Cyclosporine-treated Patients Research Articles

Efficacy of a new water-free topical cyclosporine 0.1% solution for optimizing the ocular surface in patients with dry eye and cataract.

This is a pooled analysis from 2 phase III clinical trials investigating a water-free topical cyclosporine 0.1% for the treatment of moderate to severe dry eye. The analyses included 1162 patients: 35% with cataract, 20% with pseudophakia, and 45% without cataract. Demographics or baseline characteristics were comparable across groups except for age and vision. The cyclosporine-treated patients achieved large mean improvements from baseline by day 15: -3.7 in patients without cataract, -3.2 in patients with cataract, and -3.1 in pseudophakic patients. These improvements were statistically significantly higher compared with the respective vehicle groups. In the cataract subgroup, 59% of patients treated with cyclosporine achieved ≥3 grade improvements in corneal staining score, as early as day 15. The magnitude of the effect and early onset of action make this new cyclosporine solution a promising candidate for preoperative management of ocular surface in patients undergoing cataract surgery.

Cyclosporine vs. tacrolimus after liver transplantation for primary sclerosing cholangitis – a propensity score-matched intention-to-treat analysis

There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p= 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.

Hypomagnesemia and its association with calcineurin inhibitor use in renal transplant recipients

Background Hypomagnesemia is a common electrolyte abnormality following kidney transplantation. Increased renal magnesium (Mg) waste has been linked to calcineurin inhibitors. We aimed to assess the prevalence and risk factors of hypomagnesemia and its association with calcineurin inhibitor use in renal transplant recipients. Patients and methods This is a cross-sectional study carried out on renal transplant recipients, who underwent living-related donor kidney transplantation. All participants underwent detailed history taking and complete physical examination. Serum Mg, trough level of cyclosporine or tacrolimus, fractional excretion of Mg (FEMg), and 24 h urinary Mg, Ca, Ph, Cl, and protein were measured. Results One hundred patients were screened and 80 patients, with a mean age of 39.65 ± 12.14 years, completed the study. Fifty (62.5%) patients were on tacrolimus, and 26 (32.5%) patients were on cyclosporine. Patients had a median serum Mg of 1.80 mg/dl. Hypomagnesemia (Mg&lt;1.7) was present in 17 (21.3%) patients with a median FEMg of 3.08%. There was significant negative correlation between serum Mg level and trough level of tacrolimus and FEMg with a P value of 0.038 and 0.001, respectively. The results of multivariate analyses showed that tacrolimus trough level (P=0.010) and FEMg (P=0.025) were independently correlated with serum Mg. Hypomagnesemia was significantly higher in tacrolimus-treated patients (30%) compared with only 7.7% in cyclosporine-treated patients (P=0.027). Conclusions Hypomagnesemia is common in renal transplant recipients, especially with tacrolimus use mostly due to increased renal Mg wasting. Increased tacrolimus trough level and increased FEMg were predictors of hypomagnesemia.

P472 Cyclosporine versus infliximab in patients with Acute Severe Ulcerative Colitis: A single-centre retrospective study

Abstract Background In steroid refractory acute severe ulcerative colitis (ASUC), cyclosporine or infliximab are potential rescue treatments to avoid colectomy. Our objective is to assess the short-term and long-term efficacy and safety of cyclosporine versus infliximab as rescue agents. Methods We performed a retrospective analysis of 121 patients admitted with ASUC to a single gastroenterology centre during 2010-2020. ASUC was defined by the Truelove &amp; Witts criteria. Primary outcome was short-term colectomy-free rate, secondary outcomes were severe adverse events, re-hospitalization or need of treatment with steroids within 2 years due to flare ups and colectomy rate at 2-year follow-up. Results 119 patients initially received intravenous corticosteroids, while 2 patients underwent emergency colectomy on the first day. Sixty-four (53%) were females, median age of all patients was 33 (IQR 27-49) years. 66 (55%) patients responded to intravenous corticosteroids (IVS), while 53 (45%) failed to respond to steroid therapy: 45 (37%) patients received second-line rescue therapy (29 with cyclosporine, 16 with infliximab). Evaluating the short-term efficacy of treatment there was no significant difference between cyclosporine and infliximab: during admission colectomy was performed in 10.3% vs. 12.5% of patients, respectively (p=0.826). In terms of long-term outcomes, the colectomy rate was higher in the infliximab group at 2-year follow-up, although the difference did not reach statistical significance (10.3% vs. 31.2%, p=0.079). The need for oral steroids during follow-up was comparable in both groups (38,5% vs. 50%, p=0.481). Comparing patients who did not undergo colectomy, patients in the infliximab group were more often re-hospitalized due to the need for IVS at 2-year follow-up (7.7% vs. 50%, p=0.002). No severe side effects due to infliximab and cyclosporine were observed. Conclusion In the treatment of steroid refractory ASUC infliximab and cyclosporine were equally effective in short-term period and there was no difference in safety, however cyclosporine treated patients trended to have better long-term outcomes, with significantly rarer re-hospitalization. Additional analysis is needed for other factors that may have contributed to differences in long-term outcomes between the cyclosporine and infliximab groups.

