Browsing by Author "Sharfuddin, Asif A."
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Item A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus(Wiley, 2025) So, Gerald C.; Lu, Jessica Bo Li; Koyama, Sachiko; Cheng, Ying-Hua; Gisch, Debora L.; McClara, Kelsey; Dexter, Paul R.; Sharfuddin, Asif A.; Etkins, Jumar; Tillman, Emma M.; Beamon, Travis R.; Cowsert, Zachary; Stuart, Jennifer S.; Desta, Zeruesenay; Eadon, Michael T.; Medicine, School of MedicineOne in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (Cmax) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.Item Bamlanivimab for Mild to Moderate COVID-19 in Kidney Transplant Recipients(Elsevier, 2021-09) Jan, Muhammad Y.; Sayegh, Skye E.; Webb, Hanna T.; Adebiyi, Oluwafisayo; Anderson, Melissa D.; Mishler, Dennis P.; Yaqub, Muhammad S.; Taber, Tim; Sharfuddin, Asif A.; Medicine, School of MedicineKidney transplant recipients (KTRs) are at an increased risk of hospitalization, complications, and mortality from COVID-19 compared with the general population.1, 2, 3, 4, 5 Among KTRs with COVID-19 in the United States, studies have shown hospitalization rates ranging from 32% to 100%,1,3, 4, 5, 6 intensive care unit (ICU) admission rates from 20% to 61%,2,4 and overall mortality of 13% to 39%.1,2,4, 5, 6 A high incidence of acute kidney injury was noted, ranging from 30% to 89%,2,4, 5, 6 while renal replacement therapy was required in 13% to 21% of patients.1,7 Given the natural history of COVID-19 pneumonia, most of these complications occurred ≥1 week after the diagnosis of COVID-19. Given the high impact of COVID-19 infection on KTRs, early COVID-19–directed therapies are critical. Bamlanivimab (LY-CoV555) was given Emergency Use Authorization (EUA) by the US Food and Drug Administration on November 9, 2020.8 It is a neutralizing IgG1 monoclonal antibody that binds to the receptor-binding domain of the spike protein of SARS-CoV-2, inhibiting attachment to human angiotensin-converting enzyme 2 receptor. This EUA was given for treatment of mild to moderate COVID-19 in patients ≥12 years of age weighing >40 kg who are positive with a direct viral testing for SARS-CoV-2 and have high risk for progressing to severe COVID-19 and/or hospitalization.8 KTRs with COVID-19 are considered high risk because of immunosuppressive medication use.9 Studies on the use of bamlanivimab among KTRs are limited. To provide more insight on the use of bamlanivimab in KTRs we report our experience with 24 KTRs.Item Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance(MDPI, 2020-03-26) Spiech, Katherine M.; Tripathy, Purnima R.; Woodcock, Alex M.; Sheth, Nehal A.; Collins, Kimberly S.; Kannegolla, Karthik; Sinha, Arjun D.; Sharfuddin, Asif A.; Pratt, Victoria M.; Khalid, Myda; Hains, David S.; Moe, Sharon M.; Skaar, Todd C.; Moorthi, Ranjani N.; Eadon, Michael T.; Medicine, School of MedicineA precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.Item Implementation of Clinical Cytochrome P450 3A Genotyping for Tacrolimus Dosing in a Large Kidney Transplant Program(Wiley, 2023) Tillman, Emma; Nikirk, Miley G.; Chen, Jeanne; Skaar, Todd C.; Shugg, Tyler; Maddatu, Judith P.; Sharfuddin, Asif A.; Eadon, Michael T.; Medicine, School of MedicineTacrolimus is a calcineurin inhibitor with a narrow therapeutic range and is metabolized by cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5. The Clinical Pharmacogenetic Implementation Consortium published evidence-based guidelines for CYP3A5 normal/intermediate metabolizers prescribed tacrolimus, yet few transplant centers have implemented routine testing. The objective of this study was to implement preemptive CYP3A genotyping into clinical practice in a large kidney transplant program and to evaluate workflow feasibility, potential clinical benefit, and reimbursement to identify barriers and determine sustainability. Preemptive pharmacogenetic testing for CYP3A5 and CYP3A4 was implemented in all patients