mycophenolic-acid and Cardiovascular-Diseases

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Autoantibodies; Azathioprine; Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Disease Management; Female; Glucocorticoids; Heart Valve Diseases; Humans; Hydroxychloroquine; Hypertension, Pulmonary; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Lupus Vasculitis, Central Nervous System; Macrophage Activation Syndrome; Methotrexate; Mycophenolic Acid; Myocarditis; Outcome Assessment, Health Care; Pericarditis; Phenotype; Pregnancy; Pregnancy Complications; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Recurrence; Rituximab; Severity of Illness Index; Survival Rate; Uterine Cervical Neoplasms

The treatment of SLE remains complex, and management is constrained by a lack of safe, effective, targeted therapies. Physicians, also, are constrained by a lack of evidence-based approaches with existing agents, including glucocorticoids, utilized in the majority of patients. While Cushingoid side effects of glucocorticoids are widely recognized, emerging literature now suggests that glucocorticoid use actually contributes to harmful outcomes in SLE, over and above these effects. These studies provide a compelling case for a re-evaluation of the long-term use of glucocorticoids in SLE, focusing on minimizing glucocorticoid exposure as part of the strategy to improve long-term outcomes. In this article, we review the evidence for the harmful effects of glucocorticoids in SLE, and propose therapeutic options that reduce reliance on glucocorticoids. We propose that it is time for the lupus community to have a louder conversation about glucocorticoid use, and for any residual complacency about their risk-benefit ratio to be banished.

Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Azathioprine; Cardiovascular Diseases; Cataract; Cushing Syndrome; Diabetes Mellitus; Disease Progression; Evidence-Based Medicine; Glucocorticoids; Humans; Hydroxychloroquine; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Osteonecrosis; Osteoporotic Fractures

Many studies have identified cardiovascular risk factors in patients with psoriasis. Some psoriasis therapies may increase cardiovascular disease (CVD) and others may decrease CVD.. We reviewed the literature to define the impact of common psoriasis therapies on cardiovascular measures and outcomes.. Phototherapy has no major cardiovascular impact and may reduce levels of proinflammatory cytokines. Acitretin increases serum lipids and triglycerides, but has not been shown to increase cardiovascular risk. Cyclosporine A increases blood pressure, serum triglycerides, and total cholesterol. Methotrexate is associated with a decreased risk of CVD morbidity and mortality. Among the biologics, data for tumor necrosis factor inhibitors suggest an overall reduction in cardiovascular events. Most data on short-term ustekinumab use suggest no effect on major adverse cardiovascular events, however some authorities remain concerned. Nevertheless, ustekinumab use over a 4-year period shows a decrease in major adverse cardiovascular events when compared both with the general US population and with psoriatics in Great Britain.. Most studies lack the power and randomization of large clinical trials and long-term follow-up periods. In addition, the increased risk of CVD associated with psoriasis itself is a confounding factor.. Some therapies for moderate to severe psoriasis, including methotrexate and tumor necrosis factor inhibitors, may reduce cardiovascular events in psoriatic patients. Ustekinumab appears to be neutral but there may be a long-term benefit. Appropriate patient counseling and selection and clinical follow-up are necessary to maximize safety with these agents. Further long-term study is necessary to quantify the benefits and risks associated with biologic therapies.

Topics: Acitretin; Antibodies, Monoclonal, Humanized; Biological Therapy; Cardiovascular Diseases; Cyclosporine; Humans; Immunosuppressive Agents; Keratolytic Agents; Methotrexate; Mycophenolic Acid; Psoriasis; PUVA Therapy; Tumor Necrosis Factor-alpha; Ustekinumab

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

The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.

Topics: Animals; Antioxidants; Blood Vessels; Calcineurin Inhibitors; Cardiovascular Diseases; Cardiovascular System; Cyclosporine; Endothelial Cells; Heart Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; NADPH Oxidases; Oxidative Stress; rac1 GTP-Binding Protein; Reactive Oxygen Species; Tacrolimus

The toxicity of standard triple-therapy immunosuppressive regimens has been identified as a possible factor in the failure to extend long-term renal allograft survival despite a continued decline of acute rejection rates. The result has been increasing focus on the use of mycophenolate mofetil-based, low-toxicity immunosuppressive regimens, which have been shown in randomized studies to have the potential to improve long-term graft survival. This Clinical Update discusses the likely risks and benefits for switching the immunosuppressive regimen in clinical practice.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cardiovascular Diseases; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Risk Assessment; Risk Factors; Treatment Outcome

Cardiovascular risk factors after kidney transplantation are enhanced as a result of the chronic use of immunosuppressants. Tacrolimus with mycophenolate mofetil has become the most commonly used combination after kidney transplantation. Cardiovascular risk factors that are related to the use of this combined therapy have been analyzed in various clinical trials in comparison with other immunosuppressive therapies. This review summarizes the main results of these studies regarding arterial hypertension, lipid profile, posttransplantation diabetes, renal function, and even acute rejection rate. The aim is to characterize the cardiovascular risk profile of tacrolimus and mycophenolate mofetil association when compared with older and newer immunosuppressive associations.

