Conversion From Calcineurin Inhibitors to Mammalian Target of Rapamycin Inhibitors in Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

BackgroundA systematic review and meta-analysis were performed to investigate the efficacy and safety of conversion from calcineurin inhibitors (CNIs) to mammalian target of rapamycin inhibitors (mTORi) in kidney transplant recipients (KTRs).MethodsMEDLINE, EMBASE, PubMed, and Cochrane Library were searched to identify randomized controlled trials (RCTs) that compared the continuation of CNI with conversion to mTORi therapy.ResultsTwenty-nine RCTs (5,747 KTRs) were included in our analysis. Meta-analysis of the glomerular filtration rate (SMD 0.20; 95%CI 0.10–0.31; P<0.01) and malignancy (RR 0.74; 95%CI 0.55–0.99; P=0.04) demonstrated a significant advantage of mTORi conversion over CNI continuation. However, the risk of acute rejection (RR 1.58; 95%CI 1.22–2.04; P<0.01), infection (RR 1.55; 95%CI 1.01–1.31; P=0.04), proteinuria (RR 1.87; 95%CI 1.34–2.59; P<0.01), leukopenia (RR 1.56; 95%CI 1.27–1.91; P<0.01), acne (RR 6.43; 95%CI 3.43–12.04; P<0.01), and mouth ulcer (RR 11.70; 95%CI 6.18–22.17; P<0.01) were higher in the mTORi group. More patients in the conversion group had to discontinue study medication (RR 2.52; 95%CI 1.75–3.63; P<0.01). There was no significant difference between the two groups with regard to death, graft loss, diabetes, chronic allograft nephropathy, and interstitial fibrosis/tubular atrophy.ConclusionsPosttransplant patients have a better graft function and lower incidence of malignancy after conversion from CNI to mTORi therapy. However, this conversion strategy may be prevented by the higher drug discontinuation rate due to mTORi-associated adverse events, such as more acute rejection, infection, proteinuria, leukopenia, acne, and mouth ulcer, indicating that conversion therapy may only be a treatment option in selected patients.

Rapamycin Treatment Alleviates Chronic GVHD-Induced Lupus Nephritis in Mice by Recovering IL-2 Production and Regulatory T Cells While Inhibiting Effector T Cells Activation

“…Rapamycin, also known as sirolimus, is a macrolide antibiotic with potent immunosuppressive properties and is clinically used for the prevention of acute rejection in renal transplantations and GVHD [ 32 , 33 , 34 , 35 , 36 ]. In renal transplant patients, combinations of rapamycin with cyclosporine (CsA) lower the rate of organ failure.…”

“…A most recent study reported a phase 2 trial of GVHD prophylaxis with rapamycin, posttransplant cyclophosphamide (PTCy) and tacrolimus/mycophenolate mofetil (MMF) after peripheral blood haploidentical transplantation. In this study, rapamycin and PTCy/MMF GVHD prophylaxis not only decreased the grade II–IV acute GVHD rates after HLA-haploidentical hematopoietic cell transplantation, but also permitted hematopoietic engraftment and led to low moderate/severe chronic GVHD rates and favorable survival [ 34 , 35 ]. Rapamycin acts by inhibiting mammalian target of rapamycin (mTOR), a key protein kinase necessary for cell cycle progression, thereby suppressing the proliferation and clonal expansion of interleukin-2-stimulated T lymphocytes [ 18 , 19 , 20 , 21 ].…”

Lipid management to mitigate poorer postkidney transplant outcomes

“…As hyperlipidemia associated with immunosuppression occurs in a dose-dependent fashion, the adjustment of drug dosage to achieve appropriate plasma levels is also important. The conversion from CNIs to mTORi indicated an unfavorable effect on hyperlipidemia, which was the main reason to discontinue mTORi [27]. Moreover, lipid profile significantly improved after cessation of prescribing these drugs [24].…”

HLA‐DQ eplet mismatch load may identify kidney transplant patients eligible for tacrolimus withdrawal without donor‐specific antibody formation after mesenchymal stromal cell therapy

“…Apart from the increased risk of opportunistic (viral) infections and malignancies that is inherently associated with the long‐term use of clinical immunosuppression, CNIs have adverse cardiovascular effects (hypertension, dyslipidemia, new‐onset diabetes) and direct vasoconstrictive and fibrotic nephrotoxic effects 6,7 . Consequently, CNI‐sparing regimens using other immunosuppressive agents such as mTOR inhibitors or belatacept have been investigated, as well as CNI minimization or withdrawal 8–13 . Since CNI‐withdrawal has been associated with an increased rate of subsequent acute rejection as well as graft loss, 14 there still is an unmet need for immunosuppressive strategies that prevent allograft rejection while preventing the long‐term adverse events of current clinical immunosuppression on patient and graft survival.…”

“…6,7 Consequently, CNI-sparing regimens using other immunosuppressive agents such as mTOR inhibitors or belatacept have been investigated, as well as CNI minimization or withdrawal. [8][9][10][11][12][13] Since CNI-withdrawal has been associated with an increased rate of subsequent acute rejection as well as graft loss, 14 there still is an unmet need for immunosuppressive strategies that prevent allograft rejection while preventing the long-term adverse events of current clinical immunosuppression on patient and graft survival.…”