RESUMEN
BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.
Asunto(s)
Ensayos Clínicos como Asunto , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Riñón/metabolismo , Adulto , Consenso , Técnica Delphi , Enfermedad de Fabry/genética , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/patología , Femenino , Globósidos/uso terapéutico , Glucolípidos/uso terapéutico , Humanos , Isoenzimas/genética , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Persona de Mediana Edad , Calidad de Vida , Esfingolípidos/uso terapéutico , Resultado del Tratamiento , Trihexosilceramidas/uso terapéutico , alfa-Galactosidasa/genéticaRESUMEN
The mode of inheritance of Alport syndrome (ATS) has long been controversial. In 1927, the disease was hypothesized as a dominant condition in which males were more severely affected than females. In 1990, it was considered an X-linked (XL) semidominant condition, due to COL4A5 mutations. Later on, a rare autosomal recessive (AR) form due to COL4A3/COL4A4 mutations was identified. An autosomal dominant (AD) form was testified more recently by the description of some large pedigrees but the real existence of this form is still questioned by many and its exact prevalence is unknown. The introduction of next generation sequencing (NGS) allowed us to perform an unbiased simultaneous COL4A3-COL4A4-COL4A5 analysis in 87 Italian families (273 individuals) with clinical suspicion of ATS. In 48 of them (55%), a mutation in one of the three genes was identified: the inheritance was XL semidominant in 65%, recessive in 4% and most interestingly AD in 31% (15 families). The AD form must therefore be seriously taken into account in all pedigrees with affected individuals in each generation. Furthermore, a high frequency of mutations (>50%) was shown in patients with only 1 or 2 clinical criteria, suggesting NGS as first-level analysis in cases with a clinical suspicion of ATS.
Asunto(s)
Autoantígenos/genética , Colágeno Tipo IV/genética , Patrón de Herencia/genética , Nefritis Hereditaria/genética , Secuencia de Bases , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Italia , Masculino , Datos de Secuencia Molecular , Mutación/genética , LinajeRESUMEN
Fabry Disease (FD) is an X-linked multisystemic lysosomal disorder caused by mutations of alpha-galactosidase (GLA) gene. Only a few of the 450 genetic lesions identified so far have been characterised by in vitro expression studies. Thus the significance of newly identified GLA nucleotide variants in FD patients which lead to alpha-galactosidase (GAL-A) amino acid substitutions or intronic changes can be uncertain. We identified three GLA mutations, c.155G>A (p.C52Y), c.548G>C (p.G183A), c.647A>G (p.Y216C) in as many individuals (two male; one female) and performed in vitro expression studies and Western blot analysis in order to clarify their functional effects. Reduced GAL-A activity and normal or partially reduced mutant proteins were present in all overexpressed mutant systems in which three-dimensional structural analysis showed that the active site was not directly involved. We hypothesize that the three new mutations affect the GAL-A protein, leading to conformational FD. When mutant proteins overexpressed in COS-1 cells and in patients' lymphocytes were tested in the presence of the 1-deoxygalactonojirimicin (DGJ) chaperone, the p.G183A and p.Y216C systems showed increased GAL-A enzyme activities and protein stabilisation while p.C52Y was not responsive. We underline that genetic, biochemical and functional studies are helpful in clarifying the consequences of the missense genetic lesions detected in FD. ERT is the elective therapy for Fabry patients, but it is not always possible to issue the enzyme's active form in all involved organs. Our study endorses the hypothesis that an active site-specific chemical chaperone, which could be administered orally, might be effective in treating GAL-A conformational defects.
