CyA Group Research Articles

A prospective observational cohort study comparing the treatment effectiveness and safety of ciclosporin, dupilumab and methotrexate in adult and paediatric patients with atopic dermatitis: results from the UK-Irish A-STAR register.

The main conventional systemic atopic dermatitis (AD) treatments are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomised controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA. The aim of this study was to compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD. We compared the effectiveness and safety of these systemic agents in a prospective observational cohort study of adult and paediatric patients recruited into the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children's DLQI (cDLQI). Minimum duration of treatment was 28 days and follow-up was 12 months. Adjusted Cox-regression was used to compare the hazards of achieving EASI-50, EASI-75 and EASI-90 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits. 488 patients (n=311 adults and n=177 children/adolescents) on dupilumab (n=282), methotrexate (n=149), or CyA (n=57) were included. CyA and MTX were primarily used first line, while dupilumab was mainly a second line systemic as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared to MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared to MTX. In severe patients the reduction in EASI, POEM, and PP-NRS was even greater with CyA. The incidence of AEs was similar across groups (734, 654 and 594 per 10,000 person-month on CyA, dupilumab and MTX respectively). This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within one follow-up year.

CD44 expression in renal tubular epithelial cells in the kidneys of rats with cyclosporine-induced chronic kidney disease.

Renal tubular epithelial cell (TEC) injury is the most common cause of drug-induced kidney injury (DIKI). Although TEC regeneration facilitates renal function and structural recovery following DIKI, maladaptive repair of TECs leads to irreversible fibrosis, resulting in chronic kidney disease (CKD). CD44 is specifically expressed in TECs during maladaptive repair in several types of rat CKD models. In this study, we investigated CD44 expression and its role in renal fibrogenesis in a cyclosporine (CyA) rat model of CKD. Seven-week-old male Sprague-Dawley rats fed a low-salt diet were subcutaneously administered CyA (0, 15, or 30 mg/kg) for 28 days. CD44 was expressed in atrophic, dilated, and hypertrophic TECs in the fibrotic lesions of the CyA groups. These TECs were collected by laser microdissection and evaluated by microarray analysis. Gene ontology analysis suggested that these TECs have a mesenchymal phenotype, and pathway analysis identified CD44 as an upstream regulator of fibrosis-related genes, including fibronectin 1 (Fn1). Immunohistochemistry revealed that epithelial and mesenchymal markers of TECs of fibrotic lesions were downregulated and upregulated, respectively, and that these TECs were surrounded by a thickened basement membrane. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of TECs of fibrotic lesions, whereas fibronectin protein was localized in the stroma surrounding these tubules. Enzyme-linked immunosorbent assay revealed increased serum CD44 levels in CyA-treated rats. Collectively, these findings suggest that CD44 contributes to renal fibrosis by inducing fibronectin secretion in TECs exhibiting partial epithelial-mesenchymal transition and highlight the potential of CD44 as a biomarker of renal fibrosis.

Safety Profile of the Concomitant Use of Atorvastatin and Cyclosporine in Renal Transplant Recipients.

Cyclosporine (CyA) and atorvastatin (AT) are often administered concomitantly to treat dyslipidemia in renal transplant recipients. However, CyA greatly increases the plasma concentration of AT; therefore, concomitant use might increase the frequency of statin-induced adverse effects. The aim of this study was to investigate whether concomitant use of CyA and AT increases intolerance of the latter agent in Japanese renal transplantation recipients. We performed a retrospective cohort analysis of renal transplant recipients aged 18 years and older who had concomitantly received AT and CyA, or tacrolimus (Tac) therapy. We defined statin intolerance as a decrease in dose or discontinuation of AT due to adverse effects. We evaluated the incidence of statin intolerance in concomitant therapy with CyA for 100 days after the initial administration of AT in comparison with Tac. A total of 144 renal transplant recipients who received AT and CyA, or Tac between January 2013 and December 2019 were included. There was no statistical difference in the incidence of statin intolerance in both the CyA (1.8%; 1/57 patients) and Tac (3.4%; 3/87 patients) groups. Concomitant use of CyA and AT might not increase the incidence of statin intolerance in Japanese renal transplant recipients.

