LUIZ FERNANDO ONUCHIC
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
8 resultados
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- Cardiac structural and functional findings in Persian cats with autosomal dominant polycystic kidney disease(2020) GUERRA, Juliana Mariotti; PELLEGRINO, Arine; DANIEL, Alexandre Goncalves Teixeira; FREITAS, Mariana Ferreira de; CARDOSO, Natalia Cavalca; PESSOA, Rebecca Bastos; LUCCA, Gabriel Garone de; LARSSON, Maria Helena Matiko Akao; ONUCHIC, Luiz Fernando; QUEIROGA, Felisbina Luisa; COGLIATI, BrunoAutosomal dominant polycystic kidney disease (ADPKD) has been related to left ventricular structural and functional abnormalities in human patients. The present study aimed to evaluate the cardiac structural and functional findings in Persian cats with ADPKD. Client-owned ADPKD (n=12) and non-ADPKD (n 12) Persian cats were enrolled in this study. The animals underwent echo- and electrocardiographic (ECG) examinations, and non-invasive measurements of systolic blood pressure (SBP) were obtained. Both groups were similar regarding hematological and biochemical parameters, including white blood cell count and levels of blood urea nitrogen, creatinine, total protein and thyroxine. There were no differences related to ECG parameters between ADPKD and non-ADPKD cats. Left ventricular hypertrophy (LVH) was demonstrated in 6/12 (50%) normotensive ADPKD cats with preserved renal function. There were no differences between animal groups regarding the echocardiographic parameters, including left ventricular ejection fraction and shortening fraction; however, basal interventricular septal thickness at end-diastole near the left ventricular outflow tract and aortic artery flow velocity showed slightly elevated values in ADPKD-cats. Our study revealed that Persian cats with ADPKD do not reproduce the functional and structural cardiac phenotype reported in human patients; however, large-scale cohort studies are necessary to distinguish the possibilities of a true linkage between ventricular myocardial hypertrophy and ADPKD in this breed.
- KLOTHO polymorphisms and age-related outcomes in community-dwelling older subjects: The SAo Paulo Ageing & Health (SPAH) Study(2020) PEREIRA, Rosa Maria R.; FREITAS, Thiago Quadrante; FRANCO, Andre Silva; TAKAYAMA, Liliam; CAPARBO, Valeria F.; DOMICIANO, Diogo S.; MACHADO, Luana G.; FIGUEIREDO, Camille P.; MENEZES, Paulo R.; ONUCHIC, Luiz Fernando; CASTRO, Isac deDefective KLOTHO gene expression in mice led to a syndrome resembling human ageing. This study evaluated three KLOTHO polymorphisms, namely G395A, C1818T, and C370S, in an elderly population (mean age of 73 years) and their associations with ageing-related outcomes (cardiovascular events, kidney function, osteoporosis, sarcopenia) and mortality. Estimated glomerular filtration rates (eGFR) was lower in subjects with 1818TT (P=0.047) and 370SS (P=0.046) genotypes. The 1818TT genotype (P=0.006) and 1818T allele were associated with higher frequency of myocardial infarction (MI) (CC:1.7% vs. CT+TT:7.0%; P=0.002). The 370SS genotype was associated with lower stroke frequency (P=0.001). MI (OR 3.35 [95% CI: 1.29-8.74]) and stroke (OR 3.64 [95% CI: 1.48-8.97]) were associated with mortality. Regarding MI, logistic regression showed 1818T allele was a risk factor for death-related MI (OR 4.29 [95% CI: 1.60-11.52]; P=0.003), while 370C was protective (OR 0.03 [95% CI: 0.01-0.08]; P<0.001). Regarding stroke, the 395A and 370C alleles were protective factors (respectively: OR 0.28 [95% CI: 0.20-0.80]; P=0.018; OR 0.10 [95% CI: 0.05-0.18]; P<0.001). This is the first study to determine potential associations between common ageing-related outcomes/mortality and KLOTHO polymorphisms. The 1818T allele was a risk factor for MI-related death. The 395A and 370C alleles were protective factors for stroke-related death in elderly from community.
- Identification of housekeeping genes for microRNA expression analysis in kidney tissues of Pkd1 deficient mouse models(2020) MUNOZ, J. J.; ANAUATE, A. C.; AMARAL, A. G.; FERREIRA, F. M.; MECA, R.; ORMANJI, M. S.; BOIM, M. A.; ONUCHIC, L. F.; HEILBERG, I. P.Polycystic kidney disease is a complex clinical entity which comprises a group of genetic diseases that leads to renal cyst development. We evaluated the most suitable housekeeping genes for microRNA expression by RT-qPCR analyses of kidney tissues in Pkd1-deficient mouse models from a panel of five candidates genes (miR-20a, miR-25, miR-26a, miR-191 and U6) and 3 target genes (miR-17, miR-21 and let-7a) using samples from kidneys of cystic mice (Pkd1(flox/flox):Nestin(cre), CY), non-cystic controls (Pkd1(flox/flox), NC), Pkd1-haploinsufficient (Pkd1(+/-), HT), wild-type controls (Pkd1(+/+), WT), severely cystic mice (Pkd1(V/V), SC), wild-type controls (CO). The stability of the candidate genes was investigated using NormFinder, GeNorm, BestKeeper, DataAssist, and RefFinder software packages and the comparative Delta Ct method. The analyses identified miR-26a as the most stable housekeeping gene for all kidney samples, miR-20a for CY and NC, miR-20a and miR-26a for HT and WT, and miR-25 and miR-26a for SC and CO. Expression of miR-21 was upregulated in SC compared to CO and trends of miR-21 upregulation and let-7a downregulation in CY and HT compared to its control kidneys, when normalized by different combinations of miR-20a, miR-25 and miR-26a. Our findings established miR-20a, miR-25, and miR-26a as the best housekeeping genes for miRNA expression analyses by RT-qPCR in kidney tissues of Pkd1-deficient mouse models.
