Cyclosporine Levels Research Articles

Detection of systemic immunosuppressants in autologous serum eye drops (ASED) in patients with severe chronic ocular graft versus host disease

PurposeChronic graft versus host disease is a major consequence after allogeneic stem cell transplantation (allo-SCT) and has great impact on patients’ morbidity and mortality. Besides the skin, liver, and intestines, the eyes are most commonly affected, manifesting as severe ocular surface disease. Treatment protocols include topical steroids, cyclosporine, tacrolimus, and ASED. Since these patients often receive systemic immunosuppressant therapy from their oncologists, a topical re-administration of these drugs via ASED with potentially beneficial or harmful effects is possible. The purpose of the study was to determine whether and to which extent systemic immunosuppressants are detectable in ASED.MethodsA total of 34 samples of ASED from 16 patients with hemato-oncological malignancies after allo-SCT were collected during the manufacturing process and screened for levels of cyclosporine, mycophenolic acid, everolimus, and tacrolimus via liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The study followed the tenets of the Declaration of Helsinki and informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study.ResultsCyclosporine was found in 18 ASED samples in concentrations ranging from 6.5–105.0 ng/ml (32.0 ± 22.8 ng/ml, mean ± SD). The concentration range of mycophenolic acid in 19 samples was 0.04–25.0 mg/l (4.0 ± 5.4 mg/l, mean ± SD). Everolimus and tacrolimus concentrations were well below the respective limits of quantification (< 0.6 and < 0.5 ng/ml) of the established LC-MS/MS method in all samples.ConclusionsOur study suggests that orally administered cyclosporine and mycophenolic acid for the treatment of systemic GvHD, but not everolimus and tacrolimus, are distinctly detectable in ASED in relevant concentrations. It is highly likely that these agents affect topical therapy of ocular GvHD. However, the extent of this effect needs to be evaluated in further studies.

Kidney transplant patients with SARS-CoV-2 infection: The Brescia Renal COVID task force experience.

The outcome of kidney transplant patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is still unclear. Here we describe the clinical characteristics, disease outcome, and risk factors for acute respiratory distress syndrome (ARDS) and death of a cohort of 53 kidney transplant patients with coronavirus disease 2019 (COVID‐19). Eight of 53 have been handled as outpatients because of mild disease, on average with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin; no patients required admission, developed ARDS, or died. Because of severe symptoms, 45/53 required admission: this cohort has been managed with immunosuppression withdrawal, methylprednisolone 16 mg/d, hydroxychloroquine, and antiviral drugs. Dexamethasone and tocilizumab were considered in case of ARDS. About 33% of the patients developed acute kidney injury, 60% ARDS, and 33% died. In this group, thrombocytopenia was associated to ARDS whereas lymphopenia at the baseline, higher D‐dimer, and lack of C‐reactive protein reduction were associated with risk of death. In the overall population, dyspnea was associated with the risk of ARDS and age older than 60 years and dyspnea were associated with the risk of death with only a trend toward an increased risk of death for patients on tacrolimus. In conclusion, SARS‐CoV‐2 infection may have a variable outcome in renal transplant patients, with higher risk of ARDS and death in the ones requiring admission.

Should cyclosporine be useful in renal transplant recipients affected by SARS-CoV-2?

Minimization of immunosuppression and administration of antiretrovirals have been recommended for kidney transplant recipients (KTRs) with coronavirus disease 2019 (COVID‐19). However, outcomes remain poor. Given the likely benefit of cyclosporine because of its antiviral and immunomodulatory effect, we have been using it as a strategy in KTRs diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). We studied 29 kidney transplant recipients (KTRs) who were admitted to our institution with COVID‐19 between March 15and April, 24, 2020. Mycophenolate and/or mammalian target of rapamycin inhibitors (mTORi) were discontinued in all patients. Two therapeutic strategies were compared: Group 1, minimization of calcineurin inhibitors (N = 6); and Group 2, cyclosporine‐based therapy (N = 23), with 15 patients switched from tacrolimus. Hydroxychloroquine was considered in both strategies but antivirals in none. Six patients died after respiratory distress (20.6%). Five required mechanical ventilation (17.2%), and 3 could be weaned. Nineteen patients had an uneventful recovery (65.5%). In group 1, 3 of 6 patients died (50%) and 1 of 6 required invasive mechanical ventilation (16.7%). In group 2, 3 of 23 patients died (12.5%). Renal function did not deteriorate and signs of rejection were not observed in any patient on the second treatment regime. In conclusion, immunosuppressant treatment based on cyclosporine could be safe and effective for KTRs diagnosed with COVID‐19.

