Characteristics of recipients with complete immunosuppressant withdrawal after adult liver transplantation

Characteristics of recipients with complete immunosuppressant withdrawal after adult liver transplantation

To the Editor:

Liver transplantation (LT) is an effective therapeutic method for end-stage liver diseases. Although rejection is commonly mild or moderate in LT compared with other solid organs transplantation, it is still requiring a life-long immunosuppressive therapy. Meanwhile, LT is less sensitive to rejection than other organs transplantation due to liver immune privilege which even allows the success of LT with positive across mismatches of blood group and complete major histocompatibility complex.[1,2]During the early period of transplantation, clinical operational tolerance (COT) could be achieved on account of the genetic identity between recipient and donor.[3]Over the last decades, there is solid evident supporting that approximately 20% of LT recipients could develop COT, def i ned as maintaining normal graft function beyond one year completely without administering any immunosuppressive drugs.[4]Completely withdrawal of immunosuppressive agents (ISA) extinguished the ISA related adverse effects and improved the post-transplant survival time.[5]

Hepatocellular carcinoma (HCC) and HBV-related cirrhosis are responsible for the main courses of LT in China which is different from Western countries where the HCV and non-alcoholic fatty liver disease are the main courses of end-stage liver diseases. The immune response induced by HCV promoted the development of COT after LT,[6]but the effect of immune response induced by HBV on COT is unclear now. In addition, the post-LT immunosuppressant mainly consists of tacrolimus and mycophenolate mofetil in China. The ethnic background of patients signif i cantly affected pharmacokinetics of tacrolimus. Compared with the traditional donation after brain death (DBD) in Western countries, donation after circulatory death (DCD) was popular in China. DCD LT undoubtedly prolongs the cold and warm ischemic time, but does not promote acute and chronic cell rejection.[7]Therefore, the different population between Eastern and Western countries make a deep inf l uence on COT induction or immunosuppressant withdrawal and it is still ambiguous whether the type of LT and the ethnic characteristics inf l uence the development of COT after LT. Herein, we reported cases of complete immunosuppression withdrawal from a single-center after LT to demonstrate that COT could be achieved in LT for end-stage liver diseases caused by HBV with different post-LT immunosuppressive protocols.

We observed adult recipients (aged ＞18 years) who underwent LT between March 2003 and December 2012. We investigated the characteristics of recipients among this population who achieved complete cease of the immunosuppressive therapy after LT. COT recipients are def i ned as those with normally preserved graft function in the absence of immunosuppression for at least 1 year. The clinical and biochemical follow-ups were performed every 2 months, and continued until October 2016 since one year after ceasing the immunosuppressive therapy.

Eighteen (4.4%) tolerant recipients were identif i ed among the study population. All underwent LT due to chronic HBV-related liver diseases including HCC without rejection history and histological or liver biochemistry function abnormalities prior to withdrawal. Among these, 3 cases suffered from HCC within Hangzhou criteria. The other patients developed HBV-related cirrhosis with decompensated liver function and fulminant liver failure. They received living donor liver transplantation (LDLT) or DCD. The mean age was 45.6 years (range 19-66), and the mean time from LT to immunosuppressant withdrawal was 97.9 months (range 55.3-162.6). The immunosuppression protocols following LT included tacrolimus monotherapy and double therapy combined with mycophenolate mofetil. Hepatitis B immunoglobulin and nucleos(t)ide analogs were used to prevent the recurrence of HBV after LT. Recipient characteristics including baseline demographics, donor information, immunologic data, and time from transplant to absence of immunosuppression are described in Tables 1 and 2.

Table 1. The characteristics of 18 recipients

Table 2. The information of each recipient

In 10 patients, the use of immunosuppressive drugs was gradually reduced owing to noncompliance. Seven recipients actually withdrew the ISA because of the severe adverse effects. One patient abandoned immunosuppressive medication because of HCC recurrence. There was no case of physician-directed elective or intentional withdrawal. The characteristics common to all tolerant recipients included lower model for end-stage liver disease score (mean 22.9; range 19-26), male gender, longer time from transplant to absence of immunosuppression, lower maintaining tacrolimus levels (＜3 ng/mL), no incidence of acute cellular rejection.

The patients were followed closely and graft function was monitored using biochemical tests, ultrasonography every 3 months for 2 years, and liver puncture biopsy was performed every 6 months thereafter. Eighteen recipients did not develop a rejection episode after ceasing the immunosuppression drug with normal liver function and median follow-up time was 40.3 months. No recipients died during the period of this study.

Herein, we reported 18 cases with COT after LT from one center in China to demonstrate that COT also could develop from DCD LT and ethnic background of Asian. The data from Orlando et al[4]presented that 100 LT recipients out of 461 have successfully weaned ISA with a success rate of 22%. Benítez and co-workers[7]performed a prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Out of the 98 recipients, 57 experienced rejection and 41 successfully weaned immunosuppressive drugs. Although the selection of recipients signif i cantly increased the rate of successful withdrawal of immunosuppression,[4,8,9]the accurate prediction of ISA withdrawal candidates is still not practical by now. In fact, the results of studies still remain controversy on how to predict operational tolerance in LT patients. Benítez et al[7]revealed that the signif i cant factors promoting ISA withdrawal are male gender, longer time since LT and older LT age. de la Garza and coworkers[10]revealed that the time from transplantation and the phytohemagglutinin stimulation index are the two simple basal variables which are helpful to identify ISA withdrawal recipients. A general belief is that the recipients with the longer time from LT possessed lower risk and higher successful rate in ISA withdrawal. In this study, we observed similar results that male gender and longer time from LT to ceasing immunosuppression were common characteristics in 18 recipients. Furthermore, we also found the maintenance of lower tacrolimus levels contributed to the achievement of COT, which was consistent with the previous report.[11]

Lei Geng, Jun-Jie Huang, Bing-Yi Lin, Tian-Chi Chen, Tian Shen and Shu-Sen Zheng

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Aff i liated Hospital, Zhejiang UniversitySchool of Medicine, Hangzhou 310003, China (Geng L, Lin BY, Shen T and Zheng SS); Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China (Geng L, Huang JJ, Lin BY, Chen TC, Shen T and Zheng SS)

Contributors: GL and ZSS proposed and designed this study. HJJ and ST acquired the data. LBY and CTC collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantor.

Funding: This work was supported by grants from National Natural Science Foundation of China (81373160), Major Program of National Natural Science Foundation of China (91542205) and Zhejiang Provincial Natural Science Foundation of China (LQ15H030003).

Ethical approval: This study was approved by the Ethics Committee of The First Aff i liated Hospital, Zhejiang University school of medicine.

Competing interest: No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Published online July 17, 2017.

Shu-Sen Zheng

(Email: shusenzheng@zju.edu.cn)

10.1016/S1499-3872(17)60043-2)