Comparison of Transplant Pharmacist Treatment Decisions Between Telehealth and Clinic Visits.

Introduction: Implementation of telehealth in high-risk patient populations provides opportunities for continuous interactions and has previously been shown to positively impact practice. However, there is a paucity of studies focused on telehealth in the liver transplant population specific to pharmacist care. Project Aim: Describe the importance of transplant pharmacist treatment decisions between telehealth, in-clinic, and asynchronous (eg chart review and electronic message support) visit types. Design: This was a single-center comparative evaluation of adult liver transplant recipients transplanted between May 1, 2020 and October 31, 2020 with a transplant pharmacist visit between May 1, 2020 and November 30, 2020. The primary outcome was the average number of treatment decisions per encounter and the average number of important treatment decisions per encounter. The importance of these treatment decisions was determined by a panel of three clinicians. Results: Twenty-eight patients met the inclusion criteria with 85 in-clinic, 42 telehealth, and 55 asynchronous visits. For all treatment decisions, there was no statistical difference in average number of treatment decisions per encounter between telehealth visits and in-clinic visits with an odds ratio (OR) of 0.822 (95% CI, 0.674-1.000; P = 0.051). Similarly, for important treatment decisions, there was no statistical difference between telehealth visits and in-clinic visits (OR 0.847; 95% CI, 0.642-1.116; P = 0.238). Conclusion: Transplant pharmacists can deliver recommendations with similar importance via telehealth compared to in-clinic visits based on the number of total and important treatment decisions.

Comparison of standard versus low-dose valganciclovir regimens for cytomegalovirus prophylaxis in high-risk liver transplant recipients.

PURPOSE: The purpose of this study was to compare the safety and efficacy of two valganciclovir (VGCV) institutional dosing protocols for cytomegalovirus (CMV) prophylaxis in liver transplant (LT) recipients with CMV serotype donor +/recipient- (D+/R-). METHODS: This was a single-center review of CMV D+/R- adult LT recipients who received VGCV 450 mg/day for 90 days (low-dose) or VGCV 900 mg/day for 180 days (standard-dose). The primary outcome was incidence of CMV disease at 1 year. Secondary outcomes included rates of CMV syndrome, end-organ disease, breakthrough infection, and resistance. Neutropenia, early discontinuation of VGCV, growth colony stimulating factors use (G-CSF), biopsy-proven rejection (BPAR), graft loss, and death at 1 year were analyzed. RESULTS: Ninety-six CMV D+/R- LT recipients were included. Although no difference in CMV disease was observed (low-dose 26% vs. standard-dose 23%, p = 0.71), 75% of CMV infections in the low-dose group presented with end-organ disease. Ganciclovir (GCV) resistance was observed only in the low-dose group (n = 2). Significantly more patients in the standard-dose group developed neutropenia (low-dose 10% vs 60% standard-dose, p < 0.001). In the standard-dose group, 29% required early discontinuation of VGCV (vs. 5% in the low-dose group, p < 0.001), and 20% were treated with G-CSF. Both cohorts had similar rates of BPAR, graft loss, and death at 1 year. CONCLUSIONS: VGCV 900 mg/day for 180 days had higher rates of hematologic adverse effects resulting in frequent treatment interruptions. However, the occurrence of two cases of GCV-resistant CMV disease raises concerns about routinely using low-dose VGCV prophylaxis.

Evaluation of an opioid restrictive pain management initiative in adult kidney transplant recipients.

