Endothelin 1 and cyclic guanosine monophosphate in nonimmunological progression of mesangial proliferative glomerulonephritis.
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Biomedical subjects
Publications and source records attributed to D Roccatello.
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Two hundred and one patients had biopsies of their native kidneys with ultrasound-guided needle technique. They were evaluated on the second post-biopsy day with colour-coded Doppler sonography. Ten patients out of these 201 were found to have an arteriovenous fistula, which remained asymptomatic for the whole follow-up period (follow-ups ranged from 2 to 31 months). Four of these 10 patients developed a perirenal haematoma as well and five macroscopic haematuria. Our study shows that the systematic use of colour-coded Doppler sonography after renal biopsy facilitates diagnosis of arteriovenous renal fistula.
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The finding in primary IgA nephropathy of increased levels of IgA to food antigens and particularly to gliadin prompted the hypothesis that a subgroup of these patients may have latent coeliac disease. The observation that gliadin may experimentally induce IgA mesangial deposits supported this hypothesis. We evaluated specific immunological markers of coeliac disease (antiendomysium antibodies) which parallel histological changes of gluten sensitive enteropathy, and an IgA immunofluorescent test for antigliadin antibodies in 18 patients with IgA nephropathy, in 56 untreated coeliac disease patients, in 254 controls (58 healthy and 196 disease controls). Antiendomysium antibodies were positive in 89.28% of coeliac patients, but negative in all IgA nephropathies and controls. IgA immunofluorescent test for antigliadin antibodies, negative in all IgA nephropathy patients, was positive in 76.78% of coeliac patients and in 4.91% of controls. ELISA IgA antigliadin antibodies were negative in controls, but positive in 22.22% of IgA nephropathy patients and in 60.71% of coeliac patients. Our data would suggest that in most patients with IgA nephropathy there is no evidence of latent coeliac disease.
Six hundred and sixty-seven hypertensive patients were analyzed by captopril-enhanced scintigraphy. If time to reach maximal activity (Tmax) was > or = 5 min using 99mTc-diethylenetriaminepentaacetic acid (DTPA) or > or = 3 min with 123I-o-iodohippurate (OIH) and 99mTc-mercaptoacetyltriglycine (MAG3) and washout time > or = 15 min, a control study with nifedipine was performed. If the difference between Tmax under captopril and nifedipine premedication was > or = 5 min with 99mTc-DTPA or > or = 3 min with 123I-OIH and 99mTc-MAG3, the renogram was defined highly suggestive of renovascular hypertension. In the evaluation of bilateral abnormalities an additional parameter was considered, i.e. the presence of functional asymmetry of the emuntories susceptible of partial reversal in the control study under nifedipine. Based on these criteria, 58 out of 667 (8.7%) scintigrams were found to be abnormal. Thirty-five of these 58 patients and 32 of the remaining 609 scintigraphically negative cases underwent additional arteriographic examination. A renal vascular stenosis > or = 50% was found in 33 out of 35 (94.2%) patients with positive scintigraphy and in 3 out of 32 patients with negative scintigraphy. By examining results of the 67 patients undergoing arteriography, the sensitivity of captopril-enhanced scintigraphy was estimated to be 91.6%, with a specificity of 93.5%, an accuracy of 92.5%, and predictive values of a positive or negative result of 94.2 and 90.6%, respectively. By restricting analysis to bilateral stenosis, sensitivity was found to be 76.9%.(ABSTRACT TRUNCATED AT 250 WORDS)
IgG and IgA immune complexes, mononuclear phagocytic system function, interleukin-2 (IL-2) production by peripheral blood lymphocytes (PBL), serum-soluble IL-2 receptors, tumor necrosis factor, beta 2-microglobulin and IL-1 beta, HLA-DNA polymorphisms, immuno-isoelectrofocusing, phenotype of PBL, lymphocyte cytotoxicity, activation of lymphokine-activated killer cells and natural killer cell activity were evaluated in 8 patients with tubular/fibrillary glomerulonephritis (GN). No common serologic, immunologic or immunogenetic features suggestive of plasma cell dyscrasias were found. No elements to state whether these GNs represent a new entity or just atypical forms of known GN were found.
