Serum Tacrolimus Levels Research Articles

Pregnancy Management and Outcomes in a Small Bowel, Pancreas, and Liver Transplant Recipient: A Case Report and Literature Review.

BACKGROUND Small bowel transplantation (SBT) is a rare but life-saving surgery. However, successful full-term pregnancies in individuals with SBT are exceedingly rare due to the nutritional and immunosuppression challenges this transplant poses for pregnancy. Therefore, clear guidelines for treating pregnant SBT recipients are unavailable. Here, we report the second case of a successful pregnancy in an individual with a triple organ transplant, including SBT, highlighting the need for careful immunosuppressive management and multidisciplinary care. CASE REPORT A 20-year-old woman in the third trimester of pregnancy with a history of small bowel, liver, and pancreas transplantation at age 1 year presented with elevated liver function test results. She had been taking tacrolimus, sirolimus, and prednisone before pregnancy, with no signs of organ rejection. While sirolimus and prednisone was discontinued upon conception, laboratory test results at presentation revealed low serum tacrolimus levels. The patient had an acute kidney injury and pulmonary edema during her hospitalization and received a diagnosis of preeclampsia. She underwent a successful cesarean delivery, due to labor induction complications; however, about 1 month after hospital discharge, the patient experienced elevated liver enzymes, which was treated with high-dose steroids and adjusted tacrolimus. Sirolimus was restarted, and the patient's liver enzymes have been normalized to date. CONCLUSIONS Comprehensive multidisciplinary care, as well as monitoring and optimizing immunosuppression, are essential for pregnant SBT recipients throughout the prenatal, perinatal, and postpartum periods to mitigate risks, prevent graft rejection, and ensure positive maternal and fetal health outcomes.

Impact of HLA Alleles on COVID-19 Severity in Kidney Transplant Recipients: A Single-Center Study.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted global health, particularly affecting vulnerable populations, such as organ transplant recipients. Human leukocyte antigens (HLAs) play a critical role in immune response regulation, and understanding their association with COVID-19 can provide insights into disease susceptibility and severity. This study aims to explore the association between HLA allele variability and COVID-19 susceptibility and severity among kidney transplant recipients. Methods In 2023, we conducted a study on 73 kidney transplant recipients who tested positive for COVID-19 via polymerase chain reaction. This study included assessments of clinical status, immunosuppressive drug levels, HLA allele frequencies, and donor-recipient tissue compatibility. Molecular analyses were performed using sequence-specific oligonucleotide typing, and statistical analysis was conducted using IBM SPSS Statistics, version 20.0 (IBM Corp., Armonk, NY). Results Among the participants, 31 were hospitalized and 42 were treated as outpatients. Significant differences were observed in HLA allele distributions, particularly the HLA-A*11 allele, which was more prevalent in outpatient-treated patients, suggesting a potential protective effect. No significant age differences were observed between hospitalized and outpatient groups. Serum tacrolimus levels were notably higher in outpatients. Statistical analyses revealed significant associations between certain HLA groups and the severity of COVID-19 infection. Conclusions This study highlights the importance of HLA allele compatibility in influencing the clinical outcomes of COVID-19 in kidney transplant recipients. The findings suggest that specific HLA alleles may reduce susceptibility or moderate the severity of COVID-19, indicating a need for broader genetic studies across diverse populations to validate these observations and improve management strategies for transplant recipients during pandemics.

#1888 Association between intrapatient variability of serum tacrolimus levels with the development of diabetes in post-kidney transplantation patients

