Advertisement

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients

Published:August 24, 2016DOI:https://doi.org/10.1016/j.cgh.2016.07.035

      Background & Aims

      Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy-proven acute rejection (BPAR) based on an analysis of a more recent national sample of recipients of liver transplants from living and deceased donors.

      Methods

      We analyzed data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete-survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living and deceased donors.

      Results

      At least 1 BPAR episode occurred in 239 of 890 recipients in A2ALL (26.9%) and 7066 of 45,423 recipients in SRTR (15.6%). In each database, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43–0.76; and SRTR HR, 0.78; 95% CI, 0.66–0.91) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each database, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post-BPAR period in patients whose first episode occurred more than 1 year after liver transplantation: HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64–17.45) and 4.41 in SRTR (95% CI, 3.71–5.23); HRs for death were 8.81 in A2ALL (95% CI, 3.37–23.04) and 3.94 in SRTR (95% CI, 3.22–4.83). In analyses of cause-specific mortality, associations were observed for liver-related (graft failure) causes of death but not for other causes.

      Conclusions

      Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all-cause mortality, and graft failure–related death, regardless of primary liver disease etiology. Living donor liver transplantation from a biologically related donor is associated with decreased risk of rejection.

      Keywords

      Abbreviations used in this paper:

      A2ALL (Adult-to-Adult Living Donor Liver Transplantation Cohort Study), BPAR (biopsy-proven acute rejection), CI (confidence interval), DDLT (deceased donor liver transplantation), HCV (hepatitis C virus), HR (hazard ratio), LDLT (living donor liver transplantation), LT (liver transplantation), MELD (Model for End-Stage Liver Disease), PBC (primary biliary cirrhosis), SRTR (Scientific Registry of Transplant Recipients)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Fisher L.R.
        • Henley K.S.
        • Lucey M.R.
        Acute cellular rejection after liver transplantation: variability, morbidity, and mortality.
        Liver Transpl Surg. 1995; 1: 10-15
        • Charlton M.
        • Seaberg E.
        Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.
        Liver Transpl Surg. 1999; 5: S107-S114
        • Wiesner R.H.
        • Demetris A.J.
        • Belle S.H.
        • et al.
        Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome.
        Hepatology. 1998; 28: 638-645
        • Levitsky J.
        Operational tolerance: past lessons and future prospects.
        Liver Transpl. 2011; 17: 222-232
        • Goldberg D.S.
        • French B.
        • Abt P.L.
        • et al.
        Superior survival using living donors and donor-recipient matching using a novel living donor risk index.
        Hepatology. 2014; 60: 1717-1726
        • Olthoff K.M.
        • Smith A.R.
        • Abecassis M.
        • et al.
        Defining long-term outcomes with living donor liver transplantation in North America.
        Ann Surg. 2015; 262 (discussion 473–475): 465-475
        • Shaked A.
        • Ghobrial R.M.
        • Merion R.M.
        • et al.
        Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation.
        Am J Transplant. 2009; 9: 301-308
      1. Little R. Statistical analysis with missing data, 2nd ed. Hoboken, NJ: John Wiley & Sons, 2002.

