Érika Bevilaqua Rangel

Tacrolimus in pancreas transplant: a focus on toxicity, diabetogenic effect and drug–drug interactions

Introduction: With further reduction in surgical complications and improvement in immunosuppressive protocols, pancreas transplant offers excellent outcomes for patients with diabetes. However, long-term survival of pancreas allograft is affected not only by rejection but also by immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of tacrolimus toxicity and focuses on its diabetogenic effect after pancreas transplant. Some clinically relevant drug–drug interactions with glucocorticoids and sirolimus are also highlighted. This review also summarizes the diabetogenic mechanisms of tacrolimus, the alternatives to minimize these effects, and the main differential diagnosis of hyperglycemia after pancreas transplant. Expert opinion: Tacrolimus is a potent calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus can induce β-cell apoptosis, decrease insulin exocytosis and reduce insulin gene transcription, which ultimately lead to impaired functional β-cell mass after pancreas transplant. Furthermore, insulin resistance can exacerbate the diabetogenic effect of tacrolimus due to inhibition of insulin gene transcription and β-cell proliferation. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Transplante de pâncreas e ilhotas em portadores de diabetes melito

Pancreas and kidney transplants have specific indications, benefits and risks. The procedure has become more common and more often as long-term success has improved and risks have decreased. Compared with a patient being on dialysis, simultaneous pancreas-kidney transplant offers a distinct advantage when it comes to mortality, quality of life and diabetic complications. Since there can be a living-donor kidney transplant,, a possibly similar patient and graft survival by 10 years follow-up, this procedure should be considered. Pancreas after kidney transplants, when successful, can improve microvascular complications compared with kidney transplant alone, but immediate mortality may be higher. Solitary pancreas transplantation can improve the quality of life in selected patients, but it may also increase the immediate risk of mortality due to the complexity of the surgery and the risks of immunosupression. The results of Islet transplantation differ from the higher metabolic performance achieved by whole pancreas allotransplantation and its applicability is limited to selected adult diabetic patients.

The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

Introduction: Pancreas-kidney transplant is an effective treatment for patients with insulin-dependent dabetes and chronic renal failure. Reduction in technical failure loss and early acute rejection rates contributed to prolong pancreas graft survival. However, drug toxicity affects negatively both short- and long-term follow-ups. Areas covered: This article reviews the existing literature and knowledge of the immunosuppressive drugs that are frequently used in pancreas transplant, including calcineurin inhibitors, sirolimus, corticosteroids, and mycophenolate. The article also discusses the short- and long-term adverse effects of these drugs. The article also reports and discusses the most relevant in vitro studies, providing additional information to in vivo findings. Some clinically relevant drug interactions with immunosuppressive drugs are also highlighted. Over- and underimmunosuppression effects will not be addressed. Expert opinion: Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Labile Plasma Iron Generation After Intravenous Iron is Time-dependent and Transitory in Patients Undergoing Chronic Hemodialysis

Iron supplementation in hemodialysis patients is fundamental to erythropoiesis, but may cause harmful effects. We measured oxidative stress using labile plasma iron (LPI) after parenteral iron replacement in chronic hemodialysis patients. Intravenous iron saccharate (100 mg) was administered in patients undergoing chronic hemodialysis (N = 20). LPI was measured by an oxidant‐sensitive fluorescent probe at the beginning of dialysis session (T0), at 10 min (T1), 20 min (T2), and 30 min (T3) after the infusion of iron and at the subsequent session; P < 0.05 was significant. The LPI values were significantly raised according to the time of administration and were transitory: −0.02 ± 0.20 µmol/L at the beginning of the first session, 0.01 ± 0.26 µmol/L at T0, 0.03 ± 0.23 µmol/L at T1, 0.09 ± 0.28 µmol/L at T2, 0.18 ± 0.52 µmol/L at T3, and −0.02 ± 0.16 µmol/L (P = 0.001 to 0.041) at the beginning of the second session. The LPI level in patients without iron supplementation was −0.06 ± 0.16 µmol/L. Correlations of LPI according to time were T1, T2, and T3 vs. serum iron (P = 0.01, P = 0.007, and P = 0.0025, respectively), and T2 and T3 vs. transferrin saturation (P = 0.001 and P = 0.0003, respectively). LPI generation after intravenous saccharate administration is time‐dependent and transitorily detected during hemodialysis. The LPI increment had a positive correlation to iron and transferrin saturation.

Analysis of reoperations and their impact on the results of pancreas transplantation.

BACKGROUND Many factors, including the advances in surgical techniques and immunosuppression, have been brought significant improvement to graft and patient survivals of patients undergoing pancreatic transplantations. However, one third of these patients require reoperations (ReOps). PURPOSE We sought to evaluate the distribution of ReOps in the early or late postoperative period and analyze their impact on patient and graft survivals. PATIENTS AND METHODS This unicenter, retrospective study was performed using data from 182 patient charts after pancreas transplantation from January 2000 through December 2007. RESULTS We performed 88 ReOps on 73 patients; 43 early and 41 late operations. The simultaneous pancreas-kidney transplantation group showed a greater incidence of premature ReOps. The group undergoing early ReOp showed a lower survival rate (87.2%) compared with the nonoperated group, but a similar survival rate (97.5%) to the late ReOp group. In relation to the survival of pancreatic grafts after 1 year, the early ReOp group showed inferior survival to the late ReOp group, both of which were significantly worse results then those of the group without ReOp. CONCLUSION ReOps were related to the success of the procedure. When they were performed in the first 3 months they had a negative impact on patient and graft survival.

mTOR inhibitors in pancreas transplant: adverse effects and drug-drug interactions

ABSTRACT Introduction: Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events. Expert opinion: Calcineurin inhibitor (CNI)-based regimens remain the mainstay treatment after pancreas-kidney transplant. However, long-term use of CNIs may be associated with nephrotoxicity. Switching from CNIs to mTORi (sirolimus/SRL and everolimus/EVR) may preserve kidney function, mainly EVR conversion. However, mTORi promote an imbalance of mTOR signaling during long-term follow-up and may ultimately contribute to proteinuria and hyperglycemia. These drugs disrupt autophagy, inhibit cell proliferation, and downregulate VEGF. Therefore, it is important to comprehend and interpret the experimental data. It is equally important to critically analyze clinical studies. Of importance, minimization of side effects, based on safe approaches, can prolong kidney allograft survival. Additional randomized-controlled studies are required to assess the impact of mTORi on pancreas allograft survival.

Impacto da função retardada do enxerto pancreático no transplante simultâneo pâncreas-rim

: A incidencia de funcao retardada do enxerto pancreatico foi 11%. A idade do receptor superior a 45 anos apresentou associacao com o risco de desenvolvimento de funcao retardada do enxerto pancreatico (Razao de chances 2,26; p < 0,05). Os pacientes com funcao retardada do enxerto pancreatico apresentaram maior incidencia de rejeicao aguda renal (47

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; 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; 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; 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-β: Transforming growth factor-β