PURPOSE: Evidence to guide opioid utilization following kidney transplantation is lacking. The purpose of this study is to evaluate the implementation of an opioid restrictive post-operative pain management protocol in adult kidney transplant recipients. METHODS: We analyzed patients who underwent kidney transplant between 1/1/2017 to 8/15/2018. A standardized, opioid restrictive pain management protocol was implemented in February 2018. The primary outcome was quantity of opioid tablets prescribed at discharge. Secondary outcomes included amount of opioid prescribed within first 30 days, number of patient calls for pain, and opioid prescription in electronic medical record (EMR) at 90 days and 1 year. RESULTS: After implementation, significantly fewer opioid tablets were prescribed at discharge (4 vs. 60 tablets, p < .001) and less oral morphine milligram equivalence (OME) were prescribed within 30 days of transplant (38 vs. 300, p < .001). In cohort 2, fewer patients received more than one opioid prescription, more patients received truncal block and only 5 patients received patient controlled analgesia compared to all in cohort 1. CONCLUSION: A standardized, patient-centered pain management strategy after kidney transplantation reduced opioid prescribing without increasing readmissions or clinic calls. This data may be used to inform guidelines for appropriate OME prescribing at discharge after kidney transplantation.

Oropharyngeal candidiasis outcomes in renal transplant recipients receiving nystatin versus no antifungal prophylaxis.

OBJECTIVE: To compare the incidence of oropharyngeal candidiasis (OC), or thrush, in renal transplant recipients receiving nystatin versus no antifungal prophylaxis. METHODS: This was a single-center, retrospective, non-inferiority study of adult renal transplant recipients (RTRs) who received nystatin for 30 days for OC prophylaxis (nystatin group) or no antifungal prophylaxis therapy (No PPX group). The primary outcome was the incidence of OC within 3 months post-transplant. Secondary outcomes included time to OC occurrence and severity of OC. The pre-specified non-inferiority margin was 10%. RESULTS: The incidence of OC within 3 months post-transplant among 257 RTRs was 7.8% (10/128) in the No PPX group and 4.7% (6/129) RTRs in the nystatin group, a risk difference of 3.2% (95% CI, -2.7% to 9.1%, non-inferiority P = .04). The median time to OC was 7.5 days (IQR 6.3-34.3 days) in the nystatin group and 9.5 days (IQR 5.3-30.5 days) in the No PPX group (P = .64). Esophageal candidiasis was observed in 10% (1/10) of RTRs with OC in the No PPX group compared to 16.7% (1/6) RTRs in the nystatin group (P = 1.00). All RTRs with OC achieved symptom resolution with fluconazole and/or nystatin. Two patients in the No PPX group required readmission for decreased oral intake, and OC was diagnosed and treated during their hospital day. CONCLUSIONS: In this retrospective study of adult RTRs, the absence of antifungal prophylaxis demonstrated non-inferiority to 30-day nystatin prophylaxis at reducing the incidence of OC within 3 months of transplant. OC prophylaxis may not be warranted after renal transplant.

Review of Newer Antidiabetic Agents for Diabetes Management in Kidney Transplant Recipients.

OBJECTIVE: This systematic review describes the efficacy, safety, and drug interactions of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose transport protein 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs). DATA SOURCES: Articles were identified by English-language MEDLINE search, published prior to May 2020, using the terms kidney transplant, OR PTDM, OR NODAT, AND metformin, OR DPP4, OR GLP1, OR SGLT2. STUDY SELECTION AND DATA EXTRACTION: All selected studies were included if the study population was composed of adult KTRs who were diagnosed with either impaired glucose tolerance, diabetes mellitus (DM), new-onset diabetes after transplant (NODAT), or posttransplantation diabetes mellitus (PTDM). DATA SYNTHESIS: In KTRs, there is evidence for safety with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors. However, urinary tract infections and a slight initial decrease in renal function may limit use of SGLT2 inhibitors. As compared with the nontransplant type 2 DM population, SGLT2 inhibitors are not as efficacious in KTRs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review provides an overview of the current literature on newer antidiabetic agents, addressing efficacy, safety, and drug interactions to help guide clinical decision-making for their use in KTRs. CONCLUSION: Newer antidiabetic agents have been recommended by the American Diabetes Association for potential cardiovascular, renal, and hypoglycemic benefits. Particular agents, such as DPP-4 inhibitors and GLP-1 RAs may play a role in correcting PTDM-related defects. Clinicians need to take into account both patient-specific and drug-specific characteristics when initiating these agents in KTRs.

Renal Outcomes of Liver Transplantation Recipients Receiving Standard Immunosuppression and Early Renal Sparing Immunosuppression: A Retrospective Single Center Study.