Asunto(s)
Enfermedad de Fabry/genética , Mutación , alfa-Galactosidasa/genética , Animales , Células COS , Chlorocebus aethiops , Mapeo Cromosómico , ADN/genética , ADN/aislamiento & purificación , Cartilla de ADN , Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/enzimología , Femenino , Humanos , Masculino , Modelos Moleculares , Conformación Molecular , Mutagénesis Sitio-Dirigida , Fenotipo , Conformación Proteica , Transfección , Cromosoma X/genética , alfa-Galactosidasa/químicaRESUMEN
Renal involvement in Fabry's disease in males starts at an early age with microalbuminuria and proteinuria and progresses rapidly towards end-stage renal disease requiring dialysis or renal transplantation. Renal involvement, together with cardiac and cerebral damage, is responsible for the severe morbidity and mortality in patients with Fabry's disease. In heterozygous female patients renal involvement has also been documented, but the onset of renal damage occurs later and the progression to end-stage renal disease is slower. Considering the relevance of renal damage in the prognosis of Fabry's disease, it is mandatory to point out the diagnostic criteria of Fabry's nephropathy and the modalities of follow-up of patients with renal involvement. The aim of this study is also to provide recommendations regarding the diagnosis, follow-up and indication for enzyme replacement therapy in patients with Fabry's disease.
Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/tratamiento farmacológico , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/terapia , alfa-Galactosidasa/uso terapéutico , Progresión de la Enfermedad , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/mortalidad , Estudios de Seguimiento , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/terapia , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Trasplante de Riñón , Guías de Práctica Clínica como Asunto , Pronóstico , Diálisis Renal , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Anderson-Fabry disease (AFD) is a rare X-linked disorder caused by lysosomal storage of several glycosphingolipids, affecting virtually all organs and systems. Enzyme replacement therapy (ERT) for AFD has been available since 2001. Due to the highly variable nature of clinical manifestations in patients with AFD, it is very difficult to assess disease progression and the effects of therapy. We used the Mainz Severity Score Index (MSSI) as a measure of disease severity to study the effects of ERT in a population of 30 patients treated with agalsidase alfa for a median of 2.9 years (range, 1.0-6.2 years). Our data show that the MSSI captures the correlation between disease severity and both gender and age (1 - males performing worse than females at baseline and 2 - severity of diseases progresses with age in both sex). Furthermore, after at least 1 year of ERT, total MSSI scores were significantly lower than those at baseline (p < 0.001), suggesting a marked clinical improvement under ERT. In conclusion, the MSSI is a sensitive and useful tool for monitoring disease progression and assessing the effects of ERT in a population of patients from different treatment centres.
Asunto(s)
Enfermedad de Fabry/tratamiento farmacológico , alfa-Galactosidasa/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Manejo de la Enfermedad , Enfermedad de Fabry/patología , Femenino , Humanos , Isoenzimas/uso terapéutico , Italia , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Índice de Severidad de la Enfermedad , Factores Sexuales , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity. MATERIALS AND METHODS: We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls. RESULTS: The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables. CONCLUSIONS: The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.
Asunto(s)
Enfermedad de Fabry/patología , Pulvinar/patología , Adolescente , Adulto , Anciano , Enfermedad de Fabry/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pulvinar/diagnóstico por imagen , Estudios Retrospectivos , Adulto JovenRESUMEN
AIM: Fabry disease is a rare lysosomal storage disorder caused by deficient activity of alpha-galactosidase A, resulting in progressive cellular accumulation of glycolipids, which may ultimately result in endstage renal disease. We examined the effects of enzyme replacement therapy (ERT) with Agalsidase-alpha on renal function using data from a large international database, the Fabry Outcome Survey (FOS). METHODS: This analysis was based on 1,040 serum creatinine measurements in 201 patients with Fabry disease, aged 20 - 60 years, with serum creatinine concentrations of less than 2 mg/dl and duration of ERT of up to 4.7 years. Both pretreatment and treatment data were used to examine independent predictors of changes in serum creatinine. In a second approach longitudinal serum creatinine measurements from 1 year before treatment, at baseline and 1 and 2 years after the start of treatment were analyzed in 20 patients with chronic kidney disease (CKD) Stage 2 and 3. RESULTS: We found an independent negative association between serum creatinine and time on Agalsidase-alpha treatment (p < 0.05). Renal function declined significantly (p < 0.05) in the year before treatment. After 1 year of treatment, however, the decline in estimated glomerular filtration rate had been halted, and renal function was preserved for up to 2 years. CONCLUSIONS: In conclusion, ERT with Agalsidase-alpha is associated with decrease of serum creatinine and may prevent the deterioration of renal function in patients with Fabry disease.