Differential effects of the immunosuppressive calcineurin inhibitors cyclosporine-A and tacrolimus on ovulation in a murine model.

STUDY QUESTIONDo therapeutic levels of cyclosporine-A and tacrolimus affect ovulation in a rat gonadotrophin-induced ovulation model?SUMMARY ANSWERCyclosporine-A, but not tacrolimus, decreases ovulation rate when administered for 5 days before induced ovulation.WHAT IS KNOWN ALREADYThe mainstays of immunosuppression in solid organ transplantation, to prevent rejection, are the calcineurin inhibitors cyclosporine-A or tacrolimus. These drugs could potentially affect fertility in transplanted patients. Since ovulation is an inflammation-like process with pivotal roles for several immune cells and modulators, it is possible that the calcineurin inhibitors, with broad effects on the immune system, could interfere with this sensitive, biological process.STUDY DESIGN, SIZE, DURATIONExperimental design at university-based animal facilities. A total of 45 immature Sprague–Dawley rats were used. The study was carried out over 3 months.PARTICIPANTS/MATERIALS, SETTING, METHODSImmature Sprague–Dawley rats (n = 45) were randomly assigned to receive equivalent doses of tacrolimus (0.5 mg/kg/day; TAC), cyclosporine-A (10 mg/kg/day; CyA) or vehicle (Control). Ovarian hyperstimulation was induced with 10 IU of equine chorionic gonadotrophin, and ovulation was triggered with 10 IU of hCG. Oocytes were retrieved from the oviducts and ovulation rates were calculated. Various subpopulations of white blood cells were counted in peripheral blood and ovarian tissue samples.MAIN RESULTS AND THE ROLE OF CHANCEAnimals in the CyA group showed a lower ovulation rate when compared to the TAC and Control groups (CyA: mean 9 oocytes (range 0–22); TAC: 21 oocytes (8–41); Control: 22 oocytes (6–39); P = 0.03). Regarding counts of the white blood cell subpopulations and resident neutrophils in the ovary, no significant differences were observed between the groups.LIMITATIONS, REASONS FOR CAUTIONAlthough the ovulation process is highly conserved within species, the differences between rodents and humans may limit the external translatability of the study.WIDER IMPLICATIONS OF THE FINDINGSThese findings suggest that tacrolimus should be the preferred calcineurin inhibitor of choice in transplanted patients who are aiming for pregnancy.STUDY FUNDING/COMPETING INTEREST(S)Swedish Research Council and ALF of Sahlgrenska Academy, Sweden. Rio Hortega Grant from the Instituto de Salud Carlos III, Spain (CM09/00063). There are no conflicts of interest.

