Tacrolimus Toxicity Research Articles

A248 OUTCOMES OF COVID-19 ILLNESS AND ACCESS TO APPROPRIATE TREATMENT IN LIVER TRANSPLANT RECIPIENTS IN BRITISH COLUMBIA THROUGHOUT THE PANDEMIC

Abstract Background COVID-19 continues to cause significant illness and mortality worldwide. Solid Organ Transplant Recipients (SOTR) have a higher rate of COVID-19 infection and worse outcomes than those who are immunocompetent. Dexamethasone, tocilizumab, and baricitinib have improved inpatient outcomes. Sotrovimab, remdesivir, and nirmatrelvir/ritonavir have recently been approved for used in high risk, minimally symptomatic outpatients. Previous experience has shown that use of monoclonal antibodies and oral antiviral agents have reduced morbidity and mortality of COVID-19 in SOTR. Purpose To assess the experiences and outcomes of COVID-19 and access to directed therapy in SOTR in British Columbia (BC). Method Data was compiled from patient disclosure to liver transplant clinicians on COVID-19 infection and gathered from patient charts in the SOTR Clinic at Vancouver General Hospital. Inclusion criteria were patients followed at the clinic with a positive COVID-19 test or clinical confirmation of COVID-19 syndrome. This is a retrospective, quality assurance study and did not require ethics review. Result(s) 158 SOTR reported COVID-19 infections between March 2020 and September 2022. 3 patients died within 30 days of COVID-19 infection, 2 (1.26%) of which the cause of death was directly due to COVID-19, and the other who had cholangitis with severe sepsis and multi-organ system failure. 24 patients required admission to hospital, 7 requiring critical care support. 41 patients did not receive any therapy for COVID-19: there was none available at that time (n=26), it was contraindicated due to a drug interaction (n=2) or medical condition (n=1), was refused (n=1), or the infection was reported too late to qualify (n=10). 83% (92/112) of outpatients received available anti-viral treatment: sotrovimab (n=27), remdesivir (n=63), or nirmatrelvir/ritonavir (n=2). In inpatients (n=24), 13 received corticosteroids, 6 dual treated with tocilizumab (n=4) or baracitinib (n=2). 4 inpatients received remdesivir. Three patients were treated in hospital after initiating outpatient therapy, one with progression of COVID-19 illness despite starting remdesivir. Two patients had adverse effects of medications provided: one was prescribed nirmatrelvir/ritonavir by a physician outside of the transplant program, which caused tacrolimus toxicity (serum concentration of 69.4 ng/mL) with nausea, vomiting, and diarrhea. Another patient had an episode of hypotension after receiving sotrovimab and sustained an acute kidney injury (AKI). Both patients fully recovered. There were no deaths on antiviral therapy. Of 145 patients who had laboratory investigations done within 30 days of COVID-19 infection, 16 had a transient rise in liver enzymes, 14 had an AKI and 11required an adjustment in their tacrolimus dose. Conclusion(s) Involving the liver transplant team early in the course of COVID-19 illness allows patients to safely access COVID-19 directed therapy to avoid progression of illness, and medication interactions or toxicity. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Tacrolimus Toxicity in Two Renal Transplant Recipients Treated With Nirmatrelvir/Ritonavir: A Case Series

Since the onset of the SARS-CoV-2 (COVID-19) pandemic, significant effort has been devoted toward developing therapeutics that decrease the morbidity and mortality of COVID-19 infection. The antiviral nirmatrelvir/ritonavir (Paxlovid) has shown success in reducing hospitalization and death in patients with mild-to-moderate COVID-19 infection. However, enthusiasm over nirmatrelvir/ritonavir's ability has been met with caution as the result of potential drug–drug interactions. Here, we present 2 cases of tacrolimus toxicity, both in renal transplant recipients, following nirmatrelvir/ritonavir use. These cases are significant because, although the potential for pharmacologic interactions with nirmatrelvir/ritonavir is known, few cases of actual harm have been documented.

