Cyclosporine Levels Research Articles

The pharmacogenetics of mycophenolate mofetil in Tunisian renal transplant patients.

Aim: The effects of variants in IMPDH, UGT1A9, UGT1A8, UGT2B7 and SLCO1B1 genes on the efficacy and safety of mycophenolate mofetil (MMF) in the Tunisian population were investigated. Materials & methods: A total of245 kidney transplant patients being treated with MMF wererecruited and cotreated with cyclosporine or tacrolimus. Genotyping was performed using thepolymerase chain reaction-restriction fragment length polymorphismmethod. MMF, cyclosporine and tacrolimus trough levels were measured by immunoassay. The AUC (AUC0-12hMPA) was estimated by a Bayesian method. Results: In the tacrolimus-treated group, anemia and diarrhea were associated with the UGT1A9-98C and UGT1A9-275T alleles, respectively (p<0.05). In the cyclosporine-treated group, leukopenia was associated with theSLCO1B1-521T allele (p<0.05). Both groups had an increased risk of rejection (p<0.05) associated with the variant alleles of IMPDH2-3757T>C, UGT1A9-2152C>T and UGT1A9-275C>A and the common allele of SLCO1B1-388A>G. However, no significant association was foundbetween the studied genotypes and AUC0-12hMPA or cotreatment levels. Conclusion: The results constitute preliminary evidence for the inclusion of the pharmacogenetics of MMF in kidney pretransplantation evaluations.

Advanced oxidation protein products upregulate ABCB1 expression and activity via HDAC2-Foxo3α-mediated signaling in vitro and in vivo

The unpredictable pharmacokinetics of non-renal cleared drugs in chronic kidney disease (CKD) patients is associated with the activity of drug transporters. However, the mechanisms underlying regulation of drug transporters are yet to be established. In this study, we demonstrated the involvement of a HDAC2-Foxo3α pathway in advanced oxidation protein products (AOPPs)-induced ATP-binding cassette subfamily B member 1 (ABCB1) expression and activity. The correlation of AOPPs accumulation with concentration of cyclosporine in plasma was evaluated in 194 patients with transplantation. Molecular changes in acetylation of various histones and related regulatory molecules were examined in HepG2 cell cultures treated with AOPPs. Accumulation of AOPPs in serum in relation to molecular changes in HDAC2-Foxo3α in vivo were evaluated in 5/6 nephrectomy (5/6 nx) and oral adenine (Adenine) CKD rat models. Interestingly, the cyclosporine level was negatively correlated with AOPPs in plasma. In addition, AOPPs markedly suppressed the expression of histone deacetylase 2 (HDAC2), inducing ABCB1 expression and activity in vitro and in vivo. Importantly, AOPPs modulated phosphorylation of Foxo3α and the upstream Akt protein. Our findings indicate that AOPPs regulate the expression and activity of ABCB1 via reducing HDAC2 expression and activating Foxo3α-dependent signaling. The collective results support the utility of AOPPs as a potential target for drug and/or dosage adjustment in CKD patients. Targeting of AOPPs presents a novel approach to regulate non-renal clearance.

Lower levels of cyclosporine between days 0 and +21 may reduce later relapses without increasing graft-versus-host disease in children and adolescents with acute lymphoblastic leukemia who undergo myeloablative TBI-based allogeneic hematopoietic cell transplantation.

The degree of immunosuppression required for adequate graft-versus-host disease (GVHD) prevention, while keeping an adequate graft-versus-leukemia effect, in children with acute leukemia has not been established. We report the results of a retrospective comparison of cyclosporine levels and relapse rate in children and adolescents with acute lymphoblastic leukemia (ALL). Patients <21 y/o with ALL in remission who underwent TBI-based hematopoietic cell transplantation from related or unrelated donors between 2008 and 2021 were included. Cyclosporine levels were measured twice a week and we calculated the area under the curve (AUC) from D0 to D + 7, D + 14, and D + 21. We included 76 patients. There was a trend towards a lower incidence of relapse in patients with a mean AUC < 200 ng/ml at D + 21 (HR=0.41; p=.08). The 5-year relapse rate was 26.9% for patients with a mean AUC < 200 ng/ml at D + 21 and 43.9% for patients with a mean AUC≥200 ng/ml at D + 21. Relapse protection was restricted to relapses happening after D + 120 (HR=0.21; p=.04). Our results show evidence that pediatric patients with ALL might benefit from lower cyclosporine levels between D0 and D + 21 without a detectable increase in GVHD. Large prospective studies comparing different cyclosporine levels are awaited.

