Cyclosporine Levels Research Articles

Severity of Mucositis Determines Cyclosporine Levels after Allogeneic Transplantation

Introduction Intestinal mucosal injury is a common complication following allogeneic stem cell transplant (alloHSCT), especially with myeloablative and TBI-based (total body irradiation) conditioning regimens. Prospective evaluation studies have shown that intestinal malabsorption persists for several weeks following conditioning, beyond visible resolution of mucositis and bowel integrity. Serum cyclosporine levels in the early to intermediate post-transplant period (when patients are taking oral cyclosporine) may be affected by reduced gut absorption and could influence early transplant related outcomes. Objective To determine the relationship between mucositis severity, cyclosporine 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 cyclosporine 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. Percentage increase of mean creatinine above baseline was taken as an index of renal impairment. 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 recurrence of disease were compared with patients without recurrence ( 6 months). Results Linear regression analysis showed an inverse correlation between days requiring TPN with the post SCT 100-day median cyclosporine level (p Higher median cyclosporine 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 cyclosporine levels. CMV reactivation was associated with higher cyclosporine levels (p Conclusion Our data suggest that patients who have significant mucositis have lower serum cyclosporine levels with oral cyclosporine dosing, which in turn impact upon post-transplant outcomes, in particular renal impairment and CMV reactivation.

A Retrospective Analysis of the Effect of Isavuconazole on Immunosuppressant Serum Blood Levels and Intravenous to Oral Dose Adjustments

Introduction Triazole anti-fungal drugs have been important in preventing fungal infections in immunosuppressed pts who have received an allogeneic hematopoietic cell transplant (allo-HSCT). These agents inhibit fungal cytochrome P450 (CYP) enzymes, preventing ergosterol formation that is essential for fungal wall synthesis. However they also inhibit human CYP enzymes which are responsible for metabolism of certain drugs, notably immunosuppressants (IS) commonly used in allo-HSCT. This study is a retrospective analysis of the effect of the new triazole anti-fungal, isavuconazonium sulfate (ISV), on the serum blood levels of tacrolimus (Tac), cyclosporine (CsA), and Sirolimus (Siro) in pts who have received allo-HSCT. Patients and Methods This retrospective analysis included 78 pts who received a conventional, double-umbilical cord, or haplo-identical allogeneic stem cell transplant who received Tac, CsA, or Siro and were initiated on ISV for fungal prophylaxis. The pre-ISV serum blood level of IS was compared to the serum level 48 hrs after the start of the ISV loading dose. We also examined how IS were converted from IV to oral by comparing the IS level on the day of IV to PO conversion to the IS level 48 hrs after PO was initiated while pts received ISV. Results There were 85 instances of ISV initiation in 78 pts on IS. Of the 85 instances of ISV initiation 23 (27%) received CsA, 55 (65%) received Tac, and 7 (8%) received Siro. The median age was 56 (range 21-75) and 25 (32%) of the pts were female. Pts receiving IV CsA (n = 23) had a median percent dose change (%DC) of -10% on initiation of ISV and the median 48hr percent level change (%LC) was -5.7%, with a median net difference (%ND) of +6%. For the pts who were converted from IV CsA to PO CsA (n = 20) the empiric %DC from IV to PO was +25% with a %LC of +1.71% with a %ND of -18.51%. This corresponds to an IV:PO of 1:1.2. For pts receiving IV Tac (n = 55) the median %DC was -16.7% and the %LC was -3.4% with a %ND of +12.4 %. The pts who were converted from IV Tac to PO (n = 41) had a median empiric %DC of +200% with a corresponding %LC of -30.26, with a %ND of +228.49%. This corresponds to a IV:PO of 1:2.3. For the pts receiving Siro (n = 7) the median %DC was 0% and the median %LC of +17.8% with a %ND of +23.8%. Conclusion Initiation of ISV did result in serum level elevations in patients receiving CsA, Tac, and Siro. For CsA the increase in level was minimal, however for Tac and Siro the level increased 12.4% and 23.8% respectively which may be clinically important and dose reductions should be considered in select patients. This study also showed how ISV affects the IV to PO conversion of Tac and CsA with IV:PO ratios of 1:2.3 and 1:1.2 respectively. This demonstrates that ISV affects first-pass metabolism of Tac and CsA and this should be taken into consideration when making IV to PO conversions.