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To investigate the role of dietary components in immunoglobulin A mesangial nephropathy (IgAGN), this study focused on gliadin, based on the reported association between coeliac disease and IgAGN as well as the pilot observation that a gluten-free diet was able to reduce the levels of circulating IgA immune complexes (IgAIC). IgA mesangial deposits in mice were induced by oral immunization with gliadin and in rats by inducing alcoholic liver cirrhosis, which increased the levels of IgA against dietary antigens (Ag). Gliadin was able to bind to cultured mesangial cells by a lectinic bond, which was reversed by competitive sugars. Binding increased mesangial cell tumor necrosis factor synthesis and decreased prostaglandin E2 production. Several gluten lectinic fractions modulate leukocyte oxidative metabolism, cytotoxicity, and chemotaxis. In IgAGN patients, serum IgA to dietary Ag were sporadically positive and IgAIC containing IgA to dietary components were significantly increased. The affinity of serum IgA to various lectins was increased in some patients. Conversely, no substantial deposition in renal tissue of dietary Ags was observed by immunofluorescence. A gluten-free diet, given to IgAGN patients with high levels of circulating IgAIC and positive antigliadin IgA, was followed by a decrease in the mean levels of both IgAIC and IgA to various dietary Ag, parallel to a reduction in proteinuria. These data suggest that dietary components, such as Ag or lectins, may play a role in IgAGN by promoting IgAIC formation and perhaps favoring mesangial localization via lectinic interactions.
The characteristic granular IgA immunofluorescent pattern in the kidneys of IgA nephropathy patients is consistent with immune complex pathogenesis. The possibility of a delayed clearance of IgA-containing immune complexes from circulation in IgA nephropathy patients is still under discussion. Since pure IgA immune complexes are probably nonphlogistic, (in contrast to IgG-containing IgA immune complexes), the in vivo clearance of a mixture of heat-aggregated IgA/G purified from pooled human sera was analyzed. The test probe was efficiently labeled with 123I and the time course of radioactivity was measured by a gamma-camera. Both the liver and the spleen were found to be involved in the disappearance of IgA/G complexes. Liver accumulation, which was markedly predominant, closely approximates a gamma-variate function which allowed determination of a mean transit time of 34.37 minutes, range 29.8 to 42.2, in 8 normal and 37.54 minutes, range 30.9 to 50.7 in 17 patients (p less than 0.04). At 2 hours, segmental gut accumulation was found, which demonstrated removal by hepatobiliary system as well. Compartmental analysis in patients indicated 3 major compartments represented by vascular bed, hepatobiliary and reticuloendothelial systems (including both liver and spleen phagocytes). Blood clearance rate, representing the final result of multiorgan removal of the test probe from the blood stream, was found to be significantly delayed in IgA nephropathy patients with a slope (0.035 min-1, range 0.019 to 0.052) significantly less negative compared with controls (0.047 min-1, range 0.038 to 0.053, p less than 0.01). This test probe was able to reproduce both removal routes (macrophages cells and hepatobiliary system) hypothesized for IgA-containing immune complexes in humans.
A double glomerulopathy (IgA glomerulonephritis [IgAGN] associated with thin glomerular basement membrane disease [TGBMD]) is reported in a 39-year-old woman presenting with macroscopic-microscopic hematuria. Her 3-year-old daughter was also affected by microhematuria of probable glomerular origin. The diagnosis of IgAGN was made by means of immunofluorescence investigation, which showed generalized diffuse mesangial deposits. TGBMD was identified by electron microscopic investigations, which disclosed thinning (up to 160 nm) of basement membrane of several capillary loops and prominence of the lamina densa. Bearing in mind the known frequencies of the two glomerulopathies, their association may not be coincidental, and, therefore, is worthwhile researching in hematuric patients.