Asunto(s)
Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , alfa-Galactosidasa/uso terapéutico , Adulto , Anciano , Estudios de Cohortes , Creatinina/sangre , Enfermedad de Fabry/complicaciones , Femenino , Humanos , Isoenzimas/uso terapéutico , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/etiología , Fallo Renal Crónico/fisiopatología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
Anderson--Fabry's disease is an hereditary disease with an X-linked genetic transmission, caused by the congenital deficiency of the lysosomial enzyme alpha-galactosidase A. It is a rare disease, but the estimated 1 patient every 117.000 male population is increasing and this can be demonstrated by simplifying the dosage techniques for the enzyme. The clinical picture comes from the accumulation of glycosphingolipids in many organs, mainly vessels, heart, nervous tissue, kidney and sight. The histological lesion appears as damage to the lysosomial membrane with subsequent migration of the lipid corpuscles into the cytoplasm and the breakdown of metabolic cellular activities. Prior to the advent of enzyme replacement therapy, which is based on the administration of the recombinant enzyme, the course of the disease was certainly fatal (early death by ictus or ischemic cardiopathy, terminal kidney failure). Despite the positive results achieved, information obtained from the present observation research should be help to verify the validity of the enzyme replacement therapy.
Asunto(s)
Enfermedad de Fabry , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Humanos , Enfermedades Renales/etiologíaRESUMEN
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase α-galactosidase A (α-GalA) that leads to the intra-lysosomal accumulation of globotriaosylceramide (Gb3) in various organ systems. As a consequence, a multisystems disorder develops, culminating in stroke, progressive renal and cardiac dysfunction. Enzyme replacement therapy (ERT) offers a specific treatment for patients affected by FD, though the monitoring of treatment is hindered by a lack of surrogate markers of response. Remarkably, due to the high heterogeneity of the Fabry phenotype, both diagnostic testing and treatment decisions are more challenging in females than in males; thus, reliable biomarkers for Fabry disease are needed, particularly for female patients. Here, we use a proteomic approach for the identification of disease-associated markers that can be used for the early diagnosis of FD as well as for monitoring the effectiveness of ERT. Our data show that the urinary proteome of Fabry naïve patients is different from that of normal subjects. In addition, biological pathways mainly affected by FD are related to immune response, inflammation, and energetic metabolism. In particular, the up-regulation of uromodulin, prostaglandin H2 d-isomerase and prosaposin in the urine of FD patients was demonstrated; these proteins might be involved in kidney damage at the tubular level, inflammation and immune response. Furthermore, comparing the expression of these proteins in Fabry patients before and after ERT treatment, a decrease of their concentration was observed, thus demonstrating the correlation between the identified markers and the effectiveness of the pharmacological treatment.
