RESUMO
BACKGROUND: Forceps margin biopsy and polypectomy specimen margins have both been used to assess for polypectomy resection adequacy. The interobserver reliability of the two methods has not been well described. METHODS: The interpretability of polypectomy specimens for presence of residual neoplasia at the margin was assessed by two blinded pathologists. Next, the concordance of forceps margin biopsy interpretations between three blinded pathologists was evaluated by calculation of interobserver κ. RESULTS: Rates of polypectomy specimen margin interpretability were low: 24/92 (26â%) for pathologist A, 28/92 (30.4â%) for pathologist B. Concordance of forceps margin biopsy interpretations (nâ=â129) between pathologists was high. Two internal pathologists showed substantial agreement in margin biopsy interpretations (κ 0.779; 95â%CL 0.543, 0.912). The concordance remained strong after biopsies were reviewed by a third, external pathologist (κ 0.829; 95â%CL 0.658, 0.924). There was complete agreement on 123/129 (95.3â%) between all three pathologists for presence of neoplasia. CONCLUSION: The majority of polypectomy specimen margins were uninterpretable by pathologists for presence of residual neoplasia. Forceps margin biopsy shows strong interobserver reliability in adenomatous lesions.
Assuntos
Adenoma , Colonoscopia , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Biópsia , Humanos , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Previously we found that kidney tissue and urinary exosomes from patients of diabetic kidney disease showed high levels of ceruloplasmin (CP). Because CP is an acute-phase protein of kidney origin, it could be an early marker of many other kidney diseases. To investigate this hypothesis, we first measured urine exosomal and kidney expression of CP in non-diabetic chronic kidney disease (CKD) patients (membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis and IgA nephropathy) followed by a longitudinal study in rat passive Heymann nephritis (PHN), a model of human membranous nephropathy. METHODS: Urinary exosomes were isolated from urine of patients (and rats) by differential centrifugation. The exosomal extracts were used for measuring CP using ELISA. Kidney expression of CP was evaluated by immune-staining biopsy tissues. Similar techniques were applied in rat PHN model (produced by injection of anti-gp600 antiserum) to analyze urine exosomal and kidney CP. RESULTS: Urine exosomal CP levels were 10-20 times higher in CKD patients than in controls; consistent with this we found high immune-reactive CP localized in tubules and collecting ducts of biopsies of CKD patients. In the PHN model urinary exosomal CP level was significantly higher prior to the onset of proteinuria. Early rise of urine exosomal CP, which preceded proteinuria, correlated with high immunoreactive CP found in rat kidneys at this time. CONCLUSION: We propose that urine exosomal CP, observed to increase prior to proteinuria, makes it a potential urinary biomarker to diagnose early kidney disease.
Assuntos
Ceruloplasmina/urina , Exossomos/enzimologia , Glomerulonefrite Membranosa/urina , Rim/enzimologia , Proteinúria/urina , Insuficiência Renal Crônica/urina , Adulto , Animais , Biomarcadores/urina , Estudos de Casos e Controles , Modelos Animais de Doenças , Diagnóstico Precoce , Exossomos/patologia , Feminino , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/enzimologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteinúria/diagnóstico , Proteinúria/enzimologia , Ratos Sprague-Dawley , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/enzimologia , Regulação para CimaRESUMO
Podocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR-146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. miR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a-/-) showed accelerated development of glomerulopathy and albuminuria upon streptozotocin (STZ)-induced hyperglycemia. The miR-146a targets, Notch-1 and ErbB4, were also significantly up-regulated in the glomeruli of diabetic patients and mice, suggesting induction of the downstream TGFß signaling. Treatment with a pan-ErbB kinase inhibitor erlotinib with nanomolar activity against ErbB4 significantly suppressed diabetic glomerular injury and albuminuria in both WT and miR-146a-/- animals. Treatment of