WCN23-0456 HIGH ON TACROLIMUS - A case of Tacrolimus toxicity due to CBD oil

WCN23-0456 HIGH ON TACROLIMUS - A case of Tacrolimus toxicity due to CBD oil

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

Abstract 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. CASE REPORT: 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 DISCUSSION: 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.

CYP3A5 Polymorphisms Leading to Tacrolimus Toxicity Following an Adult Renal Transplant.

Tacrolimus is one of the calcineurin inhibitors used for maintaining immuno-suppression in thoracic and abdominal transplantations including heart, lung, liver, intestine, pancreas, and renal transplants. It has a narrow therapeutic window requiring therapeutic drug monitoring (TDM). Genetic polymorphism in the expression of cytochrome P3A5 enzyme plays a significant role in the bioavailability of tacrolimus in patients, leading to toxicity or rejection. In this case, we studied a renal transplant patient who received a standard dose of tacrolimus and experienced toxicity related to the poor expression of cytochrome P450 3A5 (CYP3A5), which required the withholding of tacrolimus and cutting the dose for several days with more frequent TDM. Similar cases have been reported before, yet there is no consensus on the appropriate dosage. The projected cost of additional TDM and hospitalization significantly exceeds the one-time cost of genetic CYP3A5 testing. In high-risk renal transplant recipients, pharmacogenetic testing must be considered to cut the time to limit TDM, prevent extended hospitalization, and reduce the total cost of transplantation.

A Low Tacrolimus Concentration-to-Dose Ratio Increases Calcineurin Inhibitor Nephrotoxicity and Cytomegalovirus Infection Risks in Kidney Transplant Recipients: A Single-Center Study in Japan

Tacrolimus (TAC) has several problems due to its narrow therapeutic window and variations pharmacokinetics and pharmacodynamics. Recently, several studies reported that TAC metabolism, defined by TAC blood trough concentration to dose (C/D) ratio, was associated with TAC toxicity. Reports on once-daily extended-release TAC (TAC-ER) are limited. The present study aimed to investigate the effect of the TAC metabolic rate on TAC-ER and compare TAC area under the curve (AUC) between fast and slow metabolizers. A total of 58 recipients were included in this study. The optimal cut-off value and time of the C/D ratio on TAC-ER for fast and slow metabolizers was determined using receiver operating characteristic curve analysis for biopsy-proven calcineurin inhibitor (CNI) nephrotoxicity. The optimal time to evaluate the C/D ratio was 1 month after kidney transplantation (KT) and the cut-off value was 0.9. The multivariate analysis for CNI nephrotoxicity risk showed that only TAC metabolism was associated with CNI nephrotoxicity (hazard ratio 10.60, P=.005, 95% CI 2.03-55.22). Cytomegalovirus infection occurred more frequently in fast metabolizers when the cut-off value of the C/D ratio was set to 0.9 at 3 months after KT (P=.04). The TAC C4, AUC2-8, was higher in fast metabolizers than in slow metabolizers (P < .01, P=.03, respectively). The study revealed that TAC fast metabolizers on TAC-ER may be classified as a high-risk group for CNI nephrotoxicity and cytomegalovirus infection. The result of TAC AUC supported the hypothesis that fast metabolizers tended to be overexposed to immunosuppressive agents early after oral administration.

