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1.
J Am Soc Nephrol ; 28(1): 278-289, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27382987

RESUMO

The amount of albumin filtered through the glomeruli and reabsorbed at the proximal tubules in normal and in diabetic kidneys is debated. The megalin/cubilin complex mediates protein reabsorption, but genetic knockout of megalin is perinatally lethal. To overcome current technical problems, we generated a drug-inducible megalin-knockout mouse line, megalin(lox/lox);Ndrg1-CreERT2 (iMegKO), in which megalin expression can be shut off at any time by administration of tamoxifen (Tam). Tam administration in adult iMegKO mice decreased the expression of renal megalin protein by 92% compared with that in wild-type C57BL/6J mice and almost completely abrogated renal reabsorption of intravenously injected retinol-binding protein. Furthermore, urinary albumin excretion increased to 175 µg/d (0.46 mg albumin/mg creatinine) in Tam-treated iMegKO mice, suggesting that this was the amount of total nephron albumin filtration. By comparing Tam-treated, streptozotocin-induced diabetic iMegKO mice with Tam-treated nondiabetic iMegKO mice, we estimated that the development of diabetes led to a 1.9-fold increase in total nephron albumin filtration, a 1.8-fold increase in reabsorption, and a significant reduction in reabsorption efficiency (86% efficiency versus 96% efficiency in nondiabetic mice). Insulin treatment normalized these abnormalities. Akita;iMegKO mice, another model of type 1 diabetes, showed equivalent results. Finally, nondiabetic iMegKO mice had a glomerular sieving coefficient of albumin of 1.7×10-5, which approximately doubled in diabetic iMegKO mice. This study reveals actual values and changes of albumin filtration and reabsorption in early diabetic nephropathy in mice, bringing new insights to our understanding of renal albumin dynamics associated with the hyperfiltration status of diabetic nephropathy.


Assuntos
Albuminas/metabolismo , Nefropatias Diabéticas/metabolismo , Néfrons/metabolismo , Reabsorção Renal , Albuminúria/genética , Animais , Nefropatias Diabéticas/genética , Glomérulos Renais/metabolismo , Lipocalina-2/urina , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
Diabetologia ; 58(9): 2169-80, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26063197

RESUMO

AIMS/HYPOTHESIS: The accumulation of extracellular matrix (ECM) is a characteristic of diabetic nephropathy, and is partially caused by profibrotic proteins TGF-ß and connective tissue growth factor (CTGF). We aimed to identify microRNAs (miRNAs) targeting CTGF on podocytes in diabetic nephropathy. METHODS: We investigated miRNAs targeting CTGF on podocytes with miRNA array analysis and identified a candidate miRNA, miR-26a. Using overexpression and silencing of miR-26a in cultured podocytes, we examined changes of ECM and its host genes. We further investigated glomerular miR-26a expression in humans and in mouse models of diabetic nephropathy. RESULTS: miR-26a, which was downregulated by TGF-ß1, was expressed in glomerular cells including podocytes and in tubules by in situ hybridisation. Glomerular miR-26a expression was downregulated by 70% in streptozotocin-induced diabetic mice. Transfection of miR-26a mimics in cultured human podocytes decreased the CTGF protein level by 50%, and directly inhibited CTGF expression in podocytes, as demonstrated by a reporter assay with the 3'-untranslated region of the CTGF gene. This effect was abolished by a mutant plasmid. miR-26a mimics also inhibited TGF-ß1-induced collagen expression, SMAD-binding activity and expression of its host genes CTDSP2 and CTDSPL. Knockdown of CTDSP2 and CTDSPL increased collagen expression in TGF-ß-stimulated podocytes, suggesting that host genes also regulate TGF-ß/SMAD signalling. Finally, we observed a positive correlation between microdissected glomerular miR-26a expression levels and estimated GFR in patients with diabetic nephropathy. CONCLUSIONS/INTERPRETATION: The downregulation of miR-26a is involved in the progression of diabetic nephropathy both in humans and in mice through enhanced TGF-ß/CTGF signalling.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Nefropatias Diabéticas/metabolismo , Matriz Extracelular/metabolismo , MicroRNAs/metabolismo , Podócitos/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Regiões 3' não Traduzidas , Animais , Sequência de Bases , Biópsia , Diabetes Mellitus Experimental , Progressão da Doença , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Taxa de Filtração Glomerular , Humanos , Glomérulos Renais/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Microdissecção , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteínas Smad/metabolismo , Estreptozocina , Proteínas Supressoras de Tumor/metabolismo
3.
Clin Exp Nephrol ; 19(1): 99-106, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24599361

