RESUMEN
Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFH1H2 and ΔCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP-specific therapeutic target in AAV.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Humanos , Susceptibilidad a Enfermedades , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Factores Inmunológicos , Properdina/genéticaRESUMEN
Parietal epithelial cells (PECs) are kidney progenitor cells with similarities to a bone marrow stem cell niche. In focal segmental glomerulosclerosis (FSGS) PECs become activated and contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts via its specific receptor, CSF-1R, and has been implicated in several glomerular diseases, although its role on PEC activation is unknown. Here, we found that CSF-1R was upregulated in PECs and podocytes in biopsies from patients with FSGS. Through in vitro studies, PECs were found to constitutively express CSF-1R. Incubation with CSF-1 induced CSF-1R upregulation and significant transcriptional regulation of genes involved in pathways associated with PEC activation. Specifically, CSF-1/CSF-1R activated the ERK1/2 signaling pathway and upregulated CD44 in PECs, while both ERK and CSF-1R inhibitors reduced CD44 expression. Functional studies showed that CSF-1 induced PEC proliferation and migration, while reducing the differentiation of PECs into podocytes. These results were validated in the Adriamycin-induced FSGS experimental mouse model. Importantly, treatment with either the CSF-1R-specific inhibitor GW2580 or Ki20227 provided a robust therapeutic effect. Thus, we provide evidence of the role of the CSF-1/CSF-1R pathway in PEC activation in FSGS, paving the way for future clinical studies investigating the therapeutic effect of CSF-1R inhibitors on patients with FSGS.
Asunto(s)
Glomeruloesclerosis Focal y Segmentaria , Receptores de Hialuranos , Factor Estimulante de Colonias de Macrófagos , Podocitos , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/genética , Animales , Humanos , Podocitos/metabolismo , Podocitos/patología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Factor Estimulante de Colonias de Macrófagos/genética , Receptores de Hialuranos/metabolismo , Receptores de Hialuranos/genética , Ratones , Proliferación Celular/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Células Epiteliales/efectos de los fármacos , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Masculino , Modelos Animales de Enfermedad , Células Cultivadas , Femenino , Regulación hacia Arriba , Movimiento Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal , Ratones Endogámicos C57BL , Receptores de Factor Estimulante de Colonias de Granulocitos y MacrófagosRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2-5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients. METHODS: Twenty C57BL6J mice received 200 µg of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNFα, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression. RESULTS: Cisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity. CONCLUSIONS: Only mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker.
Asunto(s)
Quimiocina CCL2 , Cisplatino , Inhibidores de Puntos de Control Inmunológico , Ratones Endogámicos C57BL , Nefritis Intersticial , Receptor de Muerte Celular Programada 1 , Animales , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Nefritis Intersticial/orina , Nefritis Intersticial/patología , Nefritis Intersticial/inducido químicamente , Quimiocina CCL2/orina , Quimiocina CCL2/metabolismo , Cisplatino/efectos adversos , Humanos , Masculino , Femenino , Glomérulos Renales/patología , Glomérulos Renales/efectos de los fármacos , Antígeno B7-H1/metabolismo , Ratones , Persona de Mediana Edad , Anciano , Enfermedad AgudaRESUMEN
The inflammasome regulates the innate inflammatory response and is involved in autoimmune diseases. In this study, we explored the levels of IL-18 and IL-1ß in serum and urine and the influence of various single-nucleotide polymorphisms (SNPs) on kidney lesions at diagnosis in patients with ANCA-associated vasculitis (AAV) and their clinical outcomes. Ninety-two patients with renal AAV were recruited, and blood and urine were collected at diagnosis. Serum and urine cytokine levels were measured by ELISA. DNA was extracted and genotyped using TaqMan assays for SNPs in several inflammasome genes. Lower serum IL-18 (p = 0.049) and the IL-18 rs187238 G-carrier genotype (p = 0.042) were associated with severe fibrosis. The IL-18 rs1946518 TT genotype was associated with an increased risk of relapse (p = 0.05), whereas GG was related to better renal outcomes (p = 0.031). The rs187238 GG genotype was identified as a risk factor for mortality within the first year after AAV diagnosis, independent of the requirement for dialysis or lung involvement (p = 0.013). We suggest that decreased cytokine levels could be a surrogate marker of scarring and chronicity of the renal lesions, together with the rs187238 GG genotype. If our results are validated, the rs1946518 TT genotype predicts the risk of relapse and renal outcomes during follow-up.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Inflamasomas , Interleucina-18 , Interleucina-1beta , Polimorfismo de Nucleótido Simple , Humanos , Interleucina-18/genética , Interleucina-18/sangre , Masculino , Femenino , Inflamasomas/genética , Persona de Mediana Edad , Interleucina-1beta/genética , Interleucina-1beta/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Anciano , Riñón/patología , Riñón/metabolismo , Genotipo , Adulto , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