Different Clinicoradiological Characteristics of Posterior Reversible Encephalopathy Syndrome in Pediatric Oncology and Post-Bone Marrow Transplantation Cases: A Retrospective Study.

Posterior reversible encephalopathy syndrome (PRES) is receiving increasing recognition in pediatrics. However, comparisons between PRES in pediatric oncology and post-bone marrow transplantation (BMT) are lacking. Therefore, we aimed to describe the risk factors and clinical and radiological features of PRES and investigate the differences between PRES in pediatric oncology and post-BMT. The PRES data of 13 patients from our center were combined with those of 217 cases from the PubMed, Scopus, and Web of Science databases. The patients were divided into either an oncology or a post-BMT group. We included 230 patients in the analysis, 26.1% of whom belonged to the post-BMT group. Oncology patients developed PRES at a younger age (p = 0.010) and were more likely to develop encephalopathy (p = 0.004). Systemic hypertension (S-HTN) preceding PRES occurred in 43.5% (66/154) of patients. Post-BMT patients were more likely to have S-HTN (p = 0.003). Cyclosporine levels were detected in 37 patients; 40.5% had supra-therapeutic levels. The radiological findings were atypical in 74.3% of patients, and delayed repeated imaging increased the occurrence of resolution (p = 0.004). Sixteen (7%) patients developed PRES recurrence after a median of 8 weeks, with the between-group difference being non-significant. Oncology patients were more likely to develop chronic epilepsy, while BMT patients were more likely to develop rare neurologic abnormalities (p < 0.001). In conclusion, atypical clinical presentation and imaging findings should not hinder the diagnosis of PRES. S-HTN is a risk factor, particularly in post-BMT patients. Supra-therapeutic levels of cyclosporine and previous exposure to immunosuppression did not increase the risk of recurrence.

Rare Immune Dysregulatory Disorder Leading to Lung Transplantation

<h3>Introduction</h3> Interleukin-12 receptor β1 is a common receptor chain of the pro-inflammatory cytokines IL-12 and -23. IL-12/IL-23Rβ1 deficiency is a rare autosomal recessive disorder characterized by predisposition to mycobacteria infections, whereas IL-12/IL-23Rβ1 gain-of-function mutation may cause a systemic disease that manifests as a chronic inflammatory condition and organ fibrosis. We describe the first case of lung transplantation (LTx) in lung-fibrosis due to this immune dysregulatory disorder. <h3>Case Report</h3> We present a 27-year-old patient diagnosed with gain-of-function mutation in IL-12/IL-23Rβ1. The disorder led to multi-organ involvement consisting of interstitial lung disease with secondary pulmonary hypertension, hepatitis, dermatosis and hepatosplenomegaly. Multiple immunosuppressive and modulating agents were tried without improving lung function. The patient showed no susceptibility to infections. With increasing pulmonary hypertension and progressive respiratory failure, he reached indication for LTx. Prior to listing, concerns were raised due to his exceptional pro-inflammatory immunodeficiency and potentially increased risk of rejection. After extended research and with few other treatment options left, LTx was performed in 2017 (ABO-compatible and negative crossmatch) with an uncomplicated perioperative course. He received standard immunosuppression with the goal of high cyclosporine level within standard target range. In his first year post-transplant he was treated 3 times successfully for minimal acute rejection and has since then had no further rejections. In 2018 he developed Candida dubliensis sepsis and osteomyelitis and was treated for 16 months. A pan-JAK-inhibitor was initiated, while mycophenolate was reduced and stopped, to try to inhibit a progressive sterile liver and bone inflammation. The regimen had remarkable effect on the patient`s general condition. Recurring CMV reactivation ensued and in 2020 also systemic Mycobacterium avium intracellulare infection, still requiring treatment. Pulmonary function is stable. <h3>Summary</h3> Our experience suggests that LTx is a valid option for this indication resulting in much improved quality of life. It remains challenging to find the right balance between treating the underlying disease while providing adequate immunosuppression to prevent rejection and avoiding infections.

