Does mycophenolate mofetil increase the incidence of infections in renal transplant recipients?

The aim of this study was to investigate infectious complications in renal transplant recipients (RTRs) receiving mycophenolate mofetil (MMF) for prevention of acute transplant rejection. A group of RTRs (n = 47) receiving 1.0-2.0 g/day of MMF with cyclosporine A (CsA) and prednisolone to maintain immunosuppression was compared with a group (n = 47) taking triple immunosuppressive therapy including azathioprine. In both groups the etiology and incidence of infections were evaluated. During 2 years post-transplant, various infections developed in 72.3% of patients who received MMF and in 93.6% of those who received azathioprine. The incidence of viral infections was 53.2% in the MMF group and 59.6% in the azathioprine group and the incidence of bacterial infection was 55.3% and 70.2%, respectively There were two cases of active tuberculosis in the azathioprine group and one in the MMF group. MMF 1.0-2.0 g/day does not increase infection rates in RTRs compared with azathioprine.     

Malaria prophylaxis in post renal transplant recipients in the tropics: is it necessary?

OBJECTIVES: Malaria prophylaxis is usually not provided routinely for most post renal transplant recipients in malaria endemic zones. Therefore, very little information is known about the incidence and severity of this disease among the post-transplant recipients in our environment. Hence a prospective, non-randomized open label clinical trial to determine the incidence of malaria and the beneficial effect of malaria prophylaxis among renal transplant recipients in Nigeria was carried out. SUBJECTS: All seven consecutive patients who had renal transplants and returned to the unit not more than four weeks later were seen and followed up. This consisted of an initial four week period of no prophylaxis and another four weeks of prophylaxis with proguanil hydrochloride 200 mg daily. Weekly thin and thick blood films by Giemsa stain were examined and other routine investigations of liver function tests, full blood count, urea, creatinine, electrolytes and urinalysis were done. RESULTS: Only three out of the seven patients (42.8%) had positive smears for malaria parasites in the initial no prophylaxis phase. No malaria parasites were detected at the prophylactic phase. There was no significant difference in the results of other investigations including the renal function between the two phases. CONCLUSION: This study has shown the benefit of short term routine malaria prophylaxis among renal transplant recipients in malaria endemic zones.     

Ganciclovir in solid organ transplant recipients: is there a role for clinical pharmacokinetic monitoring?

The authors use a previously published decision-making algorithm to address the role of clinical pharmacokinetic monitoring of ganciclovir, the drug of choice for prophylaxis and treatment of cytomegalovirus (CMV) in solid organ transplant recipients. Ganciclovir pharmacokinetics have been studied in solid organ transplant recipients with a wide range of peak and trough concentrations reported. Numerous assays are available to measure plasma concentrations of ganciclovir, but no clear correlation has been established between peak or trough concentrations and either efficacy or toxicity of the drug. For patients receiving treatment, the pharmacological response of ganciclovir is assessed initially by clinical response. Monitoring prophylactic therapy in asymptomatic patients poses a greater challenge. Although monitoring of antigenemia or polymerase chain reaction (PCR) deoxyribonucleic acid (DNA) is not yet part of routine clinical practice, studies have shown a role for these techniques in monitoring response to antiviral therapy. Studies of subpopulations of renal failure patients show a prolonged ganciclovir half-life that requires dosage adjustments. However, ganciclovir clearance is closely correlated with creatinine clearance, which is an appropriate approach to adjusting dosages. Studies in pediatric patients also demonstrate a close correlation between dose per kilogram and AUC, suggesting that monitoring of ganciclovir levels may not be necessary. Based on the evidence presented in this review, routine clinical pharmacokinetic monitoring of ganciclovir does not appear to be warranted in solid organ transplant recipients.     

Therapeutic monitoring of antiepileptic drugs during pregnancy and in the postpartum period: is it useful?

