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Commentary

Immunosuppression for Liver Retransplantation: Babel Revisited

Peters, Anna L. MD, PhD1,2; Tremblay, Simon PharmD, PhD3,4; Alloway, Rita R. PharmD5; Woodle, E. Steve MD3

Author Information
doi: 10.1097/TP.0000000000003418
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Liver retransplantation (reLT) is thankfully a rare entity, making up ~5% of the annual adult liver transplants performed in the United States.1 However, no consensus exists on induction and maintenance immunosuppression regimens, which are fundamental to ensuring long-term allograft and recipient health, while minimizing consequences of overimmune suppression. As a result, immunosuppressive regimens vary widely between individual transplant centers, thereby limiting observations on the impact of individual immunosuppressive regimens on patient survival, graft survival, and other posttransplant outcomes including infections, development of metabolic syndrome, primary disease recurrence, and long-term kidney disease following reLT.2,3 An important confounding factor is the variations in frequency and management in early reLT (<90 d postinitial liver transplantation), which is usually due to primary nonfunction or surgical factors including hepatic artery thrombosis, whereas late reLT is often due to chronic rejection or disease recurrence.4,5 Therefore, patient factors/indication for retransplantation may influence use of immunosuppression protocols.

In this issue of Transplantation, Mezochow et al6 analyzed the current landscape of immunosuppression management pre- and postsecond liver transplant by performing a retrospective analysis of UNOS data. The objectives of the study were to determine patient and center factors associated with induction and maintenance immunosuppression and determine the effects of induction immunosuppression on 1-y mortality. The study included ~3500 reLT recipients from 2002 to 2018 representing 116 US transplant centers, with ~51% undergoing reLT at <90 d post iLT, 30% after 365 d, and the remainder undergoing reLT between 90 and 365 d post iLT. As one may expect, recurrent disease and rejection were more common indications for reLT at >365 d after iLT, and early reLT recipients were more likely to be on dialysis before reLT. In spite of this, 80% of reLT recipients received no induction, 13% received nondepleting induction (NDI: basiliximab, daclizumab), and 6.6% received lymphocyte depleting induction (DI: thymoglobulin, alemtuzumab, rituximab), induction use being more common in late reLT recipients. Interestingly, in-hospital mortality was significantly lower for reLT patients receiving either NDI (11.7%) or DI (12%) versus no induction (16.6%; P = 0.01). However, in multivariate analysis after adjusting for center and donor factors, there was no clear benefit of induction immunosuppression with respect to all-cause 1-y mortality. While induction is often used for either renal sparing, chronic rejection, or for reLT for autoimmune liver disease, no association was found in multivariate analysis between induction use and initial liver disease, cause of initial graft failure, creatinine at reLT, or dialysis use at reLT.

The limitations of the study were primarily those of the UNOS database itself, which precludes any evaluation of post-reLT outcomes aside from all-cause mortality and contains large amounts of missing data. Therefore, whether recipients of NDI or DI have increased post-reLT infections, chronic kidney disease, or post transplant lymphoproliferative disorder, or conversely have decreased rates of biopsy-proven acute rejection or late allograft loss remain important open questions. Furthermore, the study was limited because in 10% of reLT recipients, the primary reason for reLT was not listed in the UNOS database.

The study’s main conclusions highlight the striking degree of heterogeneity among centers regarding nearly every aspect of immunosuppression management over the first posttransplant year. Despite use of depleting induction in 20% of reLT recipients, there was no clear benefit of induction in all-cause mortality at 1 y. Perhaps, the most important takeaway from this study is a call to action. If centers collaborate and establish a shared approach to reLT, important associations between early IS choices and patient survival, graft survival, infection risk, disease recurrence, and off-target adverse effects of immunosuppression can be identified and mitigated. In addition, 5- and 10-y graft and patient survival outcomes were not assessed in this study, due to limiting the study to the current median end-stage liver disease era.6 Ultimately, Mezochow et al call us all to dream of a common language governing immunosuppression protocols in retransplantation: a language not based on center habits but on a more robust evidence base. Additional approaches such as examination of the European Liver Transplant Registry or establishing a working group of large transplant centers in the United States may provide greater clarity.

REFERENCES

1. Kitchens WH, Yeh H, Markmann JF. Hepatic retransplant: what have we learned? Clin Liver Dis. 2014;18:731–751.
2. Nazzal M, Lentine KL, Naik AS, et al. Center-driven and clinically driven variation in US liver transplant maintenance immunosuppression therapy: a national practice patterns analysis. Transplant Direct. 2018;4:e364.
3. Bittermann T, Hubbard RA, Lewis JD, et al. The use of induction therapy in liver transplantation is highly variable and is associated with posttransplant outcomes. Am J Transplant. 2019;19:3319–3327.
4. Uemura T, Randall HB, Sanchez EQ, et al. Liver retransplantation for primary nonfunction: analysis of a 20-year single-center experience. Liver Transpl. 2007;13:227–233.
5. Kashyap R, Jain A, Reyes J, et al. Causes of retransplantation after primary liver transplantation in 4000 consecutive patients: 2 to 19 years follow-up. Transplant Proc. 2001;33:1486–1487.
6. Mezochow AK, Abt PL, Bittermann T. Differences in early immunosuppressive therapy among liver retransplantation recipients in a national cohort. Transplantation. [Epub ahead of print. August 13, 2020]. doi: 10.1097/TP.0000000000003417.
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