podocytes in vitro with TGF-ß1 resulted in increased expression of Notch-1, ErbB4, pErbB4, and pEGFR, the heterodimerization partner of ErbB4, suggesting increased ErbB4/EGFR signaling. TGF-ß1 also increased levels of inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1) and MCP-1 induced protein-1 (MCPIP1), a suppressor of miR-146a, suggesting an autocrine loop. Inhibition of ErbB4/EGFR with erlotinib co-treatment of podocytes suppressed this signaling. Our findings suggest a novel role for miR-146a in protecting against diabetic glomerulopathy and podocyte injury. They also point to ErbB4/EGFR as a novel, druggable target for therapeutic intervention, especially because several pan-ErbB inhibitors are clinically available.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , MicroRNAs/metabolismo , Podócitos/metabolismo , Receptor ErbB-4/biossíntese , Receptor Notch1/biossíntese , Regulação para Cima , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Cloridrato de Erlotinib/farmacologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Podócitos/patologia , Receptor ErbB-4/genética , Receptor Notch1/genética , Ribonucleases/genética , Ribonucleases/metabolismo , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Predicting or diagnosing underlying kidney disease by analyzing whole urine remains the mainstay of nephrology practice. However, whole urine is a poor compartment to assess many structural changes in the kidney because whole urine contains only a few proteins derived from the kidney itself. Urinary exosomes, on the other hand, which are derived from the kidney, contain proteins secreted by the kidney. We experimentally tested the hypothesis that 'urinary exosomes more faithfully represent changes in the kidney tissue than whole urine'. A direct comparison between whole urine and urine exosomal levels of two chosen kidney disease markers, gelatinase and ceruloplasmin, was carried out on diabetic kidney disease patients. METHODS: Urinary exosomes were separated from whole urine by sequential centrifugation including ultra-centrifugation. Gelatinase activity was measured using fluorosceinated gelatin as the substrate, and ceruloplasmin was measured by sandwich ELISA. A few kidney specimens from patients biopsied for atypical features were histochemically stained for validation of the biochemical results. RESULTS: We found that changes in both, gelatinase (decreased activity) and ceruloplasmin (increased levels), in the urinary exosomes of diabetic kidney patients were in agreement with the alterations of these two proteins in the kidney tissue. In contrast, the levels of these two proteins in whole urine were highly variable and did not correlate with levels in the diabetic kidney tissue. CONCLUSION: In conclusion, these results confirmed our hypothesis that protein markers in urinary exosomes better reflected the underlying protein changes in the kidney than in whole urine samples.
Assuntos
Ceruloplasmina/urina , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/urina , Exossomos/química , Gelatinases/urina , Adulto , Albuminas/química , Biomarcadores/urina , Biópsia , Creatinina/urina , Diabetes Mellitus Tipo 2/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Fluoresceína/química , Humanos , Masculino , Pessoa de Meia-Idade , UltracentrifugaçãoRESUMO
Mastitis is a benign inflammatory process of the breast with heterogeneous histopathological findings, which clinically and radiographically may mimic a mammary carcinoma. We undertook a retrospective study on 37 cases of mastitis in our institution to correlate the radiographic imaging features and the clinical presentation with the histopathological findings. Histologically, there were 21 granulomatous, 7 fibrous, 3 plasma cell, 3 lupus, 2 lymphocytic, and 1 case of acute mastitis. Radiographically, 16/25 (64%) patients with ultrasound studies showed irregular hypoechoic masses suspicious for malignancy. Clinically, 38% of patients had an associated systemic disease.
Assuntos
Mastite Granulomatosa/diagnóstico , Mastite Granulomatosa/patologia , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Mastite Granulomatosa/diagnóstico por imagem , Humanos , Mamografia/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Ultrassonografia Mamária/métodosRESUMO
Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.