P0647ACUTE KIDNEY INJURY SECONDARY TO SUCROSE CONTAING INTAVENOUS IMMUNOGLOBULIN

Abstract Background and Aims Intravenous immunoglobulins (IVIG) are pooled polyvalent IgG antibodies extracted from the human plasma. While the initial indications were mainly immune deficiency states and some autoimmune diseases, the usage has been widened to include several immune mediated diseases, viral infections, and organ transplant rejection. Stabilizers in IVIG may include sugars, such as sucrose, glucose, or maltose. Sucrose in IVIG preparations may cause acute kidney injury. We report the case of a renal transplant patient who developed acute kidney injury due to sucrose nephropathy following the administration of sucrose containing IVIG. Method Four months after transplantation he was referred to our Hospital for deterioration of kidney function with eGFR (by MDRD formula) of 27ml/min. Cytomegalovirus virus (CMV) PCR turned positive (3300 copies/ml). Cyclosporine levels were high (C2: 2937 ng/ml) and hence, cyclosporine dose was adjusted. Induction therapy with Injection Ganciclovir for 2 weeks, followed by therapeutic dose of oral Valganciclovir was administered for the treatment of CMV infection. Skin examination revealed annular purple patches, suspicious of Kaposi Sarcoma, on the upper limbs. Skin biopsy confirmed the diagnosis. It was planned to give total IVIG of 2 gm/ kg in four daily divided doses. After completion of the second dose, serum creatinine increased to 370 µmol/L. He was clinically asymptomatic, euvolumic, vital signs were stable, and his urine output remained normal and his urinalysis was inactive. Results The ultrasound of the transplant kidney was normal with normal resistivity index. IVIG was stopped. He was well hydrated and underwent ultrasound guided biopsy. The graft biopsy showed acute tubular injury with flattening and vacuolation of tubular epithelial cells. Mitosis indicating tubular regeneration was seen. There was mild focal interstitial inflammation (20%) with mild lymphocytic tubulitis not amounting to graft rejection. Immunohistochemistry for C4d and polyomavirus (BKV) were both negative. The features were most consistent with sucrose induced nephropathy (Figure 1). Subsequent visits showed a decrease in BKV-PCR serum level and eventually undetected serum level of BKV-PCR at follow up about a month later. Conclusion In this paper, we presented a case of a living unrelated kidney transplant recipient who developed BKV nephropathy and developed impaired kidney function. The patient also had new onset diabetes mellitus after kidney transplantation (NODAT) but was otherwise in good general health. Treatment included sucrose containing IVIG. The patient subsequently developed acute kidney injury. The outcome was favorable with recovery of filtration rate to the baseline within 21 days without the need for dialysis. We conclude that the administration of sucrose containing IVIG may lead to acute kidney injury. We recommend the use of sucrose-free IVIG whenever possible. In all cases, caution is required when administrating IVIG.

Posttransplant Calcineurin Inhibitors Levels and Intrapatient Variability Are Not Associated With Long-term Outcomes Following Liver Transplantation.

There is an interest in understanding the association between early calcineurin inhibitors exposure post-liver transplantation (LT) and long-term outcomes. We aimed to analyze this association exploring median calcineurin inhibitor levels and intrapatient variability (IPV) in a multicenter, retrospective cohort. Tacrolimus (Tac) and Cyclosporine (CsA) levels obtained during the first 15 days post-LT were collected. High immunosuppression (IS) was considered as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration higher than 10, 250, or 1200 ng/mL, respectively, or a peak of Tac >20 ng/mL. Optimal IS was defined as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration levels between 7 and 10, 150 and 250, or 800 and 1200 ng/mL. Low IS was defined as below the thresholds of optimal IS. IPV was estimated during the first 15 days post-LT. The study included 432 patients with a median follow-up of 8.65 years. IS regimen was based on either Tac or CsA in 243 (56.3%) and 189 (43.8%), respectively. There were no differences in terms of graft loss among low versus optimal and high IS groups (P = 0.812 and P = 0.451) nor in high versus low IPV (P = 0.835). Only viral hepatitis and arterial hypertension were independently associated with higher graft loss (hazard ratio = 1.729, P = 0.029 and hazard ratio = 1.570, P = 0.021). In contrast to what has previously been reported, no association was found between very early postoperative over IS or high IPV and long-term outcome measures following LT. Strategies aimed at reducing these long-term events should likely focus on other factors or on a different IS time window.