As in all patient populations, epilepsy is common in pregnant women. Consequently, approximately 1 in 200 pregnancies is exposed to antiepileptic drugs (AEDs). Although exposure to AEDs in utero has been associated with an increased risk of major fetal malformations, most women with epilepsy require medication throughout pregnancy, since seizures themselves may be potentially harmful not only for the mother but also for the developing fetus. Physiological changes during pregnancy result in a reduction in the serum concentrations of most AEDs, particularly in late pregnancy. Changes in protein binding lead to a greater reduction in total than free (active) drug concentrations. Pharmacokinetic changes in pregnancy show interindividual variability and are not well understood for most newer AEDs. However, recent studies have shown that changes in lamotrigine clearance are particularly marked, with increases in each trimester and a significant fall in plasma concentrations, leading to consequent breakthrough seizures in some women. Concentrations may then rise precipitously after delivery, leading to symptoms of lamotrigine toxicity. Therapeutic drug monitoring could theoretically guide adjustment of AED dosage to achieve good seizure control while minimising fetal exposure, although there are several limitations to such monitoring. Firstly, there are wide interindividual variations in serum drug concentrations, with seizure control often correlating poorly with a given therapeutic range. Secondly, therapeutic ranges have not been well defined for newer AEDs and their measurement is often not always available. Thirdly, for highly protein-bound drugs, although measurement of free drug concentrations may more accurately reflect drug availability during pregnancy than total drug concentrations, assays for this are not always available and may be unreliable. Thus, it may be useful, prior to pregnancy, to establish the total and free drug concentrations required to achieve optimal seizure control in a given individual. Regular monitoring of AEDs has been advocated in each trimester and shortly after delivery, with adjustment of dosage to avoid seizure precipitation during pregnancy or symptoms of toxicity after birth. More frequent monitoring has been recommended for lamotrigine. However, aggressive drug monitoring of any AED has yet to be proven to be effective in improving seizure control or care. Furthermore, higher doses may be associated with a greater potential for teratogenicity and it is not yet known whether longer term adverse effects may be related to in utero exposure in the latter half of pregnancy. There is limited evidence about the relationship of maternal serum drug concentrations and teratogenicity. While there is a theoretical role for therapeutic drug monitoring in improving the risk-to-benefit ratio of AED therapy during pregnancy, there are many practical limitations. Future work is needed to clarify its role in improving seizure control during pregnancy and identifying serum drug concentrations that may be considered safe for fetal exposure.     

Immune monitoring of kidney transplant recipients: can markers predictive of over-immunosuppression be identified?

While the use of nonspecific immunosuppressive drugs has significantly reduced the incidence of acute graft rejection, the benefits of such therapies on chronic rejection and overall long-term graft survival are uncertain. Persistent excessive immunosuppression after immunosuppressive drug treatment is associated with long-term toxicity including increased incidence of cancers, severe infectious complications and metabolic diseases (for example, diabetes, atherosclerosis). One of our team's aims is to identify immunological factors that can predict such toxicities. We have previously demonstrated that CD4T cell cytopenia was correlated with high risk of cancers and infections as well as atherosclerosis in renal transplant recipients. Now, we are investigating the mechanisms involved in CD4T cell cytopenia. We are also exploring how inflammation and cells from the innate immunity influence the complications associated with kidney transplantation. This was performed through the analysis of gene polymorphism on TLR-4, NOD2/CARD15 receptors and IL-6 promoter and correlation with transplantation outcome. We already correlated IL-6 promoter gene polymorphism at position -174 with new-onset diabetes after transplantation in overweight patients. Identification of gene polymorphisms or factors associated with complications after transplantation may help physicians to determine high-risk recipient profiles and optimize pre- and post-transplantation treatment strategies.     

Therapeutic drug monitoring of mycophenolic acid: does it improve patient outcome?

