RESUMO
PURPOSE: Therapeutic drug monitoring of tacrolimus using trough concentration (Cmin) is mandatory to ensure drug efficacy and safety in solid organ transplantation. However, Cmin is just a proxy for the area under the curve of drug concentrations (AUC) which is the best pharmacokinetic parameter for exposure evaluation. Some studies suggest that patients may present discrepancies between these two parameters. AUC is now easily available through mini-invasive microsampling approach. The aim of this study is to evaluate the relationship between AUC and Cmin in patients benefiting from a complete pharmacokinetic profile using a microsampling approach. METHODS: Fifty-one transplant recipients benefited from a complete pharmacokinetic profile using a microsampling approach, and their 24-h AUC were calculated using the trapezoidal method. The correlation with Cmin was then explored. In parallel, we estimated AUC using the sole Cmin and regression equations according to the post-transplantation days and the galenic form. RESULTS: Weak correlations were found between 24-h AUC observed and the corresponding Cmin (R2 = 0.60) and between AUC observed and expected using the sole Cmin (R2 = 0.62). Therapeutic drug monitoring of tacrolimus using Cmin leads to over- or under-estimate drug exposure in 40.3% of patients. CONCLUSION: Tacrolimus Cmin appears to be an imperfect reflection of drug exposure. Evaluating AUC using a microsampling approach offers a mini-invasive strategy to monitor tacrolimus treatment in transplant recipients.
Assuntos
Transplante de Órgãos , Tacrolimo , Humanos , Tacrolimo/uso terapêutico , Tacrolimo/farmacocinética , Imunossupressores/farmacocinética , Medicina de Precisão , Transplantados , Monitoramento de Medicamentos/métodos , Área Sob a CurvaRESUMO
Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.
Assuntos
Analgésicos/efeitos adversos , Feto/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Organogênese/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Feminino , Feto/metabolismo , Humanos , Glomérulos Renais/metabolismo , Gravidez , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Prostaglandinas/metabolismoRESUMO
There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients.
Assuntos
COVID-19/diagnóstico , Rejeição de Enxerto/epidemiologia , Transplante de Rim , Pandemias , Pontuação de Propensão , Sistema de Registros , Transplantados/estatística & dados numéricos , Idoso , COVID-19/epidemiologia , Comorbidade , Feminino , França/epidemiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/uso terapêutico , Incidência , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Kidney biopsies (KBs) are performed in patients with type 2 diabetes (T2D) to diagnose non-diabetic or hypertensive kidney disease (NDHKD) potentially requiring specific management compared to diabetic and or hypertensive nephropathy (absence of NDHKD). Indications for KB are based on the presence of atypical features compared to the typical course of diabetic nephropathy. In this study, we assessed the association of different patterns of atypical features, or KB indications, with NDHKD. METHODS: Native KBs performed in patients with T2D were analyzed. Data were collected from the patients' records. KB indications were determined according to the presence of different atypical features considered sequentially: (1) presence of any feature suggesting NDHKD which is not among the following ones, (2) recent onset of nephrotic syndrome, (3) low or rapidly declining estimated glomerular filtration rate (eGFR), (4) rapid increase in proteinuria, (5) short duration of diabetes, (6) presence of hematuria, or (7) normal retinal examination. RESULTS: Among the 463 KBs analyzed, NDHKD was diagnosed in 40% of the total population and 54, 40, 24, and 7% of the KBs performed for indications 1-4 respectively. Conversely, no patient who underwent KB for indications 5-7 displayed NDHKD. Logistic regression analyses identified eGFRCKD-EPI >15 mL/min/1.73 m2, urinary protein-to-Cr ratio <0.3 g/mmol, hematuria, HbA1c <7%, and diabetes duration <5 years as predictors of NDHKD, independently from the indication group. CONCLUSION: NDHKD is frequent in T2D. Despite the association of hematuria with NDHKD, our results suggest that presence of hematuria and absence of DR are insufficient to indicate KB in the absence of concurrent atypical features. Conversely, rapid progression of proteinuria and rapid deterioration of eGFR are major signals of NDHKD.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias/diagnóstico , Nefropatias/patologia , Rim/patologia , Seleção de Pacientes , Idoso , Biópsia , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Hematúria/patologia , Humanos , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteinúria/patologia , Estudos Retrospectivos , Fatores de TempoRESUMO
