570 ng/10(6) cells in PBMC, from 0.081 to 1.432 ng/10(6) cells in T CD4+, and from 0.197 to 1.564 ng/10(6) cells in B CD19+ cell matrices. The method has potential applicability for Tac TDM in solid organ transplant recipients.
  • article 9 Citação(ões) na Scopus
    The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: a six-year follow-up study
    (2012) DAVID-NETO, Elias; SOUZA, Patricia Soares; PANAJOTOPOULOS, Nicolas; RODRIGUES, Helcio; VENTURA, Carlucci Gualberto; DAVID, Daisa Silva Ribeiro; LEMOS, Francine Brambate Carvalhinho; AGENA, Fabiana; NAHAS, William Carlos; KALIL, Jorge Elias; CASTRO, Maria Cristina Ribeiro
    OBJECTIVE: The significance of pretransplant, donor-specific antibodies on long-term patient outcomes is a subject of debate. This study evaluated the impact and the presence or absence of donor-specific antibodies after kidney transplantation on short-and long-term graft outcomes. METHODS: We analyzed the frequency and dynamics of pretransplant donor-specific antibodies following renal transplantation from a randomized trial that was conducted from 2002 to 2004 and correlated these findings with patient outcomes through 2009. Transplants were performed against a complement-dependent T-and B-negative crossmatch. Pre- and posttransplant sera were available from 94 of the 118 patients (80%). Antibodies were detected using a solid-phase (Luminex (R)), single-bead assay, and all tests were performed simultaneously. RESULTS: Sixteen patients exhibited pretransplant donor-specific antibodies, but only 3 of these patients (19%) developed antibody-mediated rejection and 2 of them experienced early graft losses. Excluding these 2 losses, 6 of 14 patients exhibited donor-specific antibodies at the final follow-up exam, whereas 8 of these patients (57%) exhibited complete clearance of the donor-specific antibodies. Five other patients developed ""de novo'' posttransplant donor-specific antibodies. Death-censored graft survival was similar in patients with pretransplant donor-specific and non-donor-specific antibodies after a mean follow-up period of 70 months. CONCLUSION: Pretransplant donor-specific antibodies with a negative complement-dependent cytotoxicity crossmatch are associated with a risk for the development of antibody-mediated rejection, although survival rates are similar when patients transpose the first months after receiving the graft. Our data also suggest that early posttransplant donor-specific antibody monitoring should increase knowledge of antibody dynamics and their impact on long-term graft outcome.
  • article 18 Citação(ões) na Scopus
    Seroconversion of 2009 pandemic influenza A (H1N1) vaccination in kidney transplant patients and the influence of different risk factors
    (2013) AZEVEDO, L. S.; GERHARD, J.; MIRAGLIA, J. L.; PRECIOSO, A. R.; TIMENETSKY, M. dC S. Tavares; AGENA, F.; GAMBA, C.; YASUDA, M. A. Shikanai; DAVID-NETO, E.; PIERROTTI, L.