P0287LONG-TERM CLINICAL OUTCOMES IN IDIOPATHIC MEMBRONOUS NEPHROPATHY TREATED BY CYCLOSPORINE AND PREDNISOLONE

Abstract Background and Aims Membranous nephropathy (MN) is the most common primary glomerular disease diagnosed in older patients. MN in adults is most often idiopathic, and risk factors of clinical findings for progressive idiopathic MN (iMN) seems to be older age at onset, male sex, and nephrotic-range proteinuria persisting for several months. Immunosuppressive therapy should be applied to the patients with iMN who have risk factors for progression, however little is known about the most effective regimen of immunosuppressive therapy. In addition, long-term prognosis of iMN for each immunosuppressive regimen is unclear. Most of the patients with iMN at our center were treated by prednisolone (PSL) and cyclosporine (CYA) combination therapy, and commencement of therapy was around the time of renal biopsy. The objective of this study is to assess medium to long-term outcome of treated iMN patients with CYA at our center. Method Retrospective data were collected from January 2000 to December 2014 on all consecutive 1080 native renal biopsy at our center. 102 cases were diagnosed as MN. Of 102 MN cases, 43 cases were iMN, which was IgG4 dominant or codominant in immunofluorescence of IgG subclass. Secondary MN is diagnosed by clinical history of possible drug use, the presence of malignancy, positive serologic tests for both infection and connective tissue diseases, hepatitis B or hepatitis C virus positive, and full house immunofluorescence. Results Of 43 iMN cases, there were 4 cases who were treated with only nonimmunosuppressive therapies, 5 cases who were treated with PSL, and 34 cases who were treated with CYA combination. Immunosuppressive therapy commenced within one month before and after renal biopsy. Immunosuppressive regimen was determined by each doctor. CYA was administered once-daily, and the area under the concentration-time curve up to 4 hour after administration of CYA (AUC0-4h) was determined in each patient. No infectious complications were found. The duration of CYA use was 194.7±848.9 days (median 786.5 days), and follow-up period of CYA group was 3026.4±1608.0 days. There were no significant differences between PSL group and CYA group in age (53.4±20.6 years vs. 64.1±10.6 years, p=0.162), sex (1 male 4 female vs. 23 male 11 female ,p=0.162), urinary protein (1.37±0.65 g/gCre vs. 5.44±3.64 g/gCre, p=0.0679), serum creatinine at the time of renal biopsy (0.66±0.19 mg/dl vs. 1.09±0.57 mg/dl, p=0.352), a 30% eGFR decline (0 cases vs. 2 cases), cases achieved complete remission (CR) (5 cases vs. 26 cases, p=0.196), and time from commencement of immunosuppressive therapy to CR (748.2±795.5 days vs. 422.2±379.9 days, p=0.242). There were no significant differences between non-remission cases in CYA group (8 cases) and remission cases in CYA group (26 cases) in age, sex, and urinary protein, but serum creatinine was significantly greater in non-remission cases than remission cases in CYA group (1.75±1.01 mg/dL vs. 0.94±0.29mg/dL, p=0.0251). There were no significant differences between non-recurrent cases in CYA group (16 cases) and recurrent cases (10 cases) in CYA group in age, sex, urinary protein, and serum creatinine at the time of renal biopsy. Conclusion Between PSL group and CYA group, there were no significant differences in age, and sex at the time of biopsy, and there was a trend that urinary protein was greater in CYA group than in PSL group (p=0.0679). Due to the tendency that urinary protein at the biopsy was greater in CYA group, no significant differences were seen in the remission rate and the time from commencement of immunosuppressive therapy to remission between PSL group and CYA group. Despite long duration of CYA use, infectious complications and renal function deterioration were not seen, so CYA can use safely by dose adjustment by AUC0-4h. Further study is needed to provide enough evidence of effectiveness of CYA combination therapy.

Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients.

Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children. A total of 42 LT recipients (21 men, age 9.93 ± 3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed. Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m, whereas PWV values were above the 95th percentile in 12%. Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long-term follow-up is needed to evaluate their impact on CV health and survival.

Analysis of predictive factors for immunosuppressive response in anti-phospholipase A2 receptor antibody positive membranous nephropathy

