Follow-up evaluation of the first patients with IgA nephropathy described at Necker Hospital.
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Biomedical subjects
Publications and source records attributed to D Droz.
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The IL6 and TNF alpha specific mRNAs are expressed in normal human kidney; IL6 protein can be detected in normal glomerular mesangium by immunochemistry while TNF alpha is not present. Increased expression of IL6 mRNA is found within the glomeruli in mesangioproliferative glomerulonephritis and IL6 protein is detectable in proliferating mesangial areas. TNF alpha is mainly detected in infiltrating macrophages. During acute rejection episodes de novo expression of TNF alpha appears in renal transplant tubular epithelial cells as well as that of HLA class II antigens, ICAM-1 and VCAM-1 molecules. In renal cell carcinomas, the tumoral cells produce in vivo and in vitro IL6 and TNF alpha at the mRNA and protein levels. Therefore parenchymatous renal cells can produce IL6 and TNF alpha in various pathological conditions. However the mechanisms which regulate the production of these cytokines as well as their role in the genesis or the amplification of tissular damage remain to be elucidated.
We report 16 patients with HIV1 infection with biopsy-proven renal involvement. Nine patients were caucasians and seven were blacks. There were 11 patients at stage II and 5 at stage IV of the HIV1 infection. Three patterns of histologic lesions were found: 6 patients, all blacks, with nephrotic syndrome and/or renal insufficiency had focal and segmental glomerulosclerosis (FSGS) with tubulo-interstitial lesions. In contrast, 6 patients, all caucasians, had various types of glomerulonephritis characterized by immunoglobulin and complement deposits; 3 of them were membranoproliferative glomerulonephritis (MPGN). The four remaining patients had predominant tubulointerstitial lesions. In three patients who had FSGS, treatment by AZT induced temporary improvement of renal function and hemodialysis could be interrupted for a few months. The cure of infectious foci was followed by improvement in renal signs in two out of the 3 MPGN patients. Our study further underlines: 1) the importance of genetic/racial factors in the occurrence of HIV1-associated glomerular lesions and 2) the relatively frequent occurrence of MPGN related to bacterial infections in caucasian patients.
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Extracapillary crescent is an elementary lesion which can be superimposed to any type of glomerulonephritis, or constitute the main lesion as in vasculitis, or appear to be idiopathic. One must oppose cellular crescent which is partially reversible, to irreversible fibrous crescent. Cellular composition of crescents has been much controversial: initially considered as having an epithelial-cell origin, then an exclusive macrophagic origin, crescents are in fact composed of epithelial cells, monocytes-macrophages and lymphocytes all together. The former are prevailing when Bowman's capsule (BC) is intact, whereas macrophages predominate when there is extensive damage of GBM and of BC. The initial event in crescent formation appear to be breaches in glomerular capillary wall, leading the deposition of fibrin within Bowman's space. The consequence is the proliferation of parietal epithelial cells and of activated macrophages followed by a production, in series, of cytokines and growth factors.
To investigate the development of glomerulopathy during the chronic phase of experimental Chagas' disease, C3H-Hej mice were infected with Trypanosoma cruzi trypomastigotes. Deposits of IgG, IgM, and C3 in renal mesangium were observed by immunofluorescence (IF) to increase in size as a function of time after infection (4-6 months). T. cruzi antigens were codeposited in glomeruli with Ig and C3. Electron-dense deposits were visualized in mesangial and paramesangial areas by electron microscopy. Anti-T. cruzi and rheumatoid factor (RF) antibodies (of IgG isotypes) were detected both in serum and in renal eluates. In serum, the titers of both antibodies progressively decreased as a function of time after infection. In renal eluates, titers of anti-T. cruzi antibodies appeared to be stable during the three time periods after infection. By contrast, titers of RF antibodies in renal eluates were shown to increase progressively during these same time periods, paralleling the increase in size of mesangial Ig deposits observed by IF. Several T. cruzi proteins were immunoprecipitated from radiolabeled renal eluates by a control anti-T. cruzi antibody. In addition, antibodies from renal eluates specifically precipitated a 85-kDa protein from radiolabeled T. cruzi lysates, whereas serum antibodies precipitated a broad pattern of T. cruzi proteins. These results demonstrate that mice experimentally infected with T. cruzi can develop a mesangial glomerulopathy during the chronic phase of the disease, which appears to be mediated through immune complexes containing parasite antigens associated with secondary deposition of RF.
