Tacrolimus Toxicity Research Articles

Revisiting the nature and pharmacodynamics of tacrolimus metabolites

The toxicity of tacrolimus metabolites and their potential pharmacodynamic (PD) interactions with tacrolimus might respectively explain the surprising combination of higher toxicity and lower efficacy of tacrolimus despite normal blood concentrations, described in extensive metabolizers. To evaluate such interactions, we produced tacrolimus metabolites in vitro and characterized them by high resolution mass spectrometry (HRMS, for all) and nuclear magnetic resonance (NMR, for the most abundant, M-I). We quantified tacrolimus metabolites and checked their structure in patient whole blood and peripheral blood mononuclear cells (PBMC). We explored the interactions of M-I with tacrolimus in silico, in vitro and ex vivo. In vitro metabolization produced isoforms of tacrolimus and of its metabolites M-I and M-III, whose HRMS fragmentation suggested an open-ring structure. M-I and M-III open-ring isomers were also observed in patient blood. By contrast, NMR could not detect these open-ring forms. Transplant patients expressing CYP3A5 exhibited higher M-I/TAC ratios in blood and PBMC than non-expressers. Molecular Dynamics simulations showed that: all possible tacrolimus metabolites and isomers bind FKPB12; and the hypothetical open-ring structures induce looser binding between FKBP12 and calcineurins, leading to lower CN inhibition. In vitro, tacrolimus bound FKPB12 with more affinity than purified M-I, and the pool of tacrolimus metabolites and purified M-I had only weak inhibitory activity on IL2 secretion and not at all on NFAT nuclear translocation. M-I showed no competitive effect with tacrolimus on either test. Finally, M-I or the metabolite pool did not significantly interact with tacrolimus MLR suppression, thus eliminating a pharmacodynamic interaction.

Hyaluronic acid-coated polypeptide nanogel enhances specific distribution and therapy of tacrolimus in rheumatoid arthritis

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels’ disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.

#2536 Bisphosphonates as a tacrolimus-sparing strategy in kidney transplantation: insights from a retrospective analysis

Abstract Background and Aims The chronic toxicity of tacrolimus makes its sparing a crucial consideration for kidney transplant recipients (KTRs). Previous research has indicated a positive association between bisphosphonate use and favorable graft outcomes in KTRs. Therefore, our study aimed to investigate whether bisphosphonate use impacts the relationship between tacrolimus trough levels (TTLs) and graft outcomes in KTRs. Method We conducted a retrospective study encompassing 1,657 KTRs who were administered tacrolimus-based immunosuppressive therapy. The primary exposure was characterized by a time-dependent cross-product of TTLs (low TTLs vs. normal-high TTLs with a reference of 6 ng/mL) and the use of bisphosphonate. The study had two primary outcomes: (1) overall graft loss, defined as either the occurrence of patient death or conversion to kidney replacement therapy, and (2) reaching an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73 m². Results Over a cumulative total of 11,211.8 person-years, overall graft loss were observed in 183 patients, equating to 11.0% of the cohort. In multivariable Cox regression analysis, it was noted that normal to high TTLs, in the absence of bisphosphonate use, were associated with a reduced risk of overall graft loss (HR, 0.61; 95% CI, 0.43-0.87) compared to low TTLs without bisphosphonate use. The use of bisphosphonate in conjunction with normal to high TTLs correlated with an even further diminished risk of overall graft loss (HR, 0.36; 95% CI, 0.16-0.83) in comparison to low TTLs without bisphosphonate use. In low TTLs, the administration of bisphosphonates was associated with a reduced risk of overall graft loss than bisphosphonate non-use (HR, 0.26; 95% CI, 0.14-0.49). Similarly, this trend was observed in cases where the eGFR was below 30 ml/min/1.73 m². Conclusion The use of bisphosphonate was associated with favorable graft outcomes, even with a low TTLs. Incorporating bisphosphonate to a conventional immunosuppressant regimen Could potentially reduce tacrolimus requirement.

