Abstract
Classical immunosuppression based on steroids, calcineurin inhibitors, and mycophenolate results in several unwanted effects and unsatisfactory long-term outcomes in kidney transplantation (KT). New immunosuppressors search for fewer adverse events and increased graft survival but may have a distinct impact on graft function and immunological biomarkers according to their mechanism of action. This prospective study evaluates the immunological effect of tacrolimus to serine/threonine protein kinase mechanistic target of rapamycin inhibitors (mTORi) conversion in 29 KT recipients compared with 16 controls maintained on tacrolimus. We evaluated renal function, human leukocyte antigen (HLA) antibodies and peripheral blood lymphocyte subsets at inclusion and at 3, 12, and 24 months later. Twenty immunophenotyped healthy subjects served as reference. Renal function remained stable in both groups with no significant change in proteinuria. Two patients in the mTORi group developed HLA donor-specific antibodies and none in the control group (7% vs. 0%, p = 0.53). Both groups showed a progressive increase in regulatory T cells, more prominent in patients converted to mTORi within the first 18 months post-KT (p < 0.001). All patients showed a decrease in naïve B cells (p < 0.001), excepting those converted to mTORi without receiving steroids (p = 0.31). Transitional B cells significantly decreased in mTORi patients (p < 0.001), independently of concomitant steroid treatment. Finally, CD56bright and CD94/NK group 2 member A receptor positive (NKG2A+) Natural Killer (NK) cell subsets increased in mTORi- compared to tacrolimus-treated patients (both p < 0.001). Patients switched to mTORi displayed a significant redistribution of peripheral blood lymphocyte subpopulations proposed to be associated with graft outcomes. The administration of steroids modified some of these changes.
Highlights
Kidney transplantation (KT) is the treatment of choice for end-stage renal disease, given the improvement in life expectancy and quality comparing with long-term dialysis [1,2,3,4]
Forty-five patients with stable renal function were included in the study: 29 switched from calcineurin inhibitors (CNI) to mechanistic target of rapamycin (mTOR) inhibitors (mTORi) (25 everolimus and 4 rapamycin, mTORi group), and 16 maintained treatment with tacrolimus, steroids, and mycophenolic acid (Tacrolimus group)
At 24 months, tacrolimus trough blood levels remained stable in the tacrolimus group (6.5 ng/mL), mTORi trough blood levels were 6.8 ng/mL in the mTORi group, and MPA dose was similar in both groups (566 mg in the tacrolimus group and 725 mg in the mTORi group)
Summary
Kidney transplantation (KT) is the treatment of choice for end-stage renal disease, given the improvement in life expectancy and quality comparing with long-term dialysis [1,2,3,4]. Despite the good results in short-term graft survival rates, half-life of renal allografts is around 10 years under immunosuppression treatment mainly based on steroids, calcineurin inhibitors (CNI), and antiproliferative agents [5,6,7]. Death accounts for around half of graft-losses, mainly due to cardiovascular disease, cancer, or infections [13,14]. These results reflect an unmet need of new immunosuppressive therapeutic regimens more efficient for improving long-term survival rates. The introduction of the serine/threonine protein kinase mechanistic target of rapamycin (mTOR) inhibitors in transplantation pursued the challenge of reducing nephrotoxicity related to the use of CNI [15], so as to increase the life of the graft and to decrease the risk of cancer [16] or infections [17]. 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]
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