Topics: Cardiovascular Diseases; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Risk Factors; Tacrolimus

Over the last two decades there has been a significant increase in the number and types of immunosuppressive agents that have been available to clinicians. The protocols for immunosuppression used in liver transplantation have been derived historically from those in renal transplantation. During the last decade there has been a shift in the use of immunosuppression, with the introduction of interleukin (IL)-2 receptor antagonists in place of anti-lymphocyte preparations, substitution of tacrolimus for cyclosporin and mycophenolate for azathioprine. The use of corticosteroids has been reduced. For a variety of reasons, these changes have not always been made on the basis of properly randomized studies. The place of newer agents, such as sirolimus and leflunomide derivatives and of the microbiological agents, is unclear. In this review, we outline briefly the mechanism of action of drugs and suggest possible approaches to the management of the liver allograft recipient, suggesting how treatment could be adjusted according to the indication for transplantation as well as the individual's comorbidities.

Topics: Adrenal Cortex Hormones; Algorithms; Antibodies, Monoclonal; Azathioprine; Calcineurin Inhibitors; Cardiovascular Diseases; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Sirolimus

The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Steroids; Tacrolimus; Young Adult

Cyclosporine and tacrolimus (TAC) are the most potent immunosuppressants. TAC is considered less nephrotoxic, but may be an important factor in chronic graft dysfunction. The aim of the study was to evaluate kidney function and cardiovascular risk profile in 2 groups of low immunological risk kidney allograft recipients receiving 2 TAC dosages.. Patients were randomly assigned to 2 TAC-based treatments (group I [n = 14], standard dose; group II [n = 15], reduced dose). Patient and graft survival, graft function, occurrence of cardiovascular events (cardiac death, myocardial infarction, stroke), incidence of new-onset diabetes mellitus after transplantation, and cardiovascular risk factors were assessed over a 5-year period.. Patient demographics and transplant characteristics were not statistically different between groups. TAC trough levels were significantly higher in group I for 24 months post transplant. Patient survival did not differ, but there were more acute rejection episodes and graft losses in group II. There were no significant differences in the rate of cardiac events. Graft function measured as serum creatinine levels and calculated glomerular filtration rate did not differ between groups. The same applies to new-onset diabetes mellitus after transplantation incidence. Office blood pressures were numerically higher in group I up to 24 months but this difference did not reach significance at any time. Similar results were obtained for serum lipids.. Immunosuppression based on low doses of tacrolimus seems to be safe in the group of low immunological risk patients but in the 60-month follow-up does not offer any clear benefits in terms of potential nephrotoxicity or cardiovascular risk.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Risk Factors; Tacrolimus; Treatment Outcome; Young Adult

Available data on the role of renin-angiotensin system blockade in renal transplantation are inconclusive. Herein, we report the long-term results of a randomized controlled trial planned to evaluate the impact of angiotensin-converting enzyme inhibitors (ACE-i) on the cardiovascular outcome of renal transplant recipients (RTRs) receiving calcineurin inhibitors, steroids, and mycophenolate mofetil.. Thirty-six RTRs were allocated to receive ACE-i and 34 served as controls. Survival free of a composite endpoint consisting of death, major cardiovascular events, renal graft loss or creatinine doubling, and survival free of each single endpoint were analyzed in both groups according to a modified intention-to-treat analysis.. During a 10-year follow-up, three patients died (one in the ACE-i group and two controls) and three lost their graft (two receiving ACE-i and one control). Three major cardiovascular events were observed in the ACE-i group and 12 among controls (P=0.008). At the end of observation, a significant increase in urinary protein excretion rate was only observed in controls (P=0.017).Compared with controls, RTRs administered ACE-i had significantly better survival free of the combined endpoint (P=0.0102, log-rank test) and free of major cardiovascular events (P=0.0027) without significant differences in renal outcome. By Cox regression analysis, ACE-i therapy resulted in the most powerful predictor of survival free of composite endpoint (hazard ratio, 0.165; 95% confidence interval, 0.053-0.512; P=0.0018) and survival free of major cardiovascular events (hazard ratio, 0.209; 95% confidence interval, 0.068-0.636; P=0.0059).. Prolonged therapy with ACE-i was associated with better general and cardiovascular outcome of RTRs without detrimental effects on renal graft function.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Calcineurin Inhibitors; Cardiovascular Diseases; Cohort Studies; Creatinine; Disease-Free Survival; Female; Follow-Up Studies; Graft Survival; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Treatment Outcome