(1030) - Acute Tacrolimus Toxicity Due to Paxlovid Successfully Managed with Phenytoin After Lung Transplantation

(1030) - Acute Tacrolimus Toxicity Due to Paxlovid Successfully Managed with Phenytoin After Lung Transplantation

Thrombotic Microangiopathy in Renal Transplant Recipients

Background and Aim: Thrombotic microangiopathy (TMA) is a disease of microvasculature, triggered by numerous immunological and nonimmunological factors. The aim of this study is to identify the incidence, etiology, and clinical characteristics of posttransplant TMA in renal allografts and its impact on graft outcome. Patients and Methods: In this retrospective study, the records of patients who underwent renal transplantation between January 2013 and December 2017 were reviewed, and those recipients who had allograft biopsy-proven TMA were analyzed. Based on the clinical characteristics and investigations, the recipients were divided into two groups: those with systemic features of TMA and those with allograft-limited TMA. The clinical course and graft outcome of both the groups were compared and analyzed. Results: The number of patients who underwent renal transplantation during the study period was 212. Out of them, 16 patients had biopsy-proven TMA. Five patients had TMA with systemic features and the remaining 11 patients had allograft-limited TMA. In this study, the incidence of TMA among postrenal transplant recipients was 7.5%. The most common cause for TMA was acute antibody-mediated rejection (ABMR), followed by TMA due to tacrolimus toxicity. In one patient, TMA was secondary to disseminated tuberculosis (TB). TB as a cause of TMA is rarely reported. One-year graft survival in patients with allograft-limited TMA was 72.7% when compared to 50% in patients with systemic TMA, but this difference was statistically insignificant (P = 0.2). The graft loss was high in patients with TMA secondary to ABMR in both the groups. Conclusion: One-year graft survival is better in patients with allograft-limited TMA. Diligent search for an etiology for TMA should be made in all patients with TMA, as the treatment differs between each category.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Phenytoin enzyme induction for management of supratherapeutic tacrolimus levels due to drug-drug interaction with nirmatrelvir/ritonavir: Case series and discussion.

Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir. Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels. These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir.

Blame COVID! A case of tacrolimus toxicity managed with phenytoin

Blame COVID! A case of tacrolimus toxicity managed with phenytoin

Influence of Cyp3A4, Cyp3A5 and ABCB1 Polymorphisms on Tacrolimus Concentrations and Rejection Risk in Indian Kidney Transplant Recipients

Background: Tacrolimus metabolism is known to be determined by gene polymorphisms. Cyp3A5 genotype has most widely been seen to be associated with tacrolimus metabolism. Studies on other genes have produced mixed results. Objective: We studied the association of three polymorphisms CYP3A4*1B (-392 G>A), CYP3A5 (6986 A>G), and ABCB1 (3435 T>C) on tacrolimus levels and their association with either rejection or nephrotoxicity (infection or tacrolimus toxicity) in renal transplant recipients from India. Materials and Methods: In this prospective cohort study, patients who underwent kidney transplantation between July 2018 and July 2023 were studied. Inclusion criteria: Patients who underwent Kidney Transplantation and were (i) on tacrolimus-based immunosuppression and (ii) not on medications known to interact with calcineurin inhibitors, such as ketoconazole, phenytoin, and diltiazem, were studied. Tacrolimus levels, tacrolimus concentration/dose (C/D) and tacrolimus C/D per kg body weight, at monthly time points posttransplant for 6 months and biopsy-proven rejection, infection, tacrolimus toxicity, and acute tubular necrosis data were collected. Results: Three hundred and twenty-seven patients were included in the study. Two hundred and fifty-seven were male and 70 were female. A total of 1402 tacrolimus samples were collected, with an average of 3.2 ± 2.1 samples per patient. Tacrolimus levels were significantly lower in the Cyp3A5 AG and AA GG genotypes versus GG (5.27 ± 2.95 and 6.22 ± 2.79 vs. 8.05 ± 4.83, P < 0.001) as were C/D (3.45 ± 2.29 and 3.37 ± 1.91 vs. 6.47 ± 4.44, P < 0.001) and C/D/W (52.45 ± 33.98 and 52.19 ± 32.61 vs. 98.09 ± 73.80, P < 0.001). Cyp3A5 AA and AG had higher rejection rates than GG (20% vs. 13 vs. 8%, P = 0.03). The relative risk of rejection with A versus G polymorphism was 1.9 (confidence interval: 1.03–3.58), P = 0.03. Cyp3A4 and ABCB1 polymorphism studies did not show any association with the parameters studied. Conclusion: Our study showed that Cyp3A5 gene polymorphisms were significantly associated with tacrolimus metabolism, rejection episodes, and rejection risk. Cyp3A4 and ABCB1 were not significantly associated with the parameters studied.

