IRENE DE LOURDES NORONHA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
78 resultados
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- Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active- controlled clinical trial(2023) HEERSPINK, Hiddo J. L.; RADHAKRISHNAN, Jai; ALPERS, Charles E.; BARRATT, Jonathan; BIELER, Stewart; DIVA, Ulysses; INRIG, Jula; KOMERS, Radko; MERCER, Alex; NORONHA, Irene L.; RHEAULT, Michelle N.; ROTE, William; ROVIN, Brad; TRACHTMAN, Howard; TRIMARCHI, Hernin; WONG, Muh Geot; PERKOVIC, Vlado; PROTECT InvestigatorsBackground Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety.Methods PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged >= 18 years) with biopsy-proven IgA nephropathy and proteinuria of 1 center dot 0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1 center dot 73 m2 and >= 60 mL/min per 1 center dot 73 m2) and urine protein excretion at screening (<= 1 center dot 75 g/day and >1 center dot 75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein- creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850.Findings Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49 center dot 8%) than the irbesartan group (-15 center dot 1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0 center dot 59; 95% CI 0 center dot 51-0 center dot 69; p<0 center dot 0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups.Interpretation Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan.
conferenceObject Effects of Human Amniotic Fluid Stem Cells in a Model of Aorta Allograft Vasculopathy(2012) SANTANA, A. C.; DELLE, H.; CAVAGLIERI, R. C.; LOPES, M. A. B.; FRANCISCO, R. P. V.; ZUGAIB, M.; BYDLOWSKI, S. P.; NORONHA, I. L.Chronic allograft vasculopathy (CAV) is an important cause of graft loss. Considering the immune-in flammatory events involved in the development of CAV, therapeutic approaches to target this process are of relevance. Human amniotic fluid derived stem cells (hAFSC), a class of fetal, pluripotent stem cells with intermediate characteristics between embryonic and adult stem cells display immunomodulatory properties. hAFSC express mesenchymal and embryonic markers, show high proliferation rates, but do not induce tumor formation and their use does not raise ethical issues. Thus, we sought to investigate the effect of hAFSC on CAV in a model of aorta transplantation. Orthotopic aorta transplantation was performed using Fisher (F344) rats as donors and Lewis rats as recipients. Rats were divided into 3 groups: syngeneic (SYNG), untreated F344 receiving aorta from F344 (n=8); allogeneic (ALLO), Lewis rats receiving allogeneic aorta from F344 (n=8); and ALLO+hAFSC, ALLO rats treated with hAFSC (106 cells) (n=8). Histological analysis and immunohistochemistry were performed 30 days post transplantation. ALLO developed a robust aortic neointimal formation, accompanied by a high number of ED1+ and CD43+ cells, and enhanced expression of α-SMA in theneointima. Treatment with hAFSC diminished neointimal thickness and induced a significant decrease of ED1+, CD43+ cells and α-SMA expression in the neointima. Comparative analyses in the differents groups PARAMETERS SYNG ALLO ALLO+hAFSC Neointima thickness (μm) 0±0 208.7±25.4* 180.7±23.7* ED-1+ (cells/mm2) 0±0 4.845±841* 1.100±276*, #CD43+ (cells/mm2) 0±0 4.064±563* 1.080±309*,#α-SMA (%) 0±0 25±6* 8±3*, #*p<0.05 vs. SYNG; #P<0.05 vs. ALLO These preliminary results showed that hAFSC suppressed inflammation and myofibroblast migration to the intima, which may contribute to ameliorate vascular changes in CAV.conferenceObject Paclitaxel Delivered With Nanoparticles Inhibits Neointimal Formation and Local Inflammation in Experimental Chronic Allograft Vasculopathy(2014) PEPINELI, R.; SANTANA, A.; TIEME, A.; DEUS, D.; MARANHAO, R.; NORONHA, I.- Transplante renal em pacientes infectados pelo HIV(2011) MORENO, Carina Nilsen; SIQUEIRA, Raquel Cruzeiro de; NORONHA, Irene L.Kidney transplantation in HIV infected patients This review presents current considerations for renal transplantation in HIV patients. In the last decade, with the advent of highly active antiretroviral therapy (HAART), life expectancy of patients infected with human immunodeficiency virus (HIV) has significantly improved, showing a marked decrease in the rates of morbidity and mortality in this population. In this setting, the number of HIV-positive patients with end stage chronic kidney disease requiring dialysis is progressively growing. Kidney transplantation, previously considered as absolute contraindication for HIV-infected patients is currently, in the HAART era, considered a possible treatment alternative. Concerns for the effects of immunosuppressive drugs in these patients and the possible effects on progression of HIV disease, in addition to the risk of opportunistic infections and cancer development are widely discussed. Clinical experience in the HAART era shows that use of immunosuppressive drugs does not adversely affect HIV-seropositive patients. Furthermore, several transplant centers have reported improved patient and graft outcomes for kidney transplant recipients infected with HIV. In summary, results obtained so far are encouraging, supporting that renal transplantation, following specific selection criteria, can be considered an alternative of renal replacement therapy in HIV-infected patients.