Organ uptake of IgA-containing immunologically active material was studied in humans by intravenous (IV) injection of 131I-labeled heat-aggregated human secretory IgA (HAS-IgA) in nine patients affected by primary IgA nephropathy and 10 normal volunteers. Aggregated secretory IgA was found to be removed almost exclusively by the liver. The peak activity in liver was reached at 21.1 minutes (range, 18 to 26 minutes) in patients and 19 minutes (range, 14 to 22 minutes) in controls. The rate of increase of liver radioactivity was found to be significantly slower in patients (with a mean slope of 5.0; range, 3.4 to 7.1 v 7.6, 5.6 to 11.4; P less than 0.02). The mean liver to precordium ratio at the peak time was significantly lower in patients (mean value, 2.3; range, 1.9 to 3.1) compared with controls (mean value, 3.3; range, 2.4 to 4.0) (P less than 0.02). These data confirm the pivotal role of the liver in the removal of aggregated IgA in humans and the defective clearance capacity of this test probe in IgA nephropathy patients.
We studied serum IgA as antibodies to dietary antigens (Ag), as lectin-binding molecules, and as conglutinin-binding immune complexes (IgAIC) in people from geographical areas in which IgA nephropathy (IgAGN) is particularly frequent. Sera from 63 Italian, 21 Australian, and 25 Japanese patients affected by IgAGN and 24 Italian, 20 Australian, and 40 Japanese healthy controls were studied. Increased values of IgAIC were detected in 42.8% of Italian patients, while only in 23.8% and 8% of Australian and Japanese patients, respectively. Mean values were significantly increased only in Italian patients (P less than 0.0001). Positive values of IgA antibodies against dietary Ag had variable prevalences, but again Italian patients showed the highest frequency, from 19% to 28.5% versus 0 to 38% in Australians and 0 to 16% in Japanese. Mean values of these antibodies were not significantly increased in any patient groups in comparison to the corresponding healthy populations. However, patients with elevated values of IgAIC had significantly higher serum concentrations of antibodies to alimentary components and a linear correlation was found between IgAIC and some IgA antibodies to food components. The relationship between these two series of data was particularly evident for Italian and Australian IgAGN patients. Moreover, the patients with positive data tended to have a cluster of increased levels of IgA antibodies against several alimentary Ag at the same time. A linear correlation was evident between values of IgA antibodies to gluten fractions and to heterologous albumins. None of these correlations was evident among healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Classic anti-neutrophil cytoplasm antibodies (cANCA), perinuclear ANCA (pANCA) and antibodies directed against myeloperoxidase (MPO-Ab) were evaluated in 25 patients with either idiopathic or secondary rapidly progressive glomerulonephritis (RPGN). While cANCA were found almost exclusively in Wegener's granulomatosis, pANCA were detectable in several disorders, including microscopic polyarteritis (mPA), but also idiopathic RPGN. MPO-Ab were frequently found in sera from patients with all types of idiopathic but not of secondary RPGN. These results support the hypothesis that some cases of RPGN are early or limited forms of systematic vasculitis. We then looked for the presence of IgA-ANCA in Henoch-Schoenlein purpura (HSP): we found IgA-ANCA with immunoenzymatic assay but not with immunofluorescence in HSP, in primary IgA-GN and in membranous GN as well, thus suggesting the poor specificity of this type of ANCA. The possible pathologic implications of ANCA were examined in vitro. Serum samples from several patients with ANCA were assessed for their capacity to enhance chemiluminescence generation from resting or PMA-stimulated macrophages. Sera from RPGN and mPA patients displaying anti-MPO activity induced granulocytes to enhance the production of oxygen free radicals, thus suggesting a phlogistic effect of MPO-Ab positive sera.
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