Therapeutic Drug Monitoring of Cyclosporine Using Single Sampling Strategy

Cyclosporine is mainly used as Immunosuppressant after different kinds of transplantation including bone marrow, lungs, kidneys, liver, heart, and other types of organ transplantations. Immunosuppressants diminish organ rejection and elongate the survival of the transplanted organs. Due to the narrow therapeutic ranges and significantly&#x0D; high interindividual and intraindividual variability in blood levels of cyclosporine, there is essential and vital need of therapeutic drug monitoring (TDM) of this drug in order to maintain the patient within the required therapeutic concentrations, which consequently lead to optimizing the clinical outcome and decrease the hazard of toxicity or rejection following organ transplantations. The current review article was aimed to present data for using a single or possibly two blood sampling strategy to be used for TDM of cyclosporine in order to assess the optimal blood levels of cyclosporine used in organ transplant recipients. The results showed that steady state blood concentration of cyclosporine obtained after 2 hours (C2) and possibly after 3 hours (C3) of drug administration are the best sampling time points which reflect total drug exposure (area under blood concentration versus time curve=AUC) and consequently reflecting the effect and the adverse effect(s) of cyclosporine. On the other hand, blood samples obtained at other time points particularly steady state trough concentration obtained before the next dose (C0) demonstrated poor correlation with total drug exposure and consequently the clinical outcome of the drug. Moreover, this study also demonstrated that for organs transplantations TDM of cyclosporine and assessing the clinical conditions of the patients should be routinely performed in order to adjust the dose to get optimal effect and to diminish the adverse effects of the drug. This review article focused on the findings which indicated that monitoring steady-state blood levels of cyclosporine after 2 hours (C2) and likely after 3 hours (C3) of drug intake may be used as ideal surrogate index in TDM of cyclosporine and for predicting the clinical outcome of the drug in all and different types of organs transplantations.

Therapeutic Drug Monitoring of Cyclosporine Using Single Sampling Strategy

Cyclosporine is mainly used as Immunosuppressant after different kinds of transplantation including bone marrow, lungs, kidneys, liver, heart, and other types of organ transplantations. Immunosuppressants diminish organ rejection and elongate the survival of the transplanted organs. Due to the narrow therapeutic ranges and significantly high interindividual and intraindividual variability in blood levels of cyclosporine, there is essential and vital need of therapeutic drug monitoring (TDM) of this drug in order to maintain the patient within the required therapeutic concentrations, which consequently lead to optimizing the clinical outcome and decrease the hazard of toxicity or rejection following organ transplantations. The current review article was aimed to present data for using a single or possibly two blood sampling strategy to be used for TDM of cyclosporine in order to assess the optimal blood levels of cyclosporine used in organ transplant recipients. The results showed that steady state blood concentration of cyclosporine obtained after 2 hours (C2) and possibly after 3 hours (C3) of drug administration are the best sampling time points which reflect total drug exposure (area under blood concentration versus time curve=AUC) and consequently reflecting the effect and the adverse effect(s) of cyclosporine. On the other hand, blood samples obtained at other time points particularly steady state trough concentration obtained before the next dose (C0) demonstrated poor correlation with total drug exposure and consequently the clinical outcome of the drug. Moreover, this study also demonstrated that for organs transplantations TDM of cyclosporine and assessing the clinical conditions of the patients should be routinely performed in order to adjust the dose to get optimal effect and to diminish the adverse effects of the drug. This review article focused on the findings which indicated that monitoring steady-state blood levels of cyclosporine after 2 hours (C2) and likely after 3 hours (C3) of drug intake may be used as ideal surrogate index in TDM of cyclosporine and for predicting the clinical outcome of the drug in all and different types of organs transplantations.

Steering of Transplant Immunosuppression by Virus-Specific T Cells (IVIST Trial)

Background: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells (Tvis) correlate with virus-specific as well as general cellular immune defense. Additional steering by Tvis levels may optimize dosing of immunosuppressants. Methods: In a multicenter, randomized controlled trial, 64 pediatric kidney recipients were randomized 1:1 to a control group with trough level monitoring of immunosuppressants or to an intervention group with additional steering by Tvis levels, quantified by cytokine flow cytometry. Both groups received immunosuppression with cyclosporine A and everolimus in the same target range of trough levels. Primary endpoint was the estimated glomerular filtration rate (eGFR) two years after transplantation. Findings: We observed an increase of eGFR in the intervention group and no substantial change in the control group. The mean difference (intervention-control) was 7.5±27.6 mL/min/1.73m2. Patients in the intervention group received lower daily doses (mg/m2) of everolimus (0.8±0.3 vs. 1.2±0.5, p=0.004) and cyclosporine A (78.4±20.0 vs. 88.4±26.5, p=0.13) resulting in lower trough levels (µg/L) of everolimus (3.5±0.7 vs. 4.5±0.8, p<0.001) and cyclosporine A (47.4±9.9 vs. 64.1±11.1, p<0.001). Fewer patients in the intervention group received glucocorticoids two years after transplantation (20% vs. 47%, p=0.04). Patients in the control group had a higher risk for rejections (p=0.11) and EBV DNAemia (p=0.09). Numbers of donor-specific antibodies and (serious) adverse events were comparable. Interpretation: Additional steering of immunosuppressive therapy by Tvis levels is safe and personalizes immunosuppressive therapy by lowering exposure to immunosuppressants, resulting in stabilization of eGFR and reduced risk for rejections and EBV DNAemia. Trial Registration: EudraCT No: 2009-012436-32, ISRCTN89806912, 17.06.2009. Funding Statement: Funded by the German Ministry of Education and Research and Novartis. Declaration of Interests: LP reports receiving research support by Novartis and Chiesi and lecture fees by Alexion, Novartis and Chiesi as well as travel grants from Neovii. LTW reports receiving research support by Chiesi, lecture fees by Novartis, advisory fees by Alexion and travel grants by Astellas. JO received research support by Chiesi, lecture fees by Chiesi and Alexion, advisory fees by Alexion, Chiesi, Boehringer Ingelheim, Neovii, Amgen and travel grants by Neovii. TA received travel grants from Novartis, Astellas and Alexion and lecture fees from Novartis. All other authors declare no conflict of interest. Ethics Approval Statement: The trial protocol was approved by the scientific ethics committees of the participating university hospitals. The trial was performed in accordance with the principles of the Declaration of Helsinki.

