Original Article
Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study

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The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0) >3 μg/L; group B had no change in TacER dose (TacER C0 7–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 μg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

KEYWORDS

alloantibody
calcineurin inhibitor: tacrolimus
clinical research/practice
glomerular filtration rate (GFR)
immunosuppressant
immunosuppression/immune modulation
immunosuppressive regimens
kidney transplantation/nephrology
maintenance
rejection

Abbreviations

aah
arteriolar hyaline thickening
ABMR
antibody-mediated rejection
BPAR
biopsy-proven acute rejection
BR
before randomization
C0
trough level
cg
glomerular double contours
ci
interstitial fibrosis
CMV
cytomegalovirus
CNI
calcineurin inhibitor
ct
tubular atrophy
cv
fibrous intimal thickening
DGF
delayed graft function
DSA
donor-specific antibody
EC-MPS
enteric-coated mycophenolate sodium
eGFR
estimated GFR
ESRD
end-stage renal disease
g
glomerulitis
HbA1c
glycosylated hemoglobin
HDL
high-density lipoprotein
LDL
low-density lipoprotein
i
inflammation
IF/TA
interstitial fibrosis/tubular atrophy
KTR
kidney transplant recipient
M
month
MMF
mycophenolate mofetil
mTOR
mammalian target of rapamycin
NS
not significant
PR
just after randomization
ptc
peritubular capillaritis
PTDM
posttransplant diabetes mellitus
t
tubulitis
TacER
extended-release tacrolimus
TCMR
T cell–mediated rejection
v
intimal arteritis

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