Asunto(s)
Enfermedad de Fabry/diagnóstico , Proteoma/análisis , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Niño , Análisis por Conglomerados , Diagnóstico Precoz , Enfermedad de Fabry/sangre , Enfermedad de Fabry/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteoma/metabolismo , Proteómica/métodos , Reproducibilidad de los Resultados , Uromodulina/sangre , Uromodulina/orina , Adulto JovenRESUMEN
Subepithelial deposits are a common feature of idiopathic membranous glomerulonephritis (MGN) and lupus membranous glomerulopathy (LMGN). We investigated the spatial arrangement of immunoglobulin G (IgG) and C3c fraction of complement (C3c) in the immune deposits of MGN and LMGN with confocal laser scanning microscopy to correlate specific patterns of IgG-C3 interactions with different diseases. Ten patients with MGN and 8 patients with LMGN (World Health Organization class VB) were selected. A determination of the spatial arrangement of the two fluorochromes and the glomerular area occupied by each fluorochrome was performed for each case. Our results showed MGN specimens have an orderly distribution of IgG and C3c, with each deposit showing an outer ring of sole IgG. IgG was always more abundant than C3c (1,619 +/- 271 v 790 +/- 105 micrometer(2), P = 0.002). In LMGN, IgG and C3c were haphazardly arranged, with deposits made of C3c only and an outer ring of IgG only rarely present. Also, the relative amounts of the two antigens were variable, and two groups could be identified (group 1: IgG, 5,515 +/- 1,179 micrometer(2) v C3c, 4,810 +/- 1,174 micrometer(2); P = 0.02; group 2: IgG, 3,358 +/- 658 micrometer(2) v C3c, 4,047 +/- 740 micrometer(2); P = 0.03). Our data show that diffuse IgG capping of the subepithelial immune deposits is diagnostic of MGN. The absence of an orderly three-dimensional arrangement in LMGN deposits (ie, outer ring of IgG) is likely to render active complement components more readily available to inflammatory activities.
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Complejo Antígeno-Anticuerpo/análisis , Glomerulonefritis Membranosa/patología , Glomérulos Renales/inmunología , Nefritis Lúpica/patología , Adulto , Anciano , Complemento C3c/análisis , Femenino , Humanos , Inmunoglobulina G/análisis , Glomérulos Renales/patología , Masculino , Microscopía Confocal , Persona de Mediana EdadRESUMEN
We report 4 cases of sepsis-induced acute renal failure (ARF) with peculiar clinical presentation in which the renal biopsy was the only clue to a correct diagnosis. We observed 66 cases of ARF in a 4-year experience. Seven (11%) were associated with sepsis; in 3 of these (4.5%) a shock was present. Clinical picture of the remaining 4 cases (6%) was characterized by ARF with oligoanuria and proteinuria (> 2 g/L), fever, resistant to antimicrobial therapy, negative hemocultures and severe systemic symptoms. Such a presentation could suggest a non-infectious systemic disease; renal biopsies were carried out. Histological findings consisted of microabscesses of variable size in the interstitium and within the tubular lumina. A full-dose, broad-spectrum, i.v. antimicrobial therapy was started, with favourable outcome and recovery of renal function. Our clinical experience points out that the clinical picture of ARF in course of sepsis may be variable and that its relationship with septicaemia could not be readily discernible.
Asunto(s)
Lesión Renal Aguda/etiología , Sepsis/complicaciones , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/patología , Adulto , Femenino , Humanos , Riñón/patología , Masculino , Persona de Mediana EdadRESUMEN
The aim of the study was to evaluate the long term antihypertensive effect of nicardipine in hypertensive patients with chronic renal disease. Eight patients (creatinine clearance ranging from 51 to 78 ml/min/1.73 m2) received nicardipine (20 mg t.i.d.). Four weeks later, patients with diastolic blood pressure greater than or equal to 90 mmHg in recumbent position, were given enalapril (10 mg/day) as well. Blood pressure control was achieved in 3 patients treated with nicardipine alone and in 5 patients on a combined nicardipine-enalapril regimen, and it was maintained throughout the whole trial period (52 weeks). In two cases serum creatinine rose from 2.3 to 3.3 and from 1.4 to 2.2 respectively. However, the slope of the creatinine ratio, plotted against time, showed a significant reduction in renal function loss as compared to expected values. In conclusion, nicardipine, alone or in combination with enalapril, is an effective and well tolerated drug for use in treatment of hypertension secondary to chronic renal disease.