Dopamine‐Capped Silver Nanoparticles as a Colorimetric Probe for On‐Site Detection of Cyclosporine

AbstractCyclosporine is an immunosuppressant drug used in organ transplants or for the treatment of autoimmune diseases. It has a narrow therapeutic index indicating that there is not a large difference between the therapeutic and amounts associated with adverse effects; so, dosage individualization by measuring the cyclosporine is necessary for desirable clinical outcomes. We implemented and validated a simple, sensitive, and selective method using spectrophotometry to determine cyclosporine levels in human plasma as well as in drug formulation. Cyclosporine was determined with minimal pretreatment from biological complex samples. This method was validated in terms of linearity, selectivity, accuracy, precision, and recovery. The method is linear in the range of 0.17‐0.85 μM with correlation coefficient values of 0.99 for plasma samples. The precision and the accuracy values were lower than 15% according to Food and Drug Administration (FDA) guideline. This method was successfully applied to find out cyclosporine concentration in two patients following oral administration as well as in drug formulation for quality control aims.

Label-free optical detection of cyclosporine in biological fluids.

In this paper, a spectroscopic method for determination of cyclosporine concentrations in biological fluids is presented. Blood plasma and hemoglobin solutions are chosen for the experiment. For various cyclosporine concentrations in blood plasma and hemoglobin, absorbance measurements in spectra range from 600 to 1100 nm are performed. The measurement results are analyzed by the use of a dedicated algorithm. The obtained data are characterized by a high coefficient of correlation R2 , which is equal to 0.9461 and 0.9808 for blood plasma and hemoglobin, respectively. The proposed method enables the selective detection of cyclosporine level and could be applied in medicine and laboratory diagnostics. The obtained result can be the base to build the point-of-care CsA level detection optical sensor.

Cyclosporine levels > 195μg/L on day 10 post-transplant was associated with significantly reduced acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Prophylaxis with cyclosporine A (CsA) is the backbone of GvHD prevention. In a retrospective analysis of patients treated with allo-HSCT, we correlated CsA levels on the day of transplantation (day 0) and on day + 10 with the incidence of acute and chronic GvHD. We assessed 660 patients with either AML n = 248, lymphoma/myeloma n = 127, MDS/MPN n = 124, ALL n = 79, CLL n = 36, CML n = 23, or bone marrow failure n = 22. In patients with clinically relevant aGvHD grade ≥ 2, mean CsA levels was lower on day 0 and day + 10 (142 ± 88μg/L and 183 ± 64μg/L, respectively) compared to patients without aGvHD (156 ± 81μg/L and 207 ± 67μg/L, respectively; day 0: p = 0.003; day + 10: p = 7.57 × 10-9). In patients with CsA level < 200μg/L, the incidence of aGvHD was significantly more frequent compared to patients with CsA levels > 200μg/L [(234/356 (66%) versus 91/248 (37%); p = 1.34 × 10-12]. In patients with cGvHD, there was no significant difference between CsA levels < 200μg/L (128/330) compared to CsA levels > 200μg/L (96/233; p = 0.312). The optimal CsA cutoff level for the prevention (i.e., roughly 50% incidence reduction) of aGvHD was > 201μg/L at day 0 and > 195μg/L at day + 10. In a competing risk analysis, time to aGvHD grade ≥ 2 (using death of other causes as competing risk) was associated with CsA levels > 200μg/L on day 0 and on day 10, unrelated donors, myeloablative conditioning (MAC), and for the diagnosis lymphoma/myeloma. Our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels above 195μg/L in the first 10days of allo-HCST to reduce aGvHD.

The Impact of Early Post-Transplant Cyclosporine Induced Acute Nephrotoxicity on Long Term Renal Function in 2-Year Survivors of Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Retrospective Study

