Alemtuzumab in Renal Retransplantation - Transplant Outcomes and Associated Infections.

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. Thirty-four 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.

Perioperative glucose management and outcomes in liver transplant recipients: A qualitative systematic review.

AIM: To investigate the relationship between post-liver transplantation (LT) glycemic control and LT outcomes. METHODS: A qualitative systematic review on relevant prospective interventions designed to control glucose levels including insulin protocols. Studies investigating an association between glycemic control and post-LT outcomes such as mortality, graft rejection, and infection rate were reviewed. PubMed, EMBASE, and other databases were searched through October 2016. RESULTS: Three thousands, six hundreds and ninety-two patients from 14 studies were included. Higher mortality rate was seen when blood glucose (BG) ≥ 150 mg/dL (P = 0.05). BG ≥ 150 mg/dL also led to higher rates of infection. Higher rates of graft rejection were seen at BG > 200 mg/dL (P < 0.001). Mean BG ≥ 200 mg/dL was associated with more infections (P = 0.002). Nurse-initiated protocols and early screening strategies have shown a reduction in negative post-LT outcomes. CONCLUSION: Hyperglycemia in the perioperative period is associated with poor post-LT outcomes. Only a few prospective studies have designed interventions aimed at managing post-LT hyperglycemia, post-transplant diabetes mellitus (PTDM) and their impact on post-LT outcomes.

An eight-year retrospective study in "flipped" pharmacokinetics courses.

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.

Use of case-based learning in a clinical pharmacokinetics course.

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.

Students perceptions of the incorporation of games into classroom instruction for basic and clinical pharmacokinetics.

OBJECTIVE: To develop classroom games as alternatives to traditional pharmacokinetic instruction. DESIGN: three classroom games were created for the following purposes: simple semester review, application of pharmacokinetics in a community-pharmacy setting, and development of critical thinking skills and concept application. All the games incorporated some degree of group activity. ASSESSMENT: A survey was conducted of students' attitudes towards the incorporation of games into the classroom. A comparison of final examination scores to scores from the previous year was used to determine whether incorporating games hindered learning. CONCLUSIONS: Overall, students found the games enjoyable, but some students questioned how much they learned. Although the games appeared to have a positive impact on grades and incorporated more than just factual, book knowledge (eg, critical thinking skills), determining how these games improved learning will require further assessment.

Gender-related differences in mycophenolate mofetil-induced gastrointestinal toxicity in rats.

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is included in current combination immunosuppressive regimens following organ transplant. Treatment with MMF often results in dose-limiting gastrointestinal (GI) side effects. The underlying mechanisms responsible for these side effects are not fully understood, but exposure of the intestinal epithelia to MPA during enterohepatic recycling may be involved. The present study demonstrated that female rats are more susceptible to MMF-induced GI toxicity than male rats. Female Sprague-Dawley rats treated chronically with an oral dose of 50 mg of MPA equivalents/kg/day experienced greater GI toxicity than male rats, as measured by diarrhea grade and weight loss. Intestinal microsomes harvested from the upper jejunum of female rats had approximately 3-fold lower MPA glucuronidation rates compared with male rats. In the remaining areas of the small and large intestine, there was also a trend toward decreased glucuronidation in the female rats. The area under the plasma concentration-time curve (AUC) for MPA following an oral dose of 50 mg of MPA equivalents/kg was roughly similar between genders, whereas the AUC for mycophenolic acid phenolic glucuronide (MPAG) was significantly lower in female rats. Female rats also excreted half of the biliary MPAG as male rats. The greater susceptibility of female rats to MMF-induced gastrointestinal toxicity, despite diminished intestinal MPA exposure via reduced biliary excretion of MPAG, may result from reduced protection of enterocytes by in situ glucuronidation. Likewise, susceptibility to MMF-induced GI toxicity in humans may also result from variable intestinal glucuronidation due to UDP glucuronosyltransferase polymorphisms or differential expression.

The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil.

