Nirmatrelvir/ritonavir treatment of patients with COVID-19 taking tacrolimus: case series describing the results of drug-drug interactions.

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.

Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

OBJECTIVES: Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. MATERIALS AND METHODS: We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. RESULTS: We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. CONCLUSIONS: In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Does Antibiotic Use Increase the Risk of Post-Transplantation Diabetes Mellitus? A Retrospective Study of Renal Transplant Patients.

BACKGROUND This study aimed to investigate the incidence of post-transplant diabetes mellitus (PTDM) in renal transplant (RT) patients at our center and to explore new risk factors for PTDM. MATERIAL AND METHODS This retrospective study included RT patients from 2010 to 2022. Clinic data on RT patients were obtained from hospital electronic medical records. CYP3A5*3, POR*28, ABCB1 (3435 C>T), and ABCB1 (1236 C>T) were genotyped in RT patients. The associations between age, BMI, concentration of tacrolimus (TAC), polymorphism of genes, antibiotics (eg, penicillins, cephalosporins, oxazolidinones, quinolones), numbers and days of antibiotic use, and PTDM were analyzed. RESULTS In this study, 409 patients with RT were included. The cumulative incidence of PTDM in the first year after RT was 9.05%. The numbers and days of antibiotic use in PTDM patients were significantly higher than those in non-PTDM patients. Multivariate logistic regression analysis identified age (OR=1.047, P=0.014), body mass index (BMI) (OR=1.178, P=0.007), dose-adjusted trough concentration of TAC (TAC C0/D) at 7 days after RT (OR=1.159, P=0.042), trough concentration of TAC (TAC C0) at 28 days after RT (OR=1.094, P=0.042), and levofloxacin (OR=5.975, P=0.003) as independent risk factors for PTDM. CONCLUSIONS In addition to age, BMI, and TAC concentration after RT, antibiotic use may be a novel factor affecting PTDM. The use of antibiotics may influence the development of PTDM.

Evaluation of the effectiveness of using prednisolone, tacrolimus, and intravenous immunoglobulin combination therapy on immune-mediated necrotizing myopathy-A non-randomized, observational research.

OBJECTIVE: To recruit immune-mediated necrotizing myopathy (IMNM) patients with extramuscular manifestations who were refractory to initial therapy with either monotherapy with prednisolone or dual therapy with prednisolone and immunosuppressants. These patients subsequently received a combination of prednisolone, tacrolimus, and intravenous immunoglobulin (IVIG), and the efficacy of this treatment regimen was assessed in patients with IMNM. METHOD: ①Clinical data and treatment measures are as follows: This study enrolled IMNM patients who were treated at the Neurology Department of the First Medical Center of PLA General Hospital from April 2020 to May 2023. These patients received a combination therapy of prednisolone, tacrolimus, and IVIG. ②Observational indicators included manual muscle test for 8 groups of muscles (MMT-8), muscle enzyme levels (creatine kinase (CK), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and myositis disease activity assessment tool (MDAAT). RESULTS: This study enrolled eight patients. All observational indicators declined after treatment compared to before treatment, and these changes were statistically significant. Moreover, extramuscular manifestations also ameliorated compared to before treatment. CONCLUSION: The combination therapy of prednisolone, tacrolimus, and IVIG has demonstrated favorable efficacy in IMNM and broadened the treatment options for this disease. However, the results still require further validation by large-scale and randomized controlled studies.

Early neonatal outcomes in infants of mothers with organ transplantation under immunosuppressive treatment.

