tacrolimus and Obesity

Focal segmental glomerulosclerosis (FSGS) is a pathologic condition that represents many disease entities. The goals of therapy are to cure the disease. When this is not possible, the secondary goals are to reduce proteinuria to avoid the complications of nephrotic syndrome and to delay progression of kidney disease. Proteinuria remission is one of the most important independent predictors of kidney survival. Children with FSGS who do not achieve partial or complete remission have a 50% risk of progression to ESRD within 5 years whereas those who enter complete remission have a 5-year kidney survival rate of 90%. Treatment of idiopathic FSGS commonly involves immune-based and nonimmunologic therapy options. This manuscript will review the current state of FSGS therapy for children.

Topics: Adrenal Cortex Hormones; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antihypertensive Agents; Child; Cyclosporine; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Obesity; Rituximab; Tacrolimus; Treatment Outcome; Vitamin D Deficiency

Diabetes mellitus continues to be a common metabolic complication after solid organ transplantation. The etiology is multifactorial and includes both modifiable and nonmodifiable factors. Immunosuppression may play a critical role in its development. Targets of treatment include oral hypoglycemics as well as insulin. More recently, several novel agents have been approved by the Food and Drug Administration for treatment of type 2 diabetes. There is limited experience with these agents in transplant recipients. Use of oral and subcutaneous therapies as well as insulin will be reviewed. As diabetes has a negative impact on patient and graft outcome, the transplant practitioner must be vigilant in screening and managing diabetes after transplantation.

Topics: Age Factors; Black or African American; Diabetes Mellitus; Hepatitis C; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Obesity; Organ Transplantation; Risk Factors; Tacrolimus

De novo obese kidney transplant recipients were randomized to receive TAC-ER 0.15 mg/kg/day based on either adjusted body weight (aBW) or ideal body weight (IBW). Post-transplant patients underwent three pharmacokinetic assessments over 14 days. The primary endpoint was the difference in TAC-ER exposure (AUC0-24) in obese patients dosed using aBW compared with IBW.. A total of 20 obese renal transplant recipients were randomized to participate in the study (10 aBW and 10 IBW). Results of the primary outcome (AUC0-24) on Study Day 1, 7, and 14 were not statistically different between the two groups. There was no difference in the number of days to therapeutic trough concentration between the two dosing weights (aBW = 5.1, IBW = 4.9, days; P = 0.90).. In a population of obese renal transplant recipients, comparable trough concentrations and overall exposure in both groups indicate that IBW may be preferred, as less initial drug was needed to attain adequate exposure.

Topics: Drug Administration Schedule; Drug Liberation; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Obesity; Prognosis; Risk Factors; Tacrolimus

Weight gain early after transplant is a risk factor for posttransplant metabolic syndrome (PTMS), cardiovascular events, and renal insufficiency. The impact of mammalian target of rapamycin inhibition on posttransplant weight gain and the development of PTMS components postliver transplantation were examined in a randomized, controlled study.. After a run-in period, patients (N = 719) were randomized at 30 ± 5 days posttransplant in a 1:1:1 ratio to 3 treatment groups: (i) everolimus (EVR) + reduced tacrolimus (TAC) (n = 245); (ii) TAC control (n = 243) or (iii) TAC elimination (n = 231). In this post hoc analysis, weight change at 12 and 24 months was compared between groups. Vital signs, lipids, and laboratory parameters at 12 and 24 months and rates of PTMS were assessed.. Mean increase in weight from baseline was higher at month 12 in the TAC control arm (8.15 ± 9.27 kg) than in the EVR + reduced TAC (5.88 ± 12.60 kg, P = 0.056) and the TAC elimination arms (4.76 ± 9.94 kg, P = 0.007). At month 24, the TAC control arm displayed a significantly greater weight increase (9.54 ± 10.21 kg) than either the EVR + reduced TAC (6.69 ± 8.37 kg, P = 0.011) or the TAC elimination groups (6.01 ± 9.98 kg, P = 0.024). Rates of PTMS were similar for the EVR + reduced TAC (71.8%), TAC elimination (70.3%) and TAC control (67.4%) arms (P = NS).. EVR with reduced-exposure TAC attenuated weight gain at 1 and 2 years posttransplant compared with a standard TAC immunosuppression regimen. Rates of PTMS were comparable between EVR-containing and TAC control regimens.

Topics: Adult; Aged; Cardiovascular Diseases; Everolimus; Female; Follow-Up Studies; Glycosylation; Graft Rejection; Graft Survival; Hemoglobins; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Obesity; Prospective Studies; Risk Factors; Signal Transduction; Tacrolimus; Weight Gain

Topics: Adult; Body Mass Index; Cholesterol; Cyclosporine; Follow-Up Studies; Humans; Liver Transplantation; Obesity; Tacrolimus; Time Factors; Triglycerides; United States; Weight Gain

Although obesity has become a significant problem in transplantation medicine, the impact of different immunosuppressive protocols on clinical outcomes in obese transplant recipients remains unclear.. We performed an analysis of the Scientific Registry of Transplant Recipients database. Kidney transplant recipients were categorized according to body mass index (BMI) categories and immunosuppressive protocols: (i) tacrolimus/mycophenolate mofetil (Tac-MMF), (ii) mTOR-inhibitor/Tac (mTORi-Tac), (iii) mTORi/cyclosporin (mTORi-Cyc) and (iv) mTORi-MMF.. Graft recipients with advanced obesity (BMI ≥35 kg/m2) exhibited significantly lower rates of acute rejection during the first year after transplantation in the mTORi-Tac (6.4%) group compared with Tac-MMF (11.2%). Obesity class 1 (30 < BMI < 35 kg/m2) was associated with a significant risk of acute rejection for the mTORi-Tac group [obesity class 1 hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.21-2.62, P = .003]. A similar trend was observed in the Tac-MMF group for advanced obesity HR 1.29; 95% CI 0.96-1.73, P = .087). For the Tac-MMF group, recipients with both overweight and obesity had significantly impaired survival due to cardiovascular events and also increased mortality due to infection in advanced obesity. Combination of mTORi and calcineurin inhibitor was associated with lower rejection rates and stable long-term kidney function while reducing cardiovascular side effects linked to calcineurin inhibitors in obese kidney graft recipients.. These results are critical for the growing number of obese graft recipients and warrant prospective evaluation.