        • Starzl T.E.
        Immunosuppressive therapy and tolerance of organ allografts.
        N Engl J Med. 2008; 358: 407-411
        • Sanada Y.
        • Matsumoto K.
        • Urahashi T.
        • et al.
        Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation.
        World J Gastroenterol. 2014; 20: 6638-6650
        • Sebagh M.
        • Samuel D.
        • Antonini T.M.
        • et al.
        Twenty-year protocol liver biopsies: invasive but useful for the management of liver recipients.
        J Hepatol. 2012; 56: 840-847
        • Jain A.
        • Reyes J.
        • Kashyap R.
        • et al.
        What have we learned about primary liver transplantation under tacrolimus immunosuppression? Long-term follow-up of the first 1000 patients.
        Ann Surg. 1999; 230 (discussion 448–449): 441-448
        • Moench C.
        • Barreiros A.P.
        • Schuchmann M.
        • et al.
        Tacrolimus monotherapy without steroids after liver transplantation: a prospective randomized double-blinded placebo-controlled trial.
        Am J Transplant. 2007; 7: 1616-1623
        • Lerut J.P.
        • Pinheiro R.S.
        • Lai Q.
        • et al.
        Is minimal, [almost] steroid-free immunosuppression a safe approach in adult liver transplantation? Long-term outcome of a prospective, double blind, placebo-controlled, randomized, investigator-driven study.
        Ann Surg. 2014; 260 (discussion 891–892): 886-891
        • Uemura T.
        • Ikegami T.
        • Sanchez E.Q.
        • et al.
        Late acute rejection after liver transplantation impacts patient survival.
        Clin Transplant. 2008; 22: 316-323
        • Wiesner R.H.
        • Steffen B.J.
        • David K.M.
        • et al.
        Mycophenolate mofetil use is associated with decreased risk of late acute rejection in adult liver transplant recipients.
        Am J Transplant. 2006; 6: 1609-1616
        • Thurairajah P.H.
        • Carbone M.
        • Bridgestock H.
        • et al.
        Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.
        Transplantation. 2013; 95: 955-959
        • Sundaram S.S.
        • Melin-Aldana H.
        • Neighbors K.
        • et al.
        Histologic characteristics of late cellular rejection, significance of centrilobular injury, and long-term outcome in pediatric liver transplant recipients.
        Liver Transpl. 2006; 12: 58-64
        • Ramji A.
        • Yoshida E.M.
        • Bain V.G.
        • et al.
        Late acute rejection after liver transplantation: the Western Canada experience.
        Liver Transpl. 2002; 8: 945-951
        • Mor E.
        • Gonwa T.A.
        • Husberg B.S.
        • et al.
        Late-onset acute rejection in orthotopic liver transplantation–associated risk factors and outcome.
        Transplantation. 1992; 54: 821-824
        • Kulik L.M.
        • Fisher R.A.
        • Rodrigo D.R.
        • et al.
        Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.
        Am J Transplant. 2012; 12: 2997-3007
        • Lucey M.R.
        • Terrault N.
        • Ojo L.
        • et al.
        Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
        Liver Transpl. 2013; 19: 3-26
        • Levitsky J.
        • Kaneku H.
        • Jie C.
        • et al.
        Donor-specific HLA antibodies in living vs. deceased donor liver transplant recipients.
        Am J Transplant. 2016; 16: 2437-2444
        • Alexander J.
        • Lord J.D.
        • Yeh M.M.
        • et al.
        Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.
        Liver Transpl. 2008; 14: 245-251
        • Curry M.P.
        • O'Leary J.G.
        • Bzowej N.
        • et al.
        Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.
        N Engl J Med. 2015; 373: 2618-2628
        • Kwo P.Y.
        • Mantry P.S.
        • Coakley E.
        • et al.
        An interferon-free antiviral regimen for HCV after liver transplantation.
        N Engl J Med. 2014; 371: 2375-2382
        • O'Leary J.G.
        • Demetris A.J.
        • Friedman L.S.
        • et al.
        The role of donor-specific HLA alloantibodies in liver transplantation.
        Am J Transplant. 2014; 14: 779-787
        • Garcia de la Garza R.
        • Sarobe P.
        • Merino J.
        • et al.
        Immune monitoring of immunosuppression withdrawal of liver transplant recipients.
        Transpl Immunol. 2015; 33: 110-116
        • Londono M.C.
        • Danger R.
        • Giral M.
        • et al.
        A need for biomarkers of operational tolerance in liver and kidney transplantation.
        Am J Transplant. 2012; 12: 1370-1377
        • Gillespie B.W.
        • Merion R.M.
        • Ortiz-Rios E.
        • et al.
        Database comparison of the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the SRTR U.S. Transplant Registry.
        Am J Transplant. 2010; 10: 1621-1633
        • Demetris A.J.
        • Seaberg E.C.
        • Batts K.P.
        • et al.
        Reliability and predictive value of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database nomenclature and grading system for cellular rejection of liver allografts.
        Hepatology. 1995; 21: 408-416