Multiple days assessments are frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when eGFR is <90 ml/min/1.73 m2 (KDIGO guidelines) or 80 ml/min/1.73 m2 (most US centres). However, age-related GFR decline results in a lower eGFR for older candidates. That may limit the number of older kidney donors. Yet, continuing the screening with a GFR measure increases the number of eligible donors. We hypothesized that in-depth screening should be proposed to all candidates with a normal eGFR for age. We compared the evolution of eGFR after donation between three groups of predonation eGFR: normal for age (Sage ) higher than 90 or 80 ml/min/1.73 m2 (S90 and S80, respectively); across three age groups (<45, 45-55, >55 years) in a population of 1825 French living kidney donors with a median follow-up of 5.9 years. In donors younger than 45, postdonation eGFR, absolute- and relative-eGFR variation were not different between the three groups. For older donors, postdonation eGFR was higher in S90 than in S80 or Sage but other comparators were identical. Postdonation eGFR slope was comparable between all groups. Our results are in favour of in-depth screening for all candidates to donation with a normal eGFR for age.
Assuntos
Falência Renal Crônica , Transplante de Rim , Taxa de Filtração Glomerular , Humanos , Rim , Falência Renal Crônica/cirurgia , Doadores Vivos , Pessoa de Meia-Idade , NefrectomiaRESUMO
Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging.
Assuntos
COVID-19/mortalidade , Transplante de Rim/mortalidade , Complicações Pós-Operatórias/mortalidade , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/terapia , Desprescrições , Feminino , França/epidemiologia , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Pandemias/estatística & dados numéricos , Complicações Pós-Operatórias/virologia , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Acute Intermittent Porphyria (AIP) is a rare inherited autosomal dominant disorder of heme biosynthesis. Porphyria-associated kidney disease occurs in more than 50% of the patients with AIP, and end stage renal disease (ESRD) can be a devastating complication for AIP patients. The outcomes of AIP patients after kidney transplantation are poorly known. METHODS: We examined the outcomes of 11 individuals with AIP, identified as kidney transplant recipients in the French Porphyria Center Registry. RESULTS: AIP had been diagnosed on average 19 years before the diagnosis of ESRD except for one patient in whom the diagnosis of AIP had been made 5 years after the initiation of dialysis. Median follow-up after transplantation was 9 years. A patient died 2 months after transplantation from a cardiac arrest and a patient who received a donation after cardiac death experienced a primary non-function. No rejection episode and no noticeable adverse event occurred after transplantation. Serum creatinine was on average 117 µmol/l, and proteinuria <0.5 g/l in all patients at last follow up. All usually prescribed drugs after transplantation are authorized except for trimethoprim/sulfamethoxazole. Critically, acute porphyria attacks almost disappeared after kidney transplantation, and skin lesions resolved in all patients. CONCLUSION: Kidney transplantation is the treatment of choice for AIP patients with ESRD and dramatically reduces the disease activity.
Assuntos
Falência Renal Crônica/terapia , Transplante de Rim , Rim/patologia , Porfiria Aguda Intermitente/terapia , Adulto , Feminino , Heme/biossíntese , Heme/genética , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/genética , Porfiria Aguda Intermitente/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Lupus nephritis (LN) affects a large proportion of patients with systemic lupus erythematosus (SLE). LN can lead to end-stage renal disease depending on when it is diagnosed and on the adequacy of the treatment administered to the patient based on the class of LN. Determination of the class and activity of LN is only possible by histological analysis of kidney biopsies. In this context, the development of non-invasive early diagnostic tools for determining the class of LN and biomarkers predicting the response to treatment would greatly benefit patients with SLE. Basophils, which are one of the rarest types of circulating leucocytes, are well-established effectors of allergic and parasitic diseases. Recent advances in the understanding of the immune regulatory role of basophils in several auto immune conditions, including SLE and LN, have demonstrated their involvement in the amplification of auto-antibody production and LN pathogenesis in both human SLE and lupus-like mouse models. The present review summarizes the currently available literature describing dysregulation of basophil counts, basophil activation status and basophil activating factors in patients with SLE and the involvement of basophils in the pathogenesis of SLE. We also discuss the potential utility of these biological and immunological parameters as diagnostic and prognostic biomarkers, used alone or in combination with other known SLE and LN activity biomarkers. Finally, considering basophils as contributors to the disease, they may also constitute a future treatment target for the management of SLE and LN.
