BackgroundCytomegalovirus (CMV) is a common infection in abdominal transplant recipients (ATR). Prevention of CMV in the highest risk population (CMV IgG donor+/recipient-) is critical as CMV is associated with negative outcomes. Guideline recommended prophylactic valganciclovir dosing is 900 mg daily for 6 months in this population. However, reduced dosing strategies are utilized in practice. MethodsThis single center, retrospective study in adult ATR compared full valganciclovir prophylactic dosing (900 mg daily for 6 months) to reduced dosing (900 mg daily for 3 months, then 450 mg daily for 3 months). The primary endpoint was incidence of CMV infection with viral load >1000 IU/mL. Secondary endpoints included incidence of CMV infection with viral load 200-1000 IU/mL, neutropenia, and leukopenia. ResultsIncidence of CMV infection with viral load >1000 IU/mL (29% vs. 27%, p = 1) or CMV infection with viral load 200-1000 IU/mL (6% vs. 12%, p = .421) did not differ significantly between 68 ATR in reduced and full dosing groups, as well as incidence of leukopenia (94% vs. 97%, p = 1) and neutropenia (77% vs. 70%, p = .586). ConclusionsThere was no difference in the incidence of CMV infection, neutropenia, or leukopenia of the two dosing regimens, although time to CMV diagnosis was different.

The use of non‐opioid analgesics following surgery has proven beneficial in managing pain and decreasing adverse outcomes following surgery. Data assessing outcomes related to opioid use is limited in kidney transplant recipients (KTRs). We evaluated the effectiveness of implementing a reduced to no opioid use protocol in KTRs. This retrospective cohort study included adult KTRs between January 2017 and July 2019 with a multimodal analgesic protocol (MAP), focused on limiting opioids, implemented in August 2018. We compared analgesic requirements in morphine milligram equivalents (MME) during transplant admissions between the MAP cohort and traditional cohort. There were 217 KTRs who met the criteria. Inpatient opioid use was significantly reduced in the MAP cohort (16.5 ± 19.2 MME/day vs 24.7 ± 19.7 MME/day; P <.05) with no significant difference in pain scores. No use of opioids within six months of discharge was significantly increased in the MAP cohort (50% vs 7%; P <.001), and there were no reported deaths at six months in either cohort. The use of multimodal analgesia is beneficial in KTRs to provide adequate pain control with limited to no exposure of opioids during admission or at discharge.

Renal retransplant patients have decreased graft survival compared with primary renal transplant patients. Alemtuzumab induction is often used at the time of retransplant; however, the literature surrounding alemtuzumab induction in renal retransplant patients is limited. In this single-center, retrospective, observational study, we aimed to determine the 1-year incidence of infections and transplant outcomes in renal retransplant patients who received alemtuzumab induction. Thirtyfour patients who received alemtuzumab met inclusion criteria and were included in the final analysis. Twenty-two (64.7%) of these patients acquired infections. Of these, 7 patients (31.8%) acquired infections that resulted in hospitalization or intravenous antibiotics. The most common infections were urinary tract infections (n = 10; 29.4%), cytomegalovirus DNAemia (n = 7; 20.6%), and BK virus (n = 6; 17.6%). The use of steroid maintenance therapy after alemtuzumab induction did not increase the number of infections compared with patients with a steroid-free interval after alemtuzumab induction. The number of patients who developed de novo donor -specific antibodies (DSA) was 11 (32.4%) with only 1 of these patients having DSA before retransplantation. The incidence of acute cellular rejection was 2.9% (n = 1). There was no graft loss, and patient survival was 97% (n = 33). There were no significant differences in infection rate or DSA development between alemtuzumab and the other induction agents, antithymocyte globulin and basiliximab, among retransplanted patients. Alemtuzumab induction in renal retransplant patients resulted in similar bacterial and viral infection rates as previously reported in the literature and did not negatively impact graft and patient survival.

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for >= 3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C >= 100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; P-interaction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for >= 3 years, if baseline LDL-C is >= 100 mg/dL, or if achieved LDL-C is low.