RESUMO

BACKGROUND: Lipocalin 2 (LCN2 or neutrophil gelatinase-associated lipocalin) is a secretory protein discovered from neutrophils, which accumulates in the blood and urine during acute kidney injury (AKI) and in the blood by bacterial infection. Little is known about the tissue source and molecular forms of this protein under normal and pathophysiologic conditions. METHODS: By sandwich ELISA, serum and urinary LCN2 levels were measured in 36 patients with hematologic malignancies who transiently became neutropenic by stem cell transplantation (SCT). To evaluate contribution of neutrophil-derived LCN2 in the physiologic blood LCN2 concentrations, we examined CCAAT/enhancer-binding protein ε (C/EBPε) knockout mice, which lack mature neutrophils. RESULTS: In patients without AKI and bacterial infection, at 1 week after SCT, the median blood neutrophil counts became zero and serum LCN2 levels were decreased by 76 ± 6 % (p < 0.01), but urinary LCN2 levels were not altered. During neutropenic conditions, bacterial infection caused only a modest rise of serum LCN2 but AKI produced a marked rise of serum and urinary LCN2 levels. Serum LCN2 concentrations in C/EBPε knockout mice were reduced by 66 ± 11 % compared to wild-type mice (p < 0.05). Blood LCN2 existed predominantly in high molecular weight forms (>100 kDa), while urinary LCN2 was mainly in low molecular weight forms. CONCLUSION: Our findings suggest that neutrophils are the major source of circulating LCN2 in normal and infected conditions, whereas blood and urinary LCN2 mainly derive from the kidney during AKI, and that the molecular forms and regulation of blood and urinary LCN2 are clearly distinct.


Assuntos
Injúria Renal Aguda/sangue , Rim/metabolismo , Lipocalinas/sangue , Neutrófilos/metabolismo , Proteínas Oncogênicas/sangue , Proteínas de Fase Aguda/urina , Animais , Infecções Bacterianas/sangue , Infecções Bacterianas/urina , Biomarcadores/sangue , Biomarcadores/urina , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Lipocalina-2 , Lipocalinas/urina , Camundongos , Camundongos Knockout , Peso Molecular , Proteínas Oncogênicas/urina
4.
Cancer Chemother Pharmacol ; 93(2): 161-167, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37608127

RESUMO

PURPOSE: Hyperammonemia is a serious adverse effect of 5-fluorouracil (5FU) administration. Hemodialysis can be used for its management, but detailed data on the concentrations and removal rate of 5FU and its metabolites during hemodialysis remain unclear. Here, we present two cases of hemodialysis patients with end-stage renal disease who received concurrent 5FU infusion. METHODS: Blood samples were collected from the hemodialysis circuit before and after the dialyzer during day 2 hemodialysis sessions, and from the internal shunt just before and after day 4 hemodialysis sessions. The serum levels of 5FU and its metabolites-α-fluoro-ß-alanine (FBAL) and monofluoroacetate (FA)-were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Seven sets of blood samples were collected for case 1; the removal rates (mean ± standard deviation) of 5FU and FBAL by the dialyzer were 81.2 ± 23.2% and 96.1 ± 8.6%, respectively (p < 0.001). Three sets of blood samples were collected for case 2; the removal rates of 5FU and FBAL were 81.7 ± 3.9% and 94.8 ± 2.7%, respectively (p = 0.03). Twenty-seven sets of blood samples were collected for case 1; reductions in blood FBAL and FA levels were 49.3 ± 8.8% (p < 0.001) and 64.2 ± 30.3% (p = 0.04), respectively. Bayesian estimation yielded similar results. Three sets of blood samples were collected for case 2; reductions in the blood FBAL and FA levels were 49.9 ± 6.9% and 50.6 ± 33.0%, respectively. CONCLUSION: In this study, 5FU and its metabolite FBAL were directly removed from the blood by approximately 90% during hemodialysis, and the blood levels of FBAL and FA were reduced by approximately 50% with a single hemodialysis session.