Utility of protocol biopsy in the management of renal allograft recipients

Background: Many studies suggest that early rejection episodes and chronic changes in the allograft kidneys were often subclinical without a concomitant rise in the serum creatinine or proteinuria. Early identification of subclinical pathology by doing protocol biopsy and appropriate intervention is likely to improve long-term graft outcomes. However, it is often not done, out of concern about the procedure-related complications. Methods: All patients who underwent live donor kidney transplantation at Aster Medcity from September 2019 to August 2021 with stable graft function were included in the study. Stable graft function is defined as variation in the creatinine values of <25% from the nadir creatinine. Protocol biopsies were taken at 3 months after transplant surgery. Biopsies were done using spring-loaded biopsy guns percutaneously under ultrasound guidance, and patients were observed for 24 h in the hospital for any complication. Biopsies were analyzed by light microscopy and C4d staining and scored based on the Banff classification 2017 update. Results: Seventy patients underwent protocol kidney biopsy at a prespecified time of 3 months. Majority of our patients (74.3%) received a kidney from the first-degree blood relatives, and the rest (25.7%) of the patients received kidneys from spouses. Induction therapy was given in 57% of the patients, and the rest (43%) were transplanted without an induction agent. Of 70 specimens studied, 44 (62.9%) had normal histology and 26 (37.1%) had varying degrees of histological abnormalities. Thirteen (18.6%) had evidence of subclinical rejection, of which 12 (17.2%) showed borderline rejection and 1 (1.4%) had acute T-cell-mediated rejection (acute TCMR). Other histological findings include chronic active TCMR in 1 (1.4%), varying degrees of interstitial fibrosis and tubular atrophy in 5 (7.1%), evidence of BK virus nephropathy in 2 (2.8%), features of tacrolimus toxicity in 2 (2.8%), and acute interstitial nephritis in one patient. None of the patients developed any complication after the procedure. With appropriate treatment interventions, all patients had stable graft functions at 6-month follow-up. Conclusions: Protocol graft biopsy under real-time ultrasound guidance has a very good safety profile and can help the clinician optimize the immunosuppression with more precision, and on a long term, it might prove cost effective to the patient.

Pediatric liver transplantation for autoimmune liver disease: Ten-year experience from a liver transplant center in India.

Liver transplantation (LT) has emerged as the best therapeutic modality for end-stage liver disease in pediatric autoimmune liver disease (AILD). We aimed to describe our experience of pediatric living donor liver transplantation for AILD from India over a period of 10 years.We did a retrospective analysis of 244 liver transplants at our center over the last 10 years to identify children with AILD (18 years or younger). We aimed to describe the demographic features, clinical profile, graft survival, patient outcome, and predictors of mortality in our cohort.Between July 2010 and May 2020, 13 liver transplants were performed for AILD out of total 244 children transplanted over the last 10 years at our center. Mean (standard deviation [SD]) age at LT was 12 (± 3.84) years. Leading indications for LT were decompensated liver disease (61.5%), acute-on-chronic liver failure (23.1%), acute liver failure (ALF) (7.7%), and recurrent cholangitis and growth failure (7.7%). Mean Pediatric End-stage Liver Disease (PELD) score/model for end-stage liver disease (MELD) score and international normalized ratio (INR) (SD) at presentation were 24 (± 12.81) and 2.48 (± 1.54), respectively. Median discharge duration was 23 days (interquartile range [IQR] 21-36 days). 30.7% (4/13) of the subjects had no postoperative complications. Diarrhea (15.3%), pneumonia (7.7%), jejunostomy site bleed (7.7%), tacrolimus toxicity (7.7%), and vascular complications (7.7%) were seen, which resolved with satisfactory graft function. Three subjects died post-LT; causes of death included sepsis (n=3), renal dysfunction (n=1), and pneumonia (n=1). Others have been well on follow-up with no graft rejection or need for re-transplantation. Overall, 1-year and 5-year patient survival rates were 76.9% and 70%, respectively. Lower platelet count, autoimmune hepatitis (AIH) 2, and PELD/MELD score were found to be significant predictors of mortality on univariate analysis, which were not significant on multivariate modelling.Thecomplications, graft and patient survival rates in our experience were quite encouraging, and are comparable with the best centers worldwide. After instituting appropriate treatment, early referral of such patients to an equipped center should be facilitated.

Purtscher-like retinopathy in a patient with systemic tacrolimus vasculopathy.