    BackgroundInfluenza may present a high morbidity and mortality in solid organ transplanted patients (SOTP). Annual influenza virus vaccine is recommended for SOTP. However, low levels of seroconversion in SOTP have been reported. The aim of this study was to evaluate the immunogenicity of 2009 pandemic influenza A (H1N1) - A(H1N1)pdm09 - vaccine in kidney transplant patients and to analyze which features might affect seroconversion. MethodsThis study was conducted from March to August 2010 at the Renal Transplantation Unit of University of SAo Paulo, Brazil. A total of 85 renal transplant patients attending the outpatient unit received one 15-g intramuscular dose of A(H1N1)pdm09 influenza vaccine (reassortant vaccine virus A/California/7/2009 [NYMC X-179A]). Blood samples were collected immediately before and 21days after the vaccine was given. Antibody response was measured by the standard hemagglutination-inhibition (HI) assay. The primary immunogenicity endpoint for this study was seroconversion in previously seronegative patients (HI titers <1:40), and the secondary endpoint was the identification of features that could affect seroconversion in this population. ResultsFive (5.9%) patients presented HI titers prevaccination 1:40 and were excluded from further analysis. Seroconversion in previously negative patients occurred in 27 (34%) of 80 patients. Prevaccination HI titers geometrical mean was 5.8 and postvaccination 19.6 (ratio 3.4). Significant seroconversion rate factors were female gender, non-Caucasian ethnicity, and post-transplant time before vaccination. No impact was seen on seroconversion for age, donor type, tacrolimus and cyclosporine blood levels, renal function, or blood lymphocyte counts. Mycophenolate (MPA) showed a lower rate of seroconversion when compared with azathioprine. Tacrolimus and cyclosporine had similar seroconversion rates. Sirolimus use was associated with the highest rate of seroconversion, although these patient numbers were low. Immunosuppresssion containing MPA was considerably less effective in seroconversion than drug combinations with no MPA. Patients receiving sirolimus had more chance of seroconversion. HI titers geometric means pre/post vaccine were as follows: MPA (n=56): 5.8/12.8; tacrolimus (n=50): 5.9/16.2; cyclosporine (n=18): 5.4/24.2; azathioprine (n=19): 6.2/51.6; and sirolimus (n=6): 8/80. By univariate analysis, being female and non-White were variables associated with 3.3 times more chance of seroconversion than being male and White. In the multivariate analysis, the variables remaining in the model showed similar hazard ratios. ConclusionsIn this study, the monovalent A(H1N1)pdm09 influenza vaccine demonstrated low rates of seroconversion, particularly in patients on MPA, but with potentially higher response rates in patients on sirolimus.
  • article 20 Citação(ões) na Scopus
    Cytomegalovirus prophylaxis in seropositive renal transplant recipients receiving thymoglobulin induction therapy: Outcome and risk factors for late CMV disease
    (2018) JR, Jose O. Reusing; FEITOSA, Emanoela B.; AGENA, Fabiana; PIERROTTI, Ligia C.; AZEVEDO, Luiz S. F.; KOTTON, Camille N.; DAVID-NETO, Elias
    BackgroundAnti-thymocyte globulin (ATG) therapy is a risk factor for cytomegalovirus (CMV) disease in renal transplant (RTx) recipients and therefore antiviral prophylaxis is commonly used. We evaluated the outcome of our current policy of 90days of CMV prophylaxis in seropositive recipients given ATG and the risk factors for the occurrence of CMV disease after prophylaxis. MethodsWe studied a retrospective cohort of 423 RTx (2010-2014) CMV-seropositive adults given ATG induction therapy. Results54 (13%) patients developed CMV disease at a median of 163days after transplant, of which 29 (54%) had viral syndrome and 25 (46%) had invasive disease. Median prophylaxis time (94days) and immunosuppressive drugs were similar between groups (CMV vs no-CMV). Those with CMV disease had more deceased donors and higher donor age, lower lymphocyte count, and lower median eGFR at day 90. Multivariable logistic regression analysis at day 90 and 180 found that eGFR 40ml/min/1.73m(2) (but not acute rejection) was associated with late CMV disease. In a separate validation cohort of 124 patients with 8% late CMV disease, eGFR 45 and lymphocyte count 800cells/mm(3) at the end of prophylaxis remained predictive of late CMV disease occurrence. ConclusionsThese data indicate that antiviral prophylaxis adequately prevented CMV in seropositive recipients given ATG, but late disease still occurred. Low eGFR and low lymphocyte count at the end of prophylaxis may help identify patients at higher risk of CMV disease.
  • article 17 Citação(ões) na Scopus
    Diminished Mycophenolic Acid Exposure Caused by Omeprazole May Be Clinically Relevant in the First Week Posttransplantation
    (2012) DAVID-NETO, Elias; TAKAKI, Kelly M.; AGENA, Fabiana; ROMANO, Paschoalina; SUMITA, Nairo M.; MENDES, Maria E.; NERI, Leticia Aparecida Lopes; NAHAS, William C.