Assuntos
Basófilos/patologia , Rim/patologia , Nefrite Lúpica/patologia , Animais , Humanos , Contagem de LeucócitosRESUMO
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. METHODS: Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. RESULTS: Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1-mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1-mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. CONCLUSIONS: These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.
Assuntos
Antibacterianos , Microbioma Gastrointestinal , Glomerulonefrite por IGA , Animais , Feminino , Masculino , Camundongos , Administração Oral , Antibacterianos/administração & dosagem , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/microbiologiaRESUMO
Idiopathic steroid sensitive nephrotic syndrome (INS), the most frequent childhood nephropathy, is thought to be mediated by a circulating soluble factor that reversibly affects the renal protein sieving. The efficiency of rituximab therapy recently highlighted the involvement of B cells. Here we studied the involvement of a specific immunoglobulin G (IgG) in the disease. After plasma fractionation by size exclusion chromatography, a detachment of cultured podocyte was observed with one IgG-containing fraction from 47% patients in relapse, 9% of patients in remission and 0% of controls. Podocyte protein lysates were immunoprecipitated by IgG from those plasma fractions identifying a list of 41 podocyte proteins after proteomic analysis. Five podocyte targets were selected on statistical and biological criteria. Specific antibodies were tested and only anti-Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) IgG led to podocyte detachment. UCHL1 was mainly found inside the podocyte but also weakly expressed on podocyte cell surface. Incubation of either anti-UCHL1 IgG or plasma fractions with recombinant UCHL1 prevented podocyte detachment. Plasma levels of anti-UCHL1 IgG were significantly increased in relapsing INS patients compared to patients in remission and controls. Proteinuria correlated with anti-UCHL1 IgG level at various stages of the disease. Purified patient anti-UCHL1 antibodies induced proteinuria and podocyte foot effacement in mice. Altogether, these results identified UCHL1 as a target podocyte protein of autoantibodies in a set of relapsing patients and support a causative role of anti-UCHL1 autoantibodies in the development of INS.
Assuntos
Síndrome Nefrótica/imunologia , Podócitos/fisiologia , Proteinúria/imunologia , Ubiquitina Tiolesterase/imunologia , Adolescente , Animais , Autoanticorpos/sangue , Adesão Celular , Células Cultivadas , Criança , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ubiquitina Tiolesterase/genéticaRESUMO
Background: Henoch-Schönlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods: This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results: We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1ß, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P < 0.005 for all comparisons). After follow-up (1 year), 22 patients showed a poor outcome. Among the tested markers, urine IgA at disease onset adequately reclassified the risk of poor outcome over conventional clinical factors, including estimated glomerular filtration rate, proteinuria and age (continuous net reclassification improvement = 0.72, P = 0.001; integrated discrimination improvement = 0.13, P = 0.009) in IgAV patients. Conclusions: Taken together, these results showed that serum Gd-IgA1 and urinary IgA, IgG, IgM, NGAL, IL-1ß, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were associated with nephritis in IgAV patients. Urinary IgA level may improve patient risk stratification for poor outcome.
Assuntos
Biomarcadores/análise , Vasculite por IgA/sangue , Imunoglobulina A/sangue , Nefrite/sangue , Adulto , Idoso , Complexo Antígeno-Anticorpo/análise , Feminino , Taxa de Filtração Glomerular , Humanos , Vasculite por IgA/complicações , Masculino , Pessoa de Meia-Idade , Nefrite/etiologia , Prognóstico , Estudos Prospectivos , Curva ROC , Adulto JovemRESUMO
Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients (n=169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF-κB and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants.