Purtscher-like retinopathy is a rare occlusive retinal microangiopathy, whose pathogenesis has not been totally defined yet. Most frequent cause of Purtscher-like retinopathy is acute pancreatitis, but it may be triggered by other systemic or toxic conditions. We report herein a case of Purtscher-like retinopathy in the context of systemic tacrolimus vasculopathy. A 56-years old male with history of kidney transplant was referred to local emergency room because of a global worsening of health conditions, with fatigue, muscular pain and diuresis contraction. During hospitalization the patient came to our attention for sudden and severe visual acuity impairment in both eyes. Extensive ophthalmological assessment, optical coherence tomography (OCT) and fluorescein angiography (FA) were performed disclosing a marked drop in best corrected visual acuity (BCVA) (20/200 in the right eye and 10/400 in the left eye) caused by a bilateral severe occlusive retinal microangiopathy complicated by diffuse retinal ischaemia and neovascular glaucoma. Muscular biopsy showed a necrotizing myopathy with autoimmune features, as indicated by conspicuous upregulation of MHC-I complex and microangiopathic changes, consistent with tacrolimus toxicity. Tacrolimus administration was interrupted, and intravenous glucocorticoids were administered. The large areas of retinal ischemia and neovascular glaucoma were treated with pan-retinal photocoagulation and intravitreal injections of bevacizumab with complete regression of iris neovascolarization. BCVA measured 20/200 in both eyes at last follow-up visit, 20 months after symptoms onset. Purtscher-like retinopathy should be suspected in patients under treatment with calcineurin inhibitors especially in case of sudden and severe bilateral visual impairment.

Treatment of acute tacrolimus toxicity with phenytoin after Paxlovid (nirmatrelvir/ritonavir) administration in a kidney transplant recipient.

Treatment of acute tacrolimus toxicity with phenytoin after Paxlovid (nirmatrelvir/ritonavir) administration in a kidney transplant recipient.

Nirmatrelvir/ritonavir Use With Tacrolimus in Lung Transplant Recipients: A Single-center Case Series.

Limited data and guidelines exist for using nirmatrelvir/ritonavir in solid organ transplant recipients stabilized on tacrolimus for the treatment of mild-to-moderate coronavirus disease. Concern exists regarding the impact of utilizing a 5-d course of nirmatrelvir/ritonavir with calcineurin inhibitors because of significant drug-drug interactions between ritonavir, a potent cytochrome P450 3A inhibitor, and other cytochrome P450 3A substrates, such as tacrolimus. We report the successful use of nirmatrelvir/ritonavir in 12 outpatient lung transplant recipients with confirmed severe acute respiratory syndrome coronavirus 2 infection stabilized on tacrolimus immunosuppression. All patients stopped tacrolimus and started nirmatrelvir/ritonavir 10 to 14 h after the last dose of tacrolimus. Tacrolimus was withheld and then reinitiated at a modified dose 48 h following the completion of nirmatrelvir/ritonavir therapy. Tacrolimus trough levels were checked during nirmatrelvir/ritonavir therapy and tacrolimus reinitiation. Ten (10/12) patients were able to resume their original tacrolimus dose within 4 d of completing nirmatrelvir/ritonavir therapy and maintain therapeutic levels of tacrolimus. No patients experienced tacrolimus toxicity or acute rejection during the 30-d postcompletion of nirmatrelvir/ritonavir therapy. In this cohort of lung transplant recipients on tacrolimus, we demonstrated that nirmatrelvir/ritonavir can be safely used with close monitoring of tacrolimus levels and appropriate dose adjustments of tacrolimus. Further confirmatory studies are needed to determine the appropriate use of therapeutic drug monitoring and tacrolimus dose following completion of nirmatrelvir/ritonavir in the solid organ transplant population.

Letermovir for cytomegalovirus prophylaxis in high-risk heart transplant recipients.

Letermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high-risk mismatch (CMV D+/R-). Median time on letermovir was 5 months (interquartile range, 2-8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre-emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low-level non-clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

S1681 Pancreatitis Secondary to Paxlovid-Induced Tacrolimus Toxicity

Introduction: Pancreatitis is a very common gastrointestinal disease that results in hospital admission. Early detection and treatment leads to better outcomes. This is the first reported case of pancreatitis secondary to elevated tacrolimus in a patient with prior renal transplantation after receiving Paxlovid for a COVID-19 infection. Case Description/Methods: A 57-year-old male with past medical history of 4 renal transplants secondary to posterior urethral valves who presented to the emergency room with acute onset epigastric pain for 24 hours. He was on tacrolimus 5 mg every 48 hours monotherapy for his immunosuppression. 10 days prior to his presentation he had developed chills and anxiety. He tested positive for COVID-19 at that time on a home rapid test. His symptoms had not significantly improved and given his immunosuppressed state he was given Paxlovid (Nirmatrelvir/ritonavir). He took 2 days of Paxlovid, however after his second day of treatment he developed severe epigastric pain requiring him to go to the emergency room. On admission his labs were notable for a lipase of 150 U/L (ULN 63 U/L). He underwent a CT scan was notable for an enlarged pancreatic head and neck with peripancreatic fat stranding (Figure). He also had a right upper quadrant ultrasound without any cholelithiasis and only trace sludge noted. His creatinine was noted to be 1.81 mg/dl which was above his baseline of 1.2 mg/dl. His tacrolimus trough level resulted at a level 45.6 ng/ml and later peaked at 82.2 ng/ml. His liver enzymes were normal. He was treated as acute pancreatitis with hydration and his tacrolimus was held with overall clinical improvement. Discussion: Tacrolimus is one of the most common medications used in solid organ transplantation. It is a calcineurin inhibitor that inhibits both T-lymphocyte signal transduction and IL-2 transcription. It is metabolized by the protein CYP3A and levels are monitored closely. Paxlovid is currently prescribed as an antiviral therapy for COVID-19 infection. The ritonavir compound in Paxlovid is potent inhibitor of CYP3A. Currently the guidelines do not recommend Paxlvoid as a therapeutic in patients taking tacrolimus as there is concern about increased drug levels. There have been several case reports of pancreatitis in setting of tacrolimus. This case report helps to demonstrate the need for close monitoring of therapeutics levels, especially in medications with high risk of drug to drug interaction to help prevent serious side effects such as tacrolimus induced pancreatitis.Figure 1.: Axial image of acute pancreatitis. Noted enlarged pancreatic head and neck with peripancreatic fat stranding

Paxlovid with Caution: Novel Case of Paxlovid-Induced Tacrolimus Toxicity in a Cardiac Transplant Patient.

Tacrolimus is commonly used as a prophylactic against acute rejection in transplant patients. Tacrolimus toxicity has numerous presentations that have been well documented in the literature and can be induced by a wide variety of agents. We present a novel case of tacrolimus toxicity in a cardiac transplant patient induced by outpatient treatment for COVID-19 pneumonia with ritonavir-nirmatrelvir, which was successfully treated with phenytoin therapy.LEARNING POINTSRitonavir-nirmatrelvir is a newly approved antiviral therapy for COVID-19 to prevent hospitalization and is increasingly prescribed in the outpatient setting.Thorough assessment of drug interactions prior to starting ritonavir-nirmatrelvir can prevent tacrolimus toxicity in patients with solid organ transplants.Phenytoin increases the metabolism of tacrolimus and can be safely utilized to treat tacrolimus toxicity.

The pharmacokinetic study of tacrolimus and Wuzhi capsule in Chinese liver transplant patients.