Asunto(s)
Enalapril/administración & dosificación , Hipertensión Renal/tratamiento farmacológico , Nicardipino/uso terapéutico , Adulto , Evaluación de Medicamentos , Quimioterapia Combinada , Femenino , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis Membranoproliferativa/complicaciones , Glomerulonefritis Membranosa/complicaciones , Humanos , Hipertensión Renal/etiología , Masculino , Persona de Mediana Edad , Nicardipino/administración & dosificación , Poliarteritis Nudosa/complicacionesRESUMEN
PURPOSE: During convective techniques, a replacement fluid (R) is necessary that is sterile and pyrogen-free. Using an integrated absorption cartridge, the ultrafiltrate (UF) can be "regenerated"; and used as R. This method is hemodiafiltration with reinfusion (HFR). This study aimed to evaluate the real UF composition after "regeneration" by the resin-charcoal integrated absorption cartridge. METHODS: In eight uremic patients treated with HFR the UF was evaluated at 5, 15, 30, 60, 120, 180 and 240 min after HFR start at the inlet and the outlet resin-charcoal cartridge using the following parameters: urea, creatinine (Cr), uric acid, phosphates, glucose, Beta 2-microglobulin (beta2-m), Na+, K+, Ca++, pH, pCO2, and HCO3-. RESULTS: Blood (%): urea -61.2 +/- 9.7; Cr -55.4 +/- 8.1; uric acid -69.8 +/- 9.3; phosphates -31.8 +/- 15.7; glucose -8.4 +/- 20.5; Beta2-m -60.3 +/- 11.1; pH +0.76 +/- 0.58; pCO2+ 3.3 +/- 8.5; HCO3- +18.1 +/- 13.5. In UF (outlet vs inlet): urea was not adsorbed; Cr and uric acid were adsorbed; phosphates were not adsorbed; glucose was partially adsorbed (only in the 1st 90 min); Beta2-m was almost totally adsorbed; Na+ and K+ were not adsorbed; for pH, pCO2, and HCO3- there were no significant variations between the inlet and the outlet. CONCLUSIONS: HFR seems to be an easy-to-perform hemodiafiltration (HDF) technique, capable of resolving the typical problems of availability and the production of sterile and ultrapure reinfusion solution.
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Hemodiafiltración/métodos , Soluciones para Hemodiálisis/administración & dosificación , Uremia/terapia , Análisis de los Gases de la Sangre , Femenino , Soluciones para Hemodiálisis/análisis , Humanos , Masculino , Persona de Mediana Edad , Uremia/sangreRESUMEN
Ten hypertensive, non-nephrotic patients with immunoglobulin (IgA) nephropathy treated with conventional therapy (vasodilators, beta-blockers, diuretics) were observed for 21.4 +/- 9 months. Treatment was then changed to an angiotensin converting enzyme (ACE) inhibitor alone for an additional 22.6 +/- 9 months. The ACE inhibitor therapy was associated with a lower diastolic blood pressure and a slowing in the rate of decline in renal function, but no change in proteinuria.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Glomerulonefritis por IGA/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Fallo Renal Crónico/prevención & control , Adulto , Antihipertensivos/uso terapéutico , Diuréticos/uso terapéutico , Quimioterapia Combinada , Enalapril/uso terapéutico , Humanos , Factores de TiempoRESUMEN
Clinical practice guidelines (GL) are multiplying and spreading throughout the scientific world. Nephrology is no exception and GL are more often recalled in the daily activity. Therefore, it can be useful to propose an excursus on the issue, to report the most important principles on the base of GL and moreover, to remember that GL are the synthesis between the scientific evidences published in literature and the critical analysis performed by an international committee of experts. Not all GL have the same clinical value. As a matter of fact, GL have a different strength of recommendation and grading according to the clinical evidences published. The number and methodological accuracy of the available studies on a specific subject are crucial to define the quality, the grading and the strength of GL. GL must also be shared with a wide number of specialists and other interested people such as patient organizations as well as health political institutions. Although the knowledge of GL is widespread, their practical use is still limited. The spreading of the knowledge regarding how GL are arranged, their appropriate reading about procedures and/or treatments to be done or not, it will convert GL into a reliable tool for daily clinical practice. Therefore it is not a confused and incomprehensible set of rules imposed by some scientific organizations.