Assuntos
Ferro/sangue , Rim/patologia , Traumatismo por Reperfusão/prevenção & controle , Adulto , Aloenxertos , Animais , Antioxidantes/metabolismo , Feminino , Ferritinas/sangue , Taxa de Filtração Glomerular , Humanos , Inflamação , Ferro/química , Rim/metabolismo , Transplante de Rim , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Peritonite/metabolismo , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de SinaisRESUMO
Strait et al. described a novel mouse model of cryoglobulinaemia by challenging mice deficient in the immunoglobulin (Ig)G1 subclass (γ1(-) mice) with goat anti-mouse IgD [5]. The phenotype of wild-type mice was not remarkable, whereas γ1(-) mice developed IgG3 anti-goat IgG cryoglobulins as well as severe and lethal glomerulonephritis. Renal phenotype could not be rescued in γ1(-) mice by the deletion of C3, fragment crystalline γ receptor (FcγR) or J chain. On the other hand, early injection of IgG1, IgG2a or IgG2b inhibited the pathogenic effects of IgG3 in an antigen-dependent manner even in the absence of the FcγRIIb, an anti-inflammatory receptor. The authors concluded that the pathogenic role of IgG3 and the protective characteristic of IgG1 in this model were not explained by their abilities to bind to FcRs or effector molecules but are rather due to structural discrepancies enhancing the precipitation properties/solubility of IgG3/IgG1-containing immune complexes. The present article aims to discuss the current knowledge on IgG biology and the properties of IgGs explaining their differential propensity to acquire cryoglobulin activity.
Assuntos
Crioglobulinemia/patologia , Crioglobulinemia/prevenção & controle , Modelos Animais de Doenças , Imunoglobulina G/uso terapêutico , Animais , Crioglobulinemia/imunologia , Humanos , CamundongosAssuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Transplante de Rim , Abatacepte/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Rejeição de Enxerto , Humanos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversosRESUMO
IgA1 complexes containing deglycosylated IgA1, IgG autoantibodies, and a soluble form of the IgA receptor (sCD89), are hallmarks of IgA nephropathy (IgAN). Food antigens, notably gluten, are associated with increased mucosal response and IgAN onset, but their implication in the pathology remains unknown. Here, an IgAN mouse model expressing human IgA1 and CD89 was used to examine the role of gluten in IgAN. Mice were given a gluten-free diet for three generations to produce gluten sensitivity, and then challenged for 30 days with a gluten diet. A gluten-free diet resulted in a decrease of mesangial IgA1 deposits, transferrin 1 receptor, and transglutaminase 2 expression, as well as hematuria. Mice on a gluten-free diet lacked IgA1-sCD89 complexes in serum and kidney eluates. Disease severity depended on gluten and CD89, as shown by reappearance of IgAN features in mice on a gluten diet and by direct binding of the gluten-subcomponent gliadin to sCD89. A gluten diet exacerbated intestinal IgA1 secretion, inflammation, and villous atrophy, and increased serum IgA1 anti-gliadin antibodies, which correlated with proteinuria in mice and patients. Moreover, early treatment of humanized mice with a gluten-free diet prevented mesangial IgA1 deposits and hematuria. Thus, gliadin-CD89 interaction may aggravate IgAN development through induction of IgA1-sCD89 complex formation and a mucosal immune response. Hence, early-stage treatment with a gluten-free diet could be beneficial to prevent disease.
