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1.
Kidney Int ; 85(2): 457-70, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24067439

RESUMO

Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies.


Assuntos
Inibidores da Angiogênese/efeitos adversos , Proteínas de Transporte/metabolismo , Nefropatias/induzido quimicamente , Glomérulos Renais/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Fator de Transcrição RelA/metabolismo , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Animais , Sequência de Bases , Sítios de Ligação , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Estudos de Casos e Controles , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/enzimologia , Humanos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Hipertensão/enzimologia , Nefropatias/diagnóstico , Nefropatias/enzimologia , Glomérulos Renais/enzimologia , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Dados de Sequência Molecular , Nefrose Lipoide/induzido quimicamente , Nefrose Lipoide/diagnóstico , Nefrose Lipoide/enzimologia , Niacinamida/efeitos adversos , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Proteinúria/induzido quimicamente , Proteinúria/diagnóstico , Proteinúria/enzimologia , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/diagnóstico , Insuficiência Renal/enzimologia , Sorafenibe , Microangiopatias Trombóticas/induzido quimicamente , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/enzimologia , Fator de Transcrição RelA/deficiência , Fator de Transcrição RelA/genética , Transcrição Gênica , Transfecção , Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
2.
Clin Exp Nephrol ; 14(5): 487-91, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20535626

RESUMO

Although uncommon, thrombotic microangiopathy (TMA) is one of the most serious complications in patients with systemic lupus erythematosus. A 30-year-old black woman admitted to our hospital because of fever, fatigue, 'dark' urine and rapidly progressive renal failure was found to have systemic lupus erythematous and atypical hemolytic uremic syndrome. Kidney biopsy showed WHO class IV lupus nephritis with crescents and TMA. Hemodialysis was initiated for worsening renal failure. The patient was treated with corticosteroids, monthly pulse intravenous Cyclophosphamide, plasmapheresis and Rituximab on a weekly basis for 4 weeks. The patient's blood pressure was aggressively controlled using antihypertensive agents. Despite this extensive therapy, she remained dialysis dependent although hematological parameters returned to normal values.


Assuntos
Injúria Renal Aguda/etiologia , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/etiologia , Nefrite Lúpica/patologia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/patologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/terapia , Corticosteroides/uso terapêutico , Adulto , Feminino , Humanos , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Nefrite Lúpica/terapia , Diálise Renal , Microangiopatias Trombóticas/terapia , Resultado do Tratamento
4.
AIDS ; 23(10): 1219-26, 2009 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-19440143

RESUMO

BACKGROUND: Hepatitis C virus (HCV) co-infection occurs in 25% of HIV-infected persons. The impact of HIV/HCV coinfection on renal and patient outcomes is unclear. METHODS: The main objective of the study is the comparison of outcomes (progression to advanced renal failure, initiation of dialysis, and death) in patients with HIV (n = 40), HCV (n = 30) or coinfection (n = 30) during the period between January 1999 and December 2007. RESULTS: Patients were predominantly white men with a mean creatinine clearance of 50.6 +/- 32.2 ml per min per 1.73 m. Membranoproliferative glomerulonephritis (MPGN) and HIV-associated nephropathy were found in 34 and 9%, respectively. Seventeen patients needed transitory or definitive hemodialysis after 2, 2.5, and 12 months in HIV/HCV (n = 5), HIV (n = 6) and HCV (n = 6) infections, respectively. In multivariate analysis, variables found to independently predict outcome in HIV/HCV coinfected patients were younger age, a longer delay to kidney biopsy, cryoglobulinemia and MPGN. Twenty-one patients died, mostly in the HCV (n = 8) and/or HIV/HCV coinfected (n = 12) groups. The relative risk of death for HIV/HCV co-infected patients was 2.1 times more than for HCV-infected patients and 7.5 times more than for HIV-infected patients. HIV/HCV co-infection [odds ratio (OR), = 4; 95% confidence interval (CI), 1.3-12.9; P = 0.015] and MPGN (OR, 6; 95% CI, 2-18.8; P = 0.0018) were independently associated with death. CONCLUSION: Kidney disease is a relatively frequent complication in HIV or HCV monoinfected individuals. The impact of kidney disease on survival of HIV/HCV coinfected patients seems deleterious but remains largely unknown.


