Wana Manitpisitkul

A Comprehensive Review of Everolimus Clinical Reports: A New Mammalian Target of Rapamycin Inhibitor

As new immunosuppressive agents are introduced to the market, clinicians are faced with the daunting task of sifting through the published literature to decide the value that the agent will add to their own practice. We often must extrapolate information provided through study in other solid-organ transplantation populations than our specific area of interest as we interpret the results and outcomes. With these challenges in mind, this compilation of published work for the newest mammalian target of rapamycin inhibitor everolimus (Certican; Novartis Pharmaceuticals, Hanover, NJ) (Zortress; Novartis Pharmaceuticals, Basel, Switzerland) is intended to provide a concise but thorough presentation of available literature so that the reader who may be unfamiliar with the agent can make their own judgment. Both Ovid and PubMed search engines were queried with a particular focus on high-impact articles noted in the Web of Science or Citation Index. Work described solely in abstract or case report form was excluded, as well as meta-analyses or those that were editorial or commentary in nature. Included were publications presented using the English language that described adult human subjects who received a heart, lung, kidney, or liver allograft. The goal of this strategy was to allow for the inclusion of pertinent literature in an unbiased fashion. Tables are provided that outline trial specific information, leaving a discussion of major outcomes to the text of the review.

Maintenance Immunosuppressive Agents as Risk Factors for BK Virus Nephropathy: A Case-Control Study

Background. The specific role of different immunosuppressive agents as risk factors for BK virus nephropathy (BKN) has not been well studied. Methods. In this case-control study, we examined the association of tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone with BKN in renal allograft recipients transplanted between 1997 and 2004 at our center who underwent biopsies for allograft dysfunction. Drug levels or doses were recorded during the 3 months before the index biopsy. Random effects logistic modeling was used for data analysis. Results. There were 33 cases with BKN, biopsied at 16.4±2.8 months and 66 matched controls with biopsies at 21.5±2.1 months posttransplant (P=0.16). After adjusting for sex, race, retransplant status, diabetes, donor source, and induction agent, TAC blood level was associated with increased risk of BKN (odds ratio [OR] 1.3, 95% confidence interval [CI] 1.02-1.7, P=0.03), whereas MMF dose was not (OR 1.0, 95% CI 0.99-1.0, P=0.2). Moreover, prednisone dose was also found to be a significant risk factor for BKN (OR 1.22, 95% CI 1.04-1.4, P=0.02). Conclusions. The results of this study show that BKN is associated with TAC level and prednisone dose and not with MMF dose. This suggests that reducing TAC and prednisone dose and maintaining MMF may be a more appropriate initial approach for the treatment of BKN. Further studies are needed to compare the efficacy and safety of this approach with the currently recommended one.

Drug interactions in transplant patients: what everyone should know.

Purpose of reviewAdverse events due to drug–drug interactions remain a challenge in the postsurgical care of transplant recipients. A combination of potent and selective immunosuppressive drugs, which have a narrow therapeutic index, with medications for the treatment of comorbidities such as dyslipidemia, infection, psychiatric conditions, and hypertension, can lead to life-threatening drug–drug interactions. Recent findingsThere are a number of important drug–drug interactions which are important for physicians to consider. It is critical to understand the pharmacodynamics and pharmacokinetics of drug–drug interactions, their potential impact on patient care, and the management strategies. SummaryClose therapeutic drug monitoring and evaluation of drug-specific side effects continue to be an important key to minimize adverse events due to drug–drug interactions.

Immunosuppressive agents as risk factors for BK virus nephropathy: an overview and update.

Important of the field: BK virus has emerged as an important cause of graft dysfunction and failure in renal transplant recipients. Risk factors for BK virus nephropathy (BKN) are not well established, but evidence suggests that it is the result of a complex interplay between multiple donor- and recipient-related factors. Areas covered in this review: The purpose of this article is to review the current understanding on the effect of various immunosuppressive agents on BK viral replication and the results of different reported immunosuppression reduction protocols. What the reader will gain: The intensity of overall immunosuppression has been accepted as a major risk factor for the development of BKN. We review the data regarding the contribution of different anti-rejection agents to the risk of BK virus-induced graft injury. Take home message: Although reduction in immunosuppression on detection of BK viral replication appears to be the most successful means in preserving allograft function, data are emerging that support the stronger association of the disease with tacrolimus, in contrast to mycophenolate compounds. Therefore, initial dose reduction for tacrolimus may be more beneficial than this anti-metabolite preemptively or after diagnosis of BKN.

Safety events in kidney transplant recipients: results from the folic Acid for vascular outcome reduction in transplant trial.