Improving Safety and Outcomes After Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience

The implementation of dual T-cell depletion comprising 4.5 mg/kg of antithymocyte globulin (ATG), post-transplantation cyclophosphamide, and cyclosporine A for reduced-intensity allogeneic hematopoietic cell transplantation (HCT) independent of donor source in 2015 significantly improved graft-versus-host disease (GVHD) control at our Institution. Further advances were made between 2017 to 2020 in supportive care of allogeneic HCT recipients and were the subject of this study, with 651 adults included. Transplant outcomes were compared between patients who underwent transplantation during Period 1 (2017–2018) and Period 2 (2019–2020). Main changes implemented during the study period were reduction of ATG dose from 4.5 to 2 mg/kg in matched unrelated donor transplants, abandoning of dual T-cell depletion in matched related donor transplants, combining dual T-cell depletion with myeloablative conditioning for selected patients, and reduction of the target therapeutic cyclosporine level from 200 to 400 ng/L to 150 to 250 ng/L. Other improvements included addition of ursodiol until day 100, implementation of a double responsible physician model, and personalized patient supportive care plan focused on activity and calorie intake. The reduction in intensity of GVHD prophylaxis provided comparable acute GVHD and moderate-severe chronic GVHD between both time periods. Altogether the described improvements in transplant methodology and supportive care showed that compared to Period 1, patients transplanted in Period 2 had superior 1-year overall survival, relapse-free survival, and non-relapse mortality and showed a trend toward better GVHD- and relapse-free survival, without an increase in relapse risk. This study reports the results of outcomes-directed improvements in transplantation design, GVHD prophylaxis, and supportive care, highlighting how transplantation outcomes can be improved through careful modifications in response to meticulously monitored outcomes.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Management of Psychiatric Disorders in Patients with Hepatic and Gastrointestinal Diseases.

Association Between Blood and Lymphocyte Levels of Cyclosporin A and Infectious Complications in Renal Transplant Patients.

ObjectivesThis study aims to investigate a potential association between whole blood and lymphocyte Cyclosporin A (CyA) levels and the occurrence and frequency of infectious complications in kidney transplant patients.MethodsThe study involves 130 kidney transplant recipients who received CyA in addition to Mycophenolate Mofetil and steroids. CyA whole blood trough and maximum level (CyA BL0 and CyA BLm) as well as the corresponding levels in the lymphocytes (CyA L0 and CyA Lm) were measured for 6 months post-transplantation.ResultsCytomegalovirus (CMV) as well as urinary tract infections (UTIs) were the most commonly diagnosed with an incidence of 24.6% and 26.2%, respectively. Only CyA L0 showed a significant association with CMV infection occurrence (adjusted OR = 1.051, 95% CI .997–1.025, P-value 0.046). A positive linear correlation was found between CyA BL0, CyA BLm and CyA Lm and the number of CMV episodes per patient.ConclusionWe showed an association between the CMV infections occurrence and the trough lymphocyte level of CyA (CyA L0). Both lymphocyte CyA levels also correlated with the frequency of CMV infections. Further studies are needed to establish the optimal range of both CyA blood and lymphocyte levels and decrease the risk of opportunistic infections in high risk patients.

Dual-lumen power injectable peripherally inserted central catheters in allogeneic hematopoietic stem cell transplantation: A prospective observational study.

To explore whether dual-lumen power injectable peripherally inserted central catheters (PICCs) could be effectively and safely applied in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and for serum cyclosporine level monitoring. Compared to conventional central venous access devices, PICC provides a feasible route not only for fluid infusion, but also for blood sample collection in patients undergoing oncological treatments. A prospective observational study was conducted according to the STROBE guidelines. We prospectively evaluated the applications and complications of power injectable PICCs in 52 consecutive allo-HSCT recipients. We also compared the cyclosporine levels in 188 paired blood samples, simultaneously obtained via power injectable PICCs and percutaneous venous puncture, to investigate whether power injectable PICC is a feasible route for cyclosporine concentration monitoring in allo-HSCT. The median PICC placement duration was 29days. The insertion-site blood oozing and central line-associated bloodstream infection rates were 36.5% (19/52) and 26.9% (14/52), respectively, indicating the feasibility of these PICCs for various applications in allo-HSCT. No power injectable PICC-related thrombotic adverse events were identified; 90.4% (47/52) of cases with power injectable PICC removal occurred because of lack of medical utility, suggesting that power injectable PICC-related complications were manageable. However, cyclosporine levels in samples obtained via these PICCs were significantly higher than those in samples obtained via percutaneous venous puncture (261.5±139.2 vs. 232.4±253.6ng/ml; p=0.019 [set 1]; 254.8±89.3 vs. 225.1±233.3ng/ml; p<0.001 [set 2]; 283.6±103.9 vs. 238.0±254.7ng/ml; p=0.006 [set 3]; 291.0±94.9 vs. 266.0±274.7ng/ml; p=0.016 [set 4]). The power injectable PICC is a feasible venous access device for allo-HSCT. The dual-lumen power injectable PICCs provided a reliable access for blood sample collection, decreasing the number of blind percutaneous venous punctures in allo-HSCT. However, its application in cyclosporine level monitoring needs further investigation.

