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Contaminantes Radiactivos del Aire/análisis , Contaminación del Aire Interior/estadística & datos numéricos , Monitoreo del Ambiente/estadística & datos numéricos , Neoplasias Pulmonares/epidemiología , Traumatismos por Radiación/epidemiología , Radón/análisis , Abastecimiento de Agua/estadística & datos numéricos , Medicina Ambiental/tendencias , Monitoreo Epidemiológico , Alemania/epidemiología , Humanos , Medición de Riesgo , Factores de Riesgo , Abastecimiento de Agua/análisisRESUMEN
BACKGROUND: Procalcitonin (PCT) is routinely measured to differentiate autoimmune disorders from infection. There are reports, however, where PCT is high in the absence of infection, i.e. in vasculitis. To investigate the value of PCT in Goodpasture's syndrome, we reviewed the charts of patients with Goodpasture's syndrome who were treated from 1996 to 2006. METHODS: PCT (normal range<0.5 ng/ml) was measured with an immunoluminometric assay, C-reactive protein (CRP; normal range<5 mg/l) with nephelometry. Anti-glomerular basement membrane antibodies (normal range<1:10) were measured with ELISA. RESULTS: During the last 10 years we diagnosed seven patients with Goodpasture's syndrome. Six out of seven patients had biopsy proven crescentic and necrotizing glomerulonephritis. Five patients had a severe manifestation with pulmonary involvement (n=3) and/or severe renal insufficiency (n=4). Mean CRP levels were 145.7 mg/l, mean PCT levels were 34.1 ng/ml. Therapy consisted of plasmapheresis (n=3), pulse cyclophosphamide therapy (n=4) and glucocorticoids (n=6). Remarkably, all patients with elevated PCT levels had life-threatening disease (n=4) and remained dialysis-dependent (as compared to with only one out of three patients with normal PCT). In two out of five patients with severe Goodpasture's syndrome, PCT levels remained high. After thorough exclusion of infection, resumption of high dose glucocorticoids normalized PCT and CRP levels. CONCLUSIONS: The measurement of PCT as a marker of infection in patients with Goodpasture's syndrome is misleading. High PCT values might rather point to a severe form of Goodpasture's syndrome with a more unfavourable prognosis. However, further studies with larger patient numbers are needed to prove this hypothesis.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular/complicaciones , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/microbiología , Calcitonina/metabolismo , Enfermedades Transmisibles/complicaciones , Precursores de Proteínas/metabolismo , Adulto , Anciano , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/sangre , Biomarcadores , Proteína C-Reactiva/metabolismo , Péptido Relacionado con Gen de Calcitonina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoAsunto(s)
Granulomatosis con Poliangitis/etiología , Enfermedades Pulmonares/etiología , Biopsia , Diagnóstico Diferencial , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Inmunosupresores/uso terapéutico , Pulmón/diagnóstico por imagen , Pulmón/patología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XAsunto(s)
Inmunosupresores/efectos adversos , Trasplante de Riñón , Tacrolimus/efectos adversos , Trombastenia/inducido químicamente , Trombocitopenia/inducido químicamente , Rechazo de Injerto/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Trombastenia/inmunología , Trombocitopenia/inmunologíaRESUMEN
BACKGROUND: Autoantibodies to neutrophil cytoplasmic antigens (ANCA), particularly to proteinase 3 (PR3), are found in the majority of patients with systemic Wegener's granulomatosis. The autoantibodies are widely used as diagnostic markers. Their role in the development and progression of the disease, however, is still under investigation. The primary target of ANCA, PR3, is located in the cytoplasm of polymorphonuclear neutrophils (PMN) or monocytes and is translocated to the cell surface upon stimulation. In patients with Wegener's granulomatosis PR3 is up-regulated most prominently during active disease. Despite the fact that both autoantibodies to PR3 and PMN expressing PR3 are present in patients with Wegener's granulomatosis, there is no evidence for binding of the autoantibodies to PMN. The present study was designed to analyze binding characteristics of autoantibodies to PR3 on PMN. METHODS AND RESULTS: PMN of patients with active Wegener's granulomatosis (N= 10) were tested for autoantibody binding. Despite high autoantibody titer and PR3 expression on the PMN, no surface-bound IgG was found on PMN ex vivo. When ANCA-containing plasma from patients was incubated with isolated PMN, stimulated to express PR3, again no specific binding of the autoantibody could be detected. Also keeping the samples on ice did not allow surface detection of IgG, ruling out degradation or internalization of the autoantibodies. Only when purified IgG fractions were used, binding to PMN was seen in 14 of 25 patients. Already 1% of plasma, however, was sufficient to greatly reduce the IgG binding. Reduced binding of the IgG fraction was also seen when a larger reaction volume was used. CONCLUSION: Our data indicate that autoantibodies to PR3 have a rather low affinity for surface-associated PR3 on PMN. This, in turn, argues against the hypothesis that ANCA contributes to the pathogenesis of the disease by stimulating viable PMN in whole blood.