BACKGROUND: This study aimed to examine early clinical and laboratory findings in infants born to mothers who had organ transplants and received immunosuppressive treatment. METHODS: Between 2016 and 2023, the study examined infants of mothers who underwent organ transplantation and were receiving immunosuppressive treatment, and followed at the Department of Neonatology at Akdeniz University. Demographic, clinical, and laboratory characteristics of mothers and infants were recorded. On the first day of life, complete blood count values were examined, as well as potassium levels on the first, third, and seventh days, and creatinine levels on the third and seventh days. The tacrolimus blood level was calculated by taking the average of the tacrolimus blood values of the mother measured during the pregnancy. The infants were evaluated for any potential morbidities caused by intrauterine immunosuppressive drug exposure. RESULTS: The study included 21 mothers (some with multiple pregnancies) and 27 infants. According to the findings of this study, 74% of these infants were born premature, 67% had low birth weight, and all were delivered via cesarean section. Prematurity was associated with the morbidities found in the infants. In the early period, lymphopenia was detected in 37%, neutropenia in 25.9%, thrombocytopenia in 11.1%, hyperkalemia in 18.5%, and creatinine elevation in 7.4%, all of which returned to normal within a few days. There was no significant relationship between maternal tacrolimus blood levels and infant potassium and creatinine levels. CONCLUSION: Apart from an increased risk of prematurity, low birth weight, and cesarean delivery, no effects were observed in these infants during the early period. However, long-term follow-up is necessary to monitor for any potential morbidities.

Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome.

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.

A case report of drug interaction between co-packaged nirmatrelvir-ritonavir and tacrolimus causing hyponatremia in a lung transplant recipient.

BACKGROUND: Coronavirus disease 2019 (COVID-19) infection in lung transplant recipients can be lethal owing to the use of immunosuppressants. Antiviral agents may be administered to these patients. Co-packaged nirmatrelvir-ritonavir is a new agent currently being used in combination. CASE PRESENTATION: In this report, we present a case of a 64-year-old woman, a lung transplant recipient, who experienced hyponatremia and showed a high serum tacrolimus concentration following the administration of the co-packaged nirmatrelvir-ritonavir combination. CONCLUSION: Although the nirmatrelvir-ritonavir and tacrolimus combination is not contraindicated, other treatment strategies should be considered first, if available, and the dose of tacrolimus should be reduced when using the nirmatrelvir-ritonavir combination. In cases where combination therapy is necessary, serum tacrolimus levels should be closely monitored in lung transplant recipients. Documentation of more such reports is important to identify drug interactions between nirmatrelvir-ritonavir and other agents, with the aim of preventing severe adverse effects.

Pharmacogenomic implications of the differential distribution of CYP3A5 metabolic phenotypes among Latin American populations.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.

Tacrolimus Drug Exposure Level and Smoking Are Modifiable Risk Factors for Early De Novo Malignancy After Liver Transplantation for Alcohol-Related Liver Disease.

De novo malignancy (DNM) is the primary cause of mortality after liver transplantation (LT) for alcohol-related liver disease (ALD). However, data on risk factors for DNM development after LT are limited, specifically in patients with ALD. Therefore, we retrospectively analyzed all patients transplanted for ALD at our center before October 2016. Patients with a post-LT follow-up of <12 months, DNM within 12 months after LT, patients not on tacrolimus in the 1st year post-LT, and unknown smoking habits were excluded. Tacrolimus drug exposure level (TDEL) was calculated by area under the curve of trough levels in the 1st year post-LT. 174 patients received tacrolimus of which 19 (10.9%) patients developed a DNM between 12 and 60 months post-LT. Multivariate cox regression analysis identified TDEL [HR: 1.710 (1.211-2.414); p = 0.002], age [1.158 (1.076-1.246); p < 0.001], number of pack years pre-LT [HR: 1.021 (1.004-1.038); p = 0.014] and active smoking at LT [HR: 3.056 (1.072-8.715); p = 0.037] as independent risk factors for DNM. Tacrolimus dose minimization in the 1st year after LT and smoking cessation before LT might lower DNM risk in patients transplanted for ALD.

Data mining and safety analysis of traditional immunosuppressive drugs: a pharmacovigilance investigation based on the FAERS database.

