Does Rapamycin Still Have a Role? Experience and Lessons from the Last Decade

Abstract

Background: Rapamycin, an mTor inhibitor, is a potent immunosuppressant agent in solid organ transplantation. Initial enthusiasm on its efficacy and reduced nephrotoxcity was tempered by unacceptable and widely publicised side effects leading to increasingly sporadic usage by transplant centres. It appears to have a niche for specific and varied indications, particularly as ‘rescue therapy’ and in situations where its anti-neoplastic or anti-fibrotic properties may confer an advantage rather than as primary maintenance immunosuppression. We aimed to assess the frequency and pattern of Rapamycin use focusing primarly on indications, usage length, outcomes and complications, in three large North of England centres since its introduction into clinical practice in 1997. Methods: All Patients who have had Rapamycin at any point following transplantation were identified through laboratory records of assays done at 3 follow up centres. A retrospective analysis was then done of a database of 1412 patients receiving either a kidney or pancreas transplant between 1997 and 2011. 123 patients received Rapamycin with data on the indications, pattern and length of usage available in 91 patients (8.7%). These comprised 2 distinct groups: Rapamycin as de novo immunosuppression (primarily in clinical trials with Mycophenolae Mofetil and steroid) or as a modification of therapy at a later date due to distinct clinical indications. End points including Biopsy proven acute rejection (BPAR), complication rates, proteinuria (>1g/24hr) and mortality were reviewed in this cohort of patients. Results: 36 patients received de novo Rapamycin treatment (Trial 35/36; non trial 1/36 - previous PTLD) 13 (36%) of these patients required immunosuppression modulation (recurrent BPAR, 38%; 10 single episodes of BPAR), impaired wound healing (23%), interstitial pneumonitis (15%) and mouth ulcers (7.6% each). Complications which did not require immunosuppressive changes included hyperlipidaemia (>6mmol/l, 83%), mouth ulceration (19%), and lymphocoele (22%). The incidence of neoplasia was 5% and mortality 14%. Rapamycin associated significant proteinurian was 5%. 53 patients were converted to Rapamycin as ‘rescue therapy’ (median interval 6 years post-transplant (range 1/12 to 42 years); indications including: allograft nephropathy 17/53 (32%), anti-neoplastic 14/53 (11 skin cancer, 1 PTLD, 1 small bowel lymphoma, 1 renal cell Ca; 26%), and intolerance of other drugs 9/53 (17%). 19/53 (36%) had changes due to intolerance (infection (11%); mouth ulcers (17%); BPAR (5%), or chest infections (interstitial pneumonitis or PCP pneumonia; 4%.) Other adverse effects included hyperlipidaemia (22%) and mouth ulcers (15%). The incidence of significant proteinuria was 20% with a mortality rate of 13%. Conclusion: Rapamycin has been sparingly used in the last decade due to severe adverse outcomes associated with de novo usage. Trends have developed for its use for allied benefits, particularly including anti-fibrotic and neoplastic properties and as rescue therapy for toxicity rather than as defined maintenance immunosuppression. This study highlights that despite not fulfilling original indications, it has a role for both maintenance and rescue therapy. Its side effect profile ensures that it is better tolerated than originally perceived thereby ensuring its continued importance in the armamentarium of immunosuppressant agents.