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Post-transplant anemia (PTA) is highly prevalent in kidney transplant recipients (KTR) and is associated with increased mortality, cardiovascular disease, and graft loss. In the early post-transplant (Tx) period, risk for a severe anemia is amplified by inflammatory status, recovering graft function and immunosuppressive medications. ESA are effective in the treatment of the anemia of patients (pts) with CKD and use has been adapted for the treatment of PTA. The purpose of this study is to investigate the effect of ESA on the correction of PTA in KTR within the first month post-Tx. Methods Retrospective analysis evaluating 114 KTRs for the incidence and management of anemia immediately post-Tx. Data was analyzed by comparing pts who received ESA therapy during the first month following Tx with pts who did not receive ESA. Hemoglobin (Hgb) values were collected for 3 month post-Tx to evaluate resolution of anemia (Hgb 12 - 13 g/dL). ESA doses were collected for one month from the time of Tx. All pts received induction therapy in addition to tacrolimus and mycophenolate therapy. Results Demographic and Tx characteristics were comparable in both groups. Of the 114 pts, 19 (17%) KTR received ESA vs 95 (83%) that did not receive ESA. Mean cumulative ESA doses of erythropoietin and darbepoetin were 575 units/kg and 1.6 mcg/kg, respectively. No difference in baseline Hgb was observed, ESA 9.5 mg/dL vs non-ESA 10 mg/dL (p=0.06). At 3 months, Hgb was higher in the non-ESA group (11 g/dL) vs ESA group (10 g/dL, p=0.01). Pts achieving Hgb goal of 12-13 g/dL in the non-ESA vs ESA group was 23% and 21% (p=1.0), respectively. Incidence of blood transfusions were similar between ESA and non-ESA groups (55% and 63%, p=0.98). Scr was similar between groups. ESA group was more likely to return to dialysis and experience rejection. Conclusion Dosing consistent with the management of anemia in CKD appears to be ineffective when applied to KTR with post-Tx anemia, particularly in the setting of myelosuppressive medications. This data suggests that factors other than erythropoietin deficiency or resistance may contribute to PTA. As ESA continues to be used in current practice, further studies are warranted to investigate appropriateness of CKD dosing in PTA or the need for alternative dosing strategies.

Chronic lithium exposure is predominantly associated with chronic tubulointerstitial nephropathy (CTN), characterized by lesions of interstitial fibrosis, thickened tubular basement membranes, and renal cysts from the distal tubule and collecting duct (1, 2). Molecular studies suggest accumulation in distal tubules and inhibition of cellular activity involving glycogen synthase kinase-3A and inositol monophosphate (3Y5). Reduced GFR develops in 15% to 20% of patients over 10 to 20 years of drug exposure (3, 6). Predisposing risk factors to developing nephropathy are long-term administration, high cumulative lithium exposure, episodes of acute toxicity, hypertension, and diabetes mellitus (2, 3). Individuals with CTN are at risk for progression to ESRD despite lithium discontinuation (1). Lithium clearance is directly proportional to GFR and its cations freely diffuse across glomerular membranes to the same extent as sodium and water (7, 8). Elimination half-life of lithium is dependent on duration of therapy. Pharmacokinetic studies during prolonged use demonstrate a two-fold increase in halflife (7). Reduced clearance combined with chronic exposure gradually increases lithium concentrations, leading to chronic toxicity (8). Maintenance treatment of bipolar disorder targets concentrations of 0.6 to 1.2 mEq/L with acceptable variation range of 0.5 to 1.5 mEq/L (7, 9). Symptoms associated with toxicity include nausea, vomiting, altered mental status, confusion, tremor, weakness, apathy, hyperreflexia, slurred speech, memory deficits, seizure, and coma (7). Chronic toxicity may occur with modest lithium elevations in patients receiving long-term therapy. Symptom severity does not correlate with serum concentration, and toxicity is frequently reported when concentrations are well within recommended range (9).

OBJECTIVE:To assess the impact on student performance of increased active learning strategies in a foundational pharmacokinetics course and a clinical pharmacokinetics course over an 8-year period.DESIGN:A foundational pharmacokinetics course with a lecture-with-active-learning (LAL) format was redesigned to a recitation-format (REC) using smaller groups of students (ie, the class divided into thirds) and eventually to a team-based learning (TBL) format. The lecture-based clinical pharmacokinetics course was redesigned to a case-based learning (CBL) format to encourage preclass preparation with class time used for application; this course format underwent minor redesigns over an 8-year period. An analysis of covariance (ANCOVA) was performed on examination scores in the clinical course based on foundational course format changes. End-of-semester student evaluations of the course were used as a secondary measure of impact.ASSESSMENT:The highest grades in the clinical course were associated with the TBL format within the foundational course compared to LAL format (effect size 0.78). The REC format in the foundational course compared to LAL was associated with higher performance in the clinical course (effect size 0.50). Examination performance in the clinical course had a small increase when the foundational course was transitioned from the REC format to the TBL format (effect size 0.27). There was a trend within the foundational course that overall student ratings of the course decreased with enhanced self-directed learning; there was no change in overall ratings of the clinical course.CONCLUSION:Increasing the amount of active learning within the foundational pharmacokinetics course increases performance in the clinical course but this increase in performance may be associated with decreases in student evaluations of the foundational course.