Introduction:Acute kidney injury (AKI) and chronic kidney disease (CKD) affect 10-70% of transplant recipients. Onset of kidney injury varies from days to months or years after transplantation. Kidney injury may be caused by multiple factors. Long-term data on cyclosporine induced nephrotoxicity post HSCT are limited. It is unclear if cyclosporine induced nephrotoxicity at early phase post HSCT will impact long term renal function. The objective of this study is to evaluate the progression of renal function in allogeneic hematopoietic stem cell transplant (HSCT) patients, before, during and after cyclosporine therapy.Methods:This is a retrospective single arm cohort study evaluating the impact of cyclosporine on renal function in patients who underwent allogeneic HSCT from 2003 through 2013. Patients age≥ 14 years who underwent allogeneic HSCT and received cyclosporine as graft-versus-host disease (GVHD) prophylaxis and alive two years post HSCT without disease relapse or GVHD were included in the study. Primary outcome was the change in serum creatinine and estimated creatinine clearance. Delta creatinine (baseline creatinine - creatinine on day 25, day 100, day 180, year 1 and year 2 post HSCT) was used to calculate the change in the serum creatinine and estimated creatinine clearance. Estimated creatinine clearance was calculated using Cockcroft and Gault formula (CG) for patients aged ≥ 18 years. Schwartz formula was used to estimate creatinine clearance for patients aged ≥ 14 years till 18 years. The secondary outcome was the incidence of acute kidney injury. AKI was defined as per RIFLE criteria. The severity grades were defined on the basis of the changes in serum creatinine. CKD was defined if estimated glomerular filtration rate (GFR) <60 ml/minute per 1.73 m2 for 3 months. All patient during the study period were screened. Descriptive statistics were used to describe the data, continuous variables were reported as mean ± stander deviation and categorical variables were summarized as frequencies and percentages. The study was approved by the Office of Research Affairs in our institution.Results: Out of 912 patients who underwent allogeneic HSCT from 2003 to 2013, 121 patients were included who met the inclusion criteria listed above in the method section (Figure 1). The majority of patients were males (55%) with sever aplastic anemia as primary disease (31%). Mean baseline serum creatinine was 52±16 µmol/l, mean baseline estimated creatinine clearance was 116±58 ml/minute per 1.73 m2 (Table 1). Mean duration of cyclosporine levels monitoring was 232±180 days. Serum creatinine increased from the baseline at day 25, day 100, day 180, 1 year and 2 years post HSCT (Mean± SD; 45.7 ±39, 66.2 ±45.9, 37.8±27.1, 31.9±22.55, 28±22.5 µmol/l, respectively) (Figure 2). This translated into reductions in the estimated creatinine clearance at day 25, day 100, day 180, 1 year and 2 years post HSCT (Mean± SD; -61.6±51 , -89.6 ±55.7,-67. ±55.34,-62.5±55.4,-57.6±56.ml/minute per 1.73 m2, respectively) (Figure 3). The highest incidence of AKI was at day 100 post HSCT in the included patients. 40% of them had supratherapeutic cyclosporine levels. There was association between developing acute kidney injury at day 100 and CKD at 2 years post HSCT, 23% of the included patients had acute kidney injury and 13 % of them found to have CKD at 2 years post HSCT as illustrated table 2.Conclusion:Our study demonstrated that cyclosporine represents a primary risk factor for progression of renal impairment in hematopoietic stem cell transplant recipients particularly in those who developed acute kindly injury at 100 days. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Association between Transplant-Associated Thrombotic Microangiopathy and Calcineurin Inhibitor and Sirolimus Levels