Objectives: Wuzhi Capsule (WZC) is often administrated with tacrolimus in liver transplant patients to reduce the toxicity of tacrolimus and relieve the financial burden of patients. We aimed to investigate the interaction between Wuzhi Capsule (WZC) and tacrolimus in liver transplant patients. Methods: We applied the LC-MS/MS analytical method previously established to study the pharmacokinetic characteristics of the analytes in 15 liver transplant patients. CYP3A5 genotypes were determined in 15 donors and recipients, and they were categorized into CYP3A5 expressers and non-expressers respectively. Results: The influences of CYP3A5 in donors and recipients on the pharmacokinetics of tacrolimus with or without WZC were also studied. We found that 1) WZC could influence the metabolism of tacrolimus, which shortened the Tmax of tacrolimus and decreased V/F and CL/F. 2) Moreover, our results showed that, in donors, the CL/F of tacrolimus were significantly lower in CYP3A5 (CYP3A5*1) expressers (decreased from 24.421 to 12.864) and non-expressers (decreased from 23.532 to 11.822) when co-administration with WZC. For recipients, the decreased trend of CL/F of tacrolimus was seen when co-administrated with WZC by 15.376 and 12.243 in CYP3A5 expressers and non-expressers, respectively. Conclusion: In this study, the pharmacokinetics effects of WZC on tacrolimus were identified. The co-administration of WZC can increase the tacrolimus blood concentration in Chinese liver transplant patients in clinical practice.

P15.01: Posterior Reversible Encephalopathy Syndrome in Transplant Patients: Diagnosis and Management

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a rare neurotoxic status composed of own brain imaging patterns. Depending on the location of the lesion, is characterized by a wide scale of neurologic symptoms. Although, the main cause of PRES is not fully enlightened, it is shown that, especially in solid organ transplant patients due to calcineurin inhibitors (CNI) toxicity, severe hypertension and any kind of infections are strongly related with PRES. The current therapy accepted is only supportive care. In this study we aim to evaluate diagnosis and management of PRES in our transplant patients. Method: From 3 November 1975 to 31 December 2021, we performed 3288 kidney transplant, 701 liver transplant and 142 heart transplants. Among these transplants 381 patient in kidney,334 patient in liver and 70 patients in heart were pediatric. 785 pediatric transplant patients were examined, and PRES was observed in 12 pediatric patients with median age 12 years (5 month - 18 year). 6 (50%) of these patients were male and median BMI is 18,5 (12,4 - 28,9). The radiology report database was analyzed for patients which PRES was cited in brain MR imaging text reports. Cases of PRES were included and searched for demographic values, laboratory values, clinical presentation, immunosuppressive they use, management we made and results. Results: Among PRES cases, 6 (50%) patients were liver transplant, 4 (33%) were kidney transplant and 2 (17%) were heart transplant patients. %66,5 (n:8) of the patients were using Tacrolimus as immunosuppressant. Causes of PRES were toxicity of Tacrolimus in 3 (25%) patients, hypertension in 4 (33%) patients, sepsis in 2 (16%) patients, hypomagnesemia in 1(8,5%) patient, hyponatremia in 1 (8,5%) patient and cyclosporine toxicity in 1(8,5%) patient. Symptoms of PRES were Seizure in 8 (66,5%) patients, vision change in 3 (25%) patients, status epilepticus in 1 (8,5%) patient and nausea/ vomiting in 1 (8,5%) patient. The average time between transplant and the diagnosis of PRES was 23 days (2 - 27 days). In brain MRI edema (n:5), hemorrhagic lesions (n:4), ischemia (n:1) and brain infarction (n:1) were observed. As medical treatment all patients consulted with pediatric neurology. Patients having hypertension (n:4) are treated with antihypertensives ACEİ combined with calcium canal blockers. Seizure is controlled with hydantoin at early period and levetiracetam (36.9 mg/kg/day) as maintenance treatment. Patients having hypertension are taken to hemodialysis. Also, patients related with tacrolimus toxicity (n:3) were switched to cyclosporine and the patient who had cyclosporine toxicity was switched to tacrolimus. End of the treatment period all patients were discharged successfully. Conclusion: PRES is a rare diagnosis which is having an unknown etiology and due to that doesn’t have a proven management strategy. When the patient is suspected of PRES, MRI should be performed immediately, in order to avoid complications, achieve a better recovery and treat PRES successfully.