Assuntos
Neoplasias Colorretais , Falência Renal Crônica , Humanos , Fluoruracila , Teorema de Bayes , Diálise Renal , Falência Renal Crônica/terapia , Neoplasias Colorretais/tratamento farmacológico
5.
J Am Soc Nephrol ; 23(7): 1198-209, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22652704

RESUMO

Natriuretic peptides produced by the heart in response to cardiac overload exert cardioprotective and renoprotective effects by eliciting natriuresis, reducing BP, and inhibiting cell proliferation and fibrosis. These peptides also antagonize the renin-angiotensin-aldosterone system, but whether this mechanism contributes to their renoprotective effect is unknown. Here, we examined the kidneys of mice lacking the guanylyl cyclase-A (GC-A) receptor for natriuretic peptides under conditions of high aldosterone and high dietary salt. After 4 weeks of administering aldosterone and a high-salt diet, GC-A knockout mice, but not wild-type mice, exhibited accelerated hypertension with massive proteinuria. Aldosterone-infused GC-A knockout mice had marked mesangial expansion, segmental sclerosis, severe podocyte injury, and increased oxidative stress. Reducing the BP with hydralazine failed to lessen such changes; in contrast, blockade of the renin-angiotensin-aldosterone system markedly reduced albuminuria, ameliorated podocyte injury, and reduced oxidative stress. Furthermore, treatment with the antioxidant tempol significantly reduced albuminuria and abrogated the histologic changes. In cultured podocytes, natriuretic peptides inhibited aldosterone-induced mitogen-activated protein kinase phosphorylation. Taken together, these results suggest that renoprotective properties of the endogenous natriuretic peptide/GC-A system may result from the local inhibition of the renin-angiotensin-aldosterone system and oxidative stress in podocytes.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Aldosterona/efeitos adversos , Aldosterona/farmacologia , Podócitos/efeitos dos fármacos , Podócitos/patologia , Receptores do Fator Natriurético Atrial/fisiologia , Injúria Renal Aguda/prevenção & controle , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hidralazina/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Podócitos/metabolismo , Proteinúria/induzido quimicamente , Proteinúria/patologia , Receptores do Fator Natriurético Atrial/deficiência , Receptores do Fator Natriurético Atrial/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Cloreto de Sódio na Dieta/efeitos adversos , Cloreto de Sódio na Dieta/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Cancer Chemother Pharmacol ; 92(1): 7-14, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37204512

RESUMO

PURPOSE: Fluoropyrimidines are anticancer drugs and can cause hyperammonemia both intravenously and orally. Renal dysfunction may interact with fluoropyrimidine to cause hyperammonemia. We performed quantitative analyses of hyperammonemia using a spontaneous report database to examine the frequency of intravenously and orally administered fluoropyrimidine, the reported frequency of fluoropyrimidine-related regimens, and fluoropyrimidine's interactions with chronic kidney disease (CKD). METHODS: This study used data collected between April 2004 and March 2020 from the Japanese Adverse Drug Event Report database. The reporting odds ratio (ROR) of hyperammonemia was calculated for each fluoropyrimidine drug and was adjusted for age and sex. Heatmaps depicting the use of anticancer agents in patients with hyperammonemia were drawn. The interactions between CKD and the fluoropyrimidines were also calculated. These analyses were performed using multiple logistic regression. RESULTS: Hyperammonemia was observed in 861 of the 641,736 adverse events reports. Fluorouracil was the most frequent drug associated with hyperammonemia (389 cases). The ROR of hyperammonemia was 32.5 (95% CI 28.3-37.2) for intravenously administered fluorouracil, 4.7 (95% CI 3.3-6.6) for orally administered capecitabine, 1.9 (95% CI 0.87-4.3) for tegafur/uracil, and 2.2 (95% CI 1.5-3.2) for orally administered tegafur/gimeracil/oteracil. Calcium levofolinate, oxaliplatin, bevacizumab, and irinotecan were the most frequently reported agents in cases of hyperammonemia with intravenously administered fluorouracil. The coefficient of the interaction term between CKD and fluoropyrimidines was 1.12 (95% CI 1.09-1.16). CONCLUSION: Hyperammonemia cases were more likely to be reported with intravenous fluorouracil than orally administered fluoropyrimidines. Fluoropyrimidines might interact with CKD in hyperammonemia cases.