    Background: Some studies have reported a decreased absorption of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) in renal transplanted (RTx) patients under proton-pump inhibitors (PPIs). There is still a lack of information regarding (1) whether this effect occurs when MMF is administered with either tacrolimus or cyclosporine A [calcineurin inhibitors (CNIs)], (2) whether the effect has the same amplitude during the first year after RTx, and finally (3) whether this decrease in exposure is clinically relevant. Methods: We retrospectively analyzed the omeprazole effect in 348 12-hour pharmacokinetic samplings [area under the curve (AUC) 0-12h] performed on days 7, 14, 30, 60, 180, and 360 after RTx in 77 patients who participated in previous trials. Results: For all periods, the groups with and without PPI did not differ in all variables. By mixed-model analysis of variance, PPI reduced the MPA AUC(0-12h) (P < 0.0008) in the patients under both CNIs mainly due to decreased absorption (P = 0.049). In the tacrolimus group, a lower exposure seemed also due to a decreased MPA reabsorption at 10-12 hours. The PPI effect remains throughout the first year but was clinically more important on day 7. By Cox analysis, the use of PPI was associated with a 25% less chance of being adequately exposed to MPA (95% confidence interval 0.58-0.99, P = 0.04). Similarly, the number of patients underexposed to MPA (AUC < 30 ng.h/mL) was higher at most periods in the PPI group but again not statistically significant. Conclusions: These data indicate that PPI decreases the MPA exposure when associated with both CNIs but particularly in the first week after RTx. In this period, the MMF dose should be increased. This effect lasts throughout the first year but does not seem to be clinically relevant after the first week.
  • article 33 Citação(ões) na Scopus
    Aging and End Stage Renal Disease Cause A Decrease in Absolute Circulating Lymphocyte Counts with A Shift to A Memory Profile and Diverge in Treg Population
    (2019) FREITAS, Geraldo Rubens Ramos; FERNANDES, Maria da Luz; AGENA, Fabiana; JALUUL, Omar; SILVA, Sergio Colenci; LEMOS, Francine Brambate Carvalhinho; COELHO, Veronica; DAVID-NETO, Elias; GALANTE, Nelson Zocoler
    There is a growing number of elderly kidney transplant (Ktx) recipients. Elderly recipients present lower acute rejection rates but higher incidence of infection and malignancies. Aging per se seems to result in a shift to memory profile and chronic kidney disease (CKD) in premature immunological aging. Understanding aging and CKD effects on the immune system can improve elderly Ktx immunosuppression. We analyzed the effects of aging and CKD in the immune system, comparing healthy adults (HAd) (n=14, 26 +/- 2y), healthy elderly (HEld) (n=15, 79 +/- 7y), end stage renal disease (ESRD) adults (EnAd) (n=18, 36 +/- 7y) and ESRD elderly (EnEld) (n=31, 65 +/- 3y) prior to Ktx regarding their naive, memory and regulatory T and B peripheral lymphocytes. Aging and ESRD presented additive effect decreasing absolute numbers of B and T-lymphocytes, affecting memory, naive and regulatory subsets without synergic effect. Both resulted in higher percentages of T memory subsets and opposing effects on regulatory T (TREG) subsets, higher percentage in aging and lower in ESRD. Combined effect of aging and ESRD also resulted in higher regulatory B cell percentages. In addition to global lymphopenia and TCD4(+) memory shift in both aging and ESRD, aging shifts to an immunoregulatory profile, inducing a increase in TREG percentages, contrasting with ESRD that decreases TREGs. Differential immunosuppression regimens for elderly Ktx may be required.