242.7: Influence of CYP3A5 Polymorphisms on Tacrolimus Dosing in Renal Transplant Recipients

Introduction: Tacrolimus is a commonly used immunosuppressant after kidney transplantation it has narrow theraupetic range and demonstrates wide interindividual variability in pharmacokinetics leading to potential under immunosuppression or tacrolimus toxicity genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailibility between individuals. Aim of the study: Ti evaluate pharmacogenomic effect of CYP3A5 gene polymorphisms on tacrolimus dosing in renal transplant recipients. Materials and Methods: Present study we investigated pharmacogenomics associations of common CYP3A5 polymorphisms with requirements of tacrolimus in renal transplant patients: □INCLUSION CRITERIA - 50 patients on tacrolimus based triple immunosuppression were genotyped for cyp3A5 polymorphism most allels- *1/*1,*1/*3,*3/*3 alleles. □EXCLUSION CRITERIA- those patients on CYP inducers or inhibitors were excluded demographic data, weight based tacrolimus doses, serum tacrolimus level at 1 month, 3 months 1 year and present tacrolimus trough level were collected. Data was statistically analysed. Results: Mean age of the recipients was 33.41+/-10.2,72% were males mean tacrolimus level at 1 month was 8ng/ml (7-10ng/ml) at 1 month post transplant cyp *1/*1 was 5.75+_0.95,tac level in cyp3a5 *1/*3 was 9.52∔_1.42,CYP3A5*3/*3 -10.26+_1.02 with significant P VALUE <0.01 among patients with high tac level 36% were poor metabolisers,50% intermediate metabolizers,none of the extensive metabolisers had higher tacrolimus level. At>3 months of transplantation tac level in cyp3a5 *1/*1 was 5.75∔0.95, cyp3a5 *1/*3 was 6.33∓1.17, cyp3a5 *3/*3 was 6.78∔-0.8 with significant P value < 0.01. 56% developed tac toxicity - 84%(*3/*3) poor metabolisers, 14.3% in intermediate *1/*3 metabolisers.125 developed rejections in first three months of transplant,90.755 were extensive metabolisers Discussion: Tacrolimus toxicity as well as rejection due to sub theraupetic levels influence graft outcomes. bioavailibility of tacrolimus varies widely due to gene polymorphisms of CYP3A5 gene. CYP3A5*1/*1 had lower tac level in blood resulting higher rates of rejection requiring 1.5 to 2 times higher dose compared to poor metabolisersand intermediate metabolizers. Poor metabolizers *3/*3 had tacrolimus related toxicity at similar dose adjusted tac levels, indicating lower dose for maintanence (0.06mg/kg). Conclusion: Genotyped based dosing may improve achievement of theraupetic drug concentrations with reduced drug related complications in the era of personalised medicine.

The Use of Machine Learning Algorithms and the Mass Spectrometry Lipidomic Profile of Serum for the Evaluation of Tacrolimus Exposure and Toxicity in Kidney Transplant Recipients.

Tacrolimus has a narrow therapeutic window; a whole-blood trough target concentration of between 5 and 8 ng/mL is considered a safe level for stable kidney transplant recipients. Tacrolimus serum levels must be closely monitored to obtain a balance between maximizing efficacy and minimizing dose-related toxic effects. Currently, there is no specific tacrolimus toxicity biomarker except a graft biopsy. Our study aimed to identify specific serum metabolites correlated with tacrolinemia levels using serum high-precision liquid chromatography–mass spectrometry and standard laboratory evaluation. Three machine learning algorithms were used (Naïve Bayes, logistic regression, and Random Forest) in 19 patients with high tacrolinemia (8 ng/mL) and 23 patients with low tacrolinemia (5 ng/mL). Using a selected panel of five lipid metabolites (phosphatidylserine, phosphatidylglycerol, phosphatidylethanolamine, arachidyl palmitoleate, and ceramide), Mg2+, and uric acid, all three machine learning algorithms yielded excellent classification accuracies between the two groups. The highest classification accuracy was obtained by Naïve Bayes, with an area under the curve of 0.799 and a classification accuracy of 0.756. Our results show that using our identified five lipid metabolites combined with Mg2+ and uric acid serum levels may provide a novel tool for diagnosing tacrolimus toxicity in kidney transplant recipients. Further validation with targeted MS and biopsy-proven TAC toxicity is needed.