We quantified the rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation. Twelve donors were studied pre-donation (baseline); 8 were retested at a mean +/- SD of 11 +/- 3 days after donation (T1), 10 were retested at a mean of 91 +/- 9 days after donation (T2), and 10 were retested at a mean of 185 +/- 17 days after donation (T3). Liver and spleen volumes were measured with computed tomography (CT) and single-photon emission computed tomography (SPECT). Hepatic metabolism was assessed with caffeine and erythromycin, and hepatic blood flow (HBF) was assessed with cholates, galactose, and the perfused hepatic mass (PHM) by SPECT. The regeneration rates (mL kg1 of body weight day1) by CT were 0.60 +/- 0.22 mL from the baseline to T1, 0.05 +/- 0.02 mL from T1 to T2, and 0.01 +/- 0.01 from T2 to T3; by SPECT they were 0.54 +/- 0.20, 0.04 +/- 0.01, and 0.01 +/- 0.02, respectively. At T3, the liver volumes were 84%+/- 7% of the baseline according to CT and 92%+/- 13% of the baseline according to SPECT. Changes in the hepatic metabolism did not achieve statistical significance. At T1, the unadjusted clearance ratios with respect to the baseline were 0.75 +/- 0.07 for intravenous cholate (P<0.001), 0.88 +/- 0.15 for galactose (P=0.07), 0.84 +/- 0.08 for PHM (P=0.002), and 0.83 +/- 0.19 for the estimated HBF (P=0.06). At T1, these ratios adjusted per liter of liver were up to 50% greater than the baseline values, suggesting recruitment of HBF by the regenerating liver. Increased cholate shunt, increased spleen volume, and decreased platelet count, were consistent with an altered portal circulation. In conclusion, initial hepatic regeneration is rapid, accounts for nearly two-thirds of total regeneration, and is associated with increases in HBF and cholate uptake. Right lobe donation alters the portal circulation of living donors, but the long-term clinical consequences, if there are any, are unknown. Liver Transpl 19:292304, 2013. (c) 2013 AASLD.

Therapeutic development includes the activities necessary to bring a new medicinal compound (chemical or biologic) or medical device to market. Following drug discovery or development of a new device, successful preclinical studies result in an Investigational New Drug (IND) application (United States only; Clinical Trials Exemption Certificate in the United Kingdom). Once the IND is filed, a team-driven process begins that tests the efficacy and safety of a new therapeutic in humans. This process, known as clinical development, has traditionally been divided into 4 phases, with large-scale phase 3 pivotal trials in patients with a specific disease leading to registration and postmarketing studies.1 The authors thank Daniel Benjamin, MD, and Paul Watkins, MD, for their critical review of the manuscript.

In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive agents such tacrolimus, cyclosporine, sirolimus and everolimus require therapeutic drug monitoring. The study of germline variation of the genome has opened novel opportunities to individualize therapy. Among the currently available immunosuppressive agents, cyclosporine, tacrolimus and mycophenolic acid are in vitro substrates of the UGT1A and 2B families of glucuronidation enzymes. Mycophenolic acid, either given as mycophenolate mofetil or mycophenolate sodium, is the most frequently used antiproliferative immunosuppressant. Mycophenolic acid is a prodrug which is rapidly de-esterified in the gut wall, blood, liver and tissue to the active moiety, mycophenolic acid (MPA). MPA undergoes significant hepatic metabolism to several metabolites. The 7-hydroxyglucuronide MPA is the major metabolite and is inactive. This paper reviews the current status of the genetic associations between germline UGT variants and the pharmacokinetics and pharmacodynamics of mycophenolic acid. Our conclusive assessment of the studies conducted so far is that these germline markers are not ready to be used in the clinic to individualize mycophenolic acid dosing and improve outcome. Novel approaches are required to identify new genetic determinants of outcomes in transplantation.