  • article 41 Citação(ões) na Scopus
    Recurrence of IgA Nephropathy after Kidney Transplantation in Adults
    (2021) UFFING, Audrey; PEREZ-SAEZ, Maria Jose; JOUVE, Thomas; BUGNAZET, Mathilde; MALVEZZI, Paolo; MUHSIN, Saif A.; LAFARGUE, Marie-Camille; REINDL-SCHWAIGHOFER, Roman; MORLOCK, Alina; OBERBAUER, Rainer; BUXEDA, Anna; BURBALLA, Carla; PASCUAL, Julio; MOOS, Seraina von; SEEGER, Harald; MANNA, Gaetano La; COMAI, Giorgia; BINI, Claudia; RUSSO, Luis Sanchez; FAROUK, Samira; NISSAISORAKARN, Pitchaphon; PATEL, Het; AGRAWAL, Nikhil; MASTROIANNI-KIRSZTAJN, Gianna; MANSUR, Juliana; TEDESCO-SILVA, Helio; VENTURA, Carlucci Gualberto; AGENA, Fabiana; DAVID-NETO, Elias; AKALIN, Enver; ALANI, Omar; MAZZALI, Marilda; MANFRO, Roberto Ceratti; BAUER, Andrea Carla; WANG, Aileen X.; CHENG, Xingxing S.; SCHOLD, Jesse D.; BERGER, Stefan P.; CRAVEDI, Paolo; RIELLA, Leonardo V.
    Background and objectives In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. Design, setting, participants, & measurements We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 ""The Post-Transplant Glomerular Disease"" study centers in Europe, North America, and South America. Results Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazardratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. Conclusions In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.
  • article 25 Citação(ões) na Scopus
    Home blood pressure (BP) monitoring in kidney transplant recipients is more adequate to monitor BP than office BP
    (2011) AGENA, Fabiana; PRADO, Elisangela dos Santos; SOUZA, Patricia Soares; SILVA, Giovanio Vieira da; LEMOS, Francine Brambate Carvalhinho; MION JR., Decio; NAHAS, William Carlos; DAVID-NETO, Elias
    Background. Hypertension is highly prevalent among kidney transplantation recipients and considered as an important cardiovascular risk factor influencing patient survival and kidney graft survival. Aim. Compare the blood pressure (BP) control in kidney transplant patients through the use of home blood pressure monitoring (HBPM) is more comparable with the results of ambulatory blood pressure monitoring compared to the measurement of office blood pressure. Methods. From March 2008 to April 2009 prospectively were evaluated 183 kidney transplant recipients with time after transplantation between 1 and 10 years. Patients underwent three methods for measuring BP: office blood pressure measurement (oBP), HBPM and ambulatory blood pressure monitoring (ABPM). Results. In total, 183 patients were evaluated, among them 94 were men (54%) and 89 women (46%). The average age was 50 6 11 years. The average time of transplant was 57 6 32 months. Ninety-nine patients received grafts from deceased donors (54%) and 84 were recipients of living donors (46%). When assessed using oBP, 56.3% presented with uncontrolled and 43.7% with adequate control of BP with an average of 138.9/82.3 +/- 17.8/12.1 mmHg. However, when measured by HBPM, 55.2% of subjects were controlled and 44.8% presented with uncontrolled BP with an average of 131.1/78.5 +/- 17.4/8.9 mmHg. Using the ABPM, we observed that 63.9% of subjects were controlled and 36.1% of patients presented uncontrolled BP with an average 128.8/80.5 +/- 12.5/8.1 mmHg. We found that the two methods (oBP and HBPM) have a significant agreement, but the HBPM has a higher agreement that oBP, confirmed P = 0.026. We found that there is no symmetry in the data for both methods with McNemar test. The correlation index of Pearson linear methods for the ABPM with the other two methods were 0.494 for office measurement and 0.768 for HBPM, best value of HBPM with ABPM. Comparing the errors of the two methods by paired t-test, we obtained the descriptive level of 0.837. Looking at the receiver operating characteristic curve for BP measurements in each method, we observed that oBP is lower than those obtained by HBPM in relation to ABPM. Conclusion. We conclude that the results obtained with HBPM were closer to the ABPM results than those obtained with BP obtained at oBP, being more sensitive to detect poor control of hypertension in renal transplant recipients.