OBJECTIVE: The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate mofetil(MMF), cyclophosphamide(CTX) and methotrexate(MTX), which have not been concerned. METHODS: The FAERS data from January 2016 and December 2022 were selected for disproportionality analysis to discover the potential risks of traditional immunosuppressive drugs. RESULTS: Compared with CsA, FK506 has more frequent transplant rejection, and is more related to renal impairment, COVID-19, cytomegalovirus infection and aspergillus infection. However, CsA has a high infection-related fatality rate. In addition, we also found some serious and rare AE in other drugs which were rarely reported in previous studies. For example, AZA is closely related to hepatosplenic T-cell lymphoma with high fatality rate and MTX is strongly related to hypofibrinogenemia. CONCLUSION: The AEs report on this study confirmed that the results were basically consistent with the previous studies, but there were also some important safety signals that were inconsistent with or not mentioned in previous published studies. EXPERT OPINION: The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to improve the safety of immunosuppressive drugs.

Reduced Prevalence of Parkinson's Disease in Patients Prescribed Calcineurin Inhibitors.

Background: Preclinical evidence suggests calcineurin inhibitors (CNIs) combat α-synuclein-induced neuronal dysfunction and motor impairments. However, whether CNIs prevent or treat Parkinson's disease (PD) in humans has never been investigated. Objective: We seek to ascertain if prescription of CNIs is linked to a decreased prevalence of PD in a varied patient population and to glimpse into the mechanism(s) and target site through which CNIs might decrease PD prevalence. Methods: We analyzed electronic health records (EHRs) from patients prescribed the brain penetrant CNI tacrolimus (TAC), the peripherally restricted CNI cyclosporine (CySp), or the non-CNI sirolimus (SIR). For comparison, EHRs from a diverse population from the same network served as a general population-like control. After propensity-score matching, prevalence, odds, and hazards of PD diagnoses among these cohorts were compared. Results: Patients prescribed CNIs have decreased odds of PD diagnosis compared to the general population-like control, while patients prescribed SIR do not. Notably, patients prescribed TAC have a decreased prevalence of PD compared to patients prescribed SIR or CySp. Conclusions: Our results suggest CNIs, especially those acting within the brain, may prevent PD. The reduced prevalence of PD in patients prescribed TAC, compared to patients prescribed SIR, suggests that mechanisms of calcineurin inhibition- other than immunosuppression, which is common to both drugs- are driving the reduction. Therefore, CNIs may provide a promising therapeutic approach for PD.

Tacrolimus-Associated Terminal Ileitis After Kidney Transplantation, Mimicking Crohn Disease: A Case Report.

The onset of gastroduodenal ulcers is a frequent complication after transplantation, whereas cases of intestinal ulcers are sporadic and poorly described in the literature. A patient on immunosuppressive therapy with tacrolimus and mycophenolate mofetil after kidney transplant for immunoglobulin A-related glomerulonephritis developed symptoms compatible with Crohn disease 7 months after the transplant. The patient was hospitalized for abdominal pain, diarrhea, fever, and weight loss. Imaging and a colonoscopy showed signs of idiopathic inflammatory bowel disease (IBD) affecting the terminal ileum. Behcet's disease, post-transplant lymphoma, cytomegalovirus, Epstein-Barr virus, or mycobacteria infection were excluded. Mycophenolate mofetil was suspended, and steroid therapy was increased without clinical improvement. Eleven units of blood were required for severe anemia. A further colonoscopy revealed ulcerations involving the cecal fundus, ileocecal valve, and distal ileum with bowel stenosis and suspected ischemia. The patient, therefore, underwent an emergency laparoscopic ileocolic resection. The histologic examination did not reveal clear signs of IBD, ischemia, or viral infection of the ileum. The findings seemed indicative of iatrogenic damage from immunosuppressive therapy. The postoperative course was regular, and after 12 months, the patient was asymptomatic, on low-dose tacrolimus and prednisone therapy. During immunosuppressive therapy, the onset of isolated ileal ulcers, which can mimic IBD, may be a sporadic complication.

Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

Tumorigenic role of tacrolimus through mTORC1/C2 activation in post-transplant renal cell carcinomas.

