The Effect of Tacrolimus Trough Variability on Kidney Transplant Outcomes.

PURPOSE: Variability in tacrolimus levels has been associated with increased rejection, graft loss, and de novo donor-specific antibody (dnDSA) development in kidney transplant recipients (KTRs); however, limited data on alemtuzumab induction or infection exist. We sought to determine the impact of tacrolimus variability in KTRs on dnDSAs, graft outcomes, and infections 3 years posttransplant after alemtuzumab induction. METHODS: Adult KTRs from January 1, 2013, to December 31, 2017, receiving alemtuzumab and tacrolimus-based immunosuppression at a single center were included. Tacrolimus variability was calculated using coefficient of variability (CV), and high CV was defined as ≥30%. Graft and infectious outcomes were assessed between high and low CV groups. RESULTS: Two hundred fourteen KTRs were included. The median tacrolimus CV from 0 to 3 months and from 3 to 12 months was 28.1% and 25.8%, respectively. Recipients with high CV had decreased glomerular filtration rate at 3 and 12 months (67.7 ± 35.48 vs 80.7 ± 29.3, P = .01 and 70.9 ± 35.4 vs 83.3 ± 30.2, P = .015). High CV was also associated with increased cytomegalovirus viremia and disease (19.6% vs 9.3%, P = .046 and 6.4% vs 17.9%, P = .015). No difference in biopsy-proven acute rejection, survival, or dnDSA development at 3 years was observed. CONCLUSIONS: High tacrolimus variability was associated with significantly reduced graft function and increased cytomegalovirus viremia and disease but not biopsy-proven acute rejection, survival, or dnDSA development.

The impact of post-transplant diabetes mellitus on liver transplant outcomes.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is common after liver transplantation (LT). Yet, how PTDM relates to graft outcomes and survival needs elucidation as more individuals are transplanted for nonalcoholic fatty liver disease (NAFLD). METHODS: This single-center, retrospective study of adult LT recipients (2003-2016) identified PTDM incidence and associations with graft steatosis, rejection, and post-LT patient survival. Multivariable analysis investigated predictors of PTDM. Kaplan-Meier curves depicted patient survival 5 years post-LT. RESULTS: Among 415 adult LT recipients, 23% had pre-LT DM and 13% were transplanted for NAFLD. PTDM incidence was 34.7%, 46.9%, and 56.2% and overall survival was 90%, 80.9%, and 71.7% at 1, 3, and 5 years, respectively. Over a third of non-NAFLD patients developed PTDM. Half of PTDM cases developed by 6 months and 75% by 12 months. The PTDM group had more rejection episodes compared to no PTDM (31.9% vs 21.8%, P = 0.055), with trends toward worse patient survival 5 years post-LT (log-rank test P = 0.254). Age was the only significant predictor of PTDM. CONCLUSIONS: Post-transplant diabetes mellitus occurs rapidly in the post-LT period and is a significant problem for both NAFLD and non-NAFLD LT recipients. Age is a significant risk factor for PTDM. Outcomes trended toward increased rejection and worse survival among PTDM individuals, suggesting the benefit of early strategies targeting glucose control.

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.

Prescribing pharmacists in the ambulatory care setting: Experience at the University of North Carolina Medical Center.

PURPOSE: The prescribing authorities, clinical activities, and productivity documentation strategies of ambulatory care clinic-based pharmacists practicing within a large academic health system are described. SUMMARY: North Carolina law encourages progressive pharmacy practice through acquisition of the clinical pharmacist practitioner (CPP) designation. Qualified CPPs are authorized to provide collaborative drug therapy management services, including medication prescribing and ordering of laboratory tests, according to defined protocols and under physician supervision. The University of North Carolina Medical Center has approximately 30 CPPs deployed across a wide range of ambulatory care clinical practice sites. This article describes (1) the pharmacy department's implementation of an ambulatory care practice model, (2) the credentialing and privileging process leading to granting of prescribing privileges, (3) metrics used to demonstrate the impact of CPP activities, (4) recommended general criteria for ambulatory care practice site identification, and (5) strategies for overcoming barriers to successful implementation of ambulatory care-focused clinical pharmacist services. Aggregated intervention-tracking data compiled by seven of the medical center's CPP ambulatory care practice sites indicate extensive CPP involvement in direct patient care encounters and patient or provider consultations, with large numbers of medication-related interventions to support institutional cost-avoidance and revenue goals. CONCLUSION: CPPs deployed at the medical center's ambulatory care clinics have had a positive impact on clinical and cost outcomes, improving patient care through interventions, contributing to readmission reduction efforts, generating indirect revenue through cost avoidance, and generating new revenue through billing for patient visits.

Evaluation of Low- Versus High-dose Valganciclovir for Prevention of Cytomegalovirus Disease in High-risk Renal Transplant Recipients.