Assuntos
Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hiperamonemia , Humanos , Antimetabólitos , Antineoplásicos/efeitos adversos , Capecitabina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Fluoruracila , Hiperamonemia/induzido quimicamente , Tegafur , Japão
7.
Kidney Int ; 81(2): 160-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21881556

RESUMO

Long-term peritoneal dialysis induces peritoneal fibrosis with submesothelial fibrotic tissue. Although angiogenesis and inflammatory mediators are involved in peritoneal fibrosis, precise molecular mechanisms are undefined. To study this, we used microarray analysis and compared gene expression profiles of the peritoneum in control and chlorhexidine gluconate (CG)-induced peritoneal fibrosis mice. One of the 43 highly upregulated genes was pleiotrophin, a midkine family member, the expression of which was also upregulated by the solution used to treat mice by peritoneal dialysis. This growth factor was found in fibroblasts and mesothelial cells within the underlying submesothelial compact zones of mice, and in human peritoneal biopsy samples and peritoneal dialysate effluent. Recombinant pleiotrophin stimulated mitogenesis and migration of mouse mesothelial cells in culture. We found that in wild-type mice, CG treatment increased peritoneal permeability (measured by equilibration), increased mRNA expression of TGF-ß1, connective tissue growth factor and fibronectin, TNF-α and IL-1ß expression, and resulted in infiltration of CD3-positive T cells, and caused a high number of Ki-67-positive proliferating cells. All of these parameters were decreased in peritoneal tissues of CG-treated pleiotrophin-knockout mice. Thus, an upregulation of pleiotrophin appears to play a role in fibrosis and inflammation during peritoneal injury.


Assuntos
Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Expressão Gênica , Fibrose Peritoneal/genética , Fibrose Peritoneal/metabolismo , Peritônio/patologia , RNA Mensageiro/metabolismo , Adulto , Idoso de 80 Anos ou mais , Animais , Biópsia , Complexo CD3 , Proteínas de Transporte/genética , Proteínas de Transporte/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Clorexidina/análogos & derivados , Fator de Crescimento do Tecido Conjuntivo/genética , Citocinas/genética , Citocinas/farmacologia , Soluções para Diálise/química , Feminino , Fibronectinas/genética , Humanos , Interleucina-1beta/metabolismo , Antígeno Ki-67 , Contagem de Linfócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Índice Mitótico , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/fisiopatologia , Peritônio/metabolismo , Peritonite/etiologia , Peritonite/metabolismo , Permeabilidade , Linfócitos T , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
8.
Cancer Chemother Pharmacol ; 86(5): 693-699, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33011861