HLA-Cw6 Status and Treatment Responses Between Psoriasis Patients.

BackgroundThe number of treatment options in psoriasis has increased considerably, so biomarkers should be searched to assist in the selection of the optimal treatment agent. The most common of these biomarkers is HLA-Cw6.Objective:The aim was to determine whether there is a relationship between HLA-Cw6-positivity (HLA-Cw6-POS) and the response of treatment agents in psoriasis.Methods:Blood samples of 124 patients were subjected to genetic study for HLA-Cw6.Results:Psoriasis area severity index (PASI) score of more than 75% (PASI75) response was received in 34 (73.9%) of the HLA-Cw6-POS methotrexate-treated patients, 30 (78.9%) of the HLA-Cw6-POS cyclosporine-treated patients, and 8 (37.5%) of the HLA-Cw6-POS acitretin-treated patients. The differences were not statistically significant (P = 0.634-0.071-0.409). PASI75 response was received in 73 (68.2%) of the HLA-Cw6-POS patients in patients treated with conventional agents. In adalimumab-treated patients, PASI75 response was received in 8 (53.3%) of the HLA-Cw6-POS patients, 6 (75%) of the HLA-Cw6-POS infliximab-treated patients, and 4 (57.1%) of the HLA-Cw6-POS ustekinumab-treated patients. The differences were not statistically significant (P = 0.245-1.00-0.322). PASI75 response was received in 24 (64.9%) of the HLA-Cw6-POS and 33 (84.6%) of HLA-Cw6 negative (HLA-Cw6-NEG) patients with biological agents. The biological agent response was statistically significantly lower in HLA-Cw6-POS.Conclusion:None of the agents were affected by HLA-Cw6. When biological agents were evaluated collectively, the treatment response of HLA-Cw6-POS patients was lower.

Early isolated optic neuropathy caused by cyclosporine.

To examine, for the first time, whether cyclosporine intake has an early isolated effect on the optic nerve. This observational case series consisted of 192 eyes of 98 patients treated with cyclosporine. Patient age and duration and dosage of cyclosporine were recorded, and visual acuity, optic nerve function, visual fields, and visual evoked potential (VEP) were tested. Fundus examination was also performed. Patients with glaucoma, vascular retinopathies, and deep amblyopia were excluded. Mean patient age was 46years, average duration of treatment was 6years, and median dosage of cyclosporine was 200mg daily. VEP was tested in 73 patients (142 eyes) and yielded a delayed P100 wave in 9 (12.32%) (14 eyes). Among these 9 patients, abnormal findings were also noted on the Ishihara colour test in 42.86% of the eyes, and on the visual field test in 64.3% of the eyes. Abnormal VEP showed a significant correlation (p < 0.05) with older age (> 46years) and a non-significant correlation with longer duration of treatment. Higher abnormal VEP potential was not correlated with higher cyclosporine dose, and there was no correlation between abnormal VEP and blood level of cyclosporine. Optic neuropathy was significantly associated with older age in cyclosporine-treated patients. A correlation between optic neuropathy with longer duration of cyclosporine treatment was noted but was not statistically significant. We suggest that tests of optic nerve function, including VEP, be a part of the follow-up of patients receiving cyclosporine.

Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach.