Abstract Background and Aims Kidney transplantation is the most cost-effective renal replacement therapy compared to dialysis. Diabetes is main cause of increased cardiovascular risk and death. Post-transplant Diabetes Mellitus (PTDM) it refers to presence of diabetes in an environment after kidney transplantation; According to the ADA (American Diabetes Association) criteria, the diagnosis must be made with a tolerance test with 75 grams of oral glucose (Oral glucose tolerance test-OGTT) or the determination of glycosylated hemoglobin 1Ac (Hb1Ac) in a post-transplant period of stability of the immunosuppression dose and without infections. There are various risk factors for the development of PTDM: hypomagnesemia, glucocorticoids, calcineurin inhibitors (tacrolimus and cyclosporine); hepatitis C virus and cytomegalovirus infections. In a Mexican kidney transplant recipients in Guadalajara, Andrade SG demonstrated that the incidence of PTDM was 10.1% at 1 year post-transplant. In the Spanish population, Porrini E demonstrated that tacrolimus represents a risk factor for the development of PTDM, increasing the incidence of prediabetes by 33% at 12 months post-transplant. Several mechanisms have been implicated in the association of calcineurin inhibitor and PTDM: decreased insulin secretion, glucose intolerance, reduced pancreatic beta cell mass, increased islet apoptosis and decreased insulin gene expression. Studies mention that tacrolimus (FK) is more diabetogenic than cyclosporine (CsA) especially at levels above 20 ng/mL. The DIRECT study (Diabetes Incidence after Renal Transplantation) showed the incidence in 73 kidney transplant patients with CsA (26%) and 96 FK patients (33.6%, p = 0.046). By the other side, Malik RF mentions that FK levels aren´t a risk factor for the development of PTDM. To demonstrate that the high intrapatient variability of tacrolimus/cyclosporine serum levels correlates with the development of diabetes (PTDM) in kidney transplant recipients at the central military hospital in Mexico City. Method Observational, analytical, longitudinal and retrospective study. All kidney transplant recipients from living donors and cadaveric donors from January 2002 to December 2020 were included. FK and CsA were used as maintenance immunosuppression. Serum levels of FK/CsA, Hb1Ac and glucose were measured at months 0, 3, 6, 9 and 12 and intra-patient variability (IPV) of FK/CsA levels was calculated for each patient. The patients were separated into 2 groups, IPV low and IPV high according to the mean the coefficient of variability (CV). The IPV of the calcineurin inhibitor was estimated by calculating the CV in each patient according to the following equation: CV(%)= (SD/mean trough concentration of FK/ CsA)×100. The diagnosis of PTDM followed the criteria of the American Diabetes Association. The Mann Whitney U test was used. Results 638 kidney transplant recipients were included. The mean age of the recipients was 36.78 (±12.81) years. At the time of kidney transplant, the BMI was 22.67 (±3.90) and 25.76 (±3.99) kg/m² BS at 1 year post-transplant for whole cohort. At 1 year post-transplant, 72.3% patients were on FK and 27.7% on CsA. Hb1Ac for whole cohort was 4.81 (±0.71)% and 4.84 (±0.77)% at month 0 and 12 post-kidney transplant, respectively. FK and CsA levels were 12.41 (±5.31) and 234.34 (±87.80) ng/mL and 9.13 (±5.3) and 194.38 (±92.44) ng/mL in the PTDM and non-PTDM groups, respectively (p = 0.029). 17.96% of patients developed PTDM. Mean CV of the entire cohort was 33.84 (±20.41)%. When performing the analysis of the IPV coefficient by subgroups of maintenance immunosuppression used at 1 year post-transplant: the IPV of FK was 43.39 (±18.49)% and 29.99 (±17.56)% in the PTDM and non-PTDM groups respectively, p = 0.000, which shows that patients with a high IPV coefficient of tacrolimus developed more PTDM than those with low variability, student's t-test to compare IPV was 0.03. The IPV of CsA was 38.61 (±18.76)% and 37.51 (±25.67)% in the PTDM and non-PTDM groups respectively, p = 0.819. Conclusion High intrapatient variability of tacrolimus was correlated with the development of PTDM in Mexican kidney transplant recipients.

De Novo Inflammatory Bowel Disease after Liver Transplantation: Eleven Years' Experience in Shiraz, Iran

Background: Colon inflammation may occur after solid and liquid organ transplantations at a rate higher than in the general population. Objectives: This study aimed to investigate the incidence of de novo inflammatory bowel disease (IBD) and assess some risk factors after Orthotopic Liver Transplantation (OLT) in liver transplant patients in Shiraz, Iran. Methods: The sample study comprised patients (n = 1702) who had received liver transplants between 2001 and 2012 at the Shiraz liver transplant center. The data were obtained from patient records, which included information on their medical history, colonoscopy reports, family history of IBD, and other risk factors. The study evaluated the status of inflammatory bowel disease (IBD) among patients who had undergone liver transplantations due to Autoimmune Hepatitis (AIH) group, Primary Sclerosing Cholangitis (PSC), and other liver transplant patients. Additionally, case groups were formed, comprising AIH patients (n1 = 10) and other patients with IBD (n2 = 10), and were compared with transplant patients without IBD as the control group (n1 = 21, n2 = 21). Results: Out of the total 1702 patients, 254 (14.92%) had AIH, 211 (12.40%) had PSC, and 1237 (72.68%) had other outcomes. The mean of leukocyte counts (P-value = 0.73), types of immunosuppressant medications, and serum levels of cyclosporine (P-value = 0.77) and tacrolimus (P-value = 0.27) did not show any significant differences between the case and control groups. However, it was observed that IBD developed earlier in patients with AIH compared to other patients (20.1 ± 2.23 vs 53.9 ± 4.42 months). Conclusions: The incidence of IBD after liver transplantation was higher compared to the general population, and it occurred earlier in patients who underwent transplantation for AIH and other groups.