Topics: Calcineurin Inhibitors; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Obesity; Propensity Score; Sirolimus; Tacrolimus; Transplant Recipients

Tacrolimus is known to exhibit significant inter- and intra-patient pharmacokinetic (PK) and pharmacodynamic (PD) variability regarding therapeutic response. LCP-tacrolimus (LCPT-Envarsus XR) was approved in 2018 for use as a de novo immunosuppressive agent in kidney transplants, but there is limited evidence to guide de novo dosing of LCPT in patients with obesity. The primary objective of this study was to evaluate the impact of different calculated weight-based de novo LCPT dosing on early transplant outcomes.. This was a retrospective study of patients with obesity (BMI ≥ 30 kg/m. There was a statistically significant, though modest, correlation between all three dosing strategies and the first tacrolimus trough level (TBW correlation coefficient = .431, p < .001; AdjBW correlation coefficient = .455, p < .001; IBW correlation coefficient = .465; p < .001). In regression modeling for supratherapeutic levels each additional .01 mg/kg increase in dose by TBW, AdjBW, and IBW increased the odds of a supratherapeutic level by 1.46, 1.34, and 1.24, respectively (p < .001).. The use of LCPT in kidney transplant recipients with obesity dosed using TBW demonstrated the strongest correlation with initial supratherapeutic tacrolimus levels. Larger prospective studies are needed to investigate the further impact of body weight on dosing regimens in the obese population.

Topics: Adolescent; Drug Administration Schedule; Humans; Immunosuppressive Agents; Kidney Transplantation; Obesity; Retrospective Studies; Tacrolimus

Topics: Adult; Cytochrome P-450 CYP3A; Genotype; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Living Donors; Male; Obesity; Tacrolimus

Tacrolimus pharmacokinetics in obese (Ob) patients has been poorly studied. In this article, the authors explored the impact of obesity on tacrolimus exposure in kidney transplant recipients (KTRs) and estimated a more suitable initial dosage in this population.. A retrospective, observational, monocentric case-control study was performed in obese KTRs (BMI > 30 kg/m2) who received tacrolimus between 2013 and 2017 (initial dose: 0.15 mg/kg/d) (actual weight). Nonobese (Nob) controls (BMI <30 kg/m2) were matched for age and sex. Weekly centralized monitoring of tacrolimus trough levels was performed by liquid chromatography/mass spectrometry until the third month (M3). Target trough levels were set between 8 and 10 ng/mL. All patients received antilymphocyte globulin, corticosteroids, and mycophenolate mofetil.. Of the 541 KTRs, 28 tacrolimus-treated Ob patients were included and compared with 28 NOb-matched controls. With a mean of 22 assays/patient, tacrolimus trough levels were higher in Ob patients (mean 9.9 versus 8.7 ng/mL; P = 0.008); the weight-related dose of Tac was lower at M3 (mean 0.10 versus 0.13 mg/kg/d, P < 0.0001). The tacrolimus concentration to dose (C0/D) was higher in the Ob cohort [mean 116 versus 76 (ng/mL)/(mg/kg/d); P = 0.001]. In Ob patients, a mean decrease of -4.6 mg/d in the 3 months after tacrolimus initiation was required (versus -1.12 in NOb; P = 0.001) to remain within the therapeutic range. Obesity, high mycophenolate mofetil daily dose at M3, and CYP3A5 expression were independently associated with higher tacrolimus exposure. Four dose-adaptation strategies were simulated and compared with the study results.. An initial dose calculation based on either ideal or lean body weight may allow for faster achievement of tacrolimus trough level targets in Ob KTRs, who are at risk of overexposure when tacrolimus is initiated at 0.15 mg/kg/d. A prospective study is required to validate alternative dose calculation strategies in these patients.

Topics: Case-Control Studies; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Kidney Transplantation; Obesity; Retrospective Studies; Tacrolimus

Kidney transplant (KT) recipients are at an increased risk for severe COVID-19 because of their immunosuppressed state. A 42-year-old KT patient was diagnosed with COVID-19 three months after KT. Despite lymphopenia and several risk factors, he had a mild disease course. Nasopharyngeal real-time reverse transcriptase polymerase chain reaction for SARS-CoV-2 became negative 48 days after detection. SARS-CoV-2 IgG antibodies became negative after day 40. TTV DNA load increased with the onset COVID-19 and reduced after its resolution. This is the first report where TTV DNA load was measured during the course of COVID-19.

Topics: Adult; Antibodies, Viral; Comorbidity; COVID-19; COVID-19 Nucleic Acid Testing; COVID-19 Serological Testing; Diabetes Mellitus; DNA Virus Infections; DNA, Viral; Glucocorticoids; Graft Rejection; Humans; Hypertension; Immunocompromised Host; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Lymphopenia; Male; Mycophenolic Acid; Obesity; Prednisolone; SARS-CoV-2; Severity of Illness Index; Tacrolimus; Torque teno virus; Viral Load

Wound complication frequently arises after kidney transplantation and its risk factors are well known. In a previous paper we analyzed these factors, and in this new retrospective study we evaluate the influence of lymphocele in the development of wound complications.. From January 2000 to December 2018, 731 consecutive kidney transplants have been performed in our center. We have analyzed the incidence of wound complication and lymphocele and their risk factors.. Out of 731 kidney transplants, we have observed wound complications in 115 patients (15.7%) and lymphocele in 158 patients (21.7%). Of these, 70 patients developed both complications (9.5%), but 6 patients have been excluded because they were in therapy with mammalian target of rapamycin inhibitors. Twenty-nine patients (45.3%) presented a first level and 35 patients (54.7%) showed second level wound complications. Lymphocele was the only present factor in just 3 cases (4.6%). The other patients showed diabetes in 28 cases (43.7%), overweight/obesity in 38 (59.3%), delayed graft function in 17 (26.5%), and 60 years or more in 38 (57.8%). The association has been found in 30 out 64 patients treated with tacrolimus (46.8%) and in 34 with cyclosporine (53.1%); 40 patients did not receive muscular layer's reconstruction (62.5%).. Our experience shows that lymphocele alone is not a predisposing factor for wound dehiscence after kidney transplantation, and they often coexist because they share the same risk factors, the most important being obesity, diabetes and delayed graft function, older age, and surgical techniques. No relation has been observed with calcineurin inhibitor therapy.