A population pharmacokinetic (PK) protein-binding model was developed to (1) predict free mycophenolic acid (fMPA) based on total MPA (tMPA) concentrations in renal transplant patients, to establish the therapeutic range of fMPA through pharmacokinetic-pharmacodynamic studies; and (2) provide a guideline for dosing mycophenolate mofetil (MMF). Full PK profiles of 56 patients (from five different occasions) during the first year after transplantation who were treated with oral MMF and cyclosporine, or macrolides (either tacrolimus or sirolimus), were analysed. fMPA protein-binding was modelled using nonlinear mixed effects modelling (NONMEM). The influence of physiological factors and coadministered immunosupressant was studied. A two-compartment model with first-order absorption and elimination, linear protein binding and enterohepatic circulation (EHC) best described the PK of MPA. Different recycling rate constants were considered depending on the coadministered immunosuppressant. The protein-binding rate constant (KB [relative standard error, RSE%]) increased nonlinearly with renal function according to K B=43.1 (3.13)·(CLCR/59.51)0.394(10.66)h-1. Furthermore, fMPA plasma clearance, given by clearance of the free mycophenolic acid (CLfMPA), CLfMPA=410 (RSE%3.00)·(1+CsA·0.594 (22.39))L/h, was 59.4% greater in cyclosporine-treated patients than in macrolide-treated patients, leading to lower MPA exposures. External evaluation proved acceptable area under the plasma concentration-time curve and trough concentration predictions. A reliable protein-binding population PK model was developed for prediction of fMPA or tMPA from each other and for dose guiding in stable renal transplant recipients.

Eight-year follow-up in pediatric living donor kidney recipients receiving alemtuzumab induction.

Recipient lymphocytes are crucial for direct and indirect pathways of allorecognition. We proposed that the administration of alemtuzumab several weeks pretransplantation could eradicate peripheral lymphatic cells and promote donor-specific acceptance. This was a single-center, retrospective review of 101 consecutive living donor kidney transplantations in pediatric patients (age 7months-18years), performed between September 2006 and April 2010. IS protocol included two 30mg doses of alemtuzumab: The first was given 12-29days prior to transplantation, and the second at the time of transplantation. Maintenance IS was based on combination of low-dose CNI and mycophenolate, with steroids tapered over the first 5days post-transplantation. Patients were followed for 7.8±1.3years, and protocol biopsies were taken 1month, 1, 3, and 5years post-transplant. The Kaplan-Meier 8-year patient and graft survival rates in the cyclosporine-treated patients were 82.0±7.3% and 71.6±7.3, and in the tacrolimus-treated patients were 97.2±5.4 and 83.8±6.0%. Biopsy-proven acute rejection developed in 35% of cyclosporine-treated patients and in 8% of tacrolimus-treated patients. Alemtuzumab pretreatment prior to LRD kidney transplantation, followed by maintenance immunosuppression with tacrolimus and MMF, is associated with reasonable long-term results in pediatric patients.

Subclinical Antibody-Mediated Rejection

Subclinical Antibody-Mediated Rejection

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

P70S6 kinase phosphorylation: a new site to assess pharmacodynamy of sirolimus.

Background:The phosphorylation of p70S6 kinase (p70S6K) represents an important target for sensitive detection on pharmacodynamic effects of sirolimus, but the methods of assessing p70S6K phosphorylation are still unclear. The aim of this study was to investigate p70S6K phosphorylation located down-stream of the mammalian target of rapamycin (mTOR) pathway in peripheral blood mononuclear cells (PBMCs) of liver transplant patients through different methods.Methods:Seventy-five liver transplant recipients from Beijing Chaoyang Hospital of the Capital Medical University were analyzed in this study. Patients were divided into three groups, patient treated with sirolimus (n = 22), patient treated with tacrolimus (n = 30), patient treated with cyclosporine (n = 23). The p70S6K phosphorylation of PBMCs in patients and healthy control (HC, n = 12) were analyzed by phospho-flow cytometry and Western blotting. A correlation analysis of data from phospho-flow cytometry and Western blotting was performed. Intra-assay variability of p70S6K phosphorylation in HC and different patients were measured.Results:Intra-assay variability of p70S6K phosphorylation in phospho-flow cytometry was from 4.1% to 8.4% and in Western blotting was from 8.2% to 18%. The p70S6K phosphorylation in patients receiving a sirolimus (19.5 ± 7.7) was significantly lower than in HC (50.1 ± 11.3, P < 0.001), tacrolimus (37.7 ± 15.7, P < 0.001) or cyclosporine treated patients (41.7 ± 11.7, P < 0.001). The p70S6K phosphorylation in HC (50.1 ± 11.3) was significantly higher than in tacrolimus (37.7 ± 15.7, P < 0.01) or cyclosporine-treated patients (41.7 ± 11.7, P < 0.01). There was correlation between data from phospho-flow cytometry and data from Western blotting (r = 0.88, P < 0.001).Conclusions:The degree of mTOR inhibition by assessing p70S6K phosphorylation was established by phospho-flow cytometry and Western blotting. Assessment of p70S6K phosphorylation may play an adjunct role to on pharmacodynamically guide and individualize sirolimus based on immunosuppression.