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

BackgroundCoronavirus 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 presentationIn 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.ConclusionAlthough 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.

Variables Associated With Hyperkalemic Renal Tubular Acidosis in Solid Organ Transplant Recipients.

The occurrence of hyperkalemic renal tubular acidosis (RTA) in the post-transplantation period is likely underestimated, and its identification remains important to offer adequate medical management. Transplant recipients frequently present with clinical and biological characteristics that may be associated with the occurrence of this complication. This was a single-center retrospective study that compared transplanted patients with hyperkalemic RTA and a control group to identify variables associated with the occurrence of this complication. Fisher's exact test and the Mann-Whitney test, followed by multivariate logistic regression, were applied to test whether there was a significant association between hyperkalemic RTA and different variables. Kidney and heart transplant recipients were at greater risk of developing RTA than lung transplant recipients (p = 0.016). There was also a significant association between the development of RTA and kalemia (p < 0.01), chloremia (p < 0.01), and bicarbonatemia (p < 0.01). The significant impact of these last three variables was confirmed by the results of the multivariate logistic regression. Residual serum tacrolimus levels (p = 0.13) and creatinine levels (p = 0.17) of renal transplant patients were not significantly associated with hyperkalemic RTA. The type of transplanted organ, kalemia, chloremia, and bicarbonatemia were significantly associated with the occurrence of hyperkalemic RTA. This study calls into question certain approaches to managing this complication proposed in a number of case reports, such as reducing the target serum residual of tacrolimus or discontinuing trimethoprim-sulfamethoxazole(TMP-SMX) in favor of another antibiotic prophylactic agent, potentially exposing patients to graft rejection and opportunistic infections.

Efficacy and Safety of Topical Tacrolimus Microemulsion Applied Twice Daily in Patients with Mild to Moderate Scalp Psoriasis.

Involvement of the scalp is common in psoriasis and severely affects the quality of life of those affected. It is difficult to treat and places special demands on the galenics of a drug formulation. Tacrolimus is a calcineurin inhibitor and is approved as an ointment formulation for the treatment of atopic dermatitis. The efficacy and safety of topically applied tacrolimus have also been studied and proven for psoriasis. However, no proprietary pharmaceutical product is currently approved for this indication. A multicenter, double-blind, vehicle-controlled phase3 study was conducted to evaluate the efficacy and safety of 0.1% tacrolimus microemulsion when applied topically twice daily in 128 patients independentlyofsex with scalp psoriasis. The primary efficacy analysis showed a scalp Investigator Global Assessment (s-IGA) of 0 (absence of disease) or 1 (very mild disease) at 8weeks in 28.6% of subjects in the tacrolimus group, indicating a significantly better response (p = 0.0476, chi-square test) versus 12.7% of subjects in the placebo group (difference of 15.9%-points). The Dermatology Life Quality Index (DLQI) improved over time and was more pronounced in the group treated with tacrolimus-containing microemulsion than in the placebo group, but showed no statistically significant difference after 8weeks of use (p = 0.193, ANCOVA). The safety analysis revealed no evidence of cutaneous side effects other than those known. Toxicologically relevant serum levels of tacrolimus could be excluded. The study data show that 0.1% tacrolimus microemulsion has good efficacy and safety in the treatment of scalp psoriasis.

