*Purpose: Assessing adequacy of immunosuppression is essential during late allograft surveillance after LT or IT.

*Methods: To explain why allograft function tests can be normal despite varying drug levels, and abnormal allograft biopsies (Bx), we evaluated 1) standard deviation in 3-6 consecutive tacrolimus blood levels (Tac SD), 2) donor-specific anti-HLA antibodies (DSA), 3) risk of acute cellular rejection (ACR-risk) with donor-specific CD154+T-cytotoxic memory cells (CD154+TcM), and 4) surveillance Bx after LT or IT.

*Results: 261 visits from 95 subjects, mean 2.8 (range 1-6) visits per subject were evaluated at median 1353 post-transplant days (369-7969). The minimum interval between visits was 12 weeks. Subjects included 52 males, 76 LT and 19 IT, with median age 12.4 years (range 1.4-27). Tac SD <2 was seen at each visit in 62 subjects. Tac SD =/> 2 was found at least once in 33 subjects. More subjects with Tac SD >/= 2 were medication-non-adherent 11/33 vs 9/62, p=0.0385, or experienced ACR, 18/33 vs 18/62, p=0.044, compared with the remaining subjects. Compared with 211 visits with Tac SD <2, the 50 visits with Tac SD =/> 2 were also associated with increased ACR-risk with CD154+TcM, 90/211 vs 32/50, p=0.008, and higher mean (SD) Tac levels, 5 (2.5) vs 8.3 (6.3) ng/ml, respectively, p<0.001. Among 133 biopsies from 74 subjects, 69 showed no ACR. Increased ACR-risk measured with CD154+TcM or DSA were present at 31/46 and 24/36 biopsies with ACR, respectively; at 3/12 and 8/9 biopsies that were indeterminate for ACR, and at 3 of 4 and 4/4 biopsies with fibrosis. Sensitivity and negative predictive values for ACR were 67% and 71% for the ACR-risk parameter CD154+TcM and 67% and 75% for DSA. Either increased ACR-risk or DSA were present during 36/40 (90%) ACR episodes. Together, absent DSA and decreased ACR-risk with CD154+TcM predicted absence of ACR in 83%. Backward stepwise logistic regression analysis confirmed a) association of ACR-risk measured by CD154+TcM, with SD=/>2 (p=0.007) and ACR (p=0.034), b) association of Tac SD=/>2 with Tac levels (p<0.001) and ACR-risk measured with CD154+TcM (p=0.051), and c) association of DSA with time after transplantation (p<0.001), ACR-risk measured with CD154+TcM (p=0.045) and immunologic injury on Bx (p<0.001).

*Conclusions: Highly variable Tac levels are associated with increased donor-specific T-cell alloreactivity measured with CD154+TcM, acute cellular rejection, and non-adherence. Late consequences of increased T-cell alloreactivity and unstable immunosuppression include humoral sensitization and allograft injury. Optimal immunosuppression is associated with immunologic and histologic quiescence.

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