CsA Group Research Articles

The Effects of Childhood Sexual Abuse and Other Trauma on Drug Court Participants

Within the context of a larger study of drug court participants, this study examined the impact of traumatic experiences on psychiatric distress and on court outcomes. In the analyses, the participants (n = 229) were separated into 3 groups: childhood sexual abuse (CSA; n = 18), other trauma (n = 134), and no trauma (n = 77). The CSA group had higher mean scores on depression, anxiety, panic disorder, social phobia, somatization, and posttraumatic stress disorder than the other trauma group. Path analyses suggest that a history of trauma is a positive predictor of psychiatric distress and negative court events (positive urine screens, sanctions, etc.), with indirect effects on substance abuse severity, and failure in the drug court. These results suggest a need for the initial assessment procedure in drug courts to include a screening for trauma history, including CSA. They also suggest a need for trauma-informed care within drug courts.

Histomorphometric and histological evaluations of the simvastatin effect on alveolar bone loss induced by cyclosporine A in rats

Background: Cyclosporin-A- has been used as an immunosuppressant to prevent the rejection of organ transplants. However, alveolar bone loss is an important negative side-effect of this drug. Simvastatin, a hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is known to inhibit cholesterol biosynthesis. It has advanced effects on bone formation in vivo and in vitro. So,we evaluated the histological and histomorphometric analysis of osteoblast and osteoclast cells after administration of simvastatin in cyclosporin-A-associated alveolar bone loss in rats. Aim of the Study: To evaluate the effect of simvastatin and cyclosporin -A- on Alveolar bone by investigating the histological and histomorphometric results of osteoblast and osteoclast cells. Materials and Methods: 24 adult male rats will be divided into 3 groups: Group I: Control group; 4 rats, Group II: cyclosporine -A- group; 10 rats (10 mg/kg) subcutaneous injection, Group III: cyclosporine -A-/simvastatin group; 10 rats, simvastatin will be taken orally daily (20mg/kg/day). Two rats from the control group and 5 rats from each of the studied experimental groups (group II & III) were sacrificed on days 15 and 30 consecutively using Histological and Histomorphometric investigations. Results: Histological results revealed higher bone volume and osteoblast cells, and decreased number of osteoclast cells in Simvastatin group than in CsA group. The same results was statistically significant in Histomorphometric results of both osteoblast and osteoclast cells counts. In Histomorphometrical analysis showed a significant increase of osteoblast cells in Simvastatin group than CsA group, and significant decrease of osteoclast cells in Simvastatin group than CsA group. Conclusion: We can conclude that Simvastatin counteract the adverse effect of CsA induced alveolar bone loss that induced new bone formation.

Effects of Calcineurin Inhibitors on Rat Thoracic and Abdominal Aortae Contractibility and Vasodilatation

Context: Calcineurin inhibitors (CNIs) therapy such as cyclosporine (CsA) and tacrolimus (Tac) are associated with hypertension. Objective: Compare the differential effect of these two agents on thoracic and abdominal aortae. Methods: Thirteen weeks old male Sprague-Dawley rats were treated with CsA (15 mg/kg), Tac (0.15 mg/kg) and vehicle for 15 days. At the end of study, rats were anesthetised, and blood pressure (BP) and heart rate (HR) were measured. Both thoracic (TA) and abdominal (AA) aortae were assessed for the contractibility responses with α1 agonist phenylephrine (PE) against terazosin, a α1 receptor blocker. In addition, vascular relaxation was assessed using endothelium-dependent, Acetylcholine-induced and endothelium-independent sodium nitroprusside-induced pathways in PEconstricted TA and AA. Results: Elevated arterial BP was noted in Tac group, however, HR did not showed any changes in Tac and CsA groups as compared to controls. PEinduced contractibility of TA but not AA was increased significantly and equally by CsA (EC50, 55 ± 7.06 nM) and Tac (EC50, 50 ± 6.6 nM) treatment as compared to control (104 ± 14 nM). ACh-induced endothelium-dependent relaxation was attenuated by both CsA (TA: Imax 66 ± 8.79 %, AA: Imax 74 ± 11.38 %) and Tac (TA: Imax 39 ± 9.55 %, AA: Imax 70 ± 20.06 %), however its intensity was higher in TA by Tac group (controls: 97-98 ± 2.6-2 %). Similarly, SNP-induced endothelium-independent vascular relaxation was also affected by CsA and Tac treatment, TA (IC50 control, 47 ± 11.2 nM, vs. CsA, 214 ± 27.9 nM and Tac, 191 ± 30.8 nM, p< 0.05) and AA (IC50 control, 164 ± 45.1 nM, vs. CsA, 424 ± 53.4 nM and Tac, 520 ± 104.1 nM, p< 0.05). Conclusions: Our functional data confirms that CNIs have differential effects on rat TA and AA via either alternation of vascular relaxations or contractions.