Association of IL-15 and IP-10 Serum Levels with Cytomegalovirus Infection, CMV Viral Load and Cyclosporine Level after Kidney Transplantation.

Cytomegalovirus (CMV) infection is the most common complications following kidney transplantation. Natural killer (NK) cells demonstrated critical anti-viral role in controlling and elimination of CMV after transplantation. Interleukin-15 (IL-15) is a pleiotropic cytokine that promotes the activity of NK cells and strengthens the acquired immune system. Also, IP10 (CXCL10) is a chemotactic factor which regulates NK cell recruitment and antiviral immune response. We aimed to determine the correlation between the serum levels of IL-15 and IP-10 cytokines with CMV infection, CMV viral load, and cyclosporine as a major immunosuppressive treatment after transplantation. Fifty-eight kidney transplant recipient patients without evidence of CMV virus disease before transplantation surgery were included in the study. From the day of transplant surgery, the patients were evaluated based on the presence of CMV Ag pp65, CMV viral load, serum levels of IL-15 & IP-10, Cyclosporine levels (C0 & C2), Glomerular Filtration Rate (GFR), and hematological & biochemical Index, up to 75 days. Comparison analysis of serum levels of IL-15 and IP-10 showed no significant association with CMV infection in kidney transplant recipients. In addition, CMV viral load and cyclosporine levels at C0 and C2 did not affect patients' IL-15 and IP-10 levels. The levels of IP-10 and IL-15 cytokines are not affected with CMV infection, even if a viral infection occurs in the early days after transplantation or long afterwards. In addition, taking the different levels of cyclosporine did not affect the cytokines levels. Other mechanisms may play a role in maintaining the levels of these cytokines.

Difference in the Cytomegalovirus-related Clinical Laboratory Findings Between Patients With Bone Marrow and Kidney Transplantations

Background: Despite close monitoring of transplant patients, Cytomegalovirus (CMV) infection has remained one of the most critical problems in transplantation. This study investigates the relationship between CMV viral load and clinical laboratory findings in transplant recipients. Materials And Methods: A total of 34 transplant recipients comprising 15 Kidney Transplant (KT) recipients and 19 Bone Marrow Transplant (BMT) recipients admitted to the Imam Reza Hospital in Kermanshah Province, Iran, were enrolled in this study. The CMV viral load was quantified by the real-time PCR technique. Results: The CMV viral load in KT recipients was significantly higher than in BMT recipients (P=0.03), and there was a positive association between the level of virus and the level of cyclosporine in the blood of patients (r=0.51, P=0.02). Besides, CMV viral load was positively correlated with WBC (r=0.32, P=0.04), urea (r=0.47, P=0.002), creatinine (r=0.39, P=0.01), aspartate aminotransferase (r=0.33, P=0.04), and lactate dehydrogenase (r=0.4, P=0.01). Also, it was negatively associated with albumin (r=-0.61, P&lt;0.001), sodium (r=-0.4, P=0.01), and calcium levels (r=-0.46, P=0.003). There were also significant differences between KT and BMT recipients regarding the CMV-related clinical laboratory findings of urea (P=0.02), creatinine (P=0.001), uric acid (P=0.005), direct bilirubin (P=0.04), albumin (P=0.04), platelet (P&lt;0.001), and sodium (P=0.04) levels. Conclusion: Based on present data, we conclude that despite careful monitoring of patients, infection with CMV is still one of the most important problems associated with organ transplantation, which is directly related to many laboratory findings.