listed for a kidney transplant as part of standard clinical care. Genotyping was performed at the listing appointment, results were reported as discrete data in the electronic medical record, and education and clinical decision support alerts were developed to provide pharmacogenetic-recommended tacrolimus dosing. During this initial phase, all patients were administered standard tacrolimus dosing, and clinical and reimbursement outcomes were collected. Greater than 99.5% of genotyping claims were reimbursed by third-party payers. CYP3A5 normal/intermediate metabolizers had significantly fewer tacrolimus trough concentrations within the target range and a significantly longer time to their first therapeutic trough compared to poor metabolizers. The challenge of tacrolimus dosing is magnified in the African American population. The US Food and Drug Administration drug label recommends increased starting doses in African ancestry, yet only ≈66% of African Americans in our cohort were normal/intermediate metabolizers who required higher doses. Routine CYP3A5 genotyping may overcome this issue by using genotype over race as a more accurate predictor of drug response.Item A National Survey of Practice Patterns for Accepting Living Kidney Donors With Prior COVID-19(Science Direct, 2021-08-01) Jan, Muhammad Y.; Jawed, Areeba T.; Barros, Nicolas; Adebiyi, Oluwafisayo; Diez, Alejandro; Fridell, Jonathan A.; Goggins, William C.; Yaqub, Muhammad S.; Anderson, Melissa D.; Mujtaba, Muhammad A.; Taber, Tim E.; Mishler, Dennis P.; Kumar, Vineeta; Lentine, Krista L.; Sharfuddin, Asif A.; Medicine, School of MedicineIntroduction A critical question facing transplant programs is whether, when, and how to safely accept living kidney donors (LKDs) who have recovered from COVID-19 infection. The purpose of the study is to understand current practices related to accepting these LKDs. Methods We surveyed US transplant programs from 3 September through 3 November 2020. Center level and participant level responses were analyzed. Results A total of 174 respondents from 115 unique centers responded, representing 59% of US LKD programs and 72.4% of 2019 and 72.5% of 2020 LKD volume (Organ Procurement and Transplantation Network-OPTN 2021). In all, 48.6% of responding centers had received inquiries from such LKDs, whereas 44.3% were currently evaluating. A total of 98 donors were in the evaluation phase, whereas 27.8% centers had approved 42 such donors to proceed with donation. A total of 50.8% of participants preferred to wait >3 months, and 91% would wait at least 1 month from onset of infection to LD surgery. The most common reason to exclude LDs was evidence of COVID-19−related AKI (59.8%) even if resolved, followed by COVID-19−related pneumonia (28.7%) and hospitalization (21.3%). The most common concern in accepting such donors was kidney health postdonation (59.2%), followed by risk of transmission to the recipient (55.7%), donor perioperative pulmonary risk (41.4%), and donor pulmonary risk in the future (29.9%). Conclusion Practice patterns for acceptance of COVID-19−recovered LKDs showed considerable variability. Ongoing research and consensus building are needed to guide optimal practices to ensure safety of accepting such donors. Long-term close follow-up of such donors is warranted.Item Native Nephrectomy with Renal Transplantation Decreases Hypertension Medication Requirements in Autosomal Dominant Polycystic Kidney Disease(Elsevier, 2016-01) Shumate, Ashley M.; Bahler, Clinton D.; Goggins, William C.; Sharfuddin, Asif A.; Sundaram, Chandru P.; Department of Urology, IU School of MedicinePurpose We assessed hypertensive control after native nephrectomy and renal transplantation in patients with autosomal dominant polycystic kidney disease. Materials and Methods Blood pressure control was studied retrospectively in 118 patients with autosomal dominant polycystic kidney disease who underwent renal transplantation