BackgroundSerum anti-phospholipase A2 receptor (PLA2R) antibody was correlated with disease activity of membranous nephropathy(MN). The predictive value of antibody titer changes on immunosuppressive response remains unknown. We investigated predictive value of dynamic change of anti-PLA2R antibody and 24-h urine protein (24hUP) for clinical response of MN.MethodsThis was a retrospective cohort study including 47 Chinese MN patients with positive anti-PLA2R antibody in a tertiary referral hospital between January 2012 and March 2014. Patients received cyclophosphamide (CTX, n = 23), or cyclosporine (CYA, n = 24) regimen, respectively. We monitored serum anti-PLA2R titer and 24hUP at one, three and six-month follow-up.ResultsAt baseline, total patients were 42 ± 14 years old with 29/18 male/female ratio. The median 24hUP was 5.80(3.56,9.41) g/d. The median baseline anti-PLA2R antibody titer was 66.4(31.9, 188.0) RU/mL. Baseline 24hUP and eGFR between subgroups were not significantly different. The differences of relative reduction between antibody titer and 24hUP at one month were statistically significant (CTX group 94.2% vs. 46.8%, P < 0.001; CYA group 54.6% vs. 4.6%, P = 0.04). Only in CTX group, the relative reduction of 24hUP at one month was correlated with composite remission at six-month(P = 0.03). Area under the curve of 24hUP relative reduction in CTX group at one-month for predicting composite remission at six months was 0.85(95%CI 0.65~1.05, P = 0.04). The cutoff value of one-month’s 24hUP relative reduction for predicting six-month’s composite remission in CTX group was 15.3%, with high sensitivity (83.3%) and specificity (100%).ConclusionsCompared with relative reduction of antibody titer, relative reduction of 24hUP at one-month follow-up in CTX group had a better predictive value for six-month’s composite remission.

Early Outcomes of Living-Donor Kidney Transplantation With Immunosuppression Therapy Induction With Tacrolimus Extended-Release: A Comparison With Cyclosporine

BackgroundExtended-release tacrolimus (TacER), administered once daily, offers improved adherence with reduced side effects while still maintaining an immunosuppressive potency equivalent to that of conventional tacrolimus preparations. MethodsThe study included 83 patients who received consecutive living-donor kidney transplants at our facility from June 2013 to December 2016. Comparisons were made between 48 cases of induction with TacER and 35 cases of induction with cyclosporine (CyA). The observation period was 3 months after transplantation. Transplanted kidney function, rejection, infectious disease, lipid abnormalities, and glucose tolerance were compared. ResultsThe 2 groups showed no significant difference in donor background or transplanted kidney function. Within the 3-month observation period, an acute rejection response was observed in 2 cases in the TacER group and in 8 cases in the CyA group. After transplantation, hyperlipidemia requiring medication was observed more frequently in the CyA group. The 2 groups did not show a marked difference in systemic infection or renal calcineurin inhibitor toxicity in histopathologic examination of the transplanted kidneys 3 months after surgery. DiscussionProactive use of TacER leads to improved adherence while yielding immunosuppressive potency equivalent to that of conventional tacrolimus preparations; however, tacrolimus has a potent blood sugar-elevating effect; thus, direct comparison with the CyA group is important for assessing the side effects. ConclusionTacER has the potential to also reduce side effects in the early stages after surgery, suggesting its potential as a drug of first choice.

Inhibition of ALDH2 expression aggravates renal injury in a rat sepsis syndrome model.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is closely associated with organ injury. The aim of the present study was to investigate the change of ALDH2 expression in a rat model of sepsis-induced acute renal injury, and to observe the effect of ALDH2 inhibition on the kidney. A model of sepsis syndrome was established in Sprague-Dawley (SD) rats by cecal ligation and puncture (CLP). The rats were divided into sham, CLP and CLP + cyanamide (CYA, an ALDH2 inhibitor) groups. The hemodynamic parameters heart rate (HR) and mean arterial blood pressure (MABP) were measured. Plasma creatinine (CRE) and urea nitrogen (BUN) levels were measured using an automatic biochemical analyzer. Malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in the kidney tissue were measured. Histological changes of the kidney tissue were observed using hematoxylin and eosin staining and NF-κB p65 expression was observed by an immunohistochemical staining method. The expression of renal ALDH2 at the mRNA and protein levels was detected by reverse transcription-polymerase chain reaction and western blotting. In the CLP compared with the sham group after 24 h, the MABP was decreased, plasma CRE and BUN levels were elevated, the renal MDA level was increased and SOD activity was decreased. In addition, glomerular atrophy occurred, the renal protein expression of NF-κB p65 was increased, and the mRNA and protein expression levels of ALDH2 were decreased. In contrast with the CLP group, in the CLP + CYA group, the MABP and ALDH2 expression were further decreased while glomerular atrophy was aggravated. Furthermore, CRE, BUN, MDA levels and NF-κB p65 expression were further increased and SOD activity was further reduced. In this rat model of sepsis syndrome, the reduction of renal ALDH2 expression was accompanied by kidney injury. Inhibition of ALDH2 with CYA aggravated the renal injury, and was associated with the overproduction of reactive oxygen species and inflammatory reaction.