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Anticuerpos Antiidiotipos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Granulomatosis con Poliangitis/inmunología , Neutrófilos/inmunología , Anticuerpos Antiidiotipos/metabolismo , Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Reacciones Antígeno-Anticuerpo , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Mieloblastina , Neutrófilos/metabolismo , Serina Endopeptidasas/inmunología , Serina Endopeptidasas/metabolismoRESUMEN
BACKGROUND: There is increased risk for the occurrence of deep venous thrombosis (DVT) and renovascular thrombosis after kidney transplantation. A disruption of the blood homeostasis caused by surgery and leading to clotting and bleeding malfunctions is widely accepted. However, other causes such as inherited or acquired disorders of the clotting system may further increase the risk of thrombosis. Here, we summarize and review data on possible causes, incidence and ways to prevent the occurrence of DVT and/or renovascular thrombosis after kidney transplantation. RESULTS: The incidence of DVT after kidney transplantation is 6.2-8.3% and approximately 25% of these patients suffer from pulmonary embolism. The DVT occurs primarily on the side of the transplant with an increased risk throughout the first 5 months after transplantation. Thereby, 2-12% of the patients develop renovascular thromboses, most of which are related directly to the surgery. However, inherited or acquired thrombophilia may also play an important role. A severe course is known for prothrombin gene G20210A polymorphism, which can result in graft loss. A great diversity of prophylactic treatments is available but adjustment to the underlying circumstances is crucial for a favourable outcome. Low-dose heparin prophylaxis for at least 2-3 weeks can be used as standard therapy to prevent the occurrence of DVT after kidney transplantation. However, this may not be sufficient for concurrent disorders of the blood homeostasis such as elevated levels of antiphospholipid antibodies, lupus anticoagulant, prothrombin gene G20210A polymorphism or a combined inherited thrombophilia. These patients may need a prophylactic anticoagulation with coumarins starting prior to transplantation and being continued for at least 1 year or even lifelong. Only randomized trials can answer the question concerning optimal duration and safety of coumarins in this setting. CONCLUSIONS: DVT and/or renovascular thromboses are severe complications after kidney transplantation. Inherited and acquired thrombophilia, apart from surgery and abnormal anatomy itself, have to be considered and proper prophylactic treatment initiated.
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Trasplante de Riñón/efectos adversos , Trombofilia/complicaciones , Trombosis de la Vena/etiología , Anticuerpos Antifosfolípidos/análisis , Supervivencia de Injerto , Humanos , Factores de Riesgo , Trombosis de la Vena/prevención & controlRESUMEN
BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.
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Amiloide/análisis , Amiloidosis/fisiopatología , Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedades Renales/fisiopatología , Melfalán/uso terapéutico , Paraproteinemias/fisiopatología , Amiloidosis/patología , Amiloidosis/terapia , Femenino , Humanos , Enfermedades Renales/inmunología , Enfermedades Renales/patología , Enfermedades Renales/terapia , Masculino , Persona de Mediana Edad , Paraproteinemias/patología , Paraproteinemias/terapia , Inducción de Remisión , Trasplante AutólogoRESUMEN
BACKGROUND: The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission. METHODS: We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point. RESULTS: Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03). CONCLUSIONS: In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.
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Anticuerpos Anticitoplasma de Neutrófilos/sangre , Azatioprina/uso terapéutico , Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Vasculitis/tratamiento farmacológico , Adulto , Anciano , Azatioprina/efectos adversos , Ciclofosfamida/efectos adversos , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Prednisolona/uso terapéutico , Recurrencia , Inducción de Remisión , Vasculitis/inmunología , Vasculitis/mortalidadRESUMEN
BACKGROUND: Replicative senescence describes the fact that somatic cells undergo a finite and predictable number of cell divisions before entering an irreversible state of growth arrest. Progressive shortening of the telomeres, a consequence of cell division, is a reliable indicator of replicative senescence. METHOD: We analyzed telomere length of DNA derived from T cells of patients suffering from Wegener's granulomatosis by Southern blotting. Moreover, expression of CD28, another marker for replicative senescence, was tested by cytofluorometry. RESULTS: In patients with disease for more than 5 years, short telomeres were detected in addition to telomeres of normal length, indicating replicative senescence of discrete T-cell clones. Reduced expression of CD28 was noted, particularly on CD8-positive T cells, derived from patients with disease for more than 5 years and short telomeres. CONCLUSION: Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.