Topics: Adult; Aged; Cyclosporine; Delayed Graft Function; Diabetes Complications; Female; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lymphocele; Male; Middle Aged; Obesity; Retrospective Studies; Risk Factors; Sirolimus; Surgical Wound Dehiscence; Tacrolimus

Tacrolimus is one of the most widely used liver transplant medications. With the increasing number of obese patients requiring liver transplants, knowledge of the effect of body size affecting post-transplant outcomes, for example drug exposure is increasingly required.. (i) To investigate whether patient body size (i.e. total bodyweight) affects trough plasma concentrations of tacrolimus when a standard mg/kg dosing regimen is used; and (ii) to investigate whether obese patients have different numbers of plasma concentrations outside the therapeutic range compared to non-obese patients in the first months after liver transplant.. Using a transplant database, data tacrolimus concentrations were available for 69 patients. Tacrolimus was initially dosed at a standard 0.1 mg/kg/day after liver transplant, and adjusted to maintain a target trough concentration. Trough blood samples, phenotypic and outcome variables were analysed.. Trough concentrations were similar between obese and non-obese patients (P > 0.05) at each sampling day. At day 7 post-transplant, 85.7% and 79.5% of the observed plasma concentrations were outside the recommended therapeutic range for obese and non-obese patients respectively, at day 30, 52.9% and 57.4%, and at 6 months, 18.7% and 27.5%.. In the first week post-transplant, tacrolimus trough concentrations after standard mg/kg dosing post liver transplant appear to be corrected by total bodyweight. Obese patients have a similar number of trough plasma concentrations outside the therapeutic range compared to non-obese patients.

Topics: Adult; Aged; Body Weight; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Obesity; Retrospective Studies; Tacrolimus

Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16

Topics: Animals; Anxiety; Astrocytes; Behavior, Animal; Brain; Cells, Cultured; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Dasatinib; Diet, High-Fat; Disease Models, Animal; Female; Fibroblasts; Lipid Droplets; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Obesity; Quercetin; Tacrolimus

Cardiovascular disease (CVD) is an important cause of morbidity and mortality after liver transplantation (LT). Serum adiponectin levels inversely correlate with CVD-related outcomes, but the relationship between hypoadiponectinemia and CVD after LT is unknown. Thus, the aim of the present study was to prospectively evaluate this relationship in LT recipients (LTR).. LTR were prospectively enrolled (N = 130) between January 1, 2012, and January 1, 2014. Baseline adiponectin levels were drawn at enrollment and patients were followed for CVD events. Hypoadiponectinemia was defined as serum adiponectin <10 µg/mL. The primary endpoint was a composite CVD outcome consisting of myocardial infarction, angina, need for coronary revascularization, stroke, or cardiac death.. The mean age was 58 ± 11 years and prevalence of obesity, diabetes, and dyslipidemia was 40%, 35%, and 40%, respectively. A total of 20 CVD events were noted, after median follow up of 45 months. Hypoadiponectinemia was significantly associated with future risk of CVD events (hazard ratio, 3.519; 95% confidence interval, 1.180-10.499, P = 0.024). This association was independent of traditional CVD risk factors including age, gender, obesity, hypertension, diabetes, and choice of immunosuppression.. Hypoadiponectinemia is a strong independent predictor of future cardiovascular events in LTR, which can be incorporated in clinical practice to assess CVD risk assessment after LT.

Topics: Adiponectin; Aged; Cardiovascular Diseases; Cyclosporine; Diabetes Complications; Dyslipidemias; End Stage Liver Disease; Female; Humans; Immunosuppression Therapy; Insulin Resistance; Liver Transplantation; Male; Metabolism, Inborn Errors; Middle Aged; Obesity; Proportional Hazards Models; Prospective Studies; Risk Assessment; Tacrolimus; Transplant Recipients; Treatment Outcome

The mechanisms of tacrolimus-induced β cell toxicity are unknown. Tacrolimus (TAC) and rapamycin (Rapa) both bind to FK506-binding protein 12 (FKBP12). Also, both molecular structures are similar. Because of this similarity, we hypothesized that TAC can also inhibit the mTOR signalling, constituting a possible mechanism of β cell toxicity. Thus, we studied the effect of TAC and Rapa over the mTOR pathway, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), and insulin secretion and content in INS-1 β cells treated with or without glucose and palmitate and in islets from lean or obese rats. TAC and Rapa inhibited the mTOR pathway as reflected by lower levels of phospho-mTOR, phospo-p70S6K, and phospo-S6. The effect of Rapa was larger than TAC. Both drugs reduced the levels of MafA, insulin secretion, and content although these effects were larger with TAC. The changes on MafA and insulin metabolism were observed in cells on glucose and palmitate, in obese animals, and were absent in cells on maintenance medium or in lean animals. In silico docking and immunoprecipitation experiments confirmed that TAC can form a stable noncovalent interaction with FKBP12-mTOR. Thus, the mTOR inhibition may be a mechanism contributing to the diabetogenic effect of TAC.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Glucose; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Obesity; Rats; Rats, Zucker; Signal Transduction; Tacrolimus; Thinness; TOR Serine-Threonine Kinases

β Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma β cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 μM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in β cells, possibly by sharing common pathways of β cell dysfunction. TAC-induced β cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.

Topics: Animals; Calcineurin; Cyclosporine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Nerve Tissue Proteins; NFATC Transcription Factors; Obesity; Rats; Rats, Zucker; Tacrolimus; Thinness

This investigation explored the hypothesis that in obesity an inflammatory response in the kidney contributed to a renal nerve-dependent blunting of the baroreflex regulation of renal sympathetic nerve activity.. Rats received a normal (12% kcal) or high-fat (45% kcal) diet for 8 weeks plus daily injections of vehicle (0.9% NaCl i.p) or tacrolimus (0.25 mg kg. The high-fat diet elevated weight gain and adiposity index by 89 and 129% (both, P < 0.001). Mean blood pressure (132 ± 4 vs 103 ± 5 mmHg), fractional noradrenaline excretion and creatinine clearance (5.64 ± 0.55 vs 3.32 ± 0.35 mL min. Obesity induced a renal inflammation and pointed to this being both the origin of autonomic dysregulation and a potential focus for targeted therapy.

