Association Between Pharmacodynamic Biomarkers and Clinical Events in the Early Phase After Kidney Transplantation: A Single-Center Pilot Study

作者：Wieland Eberhard^*; Shipkova Maria; Martius Yanina; Hasche Georg; Klett Corinne; Bolley Renate; Olbricht Christoph J

来源：Therapeutic Drug Monitoring, 2011, 33(3): 341-349.

DOI：10.1097/FTD.0b013e3182188675

• Biomarkers
• pharmacodynamics
• immunosuppression
• individualization
• cell activation
• therapeutic drug monitoring

Introduction: Strategies based on monitoring pharmacodynamic effects are increasingly evaluated to individualize immunosuppressive therapy. In the present investigation, both drug-specific and general pharmacodynamic biomarkers were assessed and their association with clinical events early after kidney transplantation was examined.
Methods: Thirty-five de novo kidney transplant patients receiving basiliximab, enteric-coated mycophenolate sodium (2 x 720 mg/day), steroids, and tacrolimus (target: 6-8 mu g/L) were included. Blood was drawn on days 7(+/- 1) and 21(+/- 2) after transplantation. Mononuclear leucocytes were isolated and the following parameters were investigated: inosine monophosphate dehydrogenase activity (high-performance liquid chromatography-diode array detection), cell proliferation (bromodeoxyuridine test), and CD marker cell surface expression (CD25, CD71, CD26) on stimulated (phytohemagglutinin 2.5 mu g/10(6) cells) and nonstimulated CD3(+) cells. Acute rejection, gastrointestinal adverse effects, leucopenia, and infections were monitored over 3 months.
Results: There was no association between clinical events and inosine monophosphate dehydrogenase activity apart from patients with diarrhea showing a significantly higher inosine monophosphate dehydrogenase activity 2 hours after the enteric-coated mycophenolate sodium dose (P < 0.05). Cell proliferation was significantly reduced in patients with leucopenia (P < 0.05). CD71 expression was less inducible in patients with infections (P < 0.05). A lower CD26 expression on non stimulated CD3(+) cells predicted freedom from rejection (Day 7; negative predictive value 100%). No associations were found between CD25 expression and events.
Conclusions: A potential benefit of pharmacodynamic monitoring to optimize immunosuppressive combination therapy has been demonstrated. In particular, CD26 and CD71 may be promising biomarkers to assess adequate immunosuppression in the early phase after kidney transplantation. The results of this pilot study require verification in further trials with more patients and events as well as with different graft types.

• 出版日期2011-6