SUMMARY Endothelial-dependent mechanisms of mononuclear cell influx are not well understood. We showed that acute stimulation of murine microvascular endothelial cells expressing the receptors TNFR1 and TNFR2 with the soluble cytokine TNF, led to CXCR3 chemokine generation. The TNF receptors signaled through Interferon regulatory factor-1 (IRF1) to induce interferon-β (IFN-β) and subsequent autocrine signaling via the type I IFN receptor and the transcription factor STAT1. Both TNFR2 and TNFR1 were required for IRF1-IFNβ signaling and, in human endothelial cells TNFR2 expression alone induced IFN-β signaling and monocyte recruitment. In vivo, TNFR1 was required for acute renal neutrophil and monocyte influx after systemic TNF treatment, whereas the TNFR2-IRF1-IFN-β autocrine loop was essential only for macrophage accumulation. In a chronic model of proliferative nephritis, IRF1 and renal expressed TNFR2, were essential for sustained macrophage accumulation. Thus, our data identify a pathway in endothelial cells that selectively recruits monocytes during a TNF-induced inflammatory response.

Tumor necrosis factor alpha (TNFalpha), a pleiotropic cytokine, plays important inflammatory roles in renal diseases such as lupus nephritis, anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and renal allograft rejection. However, TNFalpha also plays critical immunoregulatory roles that are required to maintain immune homeostasis. These complex biological functions of TNFalpha are orchestrated by its two receptors, TNFR1 and TNFR2. For example, TNFR2 promotes leukocyte infiltration and tissue injury in an animal model of immune complex-mediated glomerulonephritis. On the other hand, TNFR1 plays an immunoregulatory function in a murine lupus model with a deficiency in this receptor that leads to more severe autoimmune symptoms. In humans, proinflammatory and immunoregulatory roles for TNFalpha are strikingly illustrated in patients on anti-TNFalpha medications: These treatments are greatly beneficial in certain inflammatory diseases such as rheumatoid arthritis but, on the other hand, are also associated with the induction of autoimmune lupus-like syndromes and enhanced autoimmunity in multiple sclerosis patients. The indication for anti-TNFalpha treatments in renal inflammatory diseases is still under discussion. Ongoing clinical trials may help to clarify the potential benefit of such treatments in lupus nephritis and ANCA-associated glomerulonephritis. Overall, the complex biology of TNFalpha is not fully understood. A greater understanding of the function of its receptors may provide a framework to understand its contrasting proinflammatory and immunoregulatory functions. This may lead the development of new, more specific anti-inflammatory drugs.

Introduction: Current guidelines recommend native arteriovenous fistulas (AVF) as the vascular access of choice for hemodialysis on account of the lower incidence of complications. However, this kind of vascular access has a high rate of early failure (early thrombosis or non-maturation). Our aim was to examine whether clear risk factors for early AVF failure could be identified in our patients. Subjects and Methods: Data of all patients who underwent creation of an AVF at the Geneva University Hospital from January 1998 to December 2002 were reviewed. Early failure was defined as a non-functioning fistula (thrombosis or absence of fistula maturation). Results: 119 patients underwent the creation of 148 native AVF, 88 (59.5%) in the forearm and 60 (40.5%) in the upper arm. 48 (32.4%) fistulae were created in diabetic patients. In a multiple logistic regression analysis, significant predictive factors of early failure were a distal location (adjusted odds ratio (aOR) = 8.21, 95% CI = 2.63–25.63, p < 0.001), female gender (aOR = 4.04, 95% CI = 1.44–11.30, p = 0.008), level of surgical expertise (aOR = 3.97, 95% CI = 1.39–11.32, p = 0.010) and diabetes mellitus (aOR = 3.19, 95% CI = 1.17–8.71, p = 0.024). Conclusion: Early failure of AVF occurs mainly in forearm sites among women and diabetic patients. Surgical expertise has also a significant influence. These results suggest that selection of a distal site for a native AVF has to be rigorously made for women and diabetic patients and that surgeon’s dedication is of primary importance to avoid early AVF failure occurrence.