- Brazilian Network of Pediatric Nephrotic Syndrome (REBRASNI)(2020) FELTRAN, Luciana S.; WATANABE, Andreia; GUARAGNA, Mara S.; MACHADO, Ivan C.; CASIMIRO, Fernanda M. S.; NEVES, Precil D. M. M.; PALMA, Lilian M.; VARELA, Patricia; VAISBICH, Maria H.; MARIE, Suely K. N.; FACINCANI, Inalda; PESQUERO, Joao B.; BELANGERO, Vera M. S.; SAMPSON, Matthew G.; NOGUEIRA, Paulo C. Koch; ONUCHIC, Luiz F.
- Schistosoma mansoni infection as a trigger to collapsing glomerulopathy in a patient with high-risk APOL1 genotype(2020) NEVES, Precil D.; BRIDI, Ramaiane A.; RAMALHO, Janaina A.; JORGE, Lecticia B.; WATANABE, Elieser H.; WATANABE, Andreia; YU, Luis; WORONIK, Viktoria; PINHEIRO, Rafaela B.; TESTAGROSSA, Leonardo A.; CAVALCANTE, Livia B.; MALHEIROS, Denise M.; DIAS, Cristiane B.; ONUCHIC, Luiz F.Author summary Schistosomiasis mansoni is still a public health problem in Brazil and renal involvement is described. In such cases, a glomerulopathy is the typical manifestation, most often membranoproliferative glomerulonephritis. In the current article, we report a patient with a recent diagnosis of hepatosplenic SM who was admitted for nephrotic syndrome associated with reduced renal function and hypertension. Kidney biopsy established the diagnosis of collapsing glomerulopathy (CG) and molecular genetics investigation identified a high-risk APOL1 genotype (HRG). Of note, HRG has been associated with increased risk to develop CG, and a two-hit model has been proposed for the genesis of this glomerulopathy. According to this model, a HRG represents the increased-susceptibility component, while an infection or other environmental factors could act as triggers for the development of CG. Based on those data and model, our case raises SM infection as a new trigger for this severe form of glomerulopathy. This is the first description of a case of CG associated with SM in a patient with an HRG. This case corroborates the interactive role between genetic and environmental factors in the pathogenesis of CG but also identifies SM infection as an additional trigger for its development. Background Schistosoma mansoni schistosomiasis (SM) remains a public health problem in Brazil. Renal involvement is classically manifested as a glomerulopathy, most often membranoproliferative glomerulonephritis or focal and segmental glomerulosclerosis. We report a case of collapsing glomerulopathy (CG) associated with SM and high-risk APOL1 genotype (HRG). Case report A 35-year-old male was admitted for hypertension and an eight-month history of lower-limb edema, foamy urine, and increased abdominal girth. He had a recent diagnosis of hepatosplenic SM, treated with praziquantel, without clinical improvement. Laboratory tests revealed serum creatinine 1.89mg/dL, blood urea nitrogen (BUN) 24mg/dL, albumin 1.9g/dL, cholesterol 531mg/dL, low-density lipoprotein 426mg/dL, platelets 115000/mm(3), normal C3/C4, antinuclear antibody (ANA), rheumatoid factor (RF), and antineutrophil cytoplasmic antibodies (ANCA), negative serologies for hepatitis C virus (HCV) and human immunodeficiency virus (HIV), HBsAg negative and AntiHBc IgG positive, no hematuria or leukocyturia, 24 hour proteinuria 6.56g and negative serum and urinary immunofixation. Kidney biopsy established the diagnosis of CG. A treatment with prednisone was started without therapeutic response, progressing to end-stage kidney disease 19 months later. Molecular genetics investigation revealed an HRG. Conclusions This is the first report of CG associated with SM in the setting of an HRG. This case highlights the two-hit model as a mechanism for CG pathogenesis, where the high-risk APOL1 genotype exerts a susceptibility role and SM infection serves as a trigger to CG.