Asunto(s)
Enfermedades Renales , Nefrología , Guías de Práctica Clínica como Asunto/normas , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/terapiaAsunto(s)
Hipertensión/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Enfermedad Crónica , Dieta Reductora , Dieta Hiposódica , Diuréticos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Humanos , Hipertensión/clasificación , Hipertensión/diagnóstico , Persona de Mediana Edad , Oligopéptidos/uso terapéutico , Simpaticolíticos/uso terapéutico , Teprotido , Vasodilatadores/uso terapéuticoRESUMEN
BACKGROUND: Transforming growth factor-beta (TGF-beta) is a multipotent cytokine involved in the turnover of the extracellular matrix. Signal transduction of TGF-beta is regulated via at least five different surface receptors; most of the effects, however, are mediated through the interaction of receptors type I and II (RI and RII). We investigated the glomerular expression of TGF-beta and its receptors RI and RII in human glomerulonephritis. METHODS: Indirect immunofluorescence using monoclonal and polyclonal antibodies against TGF-beta isoforms (1,2,3 and 2,3), TGF beta-RI and TGF beta-RII has been carried out on 30 consecutive renal biopsies (5 FSGS, 11 IgAN, 4 MCGN, 6 SLE, 2 RPGN) and on normal kidney tissue. RESULTS: Glomerular immunoreactivity for TGF-beta isoforms correlated with the severity of proliferative lesions: immunofluorescent signal was absent or trace-like in normal kidneys, FSGS, and IgAN with mild mesangial cellularity, and was highest in IgAN with severe mesangial proliferation, MPGN, RPGN, and SLE. Glomerular positivity for TGF-beta-RI and -RII was detectable in SLE and RPGN; a low signal was present also in MPGN. Other types of glomerulonephritis, including focal extracapillary proliferations, and glomeruli of normal kidneys were always negative. CONCLUSIONS: Our data show that TGF-beta expression is a good indicator of the severity of proliferative glomerular lesions in most, if not all cases and that RI-RII expression occurs at levels detectable with indirect immunofluorescence in limited number of glomerulonephritides, mostly associated with systemic diseases. A complex interaction between TGF-beta and its ligand may represent a critical factor conditioning the tissue response to immunological injury.
Asunto(s)
Glomerulonefritis/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Técnica del Anticuerpo Fluorescente Indirecta , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis Membranoproliferativa/metabolismo , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Humanos , Isomerismo , Riñón/metabolismo , Nefritis Lúpica/metabolismo , Valores de ReferenciaRESUMEN
The histological picture of primary glomerulonephritis with glomerular IgA deposition (IgA nephropathy and Henoch-Schönlein disease) can vary from minimal mesangial involvement to severe endocapillary and/or extracapillary proliferation. Local activation of the complement cascade by glomerular IgA deposits and release of anaphylactoid factor are considered to be major triggers of inflammation, but clear-cut correlations between the severity of the histological findings and the intensity of glomerular deposition of immunoglobulin and complement fractions are still lacking. The purpose of this study was to investigate the spatial distribution of IgA and complement in mesangial deposits with confocal laser scanning microscopy (CLSM) and to correlate specific patterns of IgA-complement interaction with glomerular damage. Two groups of patients have been studied, one with mild to moderate diffuse mesangial proliferation and the other with diffuse proliferative endocapillary and/or extracapillary patterns. In milder forms of the disease, the majority of the immune deposits are composed of both IgA and C3, coated by an outer layer of IgA alone. Large C3 deposits, or deposits composed of IgA and C3 without an outer coat of IgA, were associated with more severe histological lesions. The results suggest that free access of active complement components to cell and/or mesangial matrix receptors could trigger a cytolytic reaction and that immunoglobulins seem to act as a protective layer on C3 components.