Introduction: Thrombotic microangiopathy (TMA) is a known complication of allogeneic hematopoietic cell transplantation (HCT). An ongoing debate is whether TMA is caused by acute graft-versus-host disease (GVHD) or calcineurin inhibitor (CNI)/sirolimus. Previous studies have not examined the impact of CNI/sirolimus average trough levels while accounting for the confounding effect of GVHD. In the current study, we examined the association between time-varying levels of CNI/sirolimus and the onset of TMA among 2105 adult allogeneic HCT recipients.Methods: We performed a retrospective cohort analysis of allogeneic HCT recipients during 2006-2015 at Fred Hutchinson Cancer Research Center who received CNI/sirolimus for GVHD prophylaxis. TMA (outcome) was ascertained and validated as previously described (Blood 130;Suppl:666). Acute GVHD (confounder) was defined and graded according to established criteria. Consecutive CNI/sirolimus trough levels (exposure) were obtained and interval values between checks were imputed via linear interpolation. We followed patients from the time of hematopoietic cell infusion until the onset of TMA and censored patients at day 100 or >1 week of missing drug levels. To examine the association between the “type” of immunosuppressant and TMA, CNI/sirolimus exposure over time was characterized as a discrete categorical variable (tacrolimus alone, cyclosporine alone, or sirolimus + CNI). To examine the impact of the “level” of immunosuppressant on TMA, CNI/sirolimus exposure was both defined as an average of the previous 7-day trough levels (continuous variable) as well as a discrete time-above-peak variable (binary variable for tacrolimus >15 ng/mL, cyclosporine >450 ng/mL, or sirolimus >10 ng/mL). Extended Cox regression models were built to examine the time-varying association between CNI/sirolimus exposures and TMA after adjusting for GVHD.Results: In the current study, 2105 adult allogeneic HCT recipients contributed 173,171 person-days and 150 cases of TMA. The median follow-up time was 94 days and trough blood levels were checked on average 3x per week. Initial GVHD prophylaxis regimen for patients included 54% on tacrolimus (n=1135), 40% on cyclosporine (n=837), and 6% on a combination of sirolimus + CNI (n=133). Nearly no one received sirolimus alone without CNI. Eight percent of patients (n=162) had at least one switch in the immunosuppression regimen within 100 days. The median (IQR) trough levels for tacrolimus, cyclosporine, and sirolimus were 9 ng/mL (7-12), 283 ng/mL (206-372), and 5 ng/mL (4-7), respectively. Acute GVHD developed in 64% of patients including 53% grade 2 (n=1115), 9% grade 3 (n=185), 2% grade 4 (n=52).In the analysis adjusted for both discrete time-varying CNI/sirolimus exposure and GVHD, higher grades of GVHD had strong associations with TMA (Table 1: grade 2 HR 2.24, P=0.001; grade 3 HR 12.38, P<0.001; grade 4 HR 26.04, P<0.001). While cyclosporine and tacrolimus had a similar risk for TMA (HR 1.23, P=0.230), sirolimus + CNI regimen was associated with a slightly higher risk compared to CNI alone (HR 1.76, P=0.051).In the analyses of individual drug levels adjusted by GVHD, higher trough levels of tacrolimus and cyclosporine (either as a linear average level or binary time-above-peak) were not associated with an increased risk of TMA (Table 2). However, higher sirolimus trough levels were associated with an appreciable risk of TMA (HR 1.44, P=0.001 for every 1 ng/mL increase in sirolimus average trough level; HR 3.23, P=0.164 for time above 10 ng/mL).Conclusion: In allogeneic HCT patients, acute GVHD was strongly associated with the onset of TMA independent of ongoing exposures of CNI/sirolimus. We did not find an association between CNI recipients (tacrolimus versus cyclosporine) or CNI levels and the risk of TMA. However, when combined with CNI, higher sirolimus trough levels were linearly associated with a higher risk for TMA. Limitations in this observational study include the inability to adjust for concomitant medications and conditions that might have altered drug levels and inability to adjust for target drug levels since recognized risk factors might have led clinicians to target higher drug levels due to higher risks of GVHD. These findings suggest that prevention and treatment of GVHD and avoidance of high sirolimus levels will decrease the risk of TMA. DisclosuresLee:Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding; Kadmon: Research Funding; Takeda: Research Funding. Garcia:Pfizer: Consultancy; Portola: Research Funding; Shingoi: Consultancy; Retham Technologies LLC: Consultancy; Janssen: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Boehringer Ingelheim: Consultancy.

A Comparative Study on the Safety and Efficacy Parameters of Cyclosporine and Tacrolimus on Renal Transplanted Patients: A Malaysia Experience

Calcineurin inhibitors, cyclosporine and tacrolimus are increasingly becoming part of the standard immunosuppresant therapies for renaltransplanted patients in Malaysia. In this study, the clinical safety and efficacy of cyclosporine and tacrolimus in a Malaysian renal-transplanted population is compared. A fourteen-year retrospective review on all renal-transplanted patients (from September 1991 to September 2015) or patients being followed up at University Malaya Medical Centre (UMMC) on cyclosporine or tacrolimus regime was conducted. We collected the clinical and laboratory parameters at 3-month, 6-month, 7-month, 8-month, 9-month, 10-month, 11-month, 12- months, 2-year and 3-year following from transplantation for each drug. The mean cyclosporine and tacrolimus trough levels were within the recommended therapeutic ranges (189.16 ± 69.10 ng/ml and 7.84 ± 2.18 mg/day respectively). The mean low-density lipoprotein (LDL) was significantly higher at eleven months for tacrolimus compared to cyclosporine. Similarly, the mean total bilirubin level was significantly higher with cyclosporine as compared to tacrolimus between 3 – 9 months post transplantation but did not show any significant difference (p = 0.49). The overall monthly means of serum uric acid levels in patients were also similar, 380 ± 87 mg/dL (cyclosporine) and 390.96 ± 95.97 mg/dL (tacrolimus) (p = 0.49). The Kaplan-Meier survival rate is significantly longer (p = 0.03) with cyclosporine-based treatment as compared to tacrolimus. Overall, cyclosporine and tacrolimus did not show any significant difference in terms of safety and efficacy parameters among Malaysian renal-transplanted patients indicating that they may be used interchangeably.