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Senescencia Celular/fisiología , Granulomatosis con Poliangitis/fisiopatología , Linfocitos T/citología , Linfocitos T/fisiología , Telómero/metabolismo , Adulto , Anciano , Antígenos CD28/genética , Expresión Génica , Granulomatosis con Poliangitis/inmunología , Granulomatosis con Poliangitis/metabolismo , Humanos , Activación de Linfocitos/fisiología , Persona de Mediana Edad , Telomerasa/metabolismoRESUMEN
In polymorphonuclear neutrophils (PMN) CD14, one of the receptors for lipopolysaccharides (LPS) is stored intracellularly as a preformed protein, with only few receptors expressed on the surface. We now report that in patients with severe bacterial infections, CD14 expression is profoundly upregulated, as is CD64 (FcgammaRI), the high-affinity receptor for IgG, whereas CD16 (FcgammaRIII) was partly lost from the surface. To further analyze regulation of these receptors, PMN of healthy donors were exposed to low doses of LPS. By brief exposure (10-120 min) to LPS, CD14 was transferred to the surface in a cytochalasin B-sensitive manner, as were CD16 and CD64. Prolonged culture (up to 48 h) resulted in a further upregulation of CD14, sustained expression of CD64, and profound decline of CD16, yielding a similar pattern of receptor expression as seen in the patients. Subsequent studies revealed that LPS induced de novo synthesis of CD14: the increase of surface expression could be inhibited by cycloheximide and by interfering with a known LPS-induced signaling event, the translocation of NFkappaB. Moreover, an up to 10-fold increase of specific mRNA was seen, as was incorporation into CD14 of 35S-methionine. The de novo synthesis prolonged expression of CD14, whereas the CD16 expression declined, generating a PMN phenotype characteristic for severe infection and indicative of escape from apoptosis of a PMN subpopulation.
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Receptores de Lipopolisacáridos/biosíntesis , Lipopolisacáridos/farmacología , Neutrófilos/metabolismo , Neutrófilos/microbiología , Receptores de IgG/biosíntesis , Apoptosis , Cicloheximida/farmacología , Citometría de Flujo , Fluoresceína-5-Isotiocianato/farmacología , Humanos , Inmunoglobulina G/metabolismo , FN-kappa B/metabolismo , Inhibidores de la Síntesis de la Proteína/farmacología , ARN Mensajero/metabolismo , Receptores de IgG/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Regulación hacia ArribaRESUMEN
UNLABELLED: Cyclosporin A (CsA) has improved patient and organ graft survival, but the dichotomy of benefit and toxicity is still an issue. In a retrospective analysis of 392 renal transplant recipients we documented CsA nephrotoxicity (striped fibrosis, arteriolar wall hyalinosis) in 28 (7.1%) patients (23 male/5 female) in a follow-up of more than one year post transplantation. Median age at renal transplantation was 41 years (13-60) and the period between transplantation and graft biopsy was 42 months (12-122). Median CsA trough levels (ng/ml) at 12 months post transplantation, at time of graft biopsy and at last follow-up were: 114 (71-265), 130 (78-285), 66 (24-115). The following parameters were assessed at 12 months post transplantation, at time of biopsy and at last follow-up: s-creatinine (micromol/l), Doppler resistive index, systolic and diastolic blood pressure (mm Hg) and the number of antihypertensives. Median s-creatinine at 12 months post transplantation was 150.3 (94.6-247.5), at biopsy 225.4 (121.1-353.6) and at last follow-up 160.0 (106.1-247.5) (p < 0.001 for biopsy vs. last follow-up). Resistive index decreased from 0.70 (0.64-0.88) to 0.68 (0.51-0.84) (p < 0.005), systolic blood pressure from 137 (100-168) to 130 (105-144) (p < 0.05) and the number of patients with more than 4 antihypertensives from 10 to 6 between biopsy and last follow-up, with no acute rejection episodes after modification of immunosuppressive therapy (50% of previous CsA trough level and addition of azathioprine or mycophenolate mofetil). CONCLUSION: CsA nephrotoxicity occurs late after renal transplantation with increased systolic blood pressure and Doppler resistive index. Reduction of CsA improves renal function, reduces graft resistive index and systolic blood pressure.