Study protocol: a pilot study to determine the safety and efficacy of induction-therapy, de novo MPA and delayed mTOR-inhibition in liver transplant recipients with impaired renal function. PATRON-study

Andreas A Schnitzbauer, Marcus N Scherer, Justine Rochon, Johannes Sothmann, Stefan A Farkas, Martin Loss, Edward K Geissler, Aiman Obed, Hans J Schlitt, Andreas A Schnitzbauer, Marcus N Scherer, Justine Rochon, Johannes Sothmann, Stefan A Farkas, Martin Loss, Edward K Geissler, Aiman Obed, Hans J Schlitt

Abstract

Background: Patients undergoing liver transplantation with preexisting renal dysfunction are prone to further renal impairment with the early postoperative use of Calcineurin-inhibitors. However, there is only little scientific evidence for the safety and efficacy of de novo CNI free "bottom-up" regimens in patients with impaired renal function undergoing liver transplantation. This is a single-center study pilot-study (PATRON07) investigating safety and efficacy of CNI-free, "bottom-up" immunosuppressive (IS) strategy in patients undergoing liver transplantation (LT) with renal impairment prior to LT.

Methods/design: Patients older than 18 years with renal impairment at the time of liver transplantation eGFR < 50 ml/min and/or serum creatinine levels > 1.5 mg/dL will be included. Patients in will receive a CNI-free combination therapy (basiliximab, MMF, steroids and delayed Sirolimus). Primary endpoint is the incidence of steroid resistant acute rejection within the first 30 days after LT. The study is designed as prospective two-step trial requiring a maximum of 29 patients. In the first step, 9 patients will be included. If 8 or more patients show no signs of biopsy proven steroid resistant rejection, additional 20 patients will be included. If in the second step a total of 27 or more patients reach the primary endpoint the regimen is regarded to be safe and efficient.

Discussion: If a CNI-free-"bottom-up" IS strategy is safe and effective, this may be an innovative concept in contrast to classic top-down strategies that could improve the patient short and long-time renal function as well as overall complications and survival after LT. The results of PATRON07 may be the basis for a large multicenter RCT investigating the new "bottom-up" immunosuppressive strategy in patients with poor renal function prior to LT.http://www.clinicaltrials.gov-identifier: NCT00604357.

Figures

Figure 1
Figure 1
IS treatment regimen for PATRON07. Basiliximab will be applied on day 0 and 4 after transplantation as 20 mg i.v. application, MMF will be applied as 2 g/d bid, center-specific steroids will be applied and tapered by month 6 after LT, Sirolimus will no be started prior to day 10 after LT aiming at trough-levels of 4 to 10 ng/ml.
Figure 2
Figure 2
Statistical flow-chart. The flow chart shows the two-step model of the single-arm prospective trial. If there are more than 8 responders (patients that do not have steroid-resistant acute rejection within 30 days after transplantation.) after inclusion of 9 patients, there will be a second stepp with additional inclusion of 20 patients. If more than 27 patients do not show steroid resistant acute rejection, the proposed treatment regimen is promising.

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