Alsharif, Muath

ABSTRACT Introduction Calcineurin inhibitors (CNIs) are the cornerstone of lung transplant immunosuppression but are associated with nephrotoxicity and other adverse effects. Although dose reduction and combination with Sirolimus, a mammalian target of rapamycin inhibitor (mTORi), have been explored, full conversion to Sirolimus remains uncommon. This study describes the characteristics and outcomes of lung transplant recipients who underwent complete CNI withdrawal and conversion to Sirolimus. Methods This retrospective case series included 52 lung transplant recipients transitioned to Sirolimus‐based immunosuppression between 2010 and 2021. Data on demographics, transplant characteristics, immunosuppression, and outcomes were collected from electronic medical records. Results The cohort included 31 males (59.6%) with a median age of 58.4 years (IQR 52.3–63.5). The primary indication for CNI withdrawal was renal dysfunction (73.1%). Sirolimus discontinuation occurred in 69.2%, most commonly due to edema (25.0%), lung toxicity (19.4%), rejection (19.4%), and surgical needs (22.2%). Clinically significant rejection occurred in 13.5%, with four patients progressing to chronic lung allograft dysfunction (CLAD) and two deaths. Sixteen patients (30.8%) tolerated CNI withdrawal for over a year. Conclusion Full conversion from CNI to Sirolimus is poorly tolerated due to side effects and has a high incidence of rejection. Further studies are needed to optimize patient selection and risk mitigation strategies.

Abstract Introduction: Calcineurin inhibitor (CNI) nephrotoxicity is a common complication following lung transplant. This is usually treated with dose reduction of CNI, addition of mammalian target of rapamycin inhibitor (mTORi), or rarely, CNI withdrawal which poses the risk of acute and chronic lung allograft rejection. Complete CNI withdrawal and transition to a mTORi based regimen for renal protection is scarcely described in literature with mixed results. Methods: We performed a single center, retrospective chart review of adult lung transplant recipients from January 2010-December 2022 to identify those who underwent complete CNI withdrawal and transition to a mTORi based immunosuppression regimen. Dual organ transplants and external transplant surgeries were excluded. Demographics, and clinical information on immunosuppressive regimens, renal function, rejection episodes, and outcomes were collected. This study was approved by the Mayo Clinic Institutional Review Board. Descriptive statistics were employed. Data is presented as N (%) or median (IQR). Results: A total of 52 patients who underwent CNI withdrawal were identified, and 38 patients (73.1%) were transitioned to a mTORi based regimen for renal failure. The median age at transplant was 59.1 years (IQR 54.2-63.3) and 57.9% were male. The most common transplant indication was pulmonary fibrosis (N = 21, 55.3%). No patients had pre-transplant chronic kidney disease stage 3 or higher. The median length of time from transplant to CNI withdrawal was 13.0 months (IQR 10.0-28.6). Most patients (N = 35 out of 38, 92%) discontinued mTORi and returned to a CNI based regimen after a median duration of use of 4.5 months (IQR 2.4-12.0) for an upcoming procedure/facilitate wound healing (N = 7, 20%), hypervolemia (N =7, 20%), death (N = 6, 17%), lung toxicity (N = 5, 14%), or worsening allograft function (N=5, 14%). Five patients (13.2%) developed ≥ A2 acute cellular rejection. Ten patients (26.3%) developed chronic lung allograft dysfunction. There was no change in creatinine at baseline (just prior to CNI withdrawal) compared to 12 (+/- 3) months after mTORi initiation (p = 0.36). Thirteen patients required dialysis (34.2%), four patients received renal transplants (10.5%), and 1 patient died on the renal transplant waitlist. Conclusions: Our case series demonstrates complete CNI withdrawal and transition to mTORi regimen is associated with short duration of therapy for most patients due to side effects and no change in creatinine one year after transition.