Incidence of Development of Obesity After Heart Transplantation According to the Calcineurin Inhibitor

BackgroundDevelopment of obesity after heart transplantation (HT) is a common complication, largely attributed to immunosuppressive therapy. The objective of this study is to compare the incidence of development of obesity after HT, according to the calcineurin inhibitor (CNI) used (cyclosporine [CsA] vs tacrolimus [Tac]). MethodsWe studied 101 consecutive HT patients from November 2006 to December 2010. A diagnosis of overweight–obesity was made by a body mass index of ≥25 kg/m2, which was assessed before HT and at 1 year after HT. Patients were randomly assigned to the administration of CsA or Tac by a simple randomization method using a computer program (56% received CsA and 44% Tac). ResultsOf the 101patients, 77% were men, and ischemic heart disease was the most common indication for HT. At baseline, there were no differences in weight between groups treated with CsA or Tac. The mean weight for each group was 71.5 ± 12 and 75 ± 14 kg, respectively (P = .2). The weight increase was greater among CsA patients: after HT, the weight gain was 6.9 ± 11 kg in the CsA group, whereas a minimal weight loss of 0.03 ± 14 kg (P = .008) was experienced in the group treated with Tac. The multivariate analysis showed that only CsA treatment was an independent predictor of development of obesity 1 year after HT (odds ratio, 3.84; 95% CI, 1.04–14.21; P = .01). ConclusionWeight gain after HT may be related to the CNI used and CsA seems to be the CNI that produces the greatest increase.

Is there a genetic predisposition to new-onset diabetes after kidney transplantation?

Kidney transplant recipients may develop new-onset diabetes after transplantation (NODAT) and transplant-associated hyperglycemia (TAH) (NODAT or new-onset impaired glucose tolerance-IGT). We studied 251 consecutive renal transplant South Asian recipients for incidence of NODAT and its risk factors between June 2004 and January 2009. Pre-transplant glucose tolerance test (GTT) identified non-diabetics (n = 102, IGT-24, NGT-78) for analysis. Baseline immunosuppression along with either cyclosporine (CsA) (n = 70) or tacrolimus (Tac) (n = 32) was given. Patients underwent GTT 20 days (mean) post-transplant to identify NODAT, normal (N) or IGT. TAH was observed in 40.2% of the patients (40% in CsA and 40.6% in Tac) (P = 0.5). NODAT developed in 13.7% of the patients (12.9% in CsA and 15.6% in Tac) (P = 0.5). Overall, Hepatitis C (P = 0.007), human leukocyte antigen (HLA) B52 (P = 0.03) and lack of HLA A28 (A68/69) (P = 0.03) were associated with TAH. In the Tac group, higher Day 1 dosage (P <0.001), HLA A1 (P = 0.04), B13 (P = 0.03) and lack of DR2 (P = 0.004) increased the risk of TAH. In the CsA group, HLA A10 (P = 0.03), failure of triglyceride (P = 0.001) or low-density lipoprotein (LDL) (P = 0.03) to lower or high-density lipoprotein to rise (P = 0.001), and higher post-transplant LDL (P <0.001) and cholesterol levels (P = 0.02) were associated with NODAT or TAH. Post-transplant fasting plasma glucose on Day 1 had sensitivity-54.5%, specificity-50.1%, positive predictive value-18.1% and negative predictive value-84.8% for detecting NODAT. In conclusion, there is a genetic predisposition to NODAT and TAH in South Asia as seen by the HLA associations, and a predisposition exists to the individual diabetogenic effects of Tac and CsA based on HLA type. This could lead to more careful selection of calcineurin inhibitors based on HLA types in the South Asian population.

Early intensified intravenous cyclosporine therapy predicts favorable response to immunosuppressive therapy with rabbit antithymocyte globulin in patients with severe aplastic anemia

Because of relapse after horse ATG (hATG) therapy, rabbit ATG (rATG) would be a realistic alternative as second line immunosuppressive therapy (IST) in severe aplastic anemia (SAA) patients. We investigated whether intensified intravenous (IV) CsA therapy with rATG would increase the response of IST in SAA patients.Sixty-one of the 123 patients received IV CsA therapy with rATG during initial 2 weeks then changed to oral form (IV CsA group), while other 62 patients just received oral CsA therapy with rATG (oral CsA group).Hematologic response rates at 3 and 6 months were not different between IV CsA group and oral CsA group (p=0.795, p=0.079). However, CsA levels during initial 15 days were higher in response-achieved group than response-not-achieved group. Intensive IV CsA group maintained CsA level ≥300ng/ml during 15 days had higher responses at 6 months than non-intensive IV CsA group and oral CsA group (p=0.009, p=0.021). Intensive IV CsA group (HR=3.239, 95% CI=1.095–8.997, p=0.013) independently predicted favorable the hematologic response at 6 months of IST.Early intensified CsA therapy was important to achieve favorable outcomes in IST including rATG.