The best immunosuppressive regimen in benefit-risk ratio in renal transplantation is debated. Nowadays, tacrolimus (Tac) and mycophenolate mofetil (MMF) are considered more efficient than cyclosporine A (CsA) and MMF, but recent studies have challenged this assumption.. We conducted a monocentric, prospective, open-labeled, randomized, and controlled trial comparing CsA/azathioprine (Aza) versus Tac/MMF in 289 kidney transplant recipients treated with antithymocyte globulins and prednisone. Primary outcome was the number of patients with clinically suspected acute rejection at 1 year. Secondary outcomes were the number of patients with biopsy-proven acute rejection (BPAR), estimated glomerular filtration rate (eGFR), patient and graft survivals, and adverse events at 1 and 3 years.. During the first year, 21 patients had clinically suspected acute rejection with CsA/Aza (14.4%) vs. 11 (7.7%) with Tac/MMF (P=0.07). BPAR, including borderline, was more frequent in the CsA/Aza group (14.4%) than in the Tac/MMF group (5.6%; P=0.013). At 1 year, patient and graft survivals were not different, and eGFR was 48±1 in the CsA/Aza group and 53±1 mL/min/1.73 m in the Tac/MMF group (P=0.007). There was no significant difference in diabetes after transplantation (16.8% and 18.8%, respectively).. With antithymocyte globulins and steroids, clinically suspected acute rejections did not differ between CsA/Aza and Tac/MMF arms. Analysis of secondary endpoints showed a lower rate of BPAR, including border line, and a higher eGFR in the Tac/MMF group. CsA/Aza allowed a low acute rejection rate, but Tac/MMF seemed as a better regimen regarding severe secondary outcomes.

Topics: Adult; Antilymphocyte Serum; Azathioprine; Cardiovascular Diseases; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Risk Assessment; Risk Factors; Steroids; Tacrolimus

Cardiovascular diseases (CVD) are the leading cause of mortality in renal transplant recipients. Various traditional and unconventional cardiovascular risk factors are potentiated by the adverse effects of immunosuppressive drugs. The mammalian target of rapamycin (mTOR) inhibitors have shown cardioprotective effects in experimental studies, but their influence on CVD in renal transplantation is unclear. The study included 115 kidney transplant recipients treated with mTOR inhibitors with steroids. A group of 38 patients received additionally small doses of calcineurin inhibitor. The control group consisted of 58 kidney transplant recipients randomly chosen among the population of patients transplanted at the same time, who received a calcineurin inhibitor, mycophenolate mofetil or sodium plus steroids. No differences in age, gender, duration of pretransplantat dialysis, time after transplantation, body mass index or glycated hemoglobin existed between the groups. Blood pressure and number of antihypertensive agents, high-density lipoprotein cholesterol, and uric acid levels were similar. The prevalence of diabetic, ischemic, or hypertensive nephropathy as the reason for end-stage renal disease was similar (P=.08). The study group showed higher mean values of total cholesterol (249 vs 204.6 mg/dL; P<.0001) and low-density lipoprotein 136.5 vs 117.7 mg/dL; (P=.015), as well as median values of triglycerides (202 vs 142 mg/dL; P<.0001) and proteinuria (P=.0002). mean estimated glomerular filtration rate was lower in the study group (42.9 vs 51.9 mL/min; P=.0003). Posttransplant diabetes appeared in 38% of the study group compared to 20% of the controls (P=.08). The incidence of coronary artery disease was higher among patients treated with mTOR inhibitors (P=.04). CVD, defined as myocardial infarction, percutaneous coronary intervention, stroke, aortic aneurysm, pulmonary thromboembolism, sudden cardiac death appeared in 26 study group compared with four control patients (P=.24). The risk of any CVD was not significantly higher among patients receiving mTOR inhibitors hazard ratio 1.94; 95% confidence interval 0.83-4.52). In conclusion, no correlation was observed between the duration of mTOR therapy and CVD.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Steroids; TOR Serine-Threonine Kinases