Factors Related to the Acute Cellular Rejection During the First Year After Heart Transplant

IntroductionThe acute cellular rejection is recognized as a factor related to the long-term viability of the heart graft. We intend to establish which factors are associated with the acute cellular rejection during the first year post heart transplant using a longitudinal model with repeated measures. MethodsA retrospective cohort study was performed with all the patients who underwent heart transplant between 2005–2018 at the Hospital Universitario San Ignacio in Bogota, Colombia. In order to determine the factors associated with the development of acute cellular rejection, a generalized estimating equation approach was used, with an interchangeable correlation structure. The lowest value of quasi-likelihood information criterion and P < .05 was considered significant. ResultsFifty-five patients (49.3 ± 11.1 years old) were included. The mortality during the first month was 16.3% and the accumulated mortality during the first year was 23.6%. The incidence of the acute cellular rejection was higher during the third month after the transplant (79.9%); most of them were acute cellular rejection grade 1. The factors associated with the development of the rejection were the cyclosporine levels out of the therapeutic range in several periods of evaluation (P < .03) and the age of the receptor (P = .049). ConclusionsUsing advanced modeling methodologies of longitudinal data we identified that the factors associated with acute cellular rejection during the first year after the transplant are related to the therapeutic levels of the calcineurin inhibitor (cyclosporin) during the first 6 months of follow-up and the age of the receptor.

The mTOR-inhibitor Sirolimus decreases the cyclosporine-induced expression of the oncogene ATF3 in human keratinocytes

BackgroundDue to their immunosuppressive therapy, organtransplant recipients (OTRs) exhibit a high incidence for the development of cutaneous squamous cell carcinoma (cSCC). Randomized studies of kidney-transplanted patients indicate a significant lower susceptibility for cSCC among patients receiving the mTOR-inhibitor Sirolimus, compared to patients without mTOR-regimen. The exact mechanism, how mTOR inhibition affects keratinocyte carcinogenesis remains unclear. ObjectiveOur aim was to investigate the impact of Sirolimus on the expression level of the oncogene ATF3, which is involved in the development and progression of cSCC. MethodsWe incubated human keratinocytes, cSSC cell lines and 3D skin equivalents with Sirolimus, exposed the cells to calcineurin inhibitors (CNI) and UVA-radiation and measured the expression level of ATF3 by real-time PCR and western blot. ResultsWe show that Sirolimus downregulates the expression of ATF3 induced by cyclosporine or cyclosporine plus UV-radiation in keratinocytes. In line with this we demonstrate a decrease in ATF3 expression, by incubating 3D skin equivalents with Sirolimus prior to cyclosporine and UV-light. However, Sirolimus has no significant impact on the ATF3 expression levels of cyclosporine stimulated cSCC cell lines. ConclusionTaken together, our study demonstrates that Sirolimus downregulates the CNI or UV-induced ATF3 expression in human keratinocytes, which could be a potential molecular mechanism how Sirolimus reduces cSCC in OTRs. The lack of ATF3 suppression by Sirolimus in cSCC cell lines fits to observations from clinical studies which demonstrated a clinical benefit from the switch to a mTOR-regimen in patients with low tumor burden in early stage of disease.

Chylothorax as a Post-Operative Complication of Orthotopic Heart Transplantation

Objectives Recognize chylothorax as a complication of OHT, and LVAD implantation and explantation. Introduction Chylothorax is a rare complication of thoracic surgery with a reported incidence of 0.24% - 0.5%, however there have been only two previous reports of chylothorax after orthotopic heart transplantation (OHT). We report the first instance of chylothorax complicating OHT at the time of ventricular assist device (VAD) explantation. Case report A 47 y.o. man with ischemic cardiomyopathy who required TandemHeart, and subsequent HeartMate 2 VAD placement with closure of ASD. He underwent a HeartMate 2 exchange four months later, and OHT 14 months later. After OHT, on post-operative day (POD) 8, he had milky fluid from a mediastinal Blakemore tube. Fluid triglyceride level was 1477 mg/dl. The patient was placed on a very low fat diet and the drainage decreased from 235mL/24hrs to 90mL/24hrs. When challenged with a high fat diet, he had a recurrent chylous effusion. On POD 28 he reported Discussion The appearance of this complication after VAD explantation may be of particular importance as continued developments and improvements in VAD technology lead to an increase in patient survival, VAD implantation, and exchange. As this occurs, awareness of this rare complication becomes more important. Chylothorax provides a particular challenge in the management of the transplant patient, as indwelling chest tubes, effects on nutritional status and the immune system are noteworthy. The primary treatment for chylothorax is low fat or medium-chain fatty acid diet. If this fails, nil per os status with total parenteral status is the second line therapy. In a patient post OHT, who is immunosuppressed, maintaining adequate nutrition is of paramount importance. Additionally, loss of chyle has potential implications in the management of post-transplant immunosuppression. Cyclosporine is secreted in chyle. The loss of chyle into the pleural cavity decreases the circulating levels of cyclosporine, which render achieving a therapeutic level difficult. Furthermore, cyclosporine has been demonstrated to increase chyle formation, which makes resolution of chylothorax more difficult in patients who require cyclosporine therapy. Lastly, chyle contains numerous lymphocytes, with a typical cell count revealing >50% lymphocytes. Loss of chyle, then, leads to a rapid and abnormal loss of lymphocytes. This may complicate administration and monitoring of lymphocyte-reducing anti-rejection therapies which are paramount to graft health in the early post-operative period. Conclusion Post-OHT chylothorax is an uncommon, but noteworthy complication. Management is similar to non-transplant patients, requires close follow-up and may adversely affect outcomes, due to effects on nutritional status and immunological risk.

