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BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.
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Glomerulonefritis por IGA/clasificación , Glomerulonefritis por IGA/patología , Riñón/fisiopatología , Adolescente , Adulto , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Masculino , PronósticoRESUMEN
BACKGROUND: Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial. METHODS: The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS. RESULTS: 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group. CONCLUSIONS: In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.
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Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Intercambio Plasmático , Complicaciones Posoperatorias/tratamiento farmacológico , Rituximab/uso terapéutico , Adulto , Anciano , Femenino , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Riñón/patología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/patología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Anti-glomerular basement membrane (GBM) antibodies are highly specific for Goodpasture's or anti-GBM disease, in which they are generally directed against the non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen(α3(IV)), and less commonly, toward the α 4(IV) or α 5(IV) chains, which form a triple helical structure in GBM and alveolar basement membrane (ABM). Alterations in the hexameric structure of the NC1 (α3 (IV)), allows novel epitopes to be exposed and an immune response to develop, with subsequent linear antibody deposition along the GBM, leading to a crescentic glomerulonephritis. Positive anti-GBM antibodies are assumed to be pathogenic and capable of binding GBM in vivo, especially in the context of rapidly progressive glomerulonephritis. We have investigated patients with circulating anti-GBM antibodies, reactive to α3 (IV) and human GBM by immunoassays and Western blotting respectively, with focal necrotising crescentic glomerulonephritis but no linear GBM antibody deposition on immunohistochemistry. Three out of four were also ANCA positive. Despite not binding native GBM, patients' sera showed linear binding to primate glomeruli by indirect immunofluorescence, in the 2 cases tested. Following treatment, significant improvements in kidney function were found in 3/4 patients. CASE PRESENTATION: We present four patients with crescentic glomerulonephritis and circulating anti-GBM antibodies, but no glomerular binding. CONCLUSIONS: These novel findings, demonstrate that in some patients anti-GBM antibodies may not bind their own GBM. This has important implications for clinical diagnosis, suggesting that histological confirmation of kidney injury by anti-GBM antibodies should be obtained, as non-binding GBM antibodies may be associated with significant renal recovery.
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Autoanticuerpos/sangre , Glomerulonefritis/sangre , Glomerulonefritis/diagnóstico , Glomérulos Renales/patología , Anciano , Femenino , Humanos , Glomérulos Renales/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Epoxygenases belong to the cytochrome P450 family. They generate epoxyeicosatrienoic acids, which are known to have anti-inflammatory effects, but little is known about their role in macrophage function. By high-throughput sequencing of RNA in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (ortholog of human CYP2J2) resulted in reduced epoxyeicosatrienoic acid synthesis. Cyp2j4(-/-) macrophages have relatively increased peroxisome proliferator-activated receptor-γ levels and show a profibrotic transcriptome, displaying overexpression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4(-/-) rats show upregulation of type I collagen following unilateral ureter obstruction of the kidney, and quantitative proteomics analysis (liquid chromatography-tandem mass spectrometry) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a profibrotic macrophage transcriptome that could have implications in various inflammatory conditions, depending on macrophage function.
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Sistema Enzimático del Citocromo P-450/metabolismo , Fibrosis/enzimología , Fibrosis/genética , Macrófagos/enzimología , Animales , Western Blotting , Cromatografía Liquida , Citocromo P-450 CYP2J2 , Familia 2 del Citocromo P450 , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Técnicas de Inactivación de Genes , Glomerulonefritis/enzimología , Glomerulonefritis/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Interferencia de ARN , Ratas , Ratas Endogámicas WKY , Reacción en Cadena en Tiempo Real de la Polimerasa , Espectrometría de Masas en Tándem , TranscriptomaRESUMEN
The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy-free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor-specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation.