BACKGROUND: Kidney transplant recipients (KTRs) face an increased risk of renal cell carcinoma (RCC), in which the immunosuppressive regimen plays an important role. This study aimed to identify intracellular signalling alterations associated with post-transplant (post-tx) tumour formation. METHODS: Expression of mTOR-related proteins were analysed in kidneys obtained from end-stage renal disease (ESRD) patients and RCCs developed in KTRs or non-transplant patients. The effects of tacrolimus (TAC) and rapamycin (RAPA) on mTOR activity, proliferation, and tumour growth were investigated through different in vitro and in vivo experiments. RESULTS: Elevated mTORC1/C2 activity was observed in post-tx RCCs and in kidneys of TAC-treated ESRD patients. In vitro experiments demonstrated that TAC increases mTOR activity in a normal tubular epithelial cell line and in the investigated RCC cell lines, moreover, promotes the proliferation of some RCC cell line. In vivo, TAC elevated mTORC1/C2 activity in ischaemic kidneys of mice and enhanced tumour growth in xenograft model. CONCLUSIONS: We observed significantly increased mTOR activity in ischaemic kidneys and post-tx RCCs, which highlights involvement of mTOR pathway both in the healing or fibrotic processes of kidney and in tumorigenesis. TAC-treatment further augmented the already elevated mTOR activity of injured kidney, potentially contributing to tumorigenesis during immunosuppression.

Tacrolimus-Induced Neurotoxicity After Transplant: A Literature Review.

Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used globally to prevent rejection after organ transplantation. Although it significantly improves outcomes for solid organ transplant patients, it is associated with various side effects such as nephrotoxicity and neurotoxicity. Tacrolimus-induced neurotoxicity is frequently encountered in clinical practice and can present with a variety of symptoms that may occur even at therapeutic levels. Although tacrolimus-induced neurotoxicity is well documented, there is limited literature available on pharmacologic management. Twenty-eight case reports of tacrolimus-induced neurotoxicity were identified and analyzed in addition to other literature including reviews, retrospective studies, and animal model studies. The severity of cases of tacrolimus-induced neurotoxicity reported ranged from mild symptoms that could be managed with symptomatic treatment to conditions such as posterior reversible encephalopathy syndrome and chronic inflammatory demyelinating polyradiculoneuropathy that may require more immediate intervention. This information was utilized in addition to clinical experience to compile potential management options for prevention and treatment of neurotoxic adverse events. This review is limited by the utilization of primarily retrospective studies and case reports. The available literature on the subject is largely narrative and there are no guidelines on treatment of tacrolimus-induced neurotoxicity at the time of this research. This comprehensive review may guide further studies to investigate the pathophysiology of tacrolimus-induced neurotoxicity and to define patient-specific strategies for mitigation or minimization of neurotoxicity. This is especially important given that management of tacrolimus-induced neurotoxicity can include changes to immunosuppression that can result in an increased risk of rejection.

Tacrolimus-induced cholestatic hepatotoxicity after renal transplantation: a case report.

BACKGROUND: In this manuscript, we report a case of tacrolimus-associated hepatotoxicity in a kidney transplant recipient. CASE PRESENTATION: In this case report, a 56 years old Arab male patient who received a kidney transplant presented with icterus, weakness, and lethargy two weeks after transplantation and tacrolimus initiation. In laboratory analysis hyperbilirubinemia and a rise in hepatic enzymes were observed. All possible causes of hepatotoxicity were examined. The panel for infectious causes was negative. Drug-induced liver injury was diagnosed. The patient's immunosuppressive regimen was changed to a cyclosporine-based regimen and after this change bilirubin and hepatic enzymes decreased and the patient was discharged without signs and symptoms of hepatitis. CONCLUSION: It seems that the patient's hyperbilirubinemia was due to tacrolimus, and the patient's bilirubin decreased after stopping tacrolimus.