Challenges of immunosuppressive and antitrypanosomal drug therapy after heart transplantation in patients with chronic Chagas disease: A systematic review of clinical recommendations.

Although contraindicated for decades, heart transplantation (HT) has finally become a feasible therapeutic option for the treatment of Chagasic patients with end-stage heart failure. Part of the success in achieving acceptable survival rates after HT is due to the enhancement of the pharmacological management of allograft rejection and reactivation of Trypanosoma cruzi infection. By using the framework of a systematic review, we investigated if Chagasic patients who have undergone a HT are treated with similar immunosuppressive and antitrypanosomal regimens in endemic and non-endemic countries and exhibits similar T. cruzi reactivation, allograft rejection and survival rates. From a structured search in PubMed/Medline, Scopus, and Web of Sciences databases, 30 clinical studies were reviewed. Although immunosuppressive regimens are variable in endemic and non-endemic countries, the current evidence supports the administration of lower doses of corticosteroids, adjusted cyclosporine levels (100-150 ng/mL) 3 months after HT, and azathioprine rather than mycophenolate mofetil to reduce the risk of T. cruzi reactivation and rejection episodes. Antitrypanosomal therapy exclusively based on benznidazole, nifurtimox, and allopurinol was consistent in endemic and non-endemic countries, achieving effective results in the control of infection reactivation. The evidence that supports prophylactic antitrypanosomal therapy or administration of allopurinol alone is limited. By highlighting the main sources of research bias, we hope that our critical analysis can help to expedite clinical research and to reduce methodological bias, thereby improving the quality of evidence in new research initiatives.

Cyclosporine Versus Tacrolimus: Which Calcineurin Inhibitor Has Influence on Cytomegalovirus Infection in Cardiac Transplantation?

IntroductionCytomegalovirus (CMV) infection is a relevant cause of morbidity and mortality in transplantation patients. Its major incidence is in the first year and viral replication is related to acute rejection, survival reduction, and graft vascular disease. ObjectiveThis study aims to evaluate retrospectively whether a high dose of calcineurin inhibitors correlates with CMV-positive polymerase chain reaction (PCR), need for treatment, and death in cardiac transplantation patients. MethodsThis is a case-control study including patients who underwent transplantation between 2014 and 2016. They were separated into two groups (positive or negative PCR) and evaluated for dosage serum levels of cyclosporine and tacrolimus. Patients were classified with adequate dose of immunosuppressant or high dose, and was analyzed that there was any association with those and positive CMV-PCR, need for treatment for CMV, and deaths. For statistical analysis, the Student t test was used for the quantitative variables and the Fisher’s Exact Test for qualitative variables. To show CMV-free survival, the Kaplan-Meier curve was used. The level of significance was set at 5%. ResultsCMV-positive PCR in the sample was 72% for a total of 50 individuals. Positive PCR correlated with a high dose of calcineurin inhibitors in a statistically significant way (P = .002), as did a high dose of cyclosporine (P = .004); however, a high dose of tacrolimus had no such association (P = .17). When a high dose was assessed with a need for treatment, the chance of needing treatment increased more than eight times (P = .024; odds ratio = 8.25; 95% CI = 1.33 to 51.26), which was different from results found with high-dose tacrolimus (P = 1.0). However, no significant association was found in relation to deaths. ConclusionsTacrolimus serum levels showed no association with CMV-PCR, which was different from serum cyclosporine, which showed association with CMV-PCR positivity, increasing the need for treatment approximately 8-fold, without association with death.