Assuntos
COVID-19 , Podócitos , Animais , Camundongos , Chlorocebus aethiops , Humanos , Vacinas contra COVID-19 , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , SARS-CoV-2 , Integrinas , ProteinúriaAssuntos
Colágeno Tipo III/metabolismo , Mesângio Glomerular/patologia , Nefropatias/patologia , Síndrome da Unha-Patela/patologia , Doenças Raras/patologia , Biópsia , Creatinina/sangue , Diagnóstico Diferencial , Feminino , Imunofluorescência , Mesângio Glomerular/ultraestrutura , Hematúria/urina , Humanos , Nefropatias/sangue , Nefropatias/diagnóstico , Nefropatias/urina , Pessoa de Meia-Idade , Síndrome da Unha-Patela/diagnóstico , Reação do Ácido Periódico de Schiff , Proteinúria/urina , Doenças Raras/sangue , Doenças Raras/diagnóstico , Doenças Raras/urinaRESUMO
BACKGROUND/AIMS: The Oxford classification of IgA nephropathy (IgAN) assesses the presence of mesangial hypercellularity ≥50% (M1 vs. 0), endocapillary proliferation (E1 vs. 0), segmental glomerulosclerosis (S1 vs. 0), tubular atrophy/interstitial fibrosis >25 or 50% (T1 or 2 vs. 0), and has been reported as having prognostic value. We studied the clinical significance of the classification in our adult patients with IgAN. METHODS: Retrospective study of 54 patients with biopsy-proven IgAN seen from 1983 to 2009. The correlation between the Oxford classification and baseline renal function was assessed. The primary endpoint was a 50% reduction in eGFR or end-stage renal disease. Predictors for progression to the endpoint were determined by multivariate analyses. RESULTS: Patients were 41 ± 15 years of age with a serum creatinine of 1.5 ± 0.8 mg/dl, eGFR of 61 ± 24 ml/min/1.73 m(2), and proteinuria of 2.0 ± 1.6 g/day. Oxford classifications were as follows: M1 = 72%, E1 = 20%, S1 = 81%, and T1 = 13%/T2 = 22%. During the follow-up of 5.8 ± 4.8 years, 19% of patients reached the primary endpoint. While the Oxford classification was associated with progressive renal disease, only the T score (T0, T1, T2) was predictive of outcome with 6, 29, and 50% of patients (p = 0.002) reaching the primary endpoint. The 10-year renal survival for T0, T1, and T2 was 100, 50, and 17%, respectively (p < 0.001). By multivariate analysis, the hazard ratio for reaching the primary endpoint was 32 for patients with T ≥1 versus T0 (p = 0.01). CONCLUSIONS: In our experience, the Oxford classification predicts progressive renal disease, but the degree of tubulointerstitial fibrosis was the only feature independently predictive of outcome.
Assuntos
Glomerulonefrite por IGA/classificação , Adulto , Feminino , Glomerulonefrite por IGA/diagnóstico , Humanos , Masculino , Estudos RetrospectivosRESUMO
Importance: Interstitial fibrosis and tubular atrophy (IFTA) is a strong indicator of decline in kidney function and is measured using histopathological assessment of kidney biopsy core. At present, a noninvasive test to assess IFTA is not available. Objective: To develop and validate a deep learning (DL) algorithm to quantify IFTA from kidney ultrasonography images. Design, Setting, and Participants: This was a single-center diagnostic study of consecutive patients who underwent native kidney biopsy at John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, between January 1, 2014, and December 31, 2018. A DL algorithm was trained, validated, and tested to classify IFTA from kidney ultrasonography images. Of 6135 Crimmins-filtered ultrasonography images, 5523 were used for training (5122 images) and validation (401 images), and 612 were used to test the accuracy of the DL system. Kidney segmentation was performed using the UNet architecture, and classification was performed using a convolution neural network-based feature extractor and extreme gradient boosting. IFTA scored by a nephropathologist on trichrome stained kidney biopsy slide was used as the reference standard. IFTA was divided into 4 grades (grade 1, 0%-24%; grade 2, 25%-49%; grade 3, 50%-74%; and grade 4, 75%-100%). Data analysis was performed from December 2019 to May 2020. Main Outcomes and Measures: Prediction of IFTA grade was measured using the metrics precision, recall, accuracy, and F1 score. Results: This study included 352 patients (mean [SD] age 47.43 [14.37] years), of whom 193 (54.82%) were women. There were 159 patients with IFTA grade 1 (2701 ultrasonography images), 74 patients with IFTA grade 2 (1239 ultrasonography images), 41 patients with IFTA grade 3 (701 ultrasonography images), and 78 patients with