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Using monoclonal antibodies against class I and class II (DR antigen) major histocompatibility complex antigens, 65 renal transplant biopsies from 21 recipients whose renal transplants survived ten years or more were studied. Seven biopsies were performed while acute rejection of the renal transplant was under way. The other biopsies were carried out on a routine basis, 6 months (10 biopsies), 2 years (15 biopsies), 4 years (12 biopsies), and 10 years (21 biopsies) after transplantation. Semiquantitative evaluation of fibrous tubulointerstitial lesions was carried out on the biopsies taken after ten years. During episodes of acute rejection, strong expression of class I and class II HLA molecules by transplant tubule epithelial cells was found. When there was no acute rejection, tubule expression of class I and class II HLA molecules was more common in earlier biopsies as compared with later biopsies. In the long-term, persistence of DR antigen in tubule epithelium was associated with increased severity of fibrous tubulointerstitial lesions. A last remarkable finding in some patients was loss of expression of class I antigens in tubule cells from transplants with the longest survivals.
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Using an indirect immunoperoxidase technique, we tested frozen specimens from one Wilms' tumour composed of numerous glomeruloid bodies devoid of blood vessels, with monoclonal antibodies directed against vimentin, cytokeratin, CALLA/CD10, CD24, CR1/CD35, endothelium factor VIII, class I and II MHC molecules, laminin, fibronectin, and non-collagenic domain NC1 of type IV collagen. Two reagents against Goodpasture determinants were used: P1 monoclonal antibody and serum IgG (GP antibodies) from a biopsy-proven Goodpasture patient. Glomeruloid bodies comprised two cell types: a peripheral layer of parietal epithelial cells (cytokeratin and CD24-positive) and central cell clumps of podocytes (vimentin and CALLA-positive). The basal lamina surrounding the glomeruloid bodies contained laminin and NC1 domain of type IV collagen, while that present between the podocytes reacted strongly with laminin, and P1 and GP antibodies. Endothelium factor VIII was not detected within the glomeruloid bodies and CR1 molecules bound to the basement membrane material within them. These data favour the hypothesis that podocytes produce the basement membrane material which bears Goodpasture determinants recently identified as a novel chain, named the alpha 3 chain, of type IV collagen.
Using an indirect immunoperoxidase technique, we tested frozen specimens from 12 Wilms' tumors with monoclonal antibodies (MoAbs) reacting against a large panel of molecules including laminin, fibronectin, cytokeratin, vimentin, villin, CD24, CALLA/CD10, CR1, CD26, class I and class II major histocompatibility complex (MHC) molecules, and endothelium factor VIII. These molecules were chosen because they are markers of specific segments of the mature kidney and because their loss or acquisition is indicative of different steps of human nephrogenesis. KI67 MoAb was used to evaluate the proliferating activity of the cells. The blastemal component (cell compact areas) of Wilms' tumors consisted of vimentin-positive cells with a fibronectin network. However, signs of epithelial maturation were present in compact areas where cytokeratin-positive cells producing laminin were observed. The cells exhibited a high degree of proliferating activity. The tubule formations consisted of cytokeratin-positive cells and had a defined laminin border. All the cells, whether in compact areas or in tubules, were strongly CD24-positive. Some tubular formations showed signs of proximal maturation with the presence of CALLA, CD26, and even villin. In four cases class I-MHC molecules were expressed by some tubular cells. Large cystic cavities present in five cases were edged by cytokeratin, CD24-positive cells, or by vimentin, CALLA, CR1-positive cells. Some glomeruloid bodies, present in two cases, were also composed of vimentin, CALLA, and CR1-positive cells which correspond to the mature podocyte phenotype. The interstitial tissue contained mainly laminin and fibronectin network with macrophages and few CD3 lymphocytes. The presence of large cells with muscular differentiation was noted; round vimentin and CD26-positive cells were also seen. The endothelial cells of the vessels exhibited vimentin, factor VIII, and class I and class II MHC molecules as do mature cells, but in some cases the endothelial cells lacked class II molecule expression and were CALLA-positive. These results which confirmed and extended those previously described show that cell differentiation in Wilms' tumor mimics that observed during metanephros development. Moreover, this study shows that tumoral cells in nephroblastoma share several antigens with cells from lymphoid lineage (CD24, CALLA, and CD26) as do developing and mature kidney cells. Such cell phenotype dissection provides a useful and reliable tool for testing the influence of various factors on the development of hetero-transplanted or cultured Wilms' tumors.
