Einfluss der Immunsuppression auf die Mikrozirkulation: Erste Ergebnisse einer prospektiven Studie an gesunden Probanden und Patienten nach Nierentransplantation

Introduction: Modern immunosuppressives have markedly improved graft survival after solid organ transplantation. However, these substances are associated with negative effects on transplant function attributing to chronic graft dysfunction. It has been speculated that recurrent microcirculatory graft dysregulation caused by peak drug levels could play an important role in this scenario. Therefore, this study examines renal microcirculation, microcirculation of oral mucosae and peripheral vasoreactivity after application of clinically relevant doses of immusuppressive drugs in healthy subjects and patients after kidney transplantation. Methods: Healthy volunteers (n = 18) after single-dose oral application of Cyclosporin A (CyA), Mycophenolat moffetil (MMF), or Tacrolimus (FK 506) (n = 6/group) as well as patients after allogenic kidney transplantation with CyA-, MMF- or FK 506- based immunosuppression (n = 5/group) were studied according to the following protocol: Microcirculation was examined pre-dose as well as 60 min., 120 min., 180 min. and 240 min post-dose. At each time point, venous blood samples were drawn and macrohemodynamic parameters recorded. Perfusion of oral mucosa was quantified by Orthogonal Polarization Spectral imaging. Furthermore, hemoglobin saturation, flow and velocity were examined quantitatively as well as peripheral vasoreactivity after 2 min. of forearm ischemia using laser-doppler-flowmetry. In addition, intrarenal resistive indices (RI) and arterio-capsular distances (ACD) as parameters of organ perfusion were measured by duplex ultrasound in healthy kidneys (healthy volunteers) and kidney grafts (patients). Results: While patient recruitment is still ongoing, serum drug concentrations measured in healthy volunteers are comparable with therapeutic levels targeted in transplanted patients. MMF application tended to reduce RI in grafts, whereas an increase in intrarenal vascular resistance was observed under CyA-treatment. Laserdoppler-flowmetry and power-doppler ultrasound demonstrated a homogenous study collective with low interindividual variances at baseline measurements, and highly reproducible measurements of peripheral vasoreactivity. While tissue oxygen saturation did not increase during reactive hyperemia in volunteers after CyA administration as opposed to MMF, the increase in venular flow after reperfusion remained unchanged after CyA treatment. Conclusion: The methods used in our study facilitate a parallel, non-invasive, reproducible and easy-to-tolerate assessment of peripheral and central microcirculation in healthy volunteers and patients after kidney transplantation. A preliminary data analysis shows a differential regulation of graft perfusion by CNI-inhibitors and MMF. After final evaluation of all results, further studies will have to show, if microcirculatory measurements can help to reduce drug side effects on transplant function.