Assessing Immunosuppression with Immunological Testing and Surveillance Biopsies Late after Liver and Intestine Transplantation (LT, IT)

L. Remaley, R. Falik, K. Soltys, G. Bond, J. Winnier, P. Kachmar, C. Ashokkumar, A. Ganoza, A. Kepler, A. Khanna, J. Squires, P. McKiernan, J. Rudolph, F. Alissa, G. Mazariegos, R. Sindhi

Pediatric Transplant, Pittsburgh, PA

Meeting: 2020 American Transplant Congress

Abstract number: 417

Keywords: Immunosuppression, Liver transplantation, Protocol biopsy, T cells

Topic:

Session Information

Session Name: Biomarkers, Immune Assessment and Clinical Outcomes IV

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

Presentation Time: 4:27pm-4:39pm

Location: Virtual

*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.

To cite this abstract in AMA style:

Remaley L, Falik R, Soltys K, Bond G, Winnier J, Kachmar P, Ashokkumar C, Ganoza A, Kepler A, Khanna A, Squires J, McKiernan P, Rudolph J, Alissa F, Mazariegos G, Sindhi R. Assessing Immunosuppression with Immunological Testing and Surveillance Biopsies Late after Liver and Intestine Transplantation (LT, IT) [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/assessing-immunosuppression-with-immunological-testing-and-surveillance-biopsies-late-after-liver-and-intestine-transplantation-lt-it/. Accessed January 19, 2022.

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