Long-term corticosteroid treatment impairs growth and increases cardiovascular risk factors. Hence, steroid withdrawal constitutes a major topic in paediatric renal transplantation and maintenance immunosuppression.. The lack of data from randomised controlled trials caused us to conduct the first prospective, randomised, multicentre study on late steroid withdrawal among paediatric kidney allograft recipients treated with standard-dose cyclosporine microemulsion (CsA) and mycophenolate mofetil (MMF) for 2 years. Forty-two low- or regular-immunologic risk patients were randomly assigned, >or=1 year post-transplant, to continue taking or to withdraw steroids over 3 months.. Two years after steroid withdrawal, they showed a longitudinal growth superior to controls [mean height standard deviation score (SDS) gain, 0.6 +/- 0.1 SDS versus -0.2 +/- 0.1 SDS (P < 0.001)]. The prevalence of the metabolic syndrome declined significantly (P < 0.05), 2 years after steroid withdrawal, from 39% (9/23) to 6% (1/16). Steroid-free patients had less frequent arterial hypertension (50% versus 93% (P < 0.05)) and required fewer antihypertensive drugs [0.6 +/- 0.2 versus 1.5 +/- 0.3 (P < 0.05 versus control)]. Additionally, they had a significantly improved carbohydrate and lipid metabolism with fewer hypercholesterolaemia and hypertriglyceridaemia (P < 0.05 versus control). Patient and graft survival amounted to 100%. Allograft function remained stable 2 years after steroid withdrawal. The incidence of acute rejections was similar in the steroid-withdrawal group (1/23, 4%) and controls (2/19, 11%).. Late steroid withdrawal in selected CsA- and MMF-treated paediatric kidney transplant recipients improves growth, mitigates cardiovascular risk factors and reduces the prevalence of the metabolic syndrome, at no increased risk of acute rejection or unstable graft function.

Topics: Adolescent; Cardiovascular Diseases; Child; Cyclosporine; Female; Glucocorticoids; Growth; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Risk Factors; Time Factors

Endothelial dysfunction occurs in hemodialysis and kidney-transplanted patients and can be enhanced by immunosuppressive therapy. Circulating endothelial cells (CEC), endothelial microparticles (EMP) and sVCAM-1 provide information on endothelium activation and damage. We compared the impact of two immunosuppressive regimens (CsA/Aza vs. Tac/MMF) on the kinetics of CEC, EMP and sVCAM-1 levels in 52 patients, both before graft and 3, 6, 9 and 12 months after graft, in reference to 50 healthy controls. CEC, EMP and sVCAM-1 levels were significantly decreased 1 year after transplantation (M12) as compared to pretransplant values. At M12, CEC and sVCAM-1 levels were significantly higher than those of controls whereas EMP reached normal values. Nine months postgraft, lower CEC and normalized EMP levels were found in patients receiving cyclosporine microemulsion/ azathioprine (CsA/Aza) when compared to patients treated with tacrolimus/ mycophenolate mofetil (Tac/MMF). Multivariate analysis evidenced positive correlations between CEC and history of cardiovascular diseases and between EMP and cytomegalovirus infection at M12. In conclusion, our combined analysis of endothelial injury markers confirms the favorable impact of renal transplantation on endothelium, and show that CEC levels discriminate treatment-associated endothelial toxicity. These results enlighten the potential of these noninvasive blood biomarkers in indexing vascular injury and optimize therapeutic options.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Cohort Studies; Endothelium, Vascular; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Vascular Cell Adhesion Molecule-1

Calcineurin inhibitor (CNI)-related nephrotoxicity significantly contributes to chronic renal failure after liver transplantation.. In this prospective study, liver transplantation patients with renal dysfunction were randomized either to receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI-trough levels (MMF group), or to continue their maintenance CNI dose (control group). Immune monitoring was performed in a subgroup of the patients.. In the MMF group (n = 50), renal function assessed by serum creatinine improved >10% in 62% of patients, was stable in 36% and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (+/- s.d.) significantly decreased from 1.90 +/- 0.44 mg/dL to 1.61 +/- 0.39 mg/dL and the corresponding calculated glomerular filtration rate significantly increased from 38.8 +/- 9.6 mL/min/1.73 m(2) to 47.0 +/- 11.8 mL/min/1.73 m(2) over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased. In the control group (n = 25), there were no significant changes with respect to the investigated parameters. The MMF group had significantly lower numbers of circulating cytotoxic T cells compared with the controls; whereas regulatory T cells significantly increased.. Combined MMF and minimal dose CNI therapy after liver transplantation is nephroprotective and may promote allograft tolerance.

Topics: Adult; Aged; Calcineurin Inhibitors; Cardiovascular Diseases; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors

The challenge in renal transplantation is to improve long-term patient and graft survival without increasing early acute rejection by minimizing immunosuppression.. This multicenter, observational study investigated the effects of withdrawal of steroids or mycophenolate mofetil (MMF) from a tacrolimus-based triple regimen (tac/MMF/steroids) 3 months posttransplant at 3 years; no additional interventions or assessments were undertaken. Adult patients, included in the intent-to-treat population of the THOMAS study, participated. Patient and graft survival, adverse events, rejection episodes, and immunosuppressive and concomitant medications were assessed.. Data at Year 3 was available for 718 patients (triple therapy, n=237; steroid stop, n=235; MMF stop, n=246). The original randomized regimen was maintained in 45.6% of patients in the triple, 62.6% in the steroid stop, and 53.9% in the MMF stop groups. Graft survival rates were 88.1% (triple), 86.4% (steroid stop), and 85.8% (MMF stop); patient survival was 96.1%, 95.9%, and 95.7%, respectively. The incidence of biopsy-proven acute rejection was similar in all groups between Month 7 and Year 3: 1.2% (triple), 2.0% (steroid stop) and 2.0% (MMF stop). Patients in the steroid stop group had less hypertension and significantly lower mean total cholesterol and LDL-cholesterol at Year 3 compared with Month 3 (P=0.02). Median serum creatinine levels remained stable throughout the follow-up and were comparable between groups.. Immunosuppression minimization initiated at Month 3 was maintained at Year 3 in over half of the patients. Steroid withdrawal was advantageous in reducing the cardiovascular risk factors hyperlipidemia, hypertension and diabetes mellitus. Renal function was stable in all groups.

Topics: Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Steroids; Tacrolimus; Treatment Outcome

It is vital that after, renal transplantation, immunosuppression is efficacious and causes few complications. It is especially important that hyperlipidaemia, hypertension and toxic influences should be avoided because these conditions can reduce patient and transplant survival. Many studies have demonstrated beneficial effects of tacrolimus in comparison with cyclosporine with regard to these conditions. These results have suggested that a conversion to tacrolimus from cyclosporine is advantageous. Our study investigated whether patients with deteriorating renal functions can profit from this conversion.. Thirty patients with a renal transplant were studied retrospectively, using data recorded from 3 years before to 3 years after conversion from cyclosporine to tacrolimus.. While renal function (glomerular filtration rate [GFR]) deteriorated progressively under cyclosporine, it stabilised and even improved under tacrolimus (creatinine: Delta(Cyc)=+1.4 mg/d; Delta(Tac=)-0.7 mg/dl; GFR: Delta(Cyc)=-35 ml/min; Delta(Tac)=14 ml/min). In addition, uric acid level (7.0 vs. 6.4 mg/dl, p<0.05) and cholesterol level (258 vs. 225 mg/dl, p<0.05) were both significantly lower under tacrolimus.. Conversion from cyclosporine to tacrolimus is recommended for patients with a kidney transplant, in which there has been a progressive fall in renal function. It leads to stabilisation or even improvement of transplant function and a reduction in cardiovascular risk factors.

Topics: Adult; Cardiovascular Diseases; Cholesterol; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Uric Acid

Mycophenolat mofetil (MMF) is a new imunosuppressant without nephrotoxic adverse effects. The aim of this study was to evaluate feasibility and effect of MMF introduction in conjunction with stepwise reduction of calcineurin inhibitors (CNI) in stable liver transplant patients with chronic CNI-induced renal dysfunction (RDF). In the MMF-group (n=27) but not in the controls (n=16), mean serum level of creatinine fell from a baseline of 227.4+/-67.9 micromol/l to 159.2+/-48.2 micromol/l (P<0,001), while mean urea level declined significantly from a baseline of 18.5+/-8.7 mmol/l to 11.4+/-4.2 mmol/l 6 months after initiation of MMF. Additionally, systolic and diastolic blood pressure values improved. In 52% of patients, dose reduction (n=11) or withdrawal (n=3) of MMF was necessary due to gastrointestinal or hematologic adverse effects. But also in patients on low dose MMF, there was a significant improvement of renal function without increased immunological risk.

Topics: Adult; Aged; Blood Pressure; Calcineurin Inhibitors; Cardiovascular Diseases; Cholesterol; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Urea; Uric Acid

Long-term use of cyclosporine (CsA) contributes to post-transplant cardiovascular disease (CVD). Hence, a reduction in CsA dosage in kidney transplant recipients (KTR) may improve long-term outcomes. We analyzed the effects of 50% CsA dose reduction on the CVD risk profile in stable KTR.. Thirty-one KTR on a regimen of CsA, prednisone and mycophenolate mofetil (MMF) were studied. Patients were randomized to either a) continue their previously determined CsA dose (control group, n = 15) or b) lower their CsA dose by 50% (CsA reduction group, n = 16). Renal function, blood pressure, lipid profile, plasma homocysteine (HCY), C-reactive protein (CRP), fibrinogen, and uric acid were compared at baseline and at 6 months.. At 6 months, there was a significant improvement in allograft function, systolic blood pressure, number of anti-hypertensive medications and serum uric acid levels in the CsA reduction group. No significant decrease in plasma HCY, CRP, fibrinogen or improvement in lipid profile was found. In contrast, in the Control group, there was a significant increase in HCY, uric acid, and triglycerides. No acute rejection occurred in either group.. A greater reduction in CsA dose could further improve CVD risk profiles, although this may increase the risk of acute or subclinical rejection.