Topics: Adiposity; Animals; Baroreflex; Cytokines; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Norepinephrine; Obesity; Rats, Sprague-Dawley; Sympathetic Nervous System; Tacrolimus

Although recent studies have shown that obesity decreases lymphatic function, the cellular mechanisms regulating this response remain unknown. In the current study, we show that obesity results in perilymphatic accumulation of inflammatory cells and that local inhibition of this response with topical tacrolimus, an inhibitor of T cell differentiation, increases lymphatic vessel density, decreases perilymphatic iNOS expression, increases lymphatic vessel pumping frequency, and restores lymphatic clearance of interstitial fluid to normal levels. Although treatment of obese mice with 1400W, a selective inhibitor of iNOS, also improved lymphatic collecting vessel contractile function, it did not completely reverse lymphatic defects. Mice deficient in CD4(+) cells fed a high fat diet also gained weight relative to controls but were protected from lymphatic dysfunction. Taken together, our findings suggest that obesity-mediated lymphatic dysfunction is regulated by perilymphatic accumulation of inflammatory cells and that T cell inflammatory responses are necessary to initiate this effect.

Topics: Administration, Topical; Animals; Biological Transport; Cell Movement; Dendritic Cells; Diet, High-Fat; Feeding Behavior; Inflammation; Lymph Nodes; Lymphatic Vessels; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Nitric Oxide Synthase Type II; Obesity; Tacrolimus

Obesity has been reported as risk factor for reduced posttransplant graft and patient survival and increased delayed graft function (DGF).. The purpose of this work is to analyze the effect of body mass index (BMI) on defined transplant outcomes in patients transplanted under defined guidelines in a kidney transplant program.. Review of a prospectively collected database in renal transplant recipients receiving rabbit antithymocyte globulin induction, mycophenolate mofetil, tacrolimus, and early corticosteroid withdrawal between 2001 and 2011.. This review was conducted in a single abdominal transplant program in the United States.. Primary outcome was death-censored graft survival categorized by posttransplant body mass groups. Secondary outcomes included DGF as well as patient survival.. Four hundred sixty seven patients were identified. No difference was observed in graft survival or DGF between BMI groups. One-year, death-censored graft survival and patient survival rates ranged from 97.5% to 100% and 96.6% to 100%, respectively. Delayed graft function was uncommon across all BMI groups, ranging from 5.3% to 9.1%, with the lowest incidence in patients with a BMI ≥ 35 kg/m(2). Biopsy-proven acute rejection rates at 1 year were similar across all groups (10.1%-14%) as were estimated glomerular filtration rates were at 1, 3, and 5 years.. Our results do not show an effect of BMI on posttransplant outcomes, suggesting that relaxation of BMI criteria may be warranted for recipient selection.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Body Mass Index; Comorbidity; Databases, Factual; Delayed Graft Function; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Obesity; Overweight; Retrospective Studies; Survival Rate; Tacrolimus; Thinness; Treatment Outcome

New-onset diabetes mellitus after transplantation (NODAT) is a serious complication following renal transplantation. The aim of this study was to identify the risk factors for the development of NODAT in Korean transplant patients.. Recipients who underwent living donor kidney transplantation between January 2009 and April 2012 at Asan Medical Center were reviewed. Diagnosis of NODAT was defined according to the American Diabetes Association criteria.. A total of 418 patients were enrolled. NODAT was diagnosed in 85 (20.4 %) patients within 1 year. By multivariate analysis, old age (odds ratio [OR], 1.05; 95 % Confidence interval [CI]: 1.01-1.08), family history of diabetes mellitus (OR, 2.48; 95 % CI: 1.04-5.94), pre-transplant high serum glucose level (OR, 1.04; 95 % CI: 1.01-1.08), and obesity (OR, 3.46; 95 % CI: 1.55-7.73) were independent risk factors for NODAT.. Old age, family history of diabetes, pre-transplant high plasma glucose level, and obesity are independent factors associated with the development of diabetes after renal transplantation. In contrast, serum magnesium levels and the use of tacrolimus are not associated with the development of NODAT.

Topics: Adult; Age Factors; Blood Glucose; Diabetes Mellitus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Magnesium; Male; Middle Aged; Obesity; Preoperative Period; Republic of Korea; Retrospective Studies; Risk Factors; Tacrolimus

Increased rates of solid organ cancers post-liver transplantation have been reported, but the contribution of environmental factors and immunosuppressive therapy is not clear. This study's aims were to compare the incidence of de novo solid organ cancers after liver transplantation; identify risk factors independent of immunosuppressive therapy associated with these cancers; and assess the influence of calcineurin inhibitors on the appearance of these cancers.. This single-centre study from 1991 to 2008 included 465 liver recipients who had survived for ≥1 year. Gross incidence rates were standardized by age and sex, using the global population as a reference. In addition, 322 of the 465 patients treated for ≥1 year with calcineurin inhibitors were studied.. Sixty-five (13.9%) of the 465 patients developed de novo solid cancers. The overall relative risk was 3.7. Significantly increased relative risks were observed for digestive, oesophageal, colorectal, oral and lung cancers, but not for genito-urinary and breast cancers. Among the 65 patients who developed solid organ cancers, 43 died (66.1%), 41 from cancer. The two independent risk factors were pretransplant smoking [P < 0.0001; odds ratio = 5.5 (.5; 12)] and obesity [P = 0.0184; odds ratio = 2.2 (1.1; 4.3)]. Of the 322 patients on calcineurin inhibitors, 55 (17%) developed de novo solid cancers. Tacrolimus exposure level was a risk factor for de novo solid cancers [P < 0.0001; OR = 15.3 (4.5; 52.2)].. We recommend a change in immunosuppressive protocols with lifestyle/dietary guidelines and smoking cessation.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Neoplasms; Obesity; Risk Factors; Smoking; Tacrolimus; Transplant Recipients

Obesity has been a relative contraindication for renal transplantation. This study evaluates the impact of pretransplant body mass index (BMI) on renal transplant outcomes in a single institution in the era of modern immunosuppression.. A 10-y retrospective analysis was undertaken of 454 consecutive patients who received a renal transplant at Westmead Hospital from January 1, 2001 to December 31, 2010. The role of pretransplant BMI on patient survival, graft survival, surgical complications, and postoperative complications was studied.. The mean age of transplant of this study population was 45.4 ± 13.0 y. Live donation rate was 53.5%, and 60.6% were male. The median preoperative BMI was 25.6 (range, 14.3-51.4). One-year and 5-y patient survival were 97.4% and 86.6%, respectively, whereas 1-y and 5-y death-censored graft survival were 97.1% and 91.9%, respectively. Patients with BMI >30 did not exhibit any significant difference in survival or graft failure but had higher surgical wound infection rates (hazard ratio 3.95, P < 0.01). Patients with preoperative BMI <18.5 were associated with a six-fold increase in both death and death-censored graft failure (P < 0.01).. Pretransplant obesity increases wound infection but is not a contraindication to renal transplantation. Future prospective studies are required to further define the impact of low preoperative BMI <18.5.

