Objective To evaluate the effect of different treatment strategies on enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome.Design Multicentre retrospective case-control study.Setting 23 hospitals in northern Germany.Participants 298 adults with enterohaemorrhagic E coli induced haemolytic uraemic syndrome.Main outcome measures Dialysis, seizures, mechanical ventilation, abdominal surgery owing to perforation of the bowel or bowel necrosis, and death.Results 160 of the 298 patients (54%) temporarily required dialysis, with only three needing treatment long term. 37 patients (12%) had seizures, 54 (18%) required mechanical ventilation, and 12 (4%) died. No clear benefit was found from use of plasmapheresis or plasmapheresis with glucocorticoids. 67 of the patients were treated with eculizumab, a monoclonal antibody directed against the complement cascade. No short term benefit was detected that could be attributed to this treatment. 52 patients in one centre that used a strategy of aggressive treatment with combined antibiotics had fewer seizures (2% v 15%, P=0.03), fewer deaths (0% v 5%, p=0.029), required no abdominal surgery, and excreted E coli for a shorter duration.Conclusions Enterohaemorrhagic E coli induced haemolytic uraemic syndrome is a severe self limiting acute condition. Our findings question the benefit of eculizumab and of plasmapheresis with or without glucocorticoids. Patients with established haemolytic uraemic syndrome seemed to benefit from antibiotic treatment and this should be investigated in a controlled trial.
These results show that in human, rat, and mouse glomeruli, alpha8 integrin is strongly and exclusively expressed in MCs. Gene expression of alpha8 is regulated in cultured MCs, and alpha8 protein abundance is regulated in vivo and in MC culture. It is currently unclear what functional properties this integrin receptor protein has with regard to MC anchorage to extracellular matrix and modulation of the MC phenotype in normal and diseased glomeruli. However, in view of its abundance in the mesangium, alpha8beta1 integrin could be an important MC receptor of matrix ligands and may play a role in the embryology, physiology, and pathophysiology of the glomerular capillary tuft.
Regulation of mesangial cell proliferation. Regardless of the in the control of MC proliferation appears to play an source of injury, an imbalance in the control of mesangial cell early and crucial role in the pathogenesis of progressive proliferation appears to play a direct role in the degree of glomerular injury and glomerulosclerosis. In experimenprogressive renal injury and glomerulosclerosis. Some of the tal models of nephritis, MC proliferation frequently preregulatory mechanisms include specific soluble or non-soluble cedes and is linked to the increase of extracellular matrix extracellular factors and a complex array of receptor-mediated signals that control the progression of the cell cycle or cell (ECM) in the mesangium and glomerulosclerosis [2, 3]. death. Understanding these regulatory processes could lead to For example, mice transgenic for the SV40 T antigen, novel therapeutic strategies to alleviate or arrest proliferative which has growth-promoting functions, develop MC proglomerular disease.
Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown to modulate cell behavior, including cellular responses to soluble regulator molecules. In addition to the long-recognized role of such interactions in cell localization, anchoring and differentiation during embryogenesis, they are also involved in diverse processes such as maintenance of tissue integrity, response of cells to mechanical stress, inflammatory response, wound healing, tumor cell growth and metastasis as well as apoptosis. Over the last several years, evidence has been reported that extensive "cross-talk" between glomerular mesangial cells (MCs), ECM molecules and soluble mediator substances also affects the proliferative and synthetic phenotype of MCs. This is likely to be relevant for the behavior of MCs during embryonic development, tissue repair and disease processes of glomeruli. The potential biologic and clinical relevance of cell-matrix interactions in the glomerulus makes their elucidation a challenging goal in current kidney research. In this brief review, we present selected aspects of recent investigations concerning the mesangial matrix and its interactions with MCs. In addition to results from cell culture studies, descriptive findings on abnormalities of the ECM and their potential role for the altered MC behavior in glomerular disease will also be discussed.
Background/Aims: α8β1-Integrin is expressed in mesangial cells. In vitro studies suggest a role for α8-integrin in the regulation of cell proliferation and apoptosis. We tested the hypothesis that α8-integrin is essential for the healing process after mesangioproliferative glomerulonephritis. Methods: Mice homozygous for a deletion of the α8-integrin chain were compared with wild-type mice. To study glomerular healing, we used the habu toxin model of reversible mesangioproliferative glomerulonephritis. Animals received 6 mg/kg habu toxin intravenously; controls received saline only. Results: Early mesangiolysis occurred in wild-type and α8-integrin-deficient mice. However, mesangiolysis was no longer detectable after 7 days in wild types but persisted after 14 days in α8-integrin-deficient animals. Mesangial activation marker α-smooth muscle actin was detectable only at day 7 in wild-type mice but persisted until day 14 in α8-integrin-deficient mice. In wild types, glomerular cell proliferation and apoptosis peaked at day 7 and decreased thereafter but remained elevated in α8-integrin-deficient mice until day 28. In cultivated mesangial cells, α8-integrin expression was associated with increased cell survival. Conclusion: Interactions between α8-integrin and the mesangial matrix may contribute to healing of glomerular injury by influencing cell proliferation and apoptosis.
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