High Incidence of Acute Kidney Injury after Cord Blood Transplant

<h3>Introduction</h3> Acute kidney injury (AKI) occurs frequently after hematopoietic cell transplant, affecting anywhere from 10-73% of patients and is associated with higher post-transplant mortality. In this retrospective study, we identified incidence and risk factors of AKI in cord blood transplant (CBT) recipients and evaluated the impact of AKI on non-relapse mortality (NRM) and overall survival (OS). <h3>Methods</h3> We focused on first CBTs performed for hematologic malignancies between 2006 and 2018. AKI was staged using the Kidney Disease Improving Global Outcomes (KDIGO) system (stages 1-3). We collected demographic data, transplant characteristics, and complications occurring within the first 60 days post-CBT. We identified risk factors for the development of AKI post-CBT and using Cox proportional hazards regression modeling, analyzed the association of AKI with both NRM and OS. Variables of clinical interest or those with a p-value <0.05 in univariable analyses were considered in a multivariable (MV) model. <h3>Results</h3> 276 patients were evaluated. 227 (82%) suffered from acute leukemia. 243 (88%) patients received myeloablative conditioning regimen, 172 (62%) with high dose total body irradiation. 248 (90%) patients received cyclosporine as Graft versus Host-Disease (GvHD) prophylaxis. 186 (67%) patients developed AKI, with 114 (41%), 43 (16%) and 29 (11%) patients achieving a maximum of stage 1, stage 2 and stage 3 AKI, respectively. Cytomegalovirus (CMV), adenovirus and BK virus reactivation were detected in 126 (46%), 5 (2%) and 41 (15%) cases. 215 (78%) patients experienced grade 2-4 acute GvHD. In univariate analysis of time to first stage 2 AKI or higher, vancomycin use, bilirubin level, cyclosporin level and CMV viral load appeared to increase AKI risk, whereas male gender, grade 2-4 acute GvHD and systemic steroid use were found to be protective. BK virus reactivation had no significant effect on AKI risk. In MV analysis, only systemic steroid and bilirubin level remained significant (Table 1). Stage 2-3 AKI was associated with higher 1-year NRM [Hazard Ratio, HR 3.26, 95% CI (1.65-6.45), p=.001] and decreased OS [HR 2.28, 95% CI (1.22-4.27), p=.01]. <h3>Conclusions</h3> Our study confirms that stage 2-3 AKI is associated with an increased risk of NRM and overall mortality in CBT recipients. We found that the use of steroids was associated with lower risk of developing AKI. The protective effect exerted by steroids is of clinical interest and warrants further investigation.

Topical treatment of oral lichen planus

Oral lichen planus (OLP) is a skin disease affecting the mouth, which can cause a burning or stinging discomfort in the mouth when eating or drinking. Ulcers may occur and these are especially painful. The cause of oral lichen planus is not known in most instances, but it is likely to be related to the body's immune system. In this study, the authors from China aimed to compare the efficacy and safety of drugs called topical calcineurin inhibitors (TCI) with medicines applied to the skin called topical corticosteroids (TCS), in the treatment of OLP. The authors looked at globally published randomized controlled trials (RCTs) reporting TCI (tacrolimus, pimecrolimus, and cyclosporine) compared with TCS for OLP from eight medical databases. Twenty‐one RCTs with a total of 965 patients published between 1995 and 2017 were included (tacrolimus‐TCS: 12 studies, 578 patients; pimecrolimus‐TCS: 3 studies, 98 patients; cyclosporine‐TCS: 6 studies, 289 patients). The authors found that TCI including tacrolimus, pimecrolimus and cyclosporine were similar to TCS in efficacy for the short‐term treatment of OLP (3‐8 weeks). In addition, tacrolimus 0.1% was similar to TCS in relapse rate. The blood levels of tacrolimus and cyclosporine were usually extremely low, while the few cases of patients with high levels may have been caused by swallowing the drug accidentally. Although a few adverse events (unwanted side effects) were observed in the tacrolimus and cyclosporine groups, no serious events were found. Therefore, TCI may be an alternative approach when OLP does not improve with use of TCS. Due to the limited trials of pimecrolimus and cyclosporine, as well as a few adverse events and high cost of cyclosporine, tacrolimus 0.1% should be the first drug of choice in TCI for the short‐term treatment of OLP that is not improving with TCS. More well‐designed RCTs are needed to evaluate the long‐term efficacy and safety of TCI compared with TCS.