Assuntos
Antígenos CD/metabolismo , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/metabolismo , Glutens/toxicidade , Imunoglobulina A/metabolismo , Mucosa Intestinal/patologia , Receptores Fc/metabolismo , Animais , Antígenos CD/sangue , Atrofia/etiologia , Dieta Livre de Glúten , Modelos Animais de Doenças , Enterite/etiologia , Proteínas de Ligação ao GTP/metabolismo , Gliadina/imunologia , Gliadina/metabolismo , Glomerulonefrite por IGA/dietoterapia , Glutens/administração & dosagem , Glutens/imunologia , Hematúria/dietoterapia , Hematúria/etiologia , Imunoglobulina A/sangue , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Proteína 2 Glutamina gama-Glutamiltransferase , Proteinúria/etiologia , Receptores Fc/sangue , Receptores da Transferrina/metabolismo , Transglutaminases/metabolismoAssuntos
Acalasia Esofágica/complicações , Gastroplastia/efeitos adversos , Hipopotassemia/diagnóstico , Nefrite Intersticial/complicações , Complicações Hematológicas na Gravidez/etiologia , Adulto , Diagnóstico Diferencial , Acalasia Esofágica/diagnóstico , Feminino , Humanos , Nefrite Intersticial/diagnóstico , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Tomografia Computadorizada por Raios XAssuntos
Colo , Doença Diverticular do Colo/induzido quimicamente , Perfuração Intestinal/induzido quimicamente , Poliestirenos/efeitos adversos , Insuficiência Renal Crônica/complicações , Idoso de 80 Anos ou mais , Resinas de Troca de Cátion/efeitos adversos , Resinas de Troca de Cátion/uso terapêutico , Doença Diverticular do Colo/diagnóstico , Humanos , Perfuração Intestinal/diagnóstico , Masculino , Pessoa de Meia-Idade , Poliestirenos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
Microscopic polyangiitis, granulomatosis with polyangiitis, Churg-Strauss syndrome and focal necrotizing glomerulonephritis are severe systemic vasculitides associated with circulating antineutrophil cytoplasmic antibodies (ANCA). Several studies reported that some malignancies can develop in these patients during follow-up, but few studies have considered the association and role of pre-existing cancers, at least in a fraction of patients. Herein, we report five patients with ANCA-associated diseases who had associated lung carcinomas or were diagnosed within 2 years after vasculitis onset. We discuss the putative role of tumor antigen in driving the auto-immune response.
Assuntos
Adenocarcinoma/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Carcinoma de Células Escamosas/complicações , Neoplasias Pulmonares/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/imunologia , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Antígenos de Neoplasias/imunologia , Biomarcadores/sangue , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/cirurgia , Evolução Fatal , Feminino , Humanos , Imunossupressores/uso terapêutico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/cirurgia , Masculino , Estadiamento de Neoplasias , Plasmaferese , Pneumonectomia , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Dialysis recovery time (DRT) and fatigue are two important patient-reported outcomes that highly affect hemodialysis patients' well-being and survival. This study aimed to identify all modifiable dialysis-related factors, associated with DRT and fatigue, that could be addressed in future clinical trials. METHODS: This multicenter observational study included adult patients, undergoing chronic hemodialysis for > 3 months during December 2023. Patients admitted to hospital, with cognitive problems, or active cancer were excluded. DRT was determined by asking over six sessions: "How long did it take you to recover from your last dialysis session?" Fatigue was assessed using the French-validated SONG-HD fatigue scale. Logistic regression analysis assessed the association between DRT>12 hours and fatigue score ≥4 with all dialysis-related factors. A sub-analysis of DRT-related factors was performed for very elderly ≥ 85 years. RESULTS: A total of 536 patients and 2967 sessions were analyzed. Mean age was 68.1 ±14.3 years, 60.9% were males, 33.2% had diabetes, 63.3% were on hemodiafiltration. Median dialysate sodium was 138 (136, 140). Median DRT was 140 (45, 440) minutes and 14.9% of patients had DRT >12 hours. Fatigue score was 3.1 ±2.3, 18% had no fatigue and 37.7% had a score ≥4. DRT and fatigue score were significantly associated. In multivariable regression analysis, intradialytic reduction in serum sodium and frequency of dialysis were significantly associated with DRT. Factors associated with fatigue included female sex and lower hemoglobin. In patients ≥85 years, hemodiafiltration was associated with prolonged DRT. CONCLUSION: Modifiable factors associated with prolonged DRT are not exactly similar to those associated with fatigue. Intradialytic reduction in serum sodium and low frequency of dialysis are two independent factors associated with longer DRT, with hemodiafiltration associated with longer recovery in very elderly patients. The hemoglobin level is the modifiable independent factor associated with fatigue. These modifiable factors can be addressed in future interventional trials in order to improve patients' outcomes.