A comprehensive update of the metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

ABSTRACT

Introduction

Despite significant advancements in immunosuppressive regimens and surgical techniques, the prevalence of adverse events related to immunosuppression remains a major challenge affecting the long-term survival rates of pancreas and kidney allografts

Areas covered

This article presents a comprehensive review of the literature and knowledge (Jan/2012-Feb/2023) concerning glucose metabolism disorders and nephrotoxicity associated with tacrolimus and mammalian target of rapamycin inhibitors (mTORi). Novel signaling pathways potentially implicated in these adverse events are discussed. Furthermore, we extensively examine the findings from clinical trials evaluating the efficacy and safety of tacrolimus, mTORi, and steroid minimization.

Expert Opinion

Tacrolimus-based regimens continue to be the standard treatment following pancreas transplants. However, prolonged use of tacrolimus and mTORi may lead to hyperglycemia and nephrotoxicity. Understanding and interpreting experimental data, particularly concerning novel signaling pathways beyond calcineurin-NFAT and mTOR pathways, can offer valuable insights for therapeutic interventions to mitigate hyperglycemia and nephrotoxicity. Additionally, critically analyzing clinical trial results can identify opportunities for personalized safety-based approaches to minimize side effects. It is imperative to conduct randomized-controlled studies to assess the impact of mTORi use and steroid-free protocols on pancreatic allograft survival. Such studies will aid in tailoring treatment strategies for improved transplant outcomes.

KEYWORDS:

• Pancreas transplant
• post-transplant diabetes mellitus
• nephrotoxicity
• tacrolimus
• mammalian target of rapamycin inhibitors
• adverse events
• signaling pathways
• steroids

Article highlights

• Patient, pancreas, and kidney allograft survival rates encourage the transplant choice for patients with insulin-dependent diabetes mellitus and chronic kidney disease

• The immunosuppressive regimen in pancreas transplant is mainly based on induction with T-lymphocyte depletion antibodies and maintenance with tacrolimus, steroids, and mycophenolate

• Tacrolimus and mTOR inhibitors-induced hyperglycemia is associated with dysregulation of biologic processes, including oxidative stress, autophagy, and apoptosis

• Tacrolimus and mTOR-induced nephrotoxicity is associated with an imbalance of anti-oxidants and oxidants, mitochondria dysfunction, induction of apoptosis, dysregulation of autophagy, and an increase in inflammation, senescence, and fibrosis

• In the pancreas, tacrolimus and mTOR-induced adverse events are associated with dysregulation of calcineurin/NFAT, mTOR, IRIS-PI3K-Akt, TGF-ß/BMP/Smad, and transcription factors (PDX-1, MafA, Neuro D, and FOXO1) signaling pathways

• In the kidney, tacrolimus and mTOR-induced adverse events are associated with dysregulation of calcineurin/NFAT, mTOR, IRIS-PI3K-Akt, TGF-ß/BMP/Smad, klotho, and TRPC6/NFAT signaling pathways

• Insulin resistance due to obesity/metabolic syndrome and glucocorticoid use may potentiate tacrolimus and mTOR-induced adverse events in the pancreas and kidney allografts

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.