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Anticuerpos , Glomérulos Renales/patología , Trasplante de Riñón , Riñón/inmunología , Riñón/patología , Virosis/patología , Células Endoteliales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Donantes de TejidosRESUMEN
BACKGROUND: Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis with renal involvement requires treatment with potentially toxic drugs to reduce morbidity and mortality, and there is a major challenge to determine clinical and histological features predictive of renal prognosis. The aim of our study was to evaluate the use of the 2010 international histological classification for ANCA-associated glomerulonephritis (AAGN) as a predictor of renal outcome when used in conjunction with other prognostic factors. METHODS: One hundred and four patients with AAGN treated at our centre were included: 23 were classified as focal, 26 as crescentic, 48 as mixed and 7 as sclerotic. Renal outcomes were based on estimated glomerular filtration rate (eGFR) at 1 and 5 years, and on renal survival. RESULTS: By univariate analysis, patients in the focal class had the best renal outcome, those in the sclerotic class the worst outcome, and those in the mixed and crescentic classes had intermediate renal survival. There was no significant difference in outcome between the mixed and crescentic classes. In multivariate models, histological class did not improve model fit or associate with renal outcome after adjusting for established prognostic factors. Lower percentage of normal glomeruli, greater degree of tubular atrophy (TA), MPO-ANCA positivity, increasing age and lower starting eGFR, all correlated with poorer renal outcomes. CONCLUSIONS: We conclude that, in our cohort of patients, the international histological classification is predictive of renal outcome in AAGN, but did not appear to be additionally informative over other established prognostic factors in multivariate analysis. However, it may be of value to combine the current histological classification with other established parameters, such as TA and percentage normal glomeruli.
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Anticuerpos Anticitoplasma de Neutrófilos/clasificación , Glomerulonefritis/diagnóstico , Glomerulonefritis/mortalidad , Riñón/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomerulonefritis/sangre , Glomerulonefritis/clasificación , Humanos , Agencias Internacionales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
Complement factor H (CFH) is a negative regulator of the alternative pathway of complement, and properdin is the sole positive regulator. CFH-deficient mice (CFH(-/-)) develop uncontrolled C3 activation and spontaneous renal disease characterized by accumulation of C3 along the glomerular basement membrane, but the role of properdin in the pathophysiology is unknown. Here, we studied mice deficient in both CFH and properdin (CFH(-/-).P(-/-)). Although CFH(-/-) mice had plasma depleted of both C3 and C5, CFH(-/-).P(-/-) animals exhibited depletion of C3 predominantly, recapitulating the plasma complement profile observed in humans with properdin-independent C3 nephritic factors. Glomerular inflammation, thickening of the capillary wall, and glomerular C3 staining were significantly increased in CFH(-/-).P(-/-) compared with CFH(-/-) mice. We previously reported that exogenous CFH ameliorates C3 staining of the glomerular basement membrane and triggers the appearance of mesangial C3 deposits in CFH(-/-) mice; here, we show that these effects require properdin. In summary, during uncontrolled activation of C3 driven by complete CFH deficiency, properdin influences the intraglomerular localization of C3, suggesting that therapeutic inhibition of properdin would be detrimental in this setting.
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Glomerulonefritis/etiología , Enfermedades Renales/complicaciones , Properdina/deficiencia , Animales , Complemento C3/metabolismo , Factor H de Complemento/deficiencia , Glomerulonefritis/metabolismo , Enfermedades por Deficiencia de Complemento Hereditario , Humanos , Glomérulos Renales/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials.