Increased Tacrolimus Exposure in Kidney Transplant Recipients With COVID-19: Inflammation-Driven Downregulation of Metabolism as a Potential Mechanism.

Kidney transplant recipients (KTRs) are at increased risk of severe COVID-19 disease compared to the general population. This is partly driven by their use of immunosuppressive therapy, which influences inflammatory responses and viral loads. Current guidelines suggest to withdraw mycophenolate while calcineurin inhibitors are often continued during a COVID-19 infection. However, clinical signs of calcineurin toxicity have been described in multiple COVID-19 positive KTRs. In this report we describe the course of tacrolimus exposure prior to, during, and post COVID-19 in observations from three clinical cases as well as four KTRs from a controlled trial population. We postulate inflammation driven downregulation of the CYP3A metabolism as a potential mechanism for higher tacrolimus exposure. To mitigate the risk of tacrolimus overexposure and toxicity therapeutic drug monitoring is recommended in KTRs with COVID-19 both in the in-, out-patient and home monitoring setting.

Sublingual Administration of Tacrolimus and Cases of Significant Nephrotic and Neurologic Toxicity

<h3>Introduction</h3> This topic warrants consideration due to the popularity of sublingual administration of tacrolimus and the possibility of deleterious effects. There are significantly different characteristics of sublingual tacrolimus compared to oral administration. In bypassing enterohepatic circulation, a greater proportion of circulating tacrolimus may be available in a 'free' form, unbound to proteins and blood cells. This is similar to a rapid intravenous delivery of calcineurin inhibitor which has noted toxicities. <h3>Case Report</h3> (Case 1) A 49 year old male underwent heart transplant without induction, sublingual tacrolimus was started and after two days of trough levels of 5ng/mL or below, the dose was increased to 4mg SL bid, levels increased from to 17.8 ng/mL. While creatinine increased from 1.7 mcg/dL (POD#2) to a peak of 5.1 mcg/dL on POD#6. The patient was otherwise quite stable. Tacrolimus was held temporarily then converted to oral administration. The creatinine eventually recovered to a value of 1.5mg/dL. The average tacrolimus trough level (while receiving oral dosing) during this period of creatinine recovery was 5.9 ng/ML. (Case 2) 64 year old man with ICM received a heart transplant with uneventful operative course and no induction. He received tacrolimus 1mg orally pre-operatively. Then he received 2mg Of the drug sublingually twice daily until POD # 2. On POD#3 he experienced a generalized tonic-clonic seizure that terminated with anticonvulsant therapy. The tacrolimus trough levels rose quickly after the initial tacrolimus sublingual dosing postoperatively, measured at 11.4 ng/mL on POD#2. Neurology recommended a switch to cyclosporine (goal trough level 200-250ng/mL). The patient remained on levetiracetam for 14 days, no further epileptic activity was observed. Renal function during this episode from a creatinine of 1.4 mg/dL on POD#1 to 4.2 mg/dL on POD#3. <h3>Summary</h3> The molecular size of tacrolimus allows for passage into the glomerulus when in the free form. This may also facilitate blood/brain barrier transport. The presented cases provide cause for consideration of possible toxicity of tacrolimus given sublingually, particularly in patients whose levels rise rapidly. Through rapid absorption, the drug may not have sufficient time to bind to proteins and cells before it reaches end organs in which toxicity occurs.