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1.
Nephrol Dial Transplant ; 36(8): 1389-1398, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32582935

RESUMO

The proteasome to immunoproteasome (iPS) switch consists of ß1, ß2 and ß5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/ß5 and LMP2/ß1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/ß5 (P < 0.0001). The LMP7/ß5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. -1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/ß5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/ß5 and low CD46 expression.


Assuntos
Glomerulonefrite por IGA , Complexo de Endopeptidases do Proteassoma , Estudo de Associação Genômica Ampla , Glomerulonefrite por IGA/genética , Humanos , Proteína Cofatora de Membrana , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro , Regulação para Cima
2.
Nephrol Dial Transplant ; 35(6): 1002-1009, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30418652

RESUMO

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.


Assuntos
Glomerulonefrite por IGA/classificação , Glomerulonefrite por IGA/patologia , Rim/fisiopatologia , Adolescente , Adulto , Criança , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Prognóstico
3.
Nephrol Dial Transplant ; 34(4): 587-596, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635535

RESUMO

BACKGROUND: Complement is thought to play a role in immunoglobulin A nephropathy (IgAN), though the activating mechanisms are unknown. This study focused on the gene expression of CD46 and CD55, two key molecules for regulating C3 convertase activity of lectin and alternative complement pathways at a cellular level. METHODS: The transcriptional expression in peripheral white blood cells (WBCs) of CD46 and CD55 was investigated in 157 patients enrolled by the Validation of the Oxford Classification of IgAN group, looking for correlations with clinical and pathology features and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous median follow-up of 6.4 (interquartile range 2.8-10.7) years and were divided into progressors and non-progressors according to the median value of their velocity of loss of renal function per year (-0.41 mL/min/1.73 m2/year). RESULTS: CD46 and CD55 messenger RNA (mRNA) expression in WBCs was not correlated with eGFR values or proteinuria at sampling. CD46 mRNA was significantly correlated with eGFR decline rate as a continuous outcome variable (P = 0.014). A significant difference was found in CD46 gene expression between progressors and non-progressors (P = 0.013). CD46 and CD55 mRNA levels were significantly correlated (P < 0.01), although no difference between progressors and non-progressors was found for CD55 mRNA values. The prediction of progression was increased when CD46 and CD55 mRNA expressions were added to clinical data at renal biopsy (eGFR, proteinuria and mean arterial blood pressure) and Oxford MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, presence of any crescents) score. CONCLUSIONS: Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.


Assuntos
Biomarcadores/sangue , Inativadores do Complemento/sangue , Glomerulonefrite por IGA/diagnóstico , Proteína Cofatora de Membrana/sangue , Adulto , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/genética , Humanos , Masculino , Proteína Cofatora de Membrana/genética , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/sangue , RNA Mensageiro/genética
4.
Pediatr Nephrol ; 32(1): 139-150, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27557557

RESUMO

BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m2 and an eGFR of <90 ml/min/1.73 m2 were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m2) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.


Assuntos
Glomerulonefrite por IGA/epidemiologia , Corticosteroides/uso terapêutico , Fatores Etários , Biópsia , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Determinação de Ponto Final , Europa (Continente)/epidemiologia , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Imunossupressores , Lactente , Rim/patologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/patologia , Masculino , Proteinúria/epidemiologia , Proteinúria/patologia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Análise de Sobrevida
5.
Biotechnol Appl Biochem ; 64(3): 443-448, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27067406

RESUMO

Bacterial-derived DNA fragments (BDNAs) have been shown to be present in a dialysis fluid, to pass through dialyzer membranes, and to induce interleukin 6 (IL-6) in mononuclear cells. DNA fragments are thought to be derived from microorganisms inhabiting hemodialysis water and fluid. The primary aim of the present study was to develop two degenerated TaqMan real-time quantitative-PCR (Q-PCR) for detection of a broad range of bacterial DNA that specifically detect 16S ribosomal DNA (rDNA) (862 and 241 bp) and evaluate the efficiency of the Bellco Selecta resin to capture the BDNAs in the dialysis fluid. For this purpose, we decided to compare measurements of unfragmented samples (9.8 × 105 Escherichia coli genome) with artificially fragmented DNA samples. We assessed two broad-range real-time PCR targeting bacterial 16S rRNA genes for detection of fragmented and unfragmented bacterial DNA in the dialytic fluid and demonstrated that Bellco Selecta resin is capable of retaining these types of bacterial DNA.