Treatment with the immunosuppressive agent mycophenolate mofetil (MMF) decreases the risk of rejection after renal transplantation and improves graft survival compared with azathioprine. The exposure to the active metabolite mycophenolic acid (MPA) is correlated to the risk of developing acute rejection. The interpatient variability in exposure of MPA is wide relative to the proposed therapeutic window of the MPA AUC(0 12) (30 - 60 mg.h/l). The pharmacokinetics of MPA are influenced by patient characteristics such as gender, time after transplantation, serum albumin concentration, renal function, comedication and pharmacogenetic factors. Therapeutic drug monitoring is likely to reduce inter-patient variability. Limited sampling strategies are used to predict the full AUC(0 12). Three prospective randomised studies compared concentration controlled MMF therapy to a fixed-dose regimen. Preliminary outcomes of these studies showed conflicting results and longer follow up is needed to further clarify the role of therapeutic drug monitoring in increasing the therapeutic potential of MMF.     

Induction therapy in renal transplant recipients: how convincing is the current evidence?

The goal of organ transplantation is to provide durable organ function while minimizing risks such as infection and cancer. Induction therapy in renal transplantation provides improved short- and long-term graft outcomes compared with placebo. Three agents are currently available and widely used in the US; rabbit anti-thymocyte globulin (rATG), basiliximab and alemtuzumab. These agents are all clinically effective in transplantation. In patients at high risk of rejection, graft outcomes are improved with the use of depleting agents, such as rATG or alemtuzumab, rather than basiliximab. Depleting agents are associated with more complications, such as infection and malignancy. The risk-benefit analysis for low-risk patients indicates that basiliximab may be the preferred agent in this population. Use of induction therapy, particularly with rATG, may not only allow for but also mandate reduction of maintenance immunosuppression. The mechanisms by which induction agents lead to improved clinical outcomes have not been elucidated. rATG and alemtuzumab lead to prompt and durable lymphocyte depletion, but many other mechanisms contribute to their suppression of alloimmunity. For instance, rATG contains antibodies specific for multiple adhesion molecules and even human leukocyte antigen, while CD52 (the target of alemtuzumab) is present on many antigen-presenting cells as well as lymphocytes. The manner in which the immune system recovers after induction may also aid in establishment of immune tolerance, with proliferation of suppressor T lymphocytes seen with rATG use. The various contributions of these mechanisms in achieving the goal of allograft tolerance are currently being investigated. The currently available data are of generally low quality, based on many small and often retrospective studies. Definitions of 'high risk' vary between studies, as do induction and maintenance dosing regimens. Standardization of definitions and establishment of large, prospective, multicentre trials would lead to a better understanding of the currently available agents and their best use in renal transplantation induction therapy.     

Therapeutic drug monitoring of digoxin: Help or hindrance?

Summary A major role of therapeutic drug monitoring services is to advise on the dose of a drug which would be required to bring the concentration in the blood to within specific therapeutic limits. Monitoring digoxin usage constitutes a substantial part of the work load.We have examined the potential variability in recommendations for digoxin dosages based on a series of serum digoxin measurements in each of 80 out-patients.In over a third of cases a dose, which seemed to be optimal on the basis of the first assay result, would have produced concentrations outside the conventional therapeutic range when the measurement was repeated. This was despite careful supervision of medication and the timing of the blood sample in relation to its administration. In routine practice the apparent variability in dose requirements would be far greater.Objectives of therapeutic drug monitoring services remain the same, the way forward would seem to lie in their taking on a heavy commitment to counsel and supervise patients before repeated blood sampling. However, effort and resources might be better channelled into producing simple prescribing aids relating the risk of cardiotoxicity directly to the size of the maintenance dose and the individual's renal function.     

Immunosuppression in elderly renal transplant recipients: are current regimens too aggressive?