Effects of Immunosuppressive Therapy on Cell Mediated Immunity in Idiopathic Acquired Aplastic Anaemia

Aplastic Anaemia is a clonal haematological disorder characterised by bone marrow hypoplasia and pancytopenia, in the absence of any abnormal cells or increased reticulin. Idiopathic acquired aplastic anaemia accounts for more than 50% cases where immune mediated pathophysiology had been proposed. Altered counts and ratio of CD4+ and CD8+ T cells result in increased apoptosis of haematopoietic stem cells, resulting in bone marrow hypoplasia. Aplastic anaemia is a clonal disorder with clonal evolution to other haematological disorders i.e. hypoplastic myelodysplastic syndrome, Paroxysmal nocturnal haemoglobinuria (PNH) and acute leukemia. Previous studies had reported that >50% cases of aplastic anaemia are transformed into PNH during the course of disease.Haemopoietic stem cells transplant is the treatment of choice however, this option is either unavailable or un-affordable for majority of people in developing countries including Pakistan. Standard immunosuppressive therapy (IST) includes anti-Thymocyte Globulin (ATG), is also an expensive option and needs extensive monitoring therefore, not a very favourable option for most of the patients. Other immunosuppressive drugs particularly calcineurin inhibitors like Cyclosporine and Tacrolimus, had shown promising results. These drugs act by decreasing the raised counts of CD4+ and CD8+ T cells. Almost all the patients diagnosed with idiopathic acquired aplastic anaemia in Pakistan are treated on these drugs either alone or in combination with other drugs. No study has been conducted so far to evaluate the effects of different immunosuppressive drugs on T cells at different stages and length of treatment. This study was planned to evaluate the effectiveness of these drugs in restoring the immunological imbalance in idiopathic aplastic anaemia.The counts and ratios of CD4+ and CD8+ T cells were performed on blood samples of 60 patients, using FACSCount system (BD Biosciences). Our study population included patients of Pakistani and Afghan nationalities, both genders and of paediatric and adults age. PNH screening was done by Hams test however, none of the patient was positive. Patients on active treatment were categorized into different groups on the basis of drugs they were receiving i.e. Cyclosporine only, Cyclosporine with Oxymetholone and Tacrolimus groups. Patients who were newly diagnosed and treatment naive at the time of inclusion, were also included along with a group of patients who had completed their treatment and were in remission (either complete or partial).Findings of our study showed that the disease was more prevalent in males of paediatric and young adult age. CD4+ T cell counts and CD4/CD8 ratios were prominently decreased in paediatric group receiving IST however, no significant difference was noted in counts or ratios in adult patients. CD8+ T cell counts did not show any remarkable reduction with treatment in adult patients but slightly decreased counts were noted in paediatric group. All the patients in different treatment groups showed an overall reduction of CD4+, CD8+ T cell counts and ratios as compared to treatment naive cases. This difference was more pronounced in patients receiving Cyclosporine with Oxymetholone and Tacrolimus. Cyclosporine levels were done and found to be consistent with the dose and treatment status but the therapeutic levels of Tacrolimus were never achieved however, significant improvement was observed even in sub-therapeutic levels. Off-treatment cases had their CD4+, CD8+ T cell counts and ratios within the lower normal range of CD4+, CD8+ T cell counts and CD4/CD8 ratio, suggestive of an alteration in T cell biology with IST, maintaining these counts within normal range for an indefinite period.Length of treatment has a great impact on the outcome of disease as well as relapse prevention however not studied in detail in aplastic patients treated on immunosuppressive drugs. Results of our study suggests that treatment for more than 6 months followed by slow tapering is more effective in normalizing the counts and ratios of CD4+ and CD8+ T cells. Our study was the first of its kind to evaluate the effects of different immunosuppressive drugs on CD4+ and CD8+ T cell counts and CD4/CD8 ratio, in our population. Further studies are needed to understand the underlying mechanisms responsible for this immunological imbalance as well as response to different treatment options available. DisclosuresNo relevant conflicts of interest to declare.

Comparing Predictions of a PBPK Model for Cyclosporine With Drug Levels From Therapeutic Drug Monitoring.