Assuntos
DNA Bacteriano/genética , DNA Ribossômico/genética , Escherichia coli/genética , Genes de RNAr , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos
6.
Blood Purif ; 44(3): 198-205, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28668963

RESUMO

BACKGROUND: Metformin-associated lactic acidosis (MALA) is a severe complication of drug administration with significant morbidity and mortality. So far no study in large population areas have examined the incidence, clinical profile and outcome of acute kidney injury (AKI)-MALA patients admitted in intensive care units (ICUs) and treated by renal replacement therapy (MALA-RRT). METHODS: Retrospective analysis over a 6-year period (2010-2015) in Piedmont and Aosta Valley regions (5,305,940 inhabitants, 141,174 diabetics treated with metformin) of all MALA-RRT cases. RESULTS: One hundred and seventeen cases of AKI-MALA-RRT were observed (12.04/100,000 metformin treated diabetics, 1.45% of all RRT-ICU patients). Survival rate was 78.3%. The average duration of RRT was 4.0 days at mean dialysis effluent of 977 mL/kg/day. At admission most patients were dehydrated, and experienced shock and oliguria. CONCLUSION: Our data showed that MALA-RRT is a common complication, needing more prevention. Adopted policy of early, extended, continuous and high efficiency dialysis could contribute to an observed high survival rate. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=471917.


Assuntos
Acidose Láctica , Cuidados Críticos , Unidades de Terapia Intensiva , Metformina/efeitos adversos , Terapia de Substituição Renal , Acidose Láctica/induzido quimicamente , Acidose Láctica/epidemiologia , Acidose Láctica/terapia , Idoso , Feminino , Humanos , Itália , Masculino , Metformina/administração & dosagem , Estudos Retrospectivos
7.
Blood ; 124(11): 1715-26, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25037630

RESUMO

Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Ativação do Complemento/efeitos dos fármacos , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Monitorização Fisiológica , Adenosina Difosfato Ribose/farmacologia , Síndrome Hemolítico-Urêmica Atípica , Complemento C3/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Glomerulonefrite Membranoproliferativa/sangue , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glomerulonefrite Membranoproliferativa/patologia , Síndrome Hemolítico-Urêmica/patologia , Humanos , Masculino , Indução de Remissão , Fatores de Tempo
8.
Pediatr Nephrol ; 31(5): 759-68, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26604087

RESUMO

BACKGROUND: The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver-kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH. METHODS: We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported. RESULTS: The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal. CONCLUSIONS: Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/terapia , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Transplante de Rim , Transplante de Fígado , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/genética , Células Cultivadas , Ativação do Complemento/genética , Fator H do Complemento/genética , Análise Mutacional de DNA , Predisposição Genética para Doença , Hereditariedade , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo , Resultado do Tratamento
9.
BMC Nephrol ; 17(1): 120, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27566671

RESUMO

BACKGROUND: Hemodiafiltration with on-line endogenous reinfusion (HFR) is an extracorporeal dialytic method that combines diffusion, convection and adsorption. HFR-Supra (HFR-S) is a second-generation system with increased convective permeability and adsorption capability. Previous studies suggested that HFR reduces oxidative stress compared to standard haemodialysis. The principal aim of the present study was to compare antioxidant vitamins behavior and oxidative status of hemodialysis patients treated with HFR and HFR-S. METHODS: The study was designed as a multicenter, randomized, crossover trial. Forty-one patients were recruited from 19 dialysis centers and after a 4-month washout stabilization period in on-line hemodiafiltration (ol-HDF), each patient was randomized to a sequence of treatments (HFR-S followed by HFR or viceversa) with each treatment applied over 6 months. Plasma levels of Advanced Oxidation Protein Products, Total Antioxidant Status, vitamins C, A and E and their ligands (Retinol Binding Protein and total lipids) were measured at baseline and at the end of each treatment period. RESULTS: Results show that the higher convective permeability of HFR-S with respect to HFR did not produce additional beneficial effects on the patients' oxidative status, a slight decrease of both Vitamin A and Retinol Binding Protein being the only difference registered in the long-term. However, as compared to ol-HDF, both the re-infusive techniques allowed to reduce the intradialytic loss of Vitamin C and, in the long-term, improve the patients' oxidative status and increase Retinol Binding Protein plasma values. No significant differences were found between the Vitamin C concentration of pre- and post cartridge UF neither in HFR-S nor in HFR showing that the sorbent resin does not adsorb Vitamin C. CONCLUSION: HFR-S and HFR are almost equivalent in term of impact on antioxidant vitamins and oxidative status of hemodialysis patients. Nonetheless, as compared to ol-HDF, both treatments produced a sensible sparing of Vitamin C and may represent a new approach for reducing oxidative stress and related complications in dialysis patients. Long-term effects of re-infusive treatments on patients' cardiovascular morbidity and mortality need to be evaluated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01492491 , retrospectively registered in 10 December 2011.