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Microscopic haematuria is the presenting symptom of several conditions, either heritable or acquired. A well-recognized familial condition is Alport syndrome, either of X-linked or autosomal recessive inheritance, as well as thin basement membrane nephropathy (TBMN) because of heterozygous collagen IV mutations. Even though microscopic haematuria of TBMN was long considered as a benign disease with excellent prognosis, more recent data suggest that development of chronic kidney disease (CKD) and even end-stage kidney disease (ESKD) is not a rare finding, perhaps owing to the cofounding role of modifier genes and other factors. Recent investigations in London and Cyprus culminated in the identification of another autosomal dominant condition that presents with microscopic haematuria because of heterozygous mutations in the CFHR5 gene, which apparently plays a pivotal role in the regulation of the alterative pathway of complement system, which constitutes a significant part of innate immunity in humans. Histologically, the hallmark observation is the isolated glomerular deposition of C3 complement in the absence of immune complexes. It is considered one of the C3 glomerulopathies, and it may or may not be accompanied by mild membranoproliferative glomerulonephritis. Interestingly, a single mutation has been identified so far, a duplication of exons 2-3 of the CFHR5 gene, and it has been described in patients of Greek-Cypriot descend only, perhaps originating on the Troodos mountains of Cyprus. Thus far, no patient with a mutation in this gene has been diagnosed in any other population. In Cyprus, it has been found in clusters of families in neighbouring villages in a total of 136 patients, and it constitutes a strong founder phenomenon. About 50% of patients over 50 years have progressed to CKD, and 14% of all patients progressed to ESKD. It is not quite well understood why males run a much higher risk to progress to CKD, compared to women.
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Complemento C3/genética , Complemento C3/fisiología , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/fisiología , Glomerulonefritis/genética , Algoritmos , Chipre/epidemiología , Enfermedades Endémicas , Efecto Fundador , Pruebas Genéticas , Glomerulonefritis/patología , Humanos , LinajeRESUMEN
Micro RNAs (miRNAs) regulate gene expression at the posttranscriptional level. Here we show that regulatory T (T reg) cells have a miRNA profile distinct from conventional CD4 T cells. A partial T reg cell-like miRNA profile is conferred by the enforced expression of Foxp3 and, surprisingly, by the activation of conventional CD4 T cells. Depleting miRNAs by eliminating Dicer, the RNAse III enzyme that generates functional miRNAs, reduces T reg cell numbers and results in immune pathology. Dicer facilitates, in a cell-autonomous fashion, the development of T reg cells in the thymus and the efficient induction of Foxp3 by transforming growth factor beta. These results suggest that T reg cell development involves Dicer-generated RNAs.
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Ribonucleasa III/fisiología , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Factores de Transcripción Forkhead/biosíntesis , Ratones , MicroARNs/biosíntesis , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Timo/citología , Timo/inmunología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
Complement activation is known to have deleterious effects on organ transplantation. On the other hand, the complement system is also known to have an important role in regulating immune responses. The balance between these two opposing effects is critical in the context of transplantation. Here, we report that female mice deficient in C1q (C1qa(-/-)) or C3 (C3(-/-)) reject male syngeneic grafts (HY incompatible) at an accelerated rate compared with WT mice. Intranasal HY peptide administration, which induces tolerance to syngeneic male grafts in WT mice, fails to induce tolerance in C1qa(-/-) or C3(-/-) mice. The rejection of the male grafts correlated with the presence of HY D(b)Uty-specific CD8(+) T cells. Consistent with this, peptide-treated C1qa(-/-) and C3(-/-) female mice rejecting male grafts exhibited more antigen-specific CD8(+)IFN-gamma(+) and CD8(+)IL-10(+) cells compared with WT females. This suggests that accumulation of IFN-gamma- and IL-10-producing T cells may play a key role in mediating the ongoing inflammatory process and graft rejection. Interestingly, within the tolerized male skin grafts of peptide-treated WT mice, IFN-gamma, C1q and C3 mRNA levels were higher compared to control female grafts. These results suggest that C1q and C3 facilitate the induction of intranasal tolerance.