New-onset stage 4-5 chronic kidney disease (CKD) after liver transplantation (LT) is associated with high morbidity, mortality, and economic burden. In 2010, we instituted an early renal sparing immunosuppression (RSI) protocol for LT recipients with severe renal dysfunction (pre-LT dialysis/estimated glomerular filtration rate (eGFR)<30mL/min/1.73 m2 or post-LT acute kidney injury) consisting of 2 doses of basiliximab for induction and delaying tacrolimus to post-LT day 4-7. We examined the effect of early RSI on post-LT renal outcomes. METHODS: Data on all adults who had LT between January 1, 2010, and December 12, 2014 were collected. We calculated the renal risk index (RRI) score for each LT recipient (https://rri.med.umich.edu). Primary outcome was new-onset post-LT stage 4-5 CKD. RESULTS: Of 214 LT recipients, 121 (57%) received early RSI and 93 (43%) received standard immunosuppression. Cumulative incidence of new-onset stage 4-5 CKD was higher in early RSI compared with standard immunosuppression (P = 0.03). Female sex and RRI score were the significant risk factors for development of post-LT stage CKD in the entire study cohort as well as the LT recipients with RRI ≥ sixth decile (high-risk group). CONCLUSIONS: Delaying tacrolimus initiation combined with basiliximab induction did not have a durable effect on long-term renal outcomes in high-risk LT recipients. Further studies are needed to identify the effective strategies to preserve renal function by targeting patients at high risk for CKD progression.

Impact of direct-acting antivirals for hepatitis C virus therapy on tacrolimus dosing in liver transplant recipients.

INTRODUCTION: Direct-acting antivirals (DAAs) have transformed hepatitis C virus (HCV) management post-liver transplant. As HCV clears during DAA treatment, hepatic metabolism improves, resulting in decreased tacrolimus concentrations that may require dose adjustment. The purpose of this study was to determine appropriate management of immunosuppression in liver transplant recipients during and following treatment of HCV. METHODS: This study was a single-center retrospective analysis of 71 liver transplant recipients who were treated for HCV with DAAs. The primary outcome was change in dose-normalized tacrolimus concentrations from the start of DAA treatment to 12 weeks following therapy. RESULTS: The mean change in log-transformed dose-normalized tacrolimus concentrations was a reduction of 0.43 ng/mL/mg (95% CI; 0.26-0.60, P < 0.0001). The greatest decrease occurred in the first 4 weeks of treatment, after which levels stabilized. The overall mean tacrolimus concentration was 4.8 ng/mL (±2.5). Two patients (3%) developed acute cellular rejection and two patients (3%) had graft loss and died. CONCLUSION: From the start of treatment to 12 weeks post-DAA therapy, liver transplant recipients experienced a significant decrease in dose-normalized tacrolimus concentrations. In conclusion, close monitoring of tacrolimus concentrations is warranted during and following treatment with DAAs, as dose increases may be indicated in order to maintain therapeutic concentrations to prevent graft rejection.

Safety and Efficacy of Biologic Agents for the Management of Inflammatory Bowel Disease After Liver Transplantation.

