DENISE MARIA AVANCINI COSTA MALHEIROS
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
LIM/16 - Laboratório de Fisiopatologia Renal, Hospital das Clínicas, Faculdade de Medicina
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- Schistosoma mansoni and membranous nephropathy(2016) NEVES, Precil D. M. M.; BEZERRA, Kalyanna S.; SILVEIRA, Marcelo A. D.; YU, Luis; WORONIK, Viktoria; JORGE, Lecticia B.; TESTAGROSSA, Leonardo A.; MALHEIROS, Denise M. A. Costa; DIAS, Cristiane B.
- Pathogenic role of innate immunity in a model of chronic NO inhibition associated with salt overload(2019) ZAMBOM, Fernanda Florencia Fregnan; OLIVEIRA, Karin Carneiro; FORESTO-NETO, Orestes; FAUSTINO, Viviane Dias; AVILA, Victor Ferreira; ALBINO, Amanda Helen; ARIAS, Simone Costa Alarcon; VOLPINI, Rildo Aparecido; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; ZATZ, Roberto; FUJIHARA, Clarke KazueNitric oxide inhibition with N-omega-nitro-L-arginine methyl ester (L-NAME), along with salt overload, leads to hypertension, albuminuria, glomerulosclerosis, glomerular ischemia, and interstitial fibrosis, characterizing a chronic kidney disease (CKD) model. Previous findings of this laboratory and elsewhere have suggested that activation of at least two pathways of innate immunity, Toll-like receptor 4 (TLR4)/NF-kappa B and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome/IL-1 beta, occurs in several experimental models of CKD and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NF-kappa B or NLRP3/IL-1 beta pathway, is involved in the pathogenesis of renal injury in chronic nitric oxide inhibition with the salt-overload model. Adult male Munich-Wistar rats that received L-NAME in drinking water with salt overload (HS + N group) were treated with allopurinol (ALLO) as an NLRP3 inhibitor (HS + N + ALLO group) or pyrrolidine dithiocarbamate (PDTC) as an NF-kappa B inhibitor (HS + N + PDTC group). After 4 wk, HS + N rats developed hypertension, albuminuria, and renal injury along with renal inflammation, oxidative stress, and activation of both the NLRP3/IL-1 beta and TLR4/NF-kappa B pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria, and interstitial inflammation/fibrosis but not glomerular injury. PDTC inhibited the renal NF-kappa B system and lowered the number of interstitial cells staining positively for NLRP3. PDTC also reduced renal xanthine oxidase activity and uric acid. Overall, PDTC promoted a more efficient anti-inflammatory and nephroprotective effect than ALLO. The NLRP3/IL-1 beta and TLR4/NF-kappa B pathways act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection.
- Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation(2011) FANELLI, C.; FERNANDES, B. H. V.; MACHADO, F. G.; OKABE, C.; MALHEIROS, D. M. A. C.; FUJIHARA, C. K.; ZATZ, R.Fanelli C, Fernandes BH, Machado FG, Okabe C, Malheiros DM, Fujihara CK, Zatz R. Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation. Am J Physiol Renal Physiol 301: F580-F587, 2011. First published June 8, 2011; doi:10.1152/ajprenal.00042.2011.-We recently standardized a model (L(Lact)) of severe chronic kidney disease based on impaired nephrogenesis by suppression of angiotensin II activity during lactation (Machado FG, Poppi EP, Fanelli C, Malheiros DM, Zatz R, Fujihara CK. Am J Physiol Renal Physiol 294: F1345-F1353, 2008). In this new study of the L(Lact) model, we sought to gain further insight into renal injury mechanisms associated with this model and to verify whether the renoprotection obtained with the association of the angiotensin II receptor blocker losartan (L) and hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, would provide similar renoprotection. Twenty Munich-Wistar dams, each nursing six pups, were divided into control, untreated, and L(Lact) groups, given losartan (L; 250 mg.kg(-1).day(-1)) until weaning. The male LLact offspring remained untreated until 7 mo of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (L(Lact)Pre), and followed no further. The remaining rats were then divided among groups L(Lact) + V, untreated; L(Lact) + L, given L (50 mg.kg(-1).day(-1)) now as a therapy; L(Lact) + H, given H (6 mg.kg(-1).day(-1)); and L(Lact) + LH, given L and H. All parameters were reassessed 3 mo later in these groups and in age-matched controls. At this time, L(Lact) rats exhibited hypertension, severe albuminuria, glomerular damage, marked interstitial expansion/inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. L monotherapy normalized albuminuria and prevented hypertension and the progression of renal injury, inflammation, and myofibroblast infiltration. In contrast to the remnant model, the LH combination promoted only slight additional renoprotection, perhaps because of a limited tendency to retain sodium in L(Lact) rats.