BACKGROUND: C3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare entity. Herein we analysed the clinical and histologic features of a cohort of C3G-MIg patients. METHODS: We conducted a retrospective, multicentre, observational study. Patients diagnosed with C3G-MIg between 1995 and 2021 were enrolled. All had genetic studies of the alternative complement pathway. The degree of disease activity and chronicity were analysed using the C3G histologic index. Descriptive statistics and propensity score matching (PSM) analysis were used to evaluate the main outcome of the study [kidney failure (KF)]. RESULTS: The study group included 23 patients with a median age 63 of years [interquartile range (IQR) 48-70], and 57% were males. Immunoglobulin G kappa was the most frequent MIg (65%). The diagnosis of C3G-MIg was made in transplanted kidneys in seven patients (30%). Five (22%) patients had C3 nephritic factor and five (22%) had anti-factor H antibodies. One patient carried a pathogenic variant in the CFH gene. During a follow-up of 40 months (IQR 14-69), nine patients (39%) reached KF and these patients had a significantly higher total chronicity score on kidney biopsy. Patients who received clone-targeted therapy had a significantly higher survival compared with other management. Those who achieved haematological response had a significantly higher kidney survival. Outcome was remarkably poor in kidney transplant recipients, with five of them (71%) reaching KF. By PSM (adjusting for age, kidney function, proteinuria and chronicity score), no significant differences were observed in kidney survival between C3G patients with/without MIg. CONCLUSIONS: The C3G histologic index can be used in patients with C3G-MIg to predict kidney prognosis, with higher chronicity scores being associated with worse outcomes. Clone-targeted therapies and the development of a haematological response are associated with better kidney prognosis.
Asunto(s)
Glomerulonefritis Membranoproliferativa , Enfermedades Renales , Gammopatía Monoclonal de Relevancia Indeterminada , Paraproteinemias , Humanos , Masculino , Persona de Mediana Edad , Femenino , Factor Nefrítico del Complemento 3 , Complemento C3 , Estudios Retrospectivos , Paraproteinemias/complicaciones , Paraproteinemias/patología , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/etiología , Inmunoglobulina G , Células Clonales/química , Células Clonales/patología , Glomerulonefritis Membranoproliferativa/patologíaRESUMEN
BACKGROUND: The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known. METHODS: We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres. RESULTS: Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001). CONCLUSIONS: MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Enfermedades Renales , Nefritis , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Anticuerpos Anticitoplasma de Neutrófilos , Femenino , Humanos , Masculino , Mieloblastina , Peroxidasa , Recurrencia , Estudios RetrospectivosRESUMEN
INTRODUCTION: The association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure. METHODS: This was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure. RESULTS: The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13-41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56-0.97; P < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up. CONCLUSIONS: The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.
Asunto(s)
Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Fallo Renal Crónico , Adolescente , Adulto , Complemento C3/análisis , Glomerulonefritis/complicaciones , Glomerulonefritis/epidemiología , Humanos , Riñón , Fallo Renal Crónico/complicaciones , Proteinuria/complicaciones , Proteinuria/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
The inflammasome is an immune multiprotein complex that activates pro-caspase 1 in response to inflammation-inducing stimuli and it leads to IL-1ß and IL-18 proinflammatory cytokine production. NLRP1 and NLRP3 inflammasomes are the best characterized and they have been related to several autoimmune diseases. It is well known that the kidney expresses inflammasome genes, which can influence the development of some glomerulonephritis, such as lupus nephritis, ANCA glomerulonephritis, IgA nephropathy and anti-GBM nephropathy. Polymorphisms of these genes have also been described to play a role in autoimmune and kidney diseases. In this review, we describe the main characteristics, activation mechanisms, regulation and functions of the different inflammasomes. Moreover, we discuss the latest findings about the role of the inflammasome in several glomerulonephritis from three different points of view: in vitro, animal and human studies.
Asunto(s)
Glomerulonefritis , Inflamasomas , Animales , Caspasa 1 , Femenino , Glomerulonefritis/genética , Humanos , Inflamación , Interleucina-1beta , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
RATIONALE & OBJECTIVE: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population. STUDY DESIGN: Multicenter, retrospective cohort study. SETTING & PARTICIPANTS: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). PREDICTORS: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score. OUTCOME: Time to kidney failure. ANALYTICAL APPROACH: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines. RESULTS: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure. LIMITATIONS: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding. CONCLUSIONS: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.
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Complemento C3/inmunología , Glomerulonefritis Membranoproliferativa/patología , Túbulos Renales/patología , Insuficiencia Renal/patología , Adolescente , Adulto , Atrofia , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Fibrosis , Tasa de Filtración Glomerular , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Glomerulonefritis Membranoproliferativa/inmunología , Glomerulonefritis Membranoproliferativa/metabolismo , Humanos , Inmunosupresores/uso terapéutico , Riñón/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Proteinuria , Insuficiencia Renal/inmunología , Insuficiencia Renal/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
Acute kidney injury in patients who suffer a malignancy is a common complication. Due to its high prevalence and effective treatment, one of the most frequent causes that both oncologists and nephrologists must be aware of is acute tubulointerstitial nephritis (ATIN). ATIN is an immunomediated condition and the hallmark of the disease, with the presence of a tubulointerstitial inflammatory infiltrate in the renal parenchyma. This infiltrate is composed mainly of T lymphocytes that can be accompanied by macrophages, neutrophils, or eosinophils among other cells. One of the major causes is drug-related ATIN, and some antineoplastic treatments have been related to this condition. Worthy of note are the novel immunotherapy treatments aimed at enhancing natural immunity in order to defeat cancer cells. In the context of the immunosuppression status affecting ATIN patients, some pathogen antigens can trigger the development of the disease. Finally, hematological malignancies can also manifest in the kidney leading to ATIN, even at the debut of the disease. In this review, we aim to comprehensively examine differential diagnosis of ATIN in the setting of a neoplastic patient.
Asunto(s)
Neoplasias Hematológicas , Inmunoterapia , Riñón , Nefritis Intersticial , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Riñón/inmunología , Riñón/patología , Macrófagos/inmunología , Macrófagos/patología , Nefritis Intersticial/etiología , Nefritis Intersticial/inmunología , Nefritis Intersticial/patología , Nefritis Intersticial/terapia , Infiltración Neutrófila , Neutrófilos/inmunología , Neutrófilos/patología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive diagnostic and follow-up markers. The gold standard for diagnosis is kidney biopsy, which shows a pattern of tubulointerstitial leukocyte infiltrate. The urinalysis findings can aid in the diagnosis but are no longer considered sensitive or specific. Atthe present time, there is a rising attentiveness tofinding trustworthy biomarkers of the disease, with special focus in urinary cytokines and chemokines that may reflect kidney local inflammation. Cell-based tests are of notable interest to identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as ATIN. Certain single-nucleotide polymorphisms in HLA or cytokine genes may confer susceptibility to the disease according to pathophysiological basis. In this review, we aim to critically examine and summarize the available evidence on this topic.
Asunto(s)
Biomarcadores/orina , Nefritis Intersticial/diagnóstico , Biomarcadores/sangre , Quimiocinas/sangre , Quimiocinas/orina , Predisposición Genética a la Enfermedad , Humanos , Nefritis Intersticial/inducido químicamente , Nefritis Intersticial/genética , Nefritis Intersticial/orina , Linfocitos T/efectos de los fármacosRESUMEN
Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.
Asunto(s)
Síndrome Hemolítico Urémico Atípico/complicaciones , Proteínas del Sistema Complemento/genética , Hipertensión Maligna/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico Urémico Atípico/genética , Síndrome Hemolítico Urémico Atípico/terapia , Inactivadores del Complemento/uso terapéutico , Femenino , Humanos , Hipertensión Maligna/diagnóstico , Hipertensión Maligna/genética , Hipertensión Maligna/terapia , Incidencia , Masculino , Persona de Mediana Edad , Plasmaféresis , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. METHODS: We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 µmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. RESULTS: Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4-5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94-20.63], p = 0.002), after adjustment for confounding factors. CONCLUSIONS: The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Diabetes Mellitus , Infecciones , Metilprednisolona , Quimioterapia por Pulso/métodos , Inducción de Remisión/métodos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/epidemiología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/terapia , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etiología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Infecciones/epidemiología , Infecciones/etiología , Pruebas de Función Renal/métodos , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Intercambio Plasmático/estadística & datos numéricos , Diálisis Renal/estadística & datos numéricos , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
: Background: The role of the T helper 17 (Th17) cell subset in anti-neutrophil cytoplasm antibodies (ANCA) associated vasculitis (AAV) is controversial. We hypothesized that a specific Th17 response to myeloperoxidase (MPO) or proteinase 3 (PR3) is detectable in AAV patients and is different among the disease phases. METHODS: We analyzed 43 AAV patients with renal involvement (21 acute and 22 remission patients), and 12 healthy controls. Peripheral blood mononuclear cells (PBMCs) were cultured with PR3/MPO over 48 h. Thereafter, frequencies of MPO/PR3-specific Th17 cells were assessed using an enzyme-linked immunosorbent spot (ELISpot) assay. Supernatant IL-17 concentration was quantified using ELISA. Finally, specific Th17 response after depletion of T regulatory lymphocytes (T-regs) in some remission patients was compared to the non T-reg-depleted response. RESULTS: Specific Th17 cell number was higher in acute patients compared to remission (p = 0.004). Specific Th17 cell number performed well in the disease activity detection (ROC curve area under the curve (AUC) = 0.87; p = 0.0001) with an optimal cut-off of 6 spots/million. Patients above this cut-off showed higher serum creatinine (p = 0.004), C-reactive protein (CRP) (p = 0.001) and ANCA titer (p = 0.032). Supernatant IL-17 concentration was higher in acute patients compared to remission (p = 0.035) and did not normalize to healthy control levels (p = 0.01). CONCLUSIONS: A specific Th17 cell response is present in AAV patients. This response is more pronounced in the acute phase, but persists in remission.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Células Th17/inmunología , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Biomarcadores/sangre , Ensayo de Immunospot Ligado a Enzimas/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloblastina/inmunología , Peroxidasa/inmunología , Pruebas Serológicas/métodosRESUMEN
OBJECTIVES: B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity. METHODS: B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system. RESULTS: Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls. CONCLUSION: In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Linfocitos B Reguladores/inmunología , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Subgrupos de Linfocitos B/inmunología , Estudios de Casos y Controles , Técnicas de Cocultivo , Femenino , Humanos , Tolerancia Inmunológica/inmunología , Inmunofenotipificación , Inmunosupresores/uso terapéutico , Interleucina-10/biosíntesis , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab , Células TH1/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Background: Acute interstitial nephritis (AIN) related to immune checkpoint inhibitors (ICI-AIN) has a not completely understood pathophysiology. Our objectives were to analyze possible biomarkers for the differentiation between acute tubular necrosis (ATN) and AIN, especially in cancer patients, and to study the participation of the immune checkpoint pathway in ICI-AIN. Methods: We performed an observational study. We recruited patients with incident diagnosis of ICI-AIN (n = 19). We measured soluble PD-1 (sPD-1), sPD-L1, and sPD-L2 in serum and urine at diagnosis and compared to it patients with non-ICI-related AIN (non-ICI-AIN) (n = 18) and ATN (n = 21). The findings were validated in an independent cohort from another institution (n = 30). Also, we performed PD-L1 and PD-L2 immunostaining of kidney biopsies from patients with ICI-AIN and compared to patients with non-ICI-AIN. Results: Urinary sPD-1 (usPD-1) was higher in patients with AIN compared to ATN (P = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN (P = .021). In cancer patients, usPD-1 <129.3 pg/ml had a 71.43% sensitivity and 94.44% specificity to differentiate ATN from ICI-AIN, with a likelihood ratio of 12.86. In the external validation cohort, the same cutoff showed a sensitivity of 80%. In kidney biopsies, patients with ICI-AIN showed higher density of PD-L1 positive tubules than patients with non-ICI-AIN (P = .02). The proportion of patients having >2.64/mm2 PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN (P = .034). There was a positive correlation (P = .009, r = 0.72) between usPD-1 and the number of PD-L1 positive tubules. Conclusions: UsPD-1 and ssPD-1 are higher in AIN than ATN. Moreover, there was a strong correlation between usPD-1 and renal tubular PD-L1 expression. Our findings suggest a role of usPD-1 as non-invasive biomarker to differentiate ICI-AIN from ATN, especially in cancer patients, which has been confirmed in an external validation cohort.
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The relation that connects cancer and renal damage is bidirectional and this renal damage worsens quality of life and increases morbidity in high-complexity patients such as patients with cancer and kidney injury. Strikingly, in the last decade, the treatment of advanced cancer has clearly advanced in terms of new therapeutic strategies with the ability to transform the advanced metastatic cancer in a chronic condition. In this new era of cancer therapies, cancer treatment including conventional chemotherapy, targeted cancer agents and immunotherapies among others are significantly associated with kidney injury. Renal toxicity that is currently seen in onconephrology departments is in part related to the new therapies such as immunotherapy, and to the prolonged survival achieved at the expense of increasing therapy lines, and a combination of different drugs. In this review, we will discuss in a practical way, nephrotoxicity caused by the main oncospecific treatments such as classical chemotherapy agents, targeted therapies, and immunotherapy. In addition, strategies for prevention and management recommendations in patients with malignancies and kidney disease will also be addressed.