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Complemento C1q/inmunología , Complemento C3/inmunología , Rechazo de Injerto/inmunología , Antígeno H-Y/inmunología , Trasplante Homólogo/inmunología , Administración Intranasal , Animales , Linfocitos T CD8-positivos/inmunología , Complemento C1q/deficiencia , Complemento C3/deficiencia , Citocinas/biosíntesis , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Antígeno H-Y/administración & dosificación , Interferón gamma/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante de Piel/inmunologíaRESUMEN
AIM: The cyclin-dependent kinase inhibitor, seliciclib (R-roscovitine, CYC202), has anti-proliferative activity through its inhibition of cyclin-dependent kinase 2. We hypothesized that treatment with seliciclib would reduce glomerular macrophage numbers and glomerular crescent formation in experimental crescentic glomerulonephritis even when treatment is started after onset of disease. METHOD: Nephrotoxic nephritis (NTN) was induced in Wistar Kyoto rats. In experiment 1, seliciclib (150 mg/kg per day) was given by oral gavage from 1 h before induction of NTN and continued to day 14. In experiment 2, treatment was started on day 4 of NTN and continued to day 14 in order to examine the effect of seliciclib in established glomerulonephritis. RESULTS: In experiment 1, seliciclib reduced proteinuria (119.5 ± 13.9 vs 191.4 ± 18.8 mg/day, P < 0.01), serum creatinine (54.0 ± 3.0 vs 81.0 ± 2.5 µmol/L, P < 0.005) and glomerular crescent score (23.9 ± 2.1 vs 44.6 ± 2.2, P < 0.005) in comparison with controls. In experiment 2, seliciclib ameliorated established glomerulonephritis, with reduction in proteinuria (58 ± 16 vs 165 ± 13 mg/day, P < 0.005), serum creatinine (39 ± 3 vs 62 ± 5 µmol/L, P < 0.05), glomerular macrophage numbers (6.8 ± 2.5 vs 18.5 ± 1.2 ED1+ cells per glomerular cross section, P < 0.05), glomerular cell proliferation (1.2 ± 0.37 vs 4.2 ± 0.80 bromodeoxyuridine (BrdU)+ cells per glomerular section, P < 0.05) and crescent score (10.8 ± 1.6 vs 43.9 ± 1.4, P < 0.05), in comparison with the controls. CONCLUSION: Seliciclib is effective in both prevention and treatment of established crescentic glomerulonephritis in Wistar Kyoto rats, in association with a reduction in the number of glomerular macrophages. We suggest that seliciclib, or other cyclin-dependent kinase inhibitors, may represent a novel therapeutic approach for patients with proliferative glomerulonephritis.
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Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Glomerulonefritis/tratamiento farmacológico , Glomérulos Renales/efectos de los fármacos , Macrófagos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Administración Oral , Animales , Proliferación Celular/efectos de los fármacos , Creatinina/sangre , Quinasas Ciclina-Dependientes/metabolismo , Modelos Animales de Enfermedad , Glomerulonefritis/enzimología , Glomerulonefritis/patología , Glomerulonefritis/prevención & control , Glomérulos Renales/enzimología , Glomérulos Renales/patología , Macrófagos/patología , Masculino , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteinuria/tratamiento farmacológico , Proteinuria/enzimología , Purinas/administración & dosificación , Ratas , Ratas Endogámicas WKY , Roscovitina , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
BACKGROUND: Hypothermic machine perfusion (HMP) is a well-established method for deceased donor kidney preservation. Normothermic machine perfusion (NMP) might offer similar or greater advantages. We compared the 2 methods in an ex vivo perfusion model using 34 porcine kidneys. METHODS: Thirty kidneys were stored on ice for 24 h before undergoing 4 h of HMP (n = 15) or NMP (n = 15) followed by 2 h of normothermic ex vivo reperfusion with whole blood. Four kidneys underwent 28 h of cold static storage followed by 2 h of normothermic ex vivo reperfusion. During the 2 h of normothermic ex vivo reperfusion, perfusate flow rates, urinary output, and oxygen consumption rates were compared between all groups. RESULTS: Porcine kidneys after HMP showed significantly higher urinary output (5.31 ± 2.06 versus 2.44 ± 1.19 mL/min; P = 0.002), oxygen consumption (22.71 ± 6.27 versus 11.83 ± 1.29 mL/min; P = 0.0016), and perfusate flow rates (46.24 ± 12.49 versus 26.16 ± 4.57 mL/min; P = 0.0051) than kidneys after NMP. TUNEL staining of tissue sections showed significantly higher rates of apoptosis in kidneys after NMP (P = 0.027). CONCLUSIONS: In our study, the direct comparison of HMP and NMP kidney perfusion in a translational model demonstrated superiority of HMP; however, further in vivo studies would be needed to validate those results.