IFTA grade 4 (1494 ultrasonography images). Kidney ultrasonography images were segmented with 91% accuracy. In the independent test set, the point estimates for performance matrices showed precision of 0.8927 (95% CI, 0.8682-0.9172), recall of 0.8037 (95% CI, 0.7722-0.8352), accuracy of 0.8675 (95% CI, 0.8406-0.8944), and an F1 score of 0.8389 (95% CI, 0.8098-0.8680) at the image level. Corresponding estimates at the patient level were precision of 0.9003 (95% CI, 0.8644-0.9362), recall of 0.8421 (95% CI, 0.7984-0.8858), accuracy of 0.8955 (95% CI, 0.8589-0.9321), and an F1 score of 0.8639 (95% CI, 0.8228-0.9049). Accuracy at the patient level was highest for IFTA grade 1 and IFTA grade 4. The accuracy (approximately 90%) remained high irrespective of the timing of ultrasonography studies and the biopsy diagnosis. The predictive performance of the DL system did not show significant improvement when combined with baseline clinical characteristics. Conclusions and Relevance: These findings suggest that a DL algorithm can accurately and independently predict IFTA from kidney ultrasonography images.
Assuntos
Algoritmos , Biópsia/normas , Aprendizado Profundo , Fibrose/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/normas , Nefropatias/diagnóstico por imagem , Ultrassonografia/normas , Adulto , Chicago , Feminino , Fibrose/fisiopatologia , Humanos , Nefropatias/complicações , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto/normasRESUMO
Spatial organization of molecules and cells in complex tissue microenvironments provides essential organizational cues in health and disease. A significant need exists for improved visualization of these spatial relationships. Here, we describe a multiplex immunofluorescence imaging method, termed SeqStain, that uses fluorescent-DNA-labeled antibodies for immunofluorescent staining and nuclease treatment for de-staining that allows selective enzymatic removal of the fluorescent signal. SeqStain can be used with primary antibodies, secondary antibodies, and antibody fragments to efficiently analyze complex cells and tissues. Additionally, incorporation of specific endonuclease restriction sites in antibody labels allows for selective removal of fluorescent signals while retaining other signals that can serve as marks for subsequent analyses. The application of SeqStain on human kidney tissue provided a spatialomic profile of the organization of >25 markers in the kidney, highlighting it as a versatile, easy-to-use, and gentle new technique for spatialomic analyses of complex microenvironments.
Assuntos
Anticorpos , Corantes , Humanos , Animais , Camundongos , Imunofluorescência , Coloração e RotulagemRESUMO
Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMß2), and plays an important role in recruitment and biological functions of these cells, and is a validated therapeutic target. Here, we describe our pre-clinical studies targeting CD11b in the context of lung cancer, using pharmacologic and genetic approaches that work via positive allosteric modulation of CD11b function. GB1275 is a novel small molecule modulator of CD11b that is currently in Phase 1/2 clinical development. We assess GB1275 treatment effects on tumor growth and immune infiltrates in the murine Lewis Lung Carcinoma (LLC) syngeneic tumor model. Additionally, as an orthogonal approach to determine mechanisms of action, we utilize our recently developed novel CD11b knock-in (KI) mouse that constitutively expresses CD11b containing an activating isoleucine to glycine substitution at residue 332 in the ligand binding CD11b A-domain (I332G) that acts as a positive allosteric modulator of CD11b activity. We report that pharmacologic modulation of CD11b with GB1275 significantly reduces LLC tumor growth. CD11b KI mice similarly show significant reduction in both the size and rate of LLC tumor growth, as compared to WT mice, mimicking our observed treatment effects with GB1275. Tumor profiling revealed a significant reduction in TAM infiltration in GB1275-treated and in CD11b KI mice, increase in the ratio of M1/M2-like TAMs, and concomitant increase in cytotoxic T cells. The profiling also showed a significant decrease in CCL2 levels and a concomitant reduction in Ly6Chi monocytes in circulation in both groups. These findings suggest that positive allosteric modulation of CD11b reduces TAM density and reprograms them to enhance the adaptive immune response and is a novel therapeutic strategy against lung cancer.
