mTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now?

Abstract

Summary Antibody‐mediated rejection (AMR) usually starts with generation of donor‐specific anti‐HLA antibodies (DSAs), arising from a B‐cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR‐mediated intracellular signaling pathway involved in AMR‐related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects in vivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR—regardless of the type of regimen—is patient adherence. To date, limited data from patients given mTOR inhibitor therapy with adequate concurrent immunosuppression, such as reduced‐exposure calcineurin inhibitor (CNI) therapy, have not shown an adverse effect on the risk of dnDSA or AMR. Early switch to an mTOR inhibitor (<6–12 months post‐transplant) in a CNI‐free regimen, in contrast, can increase the risk of dnDSA, especially if adjunctive therapy is inadequate. Late conversion to CNI‐free therapy with mTOR inhibition does not appear to affect the risk of dnDSA. More data, from prospective studies, are required to fully understand that association between use of mTOR inhibitors with different types of concomitant therapy and risk of dnDSA and AMR.

Long-Term Redistribution of Peripheral Lymphocyte Subpopulations after Switching from Calcineurin to mTOR Inhibitors in Kidney Transplant Recipients

“…In contrast with CNIs, direct effects on B cells of mTORi have been reported [53]. In vitro cultures of human B cells with mTORi showed a profound attenuation of B-cell activation and IgG production [30,31]. Moreover, sirolimus but not tacrolimus was able to inhibit the proliferation of B cells and their differentiation into plasma cells [59].…”

“…Currently, there is controversial data regarding the effect of mTORi conversion in other peripheral blood T cell subsets [20,[27][28][29]. Moreover, scarce and controversial data are available regarding peripheral blood B cells and NK cells and the use of mTORi [27,[30][31][32][33][34].…”

Effect of mechanistic target of rapamycin inhibitors on postrenal transplantation malignancy: A nationwide cohort study

“…4 The chronic antibody-mediated rejection after sustained exposure to mTORi might influence the graft survival. 45 Recent meta-analysis and literature reviews provided the evidence that early withdrawal of CNI and introduction of mTORi might induce the de novo glomerulonephritis and graft loss. 46,47 However, the Cochrane database reported that mTORi might increase the acute rejection, but the effect on long-term graft loss was still uncertain.…”

Donor‐specific antibodies in a pediatric kidney transplant population—Prevalence and association with antiproliferative drug dosing

“…This is not surprising, as our traditional chronic immunosuppression regimens, usually consisting of an antiproliferative agent plus a CNI, primarily target T cells and not the humoral immune system. However, it has been shown that optimization of B‐cell antiproliferative IS based on CNIs is less likely to be associated with DSA development than IS based on inhibitors of the mTOR, especially if there is minimal variability in CNI trough levels . A recent pediatric study has shown that a reduction in MMF dosing below the recommended amounts, for example, for gastrointestinal or hematologic side effects, is associated with a significant increase in the risk for rejection, both cellular and humoral and also suggests that lower mycophenolic acid levels are associated with the formation of DSA …”

“…However, it has been shown that optimization of B-cell antiproliferative IS based on CNIs is less likely to be associated with DSA development than IS based on inhibitors of the mTOR, especially if there is minimal variability in CNI trough levels. 9 A recent pediatric study has shown that a reduction in MMF dosing below the recommended amounts, for example, for gastrointestinal or hematologic side effects, is associated with a significant increase in the risk for rejection, both cellular and humoral and also suggests that lower mycophenolic acid levels are associated with the formation of DSA. 10 DSA surveillance, as recommended by published consensus guidelines, 1 was implemented in our institution's pediatric kidney transplant program in mid-2015 after a leadership change.…”