Transplant pharmacists have been recognized as an essential part of the transplant team by their colleagues along with several governing and professional organizations. The specific education, training and responsibilities of the transplant pharmacist have not been clearly delineated in the literature. Various pharmacists across the country have been called upon to serve on the transplant team necessitating standardization of their fundamental and desirable activities. Therefore, the purpose of this manuscript is to describe the training and role of a transplant pharmacist on the patient care team and provide a roadmap to implementation of novel transplant pharmacy services.

Journal Article Pursuing a career in transplant pharmacy Get access Alison Eisenhart, Pharm.D., Alison Eisenhart, Pharm.D. Clinical Specialist, Solid Organ Transplant University of North Carolina Hospitals 101 Manning Drive Chapel Hill, NC 27514 aeisenha@unch.unc.edu Search for other works by this author on: Oxford Academic Google Scholar Robert E. Dupuis, Pharm.D., BCPS Robert E. Dupuis, Pharm.D., BCPS Associate Professor, Clinical Pharmacy School of Pharmacy University of North Carolina Chapel Hill, NC 27514 Search for other works by this author on: Oxford Academic Google Scholar American Journal of Health-System Pharmacy, Volume 65, Issue 24, 15 December 2008, Pages 2331–2333, https://doi.org/10.2146/ajhp080061 Published: 15 December 2008

Objective. To assess the redesign of a clinical pharmacokinetics course that incorporated case-based learning to enhance group interaction and individual participation. Design. The clinical pharmacokinetics course was divided into 3 sections based on content. Section 1 utilized case-based learning with small in-class groups; section 2 used a more traditional style of teaching, and section 3 was taught with case-based learning but using large in-class groups. The case- based learning approach was assessed using examination scores and attitudinal surveys. Assessment. Students enjoyed the applied format of case-based learning. Examination scores were higher when case-based learning was used than in historical controls. Conclusions. Case-based learning allowed class-time to be used for higher levels of learning and assessment instead of the more typical content delivery.

Objectives This study was designed to prospectively determine, in patients with an acute coronary syndrome, whether the inflammatory marker, C-reactive protein (CRP), measured at hospital admission, discharge, and 1 month later has incremental value to predict outcomes at 1 year.Background The clinical utility of CRP measurements in patients with acute coronary syndromes remains uncertain. Limitations of previous studies have been retrospective design and incomplete adjustment for readily available clinical prognosticators.Methods The CRP marker was measured at admission, hospital discharge, and 1 month later in consecutive patients hospitalized for acute coronary syndromes in 8 tertiary and secondary hospitals. The primary outcome was a composite of death, nonfatal myocardial infarction (MI), and unstable angina (UA) with electrocardiogram (ECG) changes at 1 year.Results A total of 1,210 patients, age 62 +/- 12 years, 64% with acute myocardial infarction (MI) and 36% with unstable angina (UA), were recruited. At 1 year, the primary outcome occurred in 142 patients (11.7%) and included 58 deaths (4.8%), 79 nonfatal MIs (6.5%), and 26 UA episodes with ECG changes (2.1%). The unadjusted odds ratios (ORs) (95% confidence intervals) of CRP values at admission, hospital discharge, and 1 month later for the occurrence of the primary outcome were 1.20 (1.06 to 1.36), 0.98 (0.85 to 1.14), and 1.23 (1.00 to 1.50), respectively. After multivariate adjustment, ORs were 1.04 (0.91 to 1.20), 0.90 (0.77 to 1.06), and 1.12 (0.93 to 1.34), respectively. The individual components of the primary outcome were also not independently associated with any of the 3 CRP measurements.Conclusions The modest predictive ability of CRP following admission for an acute coronary syndrome disappeared after adjusting for common clinical variables. This large prospective study does not support the incremental value of measuring CRP in this clinical setting.

Objective. To assess the redesign of a clinical pharmacokinetics course that incorporated case-based learning to enhance group interaction and individual participation. Design. The clinical pharmacokinetics course was divided into 3 sections based on content. Section 1 utilized case-based learning with small in-class groups; section 2 used a more traditional style of teaching, and section 3 was taught with case-based learning but using large in-class groups. The casebased learning approach was assessed using examination scores and attitudinal surveys. Assessment. Students enjoyed the applied format of case-based learning. Examination scores were higher when case-based learning was used than in historical controls. Conclusions. Case-based learning allowed class-time to be used for higher levels of learning and assessment instead of the more typical content delivery.