Topics: Adult; Body Mass Index; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; New South Wales; Obesity; Postoperative Complications; Retrospective Studies; Tacrolimus

The evolution of metabolic and cardiovascular disease (CVD) complications after liver transplantation (LT) is poorly characterized. We aim to illustrate the prevalence of obesity and metabolic syndrome (MS), define the cumulative incidence of CVD, and characterize risk factors associated with these comorbidities after LT. A retrospective review of 455 consecutive LT recipients from 1999 to 2004 with an 8- to 12-year follow-up was performed. Obesity increased from 23.8% (4 months) to 40.8% (3 years) after LT. Increase in body mass index predicted MS at 1 year after LT (odds ratio, 1.1; P < 0.001, per point). CVD developed in 10.6%, 20.7%, and 30.3% of recipients within 1, 5, and 8 years, respectively. Age, diabetes, hypertension, glomerular filtration rate < 60 mL/minute, prior CVD, ejection fraction < 60%, left ventricular hypertrophy, and serum troponin (TN) > 0.07 ng/mL were associated with CVD on univariate analysis. Age (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.01-1.06; P = 0.019), diabetes (HR, 1.78; 95% CI, 1.09-2.92; P = 0.022), prior history of CVD (HR, 2.46; 95% CI, 1.45-4.16; P < 0.001), and serum TN > 0.07 ng/mL (HR, 1.98; 95% CI, 1.23-3.18; P = 0.005) were independently associated with CVD in the long term. Smoking history (ever), sex, hyperlipidemia, and serum ferritin levels were not predictive of CVD. Tacrolimus use versus noncalcineurin-based immunosuppression (HR, 0.26; 95% CI, 0.14-0.49; P < 0.001) was associated with reduced risk of CVD but not versus cyclosporine (HR, 0.67; 95% CI, 0.30-1.49; P = 0.322). CVD is common after LT. Independent of MS, more data are needed to identify nonconventional risk factors and biomarkers like serum TN. Curbing weight gain in the early months after transplant may impact MS and subsequent CVD in the long term.

Topics: Adult; Biomarkers; Body Mass Index; Cardiovascular Diseases; Comorbidity; Cyclosporine; Diabetes Complications; End Stage Liver Disease; Female; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppression Therapy; Incidence; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Obesity; Odds Ratio; Prevalence; Proportional Hazards Models; Retrospective Studies; Risk Factors; Tacrolimus

Switching to cyclosporine A may result in a reversion of tacrolimus-induced diabetes mellitus. However, mechanisms underlying such a reversion are still unknown.. Obese Zucker rats were used as a model for tacrolimus-induced diabetes mellitus. A cohort of 44 obese Zucker rats received tacrolimus for 11 days (0.3mg/kg/day) until diabetes development; then: (a)22 rats were euthanized at day 12 and were used as a reference group (tacrolimus-day 12), and (b)22 rats on tacrolimus were shifted to cyclosporin (2.5mg/kg/day) for 5 days (tacrolimus-cyclosporin). An additional cohort of 22 obese Zucker rats received the vehicle for 17 days and were used as a control group. All animals underwent an intraperitoneal glucose tolerance test at the end of the study.. β-cell proliferation, apoptosis and Ins2 gene expression were evaluated. Compared to rats in tacrolimus-day 12 group, those in tacrolimus-cyclosporin group showed a significant improvement in blood glucose levels in all assessment points in intraperitoneal glucose tolerance test. Diabetes decreased from 100% in tacrolimus-day 12 group to 50% in tacrolimus-cyclosporin group. Compared to tacrolimus-day 12 group, rats in tacrolimus-cyclosporin group showed an increased β-cell proliferation, but such an increase was lower than in rats receiving the vehicle. Ins2 gene expressions in rats receiving tacrolimus-cyclosporin and rats receiving the vehicle were comparable.. An early switch from tacrolimus to cyclosporin in tacrolimus-induced diabetes mellitus resulted in an increased β-cell proliferation and reversion of diabetes in 50% of cases.

Topics: Animals; Apoptosis; Calcineurin Inhibitors; Carbohydrate Metabolism; Cell Division; Cyclosporine; Diabetes Mellitus, Experimental; Drug Substitution; Glucose; Glucose Tolerance Test; Homeostasis; Insulin Resistance; Insulin-Secreting Cells; Obesity; Proinsulin; Rats; Rats, Zucker; Tacrolimus

A retrospective analysis suggested that blood tacrolimus concentrations were consistent among patients with a body mass index (BMI) that was lean (<18.5), normal (≥ 18.5 and <25) or overweight/obese (≥ 25). The average maintenance dose of tacrolimus in patients with BMI ≥ 25 was significantly lower compared with that in patients with a BMI of less than 25. Lean and obese Zucker rats fed a normal diet were given tacrolimus intravenously or orally. The blood concentrations of tacrolimus in obese rats were significantly higher than those in lean rats after administration via both routes. The moment analysis has suggested that CLtot and Vdss of tacrolimus were not significantly different between lean and obese rats. The bioavailability was higher in obese rats, compared with that in lean rats. The protein expression of Cyp3a2 in the liver was significantly decreased in obese rats, compared with lean rats, while P-gp in the small intestine was also significantly decreased in obese rats. These results suggested that the steady-state trough concentration of tacrolimus in obese patients was well maintained by a relatively low dose compared with that in normal and lean patients, presumably due to increased bioavailability.