A model has been developed in our laboratory to culture human fetal kidney (Brière 1987). This system is original because it is realized in serum-free Leibovitz's L-15 medium unsupplemented with hormones. Since the culture conditions are minimal for growth and differentiation, many parameters had to be analysed to verify the validity of the system. It was shown that the overall architecture of the explants was preserved during the culture period as well as other morphological and biochemical characteristics. Cells in different populations of the cultured explants keep synthesizing DNA although at a decreased rate. The aim of the current work was to further evaluate the model by studying the expression of some renal cell differentiation antigens (CD24, CD9, CALLA/CD10) in the fetal kidneys during culture. The 4 selected monoclonal antibodies (OKB2, IOB2, IOT5a, IOB3) detected the corresponding surface antigens in various developing renal structures present in uncultured explants. It was observed that these antigens were well preserved during culture and were still expressed on the same structures after 5 d. The present culture model appears as a valuable tool to assess kidney development, and the above mentioned cell surface antigens might be used as markers to study nephrogenesis or the differentiation of membrane specializations.
The authors tested frozen sections from 28 renal cell carcinomas (RCC)--21 clear, 1 eosinophilic, 4 basophilic, and 2 spindle-shaped cell type--with monoclonal antibodies (MAb) reacting against cytokeratin, vimentin, CD24, CALLA/CD10, villin, CD26, and HLA class I and class II molecules. These molecules are markers of specific segments of the mature kidney, and their loss or acquisition reflects the different steps of human nephrogenesis. KI67 MAb was used to evaluate cell-proliferating activity. All RCC cases expressed cytokeratin. Coexpression of vimentin was observed in 21 of 28 cases. Whether of clear or chromophilic type, all tumoral cells strongly expressed CD24 molecule, present on primitive blastema cells. All clear-type RCCs expressed CALLA/CD10 and 60% were also villin positive; some were faintly positive for CD26. CALLA, villin, and CD26 were not detected in basophilic cell type. HLA class I molecules were variably expressed in almost all cases, but HLA class II were never detected on tumoral cells. Except for the spindle-shaped population, cell-proliferating activity was low. These results favor the hypothesis that RCCs derive from cells that have 'recovered' the different options of metanephric differentiation. Clear cells show evidence of maturation toward proximal type, while basophilic cells do not. It would be of interest to evaluate the usefulness of serum measurements of villin and/or CALLA as markers in clear cell-type RCC.
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The association lung hemorrhages and crescentic glomerulonephritis caracterises severe clinical disorders where specific diagnosis is required for initiating the apropriate therapy. Goodpasture's syndrome and systemic vasculitis, mainly Wegener's granulomatosis, are the most frequent etiologies of these syndromes. The detection of circulating auto-antibodies directed against glomerular basement membrane in Goodpasture's syndrome, or against neutrophil cytoplasmic constituents in Wegener's granulomatosis, provides at the present time, helpful specific diagnostic tests making these disorders more readily identifiable.