Short- and Long-term Risk of Coronary Artery Bypass Graft Surgery in Acute Coronary Syndrome

Background: Percutaneous coronary intervention is the revascularization procedure most widely used in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). However, coronary artery bypass graft surgery is a therapeuticalternative which allows treating these patients with a favorable outcome.Objectives: The aim of this study was to compare in-hospital and long-term outcome of patients undergoing coronary arterybypass graft surgery according to their clinical presentation.Methods: Between January 1998 and July 2013, 3604 consecutive patients underwent isolated coronary artery bypass graftsurgery. The population was divided in patients with NSTEACS (ACS Group, n = 2079) or with chronic stable angina (CSAGroup, n = 1525). Postoperative and at follow-up morbidity and mortality were analyzed.Results: The CSA group had greater use of double mammary artery (58.2% vs. 50.3%; p = 0.001) and longer operative time(211 min vs. 203 min; p = 0.002). The ACS Group presented lower postoperative cardiac output (4.5% vs. 3.1%; p = 0.043) andhigher in-hospital mortality (2.8% vs. 1.8%; p = 0.046). After adjusting for risk score, there were no statistically significantdifferences in in-hospital mortality (1.3% in CSA vs. 1.6% in ACS; p = 0.681) or in the rate of postoperative complicationsbetween the two groups. Overall long-term survival at 10 years was not different between groups (CSA 85% ± 1.3% vs. ACS83% ± 1.1%; p = 0.363). The time-related freedom from reintervention was similar for both groups (CSA 89.5% ± 1.2% vs.ACS 89.1% ± 0.9%; p = 0.1680). These results did not change after adjusting for risk score.Conclusions: Patients with NSTEACS submitted to coronary artery bypass graft surgery presented greater perioperativemortality, but a long-term outcome similar to patients undergoing elective surgery. No difference in perioperative mortalitywas found between both groups after adjusting for risk score.

Immunosuppressive Treatment Combined with Nucleoside Analogues Is Superior to Nucleoside Analogues Alone in the Treatment of Severe Thrombocytopenia in Patients with Cirrhosis-Associated with Hepatitis B in China: A Multicenter, Observational Study

Introduction: Thrombocytopenia is a frequent manifestation of liver cirrhosis (LC) related to the hepatitis B virus (HBV). Severe thrombocytopenia is associated with bleeding events that increase morbidity and mortality in patients with LC. No effective treatment has been identified for patients with composited liver cirrhosis associated with HBV and severe thrombocytopenia. The pathogenesis of thrombocytopenia in liver diseases has not been well established. It has been suggested that autoantibody-mediated platelet destruction might contribute, at least in part, to hepatitis B cirrhotic thrombocytopenia. We aimed to explore the effectiveness and safety of low dose prednisone or low dose cyclosporine combined with a nucleoside analogue in patients with severe thrombocytopenia associated with HBV-related LC.Methods: In this observational cohort study, we included 145 consecutive compensated HBV-associated LC patients with severe thrombocytopenia (PLT<30,000 per cubic millimeter, accompanied by a tendency towards bleeding) between January 1, 2006 and December 31, 2013. We divided the patients into three groups by treatment strategy, including NA alone (n=57), NA plus prednisone (n=46), and NA plus cyclosporine (CsA) (n=42). Prednisone was given at a dosage of 0.5 mg/kg/d for 4 weeks until a response was observed or until the side effects became intolerable. The cyclosporine regimen consisted of oral CsA at a dosage of 1 mg/kg/d given in two divided doses. The dose of prednisone or CsA was then slowly tapered in the patients who responded to the drugs. We analyzed the platelet counts, bleeding events, liver function, replication of HBV, and outcomes in each group. The platelet counts following the treatments were estimated using mixed-effects linear models that included all available platelet counts after treatment. These models were adjusted by age, sex, the Child-Pugh score, other systemic complications, platelet transfusion, and research center. Cox proportional hazards analyses were performed to examine the factors related to bleeding events. Data was analyzed using IBM SPSS Statistics version 19.0 (SPSS Inc., an IBM company). P values less than 0.05 were considered significant. This study is registered with ClinicalTrials.gov under number NCT01987791.Results: At all time points during this observation, platelet counts in the prednisone plus NA and CsA plus NA groups were higher than those in the NA group. In the group receiving prednisone plus NA, 35 of the 46 patients (76.1%) had platelet counts of 50,000 per cubic millimeter or greater during this observation. As in the CsA plus NA group, 30 of the 42 patients (71.4%) had platelet counts of 50,000 per cubic millimeter or greater. Only 4 of the 57 patients (7.0%) in the NA treatment group had platelet counts that were higher than 50,000 per cubic millimeter. The cumulative bleeding events in the three treatment groups were 67.0% in the NA only group, 56.9% in the prednisone group and 62.2% in the CsA group. The cumulative rates of bleeding events were significantly different among the three groups (p=0.001). The platelet counts, treatment with prednisone plus NA and treatment with CsA plus NA were factors associated with bleeding events in the multivariate analysis. After treatment, serum alanine transaminase levels were significantly lower than those before treatment in all groups. The differences in the HBV-DNA negative rates, HBV-DNA elevated rates, normal serum alanine transaminase rates, serum alanine transaminase rates that elevated more than two times the baseline rate, and HBeAg seropositive conversion ratios among the groups did not reach statistical significance. Levels of the platelet-associated anti-GPIIb-IIIa antibodies after the 4-week treatment were lower than those at baseline in the prednisone group and CsA group; no difference was observed in the NA alone group. The adverse events in our study were mild in general and balanced among the three treatment groups.Conclusions: Treatment with low dose prednisone or low dose CsA plus NA could elevate the platelet count and reduce the risk of bleeding events in HBV LC patients with severe thrombocytopenia; the treatment had no obvious adverse effects on liver function and HBV DNA replication. DisclosuresNo relevant conflicts of interest to declare.

