Modifiable Variables Are Major Risk Factors for Posttransplant Diabetes Mellitus in a Time-Dependent Manner in Kidney Transplant: An Observational Cohort Study.

Modifiable and nonmodifiable risk factors for developing posttransplant diabetes mellitus (PTDM) have already been established in kidney transplant setting and impact adversely both patient and allograft survival. We analysed 450 recipients of living and deceased donor kidney transplants using current immunosuppressive regimen in the modern era and verified PTDM prevalence and risk factors over three-year posttransplant. Tacrolimus (85%), prednisone (100%), and mycophenolate (53%) were the main immunosuppressive regimen. Sixty-one recipients (13.5%) developed PTDM and remained in this condition throughout the study, whereas 74 (16.5%) recipients developed altered fasting glucose over time. Univariate analyses demonstrated that recipient age (46.2 ± 1.3vs. 40.7 ± 0.6 years old, OR 1.04; P = 0.001) and pretransplant hyperglycaemia and BMI ≥ 25 kg/m2 (32.8% vs. 21.6%, OR 0.54; P = 0.032 and 57.4% vs. 27.7%, OR 3.5; P < 0.0001, respectively) were the pretransplant variables associated with PTDM. Posttransplant transient hyperglycaemia (86.8%. 18.5%, OR 0.03; P = 0.0001), acute rejection (P = 0.021), calcium channel blockers (P = 0.014), TG/HDL (triglyceride/high-density lipoprotein cholesterol) ratio ≥ 3.5 at 1 year (P = 0.01) and at 3 years (P = 0.0001), and tacrolimus trough levels at months 1, 3, and 6 were equally predictors of PTDM. In multivariate analyses, pretransplant hyperglycaemia (P = 0.035), pretransplant BMI ≥ 25 kg/m2 (P = 0.0001), posttransplant transient hyperglycaemia (P = 0.0001), and TG/HDL ratio ≥ 3.5 at 3-year posttransplant (P = 0.003) were associated with PTDM diagnosis and maintenance over time. Early identification of risk factors associated with increased insulin resistance and decreased insulin secretion, such as pretransplant hyperglycaemia and overweight, posttransplant transient hyperglycaemia, tacrolimus trough levels, and TG/HDL ratio may be useful for risk stratification of patients to determine appropriate strategies to reduce PTDM.

Glucocorticoids use in kidney transplant setting.

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; Cmax: Mean maximal serum concentration; CNIs: Calcineurin inhibitors; COX-2: cyclo-oxygenase-2; cPLA2: cytosolic phospholipase A2; 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: HbA1c; HDL: High-density lipoproteins; HLA: Human leukocyte anrigen; HPA axis: Hypothalamic-pituitary-adrenal axis; HR: Hazard ratio; HSP: Heat shock proteins; 11ß-HSD: 11ß-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; Kd: 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-ß: Transforming growth factor-ß.