Cyclosporine Trough Levels Research Articles

#2487 Deleterious renal outcome in patients with thrombotic microangiopathy after lung transplantation: the lung TMA trial

Abstract Background and Aims Thrombotic microangiopathy (TMA) is a rare but severe complication following lung transplantation. The pathogenesis is poorly understood, involving endothelial damage and various risk factors, including calcineurin inhibitor (CNI) toxicity. We aimed to evaluate diagnostic accuracy, identify risk factors for and assess the renal and overall survival of TMA in this patient group. Method We performed a retrospective study of patients with TMA after lung transplant between 01/01/2000-01/01/2021. Matching controls were selected based on underlying lung disease, age, gender, CMV risk, and immunosuppressive regimen. Overall survival and baseline data (age, gender) were collected for the whole lung transplant group. Results A total of 29 TMA cases (2.9%) were identified out of 1025 lung transplantations. 48% of patients had a complete hematological assessment with Coombs testing as the most frequent (52%) missing test. The median time from transplantation to TMA was 5.9 months. 76% of the episodes occurred before 12 months. 77% of patients had organ damage with acute kidney injury in 72%. At the time of TMA 38% of patients had a cytomegalovirus (CMV) infection. Arterial hypertension was found in 31% and acute rejection in 11%. The immunosuppressive scheme consisted of tacrolimus/mycophenolate mofetil and corticosteroids in the majority of cases (56%). Tacrolimus (n = 22) and cyclosporine (n = 7) trough levels were respectively 11.8 and 207 µg/l at the time of TMA. Treatment consisted of change in immunosuppressive regimen (72%), 31% received plasmapheresis. When comparing the TMA patients with the control group a higher rate of donor specific antibodies were found (11% vs 1%), a lower median time till chronic lung allograft dysfunction (37 m vs 91 m) and a higher prevalence of end-stage renal disease (24% vs 6%) and overall death (97% vs 44%) with mortality being significantly higher (p < 0.01). Fig. 1 illustrates the overall outcome. Conclusion This study illustrates the clinical characteristics and outcomes of TMA after lung transplantation. Even though the prevalence is low the effects are deleterious with acute kidney injury in the majority of cases and higher risk of end-stage renal disease and mortality. Our study emphasizes the need for higher further research into risk factors, and therapeutic strategies to prevent and improve patient outcomes. Furthermore, the findings underscore the importance of vigilant monitoring and tailored interventions for TMA in lung transplant patients.

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

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

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.

Frequency and Risk Factors of Cyclosporine-Induced Neurotoxicity in Allogeneic Stem Cell Transplant Recipients.

Background and objectiveThe calcineurin inhibitor cyclosporine A is routinely used for prophylaxis against graft-versus-host-disease (GvHD) in human leukocyte antigen (HLA)-matched allogeneic stem-cell transplant patients and is a major etiological factor for neuropathological symptoms that are reversible in most cases. In this study, we aimed to determine the frequency and risk factors of cyclosporine-induced neurotoxicity (CIN) in HLA-matched allogeneic stem cell transplant patients.MethodsThe study spanned the period from January 2016 to December 2019. Consecutive HLA-matched allogeneic stem-cell transplant patients of all ages were included in the study. Descriptive and risk factor analyses for the development of CIN with respect to age, sex, primary diagnosis, conditioning regimen, electrolyte abnormalities, and cyclosporine trough levels during the neurological episode were performed.ResultsA total of 106 HLA-matched patients with a median age of 6.3 years [interquartile range (IQR): 0.5-46 years], of which 37 (35%) were females, were included in the study. The mean cyclosporine trough level was 500 ±286 mg/dl. Neurological symptoms were found in 27 (26%) patients. A total of 14 (13%) patients were diagnosed with CIN. The frequency of other neurological symptoms included headache in 46 (43%), disorientation in 17 (16%), seizures in 12 (11%), visual disturbance in 11 (10%), and aphasia in seven (7%) patients. Posterior reversible encephalopathy syndrome (PRES) was found in six (6%) patients. All patients with CIN had hypertension and none had a fever. Multivariate logistic analysis showed that the presence of seizures [odds ratio (OR): 10.0, p<0.001] and the absence of fever (OR: 0.02, p<0.001) were associated with the diagnosis of CIN.ConclusionThe prevalence of CIN is not uncommon (13%) in patients receiving cyclosporine for GvHD prophylaxis. Neurological complications, especially seizures, are common in CIN, and fever might indicate an alternative diagnosis. Prompt recognition of neurological signs and symptoms and early intervention can halt the progression of the disease.

Statin use and incident cardiovascular events in renal transplant recipients.

BackgroundStatins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users.Method622 included RTR (follow‐up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted.ResultsCox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53‐1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75‐24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04).ConclusionIn conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV‐specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction.

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.

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.

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.

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.

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.

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.

Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.

In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing. Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12weeks posttreatment with DAA-based regimens, with a median time from transplant to treatment initiation of 43days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380days (IQR 263-434) posttransplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation.

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.

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.

Improved Pulse Wave Velocity and Renal Function in Individualized Calcineurin Inhibitor Treatment by Immunomonitoring: The Randomized Controlled Calcineurin Inhibitor-Sparing Trial.