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Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvß3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvß3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvß3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvß3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvß3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvß3-selective antagonist to maintain glomerular filtration.
Assuntos
Ligante Coestimulador de Linfócitos T Induzíveis , Integrina alfaVbeta3 , Falência Renal Crônica , Podócitos , Proteinúria , Motivos de Aminoácidos , Animais , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/genética , Taxa de Filtração Glomerular/imunologia , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/genética , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/imunologia , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/genética , Falência Renal Crônica/imunologia , Falência Renal Crônica/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Podócitos/imunologia , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proteinúria/genética , Proteinúria/imunologia , Proteinúria/patologiaRESUMO
Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease, such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis. In vivo, msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria, loss of kidney function, and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3, encoding ß3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin ß3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for ß3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease.
Assuntos
Nefropatias/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/química , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Adipócitos/citologia , Animais , Biópsia , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Podócitos/citologia , Domínios Proteicos , Isoformas de Proteínas , Multimerização Proteica , Receptor PAR-2/genética , Estudos Retrospectivos , Transdução de SinaisRESUMO
Genetic variations in the ITGAM gene (encoding CD11b) strongly associate with risk for systemic lupus erythematosus (SLE). Here we have shown that 3 nonsynonymous ITGAM variants that produce defective CD11b associate with elevated levels of type I interferon (IFN-I) in lupus, suggesting a direct link between reduced CD11b activity and the chronically increased inflammatory status in patients. Treatment with the small-molecule CD11b agonist LA1 led to partial integrin activation, reduced IFN-I responses in WT but not CD11b-deficient mice, and protected lupus-prone MRL/Lpr mice from end-organ injury. CD11b activation reduced TLR-dependent proinflammatory signaling in leukocytes and suppressed IFN-I signaling via an AKT/FOXO3/IFN regulatory factor 3/7 pathway. TLR-stimulated macrophages from CD11B SNP carriers showed increased basal expression of IFN regulatory factor 7 (IRF7) and IFN-ß, as well as increased nuclear exclusion of FOXO3, which was suppressed by LA1-dependent activation of CD11b. This suggests that pharmacologic activation of CD11b could be a potential mechanism for developing SLE therapeutics.
Assuntos
Antígeno CD11b/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Receptores Toll-Like/imunologia , Animais , Antígeno CD11b/genética , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/imunologia , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores Toll-Like/genéticaRESUMO
As malignant pleural mesotheliomas are most often rapidly fatal, distant metastases are rarely detected. Here, we report a unique case in which the diagnosis of metastatic pleural mesothelioma was made via cytologic examination of a fine-needle aspiration (FNA) of the liver. Recognition of the cytomorphologic features inherent to mesothelioma cells on FNA material may become important for proper patient management. To the best of our knowledge, the diagnosis of malignant pleural mesothelioma metastatic to the liver made by FNA has not been previously documented.
