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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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.conferenceObject IMMUNOGLOBULIN DEPOSITS IN GLOMERULI OF LUPUS MEMBRANOUS NEPHROPATHIES(2015) CARNEIRO FILHO, Eduardo Jorge Duque de Sa; PIRES, Alcino Gama; TESTAGROSSA, Leonardo; MALHEIROS, Denise Mac; YU, Luis; DIAS, Cristiane Bitencourt; JORGE, Lectcia Barbosa; WORONIK, Viktoria- Immunohistochemical expression of podocyte markers in the variants of focal segmental glomerulosclerosis(2013) TESTAGROSSA, Leonardo; AZEVEDO NETO, Raymundo; RESENDE, Aline; WORONIK, Viktoria; MALHEIROS, DeniseBackground. Focal segmental glomerulosclerosis (FSGS) is the most prevalent primary glomerulopathy in Brazil and its incidence is increasing worldwide. Pathogenesis is related to podocyte injury, which may be due to several factors including viruses, drugs, immunology. In 2004, the Columbia classification of FSGS identified five histologic variants of the disease: collapsing (COL), usual (not otherwise specified, NOS), tip lesion (TIP), perihilar (PHI) and cellular variant (CEL). Several studies have demonstrated molecular changes in podocytes of FSGS patients. This study sought to classify a large series of FSGS biopsies according to the Columbia classification and analyze the occurrence of immunohistochemical differences among the five variants. Methods. Approximately 131 cases of renal biopsies with a diagnosis of primary FSGS during the period from 1996-2006 were classified according to the criteria of Columbia and were then submitted to immunohistochemical staining to the following antibodies: CD10, WT-1, Vimentin, Synaptopoclin, alpha-actinin-4, GLEPP-1, cytokeratin (CK) 8-18, CK19 and Ki-67. Results. The FSGS classification resulted in 38.2% of NOS variant, in 36.6% COL, in 14.5% TIP, in 6.9% PHI and in 3.8% CEL. COL variant distinguished themselves among the others for having loss of expression of CD10, WT1 and alpha-actinin-4 (P < 0.05). Furthermore, COL gained expression of the CK8-18 and CK19 diverging from the other variants (P < 0.05). Conclusions. COL variant of FSGS presented immunohistochemical characteristics that distinguished it from others pointing to additional studies in this area. The distinct immunohistochemical properties of COL might be of help in the comprehension of this aggressive form of FSGS.
conferenceObject CD68 POSITIVE CELLS IN RENAL BIOPSY PREDICT LONG TERM PROGNOSIS IN PROLIFERATIVE LUPUS NEPHRITIS(2013) DIAS, Cristiane Bitencourt; LEE, Jin; JORGE, Leticia; MALHEIRO, Denise; BARROS, Rui Toledo; WORONIK, ViktoriaIntroduction and Aims:Studies in proliferative lupus nephritis (LN) showed that in more severe clinical forms the renal histology showed increase macrophages detected by immunohistochemistry. However no long-term assessment of this data is known. The aim of this study was to describe any relations of renal outcomes with tecidual macrophages (CD68+) expressed in renal biopsy specimens obtained on the diagnosis. Methods:Forty six newly diagnosed patients with proliferative LN were prospectively followed-up during 3.5 (3.2 - 4.0) years. Conventional laboratory tests were collected on diagnosis and on last follow-up. Renal biopsy was done on diagnosis and immunohistochemical study was performed with monoclonal antibody anti-CD68 (DAKO) and macrophages MCP-1 (R&D), and results expressed as cells/microscopic fields. Patients were stratified in two groups according to renal outcome: GFR ≤ 60 mL/min/1.73m2at the end of follow-up (n=24) and GFR > 60mL/min/1.73m2(n=22). Considering treatment, all patients received prednisone and 6 pulses of cyclophosphamide (CYA) on induction. Maintenance treatment was conventional and applied in both groups. Results: Considering all patients (n=46) tubule and interstitial CD68+cells showed negative correlation with final MDRD (r= - 0.3, p=0.01 and r= -0.45, p=0.001). Macrophages MCP-1 interstitial had positive correlation with chronicity index (r=0.4, p=0.0031). Conclusions:Tubule and interstitial CD68+cells expression on renal biopsies may predict long term GFR in proliferative lupus nephritis.conferenceObject EXERCISE AND CALORIE RESTRICTION ATTENUATES CISPLATIN-INDUCED ACUTE KIDNEY INJURY(2014) ESTRELA, Gabriel