RESUMO

PURPOSE: Hyperammonemia is an important adverse event associated with 5-fluorouracil (5FU) from 5FU metabolite accumulation. We present a case of an advanced gastric cancer patient with chronic renal failure, who was treated with 5FU/leucovorin (LV) infusion chemotherapy (2-h infusion of LV and 5FU bolus followed by 46-h 5FU continuous infusion on day 1; repeated every 2 weeks) and developed hyperammonemia, with the aim of exploring an appropriate hemodialysis (HD) schedule to resolve its symptoms. METHODS: The blood concentrations of 5FU and its metabolites, α-fluoro-ß-alanine (FBAL), and monofluoroacetate (FA) of a patient who had hyperammonemia from seven courses of palliative 5FU/LV therapy for gastric cancer were measured by liquid chromatography-mass spectrometry. RESULTS: On the third day of the first cycle, the patient presented with symptomatic hyperammonemia relieved by emergency HD. Thereafter, the 5FU dose was reduced; however, in cycles 2-4, the patient developed symptomatic hyperammonemia and underwent HD on day 3 for hyperammonemia management. In cycles 5-7, the timing of scheduled HD administration was changed from day 3 to day 2, preventing symptomatic hyperammonemia. The maximum ammonia and 5FU metabolite levels were significantly lower in cycles 5-7 than in cycles 2-4 (NH3 75 ± 38 vs 303 ± 119 µg/dL, FBAL 13.7 ± 2.5 vs 19.7 ± 2.0 µg/mL, FA 204.0 ± 91.6 vs 395.9 ± 12.6 ng/mL, mean ± standard deviation, all p < 0.05). After seven cycles, partial response was confirmed. CONCLUSION: HD on day 2 instead of 3 may prevent hyperammonemia in 5FU/LV therapy.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Hiperamonemia/terapia , Diálise Renal , Neoplasias Gástricas/tratamento farmacológico , Idoso de 80 Anos ou mais , Amônia/sangue , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/metabolismo , Esquema de Medicação , Fluoracetatos/sangue , Fluoracetatos/metabolismo , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Fluoruracila/metabolismo , Humanos , Hiperamonemia/sangue , Hiperamonemia/induzido quimicamente , Hiperamonemia/diagnóstico , Masculino , Fatores de Tempo , Resultado do Tratamento , beta-Alanina/análogos & derivados , beta-Alanina/sangue , beta-Alanina/metabolismo
9.
Kidney Int ; 75(3): 285-94, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19148153

RESUMO

Urinary neutrophil gelatinase-associated lipocalin (Ngal or lipocalin 2) is a very early and sensitive biomarker of kidney injury. Here we determined the origin and time course of Ngal appearance in several experimental and clinically relevant renal diseases. Urinary Ngal levels were found to be markedly increased in lipoatrophic- and streptozotocin-induced mouse models of diabetic nephropathy. In the latter mice, the angiotensin receptor blocker candesartan dramatically decreased urinary Ngal excretion. The reabsorption of Ngal by the proximal tubule was severely reduced in streptozotocin-induced diabetic mice, but upregulation of its mRNA and protein in the kidney was negligible, compared to those of control mice, suggesting that increased urinary Ngal was mainly due to impaired renal reabsorption. In the mouse model of unilateral ureteral obstruction, Ngal protein synthesis was dramatically increased in the dilated thick ascending limb of Henle and N was found in the urine present in the swollen pelvis of the ligated kidney. Five patients with nephrotic syndrome or interstitial nephritis had markedly elevated urinary Ngal levels at presentation, but these decreased in response to treatment. Our study shows that the urinary Ngal level may be useful for monitoring the status and treatment of diverse renal diseases reflecting defects in glomerular filtration barrier, proximal tubule reabsorption, and distal nephrons.


Assuntos
Proteínas de Fase Aguda/metabolismo , Modelos Animais de Doenças , Glomérulos Renais/metabolismo , Túbulos Renais Proximais/metabolismo , Lipocalinas/metabolismo , Néfrons/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Injúria Renal Aguda/metabolismo , Proteínas de Fase Aguda/urina , Albuminas/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Benzimidazóis/uso terapêutico , Biomarcadores/urina , Compostos de Bifenilo , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/urina , Humanos , Túbulos Renais Proximais/citologia , Lipocalina-2 , Lipocalinas/urina , Alça do Néfron/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nefrite Intersticial/metabolismo , Nefrite Intersticial/urina , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/urina , Proteínas Proto-Oncogênicas/urina , RNA Mensageiro/metabolismo , Sensibilidade e Especificidade , Tetrazóis/uso terapêutico , Fatores de Tempo , Obstrução Ureteral/metabolismo
10.
Clin Exp Nephrol ; 13(5): 512-517, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19452242