- A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease(2020) SANTOS, Alexandra Gomes dos; WATANABE, Elieser Hitoshi; FERREIRA, Daiane Tomomi; OLIVEIRA, Jamille; NAKANISHI, Erika Shimoda; OLIVEIRA, Claudia Silva; BOCCHI, Edimar; NOVAES, Cristina Terra Gallafrio; CRUZ, Fatima; CARVALHO, Noemia Barbosa; SATO, Paula Keiko; YAMASHIRO-KANASHIRO, Edite Hatsumi; PONTILLO, Alessandra; FREITAS, Vera Lucia Teixeira de; ONUCHIC, Luiz Fernando; SHIKANAI-YASUDA, Maria AparecidaBackground Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy. Methods Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR. Results Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24-0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07-0.97, P = 0.044; and OR = 0.35, 95% CI 0.14-0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class >= 2 (OR = 0.21, 95% CI 0.06-0.68, P = 0.009; and OR = 0.48, 95% CI 0.24-0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05-0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23-0.96, P = 0.039), NYHA class >= 2 (OR = 0.15, 95% CI 0.06-0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00-0.25, P = 0.001). Digestive involvement was negatively associated with NYHA >= 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09-0.47, P < 0.001; and OR = 0.24, 95% CI 0.09-0.62, P = 0.004, respectively). Conclusions Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.
- Brazilian Consortium for the Study on Renal Diseases Associated With COVID-19: A Multicentric Effort to Understand SARS-CoV-2-Related Nephropathy(2020) TEIXEIRA JUNIOR, Antonio Augusto Lima; NEVES, Precil Diego Miranda de Menezes; LAGES, Joyce Santos; CUNHA, Kaile de Araujo; MUNIZ, Monique Pereira Rego; BRITO, Dyego Jose de Araujo; WATANABE, Andreia; WATANABE, Elieser Hitoshi; ONUCHIC, Luiz Fernando; NUNES, Lucas Lobato Acatauassu; COUTINHO FILHO, Antonio Fernando; BARCELOS, Flavia Lara; GATTO, Giuseppe Cesare; MONTEIRO, Antonio; POLIDO, Diego do Amaral; MOTTA, Douglas Rafanelle Moura de Santana; LEITE, Thaisa de Oliveira; GUEDES, Felipe Leite; GOMES, Orlando Vieira; VALENTE, Lucila Maria; ISRAEL, Karla Cristina Silva Petruccelli; LADCHUMANANANDASIVAM, Francisco Rasiah; FARIAS, Ligia Cristina Lopes de; MARQUES, Igor Denizarde Bacelar; ULIANO, Gustavo Lemos; MARAMALDO, Carlos Eduardo Campos; NETO, Lidio Goncalves Lima; LUCHI, Weverton Machado; WANDERLEY, David Campos; ARAUJO, Stanley de Almeida; SALGADO FILHO, Natalino; SILVA, Gyl Eanes BarrosKidney involvement appears to be frequent in coronavirus disease 2019 (COVID-19). Despite this, information concerning renal involvement in COVID-19 is still scarce. Several mechanisms appear to be involved in the complex relationship between the virus and the kidney. Also, different morphological patterns have been described in the kidneys of patients with COVID-19. For some authors, however, this association may be just a coincidence. To investigate this issue, we propose assessing renal morphology associated with COVID-19 at the renal pathology reference center of federal university hospitals in Brazil. Data will come from a consortium involving 17 federal university hospitals belonging to Empresa Brasileira de Servicos Hospitalares (EBSERH) network, as well as some state hospitals and an autopsy center. All biopsies will be sent to the referral center for renal pathology of the EBSERH network. The data will include patients who had coronavirus disease, both alive and deceased, with or without pre-existing kidney disease. Kidney biopsies will be analyzed by light, fluorescence, and electron microscopy. Furthermore, immunohistochemical (IHC) staining for various inflammatory cells (i.e., cells expressing CD3, CD20, CD4, CD8, CD138, CD68, and CD57) as well as angiotensin-converting enzyme 2 (ACE2) will be performed on paraffinized tissue sections. In addition to ultrastructural assays, in situ hybridization (ISH), IHC and reverse transcription-polymerase chain reaction (RT-PCR) will be used to detect Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in renal tissue. For the patients diagnosed with Collapsing Glomerulopathy, peripheral blood will be collected for apolipoprotein L-1 (APOL1) genotyping. For patients with thrombotic microangiopathy, thrombospondin type 1 motif, member 13 (ADAMTS13), antiphospholipid, and complement panel will be performed. The setting of this study is Brazil, which is second behind the United States in highest confirmed cases and deaths. With this complete approach, we hope to help define the spectrum and impact, whether immediate or long-term, of kidney injury caused by SARS-CoV-2.
- SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in Sao Paulo(2020) LERARIO, Antonio Marcondes; MOHAN, Dipika R.; MONTENEGRO, Luciana Ribeiro; FUNARI, Mariana Ferreira de Assis; NISHI, Mirian Yumie; NARCIZO, Amanda de Moraes; BENEDETTI, Anna Flavia Figueredo; OBA-SHINJO, Sueli Mieko; VITORINO, Aurelio Jose; SANTOS, Rogerio Alexandre Scripnic Xavier dos; JORGE, Alexander Augusto de Lima; ONUCHIC, Luiz Fernando; MARIE, Suely Kazue Nagahashi; MENDONCA, Berenice BilharinhoOBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), Sao Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela