RESUMEN
Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.
Asunto(s)
Síndrome Hemolítico Urémico Atípico , Microangiopatías Trombóticas , Adulto , Humanos , Riñón/patología , Microangiopatías Trombóticas/epidemiología , Microangiopatías Trombóticas/terapia , Microangiopatías Trombóticas/patología , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/epidemiología , Proteínas del Sistema Complemento , Pruebas de Función RenalRESUMEN
Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.
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Glomerulonefritis Membranosa , Trasplante de Riñón , Alelos , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/genética , Humanos , Trasplante de Riñón/efectos adversos , Polimorfismo de Nucleótido Simple , Receptores de Fosfolipasa A2/genética , Estudios RetrospectivosRESUMEN
Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.
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Nefritis Intersticial , Insuficiencia Renal , Agricultura , Animales , Francia , Humanos , India , Nefritis Intersticial/inducido químicamente , RatasRESUMEN
BACKGROUND: Moderate hyperhydration is often achieved in the early post-kidney transplantation period. Whether this strategy could lead to the development of intra-abdominal hypertension (IAH) has never been assessed so far. We aimed to study the incidence of IAH after kidney transplantation and its association with graft function recovery. METHODS: We conducted a prospective monocentric study among patients undergoing kidney transplantation at the University Hospital of Reims between May 2017 and April 2019. Intravesical pressure (IVP) was monitored every 8 h from Day 0 to 3. RESULTS: A total of 107 patients were enrolled. Among 55 patients included in the analysis, 74.5% developed IAH. Body mass index >25 kg/m2 was associated with IAH development {odds ratio [OR] 10.4 [95% confidence interval (CI) 2.0-52.9]; P = 0.005}. A previous history of peritoneal dialysis was protective [OR 0.06 (95% CI 0.01-0.3); P = 0.001]. IAH Grades III and IV occurred in 30.9% of patients and correlated with higher Day 3 creatininaemia (419.6 ± 258.5 versus 232.5 ± 189.4 µmol/L; P = 0.02), higher delayed graft function incidence (41.2 versus 7.9%; P = 0.04), lower Kirchner index measured using scintigraphy (0.47 ± 0.09 versus 0.64 ± 0.09; P = 0.0005) and decreased Day 30 estimated glomerular filtration rate (35.8 ± 18.8 versus 52.5 ± 21.3, P = 0.05). IAH patients had higher fluid balance (P = 0.02). Evolution of IVP correlated with weight gain (P < 0.01) and central venous pressure (P < 0.001). CONCLUSIONS: IAH is frequent after kidney transplantation and IAH Grades III and IV are independently associated with impaired graft function. These results question current haemodynamic objectives and raise for the first time interest in intra-abdominal pressure monitoring in these patients. CLINICAL TRIAL NOTATION: ClinicalTrials.gov identifier: NCT03478176.
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Rechazo de Injerto/etiología , Hipertensión Intraabdominal/epidemiología , Trasplante de Riñón/efectos adversos , Femenino , Francia/epidemiología , Tasa de Filtración Glomerular , Rechazo de Injerto/epidemiología , Rechazo de Injerto/patología , Hemodinámica , Humanos , Incidencia , Hipertensión Intraabdominal/etiología , Hipertensión Intraabdominal/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Equilibrio HidroelectrolíticoRESUMEN
Correction for 'Towards normalization selection of Raman data in the context of protein glycation: application of validity indices to PCA processed spectra' by Fatima Alsamad et al., Analyst, 2020, DOI: 10.1039/c9an02155h.
RESUMEN
Raman spectroscopy is a candidate technique for diagnosis applications in medicine due to its high molecular specificity. Optimizing the pre-treatment applied for Raman data is important for exploiting Raman signals and ensuring their relevance in medical diagnosis. One of the crucial steps in data pre-processing, normalization, can affect significantly the result interpretation. To select the appropriate normalization method, a strategy based on validity indices (VI) is proposed in this study. VI are based on measuring the quality of data partitioning without involving a full sequence of supervised classification. The approach was tested on Raman data acquired from control and in vitro glycated proteins (albumin and collagen). Protein glycation is a process involved in the molecular ageing of tissues that leads to the formation of products altering the functional and structural properties of proteins. Different methods of normalization were applied on the data sets: integrated intensity of the phenylalanine band, integrated intensity of the amide I band, standard normal variate (SNV), multiplicative signal correction (MSC), and extended multiplicative signal correction (EMSC) that performs simultaneously baseline correction and normalization. Following normalization, principal component analysis (PCA) was applied and VI were calculated from PCA scores resulting from each of the normalization methods mentioned. Based on VI quantitative values, our experiments permit to illustrate the effect of normalization on the data separability of control and glycated samples, and to determine the most appropriate normalization and simultaneously the most discriminant principal components to exploit vibrational information associated with glycation-induced modifications. In parallel, principal component analysis - linear discriminant analysis (PCA-LDA) was carried out for positioning the interest of VI in regard to a common chain of data processing.
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Colágeno Tipo I/análisis , Productos Finales de Glicación Avanzada/análisis , Albúmina Sérica Humana/análisis , Animales , Análisis Discriminante , Humanos , Análisis de Componente Principal , Ratas , Espectrometría RamanRESUMEN
The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.
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Trasplante de Riñón , Anticuerpos , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs. RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals. CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that in vitro cell-based assays are needed to improve risk assessments before transplant.
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Rechazo de Injerto/inmunología , Hemorragia/inmunología , Inmunoglobulina G/sangre , Receptor de Angiotensina Tipo 1/inmunología , Microangiopatías Trombóticas/inmunología , Vasculitis/inmunología , Enfermedad Aguda , Adulto , Anciano , Células Endoteliales/inmunología , Endotelina-1/inmunología , Femenino , Rechazo de Injerto/patología , Rechazo de Injerto/fisiopatología , Hemorragia/patología , Humanos , Glomérulos Renales/patología , Trasplante de Riñón/efectos adversos , Masculino , Microvasos/patología , Persona de Mediana Edad , Microangiopatías Trombóticas/patología , Factores de Tiempo , Vasculitis/patologíaRESUMEN
Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.
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Rechazo de Injerto/prevención & control , Antígenos HLA-DQ/sangre , Inmunosupresores/administración & dosificación , Isoantígenos/sangre , Trasplante de Riñón/efectos adversos , Selección de Paciente , Adulto , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Sustitución de Medicamentos , Epítopos/inmunología , Everolimus/administración & dosificación , Everolimus/efectos adversos , Femenino , Estudios de Seguimiento , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Supervivencia de Injerto/inmunología , Antígenos HLA-DQ/inmunología , Prueba de Histocompatibilidad , Humanos , Inmunosupresores/efectos adversos , Isoantígenos/inmunología , Masculino , Persona de Mediana Edad , Trasplante Homólogo/efectos adversosRESUMEN
Aging is a progressive process determined by genetic and acquired factors. Among the latter are the chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, which are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging. To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.
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Envejecimiento/metabolismo , Proteínas/metabolismo , Secuencia de Aminoácidos , Animales , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Procesamiento Proteico-PostraduccionalRESUMEN
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs and vascular alterations. SSc pathophysiology involves systemic inflammation and oxidative stress. Because the vanin-1 gene (vnn1) encodes an enzyme with pantetheinase activity that converts vasculoprotective pantethine into profibrotic pantothenic acid and pro-oxidant cystamine, we tested this pathway in the pathophysiology of SSc. Activation of the vanin-1/pantetheinase pathway was investigated in wild-type BALB/c mice with hypochlorous acid (HOCl)-induced SSc by ELISA and Western blotting. We then evaluated the effects of the inactivation of vnn1 on the development of fibrosis, endothelial alterations, and immunological activation in mice with HOCl- and bleomycin-induced SSc. We then explored the vanin-1/pantetheinase pathway in a cohort of patients with SSc and in controls. In wild-type mice with HOCl-induced SSc, the vanin-1/pantetheinase pathway was dysregulated, with elevation of vanin-1 activity in skin and high levels of serum pantothenic acid. Inactivation of the vnn1 gene in vnn1-/- mice with HOCl-induced SSc prevented the development of characteristic features of the disease, including fibrosis, immunologic abnormalities, and endothelial dysfunction. Remarkably, patients with diffuse SSc also had increased expression of vanin-1 in skin and blood and elevated levels of serum pantothenic acid that correlated with the severity of the disease. Our data demonstrate that vanin-1/pantetheinase controls fibrosis, vasculopathy, autoimmunity, and oxidative stress in SSc. The levels of vanin-1 expression and pantothenic acid determine SSc severity and can be used as markers of disease severity. More importantly, inhibition of vanin-1 can open new therapeutic approaches in SSc.
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Amidohidrolasas/metabolismo , Esclerodermia Sistémica/metabolismo , Animales , Femenino , Proteínas Ligadas a GPI/metabolismo , Ratones , Ratones Endogámicos BALB C , Ácido Pantoténico/metabolismoRESUMEN
In this review, we will highlight technologies that enable scientists to study the molecular characteristics of tissues and/or cells without the need for antibodies or other labeling techniques. Specifically, we will focus on matrix-assisted laser desorption/ionization imaging mass spectrometry, infrared spectroscopy, and Raman spectroscopy.
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Enfermedades Renales/patología , Imagen Molecular/métodos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Espectrofotometría Infrarroja/métodos , Espectrometría Raman/métodos , Humanos , Riñón/patología , Imagen Molecular/tendencias , VibraciónRESUMEN
OBJECTIVE: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. APPROACH AND RESULTS: We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager(-/-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of α-SMA. Ager transcript levels in the aorta were 6× higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA. CONCLUSIONS: Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager(-/-) animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE.
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Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína Amiloide A Sérica/metabolismo , Uremia/complicaciones , Animales , Antioxidantes/farmacología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/etiología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/etiología , Aterosclerosis/genética , Aterosclerosis/patología , Movimiento Celular , Células Cultivadas , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Nefrectomía , Estrés Oxidativo , Fenotipo , Fosforilación , Placa Aterosclerótica , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada/deficiencia , Receptor para Productos Finales de Glicación Avanzada/genética , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal , Uremia/genética , Uremia/metabolismoRESUMEN
The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that interacts with advanced glycation end products, but also with C3a, CpG DNA oligonucleotides, and alarmin molecules such as HMGB1 to initiate a proinflammatory reaction. Systemic lupus erythematosus is an autoimmune disorder associated with the accumulation of RAGE ligands. We generated mice invalidated for RAGE in the lupus-prone B6-MRL Fas lpr/j background to determine the role of RAGE in the pathogenesis of systemic lupus erythematosus. We compared the phenotype of these mice with that of their wild-type and B6-MRL Fas lpr/j littermates. Lymphoproliferative syndrome, production of anti-dsDNA Abs, lupus nephritis, and accumulation of CD3(+)B220(+)CD4(-)CD8(-) autoreactive T cells (in the peripheral blood and the spleen) were significantly increased in B6-MRL Fas lpr/j RAGE(-/-) mice compared with B6-MRL Fas lpr/j mice (respectively p < 0.005, p < 0.05, p < 0.001, and p < 0.001). A large proportion of autoreactive T cells from B6-MRL Fas lpr/j mice expressed RAGE at their surface. Time course studies of annexin V expression revealed that autoreactive T cells in the spleen of B6-MRL Fas lpr/j-RAGE(-/-) mice exhibited a delay in apoptosis and expressed significantly less activated caspase 3 (39.5 ± 4.3%) than T cells in B6-MRL Fas lpr/j mice (65.5 ± 5.2%) or wild-type mice (75.3 ± 2.64%) (p = 0.02). We conclude that the deletion of RAGE in B6-MRL Fas lpr/j mice promotes the accumulation of autoreactive CD3(+)B220(+)CD4(-)CD8(-) T cells, therefore exacerbating lymphoproliferative syndrome, autoimmunity, and organ injury. This suggests that RAGE rescues the apoptosis of T lymphocytes when the death receptor Fas/CD95 is dysfunctional.
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Apoptosis/inmunología , Nefritis Lúpica/inmunología , Trastornos Linfoproliferativos/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T/inmunología , Animales , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Apoptosis/genética , Caspasa 3/genética , Caspasa 3/inmunología , Eliminación de Gen , Regulación Enzimológica de la Expresión Génica/genética , Regulación Enzimológica de la Expresión Génica/inmunología , Nefritis Lúpica/genética , Nefritis Lúpica/patología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/patología , Ratones , Ratones Endogámicos MRL lpr , Ratones Noqueados , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Bazo/inmunología , Bazo/patología , Síndrome , Linfocitos T/patologíaRESUMEN
Renal interstitial fibrosis and interstitial active inflammation are the main histologic features of renal allograft biopsy specimens. Fibrosis is currently assessed by semiquantitative subjective analysis, and color image analysis has been developed to improve the reliability and repeatability of this evaluation. However, these techniques fail to distinguish fibrosis from constitutive collagen or active inflammation. We developed an automatic, reproducible Fourier-transform infrared (FTIR) imaging-based technique for simultaneous quantification of fibrosis and inflammation in renal allograft biopsy specimens. We generated and validated a classification model using 49 renal biopsy specimens and subsequently tested the robustness of this classification algorithm on 166 renal grafts. Finally, we explored the clinical relevance of fibrosis quantification using FTIR imaging by comparing results with renal function at 3 months after transplantation (M3) and the variation of renal function between M3 and M12. We showed excellent robustness for fibrosis and inflammation classification, with >90% of renal biopsy specimens adequately classified by FTIR imaging. Finally, fibrosis quantification by FTIR imaging correlated with renal function at M3, and the variation in fibrosis between M3 and M12 correlated well with the variation in renal function over the same period. This study shows that FTIR-based analysis of renal graft biopsy specimens is a reproducible and reliable label-free technique for quantifying fibrosis and active inflammation. This technique seems to be more relevant than digital image analysis and promising for both research studies and routine clinical practice.
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Inflamación/patología , Enfermedades Renales/patología , Trasplante de Riñón , Riñón/patología , Complicaciones Posoperatorias/patología , Femenino , Fibrosis , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).
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Azatioprina/administración & dosificación , Ciclosporinas/administración & dosificación , Inmunosupresores/administración & dosificación , Trasplante de Riñón/mortalidad , Quimioterapia de Mantención/métodos , Ácido Micofenólico/análogos & derivados , Adulto , Azatioprina/efectos adversos , Ciclosporinas/efectos adversos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Terapia de Inmunosupresión/métodos , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Estudios Prospectivos , Medición de Riesgo , Estadísticas no Paramétricas , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently leads to end-stage renal disease and kidney transplantation. However, disease recurrence often occurs after transplantation. Here we evaluated the predictive value of three markers for IgAN recurrence: the presence of galactose-deficient IgA1, IgG anti-IgA autoantibodies, and IgA-soluble (s) CD89 complexes. This was analyzed in 38 kidney transplant recipients with IgAN recurrence and compared with 22 patients transplanted for IgAN but without recurrence and with 17 healthy controls. Pre-transplantation galactose-deficient IgA1 serum levels were significantly higher in the recurrence compared with the no recurrence or control groups. IgA-IgG complexes were significantly elevated in the recurrence group. Both the recurrence and no recurrence groups had increased values of IgA-sCD89 complexes compared with healthy controls, but values were significantly lower in patients with recurrence compared with no recurrence. Areas under the receiver operating curve of the markers in pre-transplantation sera were 0.86 for galactose-deficient-IgA, 0.82 for IgA-IgG, and 0.78 for sCD89-IgA; all significant. Disease recurrence was associated with decreased serum galactose-deficient IgA1 and appearance of mesangial-galactose-deficient IgA1 deposits, whereas increased serum IgA-sCD89 complexes were associated with mesangial sCD89 deposits. Thus, galactose-deficient-IgA1, IgG autoantibodies, and IgA-sCD89 complexes are valuable biomarkers to predict disease recurrence, highlighting major pathogenic mechanisms in IgAN.
Asunto(s)
Complejo Antígeno-Anticuerpo/sangre , Antígenos CD/sangre , Autoanticuerpos/sangre , Glomerulonefritis por IGA/sangre , Inmunoglobulina A/sangre , Fallo Renal Crónico/sangre , Receptores Fc/sangre , Adulto , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Biopsia , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/cirugía , Humanos , Riñón/inmunología , Riñón/patología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/inmunología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Recurrencia , Factores de Riesgo , Resultado del TratamientoAsunto(s)
Inhibidores de la Calcineurina/efectos adversos , Hiperpotasemia/diagnóstico , Hipertensión/diagnóstico , Trasplante de Riñón/efectos adversos , Seudohipoaldosteronismo/diagnóstico , Tacrolimus/efectos adversos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Hiperpotasemia/inducido químicamente , Hipertensión/inducido químicamente , Fallo Renal Crónico/etiología , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/cirugía , Seudohipoaldosteronismo/inducido químicamente , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: C3 glomerulopathy (C3G) is characterized by predominant C3 deposits in glomeruli and dysregulation of the alternative pathway of complement. Half of C3G patients have a C3 nephritic factor (C3NeF). C3G incorporated entities with a range of features on microscopy including dense deposit diseases (DDD) and C3 glomerulonephritis (C3GN). The aim of this work was to study children cases of C3G associated with C3NeF. METHODS: We reviewed 18 cases of C3G with a childhood onset associated with C3NeF without identified mutations in CFH, CFI, and MCP genes. RESULTS: Clinical histories started with recurrent hematuria for seven patients, nephrotic syndrome for four, acute post-infectious glomerulonephritis for three and acute renal failure for four. Twelve patients had a low C3 at first investigation. Kidney biopsy showed ten C3GN and eight DDD. Twenty-three percent of the patients tested presented elevated sC5b9. Seven patients relapsed 3 to 6 years after the onset. At the end of follow-up, two patients were under dialysis, 11 had a persistent proteinuria, five had none; four patients did not follow any treatment. Steroids were first used in 80 % of cases. CONCLUSIONS: C3NeF associated C3G has a heterogeneous presentation and outcome. Anti-proteinuric agents may control the disease during follow-up, even after nephrotic syndrome at the onset. The efficiency of immunosuppressive therapy remains questionable.