Topics: Administration, Intravenous; Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Body Mass Index; Cytochrome P-450 CYP3A; Female; Humans; Intestinal Mucosa; Male; Microsomes, Liver; Middle Aged; Obesity; Rats; Rats, Zucker; Retrospective Studies; Tacrolimus

Post-transplant diabetes mellitus (PTDM), pre-diabetes-impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are frequent complications after organ transplantation. The aim of this study was to assess the frequency of PTDM, IFG and IGT in a group of renal transplant recipients, to compare the frequency of glucose metabolism disorders in subjects treated with tacrolimus and with cyclosporine, and to establish the influence of different risk factors on the development of glucose metabolism disorders.. We examined 206 non-diabetic kidney allograft recipients (age 46.4 ± 12.3 years, time since transplantation 45.5 ± ± 33.6 months, BMI 26.3 ± 4.5 kg/m2). Glucose metabolism disorders were diagnosed using an oral glucose tolerance test. Logistic regression was used to assess the influence of each risk factor (age, BMI, waist circumference, physical activity, the presence of cardiovascular disease, positive family history of diabetes, cholesterol and triglycerides concentration) on the development of glucose metabolism disorders.. In 103 patients (50%), we diagnosed glucose metabolism disorders. 19% of patients had PTDM, 14% IFG, and 17% IGT. We did not find any differences in the frequency of glucose metabolism disorders between patients treated with tacrolimus and with cyclosporine. Multivariate analysis identified BMI and a family history of diabetes as independent risk factors of glucose metabolism disorders.. We found a high prevalence of glucose metabolism disorders in the examined group. This suggests that kidney transplant recipients should be screened for these disturbances. Patients with higher BMI and with first-degree relatives with diabetes had an increased risk of glucose metabolism disorders after kidney transplantation.

Topics: Blood Glucose; Cardiovascular Diseases; Causality; Comorbidity; Cyclosporine; Female; Glucose Metabolism Disorders; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Logistic Models; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Risk Factors; Tacrolimus

Insulin resistance may interact with calcineurin inhibitors, enhancing the diabetogenic effect of tacrolimus compared with cyclosporine-A. We studied both drugs in insulin-resistant animals: obese Zucker rats (n = 45), and insulin-sensitive animals: lean Zucker rats (n = 21). During 11 days, animals received saline-buffer, cyclosporine-A (2.5 mg/kg/day) or tacrolimus (0.3 mg/kg/day). At Days 0 and 12 animals underwent intraperitoneal glucose tolerance test (0-30-60-120 min). Islet morphometry, beta-cell proliferation, apoptosis and Ins2 gene expression were analyzed. By Day 12, no lean animal had developed diabetes, while all obese animals on tacrolimus and 40% on cyclosporine-A had. In obese animals, tacrolimus reduced beta-cell proliferation and Ins2 gene expression compared with cyclosporine-A. Five days after treatment discontinuation, partial recovery was observed, with only 10% and 60% of the animals on cyclosporine and tacrolimus remaining diabetic respectively. Beta-cell proliferation increased in animals on tacrolimus while Ins2 gene expression remained unaltered. In conclusion, insulin resistance exacerbated the diabetogenic effect of tacrolimus compared with cyclosporine-A. This may be explained by greater inhibition of Ins2 gene and beta-cell proliferation by tacrolimus in the insulin resistant state. Discontinuation of the drugs may allow the recovery of the metabolic alterations.

Topics: Animals; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Experimental; Gene Expression Regulation; Glucose Tolerance Test; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Obesity; Rats; Rats, Zucker; Real-Time Polymerase Chain Reaction; RNA; Tacrolimus; Thinness

We sought to evaluate the prevalence and confounding clinical variables of hyperuricemia in pediatric kidney transplant patients.. We retrospectively evaluated the medical records of 151 pediatric renal transplant recipients who received their grafts at Akdeniz University Medical Faculty in Antalya, Turkey, with a follow-up longer than 6 months. This retrospective, single-center study included 117 pediatric renal transplant recipients, after we had excluded the patients with changes in immunosuppressive treatment and graft loss, who were receiving therapy with allopurinol and furosemide. Patient information and laboratory data were obtained from patient charts and an electronic hospital database.. Mean uric acid levels of patients were 311 ± 74 μmol/L, and 24 of all of the patients (20%) had high uric acid levels. Fifteen patients taking tacrolimus (16%), and 9 of patients taking cyclosporine (39%) had hyperuricemia. The hyperuricemia rate of patients taking cyclosporine was significantly higher than it was for those patients taking tacrolimus (P = .014). Mean levels of uric acid in patients taking cyclosporine were higher than those of patients taking tacrolimus (344 ± 62 μmol/L and 303 ± 75 μmol/L; P = .006). There was a significant positive correlation between mean uric acid concentrations, and both serum creatinine (P = .000; r=0.487) and cystatin C (P = .000; r=0.433). There was negative correlation between mean uric acid concentration and estimated glomerular filtration rate (P = .000; r=-0.417). Mean uric acid levels of patients with intact graft function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m²) was lower than the patients with a low estimated glomerular filtration rate (291 ± 67 μmol/L and 353 ± 71 μmol/L; P = .000). Mean uric acid level of patients with normal body mass index was significantly lower than that of patients who were obese-overweight (301 ± 64 μmol/L vs 343 ± 94 μmol/L; P = .045).. We found 20% of our patient group had high uric acid levels. We also found that lower glomerular filtration rate, higher serum creatinine, cystatin c, obesity, and being overweight were risk factors for hyperuricemia in pediatric renal transplant recipients.

Topics: Adolescent; Child; Child, Preschool; Creatinine; Cyclosporine; Cystatin C; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hyperuricemia; Immunosuppressive Agents; Kidney Transplantation; Male; Obesity; Overweight; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; Transplantation

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Child; Drug Therapy, Combination; Female; Histamine Antagonists; Humans; Immunosuppressive Agents; Lichen Planus; Obesity; Pruritus; Remission Induction; Tacrolimus

Follicular carcinoma of the thyroid is a relatively rare malignancy in childhood even in paediatric solid organ transplant recipients. The risk of developing de novo malignancies after liver transplantation is higher compared to the general population. We report an 18-yr-old girl who had successfully undergone liver transplantation five yr earlier for neonatal sclerosing cholangitis complicated by the development of dysplastic nodules. Baseline immunosuppression was with tacrolimus and prednisolone. Mycophenolate mofetil was later added in view of steroid-resistant episodes of graft rejection. She subsequently suffered from marked obesity and essential hypertension needing antihypertensive medication. Five yr after liver transplantation, she presented with a right-sided thyroid swelling that was rapidly progressive with no associated lymphadenopathy and normal systemic examination. Ultrasound of her neck revealed a solid lesion in the right lobe of the thyroid gland with ill-defined margins, and a diagnostic right thyroid lobectomy confirmed the diagnosis of follicular carcinoma with focal capsular and vascular invasion. She underwent total thyroidectomy and currently remains well on thyroxine supplements. Our report highlights the need for high level of suspicion and prompt investigation into any abnormal lesion in the long-term follow-up of solid organ transplant recipients.