RESUMO

Microscopic polyangiitis is a vasculitis which primarily affects capillaries, venules or arterioles. Involvement of small and medium-sized arteries may also occur. A 70-year-old Japanese female with a fever and cough was diagnosed with pneumonia and antibiotics were administered. Her symptoms initially improved, but her fever recurred and she experienced malaise and loss of appetite. Her renal function gradually worsened and she was positive for myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA). She was referred to our hospital on the suspicion of ANCA-associated glomerulonephritis. However, her depressive mental symptoms did not allow her to undergo a renal biopsy. She was clinically diagnosed with ANCA-associated glomerulonephritis, and oral corticosteroids and intravenous methylprednisolone were administered. Her symptoms and renal function were improved, but she died suddenly 15 days after admission. An autopsy disclosed approximately 700 mL bloody ascites. Coagulation adhered to the lesser curvature of the stomach, but the source of hemorrhage could not be detected macroscopically because the gastric mucosa did not show abnormal findings. The histological findings revealed that the left gastric artery showed necrotizing angiitis and rupture. In the kidneys, cellular crescents were found in approximately 10%, fibrous crescents were found in approximately 10%, sclerosis and collapse were found approximately 30% of the glomeruli, and necrotizing angiitis was observed in interlobular arteries and arterioles. From these findings, she was finally diagnosed with microscopic polyangiitis. Microscopic polyangiitis is an extremely rare cause of spontaneous intraperitoneal bleeding, but it must be carefully considered in the differential diagnosis for the appropriate management of such patients.


Assuntos
Artérias/patologia , Hemoperitônio/etiologia , Poliangiite Microscópica/complicações , Estômago/irrigação sanguínea , Idoso , Diagnóstico Diferencial , Evolução Fatal , Feminino , Hemoperitônio/patologia , Humanos , Poliangiite Microscópica/patologia
11.
Nihon Jinzo Gakkai Shi ; 50(7): 942-7, 2008.
Artigo em Japonês | MEDLINE | ID: mdl-19069153

RESUMO

A female in her late 60s with chronic kidney disease was admitted to the emergency department with complaints of dizziness four days prior to hospitalization. Cibenzoline (300 mg/day) was administered for atrial fibrillation, which was detected in an electrocardiogram. After three days, she experienced blepharoptosis and was admitted for suspected myasthenia gravis. However, the anti-acetylcholine receptor antibody and edrophonium tests were negative. On day four after hospitalization, she suffered from pneumonia with pleural effusion and she was put on a respirator for four days. From day 16 after hospitalization, she had diarrhea and her renal function worsened. At the same time, a gradual aggravation of right blepharoptosis, dull headache, weakness and difficulty in chewing were noted. She experienced dyspnea on day 31 after hospitalization. Chest X-ray film did not show a pneumonia shadow or pleural effusion, and arterial blood gases revealed hypercapnia; she was diagnosed as having CO2 narcosis due to respiratory muscle fatigue and was put on a respirator again. Myasthenia-like syndrome was suspected because of a probable overdose of cibenzoline and administration of cibenzoline was withdrawn. Her condition improved and she was taken off the respirator on day 35 after hospitalization. Repetitive stimulation of 5 Hz was applied to her right facial nerve along with evoked electromyogram(EMG) on days 2 and 11 after discontinuing cibenzoline. On day 2, the EMG showed a waning phenomenon, whereas no such phenomenon was seen on day 11. The blood concentration of cibenzoline immediately after withdrawal was extremely high (2448 ng/mL). When this drug is administered to a patient with chronic kidney disease, attention must be paid to the indication, dose, and manifestation of the possible side effects.


Assuntos
Antiarrítmicos/efeitos adversos , Imidazóis/efeitos adversos , Nefropatias/complicações , Miastenia Gravis/induzido quimicamente , Idoso , Doença Crônica , Overdose de Drogas , Feminino , Humanos
12.
CEN Case Rep ; 6(1): 79-84, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28509135