Efficacy and Safety of Gemigliptin in Post-Transplant Patients With Type 2 Diabetes Mellitus

BackgroundGemigliptin is a potent, selective dipeptidyl peptidase (DPP)-4 inhibitor that does not require any dosage adjustment based on renal function. It is also known to have no apparent interaction with commonly used drugs. In the present study, we aimed to evaluate the glucose-lowering efficacy and safety of gemigliptin in post-transplant patients with type 2 diabetes mellitus (T2D). MethodsA total of 84 patients who were prescribed gemigliptin for more than 180 days after transplantation were analyzed retrospectively. Six-month changes in blood glucose and glycated hemoglobin (HbA1c) levels were checked to assess glycemic efficacy. Safety was evaluated by examining its influence on immunosuppressive treatment, as determined by the blood trough level and dosage of calcineurin inhibitors, as well as changes in parameters related to liver and renal function. ResultsSix months of gemigliptin treatment significantly lowered blood glucose level (HbA1c: 8.16 ± 1.69 to 7.44 ± 1.26%; P < .001). There were no significant changes in blood trough levels of immunosuppressants, including tacrolimus, cyclosporine, and sirolimus. The dosage of immunosuppressants was also stable. In addition, there were no significant changes in the levels of liver enzymes and renal function during 6 months of treatment. ConclusionGemigliptin robustly lowered blood glucose levels without exerting any significant effect on immunosuppressive treatment, renal function, and liver enzymes in post-transplant patients with T2D.

Mucositis during Allogeneic Transplantation Determines Post-Transplant Serum Cyclosporin Levels

Introduction Intestinal mucosal injury is a common complication following allogeneic stem cell transplant (alloHSCT), especially with myeloablative and TBI-based (total body irradiation) conditioning regimens1. Prospective evaluation studies have shown that intestinal malabsorption persists for several weeks following conditioning, beyond visible resolution of mucositis and bowel integrity2. Serum cyclosporin levels in the post-transplant period (when patients are taking oral cyclosporin) may be affected by reduced gut absorption and could influence early transplant related outcomes. Aim To determine the relationship between mucositis severity, cyclosporin levels, and post-transplant outcomes. Methods 169 patients who received myeloablative (BuCy, CyTBI, EtoTBI) or reduced-intensity (FluMel) allo-HSCT at the Royal Melbourne Hospital were studied. Serum cyclosporin levels were measured at 2 hours post oral dosing. Days of post-transplant total parental nutrition (TPN) were used as a surrogate for severity of gastrointestinal mucositis. To determine degree of renal impairment, creatinine values were recorded at baseline, D+30, D+60 and D+100. The incidence and severity of acute graft-versus-host disease (aGVHD) was recorded before D+100. The incidence of CMV viraemia before D+100 was recorded and analysed according to serum viral load. Patients with disease relapse (&lt;6m versus &gt;6m) were compared with patients without. Results Linear regression analysis showed an inverse correlation between days requiring TPN with the post SCT 100-day median cyclosporin level (p&lt;0.0001, R2=0.23). Higher median cyclosporin level was associated with a greater percentage increase of creatinine above baseline (p=0.004, R2= 0.051). There was no significant correlation between incidence (p=0.05) and severity (p=0.47) of aGVHD with lower cyclosporin levels. CMV reactivation was associated with higher cyclosporin levels (p&lt;0.0001). There was no significant difference in cyclosporin levels according to viral copy number (p=0.067). There was no significant difference in cyclosporin levels between disease-relapsed groups and non-relapsed groups (p=0.33). Conclusion Our data suggest that patients who have significant mucositis have lower serum cyclosporin levels with oral cyclosporin dosing, which in turn impact upon post-transplant outcomes, in particular renal impairment and CMV reactivation.

Methodology for the Start-up of a Pediatric Hematopoietic Stem Cell Transplant Unit (pHSCTU) in Middle-Income Countries (MICs): An Exportable Model?