Wound complications and surgical events in de novo heart transplant patients treated with everolimus: Post-hoc analysis of the SCHEDULE trial

ObjectivesThe use of mammalian target of rapamycin (mTOR) inhibitors have been limited by adverse events (AE), including delayed wound healing. We retrospectively reviewed all AE and serious AE (SAE) in The Scandinavian heart transplant (HTx) everolimus (EVE) de novo trial with early calcineurin (CNI) avoidance (SCHEDULE). The aim of the study was to compare wound complications between EVE and CNI based regimen. Materials and methodsA total of 115 patients (mean age 51±13years, 73% men) were randomized within five days post-HTx to low dose EVE and reduced dose Cyclosporine (CyA) followed by early CyA withdrawal (EVE group; n=56) or standard CyA regimen (CyA group; n=59). All AE/SAEs were prospectively recorded according to the SCHEDULE study protocol, and re-assessed retrospectively by two independent reviewers. Wound complication as primary endpoint was defined as any complication associated with failure of tissue healing. Secondary endpoint was total number of events involving surgical intervention. ResultsThere were no significant differences between the groups with regards to wound complications (EVE=20, CyA=12)(p=0.08) or total surgical events (EVE=38, CyA=34) (p=0.44). Age>54.5years (median) was an overall risk factor for surgical wound complications regardless of treatment group (p=0.025). There was no difference in the EVE versus CyA group with regards to other surgical events. Majority of events were in 1/3 of the patients. ConclusionDe novo initiation of EVE and early CyA withdrawal in HTx patients did not show any significant differences in wound complications or in total surgical events. Majority of complications were seen in a small number of patients.

Role of Shh signal transduction pathway in vascular endothelial growth factor expression under hypoxia in cultured human retinal pigment epithelial cells

Objective To investigate the role of sonic hedgehog (Shh) signal transduction pathway in the expression of vascular endothelial growth factor (VEGF) under hypoxia in cultured human retinal pigment epithelial (hRPE) cells. Methods ARPE-19 were cultured and divided into normal ARPE-19 (Cont) and hypoxia group (100 μmol/L CoCl2 Cobalt Chloride + ARPE-19); hypoxia group was further divided into CoCl2 group, cyclopamine group (CYA) and dimethyl sulfoxide (DMSO) group. 20 μmol/L cyclopamine was added to the CYA group 1 hour before hypoxia, 1‰ DMSO was added into DMSO group at the same time. The hRPE cells were cultured under hypoxia for 4, 8, 12, 24 hours. The expression of Shh and VEGF were determined by Real-time fluorescent quantitate PCR (RT-PCR). The amount of VEGF in the hRPE-conditioned supernatant was measured using enzyme linked immunosorbent assay (ELISA) at 4, 8, 12, 24 hours, respectively. Results RT-PCR tests showed that the level of Shh and VEGF of hRPE was time dependently increased (Shh: F=45.260, P=0.001; VEGF: F=264.938, P=0.001). The level of Shh and VEGF of hRPE in the group treated with cyclopamine was decreased (P<0.01). ELISA tests showed that the amount of VEGF in hRPE supernatant was significantly increased in time-dependent manner (F=3 156.676, P=0.001), and it was down-regulated by cyclopamine under hypoxia (P<0.01). Conclusion Shh signal transduction pathway could play a role in the VEGF expression induced by hypoxia in hRPE cells. Key words: Vascular endothelial growth factors; Retinal pigment epithelium; Cells, cultured

Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine.