Topics: Adenocarcinoma, Follicular; Adolescent; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Obesity; Prednisolone; Tacrolimus; Thyroid Neoplasms; Treatment Outcome

Topics: Adolescent; Adult; Body Mass Index; Child; Graft Survival; Humans; Immunosuppressive Agents; Insulin Resistance; Kidney Transplantation; Metabolic Syndrome; Obesity; Risk; Tacrolimus

Post-transplant diabetes mellitus (PTDM) is a common and potentially serious complication after solid organ transplantation. There are only a few data, however, about the incidence of DM in patients undergoing lung transplantation.. The medical records of 119 consecutive patients who underwent lung transplantation from 1998 to September 2004 were reviewed. Patients were divided in three groups according to their diabetes status, including pre-transplant DM, the PTDM group and those without DM. Patient records and all laboratory data were reviewed and the clinical course of diabetes was monitored. All recipients were treated with tacrolimus based regimen.. Mean follow-up for all patients was 25+/-10. Twenty-three patients had DM in the pre-lung transplantation (LTX) DM group. PTDM developed in 34 of the remaining 96 patients (35.4%) with an incidence of 20%, 23% after 6 months and 12 months post-transplant. No significant difference was noted between 12 and 24 months post-LTX. The patients who developed DM were older (57+/-15 vs 53+/-13 years, p=0.009), had increased BMI (26+/-5 vs 24+/-4, p=0.0001), shorter time from diagnosis to LTX (21+/-13 vs 28+/-18 months, p=0.007) more cytomegalovirus infection and more acute rejection and hyperglycemia in the first month after LTX. Four patients died in the PTDM group compared to nine patients in the no-DM group (12% vs 14%; p=0.72).. Post-transplant diabetes is a common complication in lung transplant patients receiving tacrolimus-based immunosuppression. The risk for developing PTDM is greatest among older recipients, those obese, and among recipients with more rejections episodes.

Topics: Adult; Age Factors; Aged; Diabetes Mellitus; Female; Follow-Up Studies; Graft Rejection; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Logistic Models; Lung Transplantation; Male; Middle Aged; Obesity; Risk; Risk Factors; Tacrolimus

Topics: Antibodies, Monoclonal; Child, Preschool; Cyclosporine; Diagnostic Errors; Dwarfism; Granuloma; Hematuria; Humans; Immunosuppressive Agents; Infliximab; Male; Nephritis, Interstitial; Nephrosis, Lipoid; Nephrotic Syndrome; Obesity; Prednisolone; Proteinuria; Puberty, Delayed; Recurrence; Remission Induction; Tacrolimus; Tumor Necrosis Factor-alpha

Obesity is a frequent complication following liver transplantation and is insufficiently responsive to dietary and life style advice. We studied the safety of orlistat treatment in obese and overweight liver transplant recipients (n = 15) on a stable tacrolimus-based immunosuppressive regimen. For safety reasons, the treatment period was restricted (6 months 120 mg t.i.d., 3 months 120 mg daily). Three patients dropped out, tacrolimus dose was adjusted in six of 12 remaining patients (dose reduction in 4, increase in 2, P = N.S.). All dose adjustments occurred during the 6 months of orlistat 120 mg t.i.d. therapy. No drug intolerance, adverse events or episodes of rejection occurred during the study. Efficacy of orlistat treatment in this population could not be shown, because a formal control population was not included in this safety trial. Moreover, only a significant decrease of waist circumference (P < 0.01 versus start of the study), but not of weight or body mass index, was achieved in the treated group. Orlistat treatment is well tolerated in liver transplant recipients and can be started safely, provided immunosuppressive drug levels and dietary adherence are closely monitored.

Topics: Adult; Aged; Anti-Obesity Agents; Drug Interactions; Female; Humans; Lactones; Lipids; Liver Transplantation; Male; Middle Aged; Obesity; Orlistat; Overweight; Pilot Projects; Prospective Studies; Tacrolimus

Excessive weight gain is common after liver transplantation and frequently leads to obesity. This has been attributed to immunosuppression. The aim of the present study was to assess the extent of weight gain and the risk factors for weight gain after liver transplantation. Height and estimated dry weight were collected prospectively in consecutive adult liver-transplant patients, transplanted between January 1996 and October 2001. A total of 597 patients (45% female, median age of 50 years; range 16-73) was studied. Eighty-six percentage was transplanted for chronic liver disease. The median weight gain at 1 and 3 years was 5.1 and 9.5 kg above dry weight pretransplant. By 1 and 3 years, 24% and 31% had become obese (defined as a body mass index (BMI) >30 kg/m(2)). There was no significant difference in weight gain between the sexes, those who were obese before transplantation or those who received corticosteroids for >3 months. Weight gain was significantly greater (P < 0.05) in patients aged >50 years and those transplanted for chronic liver disease compared with fulminant liver failure. A pretransplant BMI >30 was a strong indicator that the patient would still have a BMI >30 at 3 years. There was no effect of the type of immunosuppression on weight gain. Obesity is common in the liver transplant population, but it seems to be unrelated to any specific immunosuppressive drug. The greatest weight gain occurs after the first 6 months and intervention with dietary advice at this point could be implemented to minimize the long-term morbidity and mortality risks associated with obesity.

Topics: Adolescent; Adult; Aged; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Obesity; Prospective Studies; Tacrolimus; Weight Gain

For the purpose of both efficacy and safety, exposure to tacrolimus and other immunosuppressive drugs must be monitored, since initial levels influence the development of acute rejection episodes, nephrotoxicity, and posttransplantation diabetes mellitus. The aim of this study was to identify risk factors for developing high initial tacrolimus blood levels. We analyzed clinical and biochemical parameters of 85 renal transplant recipients receiving tacrolimus-based immunosuppressive therapy by stratifying into subgroups of patients who displayed first tacrolimus concentrations higher and lower than 15 ng/mL. Patients with a first level of tacrolimus higher than 15 ng/mL were older (52 +/- 13 vs 40 +/- 12 years, P < .05) and had a larger body mass index (27 +/- 4 vs 23 +/- 3 kg/m2, P < .05) than patients with lower levels, despite receiving a lower weight-adjusted cumulative steroid dose (8.2 +/- 2.2 vs 9.3 +/- 2.5 mg/kg, P < .05). Upon logistic regression, age (RR 1.047, 95% CI 1.007 to 1.08, P = .021) and body mass index (RR 1.176, 95% CI 1.009 to 1.371, P = .036) remained significant risk factors for high initial blood levels of tacrolimus. As these subgroups of patients are most prone to develop posttransplantation glycemic disorders, attention must be paid to avoid high tacrolimus blood levels by diminishing initial tacrolimus doses or estimating them from ideal body weight.