Medication adherence in kidney transplant recipients: A cross-sectional study from a nursing clinical practice perspective

Medication non-adherence is implicated as one of the major causes of early and late kidney transplant rejection. The present study aimed to evaluate medication adherence in kidney transplant recipients. The study design was cross-sectional and descriptive. The sample was 144 kidney transplant patients, and sampling was by convenience. The researchers collected data using a three-part questionnaire, including demographic characteristics, clinical features, and simplified medication adherence questionnaire (SMAQ). Findings suggest that medication adherence in participants was at the desired level (94.4%; 95% CI: 89.8-97.3; P&lt;0.001) and the number of hospitalizations was a predictor of medication adherence in kidney transplant recipients (95% CI: 0.236-1.009; OR:0.488; P=0.053). The mean serum levels of Tacrolimus, Sirolimus, Cyclosporine, and Everolimus in kidney transplant recipients were 8.22 (SD=4.75), 59.66 (SD=82.71), 138.25 (SD=74.99), and 5.7, respectively. Glomerular filtration rate and serum levels of Tacrolimus and Cyclosporine were higher in patients with appropriate medication adherence than those with poor medication adherence (P&gt;0.05). With the increasing number of hospitalizations, medication adherence in these patients decreased. Overall, the medication adherence in kidney transplant recipients at the Kidney Transplantation Referral Center was at the desired level. Therefore, medicating related training programs are a promising approach to improve the quality of life in kidney transplant recipients and potentially reduce the incidence of transplant rejections among kidney transplant patients.

Böbrek Nakli Alıcılarında Hipomagnezemi Ve Kalsinörin İnhibitörleri

Aim: Post-transplant hypomagnesemia is a frequently encountered and significant electrolyte disorder and is more common in patients using calcineurin inhibitors (CNIs). This study aimed to evaluate the frequency of hypomagnesemia and accompanying conditions in the outpatient follow-up of renal transplant recipients.&#x0D; Methods: This cross-sectional study included 236 renal transplant patients. Demographic characteristics of the patients and their biochemical values, including drug levels, were recorded.&#x0D; Results: Of the patients, 69 (29.2%) were female, and 194 (82.3%) were living donor recipients. The mean age of the entire group was 43.1 years. The frequency of hypomagnesemia was 40% (10/25) in the first 12 months, 26.1% (23/88) between the 12th and 60th months, 26% (32/123) after 60 months, and 27.5% (65/236) in all patients. In patients with higher levels of tacrolimus compared to those with the target level, the frequency of hypomagnesemia increased in those with a posttransplant period of 12-60 months (40.9% vs. 20.8%, p: 0.018) and over 60 months (44% vs. 26%, p: 0.046). In addition, the magnesium (Mg+2) level was lower in patients using tacrolimus compared to those using cyclosporine (CsA) (1.80±0.18 vs 1.91±0.25, p: 0.003). The effect of hypomagnesemia on graft functions was statistically insignificant in all groups.&#x0D; Conclusion: Hypomagnesemia is a common electrolyte disorder in the early and late periods after transplantation. In our study, hypomagnesemia did not differ according to proton pump inhibitor (PPI) use, gender, fasting blood glucose, and glomerular filtration rate. However, the frequency increased in patients using tacrolimus and those with above-target serum tacrolimus levels.

Immunosuppressive therapy and oral anticoagulation in kidney transplant recipients: Direct oral anticoagulants versus vitamin-k antagonists

Backgrounddirect oral anticoagulants (DOACs) are an alternative to conventional antagonist of vitamin-K (AVK). However, immune suppressive drugs (ISDs) may interfere with DOACs pharmacokinetic. Aim of this studyevaluate safety and efficacy profile of DOACs compared to AVK in kidney transplant recipients (KTRs) treated with ISDs. Methodsa multi-center study from 4 Italian University hospitals enrolling consecutive KTRs on DOACs or AVK was carried out. Sixty-six patients on DOACs were compared with fifty patients on AVK with similar clinical features. Serial evaluation of renal function and serum levels of ISDs during 18 months follow-up (FU) was performed. ResultsMean age of DOACs patients was 67±9 and mean eGFR was 58,3± 30,4mL/min/1.73m2. ISDs included tacrolimus (n=47, 71%), cyclosporin (n=13, 20%), everolimus (n=10, 7%) and sirolimus (n=4, 6%). After 14 days of DOACs therapy initiation there was a slight increase of serum levels of tacrolimus (+0.19±0.67 p=0.80) and cyclosporine (+0.12±0.25 p=0.94) not statistically significant. Levels of Tacrolimus and cyclosporin were stable at serial evaluation during 18-months follow-up. There were no thromboembolic events among patients treated with DOACs or AVK and no differences in term of major bleeding (6% vs 4% p=0.69), at long-term follow-up. There was no difference in term of eGFR decline from start therapy to 18 months FU between DOACs vs AVK therapy (-3.9±1 vs -3.8±2 p=0.82). ConclusionDOACs have similar safety and efficacy than AVK among KTRs treated with ISDs. However, careful evaluation of potential drug interaction and ISDs serum levels is needed.