conferenceObject KIDNEY BIOPSIES IN HIV PATIENTS: A FIFTEEN-YEAR SINGLE CENTER EXPERIENCE IN BRAZIL(2012) CALDIN, Bruno; HUNG, James; REPIZO, Liliany; MALHEIROS, Denise M.; BARROS, Rui; WORONIK, ViktoriaIntroduction and Aims: Human Immunodeficiency Virus (HIV) is associated to many kidney pathologies, like glomerular, vascular and tubule-interstitial alterations. Few data on renal biopsies in HIV patients are available in Brazil. Our objective is to reveal the prevalence and outcomes related to the different diagnosis concerning kidney pathology in a single brazilian reference center. Methods: From 1985 to 2010, we performed 69 kidney biopsies in HIV-positive patients at the Hospital das Clínicas, University of São Paulo. We correlated clinical and laboratorial data to the results of kidney biopsies from these patients and established clinical outcomes depending on the kind of glomerular lesion. Eight biopsies were excluded from analysis due to incomplete data. Results: Mean age of this population was 39,6 ± 11,3 years (range: 15 to 65 years) and 66% were men. Only 3 patients were not under antiretroviral therapy. Main indications for biopsy were: nephrotic syndrome (47%), loss of renal function (37%) and hematuria (31%). The most prevalent glomerulopathy (GP) was focal and segmental glomerulosclerosis (FSGS), which was found in 24 patients (39%), followed by membranoproliferative glomerulonephritis (MPGN) (10 patients, 16% of the total). Six patients (10%) were diagnosed as membranous glomerulonephritis. Vascular disease (atherosclerosis, nephrosclerosis) and acute tubular necrosis were found in three patients each, representing 10% of the population. IgA nephropathy and diabetic GP were diagnosed in two patients each. Other diagnosis, like chronic and acute interstitial nephritis and mesangial glomerulonephritis were made, but represented only 5% of the population. In three patients, diagnosis was not conclusive. To evaluate whether the pattern of glomerular injury has somehow impact under renal prognosis, we divided the patients into two subgroups: FSGS and non-FSGS GP (24 vs 22 biopsies). Clinical and laboratorial aspects are depicted in table 1. Table 1 Clinical and laboratorial characteristics of the study populaton Follow-up between these two groups was slightly different: 22,8 ± 17 months for FSGS group vs 40,7 ± 31,6 months for non-FSGS GP group (p = 0,047). Only hematuria was more prevalent in the non-FSGS GP group. Composite outcome defined as hemodialysis or duplication of serum creatinine resulted in no differences between these groups (p = 0,71) during the follow up (7 patients out of 21 in FSGS group vs 5 patients out of 18 in non-FSGS GP group), as shown in figure 1. Figure 1. Composite outcome in FSGS group vs non-FGSG group FSGS was also compared to a combined group of MPGN and crioglobulinemia (12 patients). Again, only hematuria was different between these groups (22% vs 75%, p = 0,01). Nevertheless, coinfection with HCV was more prevalent in the latter group (50% of the patients, against 16% in the FSGS group, p = 0,027). Conclusions: The main indication for kidney biopsy in HIV-positive patients in our center is nephrotic syndrome and FSGS was the single most prevalent GP. MPGN was the second most prevalent diagnosis and is strongly associated to coinfection with HCV. Our composite outcome showed that the kind of GP found in kidney biopsy does not correlate to renal prognosis.- Chronic environmental hypoxia attenuates innate immunity activation and renal injury in two CKD models(2023) ZAMBOM, Fernanda Florencia Fregnan; ALBINO, Amanda Helen; TESSARO, Helena Mendonca; FORESTO-NETO, Orestes; MALHEIROS, Denise Maria Avancini Costa; CAMARA, Niels Olsen Saraiva; ZATZ, RobertoTissue hypoxia has been pointed out as a major pathogenic factor in chronic kidney disease (CKD). However, epidemiological and experimental evidence inconsistent with this notion has been described. We have previously reported that chronic exposure to low ambient Po-2 promoted no renal injury in normal rats and in rats with 5/6 renal ablation (Nx) unexpectedly attenuated renal injury. In the present study, we investigated whether chronic exposure to low ambient Po-2 would also be renoprotective in two additional models of CKD: adenine (ADE) excess and chronic nitric oxide (NO) inhibition. In both models, normobaric ambient hypoxia attenuated the development of renal injury and inflammation. In addition, renal hypoxia limited the activation of NF-?B and NOD-like receptor family pyrin domain containing 3 inflammasome cascades as well as oxidative stress and intrarenal infiltration by angiotensin II-positive cells. Renal activation of hypoxia-inducible factor (HIF)-2a, along with other adaptive mechanisms to hypoxia, may have contributed to these renoprotective effects. The present findings may contribute to unravel the pathogenesis of CKD and to the development of innovative strategies to arrest its progression.