Renal transplantation is an accepted and successful treatment modality in elderly patients with end-stage renal disease. In comparison with maintenance dialysis, transplantation has been shown to confer a mortality benefit as well as improvements in quality of life in older individuals with end-stage renal disease. Despite this, overall outcomes of renal transplantation in elderly individuals have, in general, been less successful than those of younger renal transplant recipients. Largely, this has been due to the particular vulnerability of elderly patients to the immunosuppressive medications used in renal transplantation. This review article covers these issues in some detail and briefly discusses some of the pharmacokinetic, pharmacodynamic, physiological and immunological differences between younger and older transplant recipients. Elderly renal transplant recipients have both a higher rate of patient death and allograft loss censored for death. Upon multivariate analysis, age of the recipient is strongly associated with allograft loss independent of other known factors. Acute rejections are less frequent in older individuals; however the consequence of a rejection if it occurs is negative for long-term graft survival. On the other hand, death by infection is vastly increased in older versus younger renal transplant recipients. In general, the pharmacokinetics of the immunosuppressive agents are little affected by age, but the tolerance to these agents seems to decrease with increasing age. Elderly renal transplant recipients present a very difficult clinical challenge. As the elderly become an ever-increasing segment of the renal transplant population, new and innovative immunosuppressive strategies will have to be considered and applied.     

Mycophenolate mofetil for solid organ transplantation: does the evidence support the need for clinical pharmacokinetic monitoring?

The need for clinical pharmacokinetic monitoring (CPM) of the immunosuppressant mycophenolate mofetil (MMF) has been debated. Using a previously developed algorithm, the authors reviewed the evidence to support or refute the utility of CPM of MMF. First, MMF has proven efficacy for prevention of organ rejection in renal and cardiac transplant populations. In addition, the pharmacologically active form of MMF, mycophenolic acid (MPA), can be measured readily in plasma, and relationships between the incidence of rejection and MPA predose concentrations and MPA area under the curve (AUC) have been reported. A lower limit of the therapeutic range (MPA predose concentrations >1.55 microg/mL, as measured by enzyme multiplied immunoassay technique [EMIT], or MPA AUC >30 or 40 microg. h/mL, as measured by high-performance liquid chromatography [HPLC]) has been suggested to prevent rejection in renal allograft patients. Similarly, in cardiac transplant patients, decreased incidences of organ rejection have been reported in patients with MPA concentrations >2 or 3 microg/mL (using EMIT) and total AUC values >42.8 microg. h/mL (using HPLC). However, the relationship between pharmacokinetic parameters and adverse events in renal and cardiac transplant patients remains unclear. Due to the nature of antirejection therapy, the pharmacologic response of MMF is not readily assessable, and therapy is life-long. MPA pharmacokinetics exhibit large inter- and intrapatient variability and may be altered in specific patient populations due to changes in protein binding, concomitant disease states, or interactions with concurrent immunosuppressants. Therefore, on the basis of current evidence, CPM can provide more information regarding efficacy of MMF than clinical judgment alone in select patient populations. However, further randomized, prospective trials are required to clarify unresolved issues. Specifically, an upper limit of the therapeutic range, above which the risk of side effects is increased, needs to be elucidated for MMF therapy. Other future directions for research include determining a practical limited sampling strategy for MPA AUC; clarifying the relationship between free MPA concentrations, efficacy, and toxicity; and defining the pharmacodynamic relationship between activity of inosine monophosphate dehydrogenase (the enzyme inhibited by MPA) and risk of rejection or adverse effects.     

Is C2 monitoring or another limited sampling strategy superior to C0 monitoring in improving clinical outcomes in adult liver transplant recipients?

Cyclosporine (CsA) has had a major impact on the process and success of solid organ transplantation. Early in the use of CsA, therapeutic monitoring using the predose (trough, or C0) concentration became the standard of care. However, there are complications with the use of C0 monitoring that have only partly been mitigated with the advent of the micro-emulsion formulation (CsA-ME). More recently, limited sampling strategies (LSSs) for measuring the area under the CsA concentration-time curve (AUC) have been investigated to improve the monitoring of CsA post-transplantation. Many centres now routinely monitor CsA therapy using the concentration at 2 hours postdose (C2). In this paper the strength of the evidence for C2 (or other LSSs) relative to C0 monitoring of CsA-ME for improving clinically important outcomes in liver transplant patients is critically examined. Additionally, gaps in the literature are identified and recommendations are made for clinical research that could be done to provide more definitive evidence for the use of C2 or other LSSs in monitoring liver transplant patients.     

