Calcineurin inhibitor-free immunosuppressive strategy in elderly recipients of renal allografts from deceased donors: 1-year results from a prospective single center trial.

Recently published data from our center have demonstrated the feasibility of a nephrotoxicity- and atherogenicity-free, mycophenolate mofetil (MMF)-based immunosuppressive protocol for elderly recipients of kidneys from elderly cadaveric donors. We investigated a therapeutic regimen of strictly monitored MMF (target mycophenolic acid [MPA] trough levels between 2-6 microg/mL) and steroids combined with a polyclonal-monoclonal induction regimen consisting of a low-dose, single shot of rabbit ATG (ATG-Fresenius) and the interleukin-2 receptor (IL-2R)-antibody basiliximab (d0 and d4). Between 1997 and 2007, we treated 175 elderly patients with an MMF-based, calcinearin inhibitor (CNI)-free immunosuppressive protocol. For the present cohort, 30 elderly recipients (67.8 +/- 3.8 years) of renal transplants from deceased donors (69.4 +/- 13.3 years) were recruited consecutively for this 5-year prospective, open, single center, pilot trial. One-year results of this clinical trial were patient and renal allograft survivals of 87% and 83%, respectively; death-censored 1-year graft survival was 97%. Mostly steroid-sensitive rejection episodes were observed in 46% of patients, with only 3 patients requiring serum antibody therapy. Renal allograft function was satisfactory, as reflected by a mean serum creatinine of 1.78 +/- 0.45 mg/dL and a Nankivell glomerular filtration rate (GFR) of 48.8 +/- 13.9 mg/dL at 6 months. Twenty-three percent of all patients demonstrated cytomegalovirus (CMV) infections; however, only 3.3% developed CMV disease. Application of a combined polyclonal-monoclonal induction regimen using a nephrotoxicity- and atherogenicity-free, MMF-based immunosuppressive maintenance protocol in elderly cadaveric kidney transplant recipients led to acceptable short-term outcomes, albeit at the expense of an increased rejection rate, comparable to that previously published for elderly (>50 years) recipients of allografts from elderly (>50 years) cadaveric donors.

[Antithrombogenicity of human endothelial cells]. / Antithrombogenität humaner Endothelzellen.

UNLABELLED: In the preceeding decades, our understanding of the complexity in our haemostaseologic system has been evolutionized from a purely ex vivo standpoint to an increasingly in vivo oriented approach, by more and more respecting the immense metabolic interactions of our vascular endothelium, mainly thrombin, the central serine protease in our coagulatory system. So far, investigations concerning human endothelium only relied on experiments with embryonic human endothelial cells, derived from umbilical cord veins. The underlying investigation confronts the justified question about the transferability of such embryonic results to the adult vascular system. MATERIAL, METHODS: Micro- and macrovascular endothelial cells were isolated, purified and propagated in pure cultures. Integrated into an established filtration model, their potential to mediate antithrombogenicity was investigated. RESULTS, CONCLUSION: Surprisingly, immense differences in thrombin-induced antithrombogenicity were demonstrated. This justifies doubts concerning the transferability of HUVEC-based results to the whole human vascular system.

[Thrombin: antithrombotic properties and pharmacological consequences]. / Thrombin: thrombosehemmende Wirkungen und pharmakologische Konsequenzen.

During the last few years, the availability of endothelial cell cultures isolated from different vascular regions contributed to a significant increase in understanding the complex pro- and antithrombotic mechanisms in our circulatory system. The most important key enzyme is thrombin. Due to its haemostatic properties this serin protease catalyzes fibrin formation, activation of factors V, VIII and XIII as well as irreversible platelet aggregation. These processes may occur even within the circulatory system in case of endothelial stimulation (e. g. by inflammation mediators) for expression of binding sites for factors IX, IXa, X, Xa, von Willebrand protein and PAF. Thus not only catalytically activated coagulatory cascades, but also enhanced cooperation of platelets and granulocytes will occur. Paradoxically, in low intravascular concentration, thrombin, in combination with a healthy endothelial layer, may be the critical factor for the inhibition of thromboses. Respective antithrombogenic properties will mainly affect pre-venous microvascular circulation. In detail, they include thrombin-induced endothelial formation of antiaggregatory autacoids from platelet release products, anticoagulatory activation of protein C and absorption of active coagulation factors at endothelial heparan/ATIII complexes as well as release of profibrinolytic plasminogen activator of endothelial origin. The understanding of these complex regulatory functions enables not only a critical evaluation of actually discussed haemostasiologic risk factors (enhanced platelet reactivity, high concentrations of factor VII, VIII, fibrinogen, PAI, ATIII), but also the development of new pharmacologic strategies for prevention of thrombosis.