Primary sclerosing cholangitis (PSC) frequently progresses to end-stage liver disease and cirrhosis, requiring liver transplantation. Approximately 70% of patients with PSC have concomitant inflammatory bowel disease (IBD) during their clinical course. After liver transplantation for PSC, corticosteroids and other high-intensity immunosuppressants are initiated to keep IBD in remission. Patients with IBD that is refractory to these agents may need to be managed with biologic therapies. Biologic agents, however, may further increase the risks for malignancy and infection due to their immunosuppressive effects. Thus, to gain a better understanding of the risks and benefits of these agents in this high-risk patient population, we performed a literature search of the PubMed database (2002-2017) to identify studies assessing the efficacy and safety of various biologic agents for the management of IBD in liver transplant recipients. No randomized controlled studies or retrospective comparative studies were identified; however, 15 case reports and case series were identified that met our inclusion criteria. From these case reports, we identified 67 patients who developed de novo or recurrent IBD after liver transplantation and received anti-tumor necrosis factor-α or anti-integrin therapy. Of the 13 published cases reporting clinical response or remission of IBD activity in liver transplant recipients (59 patients), clinical response or remission of IBD was reported in 38 (64.4%) of those patients. Adverse complications reported included cholangitis, oral candidiasis, Clostridium difficile colitis, bacterial pneumonia, cryptosporidiosis, Epstein-Barr virus-positive posttransplantation lymphoproliferative disease, and hepatotoxicity. Given the limited literature (case reports and case series) highlighted in this review, biologic agents such as tumor necrosis factor-α inhibitors and integrin inhibitors commonly used for moderate to severe IBD may be appropriate after liver transplantation; however, consideration of risk versus benefit should always occur in a patient-specific manner.

Pharmacologic Strategies to Prevent Blood Loss and Transfusion in Orthotopic Liver Transplantation.

Patients undergoing orthotopic liver transplantation are at risk of both life-threatening blood loss and thrombosis due to preexisting liver dysfunction and major intra- and postoperative coagulopathy. Traditional laboratory markers of hemostasis and coagulopathy are often inadequate to describe the alterations. Whole blood global viscoelastic tests, thromboelastography, and thromboelastometry may provide more complete pictures of the hematologic derangements and allow for more targeted therapy to prevent blood loss and massive transfusion. Antifibrinolytic medications such as aprotinin, tranexamic acid, and [Latin Small Letter Open E]-aminocaproic acid have been used successfully to reduce blood loss and the need for transfusion, although most published data are from small prospective trials or larger retrospective cohorts. Recombinant factor VIIa has not been shown to improve outcomes. Although transfusion needs have been associated with adverse outcomes, no studied medications for prevention of blood loss and transfusion have been associated with improved mortality or graft survival post-liver transplant.

Evaluation of a Weight-based Rabbit Anti-thymocyte Globulin Induction Dosing Regimen for Kidney Transplant Recipients.

STUDY OBJECTIVE: Although rabbit anti-thymocyte globulin (rATG) is commonly used as induction therapy for kidney transplantation, dosing is not standardized. Recently available findings suggest that even subtle differences in the cumulative dose of rATG induction may have an impact on acute rejection rates for patients receiving steroid-minimization maintenance immunosuppression. This investigation evaluated the potential consequences of rounding and capping rATG doses in patients receiving steroid-containing maintenance immunosuppression when calculating the dose based on actual body weight. DESIGN: Single-center retrospective cohort study. SETTING: A large academic medical center. PATIENTS: A total of 261 adult kidney transplant recipients between July 1, 2010, and December 31, 2012, who received rATG induction and were maintained on tacrolimus, mycophenolate, and prednisone. METHODS AND MEASUREMENTS: Incidences of biopsy-confirmed acute rejection, opportunistic infections and hematologic effects within 12 months posttransplant were assessed for patients receiving a cumulative rATG dose of 5 mg/kg or higher (5.2 ± 0.2 mg/kg, n=138) compared with those who received a cumulative rATG dose lower than  5 mg/kg (4.5 ± 0.6 mg/kg, n=123). The groups had similar baseline characteristics, immunologic risk, and indications for rATG induction. The incidence of clinically relevant biopsy-confirmed acute rejection was low and similar between the groups (8.7% for rATG of 5 mg/kg or higher vs 8.9% for rATG lower than  5 mg/kg, p=0.944). Patient survival, all-cause graft survival, and graft function did not differ between the groups. Incidences of cytomegalovirus and BK virus infection as well as the extent and duration of lymphopenia were also similar between the groups. CONCLUSIONS: In combination with triple maintenance immunosuppression consisting of tacrolimus, mycophenolate, and prednisone, modest differences in the cumulative rATG dose were not associated with increased risk of acute rejection. Measures to optimize rATG utilization present opportunities for cost-saving without sacrificing efficacy in this patient population.

Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting.

Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldaprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.