MTOR inhibitor monotherapy. A good treatment choice in renal transplantation?

Abstract

Calcineurin inhibitors have reduced acute rejection rates and improved short-term graft survival, but without any improvement in long-term outcomes, since calcineurin inhibitors cause nephrotoxicity and death with a functioning graft. mTOR inhibitors have antiproliferative and anti-angiogenic effects with no nephrotoxicity. These properties could improve patient and graft long-term survival rates in select transplant recipients. In addition, monotherapy always diminishes the rate of non-compliance in chronic patients. We examined the evolution of 47 low immunological risk kidney transplant recipients with mTOR inhibitor monotherapy. The mean age was 45 ± 10 years (range: 18-69 years), with 25 males y 22 females. We performed an immunological evaluation before and at 3 and 12 months after starting monotherapy by detection of donor-specific antibodies by microsphere cytometry and the determination of lymphocyte activity with production of ATP by CD4+ T-lymphocytes activated by PHA mitogen. We considered patients to be of low immunological risk when the patient had an ATP production less than 520 ng/dl and no history of acute rejection episode or donor-specific antibodies. Initially, 5 patients received immunosuppression induction without calcineurin inhibitors (mycophenolate, prednisone, mTOR inhibitors and anti-CD25), and 42 were converted to mTOR inhibitors due to secondary effects of calcineurin inhibitors or malignancies. A total of 34 recipients had received sirolimus and 13 everolimus. Eighteen out 47 patients (38.2%) received prednisone and 29 (61.7%) mycophenolate with mTor before starting monotherapy. The mean follow-up period after starting monotherapy was 46.9 months (95% CI: 38.8-55.0 months). At the end of the follow-up, 7 out of 47 recipients (11.5%) had to change immunosuppression without losing their grafts after 1 year, due to heavy proteinuria in 2 cases, pulmonary infection in 1, acute rejection in 1, hepatotoxicity in 1, vasculitis in 1 and a temporary inclusion on dialysis after acute pyelonephritis in 1. Four out of 47 patients (8.5%) lost their grafts, as a result of chronic rejection in 3 cases, and as a result of death with a functioning graft in 1. The rate of acute rejection was 2.1%, one episode, which was solved with steroid pulses and switching from mTOR inhibitors to tacrolimus and mycophenolate. No patients developed donor-specific antibodies, and all of them maintained an ATP production less than 520 ng/dl. The rates of graft and recipient survival were both 100% at 1 year, and 88.7% and 95.7% at 5 years. The percentages of patients on monotherapy were 97.9% and 70.5 % at 1 and 5 years, respectively. At the end of the follow-up, 36 out of 47 recipients remained on mTOR inhibitor monotherapy. Serum creatinine and glomerular filtration rates improved significantly, from 2.16 ± 1.05 mg/dl to 1.49 ± 0.56 mg/dl (P=.001) and from 39.23 ± 25.23 ml/min to 52.23 ± 23.20 ml/min (P=.001), respectively. Proteinuria increased but not significantly, from 306.6 ± 400 mg/24h to 418.1 ± 514.1mg/24h (P=.17). The patients treated with mTOR inhibitors received significantly more erythropoietin and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers than before starting mTOR, but there was no change in the treatment with statins or hypotensive agents. Body weight and the percentage of diabetic recipients were similar during the study. No cases of non-compliance were observed during the follow-up. The present study supports the safety and efficacy of monotherapy with mTOR inhibitors in select kidney transplant recipients.