#4991 IMMUNE MODULATING DRUGS AND ORAL ANTICOAGULATION IN KIDNEY TRANSPLANT: COMPARISON OF DIRECT ORAL ANTICOAGULANTS VERSUS ANTAGONIST OF VITAMIN-K

Abstract Background and Aims Direct oral anticoagulants (DOACs) are a well-known alternative to conventional antagonist of vitamin-K (avK) and have emerged as the preferred choice due to their safety and efficacy profile. However, immune modulating drugs as cyclosporine and tacrolimus, commonly used for transplant recipients, may interfere with DOACs pharmacokinetic. Our study evaluates safety and efficacy profile of direct oral anticoagulants (DOACs) compared to avK in kidney transplant recipients (KTRs) treated with immune modulating agents. Methods A multi-center retrospective observational study from 4 Italian hospitals enrolling KTRs on DOACs or avK was carried out. Sixty-six patients on DOACs were compared with fifty patients on avK with similar clinical features. Serial evaluation of renal function and serum levels of immune modulating drugs during 24 months follow-up (FU) was performed. Results Mean age of DOACs patients was 67±9 and mean eGFR was 58,3± 30,4mL/min/1.73 m2. Immune-modulating therapy included tacrolimus (n = 47, 71%), cyclosporin (n = 13, 20%), everolimus (n = 10, 7%) and sirolimus (n = 4, 6%). After 14 days of DOACs therapy initiation there was a slight increase of serum levels of tacrolimus (+0.19±0.67 p = 0.80) and cyclosporine (+0.12±0.25 p = 0.94) not statistically significant. Only a patient treated with dabigatran 150 mg required a dose adjustment. Levels of tacrolimus and cyclosporin were stable at serial evaluation during 18-months follow-up. There were no thromboembolic events among patients treated with DOACs or avK and no differences in term of mayor bleeding (5.8% vs 4% p = 0.99), at long-term follow-up. There was no difference in term of eGFR decline from start therapy to 18 months FU between DOACs or avK therapy (-3.9±1 vs −3.8±2 p = 0.82). Conclusion DOACs are a potential therapeutic option among kidney transplant recipients treated with immune modulating drugs. Careful evaluation of immunomodulating agent levels during the first two week of therapy should be recommended. No difference in term of bleeding, thromboembolic events and renal function decline was found when comparing with avK therapy.

Use of tecovirimat for mpox infection followed by JYNNEOS vaccination postinfection in a liver transplant recipient.

Use of tecovirimat for mpox infection followed by JYNNEOS vaccination postinfection in a liver transplant recipient.

Neurological Complications after Deceased Donor Liver Transplant: A Case Series from a Public Sector Hospital

This is a case series of neurological complications which occurred after Deceased Donor Liver Transplant (DDLT) in a public sector hospital. The clinical presentations were bizarre. This is because patients with End Stage Liver Disease (ESLD) commonly have hepatic encephalopathy and postoperatively can present with similar clinical picture, like tremors and altered mentation. The first patient in the series presented with tremors due to Calcineurin Inhibitor (CNI) toxicity, second had Posterior Reversible Encephalopathy Syndrome (PRES), third with Osmotic Demyelination Syndrome (ODS) with coma and fourth with Extrapyramidal Syndrome (EPS). Patients 1 and 4 had involuntary movements and other clinical manifestations which interfered with recuperation in the postoperative period. So, the dosages of the immunosuppressants were adjusted and serum tacrolimus assay were serially monitored on alternate days. Case 3 developed PRES due to hypertension, as a result of high serum tacrolimus levels. The patient presented with headache and seizures, which if uncontrolled would have been lethal. In Case 4 clinical features and management of a patient who suffered prolonged coma due to ODS for about three months has been discussed. Also, the same patient had a cerebral infarct due to embolic phenomenon inspite of thromboprophylaxis. From this case series, it needs to be emphasised that postoperative occurrence of neurological complications are likely. So careful selection of the recipients, steady titration of immunosuppressants and watchful monitoring of the neurological signs are essential to improve the outcome of the transplant. Imaging of the brain, preferably Magnetic Resonance Imaging (MRI) should not be delayed to rule out other differential diagnosis.

