While acute cellular rejection (ACR) after liver transplantation (LT) is not thought to cause long-term graft injury and inferior outcomes, this notion has been challenged recently. In order to investigate this in more detail, we examined the effect of biopsy-proven ACR in a large cohort of LT recipients with protocol biopsies maintained on standardized immunosuppression.

Methods: 787 adult LT recipients from 2000 to 2010 were identified, and their data collected. Protocol biopsies were done in all patients within 6 weeks of LT. Additional indication-specific biopsies were done when allograft dysfunction was suspected. A total of 2,870 biopsies were reviewed. All patients received methylprednisolone for induction and standardized triple immunosuppression (mycophenolate, tacrolimus and prednisone) for maintenance therapy. The median follow-up was 8.3 years. Early rejections (≤6 weeks) were analyzed using chi-square and unequal variance t-tests. Late rejections (>6 weeks) and long term survival were analyzed using Cox proportional hazard models.

Results: Early ACR occurred in 292 (37.1%) LT recipients, and had no effect on long-term graft- (HR 0.99; 95%CI 0.77-1.29; p=0.98) or patient survival (HR 0.97; 95%CI 0.74-1.27; p=0.84). Variables associated with early ACR included younger recipient age (p=0.001), female sex (p=0.035), HLA mismatch (p=0.005) and donor type (deceased vs. living) (p=0.011). Patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and acute fulminant liver failure (ALF) demonstrated a propensity for early ACR (p=0.028). Patients with a late ACR had an increased risk of graft failure within 90 days of the rejection (HR 5.40; 95% CI 2.92-9.99; p<0.001). While this risk decreased over time, late ACR continued to confer a higher risk of graft failure after the initial 90 days (HR 1.48; 95% CI 1.05-2.08; p=0.024). Similarly, late ACR was associated with increased risk of death within 90 days of the rejection (HR 2.903; 95% CI 1.23 – 6.86; p=0.0152). Non-Caucasian race was associated with late ACR (HR 2.04, 95%CI 1.31-3.21; p=0.001). Patients with AIH, PBC and ALF continued to demonstrate a propensity for late ACR.

Conclusions: Based on protocol biopsies, these results confirm earlier observations and suggest that early ACR following LT does not negatively impact patient or graft survival when treated. By contrast, late ACR occurring more than 6 weeks from LT is associated with decreased patient survival and an increased risk of graft loss.

CITATION INFORMATION: Jadlowiec C, Morgan P, Nehra A, Hathcock M, Kremers W, Wiesner R, Taner T. Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection. Am J Transplant. 2017;17 (suppl 3).

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