Assuntos
Infecções por HIV/complicações , Hepatite C Crônica/complicações , Nefropatias/virologia , Nefropatia Associada a AIDS/complicações , Adulto , Fatores Etários , Idoso , Progressão da Doença , Métodos Epidemiológicos , Feminino , Glomerulonefrite Membranoproliferativa/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Diálise Renal , Insuficiência Renal/virologia
5.
Int J Hematol ; 89(2): 218-222, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19156501

RESUMO

Waldenström's macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma characterized by a circulating monoclonal IgM. Renal involvement in classical cases of WM is rare, and the pathological hallmark finding in the renal biopsy specimen is a thrombotic microangiopathy. We report the case of a 69-year-old man with the diagnosis of WM for 3 months before he presented with acute renal failure (ARF). A renal biopsy performed suggested the diagnosis of acute tubular necrosis. The diagnosis of ARF related to IgM flare after Rituximab therapy was made.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Anticorpos Monoclonais/efeitos adversos , Imunoglobulina M , Túbulos Renais/patologia , Macroglobulinemia de Waldenstrom/complicações , Injúria Renal Aguda/patologia , Idoso , Anticorpos Monoclonais Murinos , Humanos , Túbulos Renais/efeitos dos fármacos , Masculino , Necrose/induzido quimicamente , Rituximab , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologia
8.
Nat Clin Pract Nephrol ; 4(2): 110-4, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18227804

RESUMO

BACKGROUND: A 58-year-old African American man with an uncontrolled HIV infection presented to hospital with nephrotic syndrome and diffuse lymphadenopathy. The patient had been taking highly active antiretroviral therapy (HAART; lamivudine, abacavir, fosamprenavir and ritonavir) for 10 years. A renal biopsy showed acute granulomatous interstitial nephritis. Despite a negative tuberculin skin test, he was treated with antituberculosis drugs for 12 months without improvement of his renal profile. Two months after antituberculosis treatment was discontinued, the patient was readmitted to hospital because of acute renal failure. Corticosteroid therapy (prednisone) was started and resulted in a marked improvement in renal function. However, 18 months after steroids were discontinued, renal function declined dramatically. Furthermore, the patient had CD8+ lymphocytosis as well as interstitial tissue infiltration by CD8+ T lymphocytes. INVESTIGATIONS: Physical examination, plasma HIV viral load, lymphocyte counts, urinalysis, tuberculin skin test, liver function tests, renal ultrasonography, human leukocyte antigen (HLA) typing, renal and minor salivary gland biopsies, ophthalmological examination, chest radiography and culture of bronchoalveolar lavage fluid. DIAGNOSIS: Acute granulomatous interstitial nephritis secondary to diffuse infiltrative lymphocytosis syndrome. MANAGEMENT: HAART and prednisone.


Assuntos
Injúria Renal Aguda/diagnóstico , Infecções por HIV/diagnóstico , Linfocitose/diagnóstico , Nefrite Intersticial/diagnóstico , Injúria Renal Aguda/complicações , Injúria Renal Aguda/imunologia , Biópsia por Agulha , Educação Médica Continuada , Seguimentos , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Imuno-Histoquímica , Testes de Função Renal , Contagem de Linfócitos , Linfocitose/complicações , Linfocitose/imunologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/complicações , Nefrite Intersticial/imunologia , Medição de Risco , Índice de Gravidade de Doença , Síndrome
10.
Am J Kidney Dis ; 48(1): 143-50, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16797397

RESUMO

We report a case of limb-girdle muscular dystrophy type 2B (LGMD2B) associated with minimal change disease. Immunohistochemical examination of quadriceps muscle showed a deficiency in dysferlin in sarcolemma, and dysferlin gene analysis showed 3370 G missense mutation, leading us to the diagnosis of LGMD2B. The patient also developed glomerular proteinuria. We also explored urinary protein levels in 3 other patients with dysferlinopathy and found microalbuminuria with albumin excretion of 0.14 to 0.18 g/d in 2 patients. Renal abnormalities during LGMD2B and kidney dysferlin expression have never been reported. Renal biopsy showed a lack of glomerular dysferlin expression compared with a positive immunohistochemical marking in patients with idiopathic minimal change nephropathy and healthy controls. We therefore suggest that dysferlin is present in glomeruli and may be associated with glomerular permeability.


Assuntos
Proteínas de Membrana/genética , Proteínas Musculares/genética , Adulto , Disferlina , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Glomérulos Renais/fisiologia , Masculino , Proteínas de Membrana/biossíntese , Proteínas Musculares/biossíntese , Distrofia Muscular do Cíngulo dos Membros , Mutação de Sentido Incorreto , Nefrose Lipoide , Permeabilidade , Podócitos
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