The objective of this study was to investigate the effect of concurrent antibiotic administration on the disposition of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) after oral administration of mycophenolate mofetil (MMF) in healthy subjects. Eleven healthy subjects were enrolled. The study was divided into 4 treatment periods. Subjects received MMF as a single oral 1-g dose alone and were then randomized to 3 antibiotic treatment periods. The 3 periods included norfloxacin, metronidazole, and a combination of norfloxacin and metronidazole. Antibiotic treatment was started 3 days prior to each MMF pharmacokinetic study day and was given for a total of 5 days. On day 4 of each antibiotic phase, subjects received a single 1-g oral dose of MMF. Plasma and urine samples were obtained over 48 hours after the MMF dose in all treatment periods and were quantitatively measured for MPA and MPAG. Pharmacokinetic parameters for MPA and MPAG were determined for all periods. Compared to MMF alone, the area under the plasma concentration versus time curve (AUC) of MPA was reduced by an average of 10%, 19%, and 33% when given with norfloxacin, metronidazole, and norfloxacin plus metronidazole, respectively. The AUC of MPAG was also reduced on average by 10%, 27%, and 41% in the corresponding periods. The combination of norfloxacin and metronidazole significantly reduced the AUC of MPA and MPAG in healthy subjects. This likely occurs as a result of reduced enterohepatic recirculation.

Evaluation of estimated and measured creatinine clearances for predicting the pharmacokinetics of vancomycin in adult liver transplant recipients.

This study examined the pharmacokinetics and dosing requirements of vancomycin in adult liver transplant recipients and also evaluated the predictability of determining vancomycin-dosing requirements utilizing an estimated creatinine clearance (CrCl) approach. Twenty adult liver transplant recipients were included in this analysis. Vancomycin pharmacokinetic parameters and dosing requirements calculated from estimated CrCl and population-based pharmacokinetic equations were compared with values calculated using serum concentrations and assuming a one-compartment model. Compared with the values obtained using equations to estimate the CrCl and vancomycin pharmacokinetics (t, Cl, and Vd), the actual values were statistically different for half-life and clearance (11.0 vs. 16.4 hours and 52 vs. 36 mL/min, respectively; P < 0.01). Additionally, CrCl that were estimated using population-based formulas significantly overestimated actual CrCl calculated using 24-hour urine collections (65-78 vs. 43 mL/min; P < 0.05). The results from this study indicate that serum creatinine concentrations do not adequately predict glomerular filtration rates (GFR) or vancomycin clearance in adult liver transplant recipients. Based on these results, the use of 24-hour urine CrCl to predict GFR and serum concentrations to properly dose vancomycin is advocated.

Tacrolimus dosing requirements and concentrations in adult living donor liver transplant recipients.

Living donor liver transplantation in adult recipients is becoming increasingly common. The liver metabolizes most drugs, including immunosuppressive agents. Right-lobe grafts used in adult living donor liver transplantation consist of only 50% to 60% of the total liver. The purpose of this study is to determine whether there is a difference between tacrolimus doses and concentrations in patients who received a partial liver transplant from a living donor (LRD) versus those who received a whole-liver transplant from a cadaveric donor (CAD). Thirteen LRD recipients and 13 CAD recipients who underwent transplantation between April 1998 and July 2000 were included in this analysis. A CAD control group matched for age, sex, and race was used for comparison. Tacrolimus doses and concentrations were analyzed weekly for the first 4 weeks, then monthly for 6 months posttransplantation. There was no difference in acute rejection rates, renal and liver function test results, or number of potentially interacting medications administered between groups. LRD recipients required significantly lower doses of tacrolimus compared with CAD recipients at 2 weeks (0.058 v 0.110 mg/kg/d; P <.01), 3 weeks (0.068 v 0.123 mg/kg/d; P <.02), 4 weeks (0.086 v 0.141 mg/kg/d; P <.02), 2 months (0.097 v 0.141 mg/kg/d; P <.03), and 3 months (0.099 v 0.138 mg/kg/d; P <.03). Tacrolimus 12-hour trough concentrations were similar between groups at all times except for 2 weeks posttransplantation, when LRD recipients' concentrations were significantly greater than those of CAD recipients (12.4 v 9.5 ng/mL; P <.03). In addition, in the first month posttransplantation, LRD recipients were more likely to have greater concentrations of tacrolimus (>15 ng/mL; 22.1% v 9.2%; P <.01). In conclusion, LRD recipients have significantly decreased tacrolimus dosing requirements compared with CAD recipients during the first 3 months posttransplantation despite having similar tacrolimus concentrations.