Sustained virological response to antiviral therapy in a randomized trial of cyclosporine versus tacrolimus in liver transplant patients with recurrent hepatitis C infection.

Choice of calcineurin inhibitor may influence response to antiviral therapy in liver transplant patients with hepatitis C virus (HCV) infection. In a randomized, multicenter, 80-week trial, liver transplant recipients (>6 months and £10 years post-transplant) with recurrent HCV infection received cyclosporine (n=50) or tacrolimus (n=42) with a 48-week course of pegylated interferon (peg-IFNα2a) and ribavirin. Twenty-three patients in each group completed the trial on study medication. The primary endpoint was sustained virological response (SVR) 24 weeks after the end of antiviral therapy, for which 43 patients were eligible for analysis. The rate of SVR was 60.0% (12/20) with cyclosporine and 43.5% (10/23) with tacrolimus (adjusted odds ratio 1.85; 95% CI 0.53-6.43; p=0.331). There were no significant intergroup differences for rapid or early virological response, relapse, HCV RNA viral load, or fibrosis progression. One cyclosporine-treated patient experienced acute rejection. One patient died in each group. Adverse events, treatment-related adverse events, and serious adverse events were similar between groups. Since fewer patients were recruited than planned (92 versus 355), the study was underpowered and robust conclusions cannot be drawn regarding the effect of cyclosporine and tacrolimus on virological responses to antiviral treatment for recurrent HCV after liver transplantation. However, as reported in other trials, SVR was higher in cyclosporine-treated patients.

Length of hospital stay and associated hospital costs with infliximab versus cyclosporine in severe ulcerative colitis.

Cyclosporine and infliximab (IFX) seem equally effective as rescue therapy in hospitalized patients with severe ulcerative colitis (UC), although associated hospital stay and costs may differ. The aim of this study was to compare the duration of hospital stay and associated costs from initiation of rescue therapy to time of discharge in hospitalized patients with corticosteroid-refractory UC receiving cyclosporine or IFX. Colectomy rates after 6 months were used as the outcome parameter for treatment success. Hospital records of patients admitted between November 2003 and August 2012 at a tertiary referral center were analyzed. Forty-two patients were included (cyclosporine group: 26 patients; IFX group: 16 patients). Patient characteristics were comparable, with the exception that cyclosporine-treated patients more often had a pancolitis (89 vs. 63%, P=0.046). The median length of hospital stay was 11.0 (interquartile range 7.75-13.25) versus 4.0 days (interquartile range 4.0-5.75) in the cyclosporine and IFX group (P<0.01), respectively. The mean in-hospital costs were significantly higher in the cyclosporine-treated versus IFX-treated patients (6121 vs. 4853 euros, P<0.05), whereas the total costs up to 3 months after initiation of rescue therapy were significantly higher in the IFX group (6787 vs. 9983 euros, P<0.01). There were no significant differences in colectomy rates at 6 months (23 and 31% for cyclosporine and IFX, P=0.50). More side-effects were observed during treatment with cyclosporine. Length of hospital stay and in-hospital costs have been reduced significantly since the introduction of IFX as rescue therapy for severe UC instead of cyclosporine. However, the total treatment costs are higher in IFX-treated patients.

Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study.

Conversion of living-donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265μmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5months post-transplant. In a post hoc analysis of 80 living-donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73m(2) with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73m(2) ) with cyclosporine, a difference of 10.5ml/min/1.73m(2) in favour of everolimus (P<0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73m(2) with everolimus versus -0.7 (95% CI [-4.6, 3.1]) ml/min/1.73m(2) ) (P<0.001) with cyclosporine. There were six biopsy-proven acute rejection episodes in everolimus-treated patients (five Banff grade I) and one episode in cyclosporine-treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12months post-transplant that is observed in both living and deceased-donor recipients. (clinicaltrials.gov NCT00154310).

Posttransplant Metabolic Complications in Living-Related Renal Allograft Recipients of Kashmir Valley

Renal transplant offers a definitive therapeutic modality for patients with end-stage renal disease; however, 50% to 70% of these patients have graft dysfunction after the transplant. Proactive prevention management of metabolic complications may reduce posttransplant morbidity and mortality in these patients. A retrospective and prospective review of 120 kidney transplant recipients during 5 years' follow-up was performed to analyze the incidence and status of the various metabolic complications after a renal transplant. In our study, postrenal transplant diabetes mellitus was seen in 9 of 120 patients (7.5%). The incidence of posttransplant diabetes mellitus was 5% in tacrolimus-treated patients (n=6) compared with 2.5% in cyclosporine-treated patients (n=3). Dyslipidemia, as hypercholesterolemia and hyper-triglyceridemia, was seen in 31 recipients (25.83%). Significant posttransplant hyperlipidemia was documented (P < .05). Further, it was noted that 25 patients who developed hyperlipidemia (20.83%) were taking cyclosporine-based therapy, while 6 were treated with tacrolimus-based therapy (5%; P < .05). However, most subjects with hyperlipidemia had renal graft dysfunction. Posttransplant erythrocytosis affected 9 renal transplant recipients (7.5%) with a mean (±SD) hematocrit of 41.3%±6.7%. A statistically significant correlation was seen between prerenal and postrenal transplant hematocrit by 12 months. Hyperparathyroidism was observed in 1 renal transplant patient (1.25%). On the basis of this study, we conclude that posttransplant diabetes mellitus occurred in 7.5% patients, hypercholesteremia and hyper-triglyceridemia occurred in 25.83% patients, posttransplant erythrocytosis affected 7.5% patients, and hyperparathyroidism occurred in 1 renal transplant patient (1.25%). Moreover, dyslipidemia, contributed to progressive graft dysfunction.

Magnesium loss in cyclosporine-treated patients is related to renal epidermal growth factor downregulation

Cyclosporine (CsA) treatment is associated with hypomagnesaemia due to a renal Mg(2+) leak. In animal studies a role for the Mg(2+) channel TRPM6 localized in the distal convoluted tubule and stimulated by epidermal growth factor (EGF) is suggested. We hypothesize that CsA-induced hypomagnesaemia is due to a renal magnesium leak, also in patients, resulting from a downregulation of the renal EGF production, thereby inhibiting the activation of TRPM6. Renal transplant patients treated with CsA (n = 55) and 35 chronic kidney disease (CKD) patients were included. At three time points, with an interval of at least 1 month, blood and urine samples were taken to determine creatinine, Mg(2+), sodium and EGF. Serum Mg(2+) was significantly lower in the CsA group versus the CKD group with significantly more CsA-treated patients developing hypomagnesaemia. Although the fractional excretion (FE) Mg(2+) did not differ significantly between the two groups, subanalysis of the patients with hypomagnesaemia showed a significantly higher FE Mg(2+) in CsA-treated patients compared with CKD patients (P = 0.05). The urinary EGF excretion was significantly decreased in the CsA group and was a predictor of the FE Mg(2+) in the two groups. Serum sodium was significantly decreased in the CsA group simultaneously with an increased FE Na(+). In CsA-treated patients, the association of a low urinary EGF excretion and a decreased renal Mg(2+) reabsorption is in accordance with in vitro and animal studies. In the whole study population, log urinary EGF excretion is an independent predictor of the FE Mg(2+), supporting the role of EGF in magnesium reabsorption.