  • article 2 Citação(ões) na Scopus
    BK virus salivary shedding and viremia in renal transplant recipients
    (2019) SARMENTO, Dmitry Jose de Santana; PALMIERI, Michelle; GALVAO, Gustavo Souza; TOZETTO-MENDOZA, Tania Regina; CANTO, Cynthia Motta do; PIERROTTI, Ligia Camera; DAVID-NETO, Elias; AGENA, Fabiana; GALLOTTINI, Marina; PANNUTI, Claudio Sergio; FINK, Maria Cristina Domingues; BRAZ-SILVA, Paulo Henrique
    Objectives: This study aimed to verify the presence of polyomavirus BK (BKPyV) in the saliva of kidney transplant recipients and to correlate it with blood viremia. Material and Methods: We have conducted a cross-sectional study with a sample involving 126 renal transplant recipients. 126 samples of saliva and 52 samples of blood were collected from these patients. Detection and quantification of BKPyV were performed using a real-time PCR. To compare the presence of BKPyV in blood and saliva, the binomial proportion test was used. To verify associations between salivary shedding BKPyV and post-transplant periods (in months), the Mann-Whitney test was used. Spearman's correlation was used to correlate the viral load in the saliva with blood of kidney transplant recipients. Results: The mean age of the study group was 51.11 +/- 12.45 years old, and 69 participants (54.8%) were female, with a mean post-transplantation time of 4.80 +/- 6.04 months. BKPyV was quantified in several samples of saliva and blood, with medians of 1,108 cp/mL and 1,255 cp/mL, respectively. Only 16/52 (30.8%) participants presented BKPyV in blood, and 59/126 (46.8%) excreted the virus in saliva (p=0.004). BKPyV shedding was found in patients at a shorter post-transplantation period (3.86 +/- 5.25, p=0.100). A weak correlation was observed between viral quantification in saliva and blood (Spearman's correlation coefficient=0.193). Conclusion: The results of this study suggested that, although saliva excretes more BKPyV than blood, there is no reliable correlation between salivary shedding and blood viremia, showing two independent compartments of viral replication.
  • article 3 Citação(ões) na Scopus
    Discovery and cross-validation of peripheral blood and renal biopsy gene expression signatures from ethnically diverse kidney transplant populations
    (2019) VENTURA, Carlucci G.; WHISENANT, Thomas; GELBART, Terri; DAVID, Daisa S. R.; AGENA, Fabiana; SALOMON, Daniel R.; DAVID-NETO, Elias; KURIAN, Sunil M.
    We determined peripheral blood (PB) and biopsy (Bx) RNA expression signatures in a Brazilian and US cohort of kidney transplant patients. Phenotypes assigned by precise histology were: acute rejection (AR), interstitial fibrosis/tubular atrophy/chronic rejection (CR), excellent functioning transplants (TX), and glomerulonephritis recurrence (GN). Samples were analyzed on microarrays and profiles from each cohort were cross-validated on the other cohort with similar phenotypes. We discovered signatures for each tissue: (1) AR vs TX, (2) CR vs TX, and (3) GN vs TX using the Random Forests algorithm. We validated biopsies signatures of AR vs TX (area under the curve [AUC] 0.97) and CR vs TX (AUC 0.87). We also validated both PB and Bx signatures of AR vs TX and CR vs TX with varying degrees of accuracy. Several biological pathways were shared between AR and CR, suggesting similar rejection mechanisms in these 2 clinical phenotypes. Thus, we identified gene expression signatures for AR and CR in transplant patients and validated them in independent cohorts of significantly different racial/ethnic backgrounds. These results reveal that there are strong unifying immune mechanisms driving transplant diseases and identified in the signatures discovered in each cohort, suggesting that molecular diagnostics across populations are feasible despite ethnic and environmental differences.