- Regulatory/inflammatory cellular response discrimination in operational tolerance(2019) CARMONA, Priscila; MEDINA-ARMENTEROS, Yordanka; CABRAL, Amanda; MONTEIRO, Sandra Maria; FONSECA, Simone Goncalves; FARIA, Ana Caetano; LEMOS, Francine; SAITOVITCH, David; NORONHA, Irene L.; KALIL, Jorge; COELHO, VeronicaBackground. Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation-donor antigens, pathogenic antigens and self-antigens. Methods. We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. Results. We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. Conclusions. The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-gamma and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.
- Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury(2017) RODRIGUES, Camila Eleuterio; CAPCHA, Jose Manuel Condor; BRAGANCA, Ana Carolina de; SANCHES, Talita Rojas; GOUVEIA, Priscila Queiroz; OLIVEIRA, Patricia Aparecida Ferreira de; MALHEIROS, Denise Maria Avancini Costa; VOLPINI, Rildo Aparecido; SANTINHO, Mirela Aparecida Rodrigues; SANTANA, Barbara Amelia Aparecida; CALADO, Rodrigo do Tocantins; NORONHA, Irene de Lourdes; ANDRADE, LuciaBackground: Mesenchymal stromal cells (MSCs) represent an option for the treatment of acute kidney injury (AKI). It is known that young stem cells are better than are aged stem cells at reducing the incidence of the senescent phenotype in the kidneys. The objective of this study was to determine whether AKI leads to premature, stress-induced senescence, as well as whether human umbilical cord-derived MSCs (huMSCs) can prevent ischaemia/reperfusion injury (IRI)-induced renal senescence in rats. Methods: By clamping both renal arteries for 45 min, we induced IRI in male rats. Six hours later, some rats received 1 x 10(6) huMSCs or human adipose-derived MSCs (aMSCs) intraperitoneally. Rats were euthanised and studied on post-IRI days 2, 7 and 49. Results: On post-IRI day 2, the kidneys of huMSC-treated rats showed improved glomerular filtration, better tubular function and higher expression of aquaporin 2, as well as less macrophage infiltration. Senescence-related proteins (beta-galactosidase, p21Waf1/Cip1, p16INK4a and transforming growth factor beta 1) andmicroRNAs (miR-29a and miR-34a) were overexpressed after IRI and subsequently downregulated by the treatment. The IRI-induced pro-oxidative state and reduction in Klotho expression were both reversed by the treatment. In comparison with huMSC treatment, the treatment with aMSCs improved renal function to a lesser degree, as well as resulting in a less pronounced increase in the renal expression of Klotho and manganese superoxide dismutase. Treatment with huMSCs ameliorated long-term kidney function after IRI, minimised renal fibrosis, decreased beta-galactosidase expression and increased the expression of Klotho. Conclusions: Our data demonstrate that huMSCs attenuate the inflammatory and oxidative stress responses occurring in AKI, as well as reducing the expression of senescence-related proteins and microRNAs. Our findings broaden perspectives for the treatment of AKI.