Introduction: Blood or marrow transplantation (BMT) programs are largely insufficient to meet the growing need in MICs. Where BMT is not available families, charities or governments often seek for alternative programs, usually to send children abroad for BMT; this policy is associated with many drawbacks, including costs, and difficulties to manage transplant related complications after the patient return home. Evaluation of feasibility and sustainability plays a crucial role in the success of all cooperative projects but especially of high specialization ones. Materials and methods: In 2016 the first HSCTU inclusive of a pediatric section was developed in Iraqi Kurdistan at Hiwa Cancer Hospital of Sulaymaniah, thanks to a cooperative project funded by the Italian Agency for Development Cooperation and to the availability of professionals from specialized centers to train local personnel. After verifying with an appropriate grid that essential requirements were in place, a capacity building project was started. An intensive educational course was carried on initially and then, using a training on the job approach, all specific skills were set-up and/or implemented. A complete protocol handbook was created with involvement of the local staff; a staggered approach to the disease was chosen, starting from low risk diseases and moving later to high risk ones. After 3 years project the center is now completely autonomous; up to now they have been performed 158 transplants (autologous and allogeneic, both in adult and children) with results comparable with those of high-income countries (HICs). In a cohort of 26 pediatric patients with thalassemia the event free survival (EFS) is over 90% with a median follow up of 492 days. Next to this experience, in 2018 a new project has been activated in Paraguay, following a specific request from the pediatric hospital Ninos de Acosta Nu in Asuncion. The similar methodology has been applied. After documenting the feasibility, a 3 years project has been set-up, with an initial intensive educational course, followed by training on the job by experts in the field and also limited training of the local staff abroad. A six months continuously oversight by experienced nurses and periodically by expert physicians has been planned along with the continuous support through on line contacts; focused training in Europe on minimal residual disease, chimerism, apheresis and HLA typing has been scheduled. The first allogeneic transplant from matched sibling donor is planned in autumn 2019. Discussion: Based on our experience new centers should start with patients highly curable, low-risk matched sibling transplants, well-established context-appropriate protocols with minimal toxicity, proven high success rates and contained costs. If socio-economical context of the country and needs of the population allow to move to oncological patients, a staggered approach is suggested: from matched sibling donor transplant to mismatched ones. Minimal essential requirements for a pediatric BMT start-up activity may be affordable in many MICs, if health authorities and/or local charities/foundations are committed. This shall include good quality blood products (leuco-reduced or irradiated); drugs for conditioning regimens (busulphan, tiothepa, fludarabine, cyclophosphamide, melphalan), GVHD prophylaxis and treatment (methotrexate, thymoglobuline, cyclosporine, mycophenolate mofetil), infections control (broad spectrum antibiotics, one anti-mold drug, ganciclovir) and essential laboratory tests (at least cyclosporin levels and citomegalovirus copies count). Conclusion: The strategy described above requires the availability of expert BMT physicians and nurses willing to rotate periodically in MICs Units for training on the job and supervision. This model is replicable in different contexts, allows a fast development of BMT units in MICs, and in our opinion compares favorably with that of offering training to multiple professionals in specialized centers. Figure Disclosures No relevant conflicts of interest to declare.

Monitoring trough levels in cyclosporine for atopic dermatitis: A systematic review.

Cyclosporine is a useful immunosuppressive agent for achieving disease control in moderate to severe atopic dermatitis in children and adults. However, it carries the potential for nephrotoxicity. Monitoring of drug levels is performed in other patient groups, such as transplant recipients, but is not commonplace in the management of atopic dermatitis. To investigate levels of nephrotoxicity associated with cyclosporine use in atopic dermatitis and assess potential correlation with trough levels of cyclosporine. An electronic search was conducted on MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials and cohort studies assessing the safety profile of cyclosporine compared to placebo or other atopic dermatitis treatments, in adult and pediatric atopic dermatitis patients from 1966 to May 2019. Studies that did not assess renal toxicity were excluded from analysis. Thirty-eight trials were included for analysis, excluding 11 that did not assess renal toxicity. Descriptive statistical analysis only was performed, due to the high heterogeneity between study methodologies. Significant renal toxicity was seen in 0%-9% of pediatric participants. Monitoring of trough cyclosporine levels was performed in only 10 of the studies, and their correlation to toxicity or disease activity was not explored. There is limited evidence in atopic dermatitis regarding trough level monitoring of cyclosporine. Currently, the practice is not commonplace, particularly in pediatrics, and this is reflected in trial methodology. Monitoring may be useful in specific pediatric groups, such as those on multiple concurrent medications, patients with hepatic or renal dysfunction and non-responders to therapy.

Possible Role of P-Glycoprotein in Cyclosporine -Acitretin Drug Interaction

P-glycoprotein, an efflux transporter prevents intracellular accumulation of xenobiotics. Cyclosporine A and acitretin are used to treat psoriasis. The present research work aims to investigate the possible role of P-glycoprotein in Cyclosporine- Acitretin drug interaction due to evidence of both drugs having affinity for P-glycoprotein.The study has three different objective namely to assess apparent permeability coefficient of cyclosporine in presence of acitretin by non-everted sac technique, to study the intestinal permeation and absorption kinetics of cyclosporine in presence of acitretin by single pass intestinal perfusion (SPIP) technique and to study the influence of acitretin on oral bioavailability of cyclosporine in Wistar rats.The result of ex vivo, in situ and in vivo study showed that cyclosporine level increased in a time dependent manner. As the dose of acitretin increases the cyclosporine concentration in all three methods tend to increase and was statistically significant. The improvement in absorption of cyclosporine may be due to the inhibition of P-glycoprotein transporter in the intestine by acitretin. Thus acitretin may enhance the oral pharmacokinetics of cyclosporine. Hence this combination may require close monitoring for better therapeutic outcome. Our study confirmed the inhibitory role of acitretin on P-glycoprotein leading to increase concentration of cyclosporine.