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Trasplante de Riñón/métodos , Preservación de Órganos/métodos , Animales , Consumo de Oxígeno , Perfusión/métodos , PorcinosRESUMEN
Previous work suggests that testosterone and cortisol interactively predict psychopathy. This effect represents a reversal of the established dual-hormone hypothesis, whereby testosterone is positively correlated with psychopathic traits, but only among individuals with elevated cortisol concentrations. This study aims to replicate the dual-hormone moderation of psychopathy in two independent samples. Enzyme-linked immunoassays (ELISAs) were used to assess cortisol across both samples and testosterone in Sample 1 (n = 165, 100% males). To address recent criticism of ELISAs and potentially extend these findings to women, testosterone concentrations were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in Sample 2 (n = 213, 44.1% males). We found conflicting evidence of the dual-hormone moderation of psychopathic traits. Although results were non-significant in Sample 1, a reversal of the dual-hormone hypothesis was found in Sample 2, in which testosterone was positively correlated with psychopathic traits, but only among individuals with high cortisol. This replication provides mixed support for less common reversals to the dual-hormone hypothesis. These findings emphasize the importance of using LC-MS/MS to measure testosterone and adds to the growing body of work on the relationship between hormones and psychopathology in general.
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Trastorno de Personalidad Antisocial/metabolismo , Hidrocortisona/fisiología , Testosterona/fisiología , Adulto , Cromatografía Liquida/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Hidrocortisona/análisis , Masculino , Saliva/química , Espectrometría de Masas en Tándem/métodos , Testosterona/análisisRESUMEN
IgA nephropathy is the most common biopsy-proven pattern of glomerulonephritis in the world. Many factors, both clinical and histologic, have been suggested to impact on prognosis. We review the wide variations in how patients with immunoglobulin A nephropathy can present and the important differences derived from the clinical pathologic setting through the description of 4 cases. These include the clinical scenarios of modest proteinuria, acute kidney injury, and the nephrotic syndrome.
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Mesangio Glomerular/patología , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/fisiopatología , Adulto , Biopsia con Aguja , Progresión de la Enfermedad , Femenino , Hematuria , Humanos , Masculino , Persona de Mediana Edad , Nefrosis Lipoidea/patología , Síndrome Nefrótico/patología , ProteinuriaRESUMEN
Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of end-stage kidney disease. Unlike the slowly progressive course seen among Caucasian and East Asian subjects (actuarial survival 80-85% over 10 years), in India about 30-40% of patients have nephrotic syndrome and renal dysfunction at presentation and a 10-year renal survival of 35%, as reported from a retrospective registry. These observations cannot be entirely attributed to a lack of uniform screening protocols or late referral and attest to the probability that IgAN may not be the same disease in different parts of the world. Methods: We will prospectively recruit 200 patients with IgAN (the GRACE IgANI- Glomerular Research And Clinical Experiments- Ig A Nephropathy in Indians-cohort) and stratify them into low and high risk of progression based on published absolute renal risk scores. We will test the validity of this risk score in an unselected Indian IgAN population over a 5-year follow-up period. In parallel, we will undertake extensive exploratory serum, urine, renal and microbiome biomarker studies, firstly, to determine if the underlying pathogenic pathways are the same in Indian IgAN compared to those reported in Caucasian and East Asian IgAN. Secondly, we will systematically assess the value of measuring selected biomarkers and adding this data to traditional measures of risk in IgAN to predict kidney failure. We ultimately hope to generate a composite IgAN risk score specific for the Indian population. Ethics and data dissemination: Approval was obtained from the Institutional Review Board (Silver, Research and Ethics Committee) of the Christian Medical College, Vellore, India (Ref. No. IRB Min. No. 8962 [Other] dated 23.07.2014 and IRB Min. No. 9481 [Other] dated 24.06.2015). It is anticipated that results of this study will be presented at national and international meetings, with reports being published from late 2018.