Regulatory effect of As₂O₃on imbalance between adipogenic and osteogenic differentiation of BM-MSC from patients with aplastic anemia

This study was aimed to explore the regulation of arsenic trioxide (As₂O₃) on imbalance between adipogenic and osteogenic differentiation of BM-MSC from patients with aplastic anemia(AA). The BM-MSC from AA patients were separated and purified, placed into the adipogenic and osteogenic differentiation culture system, then added the As₂O₃, CsA, As₂O₃combined with CsA were added to corresponding differentiation culture system, the concentration of As₂O₃and CsA were set at 0.001 µmol/ml and 2.5 mmol/ml respectively, the cells were divided into As₂O₃group, the CsA group, combined group and control group (no drug). The cell morphological observation, oil red 'O' staining, Von-Kossa staining, and RT-PCR were used to detect corresponding differentiation marks. The results indicated that in respect to adipogenic differentiation, cellular morphology observing and oil red 'O' staining showed that the rate of adipocyte differentiation in As₂O₃group was (18.3 ± 1.9)%, which was lower than the (91.8 ± 2.7)% in the CsA group and (92.1 ± 1.2)% in control group (P < 0.05), there was no significant difference in comparison with (8.3 ± 1.9)% in the combined group (P > 0.05), but the rate of differentiation in CsA group was higher than that in combined group (P < 0.05), and there was no significant difference in comparison wtih control group. RT-PCR showed that the LPL-mRNA expression level in As₂O₃group were significantly lower than that in the CsA group and the control group (P < 0.05), no difference was observed while compared with the combined group (P > 0.05), but the LPL-mRNA expression level in CsA group was significantly higher than that in the combined group (P < 0.05). In terms of osteogenetic differentiation, the calcium deposition in As₂O₃group and combined group was obviously observed while rarely in the CsA group and the control group when detected by the Von-Kossa staining. OST-mRNA expression level in As₂O₃group were higher than that in CsA group and the control group (P < 0.05), while compared with the combined group, there was no significant difference (P > 0.05), but the OST-mRNA expression level in the CsA group was lower than that in the combined group (P < 0.05). It is concluded that As₂O₃can significantly enhance the ability of BM-MSC from AA patients to differentiate into osteoblast, also can inhibit the adipogenic differentiation, in contrast, the CsA can not promote the osteoblast differentiation of BM-MSC from AA patients.

