Glucocorticoids use in kidney transplant setting

ABSTRACT

Introduction: Despite major advances in kidney transplant, glucocorticoids (GCs) or steroids remain one of the mainstay treatments. They possess adverse events (AEs) that are related to cumulative dosage, as documented in experimental and clinical studies. Therefore, it is important to comprehend and interpret experimental data and equally important to critically review clinical studies.

Areas covered: This article provides a broad overview of the structure, pharmacokinetics, and pharmacodynamics of systemically administered GCs in transplant setting. It further discusses at length the results of in vitro and pre-clinical studies, as well as steroid avoidance (SA) or withdrawal (SW)-based clinical studies. We summarized the main AEs and discussed the alternatives to minimize these events. Some clinically relevant drug-drug interactions are also highlighted.

Expert opinion: Although SA/SW in kidney transplant is a desirable strategy due to its AEs, there is no evidence to support that strategy based on the available data, despite some encouraging reports. Furthermore, early diagnosis and treatment of GC-induced AEs seem to be the most efficacious strategies. Likewise, some risks factors predate transplant and could be used to risk-stratify patients to determine appropriate risk-reduction strategies. Additional randomized-controlled studies are required to assess the impact of SA/SW during short and long follow-ups.

Abbreviations: ACTH: Adrenocorticotropic hormone (also adrenocorticotropin and corticotropin); ADA: American Diabetes Association; AEs: Adverse events; ADX: Adrenalectomized; AR: Acute rejection; AUC: Area under the curve; BMI: Body mass index; BMD: Bone mineral density; BPAR: Biopsy-proven acute rejection; cAMP: cyclic adenosine monophospahte; CBG: Corticosteroid-binding globulin; CBP: CREB binding protein; C_max: Mean maximal serum concentration; CNIs: Calcineurin inhibitors; COX-2: cyclo-oxygenase-2; cPLA₂: cytosolic phospholipase A_2; CSA: Cyclosporine; CYP: Cytochrome; DEX: Dexamethasone; DM: Diabetes mellitus; ESW: Early steroid withdrawal; GCs: Glucocorticoids; GRs: Glucocorticoid receptors; GREs: Glucocorticoid receptor elements; CSA: Cyclosporine; DEX: Dexamethasone; Glycated hemoglobin: HbA_1c; HDL: High-density lipoproteins; HLA: Human leukocyte anrigen; HPA axis: Hypothalamic-pituitary-adrenal axis; HR: Hazard ratio; HSP: Heat shock proteins; 11β-HSD: 11β-Hydroxysteroid dehydrogenase; IC₅₀: Half of maximal inhibitory concentration; IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance; imTOR: Inhibitors of mammalian target of rapamycin; iNOS: Inducible oxide nitric synthase; K_d: Dissociation constant; KDIGO: Kidney Disease: Improving Global Outcomes; LSW: Late steroid withdrawal; LDL: Low-density lipoproteins; MCP-1: Monocyte chemoattractant protein-1; MMF: Mycophenolate mofetil; MPS: Mycophenolate sodium; NSAIDS: non-steroidal anti- inflammatory drugs; NF-κB: Nnuclear factor-κB TNF; OPTN/UNOS: Organ Procurement and Transplant Network/United Network of Organ Sharing database; PK/PD: Pharmacokinetic/pharmacodynamics; PRA: Panel reactive antibodies; PTDM: Post-transplantation diabetes mellitus; PTH: Parathyroid hormone; RCT: Randomized controlled trial; RR: Risk ratio; SA: Steroid avoidanceSGLT-2: Sodium-glucose co-transporter 2; SW: Steroid withdrawal; TAC: Tacrolimus or FK506; TG/HDL: Triglyceride to high-density lipoprotein ratio; TNF-α: Tumor necrosis factor-α; TGF-β: Transforming growth factor-β

KEYWORDS:

• Glucocorticoids
• kidney transplant
• pharmacokinetics
• adverse events

Article highlights

• GCs form the backbone of many diseases and are used therapeutically to suppress inflammatory and immune responses in kidney transplant setting.

• GCs are lipophilic molecules and therefore can easily pass through membranes. The genomic mechanisms of action of GCs occurs through GC receptors (GRs).

• GCs induce increase gluconeogenesis in the liver and in the kidneys, net muscle protein breakdown to provide gluconeogenic substrates, insulin resistance of peripheral tissues including skeletal muscle, and promote lipid mobilization.

• GCs are associated to increased risk of PTDM, osteopenia/osteoporosis/fractures, cardiovascular events, and cataracts.

• While it is appreciate that GCs or steroids exhibit a key role in immunosuppressive regimen of kidney transplant, the roles of SA or ESW/LSW in that setting remain controversial.

• Early diagnosis and treatment of GC-induced AEs seem to be the most efficacious strategies. Likewise, some risks factors predate transplant and could be used to risk-stratify patients to determine appropriate risk-reduction strategies.

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.