RESUMO

Renal-limited vasculitis (RLV) is a type of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis that presents with crescentic glomerulonephritis with no other organ involvement. Although several studies reported patients with crescentic glomerulonephritis who were dual positive for proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA or ANCA and anti-glomerular basement membrane (GBM) antibody, patients positive for all three antibodies, i.e., triple-positive patients, were rarely reported. We herein report the case of a male with pauci-immune type crescentic glomerulonephritis positive for MPO-ANCA, PR3-ANCA, and anti-GBM antibody. Renal biopsy led to the definitive diagnosis of RLV with pauci-immune-type crescentic glomerulonephritis. Fluorescence immunostaining showed no linear deposition of IgG on GBM, indicating no involvement of anti-GBM associated diseases. Intensive therapy, including prednisolone, plasma exchange, and intravenous cyclophosphamide, was effective. We report the case of triple-positive patient with crescentic glomerulonephritis, who was successfully treated with glucocorticoid, plasma exchange, and cyclophosphamide, suggesting that treatment for RLV in the patient with serological triple antibodies positivity in the absence of linear IgG deposition could benefit from the combination therapy regimen for plasma exchange and primary induction of remission against microscopic polyangiitis.

13.
Sci Rep ; 7(1): 15501, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29138470

RESUMO

Neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2 or LCN2) is an iron carrier protein whose circulating level is increased by kidney injury, bacterial infection and obesity, but its metabolic consequence remains elusive. To study physiological role of LCN2 in energy homeostasis, we challenged female Lcn2 knockout (KO) and wild-type (WT) mice with high fat diet (HFD) or cold exposure. Under normal diet, physical constitutions of Lcn2 KO and WT mice were indistinguishable. During HFD treatment, Lcn2 KO mice exhibited larger brown adipose tissues (BAT), consumed more oxygen, ate more food and gained less body weights as compared to WT mice. When exposed to 4 °C, KO mice showed higher body temperature and more intense 18F-fluorodeoxyglucose uptake in BAT, which were cancelled by ß3 adrenergic receptor blocker or iron-loaded (but not iron-free) LCN2 administration. These findings suggest that circulating LCN2 possesses obesity-promoting and anti-thermogenic effects through inhibition of BAT activity in an iron-dependent manner.


Assuntos
Tecido Adiposo Marrom/metabolismo , Lipocalina-2/genética , Obesidade/genética , RNA Mensageiro/genética , Termogênese/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Transporte Biológico , Temperatura Baixa , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/genética , Metabolismo Energético/genética , Enterobactina/farmacologia , Feminino , Fluordesoxiglucose F18/metabolismo , Regulação da Expressão Gênica , Lipocalina-2/sangue , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Consumo de Oxigênio/genética , Propanolaminas/farmacologia , RNA Mensageiro/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais
14.
Sci Rep ; 6: 27192, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27273361

RESUMO

Pharmacological blockade of the N- and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Cav2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Cav2.2(-/-) mice with db/db (diabetic) mice on the C57BLKS background. Cav2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Cav2.2(-/-) mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Cav2.2(+/+) mice. Interestingly, diabetic heterozygous Cav2.2(+/-) mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Cav2.2(+/+) mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Cav2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-ß (TGF-ß) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Cav2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes.


Assuntos
Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Canais de Cálcio Tipo N/genética , Nefropatias Diabéticas/tratamento farmacológico , ômega-Conotoxinas/administração & dosagem , Animais , Glicemia/efeitos dos fármacos , Canais de Cálcio Tipo N/efeitos dos fármacos , Canais de Cálcio Tipo N/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Túbulos Renais Distais/citologia , Túbulos Renais Distais/metabolismo , Camundongos , Podócitos/citologia , Podócitos/metabolismo , ômega-Conotoxinas/farmacologia
16.
PLoS One ; 10(7): e0132539, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26161663