Tacrolimus toxicity in a liver-kidney transplant patient receiving Nirmatrelvir/Ritonavir for COVID-19

Due to the rapid approval of some of the newer therapies for COVID-19 infection, there are several pharmacologic aspects of these therapies that are not fully known, including drug-drug interactions. Transplant recipients face notable risks in relation to these interactions. This article outlines complications arising from the concurrent administration of nirmatrelvir/ritonavir and tacrolimus in a patient with history of combined kidney and liver transplantation. Additionally, it highlights the effective utilization of phenytoin as an inducer to correct the supratherapeutic levels of tacrolimus.

Abstract 17626: Apolipoprotein A-IV-Associated Cardiac Amyloidosis: A Classic Presentation of a Rare Condition

Introduction: A 65-year-old male with type one diabetes mellitus underwent a pancreas and kidney transplant approximately seven years ago and has received chronic tacrolimus. He presented with subacute dyspnea on exertion, orthopnea, and edema. His background also includes ongoing chronic kidney disease stage 3A, orthostatic hypotension, and spinal stenosis. On exam, he had abdominal and lower extremity swelling. An echocardiogram showed preserved LVEF, concentric hypertrophy, hyperrefractile myocardium, reduced longitudinal strain with apical sparing, and a tiny pericardial effusion. Hypothesis: His echocardiogram indicated an infiltrative process such as amyloidosis or tacrolimus cardiotoxicity or possibly hypertrophic cardiomyopathy. Methods: Free light chains and protein studies with mass-fixation demonstrated no monoclonal gammopathy. PYP scan was negative for transthyretin amyloidosis. A cardiac MRI showed patchy subendocardial and midmyocardial delayed gadolinium enhancement, supporting the clinical suspicion for cardiac amyloidosis. With the need to exclude tacrolimus toxicity as well, subsequent endomyocardial biopsy revealed apolipoprotein A-IV-associated cardiac amyloidosis (Figure 1). Results: Apolipoprotein A-IV-associated cardiac amyloidosis occurs in about 0.6% of patients with cardiac amyloid and has classic manifestations of LV outflow obstruction, microvascular disease, and especially renal insufficiency. When these features occur in patients with clinical and imaging findings suggesting cardiac amyloidosis despite negative testing for more common types of amyloidosis, clinicians should proceed with endomyocardial biopsy to evaluate for less common forms. Conclusions: We report a rare case of apolipoprotein A-IV-associated cardiac amyloidosis. This case highlights the need for endomyocardial biopsy when clinical suspicion for cardiac amyloidosis persists despite negative testing.

The impact of CYP3A4 and CYP3A5 genetic variations on tacrolimus treatment of living-donor Egyptian kidney transplanted patients.

Tacrolimus (TAC) is the mainstay of immunosuppressive regimen for kidney transplantations. Its clinical use is complex due to high inter-individual variations which can be partially attributed to genetic variations at the metabolizing enzymes CYP3A4 and CYP3A5. Two single nucleotide polymorphisms (SNPs), CYP3A4*22 and CYP3A5*3, have been reported as important causes of differences in pharmacokinetics that can affect efficacy and/or toxicity of TAC. Investigating the effect of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration in Egyptian renal recipients. Overall, 72 Egyptian kidney transplant recipients were genotyped for CYP3A4*22 G>A and CYP3A5*3 T>C. According to the functional defect associated with CYP3A variants, patients were clustered into: poor (PM) and non-poor metabolizers (Non-PM). The impact on dose adjusted through TAC concentrations (C0) and daily doses at different time points after transplantation was evaluated. Cyp3A4*1/*22 and PM groups require significantly lower dose of TAC (mg/kg) at different time points with significantly higher concentration/dose (C0/D) ratio at day 10 in comparison to Cyp3A4*1/*1 and Non-PM groups respectively. However, CyP3A5*3 heterozygous individuals did not show any significant difference in comparison to CyP3A5*1/*3 individuals. By comparing between PM and Non-PM, the PM group had a significantly lower rate of recipients not reaching target C0 at day 14. This is the first study on Egyptian population to investigate the impact of CYP3A4*22 and CYP3A5*3 SNPs individually and in combination on the TAC concentration. This study and future multicenter studies can contribute to the individualization of TAC dosing in Egyptian patients.