Retrospective analysis on incidence and risk factors of post-transplant diabetes mellitus after lung transplantation and its association with clinical outcomes.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a common complication after transplantation. We aim to explore potential risk factors of PTDM and its association with outcomes after lung transplantation (LTx). METHODS: A retrospective study was conducted in 100 patients who underwent LTx at our institution from 2017 to 2021. Patients' information was collected, and genotyping for single nucleotide polymorphisms known to potentially increase the risk of Type 2 DM was performed. Univariate and multivariate analyses were conducted to identify risk factors for PTDM. The primary outcome was the incidence of PTDM. Secondary outcomes were associations between PTDM and clinical outcomes following LTx. RESULTS: Thirty-nine patients (39.0%) developed PTDM, while 10 patients (25.6%) recovered subsequently. The incidence of PTDM was associated with age > 45 (HR: 2.919, 95% CI [1.021-8.348]), pre-transplant HbA1c > 5.7% (HR: 2.344, 95% CI [1.201-4.573]), KCNJ11 rs5215 (HR: 2.090, 95% CI [1.050-4.162]) and tacrolimus concentration > 8 ng/mL in the first month (HR: 2.090, 95% CI [1.050-4.162]). Patients with PTDM experienced elevated fasting blood glucose levels (FBG) during the first month post-transplantation (p < 0.001), and required a longer duration for FBG to return to normal levels (p < 0.001). However, the presence of PTDM did not significantly impact renal function, incidence of infection episodes, chronic lung allograft dysfunction or mortality following LTx. CONCLUSION: Advanced age, elevated HbA1c levels, KCNJ11 gene polymorphism, and early exposure to tacrolimus are all significant risk factors for PTDM following LTx. The clinical implications of these factors warrant attention.

Conversion from twice-daily everolimus to once-daily sirolimus in long-term stable liver transplant recipients.

BACKGROUND: After organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients. METHODS: We included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR). RESULTS: The median age at the time of conversion was 68.9 years (range: 26.1-83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3-31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5-4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5-3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%. CONCLUSION: The results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

Tacrolimus-Associated Posterior Reversible Encephalopathy Syndrome in Renal Transplant Recipient in Early Posttransplant Period: Case Report.

Posterior reversible encephalopathy syndrome is an emergency medical condition with varied causes presenting as reversible subcortical vasogenic brain edema caused by endothelial injury, resulting from changes in blood pressure or direct effects of cytokines on endothelium. Posterior reversible encephalopathy syndrome is manifested by neurologic symptoms. Common causes include hypertensive emergency, renal disease, preeclampsia, eclampsia, and immunosuppressive drugs. In this case report, a 17-year-old female patient on hemodialysis as a result of lupus nephritis who had previously undergone deceased donor organ transplant and was on triple immunosuppression presented with neurological symptoms of posterior reversible encephalopathy syndrome in the early posttransplant period. She was normotensive, and tacrolimus level was in desired level. She improved after cessation of tacrolimus from immunosuppression with complete resolution of radiological lesions. Posterior reversible encephalopathy syndrome can occur in solid-organ transplant recipients who are on tacrolimus as a part of immunosuppression.

Management of Tacrolimus-Induced Toxicity With Normal Serum Levels After Liver Transplant.

Drug-induced liver injury after liver transplant occurs in 1.7% of patients. Tacrolimus is an effective immunosuppressant that is used to treat acute rejection. Although rare, it can cause toxicity, which is demonstrated by cholestatic liver injury. Here, we present a case of a young male patient who was diagnosed with Wilson disease, had penicillaminechelating therapy, and underwent living related liver transplant. Within 1 month posttransplant, he developed deranged, predominantly cholestatic pattern liver function tests. Laboratory parameters showed total bilirubin of 1.12 mg/ dL, alanine aminotransferase of 553 IU/L, gammaglutamyltransferase of 624 IU/L, and tacrolimus level of 10.2 ng/mL. After thorough evaluation, a liver biopsy was performed. Liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. However, with normal level of tacrolimus, the biopsy was suggestive of drug-induced liver injury. Thus, tacrolimus dose was reduced, resulting in improved liver function tests and patient discharge from the hospital. Tacrolimus is an effective immunosuppressant after liver transplant and has the ability to treat early acute rejection. The patient's liver biopsy showed hepatocellular necrosis with centrilobular cholestasis without any evidence of graft rejection. Cholestatic liver injury after tacrolimus usually resolves after dose reduction or by switching to another agent. With demonstrated tacrolimus-induced toxicity in liver transplant recipients, despite normal serum levels, transplant physicians should keep high index of suspicion regarding toxicity in the posttransplant setting.