RESUMO

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL or LCN2) is an iron-transporting factor which possesses various activities such as amelioration of kidney injury and host defense against pathogens. Its circulating concentrations are elevated in acute and chronic kidney diseases and show a positive correlation with poor renal outcome and mortality, but its clinical significance in maintenance hemodialysis (HD) patients remains elusive. METHODS: Serum NGAL levels were determined by enzyme-linked immunosorbent assay in out-patient, Japanese HD subjects. Their correlation to laboratory findings and morbidity (as development of severe infection or serum albumin reduction) was investigated using linear regression analysis and χ2 test. RESULTS: Pre-dialysis serum NGAL levels in HD patients were elevated by 13-fold compared to healthy subjects (n=8, P<0.001). In a cross-sectional study of 139 cases, serum NGAL concentrations were determined independently by % creatinine generation rate (an indicator of muscle mass, standardized coefficient ß=0.40, P<0.001), peripheral blood neutrophil count (ß=0.38, P<0.001) and anion gap (which likely reflects dietary protein intake, ß=0.16, P<0.05). Iron administration to anemic HD patients caused marked elevation of peripheral blood hemoglobin, serum ferritin and iron-regulatory hormone hepcidin-25 levels, but NGAL levels were not affected. In a prospective study of 87 cases, increase in serum albumin levels a year later was positively associated to baseline NGAL levels by univariate analysis (r=0.36, P<0.01). Furthermore, within a year, patients with the lowest NGAL tertile showed significantly increased risk for marked decline in serum albumin levels (≥0.4 g/dl; odds ratio 5.5, 95% confidence interval 1.5-20.3, P<0.05) and tendency of increased occurrence of severe infection requiring admission (odds ratio 3.1, not significant) compared to the middle and highest tertiles. CONCLUSION: Low serum NGAL levels appear to be associated with current malnutrition and also its progressive worsening in maintenance HD patients.


Assuntos
Lipocalinas/sangue , Desnutrição/sangue , Proteínas Proto-Oncogênicas/sangue , Diálise Renal , Proteínas de Fase Aguda , Fatores Etários , Idoso , Aorta/metabolismo , Biomarcadores/sangue , Progressão da Doença , Feminino , Seguimentos , Humanos , Inflamação/patologia , Ferro/administração & dosagem , Ferro/farmacologia , Modelos Lineares , Lipocalina-2 , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Veias Renais/metabolismo , Albumina Sérica/metabolismo
17.
PLoS One ; 9(2): e88942, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24558454

RESUMO

BACKGROUND AND OBJECTIVE: We have reported that toll-like receptor 4 (TLR4) and one of its endogenous ligands, myeloid-related protein 8 (MRP8 or S100A8), play an important role in the progression of diabetic nephropathy in mice. The aim of this study was to evaluate significance of kidney MRP8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases. METHODS: In diabetic, obese or control subjects, MRP8 mRNA and protein expression levels in renal biopsy samples were determined by real-time RT-PCR and immunohistochemistry (n = 28 and 65, respectively), and their associations with baseline and prognostic parameters were analyzed. Effects of MRP8 upon pro-inflammatory gene expressions were examined using macrophages. RESULTS: Kidney MRP8 gene and protein expression levels were elevated in obese or diabetic groups compared to control group. Among all subjects, by univariate linear regression analysis, glomerular MRP8-positive cell count and tubulointerstitial MRP8-positive area at baseline were both, respectively, correlated not only with various known risk factors for diabetic nephropathy (such as systolic blood pressure, proteinuria and serum creatinine) but also with extent of glomerulosclerosis and tubulointerstitial fibrosis. Independent factors predicting urinary protein levels a year later were examined by multivariate analysis, and they included glomerular MRP8-positive cell count (ß = 0.59, P<0.001), proteinuria (ß = 0.37, P = 0.002) and systolic blood pressure (ß = 0.21, P = 0.04) at baseline, after adjustment for known risk factors. MRP8 protein expression was observed in CD68-positive macrophages and atrophic tubules. In cultured mouse macrophages, MRP8 protein induced proinflammatory cytokine expressions and also triggered auto-induction of MRP8 in a TLR4-dependent manner. CONCLUSIONS: Glomerular MRP8 expression appears to be associated with progression of proteinuria in obese or type 2 diabetic patients, possibly by inducing inflammatory changes in macrophages through TLR4 signaling.


Assuntos
Calgranulina A/metabolismo , Diabetes Mellitus Tipo 2/complicações , Regulação da Expressão Gênica , Nefropatias/complicações , Nefropatias/metabolismo , Rim/metabolismo , Obesidade/complicações , Adulto , Animais , Calgranulina A/genética , Feminino , Humanos , Nefropatias/diagnóstico , Nefropatias/urina , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico
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