AIMTo compare the impact of tacrolimus (FK) and cyclosporine (CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors (CNIs).METHODSRetrospective review of 1835 patients who received a kidney transplant (KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed.RESULTSCumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group (P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejection rates [odds ratio (OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival (OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group.CONCLUSIONThe use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients.

Do calcineurin inhibitors influence the serum concentrations of mizoribine?

Background: Mizoribine (MZR) is an antimetabolite that inhibits inosine-monophosphate dehydrogenase and has been used for preventing rejection in renal transplantation. However, the effect of calcineurin inhibitors (CNIs) on the pharmacokinetics of MZR has not been shown. This study was performed to show the influence of CNIs (tacrolimus [Tac] or cyclosporine [CyA]) on the serum concentration of MZR. Methods: Thirty-four living-donor renal transplant recipients administered a four-drug immunosuppressive therapy regimen (steroid, CNIs, basiliximab and MZR 6 mg/kg/day) were investigated. 20 recipients were treated with Tac and 14 were with CyA. Serum concentrations of MZR were obtained retrospectively at 464 points and at 243 points for each. Population pharmacokinetic (PPK) analysis was used to make pharmacokinetic models of serum MZR. After statistically evaluating the correlation of the pharmacokinetic models with the actual data, areas under the curves (AUCs) of each CNI were also estimated in these models and statistically evaluated. Results: The mean values of the PPK parameters (absorption lag time, absorption rate constant [Ka], apparent volume of distribution [V/F] and oral clearance of MZR [CL MZR /F]) were 0.600 hr and 0.643 hr, 1.14/hr and 0.911/hr, 0.732×body weight (WT) (L) and 0.784×WT (L), and 1.64×creatinine clearance (CL cr ) (L/hr) and 1.81×CL cr (L/hr), respectively. Moreover, the serum concentrations of MZR at all-time points were estimated with these parameters. The correlation coefficients between the individual actual and estimated serum concentrations of MZR in the Tac group and the CyA group were 0.988 and 0.992, respectively. The average value of the AUCs of MZR corrected by the CL cr in the Tac group, and the CyA group were 0.61±0.21 and 0.55±0.19 (average value±standard deviation) for each (p=0.19). Conclusion: These findings suggest the pharmacokinetics of MZR were well-described by 1-compartment model with first-order absorption. Moreover, concomitant use of CNIs, e.g., Tac and CyA, may have no significant influence on the pharmacokinetics of MZR.

Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single‐center experience

There are limited published data concerning the effects of different immunosuppressive regimens on the development of polyomavirus (BKV) viremia. We examined the risk of developing BKV viremia in kidney transplant recipients receiving everolimus (EVR) or mycophenolic acid (MPA) as maintenance therapy. We observationally analyzed 296 patients who underwent renal transplantation at our center between 2005 and 2010: 58 were treated with EVR and low-dose cyclosporine (LD-CyA) (group 1) and 238 with MPA and standard-dose CyA (group 2). All of the patients received induction therapy with basiliximab and maintenance steroids. BKV viremia (a whole-blood viral load of >850 copies/mL) was measured by means of real-time polymerase chain reaction at least once a month during a 12-month follow-up period. BKV viremia was detected in 57 patients (19%), five (9%) in group 1 and 52 (22%) in group 2. Kaplan-Meier analyses showed that freedom from BKV viremia was significantly more frequent in group 1. The mean time of onset of BKV viremia was about four months after transplantation in both groups. The median viral load was greater in group 2 (12.5 ± 6.1 vs. 2.5 ± 1.8 × 10(4) copies/mL; p = 0.01). After the onset of BKV viremia, graft function significantly declined in group 2: 11 patients developed polyomavirus-associated nephropathy (PVAN) and four presumptive PVAN; nine experienced an acute rejection after the discontinuation of MPA, and 11 (21%) lost their graft. There was no graft loss in group 1. These findings suggest that in comparison with MPA and Cya, an EVR and LD-CyA regimen lowers the risk of BKV viremia after kidney transplantation and favorably alters outcomes.