Assuntos
Antioxidantes/metabolismo , Ácido Ascórbico/sangue , Hemodiafiltração/métodos , Falência Renal Crônica/terapia , Vitamina A/sangue , Vitamina E/sangue , Adulto , Produtos da Oxidação Avançada de Proteínas/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Estudos Prospectivos , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Adulto Jovem
10.
Pediatr Nephrol ; 30(1): 167-72, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25173358

RESUMO

BACKGROUND: Treatment of systemic lupus erythematosus (SLE) with severe diffuse proliferative nephritis is often challenging, particularly in small children in whom a genetic conditioning is likely to play a role. The effectiveness of standard therapy based on glucocorticoid and immunosuppressive drugs is often unsatisfactory. CASE: A 4 year-old girl, whose parents were first-grade cousins of Moroccan ancestry, developed SLE that progressed to severe renal involvement despite standard therapy. She had persistently undetectable serum C4 levels and very low C3 levels (<30 mg/dl), and extremely high anti-DNA titers (>1:640) that remained unmodified during 2 years of follow-up. No mutations of genes encoding for complement inhibitors were detected. Despite aggressive therapy based on prednisone, plasma exchanges, and cyclosporine, the child worsened and eventually developed features of atypical hemolytic uremic syndrome (aHUS). Treatment with eculizumab provided prompt remission of vasculitis, proteinuria, and hematuria, with normalization of renal function. Two attempts to withdraw eculizumab were followed by severe relapses and rescued by reinstating treatment. The child has been treated with eculizumab for > 17 months without relevant side effects. CONCLUSION: C5 inhibition by eculizumab completely reversed clinical symptoms and laboratory renal signs of severe lupus nephritis. Blocking complement-system activation with the use of targeted drugs may be a new and exciting strategy to treat SLE patients unresponsive to conventional therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Pré-Escolar , Feminino , Humanos , Nefrite Lúpica/patologia , Nefrite Lúpica/fisiopatologia
11.
Curr Opin Organ Transplant ; 20(5): 536-42, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26348571

RESUMO

PURPOSE OF REVIEW: Over the last five decades, the attention of nephrologists has focused on cellular rejection which was considered to be responsible for the early loss of function of the transplanted kidney. The use of new drugs in different combinations with steroids resulted in an improved short-term survival of the graft, which has significantly reduced the incidence of acute rejections. The main problem now, however, is ensuring the long-term survival of the transplanted kidney. This has become the challenge of the new millennium. RECENT FINDINGS: The current literature clearly focuses on donor-specific alloantibodies, directed against human leukocyte antigen (HLA) and non-HLA antigens [donor-specific antibodies (DSA)], which have been shown to play an important role in graft dysfunction, longevity, and loss. To mitigate allograft loss due to antibodies, it is important to treat the source of antibody production, the plasma cells. Drugs used prior to 2007, such as Rituximab, intravenous immunoglobulins, and plasmapheresis, lack effects on these long-lived plasma cells. Their ability to remove DSA is incomplete and/or cost prohibitive. Since 2007, Bortezomib, a proteasome inhibitor, has been used to deplete plasma cells, thus eliminating the synthesis of DSA. SUMMARY: Antibody-mediated rejection (AMR) is common in patients with DSA and is associated with a poor prognosis. Novel medications that target each step of AMR pathogenesis have been produced and are successful when compared with more traditional therapies.


Assuntos
Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Especificidade de Anticorpos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Prognóstico , Transplante Homólogo
12.
Kidney Int ; 86(4): 828-36, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24694989

RESUMO

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin-angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m(2), the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.


