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Presenter: Johannes, Hoffmann, Munich, Germany
Authors: Hoffmann J., Fertmann J., Wirsching K., Mauer M., Jauch K.
CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY
J.N. Hoffmann, J.M. Fertmann, K. Wirsching, M. Mauer, K. Jauch
University Of Munich, Dept. of Surgery - Transplant Surgery, Munich/GERMANY
Body: Chronic allograft dysfunction after kidney transplantation is a multi-factorial pathophysiological entity. Several trials indicate a potential role of immunosuppressants (IS) per se in this context. Especially calcineurin inhibitors are known to reduce dose-dependently reduce renal blood flow by renal vascular vasoconstriction in animal models (Murray et al., Kidney Int, 1985). This study evaluates microcirculatory changes of cyclosporine (CyA), tacrolimus (Tac) and mycophenolat mofetil (MMF) in healthy volunteers and patients after kidney transplantation. Methods: After approval of the University of Munich ethical committee n=18 healthy volunteers and n=18 patients 10-14 days after renal transplantation were assigned to receive CyA, Tac, and MMF (n=6 per group). Exclusion criteria healthy subjects/ patients: chronic medication, hypertension, history of tumor/ >2 or i.v. anti-hypertensive drugs. Measurements (macrohemodynamics, intravital microscopy (OPS imaging, Cytoscan), tissue spectroscopy with laserdoppler flowmetry (O2C) and colour-coded ultrasound) were performed 30 min. before oral IS application, and 30, 60, 120, 180, and 240 min. after application under standardized conditions (20°C, dark room). Plasma concentrations of IS were measured as well as standard laboratory parameters. Microcirculatory analysis discriminated between arteriolar and venular flow. Vasoreactivity was quantified after 90s forearm ischemia. Resistive indices as well as arteriole-capsular distances were measured to quantify kidney perfusion. Results: Patients receiving MMF (66.0±0.4 ys.) were significantly older than patients receiving CyA and Tac (CyA: 49.5±5.9; Tac: 43.7±3.4; p<0.05). Serum creatinine and BUN were higher in Tac patients compared to CyA and MMF (higher immunological risk transplants). Standard coagulation parameters, HLA mismatches, cold ischemia times, blood haemoglobin and hematocrit as well as leukocyte counts did not differ between groups. There were no differences in healthy volunteer subgroups in terms of age (mean age: 26.7 ys.), creatinine, BUN, INR, PT., D-Dimer, hemoglobin, hematocrit, platelet counts, and leukocyte counts (p>0.05). IS plasma concentrations 120min. after IS application were comparable between healthy volunteers and patients (about 1,100 ng/ml for CyA, 8ng/ml for TAC, and 12-15 yg/ml for MMF). Mean arterial pressures and arterial oxygen saturations were not changed by IS application, and did not show significant discrepancies between groups. In healthy volunteers TAC induced a significant reduction in the number of perfused vessels 30 min. (p<0.01) and 180min. (p<0.01) in healthy subjects. A comparable trend was seen with CyA. In patients resistive indices in kidneys were significantly increased (p=0.005) after CyA, whereas MMF and TAC application did not induce significant changes. Conclusions: The combination of different devices allows non-invasive analysis of the microcirculation in healthy subjects and after kidney transplantation. We could not show an effect of IS on macrohemodynmics and oxygen saturation. CyA induced a distinctive microhemodynamic regulation that was not observed with MMF. This changes correlated with an increase in resistive index in the renal grafts. These non-invasive microcirculatory measurements could allow to quantify CNI toxicity in humans, and could be used to optimize immunosuppressant protocols.
Disclosure: All authors have declared no conflicts of interest.
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