Topics: Adult; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cyclosporine; Female; Graft Survival; Homocysteine; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Period; Prednisolone; Prospective Studies; Risk Assessment; Risk Factors; Uric Acid

The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage.. Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded.. Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08).. At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.

Topics: Adult; Aged; Cardiovascular Diseases; Cyclosporine; Female; Graft Rejection; Heart Transplantation; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Treatment Failure

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI (n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose (n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 +/- 0.36 versus 1.58 +/- 0.33 mg/dL, P < .001) and BUN (39.2 +/- 11.8 versus 29.9 +/- 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 +/- 10.8 versus 61.6 +/- 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 +/- 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 +/- 19 versus 130 +/- 14 mm Hg, P < .01) and diastolic (82 +/- 9 to 74 +/- 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 +/- 25.9 versus 25.2 +/- 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.

Topics: Aged; Calcineurin Inhibitors; Cardiovascular Diseases; Creatinine; Diastole; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Infant, Newborn; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Survivors; Systole; Tacrolimus

This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented.. Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events.. By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group.. Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.

Topics: Acute Disease; Adult; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Time Factors

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cardiovascular Diseases; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Time Factors

SLE patients have elevated cardiovascular disease (CVD) risk, but it is unclear whether this risk is affected by choice of immunosuppressive drug. We compared CVD risks among SLE patients starting MMF, CYC or AZA.. Using Medicaid Analytic eXtract (2000-2012), adult SLE patients starting MMF, CYC or AZA were identified and propensity scores (PS) were estimated for receipt of MMF vs CYC and MMF vs AZA. We examined rates of first CVD event (primary outcome), all-cause mortality, and a composite of first CVD event and all-cause mortality (secondary outcomes). After 1:1 PS-matching, Fine-Gray regression models estimated subdistribution hazard ratios (HRs.d.) for risk of CVD events. Cox regression models estimated HRs for all-cause mortality. The primary analysis was as-treated; 6- and 12-month intention-to-treat (ITT) analyses were secondary.. We studied 680 PS-matched pairs of patients with SLE initiating MMF vs CYC and 1871 pairs initiating MMF vs AZA. Risk of first CVD event was non-significantly reduced for MMF vs CYC [HRs.d 0.72 (95% CI: 0.37, 1.39)] and for MMF vs AZA [HRs.d 0.88 (95% CI: 0.59, 1.32)] groups. In the 12-month ITT, first CVD event risk was lower among MMF than AZA new users [HRs.d 0.68 (95% CI: 0.47, 0.98)].. In this head-to-head PS-matched analysis, CVD event risks among SLE patients starting MMF vs CYC or AZA were not statistically reduced except in one 12-month ITT analysis of MMF vs AZA, suggesting longer-term use may convey benefit. Further studies of potential cardioprotective benefit of MMF are necessary.

Topics: Adult; Azathioprine; Cardiovascular Diseases; Cause of Death; Coronary Artery Bypass; Cyclophosphamide; Female; Heart Disease Risk Factors; Heart Failure; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Mortality; Mycophenolic Acid; Myocardial Infarction; Percutaneous Coronary Intervention; Propensity Score; Proportional Hazards Models; Protective Factors; Risk Factors; Stroke; Young Adult

Systemic Lupus Erythematosus (SLE) an autoimmune rheumatic disease with a complex pathogenesis, remains potentially life-threatening. SLE patients have increased morbidity and premature mortality compared to non-SLE patients. The five-year survival rate has improved from <50% in the 1950s to >90% in the 1980s. Lupus patients still have a mortality risk three times that of the general population.. To provide a detailed analysis of the causes of death, main characteristics and trends in the management of the deceased SLE patients from the lupus clinic at the University College London Hospital (UCLH); during the past four decades.. This was a non-interventional, retrospective study based on historical real-world data from paper and electronic records of patients followed up at UCLH. The analysis focused on data collected between 1st January 1978 and 31th December 2018. We collected the: causes of death, duration of disease, key laboratory and clinical parameters and the treatment received. We compared the results from the four decades to ascertain trends in the causes of mortality. All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS), version 22.0. The 95% confidence intervals for the means of data were calculated.. 111 SLE patients (15%), died during follow-up. Their median age was 51 years (interquartile range (IQR) = 38-63 years) and the median duration of disease, 15 years (IQR = 8.5-24 years). The main causes of death in the past 40 years were infection (31.7%), cancer (26.7%) and cardiovascular disease (CVD) (21.8%). 93.6% of these patients were immunosupressed. During the 40-year period, there were several therapeutic developments notably the introduction of mycophenolate mofetil (MMF) and rituximab; the latter initially only given to patients when more conventional inmunosupressants had failed, but more recently offered to patients at diagnosis. There was a statistically significant increase in the use of hydroxycloroquine (HCQ), MMF and rituximab. In contrast, the use of Azathioprine (AZA) and steroids, hardly changed over time.. This retrospective review shows how epidemiological factors, causes of death and treatment of SLE patients have changed during the last 40 years in the UCLH cohort.