between 2003 and 2013. Overall 54 patients underwent transplantation alone (group 1) and 64 underwent transplantation with concurrent ipsilateral nephrectomy (group 2). Of these 64 patients 32 underwent ipsilateral nephrectomy only (group 2a) and 32 underwent eventual delayed contralateral native nephrectomy (group 2b). The number of antihypertensive drugs and defined daily dose of each antihypertensive was recorded at transplantation and up to 36-month followup. Results Comparing preoperative to postoperative medications at 12, 24 and 36-month followup, transplantation with concurrent ipsilateral nephrectomy had a greater decrease in quantity (−1.2 vs −0.5 medications, p=0.008; −1.1 vs −0.3, p=0.007 and −1.2 vs −0.4, p=0.03, respectively) and defined daily dose of antihypertensive drug (−3.3 vs −1.0, p=0.0008; −2.9 vs −1.0, p=0.006 and −2.7 vs −0.6, p=0.007, respectively) than transplantation alone at each point. Native nephrectomy continued to be a predictor of hypertensive requirements on multivariable analysis (p <0.0001). The mean decrease in number of medications in group 2b from after ipsilateral nephrectomy to 12 months after contralateral nephrectomy was −0.6 (p=0.0005) and the mean decrease in defined daily dose was −0.6 (p=0.009). Conclusions In patients with autosomal dominant polycystic kidney disease undergoing renal transplantation, concurrent ipsilateral native nephrectomy is associated with a significant decrease in the quantity and defined daily dose of antihypertensive drugs needed for hypertension control. Delayed contralateral native nephrectomy is associated with improved control of blood pressure to an even greater degree.Item Nondirected Living Kidney Donation and Recipient Outcomes in the United States: A 20-Year Review(Elsevier, 2022-03-22) Jan, Muhammad Y.; Yaqub, Muhammad S.; Adebiyi, Oluwafisayo O.; Taber, Tim E.; Anderson, Melissa D.; Mishler, Dennis P.; Burney, Heather N.; Li, Yang; Li, Xiaochun; Sharfuddin, Asif A.; Medicine, School of MedicineIntroduction: Nondirected donation (NDD) of the kidneys is a growing practice where donors who do not have any genetic or emotional relationship are selected to donate to a wide variety of recipients with a range of selection criteria and decisions which are left up to individual transplant centers. Methods: We review all adult living kidney donor-recipient (DR) pairs and outcomes from NDDs who were recorded in United Network for Organ Sharing (UNOS) database as code 10 (anonymous) from October 1997 to September 2017 for demographics and outcomes. Results: A total of 2174 DR pairs were identified. The number of NDDs increased from 18 in 2000 to 256 in 2016. Survival analysis showed higher death-censored-graft survival (DC-GS) when recipient was 20 years or more older than donor followed by recipient-donor within 20 years of age and lowest when donor was 20 years or more older than recipient (P = 0.0114). Conclusion: Overall, the number of NDDs has increased significantly in the 20-year review period. Transplants from NDDs have excellent long-term outcomes. Better matching of controllable DR factors, such as age and body mass index (BMI), could further improve GS. Further research is needed to incorporate these DR factors into paired kidney donation programs potentially enhancing the utility and beneficence of this invaluable donation.Item Rabbit anti‐thymocyte globulin administration to treat rejection in simultaneous pancreas and kidney transplant recipients with recent COVID‐19 infection(Wiley, 2020) Barros, Nicolas; Sharfuddin, Asif A.; Powelson, John; Yaqub, Muhammad; Adebiyi, Oluwafisayo O.; Beeler, Cole; Lutz, Andrew; Fridell, Jonathan A.; Medicine, School of MedicineTransplant recipients may be more susceptible to COVID‐19 and itsrelated complications.1‐3Despite most patients being managed with reduction of immunosuppression, the risk of rejection or graft loss does not seem to be increased during COVID‐19.Item The Use of