This study compared simulations of a physiologically based pharmacokinetic (PBPK) model implemented for cyclosporine with drug levels from therapeutic drug monitoring to evaluate the predictive performance of a PBPK model in a clinical population. Based on a literature search model parameters were determined. After calibrating the model using the pharmacokinetic profiles of healthy volunteers, 356 cyclosporine trough levels of 32 renal transplant outpatients were predicted based on their biometric parameters. Model performance was assessed by calculating absolute and relative deviations of predicted and observed trough levels. The median absolute deviation was 6 ng/ml (interquartile range: 30 to 31 ng/ml, minimum = −379 ng/ml, maximum = 139 ng/ml). 86% of predicted cyclosporine trough levels deviated less than twofold from observed values. The high intra-individual variability of observed cyclosporine levels was not fully covered by the PBPK model. Perspectively, consideration of clinical and additional patient-related factors may improve the model’s performance. In summary, the current study has shown that PBPK modeling may offer valuable contributions for pharmacokinetic research in clinical drug therapy.

Drug-drug Interactions in Kidney Transplant Patients with Coronavirus Disease 2019: A Report of Two Cases and Literature Review

On February 19, 2020, the first confirmed case of Coronavirus disease 2019, known as COVID-19, was identified in Iran. Afterward, the disease spread rapidly throughout the country. Some of the cases were asymptomatic, some had mild to severe symptoms, and some of them died. Transplant patients are highly at risk due to long-term immunosuppressive therapy, and precise treatment approaches are needed to not only cure the disease but also protect graft function. This study reports two kidney transplant patients with COVID-19 pneumonia, both of whom showed respiratory and gastrointestinal symptoms. High cyclosporine and tacrolimus trough levels were observed despite initial dose reduction. After a treatment program containing reduced immunosuppressant dose and the addition of pulsatile hydrocortisone, these patients recovered effectively. We also discuss the importance of drug-drug interactions related to COVID-19 treatment protocol medications, especially with immunosuppressants, in these patients. In conclusion, frequent monitoring of the trough levels of calcineurin and mammalian target of rapamycin inhibitors during hospitalization is recommended since it helps to determine the ideal treatment and prevent serious clinical toxicity.

Echocardiography Surveillance of Rejection after Heart Transplant without Endomyocardial Biopsy

Purpose Surveillance for acute rejection (AR) and cardiac allograft vasculopathy ( CAV) is essential for graft and patient survival. CAV can arise and progress without symptoms and subclinical AR can facilitate CAV .Standard surveillance of AR and CAV is based on routine endomyocardial biopsies (EMBs) and coronary angiographies (CA) at predefined intervals , 9 to 13 times during first post transplant year , there after 3-4 biopsy annually . These invasive screening tests are distressing ,costly and not without complications , yet they cannot identify all sub-clinical ARs . We adopted Biospy free Echocardiography surveillance for detection and treatment of Rejection . Methods From June 2016 till August 2020 , 12 heart transplant recipients,7 male and 5 female , were followed by Echocardiography with Doppler Tissue / strain imaging every 3 months or earlier if indicated. Routine Complete Blood Count , Renal &Liver Function test, Cyclosporine or Tacrolimus level also done .Eleven recipients are free of any rejection.Total Echo-surveillance follow up in study is > 510 months. Results Doppler tissue-imaging (DTI) and strain-imaging for myocardial wall motion and deformation analysis, allowed quantification of minor myocardial dysfunction for early detection of subclinical AR and CAV. Two patients had mild rejection Grade IIB were treated by increasing dose of steroid and raising level of Calcineurine inhibitor. One recipient found to have acute rejection on Echocardiography ,EMB, proved grade III rejection ,treated with Methyl prednisolone, Anti-thymic antibody Conclusion DTI and strain-imaging is an important tool enabling more efficient AR monitoring with fewer EMBs instead of routine EMB-screenings. Myocardial velocity and deformation imaging is also allows early detection of myocardial dysfunction induced by CAV, prognostic evaluation of CAV and timing of CAs aimed to reduce the number of routine CA-screenings. Donor specific antibody with protocol Echocardiography or same in symptomatic patients can yield good surveillance without endomyocardial biopsy.