Comparison between two different dose of r-ATG combined with CsA for treating children with severe aplastic anemia

This study was purposed to compare the efficacy and safety of two different doses of rabbit anti-thymocyte globulin (r-ATG) combined with cyclosporine (CsA) for treating children with severe aplastic anemia (SAA). From January 2005 to July 2010, a total of 95 children with SAA accepted intensive immunosuppressive therapy (IIST) in our department, out of them 55 cases were treated with r-ATG 2.5 mg/(kg·d) for 5 days in combination with CsA (group I) and other 40 cases were treated with r-ATG 3.5 mg/(kg·d) for 5 days in combination with CsA (group II). The responsive rate, adverse reactions, early mortality, relapse and clonal disease were analyzed retrospectively and results between the two groups were compared. Out of 95 patients 43 were boys and 52 were girls, their ages were from 1 to 16 years. The sex, age, severity and course of the disease were comparable between the two groups. The results showed that after treating for 3 and 6 months, the response of patients in group II was higher than that of patients in group I (50% vs 32.1%, P = 0.08 and 65% vs 45.3%, P = 0.059), at 9 and 12 months the response rate of patients in group II and group I did not show significant difference (70.0% vs 71.1%,P = 0.904 and 82.5% vs 80.8%,P = 0.832); at 12 months of treatment, the complete response rate of patients in group II was significantly higher than that of patients in group I (40.0% vs 23.1%,P = 0.08); at 3, 6, 9 months of treatment, the complete response rate of 2 groups showed no obvious difference. The incidence of serum disease, early infection and early mortality did not show statistical difference between two groups. There was no statistical difference in 2 year overall survival rate of two groups. In group I 39 patients were followed-up for more than 2 years, among them 3 patients relapsed, 1 patient died and 1 patient was diagnosed as acute monocytic leukemia (M5). In group II 15 patients were followed up for more than 2 years, there were no relapse, death and clonal disease. It is concluded that the r-ATG combined with CsA is an effective and safe therapeutic regimen for the SAA children. The effect of r-ATG 3.5 mg/(kg·d) is better than the 2.5 mg/(kg·d). The early safety is comparable between the two groups. However, the long-term effect, complications and survival rate need longer follow-up study to evaluate.

Effect of Immunosuppressive Therapy on the Serum Fatty Acids of Phospholipids Fraction in Patients After Heart Transplantation

BackgroundThe effects of tacrolimus (Tac) and cyclosporine (CsA) on lipid profile is well known; however, little is known about the changes in fatty acids (FA) of phosholipids fraction (PL) in heart transplant patients after treatment with these immunosuppressants. This study aimed to investigate the effect of Tac and CsA on serum FA of PL in heart transplant patients. MethodsThe study included 23 patients after heart transplantation on Tac (n = 14; group II) or CsA (n = 9; group I). Eleven healthy persons served as a control group. Serum FA of PL were extracted, separated on Sep-Pak NH2, methylated, and measured with the use of gas chromatography. Chemstation software was used to analyze the data. ResultsNo differences between the studied groups and control were noted for saturated FA, monounsaturated FA, polyunsaturated FA (PUFA), total FA, and PUFA n-6. The mean value of PUFA n-3 was significantly higher in the CsA group compared with the Tac group (P < .015) and control (P < .002) as well as in the Tac group compared with control (P < .001). For individual FA, higher mean concentration, compared with control, was found for C24, C20:2, C20:4, and C22:6 (P < .001 in all cases) and lower for C18:2cis (P < .001 in both groups) and for C18:3 in the Tac group. The mean values of PUFA n-6 to PUFA n-3 ratios were lower than in control (both P < .001). ConclusionsDifferent pattern of FA of PL may indicate the different FA metabolism in heart transplant patients treated by different immunosuppressants. This should be taken into account when FA supplementation in these patients is considered.

Increase in de novo food allergies after pediatric liver transplantation: tacrolimus vs. cyclosporine immunosuppression.

Post-TAFA is an uncommon but serious complication of organ transplantation. This study aimed to compare the incidence of FA in CsA and tacrolimus-treated children following OLT and identify risk factors. The medical charts of all patients who underwent OLT at our institution were reviewed. Between 1985 and 2010, 218 OLTs were performed on 188 pediatric recipients, of which 154 were included in the study. Three patients (3%) of the 102 receiving CsA developed FA, compared with nine (17%) in the 52 tacrolimus-treated patients, the latter exceeding general population reported FA prevalence (RR 5.88; 95% CI: 1.66-20.81). All TAFA cases underwent transplantation before the age of three with an incidence of 29% (9/31) in the tacrolimus-treated children in comparison with 7% (3/41) in the CsA group (RR 3.97; 95% CI: 1.17-13.45). Eosinophilia was present in 81% of children receiving tacrolimus compared with 54% in the CsA group (p=0.002). We observed a statistically significant increase incidence of FA in tacrolimus-treated children following an OLT and those under the age of three are particularly vulnerable. The underlying process is still unknown and probably multifactorial.

