Jürgen Floege

Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats.

Mesangial cell (MC) proliferation and extracellular matrix expansion are involved in the pathogenesis of glomerulosclerosis and renal failure. In vitro, PDGF and basic fibroblast growth factor (bFGF) regulate MC proliferation and/or matrix production. To elucidate the role of PDGF and bFGF in vivo, equimolar concentrations of recombinant PDGF-BB or bFGF or vehicle were infused intravenously into rats over a 7-d period. Rats were either nonmanipulated (normals) or had received a subnephritogenic dose of anti-MC antibody (anti-Thy 1.1 rats) before the infusion period. Glomerular cell proliferation (anti-proliferating cell nuclear antigen immunostaining) on days 2, 4, and 7 was unchanged in vehicle-infused normals or anti-Thy 1.1 rats. PDGF infusion increased glomerular cell proliferation 32-fold in anti-Thy 1.1 rats and an 11-fold in normals on day 2. bFGF increased glomerular cell proliferation fourfold in anti-Thy 1.1 rats but was ineffective in normals. Induction of cell proliferation in all kidneys was limited to the glomerulus. The majority of proliferating cells were identified as MC by double immunolabeling. No significant proteinuria, glomerular leukocyte, or platelet influx developed in any group. Glomerular matrix expansion with increased deposition of type IV collagen, laminin, and fibronectin, as well as upregulated laminin and collagen IV mRNA expression was confined to PDGF-infused anti-Thy 1.1 rats. These results show that PDGF and, to a lesser degree, bFGF are selective MC mitogens in vivo and that previous subclinical injury can enhance this MC response. The data thereby support a role of these cytokines in the pathogenesis of glomerulosclerosis.

Beta-2-microglobulin-associated amyloidosis

beta2-Microglobulin-associated amyloidosis has emerged as a major complication of long-term renal replacement therapy. The syndrome is confined to those patients on nontransplant modes of therapy. It does not occur in patients with a functioning renal transplant or, if already present, it does not progress any further in such patients. In the population of ESRD patients on dialysis, beta2-microglobulin-associated amyloidosis affects most patients treated for more than 15 years and is a cause of significant morbidity and in rare cases even mortality. The present review, which is based on the presentation of a typical case, discusses the current knowledge on the pathogenesis, clinical manifestations, diagnosis, prevention and therapy of beta2-microglobulin-associated amyloidosis.

Comparative Study of C5a Plasma Levels with Different Hemodialysis Membranes Using an Enzyme-Linked Immunosorbent Assay

Using a specific and sensitive ELISA for C5a, the present study shows that predialysis levels of C5a in end-stage renal disease patients are not elevated and that all membranes studied (Cuprophan, Hemophan, Gambrane and hydrophilic polysulfone) cause significant increases of C5a plasma levels albeit to different degrees. Higher increases of C5a were accompanied by larger decreases of circulating granulocytes and monocytes. Dialyzers with a newly introduced modified regenerated cellulose membrane, Hemophan, showed lower C5a plasma levels during hemodialysis than Cuprophan. With Hemophan C5a plasma levels were comparable to those with polysulfone membranes.

Is the Rise in Plasma Beta-2-Microglobulin Seen during Hemodialysis Meaningful?

Beta 2-Microglobulin (beta 2M) plasma levels and levels of a second low-molecular-weight protein (myoglobin) were studied during a 2- to 4-hour sham dialysis period (no dialysate flow, no weight loss) and during a 4- to 5-hour hemodialysis (HD) with a Cuprophan capillary dialyzer. While no rise of the beta 2M or myoglobin levels occurred during sham dialysis, a rise of 22.1 +/- (SD) 8.5% (beta 2M) or 19.9 +/- 12.1% (myoglobin) was seen during regular HD. The increases of both molecules showed a significant correlation (r = 0.44; p less than 0.03). Both rises could not be completely abolished using correction factors for hemoconcentration. The rises occurred irrespectively of the dialysate buffer. The results suggest that neither the Cuprophan membrane nor the extracorporeal circuit were responsible for the rise of both molecules during HD. It seems more likely that changes of the extracellular volume and extra- to intracellular water shifts are involved and account for the majority of the rise. However, the possibility of minor increase in the extracellular mass of beta 2M or myoglobin cannot be excluded completely.