Assuntos
Biópsia por Agulha Fina , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Mesotelioma/complicações , Mesotelioma/patologia , Mesotelioma/secundário , Neoplasias Pleurais/patologia , Citodiagnóstico , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Synchronous renal cell neoplasms (RCNs) and angiomyolipomas (AML) occurring in the same kidney are rare. The aim of this retrospective study is to investigate the incidence and clinicopathological features of concurrent AML and RCN in patients without tuberous sclerosis complex (TSC). Partial and radical nephrectomy specimens with a diagnosis of RCN and AML from 1995 to May 2013 were reviewed. Cases were assessed for histological subtype of AML and RCN, topographic relationship between the AML and the RCN, and clinical characteristics. A total of 565 RCNs and 19 AMLs were identified. Of 19 cases of AML, 9 (47%) were associated with renal tumors. Clear-cell renal cell carcinoma (RCC) was the most common malignancy associated with AML (56%). The mean age of patients with concomitant AML and RCN was higher than the mean age of patients with only AML (58.6 vs 55.5 years). The majority of patients with concomitant AML and RCN were female (78%). All concurrent sporadic AMLs were benign. We identified one case of bilateral clear-cell RCC with concomitant multiple bilateral AMLs in a patient with TSC.
Assuntos
Angiomiolipoma/patologia , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Neoplasias Primárias Múltiplas/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Angiomiolipoma/epidemiologia , Carcinoma de Células Renais/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Estudos Retrospectivos , Esclerose TuberosaRESUMO
Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2(b)) recipients received kidney allografts from Balb/c mice (H-2(d)). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3 + Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.
Assuntos
Nefropatias/diagnóstico , Nefropatias/etiologia , Paraproteinemias/diagnóstico , Paraproteinemias/etiologia , Biomarcadores , Biópsia , Terapia Combinada , Gerenciamento Clínico , Feminino , Humanos , Imunoglobulina A/imunologia , Nefropatias/terapia , Testes de Função Renal , Gamopatia Monoclonal de Significância Indeterminada , Paraproteinemias/terapia , Índice de Gravidade de Doença , Avaliação de SintomasRESUMO
X-linked Alport syndrome (XLAS) arises from mutations in the COL4A5 gene encoding the α5-chain of type IV collagen and is associated with hematuria, ocular abnormalities and high-tone sensorineural hearing loss. Nearly all affected males have decreased kidney function resulting in end-stage renal disease (ESRD) as early as the second decade of life. It was long thought that affected females had a benign outcome; however, in recent decades, it has become quite clear that they too are at risk for developing nephrotic syndrome, decreased kidney function and ESRD. We report two young females presenting with microscopic hematuria and proteinuria diagnosed with XLAS on renal biopsy. Both developed nephrotic-range proteinuria and progressive renal insufficiency. Additionally, both developed extra-renal manifestations of XLAS. The ultrastructural and immunofluorescence features on kidney biopsy were instrumental in making the diagnosis of heterozygous XLAS as neither patient had a family history of AS.
RESUMO
BACKGROUND: It is well established that the incidence of focal segmental glomerular sclerosis (FSGS) increased from 1970-1990 to become the leading primary glomerular disease in patients of African descent. METHODS: To determine whether this trend has continued in the past years in Chicago, adult, native kidney biopsies from January 2001 to December 2011 at our hospital were reviewed and collected relevant clinical information in patients with a primary glomerular disease including FSGS, membranous nephropathy (MN), minimal change disease (MCD), membranoproliferative glomerulonephritis (MPGN), and IgA nephropathy (IgAN). RESULTS: In the 204 patients analyzed, MN was the most prevalent (32.7%), followed by FSGS (29.7%), IgAN (15.8%), MCD (14.4%), and MPGN (4.5%). Patients with MN had the highest proteinuria (7.9 gms/d) and were significantly older, more edematous, hypoalbuminemic, and hypercholesterolemic than those with FSGS. In both African Americans and Hispanics, MN was the most prevalent primary glomerular lesion at 39.2% and 34% respectively. CONCLUSIONS: Comparable in size to prior cohorts of African Americans and Hispanics, our report demonstrates a reversal in the incidence of FSGS and MN in both ethnic groups where MN is now more prevalent. To our knowledge, this is the first demonstration of a reverse in the upward trend of the prevalence of FSGS in African Americans.