Minimization of steroids in liver transplantation

Abstract

Summary Because of the markedly improved short‐term results of liver transplantation (LT) and persistently high number of long‐term complications, the attention of transplant physicians should be focused on minimizing immunosuppressive therapy as much as possible. Steroid‐based immunosuppression is responsible for a substantial post‐LT morbidity and mortality, hence, minimization of its use is of utmost importance to improve the quality of life of the successfully transplanted liver recipient. This literature review shows that LT can be performed safely with steroid‐minimal immunosuppression without compromising graft and patient survival. The tendency in clinical practice is to move more and more from steroid withdrawal to steroid avoidance protocols.

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

“…4 These findings indicate that any minimization IS regimen should be void of this drug. 4,5,21,26,27 Unfortunately, almost all steroid sparing trials are based on a triple or even quadruple IS regimen, thereby eliminating the advantage of the minimization concept. 4,21,39,40 The same holds true for most CNI sparing trials, which aim to counteract early and late post-LT nephrotoxicity.…”

“…This diverse approach has been largely triggered by a multitude of multicentric studies, set up by the pharmaceutical industry, to minimize CNI and/or steroid toxicity. [3][4][5][6][7][8] The frequent insufficient sample size, heterogeneous trial design, lack of relevant RCTs, and most of all absence of well documented, long-term follow-up do not allow firm conclusions to be made in relation to which IS strategy to follow. Despite this, several messages can be taken to the clinical arena: (a) the superiority of CNIs as the mainstay of IS 3 ; (b) and of TAC in terms of overall and rejection-free survival rates 24 ; (c) inadequacy of CNI-free induction IS due to high ACR rates 23 ; (d) misleading of conclusions in most studies focusing on the superiority of several drug combinations in relation to steroid and CNI sparing as CNI dosing in the control arms is usually higher than advocated in the sparse, well-designed minimization RCTs 23,[25][26][27] ; (e) the necessity for individualized IS in HCV-infected and cancer patients [28][29][30] ; (f) interference of heavy IS with the active process of tolerance induction 21,22,31 ; and last but not least (g) the inability to make firm conclusions about the "optimal" lS regimen in absence of well-documented long-term pathologic follow-up.…”

“…1,2 All these different approaches have been triggered by a multitude of, mostly industry-driven, studies [3][4][5][6][7][8] and, most importantly, by the lack of well-documented long-term follow-up. [9][10][11][12] This is surprising if one takes into account the many important consequences of heavy IS such as the high incidence of allograft loss due to cardiovascular, infectious, and oncologic complications 13,14 ; the development of metabolic syndrome 15 and renal insufficiency 16,17 ; the reduced quality of life 18 ; and the immunoprivileged status of the liver.…”

Clinical Operational Tolerance After Renal Transplantation

“…5 This status is exemplified by a number of interesting observations after liver transplantation, including (1) the relative lack of an effect of either a positive cross-match or blood type incompatibility, the irrelevance of human leukocyte antigen (HLA) matching; (2) the reduced incidence of hyperacute rejection and spontaneous recovery after severe rejection; (3) the fact that acute rejection does not impact adversely on long-term graft and patient-survival outcomes; (4) the ability of liver allografts to protect other extrahepatic allografts from rejection if the latter are derived from the same donor; and (5) a lower overall incidence of chronic rejection that is reversible in up to 30% of cases. 6,7 To date, 168 cases of COT established after liver transplantation have been reported 5,8 out of a sample of 473 individuals in whom a weaning protocol was attempted. Notably, patients who developed acute rejection during the protocols designed to discontinue IS were not exposed to further risks of graft loss, once maintenance IS was resumed.…”

Tolerance in clinical transplantation: progress, challenge or just a dream?

“…A number of interesting observations could demonstrate that liver organs bear an inherent immunological privilege (IP) which renders them somewhat more capable of developing COT. Liver associated IP comprises (a) irrelevance of human leukocyte antigen (HLA) matching, (b) independency of a positive cross match or (c) blood type incompatibility, (d) spontaneous recovery after severe rejection crisis, (e) acute rejection itself does not impair long-term graft and patient outcome, (f) liver organs confer immune privilege to other extrahepatic allografts co-transplanted from the same donor and (g) incidence of chronic rejection episodes are lower and reversible (in up to 30%) in comparison to other solid allografts [2,3]. To date, out of a sample of 473 individuals who underwent a weaning protocol following liver transplantation (LTx), 168 cases of COT have been documented.…”