A Rare and Complex Case of Multifactorial Thrombotic Microangiopathy in A Kidney Transplant Recipient: Interplay Between Antibody Mediated Rejection, Tacrolimus Toxicity, Cytomegalovirus Disease and BNT162b2mRNA Vaccine

Thrombotic microangiopathy (TMA) in kidney transplant recipients is uncommon and difficult to manage, often with poor graft outcomes [1]. This is a complex and interesting case of an older, highly sensitised kidney transplant recipient who presented with <em>de novo</em> post-transplant TMA in the setting of antibody mediated rejection (ABMR), with other drivers being tacrolimus toxicity, cytomegalovirus (CMV) infection and anti-SARS-CoV-2 BNT162b2 mRNA vaccination. This led to rapid, irrecoverable graft loss. 76-year-old female presenting three years post deceased donor renal transplant with ABMR. Her three-year course post-transplant was complicated with further opportunities for sensitisation. Firstly, with two discrete episodes of CMV disease requiring alteration in immunosuppression regimen. Secondly, she had a biopsy-confirmed episode of cell mediated rejection after switching from tacrolimus to everolimus due to tacrolimus toxicity. Finally, her admission with fulminant rejection was preceded by almost 6 months of sub-therapeutic tacrolimus levels. 4 weeks prior to this admission, the patient also had her second dose of BNT162b2 mRNA vaccine. Her graft function deteriorated rapidly, with final transplant biopsy showing severe TMA with graft infarct. This case illustrates a complex case of a highly sensitised patient with a difficult post-transplant course who unfortunately suffered a very severe episode of ABMR-associated TMA after further sensitisation during her post-transplant course, with other drivers including CNI toxicity and CMV disease as well as potential further immune stimulation from BNT162b2 mRNA vaccine.

Effect of Genetic Polymorphism on Clinical Efficacy of Tacrolimus in Adult Living Donor-Liver Transplant Patients

Background and Aim The influence of genetic polymorphism on the clinical outcome including response and safety of immunosuppression in liver transplant (LT) recipients remains controversial among different races and ethnicities, especially for calcineurin inhibitors (CNIs). This study aims to evaluate the effect of different genotypes of the single nucleotide polymorphism (SNP) in the genes encoding CYP3A5 on the therapeutic response to the widely used calcineurin inhibitor; tacrolimus. Method In 49 living donor liver transplant (LDLT) recipients with tacrolimus as the backbone immunosuppressive, the rejection, delayed graft function, laboratory evidenced nephrotoxicity, new onset diabetes and hypertension rates were considered the primary therapeutic and safety outcomes of tacrolimus. The biochemical parameters of tacrolimus response and safety as evidence by the status of liver functions, renal functions, complete blood counts and serum electrolytes, as well as the need for Mycophenolate mofetil (MMF) were considered the secondary outcomes. Results the rejection and delayed graft function rates didn’t differ significantly among different genotypes (p = 1), similarly; the incidence of new onset diabetes and hypertension didn’t differ significantly among different genotypes (p = 1, and 0.4143 respectively). Moreover; laboratory evidenced nephrotoxicity rates didn’t differ significantly among different genotypes (p = 0.5040). No significant intergenotype differences were observed in the all biochemical outcomes. However the need for MMF was significantly higher among carriers of the CYP3A5*3 allele. Conclusion different genotypes did not offer an advantage over one another in predicting therapeutic response or toxicity of tacrolimus among LDLT recipients.

Artificial Neural Network Analysis of Determinants of Tacrolimus Pharmacokinetics in Liver Transplant Recipients.

The efficacy and toxicity of tacrolimus are closely related to its trough blood concentrations. Identifying the influencing factors of pharmacokinetics of tacrolimus in the early postoperative period is conducive to the optimization of the individualized tacrolimus administration protocol and to help liver transplant (LT) recipients achieve the target blood concentrations. This study aimed to develop an artificial neural network (ANN) for predicting the blood concentration of tacrolimus soon after liver transplantation and for identifying determinants of the concentration based on Shapley additive explanation (SHAP). In this retrospective study, we enrolled 31 recipients who were first treated with liver transplantation from the Department of Liver Transplantation and Hepatic Surgery, the First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital) from November 2020 to May 2021. The basic information, biochemical indexes, use of concomitant drugs, and genetic factors of organ donors and recipients were used for the ANN model inputs, and the output was the steady-state trough concentration (C0) of tacrolimus after oral administration in LT recipients. The ANN model was established to predict C0 of tacrolimus, SHAP was applied to the trained model, and the SHAP value of each input was calculated to analyze quantitatively the influencing factors for the output C0. A back-propagation ANN model with 3 hidden layers was established using deep learning. The mean prediction error was 0.27 ± 0.75 ng/mL; mean absolute error, 0.60 ± 0.52 ng/mL; correlation coefficient between predicted and actual C0 values, 0.9677; and absolute prediction error of all blood concentrations obtained by the ANN model, ≤3.0 ng/mL. The results indicated that the following factors had the most significant effect on C0: age, daily drug dose, genotype at CYP3A5 polymorphism rs776746 in both recipient and donor, and concomitant use of caspofungin. The predicted C0 value of tacrolimus in LT recipients increased in a dose-dependent manner when the daily dose exceeded 3 mg, whereas it decreased with age when LT recipients were older than 48 years. The predicted C0 was higher when recipients and donors had the genotype CYP3A5*3*3 than when they had the genotype CYP3A5*1. The predicted C0 value also increased with the use of caspofungin or Wuzhi capsule. The established ANN model can be used to predict the C0 value of tacrolimus in LT recipients with high accuracy and good predictive ability, serving as a reference for personalized treatment in the early stage after liver transplantation.