Evaluation of Cyclosporine and Tacrolimus Dose Changes During Post-transplantation Period and Their Association with Endomyocardial Biopsy Grading

Background: Changes in the dosage of immunosuppressive drugs following organ transplantation, especially the heart, can be a potential predictor of long-term post-transplant outcomes. It may also be related to the degree of histopathological involvement of endomyocardium. Objectives: We aimed to evaluate cyclosporine and tacrolimus dose changes during post-transplantation biopsies and their association with endomyocardial biopsy grades. Methods: This retrospective study was performed on 100 cardiac transplant patients who underwent endomyocardial biopsies to assess graft stability. In the present study, the patients were divided into two groups receiving cyclosporine (13 cases) and tacrolimus (87 cases). The data was collected by reviewing the recorded files. Results: Regarding the administration of cyclosporine, at different times after biopsy, there was no significant relationship between the plasma level of the drug and the grade of biopsy. Concerning tacrolimus, there was a significant reverse association between serum concentration and biopsy grade at the first biopsy after transplantation (about one month after transplantation), although this relationship was not observed in the subsequent steps of biopsy. Also, the Quilty effect frequency was not significantly associated with biopsy grade in different biopsies for both drugs. Conclusions: There is a lack of association between endocardial biopsy grade in the heart and the serum level of cyclosporine after transplantation. However there is a significant reverse relationship between endomyocardial biopsy grade and serum Tacrolimus concentration in the first weeks after transplantation and thus monitoring serum Tacrolimus after transplantation may play an important role in predicting acute rejection.

Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial.

Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912.

Incidence, Outcomes and Predictors of Acute Kidney Injury Post Allogeneic Stem Cell Transplant

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers cure for some patients with hematological diseases but is associated with significant risk of morbidity and mortality. Acute kidney injury (AKI) represents an important cause of post-transplant complications, often multifactorial in the unique setting of allo-HSCT. However, to date, there is limited information on the overall impact of AKI in this patient population. To address this, we retrospectively reviewed the effect of AKI on transplant outcomes at Princess Margaret Cancer Centre (PMCC). METHODS: The study included 408 patients transplanted at PMCC between January 2015-January 2018 for any indication, using either reduced intensity (RIC) or myeloablative conditioning (MAC). Median follow-up time was 23 months. AKI was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Demographics, clinical characteristics and transplant related variables were extracted from patient records and the institutional allo-HSCT database. Univariate and multivariate Cox proportional hazard models were used to examine associations between AKI and outcomes including overall survival (OS), relapse free survival (RFS), graft versus host disease (GVHD) and relapse-free survival (GRFS). Univariate and multivariate Fine and Gray competing risk models were used to examine the association between AKI and incidence of relapse, treatment related mortality (TRM), grade 2-4 acute GVHD (aGVHD), grade 3-4 aGVHD and moderate-severe chronic GVHD (cGVHD). Multivariate models were used to examine the association of AKI and outcomes of interest, while adjusting for potential risk factors. RESULTS: The overall incidence of AKI at 100 days was 64% (stage 1: 62.6%, stage 2: 22.5% and stage 3: 14.8%). Dialysis was required in 2% of these patients. Mean baseline eGFR in the AKI group was 94.4 mL/min/1.73m2 (IQR 42, 141) vs 96.9 mL/min/1.73m2 (IQR 45.7, 142.9) in the non-AKI group. Patient-related risk factors for development of AKI were age over 60 (p=0.001), male gender (p=0.05), diabetes (p=0.004) and hypertension (p=0.003). Transplant related characteristics associated with AKI were MAC conditioning (p=0.02), veno-occlusive disease (p&amp;lt;0.0001), BK viremia (p=0.01), thrombotic microangiopathy (p=0.009), bacterial infections (p=0.001) and more than two cytomegalovirus (CMV) reactivations (p=0.02). There was no difference in mean cyclosporine levels in the first 100 days between patients who developed AKI and those who did not (p=0.80). AKI was less common in patients who received GVHD prophylaxis with dual T-cell depletion (TCD) with anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) (p&amp;lt;0.001) than those who received alternative GVHD prophylaxis. In the univariate analyses, compared with patients who did not have AKI, those with AKI had inferior 2-y OS: 46% versus 63% (p=0.0004). AKI patients had lower 2-y GRFS (29% vs 45%, p=0.0002), higher 2-y TRM (31% versus 17%, p=0.0003), and higher incidence of day 100 grade 3-4 aGVHD (13% vs 6%, HR 2.18, 95% CI=1.18-4.01, p=0.01). In multivariate analysis, AKI was associated with decreased 2-y OS (HR= 1.36, 95% CI 1.00-1.65, p=0.048), 2-y GRFS (HR= 1.42, 95% CI 1.10-1.82, p=0.006), and increased risk of day 100 grade 3-4 aGVHD (HR= 1.93, 95% CI 1.04-3.58, p=0.03). There was an association between AKI and TRM, specifically in those patients with stage 2 (HR= 1.76, 95% CI 1.06-3.30, p=0.03) and stage 3 AKI (HR= 2.64, 95% CI 1.44-4.83, p=0.002) compared to no AKI. In multivariate models, there was no association between AKI and relapse (p=0.65), grade 2-4 aGVHD (p=0.7) or moderate-severe cGVHD (p=0.81). CONCLUSION: Patients who develop AKI within 100 days of transplant have lower OS, GRFS, and higher grade 3-4 aGVHD and TRM. The use of dual TCD for GVHD prophylaxis is associated with lower risk of AKI, suggesting this may be a favorable regimen for those at increased risk for AKI. Contrary to previously published literature, there was no difference in cyclosporine levels between the non-AKI and AKI groups, suggesting that it may not be a significant cause of AKI post-transplant. AKI was more common in patients who had multiple episodes of CMV reactivation, highlighting the importance of CMV prophylaxis. AKI patients require close follow up, preventative strategies and monitoring for new or progression of chronic kidney disease post transplant. Disclosures Madsen: Jazz Pharmaceuticals: Honoraria. Pelletier:Celgene: Honoraria; International Kidney and Monoclonal Gammopathy: Membership on an entity's Board of Directors or advisory committees. Mattsson:Jazz Pharmaceuticals: Honoraria; ITB: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Mallinkrodt: Honoraria; Gilead: Honoraria.