Comparison of the effect of direct-acting antiviral with and without ribavirin on cyclosporine and tacrolimus clearance values: results from the ANRS CO23 CUPILT cohort.

Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse. Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays. Sixty-seven mainly male patients (79%) were included, with a mean age of 57years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p =0.02) and lower haemoglobin during direct-acting antiviral treatment (p =0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range. Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels. NCT01944527.

MON-167 TRANSPLANT RENAL ARTERY STENOSIS AS A POTENTIAL COMPLICATION AFTER KIDNEY TRANSPLANTATION FROM DONOR WITH MOYAMOYA DISEASE: A CASE REPORT

Moyamoya disease is a rare chronic cerebrovascular disorder with progressive stenosis of intracranial internal carotid arteries and their proximal branches resulting in the development of severe collateral circulations and associated with a high risk of stroke. Moyamoya disease may have extracranial manifestations such as coronary artery fistulas and stenosis, cardiac valve stenosis, congenital heart disease, and renal artery stenosis. Although organs from donors with Moyamoya disease are considered safe for transplantation, there are few reports describing the use of the organs. Here, I described the unfortunate case of kidney transplant (KT) recipient who received transplanted kidney from donor with Moyamoya disease presented with early transplant renal artery stenosis (TRAS). A 42-year-old Thai male with end-stage renal disease from unknown cause underwent KT from a 32-year-old Thai male deceased donor who was firstly diagnosed Moyamoya disease with catastrophic cerebral infarction. The KT was complicated by delayed graft function and his kidney function recovered after 2 sessions of hemodialysis. The maintenance immunosuppressive drugs included cyclosporine, mycophenolate mofetil and prednisolone. Routine Doppler ultrasound examination of transplanted kidney was done at postoperative day 7 without abnormal findings. Three months after KT, he presented with kidney allograft dysfunction, hypertension and volume overload. His serum creatinine increased from 2.08 to 5.53 mg/dL. The Cyclosporine level was within normal range. Serum BK virus and cytomegalovirus were undetectable. Kidney biopsy pathology showed diffuse ischemic tubular atrophy and interstitial edema and fibrosis without evidence of rejection. Repeat Doppler ultrasound examination of transplanted kidney revealed good transplant perfusion with a turbulent flow and a peak systolic velocity > 2 m/s at mid to distal main renal artery. Magnetic resonance angiography of transplant renal artery was also confirmed the stenosis. TRAS was diagnosed and percutaneous transluminal renal artery angioplasty (PTRA) was done without stent placement. His kidney function improved with serum creatinine of 2.53 mg/dL 2 weeks after the procedure. Then his serum creatinine increased again to the level of 5.52 mg/dL two months after the 1st procedure. PTRA was done again with renal artery stent placement. Finally, his kidney function recovered with serum creatinine of 1.72 mg/dL six month s after the 2nd procedure. Figure 2. To the best of my knowledge, this is the 1st reported case of PTRAS in KT recipient who received transplanted kidney from donor with Moyamoya disease. I believe that transplant physicians should continue using organs from donors with Moyamoya disease but must be aware of the possible extracranial complications like in my case.

Pretransplant assessment of cyclosporine level as a predictor of cyclosporine dose requirements after kidney transplantation

Introduction and aimsPretransplant administration of cyclosporine (CsA) may reduce post-transplant maintenance dose and consequently CsA inhibitor nephrotoxicity and helps in achieving the desired target C2 levels earlier. The optimum dose or timing of administration of CsA induction dose is still debatable.Patients and methodsWe compared three different protocols for pretransplant administration of CsA aiming to reach a target C2 therapeutic level of greater than 800 ng/ml on the third day post-transplant. Sixty kidney transplant recipients from Cairo University hospitals were divided into: group 1 (n=20) who received a single CsA induction dose of 2 mg/kg 12 h pretransplant; group 2 (n=20) who received four CsA consecutive doses of 4 mg/kg 48 h pre-transplant; and group 3 (n=20) who received four CsA consecutive doses of 2 mg/kg 48 h pretransplant.ResultsThe desired therapeutic level in the earlier post-transplantation period was achieved in 65% in group 1, 100% in groups 2 and 3). In group 2 a lower dose was needed to maintain C2 within the therapeutic range during the first year post-transplantation (P<0.01). Furthermore, a lower number of cases were complicated by CsA nephrotoxicity in group 2 in comparison to groups 1 and 3 (25, 0, 5% in group 1, 2, 3, respectively, P<0.039). A higher longer dose of CsA pretransplant associated with early withdrawal of CsA had a better effect on graft function than lower or shorter induction doses with late withdrawal as evidenced by lower serum creatinine levels all through the follow-up period in group 2 compared with group 3.ConclusionForty-eight-hour pretransplant induction with CsA at a dose of 4 mg/kg with early dose reduction post-transplant was associated with lower CsA maintenance and a better 1-year graft function.

