sirolimus and Hyperuricemia

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.. 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.. 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.

Topics: Adrenal Cortex Hormones; Bone Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperkalemia; Hyperuricemia; Immunosuppressive Agents; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Pneumonia; Renal Insufficiency, Chronic; Sirolimus

Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy.. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, χ(2), and Fisher tests with the SPSS 18.0 statistical program.. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 ± 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75-41.16, P = .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45-416.17, P = .003) than those treated with tacrolimus.. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Cyclosporine; Female; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Young Adult

The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice. Similarly, the subcutaneous co-administration of nanoparticles with adalimumab resulted in the durable inhibition of ADAs, leading to normalized pharmacokinetics of the anti-TNFα antibody and protection against arthritis in TNFα transgenic mice. Adjunct therapy with tolerogenic nanoparticles represents a novel and broadly applicable approach to prevent the formation of ADAs against biologic therapies.

Topics: Adalimumab; Anaphylaxis; Animals; Arthritis, Experimental; Bone Resorption; Drug Delivery Systems; Female; Hyperuricemia; Immune Tolerance; Lactic Acid; Macaca fascicularis; Mice, Transgenic; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats, Sprague-Dawley; Sirolimus; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha; Vaccines, Synthetic

Gout is a chronic metabolic disease caused by disturbance of purine metabolism that leads to hyperuricemia. Hyperuricemia prevalence after renal transplant is reported as 19% to 84% in different studies. Tophaceous gout in renal transplant recipients is a consequence of increased hyperuricemia. Although tophus formation in skin and soft tissues is an indicator of chronic gout (also referred to as tophaceous gout), tophi may be the first sign of gout. In this study, we report a case of a 62-year-old male renal transplant recipient who had tophi as the first clinical sign of gout. After confirming gout diagnosis, cyclosporine was changed to sirolimus, and allopurinol was added to therapy to decrease uric acid levels. In conclusion, hyperuricemia is a common complication in renal transplant recipients. Presentation might be atypical, and diagnosis can be challenging.

Topics: Allopurinol; Cyclosporine; Drug Substitution; Gout; Gout Suppressants; Humans; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Risk Factors; Sirolimus; Skin; Treatment Outcome

Cardiovascular disease (CVD) accounts for 35% to 50% of deaths among renal transplant recipients. Beside the atherogenic risk factors related to hemodialysis, renal function, and use of immunosuppressive agents, other relevant risk factors for CVD include acute rejection episodes, microalbuminuria (muAlb), diabetes, arterial hypertension, lipid disorders, inflammatory triggers, hyperhomocysteinemia, anemia, erythrocytosis, obesity, and hyperuricemia. We studied the prevalence of risk factors and the impact of various drugs on CVD among 103 renal transplant recipients with measured glomerular filtration rates showing values >45 mL/min. We measured uric acid, triglycerides (TG), low-density lipoprotein (LDL)/high-density lipoprotein (HDL) LDL/HDL ratio, homocysteine (HOMO), insulin resistance, muAlb, C-reactive protein (CRP), and fibrinogen. Subsequently, patients were divided into 8 groups based on the immunosuppressive protocol to evaluate its impact on CVD risk factors. Insulin resistance and hyperhomocysteinemia were present in >2/3 of patients. Considering the impact of protocols, the combination of cyclosporine (CsA) + everolimus (EVL) resulted in the most favorable profile in terms of reduction of hyperuricemia, hyperlipidemia, and hyperhomocysteinemia. Insulin resistance tended to be more frequent among patients treated with protocols including calcineurin inhibitors (CNI) and steroids. The prevalence of hyperhomocyteinemia was similar among patients on CsA and on tacrolimus (Tac). Sirolimus (SRL) was associated with higher levels of HOMO. The combination of CNI and proliferative signal inhibitors (PSI) seemed to be the most promising one to reduce the impact of CVD risk factors. The reduction in CVD morbidity can improve expectancy and quality of life, as well as graft function and survival among renal transplant patients.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Glomerular Filtration Rate; Humans; Hyperhomocysteinemia; Hyperlipidemias; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Lipoproteins, HDL; Middle Aged; Risk Factors; Sirolimus; Tacrolimus; Transplant Recipients