COLON-TARGETED CYCLOSPORINE IN THE IL10 KNOCK OUT MODEL OF CROHN'S COLITIS

IntroductionCyclosporine A (CyA) is a powerful immunosuppressive agent and has been used off label for steroid-dependent or steroid-refractory ulcerative colitis. However, systemic exposure results in a number of side effects....

THU0280 Extended Follow-Up of the Cyclofa-Lune Trial Comparing Two Sequential Induction and Maintenance Treatment Regimens for Proliferative Lupus Nephritis Based Either on Cyclophosphamide or Cyclosporine a

BackgroundIn the investigator-initiated prospective trial CYLOFA-LUNE [1] we tested the hypothesis that immunosuppressive regimen based on Cyclosporine A (CYA) may have similar efficacy but greater safety than that based on...

Do Calcineurin Inhibitors Influence the Serum Concentrations of Mizoribine?

Background, Objectives and Subjects: Mizoribine (MZR) is an antimetabolite that inhibits inosine-monophosphate dehydrogenase just like mycophenolate mofetil (MMF), and has been used for preventing rejection in cases of renal transplantation. It has been reported that the biokinetics of mycophenolic acid (MPA), which is the metabolically activated form of MMF, shows large variations among individuals, depending on the renal function, concomitant use of a calcineurin inhibitor (CNI), corticosteroid, etc. On the other hand, the biokinetics of mizoribine (MZR) is known to be influenced strongly by the renal function, but not by concomitant use of drugs, including CNIs. However, there are no reports referring to clinical investigations of the effect of CNIs on the biokinetics of MZR. Therefore, we conducted this study, based on population pharmacokinetic analysis (PPK), to determine whether concomitant use of CNIs (tacrolimus (Tac) or cyclosporine (CyA)) may exert any influence on the biokinetics of MZR, in living-donor renal transplant recipients administered a 4-drug immunosuppressive therapy regimen, including MZR 6 mg/kg/day. Results: The PPK analysis revealed that the correlation coefficients between the actual and estimated serum concentrations of MZR in the CyA group and Tac group were 0.992 and 0.988 respectively, indicative of a good correlation. The PPK parameters (ka, V/F and CL/F) in both groups were nearly identical, therefore, it was considered that concomitantly used CNIs were unlikely to have any significant influence on the biokinetics of MZR (absorption, distribution and excretion). Actually, the average value of the areas under the curve (AUCs) of MZR corrected by the creatinine clearance in the CyA group and Tac group were 9.24 ± 3.24 and 10.23 ± 3.46 (μg·hr/mL)/μg·mL/min, respectively, which confirmed that concomitant CNI use exerts little influence on the serum concentration of MZR. Conclusion: It was concluded that concomitant use of CNIs, e.g., Tac and CyA, may have no significant influence on the pharmacokinetics of MZR.

Beneficial effect of ubiquinol, the reduced form of coenzyme Q10, on cyclosporine nephrotoxicity

Cyclosporine (CyA) nephrotoxicity is partly due to some oxidative stress. Ubiquinol, the reduced form of coenzyme Q10 (rCoQ10), has recently gained attention for its anti-oxidative potential. The aim of this study is to evaluate the effect of rCoQ10 on a CyA nephrotoxic rat model. Six-week-old male Wistar rats were divided into three groups (five animals each). Group 1 received a medium only. Group 2 received 30 mg/kg/day of CyA only. Group 3 received both the same dose of CyA and 600 mg/kg/day of rCoQ10. CyA and rCoQ10 were both given orally for four weeks. Systolic blood pressure (BP), daily urinary albumin secretion (u-Alb), serum creatinine (s-Cr) level, and super-oxide anion (SO) level in the renal tissue were measured and compared among those three groups. Immunohistochemistry using an antibody for the transforming growth factor-beta (TGF-beta) was also examined. BPs, u-Albs, s-Crs, and SO levels of groups 1, 2, and 3 were 114 ± 3, 132 ± 4, and 129 ± 5 mmHg, 2.6 ± 0.5, 42.1 ± 7.2, and 22.8 ± 3.4 micro-g/day, 1.1 ± 0.2, 1.7 ± 0.2, and 1.3 ± 0.2 mg/dL, and 224 ± 84, 1251 ± 138, and 512 ± 109 RLU/g kidney respectively. U-Albs, s-Crs, and SO levels were signifi cantly ameliorated by rCoQ10. Micro-vacuolar changes and TGF-beta positive deposits in the proximal renal tubular cells of CyA group rats disappeared in those of CyA and rCoQ10 group rats. RCoQ10, an antioxidants, may have potential for preventing CyA nephrotoxicity.