Ginseng treatment attenuates autophagic cell death in chronic cyclosporine nephropathy

Chronic cyclosporine (CsA) treatment induces autophagic cell death characterized by excessive autophagosome formation and decreased autophagic clearance. In this study, we evaluated the influence of ginseng treatment on autophagy in chronic CsA nephropathy. Mice were treated with CsA (30 mg/kg) with or without Korean red ginseng (KRG) extract (0.2, 0.4 g/kg) for 4 weeks. The effect of KRG on CsA-induced autophagosome formation was measured using phospholipid-conjugated form of LC3-II, beclin-1, and autophagic vacuoles were visualized with electron microscopy. Autophagic clearance was evaluated by accumulation of p62/sequestosome 1 (p62) and ubiquitin, then double immunolabeling for p62 and either LC3-II or ubiquitin. To demonstrate the association between the effects of KRG treatment on autophagy and apoptosis, double immunolabelling for LC3-II and active caspase-3 was performed. Multiple autophagy pathways were also examined. KRG co-treatment significantly decreased the expression of LC3-II, beclin-1, and the number of autophagic vacuoles compared with the CsA group, and these changes were accompanied by improvements in renal dysfunction and fibrosis. CsA-induced accumulation of p62 and ubiquitin was also decreased by KRG treatment, and these proteins were colocalized with LC3-II and with each other. KRG treatment simultaneously reduced the expression of both active caspase-3 and LC3-II in the injured area. KRG treatment during chronic CsA nephropathy induced the expression of AKT/mTOR, which is a pathway that inhibits autophagy, and reduced AMPK expression. Ginseng treatment attenuated CsA-induced excessive autophagosome formation and autophagic aggregates. These findings suggest that ginseng has a renoprotective effect against CsA-induced autophagic cell death.

The Spiesser Study: Results at 8 Years.

Introduction. The Spiesser study was a randomized trial comparing de novo sirolimus (SRL) and cyclosporine (CsA) in low immunologic risk kidney translant recipients. SRL-based regimen provided a better kidney graft function at 5 years. We therefore extended follow-up to 8 years. Methods. Data of all patients with a functioning graft at 5 years were retrospectively collected. In intent-to-treat analysis was performed. Quantitative values and actuarial survivals were compared using the Fisher test and the log rank test, respectively. Results. Data from 112 (55 SRL, 57 CsA) out of 119 patients were available. Between 5 and 8 years post-transplantation, SRL was withdrawn in 6 patients (2 in CsA group). Thus, 37% of SRL patients versus 46% of CsA patients were still on the allocated treatment at 8 years. Mean MDRD eGFR was higher in SRL-group than in CsA group (64.0±29.5 vs. 49.6±18.2 ml/min, p=0.012). No difference was observed for proteinuria (SRL 0.8±1.2 vs CsA 0.6±1.7 g/day, p=0.163). After 5 years, 8 ESRD (2 SRL, 6 CsA) and 5 deaths (SRL 3, CsA 2) occurred. There was no difference for graft survival (p=0.615), patient survival (p=0.724) and death-censored graft survival (p=0.721). De novo DSA were observed in 17 patients, without any difference between SRL- and CsA groups (p=0.520). No differences were observed for incidence of solid and/or cutaneous cancer. Conclusion. At 8 years post-transplantation, renal function remains better in SRL-patients without increase de novo donor specific anti-HLA immunization. DISCLOSURES:Lebranchu, Y.: Grant/Research Support, Roche Laboratory funded this extension study.

Comparison of Interleukin-2 (Il-2) Blockade in Kidney Transplant Patients Randomized to 40mg or 80mg Basiliximab (BSX) With Cyclosporine (CsA) or 80mg BSX With Everolimus (EVR).