SUN-174 Severe Insulin Resistance and Diabetic Ketoacidosis after Brentuximab Vendotin and Cyclosporin Treatment

Introduction: Brentuximab Vendotin(BV) is antibody-drug conjugate that selectively delivers cytotoxic agent, monomethyl auristatin E, targeting cells expressing surface CD30, treatment approved for refractory Hodgkin’s lymphoma. Previous research suggested MDR1 inhibition (cyclosporine) can overcome BV resistance. Case: 23 year old male with relapsed and refractory classical Hodgkin lymphoma underwent clinical trial with BV and Cyclosporin( CyA). He was given one dose of BV( 1.8mg/kg) and CyA ( 725mg 2 times a day for 5 days). A week after BV and 3 days after the last dose of CyA, patient had acute onset of hyperglycemia and ketoacidosis; glucose 435 mg/dL, bicarbonate 14 mmol/L, anion gap 14( 8-14), beta hydroxybutyrate 40.3 mg/dL (0.0-3.0 mg/dL), urine ketone +3, C-peptide 9.0 ng/ml (0.8-3.5 ng/ml). Serum cyclosporine level was high as 453 ng/ml (150-300ng/ml) at the time of presentation, which was reduced to 116 ng/ml within a week. He had no previous diabetes history. His severe hyperglycemia and metabolic acidosis persisted after aggressive hydration and multiple daily insulin injections. He was started on modified intravenous insulin infusion protocol. Within 24 hours, his glycemic control was improved at goal requiring average 34 units/h of regular insulin with NPO status. This was transitioned to U500 regular insulin divided dose injection every 8 hours with holding criteria. 10 days after initial clinical presentation, patient's insulin requirement was abruptly reduced and eventually discontinued. Patient was discharged and glucose level remained within reference range (80-128 mg/dl) without additional medical management from follow-up. Patient had completed given clinical trial with reduced dose of BV and CyA, and there was no further similar episode. During the hospital course, underlying endocrine disease related to insulin resistance was ruled out including thyroid, glucagon, cortisol, catecholamine, or growth hormone excess. Autoimmune workup was negative except elevated ESR. Insulin autoantibody panels were negative. Pancreatitis and infections were also ruled out. Lymphocytes were reduced and monocytes were increased in CBC during the episode. Peripheral blood mononuclear cell (PBMC) analysis by flow cytometry showed that absolute B and T cell counts were low but in the residual CD4+ and CD8+ T cells, expression of CD25 and PD-1 was increased. Major portion of the PBMC did not stain with our standard immune phenotype panel, which may include plasma cells, NKT, or dendritic cells. Discussion: Adverse events ≥ Grade 3 hyperglycemia (12%) has been reported with BV treatment. On the other hand, CyA is known to be related to insulin resistance as well. This is the first case report of a patient who developed rare condition of severe insulin resistance and diabetic ketoacidosis in the context of hyperinsulinemia likely due to impaired insulin signaling induced by BV and CyA.

Therapeutic drug monitoring of cyclosporine and tacrolimus in Myanmar kidney transplant patients

IntroductionRenal transplantation is one of the best options for patients suffering from end stage renal disease (ESRD). Cyclosporine and Tacrolimus are mainly applied in immunosuppressive therapy after transplantation of liver, kidney, heart, and other organs. The used of immunosuppressant drugs improve the survival of transplanted organs and reduce organ rejection. Because of their narrow therapeutic index and significant inter-individual variability in blood concentrations, they need to monitor carefully. Therapeutic drug monitoring of tacrolimus and cyclosporine were needed to optimize the outcome in patients after renal transplantations. Maintaining the drugs levels reduce the risks of toxicity or rejection, respectively. ObjectiveThe aim of this study is to identify the optimum blood trough level for cyclosporine and tacrolimus in Myanmar kidney transplant recipients. Materials and methodA retrospective cross sectional design was used and data collected from 50 patients who underwent kidney transplantation and receiving either cyclosporine or tacrolimus within six months after kidney transplantation. Among them 15 and 35 patients are taking cyclosporine and tacrolimus, respectively. For cyclosporine or tacrolimus trough-level monitoring, whole blood sample was drawn 15 min before the next dose and measured by immunoassay method. ResultsThe results showed that majority of cyclosporine and tacrolimus whole blood levels based on C0 (before the dose) concentration were achieved the therapeutic range. ConclusionTherefore, drugs concentration and the recommended clinical conditions should be routinely monitored to adjust the treatment and reduce adverse reactions. Therapeutic drug monitoring of cyclosporine and Tacrolimus are important for the benefits of renal transplant patients in Myanmar.