A new immune monitoring tool which assesses the expression of nuclear factor of activated T cells (NFAT)-regulated genes measures the functional effects of cyclosporine A. This is the first prospective randomized controlled study to compare standard pharmacokinetic monitoring by cyclosporine trough levels to NFAT-regulated gene expression (NFAT-RE). Expression of the NFAT-regulated genes was determined by qRT-PCR at cyclosporine trough and peak level. Cardiovascular risk was assessed by change of pulse wave velocity from baseline to month 6. Clinical follow-up was 12 months. In total, 55 stable kidney allograft recipients were enrolled. Mean baseline residual NFAT-RE was 13.1 ± 9.1%. Patients in the NFAT-RE group showed a significant decline in pulse wave velocity from baseline to month 6 versus the standard group (-1.7 ± 2.0 m/s vs 0.4 ± 1.4 m/s, P < 0.001). Infections occurred more often in the standard group compared with the immune monitoring group. No opportunistic infections occurred with NFAT-RE monitoring. At 12 months of follow-up, renal function was significantly better with NFAT-RE versus standard monitoring (Nankivell glomerular filtration rate: 68.5 ± 17.4 mL/min vs 57.2 ± 19.0 mL/min; P = 0.009). NFAT-RE as translational immune monitoring tool proved efficacious and safe in individualizing cyclosporine therapy, with the opportunity to reduce the cardiovascular risk and improve long-term renal allograft function.

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.

Nephrotoxicity in children with frequently relapsing nephrotic syndrome receiving long-term cyclosporine treatment.

Steroid-sparing drugs, such as cyclosporine, are recommended as treatment for children with frequently relapsing nephrotic syndrome (FRNS) and steroid-related toxicities. We recently reported a high rate of relapsing nephrotic syndrome 2years after discontinuation of cyclosporine treatment, suggesting that long-term treatment is necessary. Cyclosporine-associated nephrotoxicity (CAN) is a potential side effect of long-term cyclosporine treatment. We retrospectively reviewed pediatric patients with FRNS treated with cyclosporine for ≥3years at a single center between 1999 and 2012. The cyclosporine dose was adjusted to maintain the whole-blood cyclosporine trough level at 80-100ng/ml for 6months, at 60-80ng/ml for 18months, and then at around 50-60ng/ml thereafter. Maintenance dose of prednisolone was not prescribed. CAN was graded in terms of arteriolar hyalinosis and the degree of interstitial fibrosis. Thirty-six children (28 males) were enrolled in the study. The median age at the start of long-term cyclosporine treatment was 9.4years. The median duration of the longest period of cyclosporine treatment was 4.5years. Most CAN cases were characterized by arteriolar hyalinosis. The frequency of CAN was positively correlated with the duration of cyclosporine treatment, with an odds ratio (95% confidence interval) for CAN of 3.84 (0.79-18.74) after 2-5 years and 6.60 (1.18-36.94) after >5years of cyclosporine treatment (vs. 0-2 years). Although the frequency of CAN was correlated with the duration of cyclosporine treatment in our pediatric patient population, most cases of CAN involved arteriolar hyalinosis. We conclude that long-term cyclosporine treatment is useful for treating FRNS in children, providing its dose is controlled and kidney biopsies are regularly performed.

Immunosuppressive Therapy for Elderly Kidney Transplant Recipients

ObjectivesIn elderly kidney transplant (KT) recipients, the incidence of acute rejection is decreased, while that of fatal infections is increased. There are currently no guidelines for an upper age limit for KT, which is very difficult to determine. Here we examined several cases of elderly KT recipients. MethodsWe evaluated 127 KT patients treated at our department between 2003 and 2012 and followed them for 3 years post-transplant. The subjects were divided into two groups by age: ≥60 years (elderly group; n = 24); and <59 years (non-elderly group; n = 103). The presence or absence of acute rejection and infection, dose of immunosuppressive drugs, trough calcineurin inhibitor level, renal function, and graft and patient survival rates were retrospectively examined. ResultsOur basic immunosuppressive regimen was a combination of calcineurin inhibitor, methylprednisolone, mycophenolate mofetil, and basiliximab. At 1 year post-transplantation, the average tacrolimus and cyclosporine dose and trough levels were not significantly different. The mean dose of mycophenolate mofetil in the elderly group at 1 year post-transplantation was significantly lower than that of the non-elderly group. The incidences of cytomegalovirus infection and acute rejection during follow-up did not differ significantly between groups. There were no significant differences in creatinine level between the two groups. In the elderly group, the graft survival rates at 1 and 5 years were 100% and 95.4%, respectively, while those in the non-elderly group were 98.1% and 92.5%, respectively. ConclusionUsing our current immunosuppressive protocol, the outcomes of patients in the elderly group were considered acceptable.

Effects of Dipeptidyl Peptidase-4 Inhibitors on Hyperglycemia and Blood Cyclosporine Levels in Renal Transplant Patients with Diabetes: A Pilot Study.

BackgroundThe use of dipeptidyl peptidase-4 (DPP-4) inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes.MethodsSixty-five renal allograft recipients who received treatment with DPP-4 inhibitors (vildagliptin, sitagliptin, or linagliptin) following kidney transplant were enrolled. The glucose-lowering efficacies of the DPP-4 inhibitors were compared according to the changes in the hemoglobin A1c (HbA1c) levels after 3 months of treatment. Changes in the trough levels of the cyclosporine were also assessed 2 months after treatment with each DPP-4 inhibitor.ResultsHbA1c significantly decreased in the linagliptin group in comparison with other DPP-4 inhibitors (vildagliptin –0.38%±1.03%, sitagliptin –0.53%±0.95%, and linagliptin –1.40±1.34; P=0.016). Cyclosporine trough levels were significantly increased in the sitagliptin group compared with vildagliptin group (30.62±81.70 ng/mL vs. –24.22±53.54 ng/mL, P=0.036). Cyclosporine trough levels were minimally changed in patients with linagliptin.ConclusionLinagliptin demonstrates superior glucose-lowering efficacy and minimal effect on cyclosporine trough levels in comparison with other DPP-4 inhibitors in kidney transplant patients with diabetes.