R.; WASINSKI, Frederick; PEREIRA, Rafael; MALHEIROS, Denise; CAMARA, Niels O. S.; ARAUJO, Ronaldo C.conferenceObject HYPERTENSION REQUIRES RENAL CYST FORMATION AND IS ASSOCIATED WITH INCREASED INTRARENAL EXPRESSION OF RENIN-ANGIOTENSIN SYSTEM COMPONENTS IN PKD1-DEFICIENT MICE(2012) FONSECA, Jonathan M.; BASTOS, Ana P.; AMARAL, Andressa G.; SOUSA, Mauri F.; SOUZA, Leandro E.; MALHEIROS, Denise M.; PIONTEK, Klaus; IRIGOYEN, Maria C.; WATNICK, Terry J.; ONUCHIC, Luiz F.Introduction and Aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease, being responsible for ∼4-5% of end-stage renal disease cases worldwide. Systemic arterial hypertension (SAH) is an early manifestation of this disorder and is detected in more than half of affected individuals before a significant decline in renal function. A current model proposes that activation of the renin-angiotensin system (RAS) is the primary determinant of SAH in ADPKD. This is mainly due to cyst expansion that results in intrarenal ischemia followed by angiotensin II generation. Methods: By combining a Pkd1 floxed allele with a nestin Cre transgene, we have obtained male, adult cystic mice (Pkd1cond/cond:Balcre aka CondCre). These mice were alive at the age of 10-13 weeks with preserved GFR. This model allowed us to investigate the effects of renal cyst growth on blood pressure and RAS activation. Direct measurement of blood pressure and analyses of a series of renal parameters were performed in CondCre mice and compared with littermate controls (Pkd1cond/cond; Cre-) and Pkd1-haploinsufficient mice (Pkd1+/-). The latter two sets of mice do not develop visible renal cysts at the analyzed age range. Results: CondCre mice were hypertensive, displaying higher mean arterial pressure compared with Cre-animals (150.34 + 3.90, n=6 vs 136.10 + 3.44 mmHg, n=6; p<0.01). Pkd1+/- mice were not hypertensive compared to their wild-type littermates (131.03 + 4.36, n=6 vs 127.54 + 2.99 mmHg, n=8, respectively; p=0.10). Our data also revealed lower fractional excretion of Na+(FENa) in CondCre mice compared with Cre- controls (0.60 + 0.06%, n=9 vs 0.74 + 0.09%, n=9; p<0.001). BUN was slightly higher in CondCres compared to Cre-s [26.3 (26.1-27.9), n=9 vs 24.7 (24.5-25.2), n=9; p<0.01] while serum creatinine was slightly lower [0.32 (0.30-0.34) in CondCres, n=9 vs 0.36 (0.35-0.38) in Cre-s, n=9; p<0.01]. No differences in plasma renin and serum aldosterone could be detected between the two groups but a trend for higher plasma vasopressin was observed in CondCres (711.6 + 647.3 pg/mL, n=9 vs 263.0 + 373.5 inCre-s, n=8; p=0.11). Analyses performed using qPCR at 18 weeks of age revealed increased angiotensinogen gene expression in CondCre kidneys compared to Cre-s (1.76 + 0.65 AU, n=9 vs 1.05 + 0.39 AU, n=8; p<0.05) but no differences were seen in renin and angiotensin converting enzyme (ACE) gene expression. Immunohistochemical analyses performed at 15 weeks revealed specific ACE and AT1 receptor (AT1R) staining in cystic epitelia of CondCre kidneys. As expected, immunohistochemical assays for Ki-67 and TUNEL revealed higher cell proliferation and apoptosis rates in kidneys of CondCres when compared with Cre-s [17%(9-35), n=9 vs 5% (1-9), n=8; p<0.05; and 16,6% (14.0-30.2) vs 0.0% (0.0-4.6); p<0.001, respectively]. Conclusions: Our results suggest that SAH in CondCre mice is primarily caused by renal cyst expansion. There are several pieces of data that support this conclusion. First, we observed a decreased FENa along with mildly elevated BUN in CondCre animals, which is consistent with renal vascular compression and decreased renal perfusion. In addition, we detected increased expression of angiotensinogen in cystic kidneys, along with an increase in immunoreactivity for ACE and AT1R in cyst lining epithelia. These findings are consistent with the notion that intrarenal RAS activation plays a critical role in the genesis of hypertension in ADPKD.conferenceObject INHIBITION OF THE TLR4/NF-kappa B AXIS ATTENUATED GLOMERULAR INFLAMMATION AND SCLEROSIS IN LONG TERM EXPERIMENTAL DIABETIC KIDNEY DISEASE(2018) FORESTO-NETO, Orestes; ALBINO, Amanda; ARIAS, Simone; FAUSTINO, Viviane; AVILA, Victor; SENA, Claudia; FANELLI, Camilla; VIANA, Vivian; CENEDEZE, Marcos; MACHADO, Flavia; MALHEIROS, Denise; CAMARA, Niels; FUJIHARA, Clarice; ZATZ, Roberto