Topics: Adult; Antirheumatic Agents; Azathioprine; Cardiovascular Diseases; Cause of Death; Cohort Studies; Enzyme Inhibitors; Female; Humans; Hydroxychloroquine; Immunocompromised Host; Infections; Lupus Erythematosus, Systemic; Male; Middle Aged; Morbidity; Mortality, Premature; Mycophenolic Acid; Neoplasms; Retrospective Studies; Risk Factors; Rituximab; Steroids; Survival Rate; Time Factors; United Kingdom

Topics: Animals; Antioxidants; Cardiotoxicity; Cardiovascular Diseases; Catalase; DNA Damage; Graft Rejection; Male; Malondialdehyde; Mycophenolic Acid; Organ Transplantation; Protein Carbonylation; Rats; Rats, Wistar; Superoxide Dismutase; Tacrolimus

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Cyclosporine; Diabetes Mellitus, Type 1; Dyslipidemias; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prevalence; Prospective Studies; Risk Factors; Severity of Illness Index; Spain; Survival Analysis; Tacrolimus; Transplant Recipients

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

Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), affecting ∼50% of patients, and both renal disease and treatment-related toxicity contribute to significant morbidity and mortality. Although our understanding of the aetiopathogenesis of LN is improving, treatment still remains a challenge, with the achievement of complete remission at 1 year in <50% of patients treated with current standard of care immunosuppressive therapy; this is associated with considerable short- and long-term side effects, some of which further contribute to non-adherence. Calcineurin inhibitors (CNIs) have been successfully used in organ transplantation and there is increasing evidence that cyclosporin A (CSA), and especially tacrolimus (TAC), are also effective in the treatment of LN. Randomised controlled trials showed similar efficacy for TAC when compared with mycophenolate mofetil (MMF) and multitarget therapy, including TAC and low-dose MMF, and resulted in significantly more complete remissions and overall responses compared with intravenous cyclophosphamide (CYC). Flares are observed in up to 45% of patients with LN, and an increase in relapse rate following induction with CNIs may be an issue. Most studies on this matter have been restricted to patients from Asia, and studies in more balanced cohorts are desirable. Moreover, there is a need to understand and determine the long-term effects of CNIs on renal function, proteinuria and comorbidities, with a special focus on cardiovascular risk. In this 'Pros and Cons' debate, the potential benefits and disadvantages of CNIs in the treatment of LN will be critically highlighted.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Lupus Nephritis; Maintenance Chemotherapy; Mycophenolic Acid; Proteinuria; Risk Factors; Tacrolimus

There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients.. This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors.. 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients.. AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Topics: Adult; Aged; BK Virus; Black or African American; Cardiovascular Diseases; Cohort Studies; Dyslipidemias; Female; Graft Rejection; Graft Survival; Health Status Disparities; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Medicare; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; United States

The past year has been characterized by significant novelties from the point of view of the clinical immunologist. With the BLISS 52 study showing that belimumab has the ability to decrease the activity of systemic lupus erythematosus (SLE) resistant to conventional therapy an important step towards the control of this difficult disease has been carried forward. In addition, the long-term results of the ALMS study have demonstrated that mycophenolate mofetil is superior to azathioprine in maintaining the remission in patients with severe lupus nephritis. Furthermore, the results of the RAVE and RITUXVASC studies have documented that rituximab is a valid alternative to cyclophosphamide in the control of ANCA associated vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antirheumatic Agents; Azathioprine; Cardiovascular Diseases; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Remission Induction; Rituximab; Severity of Illness Index; Treatment Outcome

The aim of this prospective study was to compare the cardiovascular risk (CVR) profile in patients treated with 2 different immunosuppressive regimens: tacrolimus and mycophenolate mofetil (TAC) compared with everolimus and low-dose cyclosporine (EVL).. Sixty consecutive renal transplant recipients prospectively assigned to TAC (n = 30) or to EVL (n = 30) were followed for 6 months. TAC group immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil (MMF), and steroid. EVL group immunosuppression consisted of basiliximab, everolimus, and low doses of cyclosporine and steroid. Main CVR factors analyzed were: hypertension, dyslipidemia, posttransplant diabetes mellitus, and weight gain.. Six months posttransplantation, patients in the EVL group showed significantly higher mean serum cholesterol (P < .003) and serum triglyceride levels (P < .027), as well as a greater number of patients were receiving statin treatment (P < .05). Mean systolic blood pressure, mean diastolic blood pressure, number of patients treated for hypertension, number of antihypertensive medications prescribed per patient, posttransplant weight gain, and posttransplant diabetes mellitus were not significantly different among the EVL and TAC groups after 1, 3, and 6 months posttransplantation.. This study showed that at 6 months posttransplantation, patients on EVL displayed significantly greater dyslipidemia with respect to the TAC group. A longer follow-up will be necessary to discover whether the presence of everolimus in the immunosuppressive regimen provides significant benefits for the CVR of renal transplant recipients.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Risk Adjustment; Risk Factors; Sirolimus; Tacrolimus; Transplant Recipients