Assuntos
Glomerulonefrite por IGA/classificação , Glomerulonefrite por IGA/patologia , Falência Renal Crônica/patologia , Rim/patologia , Adolescente , Adulto , Atrofia , Criança , Progressão da Doença , Europa (Continente) , Feminino , Fibrose , Seguimentos , Taxa de Filtração Glomerular , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Imunossupressores/uso terapêutico , Rim/irrigação sanguínea , Falência Renal Crônica/fisiopatologia , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Valor Preditivo dos Testes , Proteinúria/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos , Adulto Jovem
13.
Pediatr Nephrol ; 29(9): 1545-51, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24687448

RESUMO

BACKGROUND: Henoch-Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomerular IgA deposits, but differ with regard to clinical features. The suspected involvement of different immune system pathways is largely unknown. METHODS: This study was aimed at investigating some of the immunological features including Toll-like receptors (TLR), proteasome (PS)/immunoproteasome (iPS) switch, and the regulatory T cell system (Treg/Th17 cells) in 63 children with HSP with/without renal involvement and in 25 with pIgAN. Real-time PRC (Taqman) was used to quantify mRNA levels in peripheral blood mononuclear cells (PBMC). RESULTS: The expression of mRNAs encoding for TLR4 in both HSP and pIgAN was higher than in controls (HC) and in both diseases FoxP3mRNA and TGF-ß1mRNA expression was significantly lower than in HC. A switch from PS to iPS (LMP2/ß1) was detected only in PBMC of HSP and it correlated with the level of TLR2mRNA, which was selectively increased only in children with HSP. CONCLUSION: Children with HSP and pIgAN present with similar signs of engagement of the innate immunity and regulatory T cell depression. The increased immunoproteasome switch, which correlated with TLR2 activation, may suggest an innate immunity pathway peculiar to HSP vasculitic presentation. This research area also deserves further investigation for possible therapeutic applications.


Assuntos
Glomerulonefrite por IGA/imunologia , Vasculite por IgA/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Linfócitos T Reguladores/imunologia , Receptores Toll-Like/imunologia , Criança , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real
14.
Nephrol Dial Transplant ; 27(5): 1902-10, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22431705

RESUMO

BACKGROUND: Some difficult cases of idiopathic nephrotic syndrome (NS) have been treated with a HIV protease inhibitor provided with proteasome-inhibiting activity. The objective of this study was to limit nuclear factor κB (NF-κB) activation which is up-regulated in these patients, aiming at decreasing proteinuria and prednisone need. METHODS: Ten cases with long-lasting (up to 15 years) history of NS with steroid dependence (six cases, of which three with secondary steroid resistance) or resistance to steroids (four cases) unsuccessfully treated with multiple immunosuppressive drugs, accepted a treatment with the protease inhibitor saquinavir. p50/p65 NF-κB nuclear localization and immunoproteasome/proteasome messenger RNA (mRNA) were monitored in peripheral blood mononuclear cells (PBMCs). The effects of saquinavir on NF-κB nuclear localization in cultured PBMCs and in immortalized human podocytes were assessed. RESULTS: After a median follow-up of 14.7 months (6-68.7), 1/4 primary steroid-resistant NS (SRNS) and 5/6 steroid-dependent NS or secondary SRNS became infrequent (5) or frequent (1) relapsers, with 63% prednisone reduction (from 25.3 to 8.4 mg/kg/month, P = 0.015). Saquinavir was effective in association with low doses of calcineurin inhibitors (cyclosporine 2 mg/kg/day or tacrolimus 0.01-0.06 mg/kg/day). No side effects were observed apart from transitory mild diarrhoea. In PBMCs, NF-κB was down-regulated, while MECL-1 immunoproteasome/beta2 proteasome mRNA ratio was reversed to normal values. In culture, saquinavir blunted NF-κB activation in human podocytes and in PBMCs. CONCLUSIONS: In this pilot study, a HIV antiprotease drug reduced proteinuria and had a steroid-sparing effect in some multidrug-resistant/-dependent NS. This observation warrants further investigation.


Assuntos
Resistência a Medicamentos , Inibidores da Protease de HIV/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Prednisona/uso terapêutico , Saquinavir/uso terapêutico , Esteroides/uso terapêutico , Adolescente , Adulto , Células Cultivadas , Criança , Quimioterapia Combinada , Feminino , Seguimentos , Inibidores da Protease de HIV/farmacologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , NF-kappa B/metabolismo , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Projetos Piloto , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/prevenção & controle , Saquinavir/farmacologia , Resultado do Tratamento , Regulação para Cima , Adulto Jovem
16.
G Ital Nefrol ; 29 Suppl 54: S84-90, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-22388837