- Academic health centers: integration of clinical research with healthcare and education. Comments on a workshop(2018) ARAI, Roberto Jun; NORONHA, Irene de Lourdes; NICOLAU, Jose Carlos; SCHMIDT, Charles; ALBUQUERQUE, Gustavo Moreira de; MAHAFFEY, Kenneth W.; KRIEGER, Eduardo Moacyr; AULER JUNIOR, Jose Otavio Costa
- Hyperbaric Oxygen Therapy Induces Kidney Protection in an Ischemia/Reperfusion Model in Rats(2012) RAMALHO, R. J.; OLIVEIRA, P. S. T. de; CAVAGLIERI, R. C.; SILVA, C.; MEDEIROS, P. R. B.; MARTINI FILHO, D.; POLI-DE-FIGUEIREDO, L. F.; NORONHA, I. L.Ischemia/reperfusion (I/R) injury remains a major cause of graft dysfunction, which impacts short- and long-term follow-up. Hyperbaric oxygen therapy (HBO), through plasma oxygen transport, has been currently used as an alternative treatment for ischemic tissues. The aim of this study was to analyze the effects of HBO on kidney I/R injury model in rats, in reducing the harmful effect of I/R. The renal I/R model was obtained by occluding bilateral renal pedicles with nontraumatic vascular clamps for 45 minutes, followed by 48 hours of reperfusion. HBO therapy was delivered an hypebaric chamber (2.5 atmospheres absolute). Animals underwent two sessions of 60 minutes each at 6 hours and 20 hours after initiation of reperfusion. Male Wistar rats (n = 38) were randomized into four groups: sham, sham operated rats; Sham+HBO, sham operated rats exposed to HBO; I/R, animals submitted to I/R; and I/R+HBO, I/R rats exposed to HBO. Blood, urine, and kidney tissue were collected for biochemical, histologic, and immunohistochemical analyses. The histopathological evaluation of the ischemic injury used a grading scale of 0 to 4. HBO attenuated renal dysfunction after ischemia characterized by a significant decrease in blood urea nitrogen (BUN), serum creatinine, and proteinuria in the I/R+HBO group compared with I/R alone. In parallel, tubular function was improved resulting in significantly lower fractional excretions of sodium and potassium. Kidney sections from the I/R plus HBO group showed significantly lower acute kidney injury scores compared with the I/R group. HBO treatment significantly diminished proliferative activity in I/R (P < .05). There was no significant difference in macrophage infiltration or hemoxygenase-1 expression. In conclusion, HBO attenuated renal dysfunction in a kidney I/R injury model with a decrease in BUN, serum creatinine, proteinuria, and fractional excretion of sodium and potassium, associated with reduced histological damage.
- Expression Patterns of B Cells in Acute Kidney Transplant Rejection(2014) CARPIO, Virna Nowotny; NORONHA, Irene de Lourdes; MARTINS, Hugo Ludovico; JOBIM, Luiz Fernando; GIL, Beatriz Chamun; KUELZER, Adriane Silva; LORETO, Melina da Silva; GONCALVES, Luiz Felipe Santos; MANFRO, Roberto Ceratti; VERONESE, Francisco VerissimoObjectives: To evaluate B-cell expression patterns and association with function and survival in dysfunctional kidney allografts. Materials and Methods: There were 110 kidney transplant recipients included who had for-cause biopsies. Demographic and transplant data were collected. Immunostaining for B cells, plasma cells, and C4d was performed by the immunoperoxidase technique in paraffin-embedded samples. Circulating antihuman leukocyte antigen donorspecific antibodies were detected in a single-antigen assay at biopsy. The main outcomes were kidney graft survival and function. The patients were evaluated in 3 groups according to the Banff classification: no rejection (40 patients), T-cell-mediated rejection (50 patients), and antibody-mediated rejection (20 patients). Results: The CD138-positive plasma cell-rich infiltrates predominated in antibody-mediated rejection and were associated with stronger reactivity against panel antibodies (r = 0.41; P <= .001) and positive donor-specific antibodies (r = 0.32; P <= .006). The CD20-positive lymphocytes were associated with T-cell-mediated rejection, increased human leukocyte antigen mismatch, and frequency of retransplant. The CD138-positive cell infiltrates also were significantly greater in patients who had late than early rejection. There was no correlation between cellular CD20 and CD138 expression, and neither CD20 nor CD138 predicted worse graft function or survival. Other markers of antibody-mediated rejection such as C4d and donor-specific antibodies were associated with worse graft function and survival at 4 years after transplant. In multivariate analysis, C4d was the only risk factor associated with graft loss. Conclusions: After kidney transplant, CD20-positive B-cell infiltrates were associated with T-cell-mediated rejection, and CD138-positive plasma cells were associated with antibody-mediated rejection. Graft loss was associated with the presence of C4d.
conferenceObject ACTION3 PHASE 3 STUDY: EVALUATING A NOVEL THERAPEUTIC STRATEGY OF A CCR2 INHIBITOR (DMX-200) WITH ANGIOTENSIN RECEPTOR BLOCKADE IN FSGS(2023) SOMAN, Ash; BARRATT, Jonathan; FORNONI, Alessia; INKER, Lesley; NORONHA, Irene L.; SMITH, Alisha; TRIMARCHI, Hernan; WAHBA, Mona; WONG, Muh; HEERSPINK, Hiddo Lambers