Interaction between calcineurin inhibitors and IL-28B rs12979860 C&gt;T polymorphism and response to treatment for post-transplant recurrent hepatitis C

The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response. Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients. Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤ 1 T allele (56.1%) to tacrolimus-treated patients carrying ≤ 1 T allele (44.7%) to patients carrying ≥ 2 T alleles (25.0%, p=0.0009). Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying <2 T alleles cyclosporine favours a better response than tacrolimus, while no difference was found in the presence of ≥ 2 T alleles.

Belatacept in kidney transplantation

In June 2011 the US Food and Drug Administration approved belatacept (Nulojix; Bristol-Myers Squibb, Princeton, New Jersey, USA) for the prophylaxis of organ rejection in adult kidney transplant recipients. This review will discuss the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase 3 trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. Overall, there seemed to be an improvement in cardiometabolic parameters in patients treated with belatacept compared with cyclosporine. There was a trend toward higher rates of early rejection episodes in patients treated with belatacept. One safety issue that must be considered when using belatacept is the potential for increased risk of posttransplant lymphoproliferative disease, especially in Epstein-Barr virus-seronegative recipients or patients treated with lymphocyte-depleting agents. Belatacept is the first new agent available in kidney transplant that may achieve the goal of improved long-term renal function.

Belatacept: a novel immunosuppressive agent for kidney transplant recipients

Long-term graft and patient survival remain the most significant challenges in kidney transplantation, and new therapies are needed to improve long-term outcomes. Belatacept, a first-in-class selective costimulation blocker, has been approved for prophylaxis of organ rejection in kidney transplant recipients who are positive for EBV. In Phase III trials, belatacept demonstrated superior preservation of renal function and comparable patient/graft survival compared with cyclosporine, while avoiding the renal toxicities and other adverse events associated with the use of a calcineurin inhibitor. Patients treated with belatacept had higher rates of acute rejection than cyclosporine-treated patients. However, acute rejection episodes that occurred early and did not recur were generally not associated with donor-specific antibodies, and few belatacept patients had graft loss due to rejection. The improved renal benefit with belatacept may translate into improvements in long-term graft and patient outcomes. Targeting T-cell costimulation is an important new option for maintenance immunosuppression in kidney transplant recipients.

Changes in Oxidative Stress in Renal Graft Patients Receiving Calcineurin Inhibitors: Cyclosporine Versus Tacrolimus

The effects of calcineurin inhibitors on oxidative stress after renal transplant are obscure. This study sought to investigate the changes in plasma oxidative stress and lipid levels in patients receiving cyclosporine or tacrolimus before and after renal transplant for 6 months. Twenty-one patients and 15 healthy controls were involved in our study. Twelve of the patients were treated with cyclosporine and 9 were treated with tacrolimus. Plasma malondialdehyde, nitrite/nitrate, vitamin C, vitamin E, and plasma glutathione levels, as well as total cholesterol and triglyceride levels, were evaluated before and after transplant for 6 months. Before the transplant, patients had higher malondialdehyde and plasma glutathione levels than did healthy controls (3.76 ± 0.79 nmol/mL vs 3.21 ± 0.57 nmol/mL; P < .05, and 66.6 ± 23.2 μmol/L vs 43.3 ± 26.9 μmol/L; P < .05). In the overall group of patients, a significant increase in malondialdehyde levels was detected 3 and 6 months after transplant (3.76 ± 0.79 nmol/mL vs 4.38 ± 0.87 nmol/mL in the third month; P = .02; and 3.76 ± 0.79 nmol/mL vs 4.28 ± 0.69 nmol/mL in the sixth month; P = .04). A significant reduction in plasma glutathione levels 1 month after transplant and nitrite/nitrate levels 6 months after transplant was found. No changes in vitamin C and vitamin E levels were detected before and after transplant. After 3 and 6 months of transplant, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides when compared with tacrolimus-treated patients. An enhancement in plasma malondialdehyde levels was found after transplant at 6-month follow-up. However, no significant change in vitamin C, vitamin E, nitrite/nitrate levels between patients and controls was recorded. Although both calcineurin inhibitors showed similar effects on oxidative stress, cyclosporine-treated patients had higher levels of total cholesterol and triglycerides.