RESUMO

The refinement of our knowledge of the functioning of the immune system, both innate and adaptive, in the last decade has fundamentally modified the interpretation of the pathogenesis of systemic lupus erythematosus (SLE). In this autoimmune disease the main pathogenetic mechanism leads to the production of autoantibodies specific to self antigens (tolerated or not) favored by a genetic condition and triggered by endogenous factors, such as estrogens or exposure to sunlight, and exogenous factors, such as viruses. T cells were thought to play a predominant role. The identification of a population of B cells located in marginal areas of the germinal centers and equipped with receptors belonging to the family of Toll-like receptors (TLR) (either extracellular, such as TLR4, or intracellular, such as TLR3, which recognize DNA and RNA) and High Mobility Box Protein 1 (HMBP1), capable in a T-independent manner of self-reactive activities with IgG autoantibody production and release, has greatly advanced the understanding of the pathogenesis of SLE. The T and B lymphocyte populations interact in complex ways, with interference of tolerance-inducing regulatory T cells and inflammation-inducing Th17 cells, finely regulating the cross-talk in the lymphocyte system. This review will discuss the latest knowledge on the pathogenesis of SLE.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Lúpus Eritematoso Sistêmico/imunologia , Autoanticorpos/sangue , Autoantígenos/sangue , Linfócitos B/metabolismo , Biomarcadores/sangue , Proteína HMGB1/sangue , Humanos , Fatores Imunológicos/sangue , Lúpus Eritematoso Sistêmico/sangue , Fatores de Risco , Linfócitos T/metabolismo , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Receptores Toll-Like/sangue
17.
G Ital Nefrol ; 29(4): 473-83, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-22843159

RESUMO

The Piedmont Group of Clinical Nephrology has compared the activity of 18 nephrology centers in the region Piedmont/Valle d'Aosta with regard to renal biopsy (RB). Data on the RBs performed in every nephrology unit, taking into account their entire experience (in some cases spanning more than 30 years), were analyzed. 3396 RBs were performed between 1996 and 2011. Thirty to forty percent were done in patients aged >-65 years (1568 in patients >-65 years, 29 in patients >-85 years). 598 BRs were performed in children over the last 20 years. The following contraindications to RB were considered: chronic renal failure by 8 centers (44.4%), serum creatinine (SCr >3 mg/dL) by 3 centers, longitudinal renal size <8 cm by 3 centers, and renal cortex thickness <1 cm by 2 centers. 1798 RBs were performed in patients with SCr >2 mg/dL and 275 in patients on dialysis. The percentage of RBs performed in patients with SCr >2 mg/dL ranged from 27% to 55% between centers. As regards RB in the course of acute renal failure in an ANCA-positive context, 4 centers allowed administration of corticosteroids and 8 centers administration of immunosuppressive treatment as well, even in the absence of histological data. In drug-related nephropathies, RB was considered indicated to confirm the farhypothesis of immunoallergic interstitial nephropathy either if the responsible drug was not among the traditional ones known to induce tubulo-interstitial renal disease or if the pharmacological hypothesis seemed no longer sufficient to justify the renal presentation. All centers but one were against performing RB in case of atheroembolic disease. Three centers performed RB in the intensive care unit. As regards RB in patients undergoing treatment with anticoagulants, aspirin was discontinued 5-14 days before the procedure (mean 8 days) and given again 7-15 days afterwards (mean 11.4 days). Ten centers replaced the anticoagulants with low-dose heparin, which was discontinued the day before the procedure; 11 centers asked advice from cardiologists. RB was repeated in 113 cases after a delay of 1 month to 8 years from the first RB. Our analysis shows uniformity in the approach to RB in this Italian region, with some differences compared with the literature: particular attention was paid to severely critical patients, elderly patients, and patients treated with anticoagulant drugs.


Assuntos
Rim/patologia , Insuficiência Renal/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Humanos , Itália , Estudos Retrospectivos , Inquéritos e Questionários
18.
G Ital Nefrol ; 29(5): 621-7, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-23117742