To evaluate cardiovascular disease (CVD) after renal transplantation we established a CVD database (no-intervention) including all patients transplanted among 2000-2002 in 14 hospitals from Spain (Renal Forum Group) (n=2600). They were prospective followed annually thereafter and we present herein the most important results concerning survival figures and CVD at four years. Mean recipient age was 49.7+/-13.7 years: 16% retransplanted and 12.5% hyperimmunized. Tacrolimus, mycophenolate mofetil, and steroids was used in 63%. Acute rejection (AR) rate at 1 year was 14.8%. Graft and patient survival at 48 months were 85.6% (death censored) and 91.7% respectively. The first cause of graft loss was vascular in the first year, death with function during the 2-3 years, and chronic allograft nephropathy at the 4th year. Donor age, time on dialysis, acute tubular necrosis (ATN), AR, SCr at 6 months, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in the first year, and systolic blood pressure at 24 months were independent risk factors for graft loss at 4th year. The first cause of death was CVD (predominantly ischemic heart disease (IHD) in the first year). Recipient age, ATN, and SCr at 6 months were independent predictors of mortality. Despite worsening of donor age, comorbidity, and advanced age of recipients, survival figures at four years are considered good in our Spanish non-selected population. Cardiovascular mortality is the most important cause of death and graft loss particularly, IHD in the first year. Therefore, to decrease post-transplant mortality a careful cardiovascular evaluation and treatment in the waiting list and a close follow-up of patients after transplantation is mandatory.

Topics: Adult; Cardiovascular Diseases; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Risk Factors; Spain; Tacrolimus

Immunosuppressive protocols in dual kidney transplantation (DKT) are based on calcineurin inhibitors (CNI). We wonder whether a CNI-free immunosuppression can improve outcome in older patients receiving a DKT with marginal donor organs. Thirty-six were treated with CsA, MMF and prednisone (CsA group) and 42 with rATG, SRL, MMF and prednisone (SRL group). Incidence of delayed graft function and acute rejection was 44% and 11% in the CsA group, and 40% and 8% in the SRL group. CMV infection incidence was low in both protocols. Three-year patient survival was 89% in the CsA and 76% in the SRL group. One- and 3-year graft survival after censoring for dead with a functioning allograft was 94.2% and 94% in CsA and 95% and 90% in SRL, respectively. Renal function was similar in both groups whereas proteinuria was higher in the SRL group. Uninephrectomy due to graft thrombosis or urinary-related complications was numerically higher in the SRL (21%) than in the CsA group (8%) (p = 0.13) and it was associated with renal failure and proteinuria. In DKT, a new induction immunosuppressive protocol based on rATG, SRL, MMF and prednisone does not offer any advantage in comparison to the old CsA, MMF and prednisone.

Topics: Calcineurin Inhibitors; Cardiovascular Diseases; Cyclosporine; Delayed Graft Function; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Risk; Treatment Outcome

Steroid sparing with tacrolimus and mycophenolate mofetil (MMF) is associated with good short-term renal transplant outcomes. However, late allograft dysfunction and failure remain concerns. In this study, 101 consecutive patients underwent renal transplantation with tacrolimus, MMF, and 7 days of corticosteroids only. After a median follow-up of 51 months (range 36-62), overall patient survival is 97%, and overall survival with graft function is 91%. The acute rejection rate at 12 months was 19%. Late rejection was uncommon, with only three further episodes beyond 12 months. Graft function was stable during the study, with a mean creatinine of 140 micromol/L and mean estimated creatinine clearance of 57 ml/min at the end of follow-up. Six patients developed posttransplant diabetes mellitus (three cases beyond 12 months). This steroid avoidance regimen is associated with excellent medium-term patient and graft outcomes, and a low incidence of side effects.

Topics: Adult; Cardiovascular Diseases; Creatine; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Mycophenolic Acid; Risk Factors; Steroids; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Cardiovascular Diseases; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Reoperation; Retrospective Studies; Risk Factors; Sirolimus; Steroids; Tacrolimus