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.

Evaluating the Effects of Ertapenem and Meropenem on Tacrolimus

Purpose: Further elucidate the potential drug interaction between tacrolimus and carbapenems in order to appropriately maintain the balance between infection treatment and therapeutic immunosuppression. Methods: This study was a retrospective evaluation of solid organ transplant recipients on a stable dose of tacrolimus who received either ertapenem or meropenem. Patients were excluded if they had acute kidney injury, acute liver failure, concomitant initiation of medications that interact with tacrolimus, or were pregnant. The primary endpoint was the change in the median daily tacrolimus dose after meropenem or ertapenem administration. The secondary endpoint was the change in serum tacrolimus levels after meropenem or ertapenem administration. Results: A total of 28 patients on tacrolimus were included in the study, 12 received ertapenem and 16 received meropenem. The median daily tacrolimus dose was 4.5 mg [IQR 3.0 mg – 8.8 mg] prior to and 3.4 mg [IQR 2.3 mg – 8.8 mg] after ertapenem administration. The median daily tacrolimus dose was 3.0 mg [IQR 1.6 mg – 5.5 mg] before and 3.0 mg [IQR 1.6 mg – 5.5 mg] after meropenem administration. No statistically significant difference in regard to the change in the median daily tacrolimus dose after ertapenem (P =.173) or meropenem administration (P =.755) was observed. There was no statistically significant difference found after ertapenem (P =.583) or meropenem (P =.317) administration when comparing pre- and post-administration median serum tacrolimus levels. Conclusion: The administration of ertapenem or meropenem did not affect serum tacrolimus levels or daily tacrolimus dose suggesting against empiric dose adjustments with co-administration.

Preventive effect of tacrolimus on patients with post-endoscopic retrograde cholangiopancreatography pancreatitis.

Background/AimsIn patients undergoing endoscopic retrograde cholangiopancreatography (ERCP), calcineurin activates zymogen, which results in pancreatitis. In this study, we aimed to determine the efficacy of tacrolimus, a calcineurin inhibitor, in preventing post-ERCP pancreatitis (PEP). MethodsThis was a prospective pilot study in which patients who underwent ERCP received tacrolimus (4 mg in two divided doses); this was the Tac group. A contemporaneous cohort of patients was included as a control group. All patients were followed-up for PEP. PEP was characterized by worsening abdominal pain with an acute onset, elevated pancreatic enzymes, and a duration of hospital stay of more than 48 hours. Serum tacrolimus levels were measured immediately before the procedure in the Tac group. ResultsThere were no differences in the baseline characteristics between the Tac group (n=48) and the control group (n=51). Only four out of 48 patients (8.3%) had PEP in the Tac group compared to eight out of 51 patients (15.7%) who had PEP in the control group. The mean trough tacrolimus level in patients who developed PEP was significantly lower (p<0.05). ConclusionsOral tacrolimus at a cumulative dose of 4 mg safely prevents PEP. Further randomized controlled studies are warranted to establish the role of tacrolimus in this context.

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.

Comparison of Tacrolimus Serum Levels During First Month After Lung Transplant in Patients with and without Gastroparesis

<h3>Purpose</h3> Gastroparesis is suspected to alter the absorption of immunosuppressive medications in solid organ transplant recipients. Limited data exists in lung transplant recipients (LTRs), who typically have high rate of post-transplant gastroparesis. The objective of this study was to compare the post-transplant route of tacrolimus administration and variation in serum tacrolimus levels in LTRs with and without gastroparesis. <h3>Methods</h3> All recipients who underwent lung transplant in 2019 were included. Objective gastric emptying data was documented. Daily tacrolimus dose, route of administration and serum levels for 30 days post-transplant were evaluated and compared. <h3>Results</h3> There were 123 LTRs in 2019, of which 31 (25%) developed gastroparesis. After matching, baseline characteristics were similar amongst the 2 groups, however, gastroparesis patients were younger (54 ±14 vs 59 ±14 years, p<0.05). Majority (118) of patients started with sublingual tacrolimus postoperatively, of which 82 (69%) were switched to the oral route. Patients with gastroparesis had longer duration of sublingual administration compared to patients with normal gastric emptying (median days 14 vs 7, p<0.05) . Median time to reach 10mg/dl serum level was 9 days in gastroparesis patients vs 7 days in non-gastroparesis group. Overall, there was no significant difference in mean serum tacrolimus levels amongst the 2 groups over 30 days (<b>Figure 1</b>). <h3>Conclusion</h3> Gastroparesis is common after lung transplant and may require longer sublingual administration of tacrolimus. Ultimately, however, gastroparesis patients can be switched safely from sublingual to oral tacrolimus as there is no significant difference in the postoperative trend of serum tacrolimus levels, even when accounting for change in route of tacrolimus administration.