RESUMO

In 2010 a questionnaire was administered to the renal units of Piedmont and Valle d'Aosta to analyze their procedures for renal biopsy (RB). Seventy-eight percent of units performed RBs, 57% for more than 20 years, but only 43% performed at least 20 BRs per year. 20/21 units performed RB in an inpatient setting and 1/21 in day hospital with the patient remaining under observation the night after. Thirty-two percent did not consider a single kidney as a contraindication to RB, 59% considered it a relative contraindication and 9% considered it an absolute contraindication. In 90.5% of units there was a specific protocol for patient preparation for RB and 86% used a specific informed consent form. Ninety-five percent of units performed ultrasound-guided RB, 60% of them using needle guides attached to the probe. In 81% of units the left side was preferred; 71% put a pillow under the patient's abdomen. All units used disposable, automated or semi-automated needles. Needle size was 16G in 29%, 18G in 58%, and both 16G and 18G in 14% of units; 1 to 3 samples were drawn. One third of units had a microscope available for immediate evaluation of specimen adequacy. After RB, 86% of units kept patients in the prone position for 2-6 hours and all prescribed a period of bed rest (at least 24 hours in 90.5%). 90.5% of units followed a specific postbiopsy observation protocol consisting of blood pressure, heart rate and red blood cell measurements at different times, and urine monitoring and ultrasound control within 12-24 hours (only half of them also employing color Doppler). One third of all units discharged patients after 1 day and two thirds after 2-3 days; all prescribed abstention from effort and from antiplatelet drugs for 7-15 days. In 9 units both RB and tissue processing and examination were done in the same hospital, while 12 units sent the samples elsewhere. 76% obtained results in 2-4 days, 19% in 6-7 days, and 5% in 10-15 days. Less than 20% of the interviewed operators were fully familiar with the clauses of hospital insurance securing their activity. Use of RB is widespread in Piedmont and Valle d'Aosta but its practice shows variation between centers.


Assuntos
Rim/patologia , Biópsia por Agulha , Humanos , Itália , Padrões de Prática Médica
19.
G Ital Nefrol ; 28(3): 289-95, 2011.
Artigo em Italiano | MEDLINE | ID: mdl-21626497

RESUMO

Over the last 20 years a large body of evidence has demonstrated that in chronic renal failure there is progressive chronic inflammation, which increases after the start of dialysis. In this phase a fundamental role is played by bioincompatibility reactions induced by contact with the different dialysis materials: membranes, plastic lines, dialysis fluids as well as contaminants present in water. Clinically evident symptoms induced by bioincompatibility reactions are usually taken into serious account by nephrologists, while more subtle chronic effects, noxious in the long term, are often underconsidered. Since the 1990s many efforts have been addressed to membrane improvement and water treatment, while there is still a lot to be done for better dialysates. Acetate dialysis is routinely used in only about 5% of patients worldwide but over 80% of patients are exposed to the lower acetate concentrations present in standard bicarbonate dialysate. These concentrations are not negligible and are able to induce chronic reactions mainly converging on the endothelium, stimulating and maintaining the atherogenesis process with important long-term implications for cardiovascular morbidity. This review presents and discusses the available data on the cellular and molecular effects induced by acetate, even at low concentrations.


Assuntos
Acetatos/efeitos adversos , Diálise Renal , Acetatos/análise , Acetatos/metabolismo , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia
20.
Kidney Int ; 77(5): 417-27, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20016469

RESUMO

The reaction of mesangial cells with aberrantly glycosylated IgA1 has been implicated in the etiology of IgA nephropathy (IgAN). Tumor necrosis factor, which is assumed to mediate the interaction between mesangial cells and podocytes, also induces the expression of platelet-activating factor (PAF). In this study, we determined whether PAF affects the expression of nephrin (an adhesion molecule critical to glomerular permselectivity) and cytoskeletal F-actin organization in podocytes. We treated human mesangial cells with atypically glycosylated IgA1 either prepared in vitro or derived from the sera of patients with IgAN. We then prepared conditioned media from these cells and added them to cultured human podocytes in the presence of PAF receptor antagonists. Podocytes transfected to overexpress acetylhydrolase, the main catabolic enzyme of PAF, served as controls. Downregulation of nephrin expression and F-actin reorganization occurred when podocytes were cultured with mesangial cell-conditioned medium. Preincubation of podocytes with a PAF receptor antagonist prevented the loss and redistribution of nephrin. In control podocytes overexpressing acetylhydrolase, nephrin loss was abrogated. Our results suggest that atypically glycosylated IgA-induced PAF from mesangial cells is a mediator of podocyte changes, which, when more directly tested elsewhere, were found to be associated with proteinuria. Hence, it is possible that these in vitro findings may be relevant to the proteinuria of IgAN.


Assuntos
Imunoglobulina A/metabolismo , Proteínas de Membrana/fisiologia , Células Mesangiais/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Podócitos/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Meios de Cultivo Condicionados , Técnica Indireta de Fluorescência para Anticorpo , Glicosilação , Humanos , Fator de Ativação de Plaquetas/genética , Adulto Jovem
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