Ombitasvir–Paritaprevir–Ritonavir Therapy in a Kidney Transplant Recipient With Chronic Hepatitis C Virus Genotype 1 Infection: A Case Report on the Importance of Considering Drug–Drug Interactions and Monitoring Cyclosporine Levels

A 74-year-old Japanese man with a history of chronic hepatitis C and kidney transplant (KT) was administered pegylated-interferon plus ribavirin therapy. However, this therapy was ineffective. The patient was then hospitalized to receive ombitasvir (OBV) plus paritaprevir (PTV) plus ritonavir (r) antiviral combination therapy. He tested negative for the virus after 4 weeks, and completed 12 weeks of treatment. The patient ultimately achieved a sustained virological response after the 12 weeks of treatment. Cyclosporine (CyA) trough levels, during the OBV-PTV-r therapy, reached a peak within 5 days of initiating therapy, and increases in serum creatinine and total bilirubin were also observed. However, onset of irreversible nephropathy and hepatopathy were avoided by reducing the CyA dosage. The OBV-PTV-r therapy demonstrated a sufficient antiviral effect and could be safely administered postoperatively to patients having undergone KT. When a combination therapy with interferon-free, direct-acting antivirals is used in patients post-transplantation, consideration of drug-drug interactions with and monitoring CyA are of vital importance.

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.

P532 Efficacy of combination therapy with cyclosporin and vedolizumab in inflammatory bowel diseases refractory to anti-TNF agents

Vedolizumab it is a promising agent in IBD patients refractory to anti-TNF therapy. However, a potential slower response has been documented in both GEMINI 2 and 3 trials, and also in clinical settings. Because of the slower onset of action of vedolizumab, monotherapy does not seem to be effective in more severe cases of IBD. However, cyclosporin is an effective “rescue therapy” which may serve as a rapidly acting “bridge” to maintenance therapy with the slowly acting agents such as thiopurines in patients with severe UC. The aim of the study to report our experiences with the use of combined cyclosporine and vedolizumab therapy in active IBD failed to respond to anti TNF therapy. Vedolizumab was registered in Hungary in 2016. Data were collected retrospectively from the Hungarian Registry on Vedolizumab therapy. We assessed clinical and endoscopic disease activity with CDAI and Mayo Score. Clinical outcome and safety profile was registrated. Six of 106 vedolizumab-treated patients (four colonic CD, two UC) diagnosed with moderate-to-severe IBD requiring rescue therapy received intravenous cyclosporine of 4 mg/kg for 5 days following oral treatment a mean of 69 days before the initiation of vedolizumab. The reason for late initiation of vedolizumab therapy was the awaiting time of the evaluation process. Cyclosporine levels were closely monitored and adjusted if needed. Mean values of CD activity index and partial Mayo score were 276 and 8, respectively. Three patients received concomitant immunomodulator therapy and 3 had azathioprine intolerance. Primary and secondary non-response to previous anti-TNF therapy was reported in two and four patients, while two patients developed infusion reaction. Combination therapy was effective in all cases and cyclosporine was discontinued after a mean of 130 days. After the induction phase of vedolizumab, control colonoscopy was performed. One patient had complete mucosal healing, the other patients had moderate regression in mucosal inflammation. Side-effect of cyclosporine occurred in one patient leading to the discontinuation of the drug after the third infusion of vedolizumab. After the induction phase of vedolizumab, one patient underwent colectomy because of severe CD. On the basis of our data we do think that cyclosporin therapy is a useful and safe option in combination with vedolizumab induction therapy in moderate-to-severe activity of IBD.

Polymorphisms of CYP3A5 Affect Serum Levels and Maintenance Doses of Tacrolimus in Myasthenia Gravis Patients

Objectives: To evaluate the influences of polymorphisms of cytochrome P450 (CYP) 3A5 (A6986G, CYP3A5*3) on serum levels of tacrolimus and cyclosporine (CyA) in patients with myasthenia gravis (MG). Methods: This study included 74 MG patients treated with tacrolimus (n=65) or CyA (n=22). Genomic DNA was extracted and amplified with specific primers, and CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 DNA sequencer. We measured blood trough level (C0) of tacrolimus and CyA. Clinical disabilities were evaluated with the MG-ADL scale. Results: For tacrolimus C0, the CYP3A5*3/*3 genotype was associated with higher levels than the CYP3A5*1/*3 genotypes (7.1 ng/ml versus 2.9 ng/ml; P<0.0001) and CYP3A*1/*1 (7.1 ng/ml versus 1.3 ng/ml; P<0.0004). The improvement in the mean MG-ADL scores tended to be better in MG patients with the CYP3A5*3/*3 or CYP3A5*1/*3 than those with CYP3A5*1/*1. For the CyA concentrations, CYP3A5 genotypes did not have significant effects. Conclusion: In MG patients, CYP3A5 polymorphism significantly affects serum levels of tacrolimus and thereby treatment effects, but not those of CyA. The maintenance dose of tacrolimus should be determined considering CYP3A5 polymorphism.

Assessment of the Measurement Error in Cyclosporine Levels Drawn Between Peripheral and Central Sources.