Long‐Term Monthly Basiliximab Infusions as Rescue Maintenance Immunosuppression in Pancreas Transplant Recipients(Wiley, 2024) Chen, Jeanne M.; Mangus, Richard S.; Sharfuddin, Asif A.; Powelson, John A.; Yaqub, Muhammad S.; Adebiyi, Oluwafisayo O.; Jan, Muhammad Y.; Lutz, Andrew J.; Fridell, Jonathan A.; Surgery, School of MedicineThis single-center retrospective study was designed to evaluate the use of basiliximab as an alternative rescue maintenance immunosuppression in situations where standard maintenance immunosuppression is not tolerated after a pancreas transplant. All pancreas transplants performed between January 11, 2006, and January 6, 2022, were reviewed. All recipients received rabbit antithymocyte globulin (rATG) induction with tacrolimus + sirolimus maintenance for simultaneous pancreas and kidney (SPK) and additional low-dose mycophenolic acid for pancreas transplant alone (PTA). Basiliximab 40mg IV q 4 weeks was either added to or in replacement of adjunct immunosuppression in cases of medication intolerance. All recipients who received ≥3 months of basiliximab with ≥1 year follow-up were included. 29/557 (5.2%) recipients (5 SPK and 24 PTA) were identified. Median time to switch was 13 months. When compared 1:2 to matched controls on standard immunosuppression, there was no difference in pancreas rejection, allograft loss, or mortality. Eleven recipients had 13 episodes of pancreas rejection at a median of 28 months post conversion. Eight pancreas allografts failed at a median of 28 months post conversion, and there were five deaths-all occurring in PTA, 4/5 occurring ≥1 year after discontinuation of basiliximab. Renal allograft rejection occurred in one SPK and there was one renal allograft loss. Five PTA developed renal failure. Ten remain on basiliximab (2/5 SPK, 8/24 PTA) at a median of 44 months with good pancreas and kidney function; 4 pts > 4 years. Basiliximab can be considered an alternative rescue maintenance strategy in pancreas transplant recipients who failed other conventional agents.Item Vasopressin for Post-kidney Transplant Hypotension(Elsevier, 2022-04-07) Jan, Muhammad Y.; Moe, Sharon M.; Adebiyi, Oluwafisayo; Chen, Jeannie; Powelson, John; Burney, Heather N.; Yaqub, Muhammad S.; Mishler, Dennis P.; Moorthi, Ranjani N.; Taber, Tim E.; Anderson, Melissa D.; Li, Yang; Li, Xiaochun; Fridell, Jonathan A.; Goggins, William C.; Sharfuddin, Asif A.; Medicine, School of MedicineIntroduction: Hypotension after deceased donor kidney transplant (DDKT) is a risk factor for delayed graft function (DGF) and poor graft survival (GS). We hypothesize that vasopressin use in hypotensive DDKT recipients (DDKTRs) to increase blood pressure (BP) reduces DGF rates and is safe without increasing mortality. Methods: Group with vasopressin "study group" (n = 45) was defined as DDKTRs between 2012 and 2017 who required vasopressin for hypotension systolic BP (SBP) <120 mm Hg or diastolic BP (DBP) <60 mm Hg. DDKTRs with no-vasopressin "comparison group" (n = 90) were propensity score-matched DDKTRs between 2012 and 2017 without vasopressin use. Primary outcomes were GS, creatinine and allograft biopsy rate at 1 year, DGF rate, and death during transplant hospitalization. Results: Vasopressin group had lower mean maximum and minimum SBP and DBP in the operating room (OR). Median vasopressin start time post-DDKT was 2 hours (interquartile range [IQR] 1-6), and duration of use was 42 hours (IQR 24-63). DGF, creatinine at 1 year, and allograft biopsy rates were comparable. No deaths occurred during transplant hospitalization. Multivariable analysis did not find an effect of vasopressin use on GS. Conclusion: Treatment of hypotensive DDKTRs with vasopressin is safe and facilitated similar graft function and survival with that of nonhypotensive patients. In the absence of a randomized control trial, our study supports the safety of vasopressin therapy to prevent the adverse effects of hypotension.