Topics: Area Under Curve; Body Mass Index; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Male; Middle Aged; Obesity; Regression Analysis; Renal Dialysis; Retrospective Studies; Tacrolimus

We report a 20-year-old-male with severe aplastic anaemia who was treated with nonmyeloablative haematopoietic stem cell transplantation (NSCT) from a sibling donor. As the patient presented with complications consisting of mental retardation, severe obesity, a bone fracture, and recurrent infections, we selected NSCT instead of a myeloablative regimen, to reduce regimen-related toxicity (RRT). Conditioning therapy consisting of busulfan, fludarabine, antithymocyte globulin and FK506 was used to obtain immune suppression. RRT was limited and he is now in complete remission 19 months after NSCT. On day 91, he developed chronic graft-vs.-host disease; it was resolved by the combination of FK506, corticosteroids, and mycophenolate mofetil. Our experience contributes to the growing interest in NSCT as a modality for treating not only malignant haematological disorders associated with complications, but also nonmalignant haematological diseases.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Busulfan; Female; Fractures, Bone; Graft Rejection; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Intellectual Disability; Male; Methylprednisolone; Mycophenolic Acid; Obesity; Peripheral Blood Stem Cell Transplantation; Prednisolone; Remission Induction; Siblings; T-Lymphocytes; Tacrolimus; Tissue Donors; Transplantation Chimera; Transplantation Conditioning; Vidarabine

In a retrospective study the records of 302 adult patients (167 male, 135 female) after orthotopic liver transplantation (OLT) with a minimum follow-up of 6 months (median follow-up 18 months, maximum 5 yr) were reviewed with regard to cardiovascular risk factors. In 197 patients data concerning the occurrence of arterial hypertension, hyperglycemia, or hypercholesterolemia prior to OLT were available. We found a highly significant increase of cardiovascular risk factors following OLT. Obesity was found in 17.4% of male and 22.2% of female recipients after OLT. Hypercholesterolemia was evident in 66.2% of liver graft recipients. Hypertriglyceridemia occurred in 49.7% of all male patients. In females there was a significantly different prevalence of hypertriglyceridemia comparing patients with a follow-up period up to 2 yr and more than 2 yr (50% vs. 24.6%, p = 0.018). Nearly 45% of all patients met the criteria for arterial hypertension, with a slight increase in male patients beyond the second year of survival (p = 0.094). Hyperglycemia had a significantly higher frequency in male than in female patients (30.5% vs. 10.4%, p < 0.005). Furthermore we observed a clear trend towards reduction of occurrence of hyperglycemia more than 24 months after OLT, but not reaching statistical significance. No correlation was detected when serum levels of triglycerides, and cholesterol, body-mass-index, and arterial blood pressure were compared with applied dosages of immunosuppressive agents [cyclosporin A (CyA), tacrolimus, and prednisolone]. Only decreasing tacrolimus application was significantly correlated with decreasing glucosemia (p = 0.041). Patients receiving tacrolimus instead of CyA as primary immunosuppressant showed a significantly lower prevalence of hypercholesterolemia. Even hypertension, hyperglycemia, hypertriglyceridemia, and obesity had a lower occurrence in patients treated with tacrolimus although not reaching statistical significance.

Topics: Adolescent; Adult; Aged; Blood Glucose; Cardiovascular Diseases; Cyclosporine; Female; Follow-Up Studies; Glucocorticoids; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Obesity; Prednisolone; Retrospective Studies; Risk Factors; Tacrolimus

The development of atherosclerotic cardiovascular complications is a common and serious problem for the long-term survivors of organ transplantation. Cyclosporine A plus steroid-based immuno-suppression regimens in these patients are associated with the development of hypertension, hyperlipidemia, obesity, and diabetes mellitus. Whether the new immunosuppressive agent tacrolimus (FK506) confers any advantage in terms of these cardiovascular risk factors has been less well studied. We compared serial changes in blood pressure, lipids, body weight, and glucose levels during the first 12 months after liver transplantation in patients using either cyclosporine A (n = 39) or tacrolimus (n = 24)-based immunosuppression. By 12 months, the prevalence of hypertension, hypercholesterolemia, and obesity was increased in the cyclosporine A group compared to tacrolimus: 82% versus 33%, 33% versus 0%, and 46% versus 29%, respectively (all p < .05). Triglyceride and total cholesterol levels were 196 +/- 23 versus 125 +/- 13 mg/dL and 225 +/- 9 versus 159 +/- 7 mg/dL for the cyclosporine A versus tacrolimus groups, respectively (p < .05). Cumulative posttransplant steroid dose was not related to the observed lipid changes in either group, although the increase in triglycerides was positively correlated to weight gain and diuretic use in the cyclosporine A group. The incidence of diabetes mellitus was not increased from baseline in either group. These results indicate that tacrolimus, compared to cyclosporine A, is associated with a less adverse cardiovascular risk profile in the first year after liver transplantation. Whether these differences persist and become clinically relevant to a liver transplant recipient population that is increasingly older and has more preexisting cardiovascular disease remains to be determined.

Topics: Adult; Benzothiadiazines; Blood Glucose; Blood Pressure; Body Weight; Cyclosporine; Diabetes Mellitus; Diuretics; Female; Humans; Hypercholesterolemia; Hypertension; Hypertriglyceridemia; Lipids; Liver Transplantation; Male; Middle Aged; Obesity; Prednisone; Risk Factors; Sex Factors; Sodium Chloride Symporter Inhibitors; Tacrolimus

Topics: Biomarkers; Cardiovascular Diseases; Cross-Sectional Studies; Cyclosporine; Follow-Up Studies; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Obesity; Prevalence; Retrospective Studies; Risk Assessment; Risk Factors; Survival Rate; Tacrolimus