Cyclosporine is often monitored by drug levels drawn through central venous catheters (CVCs), which may be falsely elevated due to reversible drug adsorption onto the catheter. Therefore, we assessed the correlation between cyclosporine levels drawn peripherally and through CVCs. Bone marrow transplantation patients had a weekly collection of both peripheral and CVC draws from dual-lumen catheters simultaneously to assess cyclosporine levels after research ethics approval. Our primary outcome was the proportion of paired samples that were incongruent-defined as the mean of the CVC level being greater than 2 standard deviations from the peripheral level mean. After approaching 27 eligible patients, 20 patients (77.8%) provided samples. Of 53 paired samples, seven were incongruent (13.2%). Peripheral and CVC levels correlated (r = 0.91) and agreed well. Despite potential for preanalytical error due to adsorption, cyclosporine infusion and monitoring via CVCs produce results similar to monitoring via peripheral blood draws.

Extended-Spectrum Beta-Lactamase–Producing Enterobacteriaceae–Related Urinary Tract Infection in Kidney Transplant Recipients: Risk Factors, Treatment, and Long-Term Outcome

BackgroundPrevalence of extended-spectrum beta-lactamase–producing Enterobacteriaceae (ESBL-E) has risen in kidney transplant (KT) patients, with no long-term data so far on graft function or survival. MethodsKT patients with ESBL-E–positive urine culture were retrospectively analyzed regarding initial adequate antimicrobial therapy, recurrent infection, transplant function, and survival compared with an ESBL-E–negative KT control cohort. ResultsESBL-E–positive KT patients (n = 93) were older (55.5 ± 16.1 vs 49.5 ± 16.8 y; P = .001), presented with higher trough levels of cyclosporine and tacrolimus (121 ± 71 vs 102 ± 32 ng/mL [P = .04]; and 7.9 ± 3.3 vs 7.0 ± 2.3 ng/mL [P = .04], respectively), higher dosages of mycophenolate (1,533 ± 670 vs 1,493 ± 436; P = .001), and more acute rejection episodes within 3 months before diagnosis (12.9% vs 0.8%; P < .0001) compared with control subjects (n = 591). Five-year patient survival was superior in control subjects compared with ESBL-E–positive patients (91.2% vs 83.5%; P = .034) but long-term graft function was similar. Hospitalization rates were higher in patients presenting with ESBL-E–related urinary tract infection (UTI) compared with control subjects with ESBL-E–negative UTI (60.3% vs 31.3%; P = .002) but 5-year graft survival was superior in patients presenting with ESBL-E–related UTI (88.6% vs 69.8%; P = .035) compared with control subjects with ESBL-E–negative UTI. Recurrence rates were similar in patients with or without ESBL-E–related UTI. Initial antibiotic treatment was adequate in 41.2% of patients presenting with ESBL-E–related urosepsis, resulting in a reevaluation of antibiotic stewardship in our clinic. ConclusionsESBL-E detection in general was associated with higher mortality, but graft survival in patients with ESBL-E–related UTI was significantly better compared with ESBL-E–negative UTI.

Acute Graft Rejection and Formation of De Novo Donor-Specific Antibodies Triggered by Low Cyclosporine Levels and Interferon Therapy for Recurrent Hepatitis C Infection After Liver Transplantation: A Case Report

BackgroundWe report a case of acute rejection of a liver graft, together with the occurrence of de novo donor-specific antibodies (DSAs), in a 53-year-old Japanese man who had undergone deceased-donor liver transplantation. MethodsThe graft rejection was triggered by low cyclosporine levels and pegylated interferon treatment for the recurrence of hepatitis C virus (HCV) infection 18 months after transplantation. Although the graft was ABO-compatible, pre-formed DSA B51 was detected; therefore, total plasma exchange was performed and intravenous rituximab (500 mg/body) was administered before transplantation. ResultsDSA was absent 6 months after transplantation. HCV recurrence was treated with pegylated interferon-α-2a. Renal function deteriorated with this anti-HCV therapy, with serum cyclosporine levels decreasing to 50 ng/mL. A rapid virologic response was achieved, but liver function deteriorated after 3 months of anti-HCV therapy, with histologic evidence of acute cellular rejection and formation of de novo DSAs. Anti-thymocyte globulin was administered for 5 days, which led to immediate improvement in liver function. However, renal function declined, warranting hemodialysis. The patient recovered 2 months after acute rejection, although de novo DSAs persisted. ConclusionsCareful immunologic monitoring may be required for patients receiving interferon therapy for HCV infection to maintain sufficient blood levels of immunosuppressive agents and to prevent acute liver graft rejection.