Arabic Gum Role In Ameliorating Cyclosporine- A Initiated Nephrotoxicity In Albino Rats

Recently many researchers reported that treatment using cyclosporine A in extended period in order to avoide the rejection of allograft is connected with renal impairment progress. Arabic gum is a valuable antioxidants and anti-carcinogenic factor with a protective effect against renal intoxications. This research aims at assessing the improving function of Arabic gum in ameliorating nephrotoxicity of cyclosporine A in adult rats by measuring urea and creatinine as renal function tests and histopathological changes plus redox status parameters. 80 mature rats males and females were classified into four groups during the period of expirment (45 days) first one act as control given saline; the second one was given 7.5gm/kg/day of Arabic gum ,while third group was given cyclosporine A( 25 mg/kg /day ) finally the fourth one was given 7.5gm/kg/day of Arabic gum together with the 25 mg/kg /day of cyclosporine A. Cyclosporine A group three rats had renal impairment beside injury, when reported by elevated values of urea and creatinine and renal pathological changes, relative to the first group(control) with high level of cyclosporine A in blood and bad parameters of redox status. Receiving of (Arabic gum) accompanied with (cyclosporine A) ameliorating renal damage by decreasing the level of urea and creatinine in the blood, renal histo pathological amelioration, moreover the improved parametersof antioxidant. The levels of catalase, glutathione, peroxidase and superoxide dismutase were statistically reduced as regard group three G3 (cyclosporine) which was significant relative to the control & second groups G1,G2 although significantly elevated in the fourth group which given cyclosporine plus Arabic gum when compared with the third group (cyclosporine). Arabic gum has likely to behave like natural agent opposing cyclosporine A -provoked nephrotoxicity.

Safety and efficacy of Sofosbuvir and Velpatasvir in children with active hepatitis C virus infection undergoing haploidentical transplantation.

Direct Acting Antivirals (DAA) have changed the landscape of hepatitis C virus (HCV) infection with high cure rates across genotypes. However, the use of these agents in the setting of allogeneic hematopoietic cell transplantation (HCT) has been limited. In this context, we report the outcome of five children (5-12years) with relapsed and refractory leukemia and active HCV infection (genotype 1b), who underwent urgent haploidentical HCT and were treated with Sofosbuvir and Velpatasvir (Sof-Vel) from initiation of treatment to 24weeks post-HCT. All achieved complete virologic response (VR) at a median of 2weeks, with normalization of liver enzymes. There were no adverse events related to the use of Sof-Vel, with no major fluctuations in cyclosporine levels. Two of the patients developed chronic GVHD and one relapsed. Sof-Vel was continued in one of them along with sirolimus without affecting drug levels. With a median follow-up of 15months, four patients are disease free with sustained VR. Our study shows that combination of Sof-Vel might be effective in inducing rapid complete and sustained VR during HCT without any major untoward drug interaction.