Expression of interferon-inducible Mx-proteins in patients with IgA nephropathy or Henoch-Schönlein purpura★

Both viral infections and dysregulated cytokine synthesis have been implicated in the pathogenesis of immunoglobulin A nephropathy (IgAN) and Henoch-Schönlein purpura (HSP). Mx proteins are specifically induced by type I interferons (IFN-alpha, -beta, -omega) and are very sensitive in detecting, for example, virus-induced, in vivo production of IFN-alpha/-beta, because the biological half-life of Mx (approximately 3 days) markedly exceeds that of IFN-alpha/-beta (20 to 90 minutes). Mx concentrations in leukocytes were measured by enzyme-linked immunosorbent assay (ELISA) in 79 blood samples of 35 patients with IgAN and five with HSP. No patient showed symptoms of infections at the time of the examination. Compared with normal leukocyte Mx concentrations (<2 mU/1,000 leukocytes), only 3 of 79 samples of IgAN/HSP patients showed mildly elevated Mx concentrations (range, 2.2 to 3 mU/1,000 leukocytes). By contrast, patients with increased endogenous IFN production (lupus erythematosus) or patients treated with IFN-alpha2 showed leukocyte Mx concentrations of up to 35 mU/1,000 leukocytes. In patients with IgAN and HSP, leukocyte Mx concentrations were not correlated with various clinical parameters. Immunohistochemically, no renal Mx expression could be detected in eight renal biopsy specimens of patients with various stages of IgAN, whereas control specimens (skin of patients treated with IFN-alpha2) showed abundant cellular Mx expression. Furthermore, human mesangial cells in vitro showed marked Mx production after exposure to IFN-alpha or IFN-beta. We conclude that, in patients with IgAN/HSP, no evidence of an activation or dysregulation of the type I interferon system can be detected.

Cytokines and glomerular injury.

Since reports of the first data on cytokines in renal diseases about 10 years ago, the field has seen an explosive growth over the last decade. It is now realized that cytokines can be synthesized by many different types of cells, including glomerular cells, upon adequate stimulation and exert a wide range of actions mostly in an autocrine or paracrine fashion. Cytokines not only contribute to developmental processes, but also to the maintenance of normal tissue integrity and in particular to the initiation and modulation of tissue injury, healing, or scarring. This review summarizes some recent data on the role of cytokines in glomerular disease and describes some of the first experimental approaches to therapeutically interfere with cytokine actions.

IgA-Nephropathy: how does IgA activate the mesangial cell?

Immunoglobulin (Ig)A-nephropathy (IgAN), the most common glomerulonephritis worldwide, is immunohistochemically characterized by the deposition of IgA in the renal mesangium. The mechanism of binding and deposition of IgA in the kidney is still not clear. It has been demonstrated that IgA-binding to mesangial cells (MCs) is followed by cell activation, as indicated by the enhanced expression of proinflammatory cytokines, the nuclear transcriptional factor (NF)κB, or the protooncogene c-jun. The binding of IgA to MC is mediated via the Fc part of the immunoglobulin, as demonstrated by blocking experiments using Fc-fragments of IgA. The known myeloid Fc receptor for IgA (FcαRI/CD89), as well as other known receptors able to bind IgA (asialoglycoprotein receptor, mannose receptor, secretory component), are not expressed on MC. However the hepatic asialoglycoprotein receptor, as well as the myeloid FcαRI, play an important role in the clearance of IgA from the circulation. In patients with IgAN, this function seems to be impaired, possibly as a consequence of reduced glycosylation of the hinge region of IgA1 which affects IgA-receptor interactions. This could lead to increased plasma levels of IgA, resulting in increased binding of IgA to MC via a hitherto unidentified Fc receptor for IgA. Recently, the expression of mRNA transcripts with partial identity to CD89 was reported on human MC in vitro. These transcripts could be part of this new receptor, with partial homology to recently discovered genes that map to chromosome 19Q13.4 and encode a family of type I transmembrane proteins.