Background. The IL-2 receptor antibody BSX at a total dose of 40mg is known to achieve saturation of the CD25 antigen on activated T-lymphocytes for approximately five weeks in kidney transplant patients receiving concomitant CsA, an inhibitor of IL-2 production. A total BSX dose of 40mg may be inadequate to achieve CD25 saturation without concomitant CsA. The effect of higher BSX doses in CsA-free patients is unknown. Methods. In a 12-week, 3-arm, randomized, multicenter, prospective trial of BSX pharmacodynamics, 16 de novo KTP at low immunological risk received BSX at a total dose of 40mg+CsA (controls, n=3), 80mg+CsA (n=6) or 80mg+EVR (n=7), all with mycophenolic acid and steroids. The primary endpoint was the saturation kinetics of CD25 receptors by BSX to week 12, measured by the % of CD25+ T-cells at specified time points and expressed as saturation AUC (weeks). The AUC to week 12 for the % of T-cells binding BSX was also studied. Study recruitment ended prematurely due to a high number of biopsy-proven acute rejection (BPAR) episodes in BSX 80mg+EVR patients. Results. Mean [SD] AUC of CD25 saturation was 8.4 [1.6] weeks for BSX 40mg+CsA, 11.1 [1.1] weeks for BSX 80mg+CsA, and 9.7 [0.7] weeks for BSX 80mg+EVR. Mean [SD] AUC of basiliximab binding to CD25 receptors was 7.0 [1.8] weeks, 9.9 [2.2] weeks and 8.4 [0.8] weeks, respectively. Pharmacokinetic and pharmacodynamic analyses are currently being undertaken. BPAR occurred in one BSX 40mg+CsA patient, one BSX 80mg+CsA patient and four BSX 80mg+EVR patients. There were no deaths and one graft loss (BSX 40mg+CsA group). One adverse event with a suspected relation to BSX was reported, in the BSX 80mg+EVR group (BK virus infection). Conclusion. BSX at a total dose of 80mg with a CsA-free regimen may achieve similar CD25 saturation to 40mg with concomitant CsA during the first 3 months post-transplant. Although the total dose of BSX was doubled it did not seem to provide adequate immunosuppression in kidney transplant patients to prevent early acute rejection when combined with EVR. BSX at a dose of 80mg vs 40mg does not appear to be associated with increased BSX-related adverse events. DISCLOSURES:Lebranchu, Y.: Grant/Research Support, Novartis, Genzyme, Pfizer, Roche, Astellas, Other, Novartis, Genzyme, Pfizer, Roche, Astellas, Consulting fees. Merville, P.: Grant/Research Support, Novartis, Astellas, Speaker's Bureau, Novartis. Rostaing, L.: Speaker's Bureau, Novartis. Thibault, G.: Grant/Research Support, Novartis. Paintaud, G.: Grant/Research Support, Novartis. Quere, S.: Employee, Novartis. Di Giambattista, F.: Employee, Novartis.

Does Timng of MSC Infusion Determines Optimal Immunomodulation in a Renal Transplant Model in Rat?

Aim: To investigate the effectiveness and timing of the immunomodulatory response produced by mesenchymal stromal cells (MSCs) in a rat model of allogeneic kidney transplantation. Methods:To study the immunologic/immunosupressor effects of MSCs (donor), Lewis rats received an allogeneic kidney from Wistar rats. The infusion pattern of MSCs was determined in a previous experimental design where naïve rats were injected with 106cells and the principal cellular blood subpopulations were analyzed each 24 h.Rats were randomized into the four groups listed below and followed for 21 days. 1. NT, in which rats received infusion of PBS (n =7) 2. CsA, in which rats received a single daily dose of 5 mg/kg cyclosporine by oral gavages for 21 days (n =7) 3. MSC4, in which rats received two infusion of MSCs (106cells), Day -4 before renal transplantation and 1 hour after the surgery (n = 5) 4. MSC7, in which rats received two infusion of MSCs (106cells), Day -7 before renal transplantation and 1 hour after the surgery (n = 5). To study the principal cellular blood subpopulations and the renal function, samples were collected before the surgery, on day 7 post-transplant, and on the day of sacrifice. Results: Analyzing the three major subpopulations of lymphocytes in peripheral blood (T cells, B cells and NK cells), we observed that both MSC treatments decrease the percentage of the three lymphocyte subpopulations at 7 days post-transplantation. But the MSC7 group showed a percentage of lymphocytes similar to the CsA group. The renal function, measured by creatinine clearance, in the MSC7 group was significantly lower than the MSC4 and NT. The MSC7 group had significantly increased the survival respect to MSC4 and NT groups. Conclusions: MSC have a beneficial effect on the immune system of transplanted rats which improved graft function. However, the infusion pattern of MSCs plays a crucial role in the immune system modulation.

Long-Term Follow-Up of a Phase III Clinical Trial Comparing Tacrolimus Extended-Release/MMF, Tacrolimus/MMF, and Cyclosporine/MMF in De Novo Kidney Transplant Recipients