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BACKGROUND: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. METHODS: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. RESULTS: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. CONCLUSION: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.
Asunto(s)
Glomerulonefritis por IGA/cirugía , Tonsilectomía/estadística & datos numéricos , Adulto , Factores de Edad , Estudios de Cohortes , Progresión de la Enfermedad , Etnicidad , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Estudios Retrospectivos , Factores Sexuales , Resultado del TratamientoRESUMEN
Therapy with naked oligodeoxynucleotides (ODNs, molecular weight: 3000 to 7500) provides an elegant means of modulating gene expression without the problems associated with conventional gene therapy, but the relatively low transfer efficiency on intravascular administration is a limitation to clinical application. Ultrasound, which can be potentiated by microbubbles, shows promise as a method of delivering macromolecules such as plasmid DNA and other transgenes into cells. Since uptake of molecules into cells depends on their molecular weight, it might be expected that the delivery of ODNs, which are relatively small, will be facilitated by ultrasound and microbubbles. In the present study, we delivered ODNs into veins using ultrasound and microbubbles. First, we quantified the uptake of fluorescent-labeled ODNs into intact ex vivo human saphenous veins and isolated smooth muscle cells from the veins, evaluating the effect of ultrasound and microbubbles on uptake. Ultrasound potentiated the delivery of ODN in cells, except at high concentrations. When intact veins were studied, we achieved nuclear localization of fluorescent-labeled ODNs in cells. This increased with increasing concentration and incubation time and was not potentiated by ultrasound, even when microbubbles were used. We then applied a therapeutic ODN (antisense to intercellular adhesion molecule 1, ICAM-1) to vein samples and documented a functional inhibition of gene expression in a sequence-specific manner at the protein level with immunohistochemistry and western blot analysis. Again, no significant difference was seen with adjunct ultrasound. These observations suggest high diffusion of ODNs into human saphenous veins in this ex vivo model, indicating potential applications to inhibition of vascular bypass graft occlusion and other vasculopathies. Although microbubble-ultrasound was of value with cells in culture, it was not beneficial with intact veins.
Asunto(s)
Terapia Genética/métodos , Oligonucleótidos Antisentido/uso terapéutico , Vena Safena/metabolismo , Ultrasonografía Intervencional/métodos , Anciano , Anciano de 80 o más Años , Western Blotting/métodos , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ , Molécula 1 de Adhesión Intercelular/análisis , Molécula 1 de Adhesión Intercelular/genética , Microburbujas , Persona de Mediana Edad , Músculo Liso Vascular/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1ß p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases.
Asunto(s)
Glomerulonefritis/metabolismo , Glomerulonefritis/prevención & control , Interleucina-17/biosíntesis , Riñón/metabolismo , Animales , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Glomerulonefritis/genética , Glomerulonefritis/patología , Interleucina-10/biosíntesis , Interleucina-10/genética , Interleucina-17/genética , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Interleucina-23/biosíntesis , Interleucina-23/genética , Riñón/patología , Ratones , Ratones Noqueados , Tolerancia a RadiaciónRESUMEN
IgG4-related tubulointerstitial nephritis is an uncommon cause of renal impairment. It has been associated with dysfunction in a number of other organs giving rise to the term IgG4-related systemic disease; organ involvement can occur metachronously, hence, making it more difficult to identify patients. The exact cause of this condition remains unknown. Here, we present a case of isolated renal involvement which demonstrates how particular biochemical, radiological and histopathological changes should raise the suspicion of IgG4-related nephropathy, especially when there is an absence of clues from any other organ.