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Antineoplásicos , Enfermedades Renales , Neoplasias , Insuficiencia Renal , Humanos , Calidad de Vida , Antineoplásicos/efectos adversos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Enfermedades Renales/terapia , Enfermedades Renales/tratamiento farmacológicoRESUMEN
Background: CD163 and calprotectin have been proposed as biomarkers of active renal vasculitis. This study aimed to determine whether the combination of serum/urine calprotectin (s/uCalprotectin) and urinary soluble CD163 (suCD163) increases their individual performance as activity biomarkers. Methods: We included 138 patients diagnosed with ANCA vasculitis (n = 52 diagnostic phase, n = 86 remission). The study population was divided into the inception (n = 101) and the validation cohorts (n = 37). We determined the s/uCalprotectin and suCD163 concentration using enzyme-linked immunoassay at the diagnostic or at the remission phase. Receiver operating characteristic (ROC) curves were conducted to assess the biomarkers' classificatory values. We elaborated a combinatorial biomarker model in the inception cohort. The ideal cutoffs were used in the validation cohort to confirm the model's accuracy in the distinction between active disease and remission. We added the classical ANCA vasculitis activity biomarkers to the model to increase the classificatory performance. Results: The concentrations of sCalprotectin and suCD163 were higher in the diagnostic compared with the remission phase (P = .013 and P < .0001). According to the ROC curves, sCalprotectin and suCD163 were accurate biomarkers to discern activity [area under the curve 0.73 (0.59-0.86), P = .015 and 0.88 (0.79-0.97), P < .0001]. The combinatory model with the best performance in terms of sensitivity, specificity and likelihood ratio included sCalprotectin, suCD163 and haematuria. Regarding the inception and the validation cohort, we obtained a sensitivity, specificity and likelihood ratio of 97%, 90% and 9.7, and 78%, 94% and 13, respectively. Conclusions: In patients with ANCA vasculitis, a predictive model combining sCalprotectin, suCD163 and haematuria could be useful in detecting active kidney disease.
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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), characterized by the presence of autoantibodies to neutrophil cytoplasmic antigens, proteinase 3 (PR3), and myeloperoxidase (MPO), typically involves small blood vessels of the respiratory tract and kidneys. It includes distinct clinical syndromes: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA. GPA is commonly associated with PR3-ANCA, while MPA is associated with MPO-ANCA. AAVs have a complex pathogenesis, influenced by genetics and environmental factors. There is evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation and injury, with effector T cells and activation of the alternative pathway of the complement also involved. Advances in immunosuppressive treatment have drastically reduced mortality of AAV in the past decades, opting for a more individualized approach. Careful assessment of ANCA specificity, disease activity, organ damage, and quality of life allows for a tailored immunosuppressive therapy. Contemporary AAV treatment is characterized by regimens that minimize the cumulative exposure to glucocorticoids and cyclophosphamide, and novel approaches including complement blockage and immunosuppressant combinations might be the standard of care in the future. In this review, we examine the pathogenesis, clinical approach, and evidence-based treatment options for the management of AAV patients.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Anticuerpos Anticitoplasma de Neutrófilos , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Mieloblastina , Calidad de VidaRESUMEN
mRNA-based vaccines have dramatically shifted the course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. IgA nephropathy (IgAN) flare is the most reported renal adverse effect after the administration of these vaccines. Unraveling the mechanistic pathways leading to these flares is necessary to confirm a causal association. Herein, we report 2 cases of IgAN flare after SARS-CoV-2 vaccination in patients previously diagnosed with IgAN. We describe and compare the clinical and analytical features of the disease at the time of the diagnostic with the post-vaccine flare. In addition, we obtained serum and urine of these patients at the moment of the flare and determined the levels of IL-2, TNF-α, and IFNγ using a multiplex bead-based assay. As diseased controls, we included n = 13 patients diagnosed with IgAN who had available serum and urine samples at the moment of the diagnostic stored in our biobank. We also included 6 healthy controls. Compared to the first episode, postvaccination flares were more severe in terms of peak serum creatinine, albuminuria, and urinary erythrocyte count. The histological lesions found at the biopsy performed during the post-vaccine flare were similar to those found at the diagnostic. One of the patients who suffered a post-vaccine flare showed increased serum IL-2 and TNFα compared to the IgAN-diseased controls and the healthy controls. In conclusion, although several cases of post-vaccine IgAN flares have been reported, there are no mechanistic studies on the occurrence of these flares. We here suggest that hyperactivation of the Th1 pathway may be involved, but larger studies with more refined methods for numerical and functional Th1 lymphocytes evaluation are required.