Reversal of uniocular blindness with corticosteroids in a solid organ transplant recipient with cryptococcal meningitis and immune reconstitution syndrome (IRIS): A case report

Cryptococcal meningitis is a life-threatening infection commonly seen in patients with advanced HIV infection and solid organ transplant recipients. We report a case of cryptococcal meningitis with immune reconstitution syndrome (IRIS) who presented to us with a headache and complete loss of vision in the left eye. He was managed with antifungals and a short course of steroids, and he regained vision completely. In the hospital, he developed complications including tacrolimus toxicity, fluconazole-induced QT prolongation, and flucytosine-induced thrombocytopenia. Our case demonstrates the importance of a multidisciplinary approach in the management of complex cases like cryptococcal meningitis in solid organ transplant recipients.

Prediction of diabetes mellitus after kidney transplantation using patient-specific induced pluripotent stem cells.

Multiple risk factors are involved in new-onset diabetes mellitus (DM) after organ transplantation; however, their ability to predict clinical prognosis remains unclear. Therefore, we investigated whether patient-specific induced pluripotent stem cells (iPSCs) could help predict DM development before performing kidney transplantation (KT). We first performed whole transcriptome and functional enrichment analyses of KT patient-derived iPSCs. Our results revealed that insulin resistance, type 2 DM, and transforming growth factor beta signaling pathways are associated between the groups of DM and non-DM. We next determined whether the genetic background was associated with development of iPSCs into pancreatic progenitor (PP) cells. The levels of differentiation-related key markers of PP cells were significantly lower in the DM group than in the non-DM group. Moreover, the results of tacrolimus toxicity screening showed a significant decrease in the number of PP cells of the DM group compared with the non-DM group, suggesting that these cells are more susceptible to tacrolimus toxicity. Taken together, these results indicate that PP cells of the DM group showed low developmental potency accompanied by a significantly different genetic background compared with the non-DM group. Thus, genetic analysis can be used to predict the risk of DM before KT.

Pathway-level multi-omics analysis of the molecular mechanisms underlying the toxicity of long-term tacrolimus exposure

Tacrolimus (TAC)-based treatment is associated with nephrotoxicity and hepatotoxicity; however, the underlying molecular mechanisms responsible for this toxicity have not been fully explored. This study elucidated the molecular processes underlying the toxic effects of TAC using an integrative omics approach. Rats were sacrificed after 4 weeks of daily oral TAC administration at a dose of 5 mg/kg. The liver and kidney underwent genome-wide gene expression profiling and untargeted metabolomics assays. Molecular alterations were identified using individual data profiling modalities and further characterized by pathway-level transcriptomics-metabolomics integration analysis. Metabolic disturbances were mainly related to an imbalance in oxidant-antioxidant status, as well as in lipid and amino acid metabolism in the liver and kidney. Gene expression profiles also indicated profound molecular alterations, including in genes associated with a dysregulated immune response, proinflammatory signals, and programmed cell death in the liver and kidney. Joint-pathway analysis indicated that the toxicity of TAC was associated with DNA synthesis disruption, oxidative stress, and cell membrane permeabilization, as well as lipid and glucose metabolism. In conclusion, our pathway-level integration of transcriptome and metabolome and conventional analyses of individual omics profiles, provided a more comprehensive picture of the molecular changes resulting from TAC toxicity. This study also serves as a valuable resource for subsequent investigations aiming to understand the mechanism underlying the molecular toxicology of TAC.

DRUG INTERACTION BETWEEN PAXLOVID AND TACROLIMUS IN AN ADOLESCENT WITH INFLAMMATORY BOWEL DISEASE

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient’s UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml . Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL. Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.

75 Paxlovid-Induced Tacrolimus Toxicity in Kidney Transplant Recipients

75 Paxlovid-Induced Tacrolimus Toxicity in Kidney Transplant Recipients