Comparison of the Clinical Efficacy of Two Different Immunosuppressive Regimens in Patients with Chronic Vogt-Koyanagi-Harada Disease

Purpose: To prospectively compare 2 immunosupressive regimens in patients with active Vogt-Koyanagi-Harada disease in spite of systemic glucocorticoid treatment.Methods: Forty-four patients were diagnosed between 1998 and 2005. Twenty-one developed chronic intraocular inflammation in spite of glucocorticoid treatment and were randomized to receive either prednisone and azathioprine (AZA) (n = 12) or prednisone and cyclosporine (CyA) (n = 9).Results: In the AZA group Tyndall score decreased from 1.21 ± 1.10 to 0.29 ± 0.62 (p < .01), and visual acuity (LogMAR) improved from 0.32 ± 0.35 to 0.09 ± 0.16 (p < .001). In the CyA group Tyndall score decreased from 1.67 ± 1.08 to 0.16 ± 0.51 (p < .001), and visual acuity improved from 0.41 ± 0.40 to 0.25 ± 0.42 (p < .001). Patients in the AZA group needed a significantly higher average prednisone dose and total cumulative dose than those in the CyA group, p < .01 for each comparison.Conclusions: Both regimens showed a good clinical efficacy, but CyA seems to be a better glucocorticoid-sparing agent than AZA.

Predictors of sustained virological response after antiviral treatment for hepatitis C recurrence following liver transplantation

Factors associated with sustained virological response (SVR) in patients treated for hepatitis C virus (HCV) recurrence after liver transplantation (LT) are unclear. Ninety-nine HCV-positive/hepatitis B surface antigen-negative patients received antiviral treatment (AVT) with interferon/peginterferon plus ribavirin for HCV recurrence after LT. Cyclosporine (CyA) or tacrolimus (TAC) was used as the main immunosuppressor in 37 (37%) and 62 (63%) patients, respectively. Twenty-five patients (25%) achieved an SVR. Twenty-seven donor-related, recipient-related, HCV-related, and immunosuppression-related variables were investigated for their association with SVR. In logistic regression analysis, donor age < 60 years (odds ratio = 4.45, 95% confidence interval = 1.39-14.19, P = 0.01), viral genotype other than 1 (odds ratio = 4.97, 95% confidence interval = 1.59-15.48, P = 0.006), and the use of CyA during treatment (odds ratio = 6.85, 95% confidence interval = 2.15-21.73, P = 0.001) were predictors of SVR. Patients treated with CyA (SVR rate: 43%) and those treated with TAC (SVR rate: 14%) were comparable for all variables, except for a shorter ischemia time and shorter timing of AVT initiation in the TAC group (P = 0.02 and P = 0.005, respectively) and a greater use of anti-CD25 antibodies, azathioprine, and mycophenolate mofetil in the CyA group (P = 0.03, P < 0.001, and P = 0.001, respectively). The rate of AVT discontinuation due to side effects was similar between groups (16% versus 8%, P = 0.3). In conclusion, the type of immunosuppression during AVT may predict SVR in patients treated for HCV recurrence after LT.