Background Kidney transplant recipients are at increased risk for adverse safety events related to their reduced renal function and many medications. Methods We determined the incidence of adverse safety events based on previously defined Agency for Healthcare and Research Quality (AHRQ) International Classification of Diseases-9 (ICD-9) code-derived patient safety indicators (PSI) in the Folic Acid for Vascular Outcome Reduction in Transplant trial participants who had a hospitalization stratified by tertiles of estimated glomerular filtration rate (GFR). We also examined the frequency of Micromedex defined two precautionary drug-drug interactions, and two medications whose use may be contraindicated because of reduced GFR from the Folic Acid for Vascular Outcome Reduction in Transplant trial medication thesaurus at baseline, and annually among 4,110 participants. Logistic regression was used to examine the relationship between patient safety events and baseline demographic and clinical variables at a participant level. Event rates were estimated at participant and visit levels. Results Of the 2,514 patients with a hospitalization, 978 (38.9%) experienced an AHRQ PSI. Factors which were associated with more common AHRQ PSI included: U.S. location, history of cardiovascular disease or diabetes, and lower tertile of estimated GFR. At a participant level, 2,524 of the 4,110 participants (61.4%) were taking calcineurin inhibitor and statin, 378 (9.2%) were taking azathioprine and an angiotensin-converting enzyme inhibitor, 171 (12.9%) were taking a sulfonylurea), 45 (3.4%) were taking metformin despite a baseline GFR below 40 mL per min per 1.73 m2. Conclusion We conclude that patient safety events are not uncommon in kidney transplant recipients. Careful monitoring is necessary to prevent adverse outcomes.

Liver Failure Requiring Transplantation After Orlistat Use

Orlistat is a United States Food and Drug Administration (FDA)‐approved drug indicated for the management of obesity. The FDA has issued a warning of rare, but severe, reports of liver injury after orlistat use. We describe a 40‐year‐old woman with no significant medical history who experienced fulminant liver failure after orlistat use. Two weeks after taking the drug at a low dosage of 60 mg/day for 4 days, she developed significant fatigue, nausea, right upper abdominal discomfort, and icterus, and her liver enzyme panel showed significant abnormalities. Five weeks later, after further deterioration in her clinical status, she was transferred to our medical center with severe cholestasis and coagulopathy Liver ultrasonography, serologies for viral hepatitis, and autoimmune markers were unremarkable. Early cessation of the drug was not sufficient to stop the progression of liver injury, and she required an orthotopic liver transplant. Two weeks after transplantation, she was discharged in good condition. Published reports of liver injury associated with orlistat use describe a presentation similar to that of our patient. Although use of the Naranjo adverse reaction probability scale indicated a possible relationship (score of 3) between the patients development of fulminant liver failure and orlistat, we believe this was a drug‐induced case and is consistent with previous reports. To our knowledge, this is the first published report of orlistat‐induced liver failure in the United States. Although orlistat may be a useful drug for weight loss, clinicians should be aware that its use can rarely cause idiosyncratic hepatotoxicty characterized by subacute hepatitis, which may progress to serious injury.

Drug Interactions in Solid Organ Transplant Recipients

Recipients of solid organ transplants not only are exposed to a large number of medications with potential interactions but also often have reduced renal function. These two factors markedly increase the risk for patient safety events.

Mycophenolic acid agents: is enteric coating the answer?

Correspondence: Matthew Cooper Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA Tel +1 410 328 7336 Fax +1 410 328 6343 email mcooper@smail.umaryland.edu Abstract: Addition of mycophenolate mofetil (MMF) to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological and gastrointestinal (GI) side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.

Impact of antiretroviral regimen on renal transplant outcomes in HIV-infected recipients

Protease inhibitors (PI) pose a challenge post‐transplant due to significant drug interactions with calcineurin inhibitors, prompting many clinicians to convert patients to non‐interacting regimens prior to transplant. The purpose of this study was to examine the impact of PI‐based regimens on graft outcomes in HIV‐infected renal transplant recipients.

A-112 Impact of antiretroviral regimen on renal transplant outcomes in HIV-infected recipients

Background:Renal transplantation has become a more common occurrence in HIV-infected individuals. The post-transplant antiretroviral regimen is one of the challenges in this population due to drug interactions with common immunosuppressive agents. Regimens containing protease inhibitors (PI) pose a challenge post-transplant, leading to altered calcineurin inhibitor (CNI) dosing and the potential for increased CNI exposure. This has led to increased utilization of newer agents that lack significant interactions with CNI. The purpose of this study was to examine the impact of PI-based regimens on graft outcomes in HIV-infected renal transplant recipients. Methods:Retrospective study of renal allograft recipients transplanted between 2003 and 2015 with ≥6 months of follow-up. Maintenance immunosuppressive medications included CNI+ mycophenolic acid ± steroids. Results:During this period, our center performed 50 renal transplants in HIV-infected recipients. Twenty-six patients (52%) received a PI based regimen and 24 patients (48%) received a non-PI based regimen. There were no significant differences between groups in terms of age, race, gender, or cause of CKD. The majority of patients in each group received deceased donor renal transplants, and greater than 50% of patients in each group experienced delayed graft function. Significantly more patients in the non-PI group received induction with T-cell depleting agents. The cumulative rejection rate in both groups was 64%. The estimated GFR did not differ between groups at time points evaluated (30 days to 4 years post-transplant). At last follow-up, patient and graft survival was 92% vs. 83% and 81% vs. 58% in the PI and non-PI groups, respectively. Conclusions:HIV-infected renal transplant recipients experienced high rates of rejection regardless of antiretroviral regimen. However, PI-based ARV regimens appear to be associated with better graft survival, suggesting that converting patients to non-PI regimens may not be warranted.