BACKGROUND: Despite proven efficacy of prolonged cytomegalovirus (CMV) prophylaxis using valganciclovir 900 mg/day, some centers use 450 mg/day due to reported success and cost savings. This multicenter, retrospective study compared the efficacy and safety of 6 months of low-dose versus high-dose valganciclovir prophylaxis in high-risk, donor-positive/recipient-negative, renal transplant recipients (RTR). METHODS: Two hundred thirty-seven high-risk RTR (low-dose group = valganciclovir 450 mg/day [n = 130]; high-dose group = valganciclovir 900 mg/day [n = s7]) were evaluated for 1-year CMV disease prevalence. Breakthrough CMV, resistant CMV, biopsy-proven acute rejection (BPAR), graft loss, opportunistic infections (OI), new-onset diabetes after transplantation (NODAT), premature valganciclovir discontinuation, renal function and myelosuppression were also assessed. RESULTS: Patient demographics and transplant characteristics were comparable. Induction and maintenance immunosuppression were similar, except for more early steroid withdrawal in the high-dose group. Similar proportions of patients developed CMV disease (14.6% vs 24.3%; P = 0.068); however, controlling CMV risk factor differences through multivariate logistic regression revealed significantly lower CMV disease in the low-dose group (P = 0.02; odds ratio, 0.432, 95% confidence interval, 0.211-0.887). Breakthrough and resistant CMV occurred at similar frequencies. There was no difference in renal function or rates of biopsy-proven acute rejection, graft loss, opportunistic infections, or new-onset diabetes after transplantation. The high-dose group had significantly lower mean white blood cell counts at months 5 and 6; however, premature valganciclovir discontinuation rates were similar. CONCLUSIONS: Low-dose and high-dose valganciclovir regimens provide similar efficacy in preventing CMV disease in high-risk RTR, with a reduced incidence of leukopenia associated with the low-dose regimen and no difference in resistant CMV. Low-dose valganciclovir may provide a significant cost avoidance benefit.

Genes and beans: pharmacogenomics of renal transplant.

Advances in the management of patients after solid organ transplantation have led to dramatic decreases in rates of acute rejection, but long-term graft and patient survival have remained unchanged. Individualized therapy after transplant will ideally provide adequate immunosuppression while limiting the adverse effects of drug therapy that significantly impact graft survival. Therapeutic drug monitoring represents the best approximation of individualized drug therapy in transplant at this time; however, obtaining pharmacogenomic data in transplant patients has the potential to enhance our current practice. Polymorphisms of target genes that impact pharmacokinetics have been identified for most immunosuppressants, including tacrolimus, cyclosporine, mycophenolate, azathioprine and sirolimus. In the future, pre-emptive assessment of a patient's genetic profile may inform drug selection and provide information on specific doses that will improve efficacy and limit toxicity.

Current trends in immunosuppressive therapies for renal transplant recipients.

PURPOSE: Current trends in immunosuppressive therapies for renal transplant recipients are reviewed. SUMMARY: The common premise for immunosuppressive therapies in renal transplantation is to use multiple agents to work on different immunologic targets. The use of a multidrug regimen allows for pharmacologic activity at several key steps in the T-cell replication process and lower dosages of each individual agent, thereby producing fewer drug-related toxicities. In general, there are three stages of clinical immunosuppression: induction therapy, maintenance therapy, and treatment of an established acute rejection episode. Only immunosuppressive therapies used for maintenance therapy are discussed in detail in this review. The most common maintenance immunosuppressive agents can be divided into five classes: (1) the calcineurin inhibitors (CNIs) (cyclosporine and tacrolimus), (2) costimulation blockers (belatacept), (3) mammalian target of rapamycin inhibitors (sirolimus and everolimus), (4) antiproliferatives (azathioprine and mycophenolic acid derivatives), and (5) corticosteroids. Immunosuppressive regimens vary among transplantation centers but most often include a CNI and an adjuvant agent, with or without corticosteroids. Selection of appropriate immunosuppressive regimens should be patient specific, taking into account the medications' pharmacologic properties, adverse-event profile, and potential drug-drug interactions, as well as the patient's preexisting diseases, risk of rejection, and medication regimen. CONCLUSION: Advancements in transplant immunosuppression have resulted in a significant reduction in acute cellular rejection and a modest increase in long-term patient and graft survival. Because the optimal immunosuppression regimen is still unknown, immunosuppressant use should be influenced by institutional preference and tailored to the immunologic risk of the patient and adverse-effect profile of the drug.

Bortezomib in kidney transplant recipients with antibody mediated rejection: three case reports.

Here, we report our experience on three patients with AMR who were treated with bortezomib after other therapeutic interventions had failed. Bortezomib was well tolerated by two of the three patients. The third patient developed worsening thrombocytopenia following the second dose. Despite a low adverse event profile, none of the three patients conclusively responded to the bortezomib treatment. As a result of the difference in our results from that of other centers we feel that a larger prospective study is needed to define appropriate guidelines for the use of bortezomib in cases of acute rejection.