Factors Influencing Survival Outcome in Deceased Renal Transplant Recipients

Background: Renal replacement therapy is the gold standard treatment of end-stage renal disease. Since the number of cases of chronic kidney diseases are increasing exponentially in our country, only live-related transplant is not enough to bridge the gap between disease and their treatment which increased the demand for deceased renal transplant program in our country. Objective: The objective is to study donors and recipients' characteristics for association with survival of patients in deceased renal allograft transplant. Materials and Methods: It is an ambispective observational analysis of 42 deceased donor renal transplants performed in our institute from January 2012 to December 2019. The difference among donors and recipients' characteristics was analyzed for association with the outcome for survival or death of the patient. Statistical analysis was done using SSPS 21.0 software and P value &lt; 0.05 was taken as statistically significant. Results: In association with survival and expired outcomes, donors and recipients age, donors sex, cause of brain death (traumatic/nontraumatic), standard or extended criteria of donor, serum creatinine at the time of death, dialysis vintage period, warm and cold ischemia time, duration of hospital stay had shown no significant association with survival. While donors' urine output at the time of death, recipients sex, previous sensitization of recipients either by previous episodes of blood transfusion or pregnancy, achievement of normal renal function at day 14 of transplant, and tacrolimus level at 1 month of transplant shown significant association with the outcome. Conclusion: Deceased donors' characteristics, mainly urine output at death, recipients characteristic, namely any previous sensitization, achievement of normal renal function at day 14, serum tacrolimus level at 1-month posttransplant have a significant association with survival of deceased renal allograft transplant recipients. Sepsis and severe acidosis were the main complications contributing to mortality.

The Gut Microbiome and Tacrolimus Dosing in the Peri-Heart Transplant Period

<h3>Purpose</h3> Recent evidence suggest that the gut microbiome may influence tacrolimus dosing requirements, potentially through direct metabolism. The impact of the gut microbiome on tacrolimus requirements among heart transplant (HT) recipients during medication initiation is unknown. We aimed to evaluate the effect of the gut microbiome on tacrolimus dosing requirements among HT recipients in the peri-HT period. <h3>Methods</h3> We conducted a prospective, observational cohort study of all single organ HT recipients at a single center from 2020-2021. Stool samples were collected within 2 weeks of HT and underwent shotgun metagenomic analysis. Measures of microbial diversity, composition, and metabolomics were correlated to the ratio of tacrolimus serum level (L) to the total 24-hour dose (D) at time of post-HT discharge. HT recipients were further divided into 2 groups: above-median L/D ratio (slow metabolizers) and below-median L/D ratio (fast metabolizers). <h3>Results</h3> Thirty-two patients were included in the study. Stool samples were collected a median of 8 days (IQR [5, 11]) post-HT. Median time to discharge was 18 days (IQR [12, 23]). Median L/D ratio was 0.86 (IQR [0.52, 1.13]) with 18 patients in the slow metabolizer group and 16 in the fast metabolizer group (median L/D 1.28 vs 0.61, p = 0.001). The fast metabolizer group was on a higher tacrolimus dose at discharge than the slow metabolizer group (19 vs 9 mg/day, p<0.001). Demographic factors and within sample microbial diversity, i.e. α-diversity, as measured by inverse Simpson index was similar between groups. The fast metabolizer group was found to have lower abundance of the phylum <i>Bacteroidetes</i> (19% vs 39%, p = 0.03) and higher abundance of <i>Firmicutes</i> (67% vs 47%, p = 0.04) (Fig. 1). Both groups had similar levels of the gut microbial metabolites, secondary bile acids and short chain fatty acids. <h3>Conclusion</h3> HT recipients have variable tacrolimus dosing requirements in the immediate post-HT period. Differences in the abundance of gut microbes in the peri-HT period may influence these needs.