- KIDNEY TISSUE PROTECTIVE RESPONSE OF LIVING RENAL TRANSPLANTATION: COMPARISON TO OPEN AND LAPAROSCOPIC DONOR NEPHRECTOMY.(2012) MACHADO, Christiano; MALHEIROS, Denise Maria Avancini C.; ANTONOPOULUS, Ioannis; SAITO, Fernando; URBAN, Cero de Andrade; KALIL, Jorge; LEMOS, Francine Brambate Carvalhinho; NAHAS, William Carlos
- Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis(2011) PEREIRA, Rafael L.; BUSCARIOLLO, Bruna N.; CORREA-COSTA, Matheus; SEMEDO, Patricia; OLIVEIRA, Cassiano D.; REIS, Vanessa O.; MAQUIGUSSA, Edgar; ARAUJO, Ronaldo C.; BRAGA, Tarcio T.; SOARES, Maria F.; MOURA, Ivan C.; MALHEIROS, Denise M. A. C.; PACHECO-SILVA FILHO, Alvaro; KELLER, Alexandre C.; CAMARA, Niels O. S.Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and alpha-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling. Kidney International (2011) 79, 1217-1227; doi:10.1038/ki.2011.14; published online 16 March 2011
- Expression patterns of CD56+and CD16+cells in renal transplant biopsies with acute rejection: Associations with microcirculation injuries and graft survival(2017) SANTOS, Daniela Cristina Dos; CAMARA, Niels Olsen Saraiva; DAVID, Daisa Silva Ribeiro; MALHEIROS, Denise Maria Avancini CostaBackgroundThe study investigated whether immunohistochemical features of interstitial and glomerular CD56 and CD16 infiltrates - NK cells markers - could be associated with microcirculation injury scores - peritubular capillaritis (ptc) and glomerulitis (g) - and graft survival. MethodsThe research analyzed the immunohistochemical pattern of CD56 and CD16 in interstitial and glomerular compartments of biopsies for-cause biopsies from 59 recipients diagnosed with acute rejection (mean=135.5days post-transplant). ResultsInterstitial CD56+ cells had an increased expression for glomerulitis (g1) (P=0.02) and peritubular capillaritis (ptc2) (P=0.003) presence. It was noted that interstitial CD56+cells with mean above 0.56cells/mm(2) had worse allograft survival. CD56+ cells in the interstitial compartment with mean less than or equal to 0.56cells/mm(2) was related with absence or mild peritubular capillaritis (P=0.012) and mean above 0.56cells/mm(2), respectively, with glomerulitis (P=0.002) presence. Interstitial CD16 cells showed greater positive results in relation to peritubular capillaritis (P=0.0001) cases. Similarly, it was observed that glomerular CD16+ cells had higher positive results in glomerulitis (P=0.009) presence. ConclusionsThe study findings showed that CD56+ cell infiltrated in the interstitial compartment was significantly associated with microcirculation injury scores, especially the glomerulitis, and graft survival. Summary at a Glance This study suggests that increased expression of interstitial natural killer cells in renal allograft biopsies of kidney transplant recipients with rejection may be associated with poorer graft outcomes.
- The immunohistological profile of membranous nephropathy associated with chronic Schistosoma mansoni infection reveals a glomerulopathy with primary features(2019) ARAUJO, Stanley de Almeida; NEVES, Precil Diego Miranda de Menezes; WANDERLEY, David Campos; REIS, Marlene Antonia dos; DIAS, Cristiane Bitencourt; MALHEIROS, Denise Maria Avancini Costa; ONUCHIC, Luiz Fernando
- Role of renal expression of CD68 in the long-term prognosis of proliferative lupus nephritis(2017) DIAS, Cristiane B.; MALAFRONTE, Patricia; LEE, Jin; RESENDE, Aline; JORGE, Lecticia; PINHEIRO, Cilene C.; MALHEIROS, Denise; WORONIK, ViktoriaIntroduction Renal histology of proliferative lupus nephritis (LN) shows increased macrophage infiltration, but its association with renal outcome is a matter of debate. Here, we investigate the potential relationship that macrophage expression has with renal prognosis in patients with proliferative LN. Methods Fifty patients newly diagnosed with proliferative LN were followed for a median of 8 years. Laboratory testing was conducted at diagnosis, after induction therapy and at the final follow-up evaluation. Renal biopsies were obtained at diagnosis and underwent immunohistochemical analysis with anti-CD68 and monocyte chemoattractant protein 1 monoclonal antibodies. Patients were stratified at final follow-up evaluation into glomerular filtration rate (GFR) > 60 ml/min/1.73 m(2) (non-progressor group; n = 24) and GFR <= 60 ml/min/1.73 m(2) (progressor group; n = 26). All patients were treated with prednisone and six pulses of cyclophosphamide on induction therapy. Conventional maintenance therapy was administered in both groups. Results Compared to progressors, the non-progressor group showed a lower chronicity index (p = 0.01) and fewer CD68-positive cells in the renal tubules (p = 0.01) and particularly in the renal interstitium (p = 0.0003). Baseline and final serum creatinine correlated positively with the chronicity index (r = 0.3, p = 0.01 and r = 0.3, p = 0.04, respectively), and final serum creatinine correlated positively with interstitial expression of CD68 (r = 0.4, p = 0.0006). Conclusion Renal expression of CD68 and the chronicity index are associated with progression to chronic kidney disease in patients with proliferative LN.