BackgroundIn a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported.MethodsEvaluations included patient and graft survival, study drug discontinuations, laboratory values including renal function and development of new-onset diabetes after transplantation, concomitant medications, and adverse events.ResultsAt study termination, 129 Astagraf XL, 113 Prograf, and 79 CsA patients had continued follow-up. Demographic and baseline characteristics were similar in all arms. Four-year Kaplan-Meier estimates of patient survival in the Astagraf XL, Prograf, and CsA groups were 93.2, 91.2, and 91.7%, respectively, while graft survival was 84.7, 82.7, and 83.9%, respectively. At least one serious adverse event was reported in the majority of patients in each group during the study (65.9% Astagraf XL, 69.8% Prograf, and 65.6% CsA). Renal function was not significantly different between Astagraf XL and Prograf. HgbA1c levels were collected every 6 months; the 4-year Kaplan-Meier estimate for incidence of HgbA1c levels ≥6.5% was significantly higher for both tacrolimus formulations compared to CsA; 41.1% (Astagraf XL), 33.6% (Prograf), and 21.3% (CsA).ConclusionsIn this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new-onset diabetes after transplantation but superior renal function compared to patients receiving CsA.

Progression of pulse pressure in kidney recipients durably exposed to CsA is a risk factor for epithelial phenotypic changes: an ancillary study of the CONCEPT trial

In this ancillary study of the CONCEPT trial, we studied the role of CsA withdrawal at 3 months (3M) post-transplant on the intensity of epithelial phenotypic changes (EPC, an early marker for kidney fibrogenesis) on the 12 M surveillance biopsy. Although conversion from CsA to sirolimus (SRL) at 3M was reported to have improved mean graft function at 12 M, it did not reduce the score of EPC (1.73 ± 1.15 in the SRL group vs. 1.87 ± 1 in the CsA group, P = 0.61). Acute rejection, which had occurred twice more frequently in SRL-converted patients included here, was associated with 12 M EPC. Interestingly, we observed that the patients durably exposed to CsA and who developed 12 M EPC had a significant progression of blood pulse pressure (pp) from 1 to 6M post-transplantation (Δpp = +12.3 mmHg, P = 0.0035). Pulse pressure at 4, 6, and 9 M and pp progression from 1 to 6M were significantly associated with the development of EPC at 12 M in renal grafts. Logistic regression analysis revealed that a high 6M pp (≥ 60 mmHg) was an independent risk factor for 12 M EPC with an odds ratio of 2.25 per additional 10 mmHg pp (95%CI: 1.14-4.4, P = 0.02) after adjustment with recipient's and donor's age, acute rejection incidence and immunosuppressive regimen. A post hoc analysis of the data collected in the whole population CONCEPT study revealed that pp was significantly higher at 6 months in patients maintained on CsA and that at this time point pp correlated negatively with GFR at 1 year.

Association between transforming growth factor beta-1 + 869 T/C polymorphism and acute rejection of solid organ allograft: A meta-analysis and systematic review

BackgroundTransforming growth factor beta-1(TGFB1) is involved in the acute rejection (AR) episodes of solid organ transplant recipients. However, results from published studies on the association between donor/recipient TGFB1 +869T/C polymorphism and AR risk are conflicting and inconclusive. MethodsPUBMED, EMBASE, CNKI and Wanfang Database were searched to identify eligible studies investigating the association between donor/recipient TGFB1 +869T/C polymorphism and AR risk. Statistical analysis was performed by using STATA 10.0. ResultsA total of 29 studies were included. Overall, the donor TGFB1 +869T/C polymorphism was significantly associated with AR risk in heterozygote comparison (CT vs. TT: OR=1.67, 95%CI, 1.17–2.39; P heterogeneity=0.285) and dominant model (CC vs. TC/TT: OR=1.47, 95%CI, 1.05–2.06; P heterogeneity=0.445). In addition, subgroup analysis revealed that CT variant (CT vs. TT: OR=1.97, 95%CI, 1.20–3.25; P heterogeneity=0.777) and CC/CT genotype (CC/CT vs. TT: OR=1.72, 95%CI, 1.07, 2.78; P heterogeneity=0.619) within donors contributed to higher risk of AR in recipients administrated with CsA or FK506, compared with those applied only CsA. On the other hand, no significant association between recipient TGFB1 +869T/C polymorphism and AR was detected in all genetic models. ConclusionsThis meta-analysis and systematic review suggested that donor TGFB1 +869T/C polymorphism was significantly associated with AR of solid organ transplant recipients, and especially among patients in CsA/FK 506 group compared with those in CsA group.

Reflections on some aspects of infinite groups

AbstractIn this paper we survey and reflect upon several aspects of the theory of infinite finitely generated and finitely presented groups that were originally motivated by work of Gilbert Baumslag. All but the last of the topics we have chosen are all related in one way or another to the theory of limit groups and the solution of the Tarski problems. These include the residually free and fully residually free properties and the big powers condition; Baumslag doubles and extensions of centralizers; residually-𝒳 groups and extensions of results of Benjamin Baumslag and finally the relationship between CT and CSA groups.