Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial

Abstract

Earn MOC for this article: www.wileyhealthlearning.com/aasld.aspx Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.

Current Status of Glucocorticoid Usage in Solid Organ Transplantation

“…Patients were followed for two years. Biopsy proven acute cellular rejection was the same between the two groups (5% in each group), while PTDM (0% versus 15%) and infection rates (0% versus 30%) were significantly lower in the budesonide taking group [23] .…”

“…Recent studies indicate that some of the side effects of GCs on the heart, kidney, and adipose tissues may be due to the activation of MR by GCs [138][139][140][141] . Therefore, GCs with higher selectivity for GR over MR, such as dexamethasone and budesonide, may have less side effects in SOT patients [23,142] . Additionally, GCs' metabolic actions can be modulated by AMP-activated protein kinase (AMPK), a master regulator of energy metabolism.…”

Current status of glucocorticoid usage in solid organ transplantation

“…Recent studies indicate that some of the side effects of GCs on the liver, heart, kidney, and adipose tissues may be due to the activation of MR by GCs[ 138 - 141 ]. Therefore, GCs with higher selectivity for GR over MR, such as dexamethasone and budesonide, may have fewer side effects in SOT patients[ 23 , 142 ]. Additionally, GCs’ metabolic actions can be modulated by AMP-activated protein kinase (AMPK), a master regulator of energy metabolism.…”

“…Patients were followed for 2 years. Biopsy-proven acute cellular rejection was the same between the two groups (5% in each group), while post-transplant diabetes mellitus (PTDM) (0% vs 15%) and infection rates (0% vs 30%) were significantly lower in the budesonide-taking group[ 23 ].…”

Budesonide with Low-Dose 6-Mercaptopurine as a Possible New Treatment for IgG4-Related Sclerosing Cholangitis and Systemic IgG4-Related Disease: A Case Report

“…Budesonide is a synthetic steroid with potent immunosuppressive effects in the liver [38][39][40]. After oral administration, it undergoes high first-pass metabolism in the liver (90%).…”