What is a significant response in drug studies of attention-deficit/hyperactivity disorder: statistical significance is necessary, but is it sufficient?

The methods used to report data of clinical treatment trials can influence the interpretation of the results. Reporting that a study drug achieves a statistically significant result does not provide the absolute likelihood and magnitude of benefits. Reporting results using an absolute definition of clinical expectation from a pharmacological intervention may be useful, and characterization of placebo response may help to frame such an absolute definition. The objective of this report was to characterize placebo response in patients with attention-deficit/hyperactivity disorder (ADHD). The design was a double-blind, placebo-controlled trial of a study drug that did not produce a statistically significantly different response from placebo in a multi-center trial. Data from placebo and study drug groups at a single site were collapsed into one group to evaluate response to placebo (or ineffective drug) in a double-blind fashion. Sixty-four children aged 6 to 12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of ADHD (combined type), were enrolled; 57 completed the study. Subjects were randomized to receive either transdermal buspirone patches or matching placebo patches. Mean ADHD Rating Scale (ADHD-RS) score was 44.3 (SD 5.4) at baseline, and 37.4 (SD 10.9) after 6 weeks. Mean ratio of week 6 to baseline ADHD-RS was 0.84 (SD 0.22). Less than 5% of the sample had a 60% or greater decrease in ADHD-RS in response to placebo or ineffective medicine. A 60% decrease in the ADHD-RS seems to constitute one clear definition of clinical expectation from a pharmacological intervention, with minimal possibility of such a decrease occurring as a placebo effect.     

Vascular resection in pancreaticoduodenectomy: is it worthwhile?

Pancreaticoduodenectomy (PD) is the gold standard treatment for cancer of pancreatic head in all the cases that are supposed to be resectable. Although the overall survival depends on many heterogeneous factors, the main aim of the treatment must be to achieve a R0 resection with microscopically and macroscopically free margins. As in recent reports vascular involvement does not represent anymore a technical limit, it is mandatory pointing out whether or not vascular resection modifies overall survival and if that is the case vascular invasion should not be considered as an exclusion criterion but as part of a standard resection. The review analysis demonstrated a progressive trend of inversion in the treatment of head pancreatic cancer over the last years. Recently, provided that a R0 resection may be performed, a more aggressive surgical approach has led to consider the possibility of venous and arterial resections. The basis for this new approach has been that the superior mesenteric vein or spleno-portal mesenteric vein invasion is not a measure of the tumor malignancy but merely a consequence of the tumor location. On the contrary, the controversial results in terms of overall survival and local recurrences achieved with major arterial resections are more likely due to a biological aggressivity than to the tumor site. The "artery first" technique seems to be the most promising approach to the problem although it needs further trials to determine whether or not this approach may be beneficial for patients in terms of overall survival and local recurrences.     

Pharmacogenetics in transplant patients: can it predict pharmacokinetics and pharmacodynamics?

Pharmacogenetics holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic effect while minimizing adverse effects. As more pharmacogenetic information accumulates, the prospect of reducing or discontinuing the intensive therapeutic drug monitoring of immunosuppressants looks attractive. However, the long process of developing useful clinical information from basic information on the genes of interest is at a very early stage, and our present information does not supercede pharmacokinetic or blood concentration monitoring of immunosuppressants. The most extensive blood concentration/dose information available is on tacrolimus and its dosing related to CYP3A5 and ABCB1 gene polymorphisms. Although CYP3A5 genotype is definitely associated with tacrolimus dosing, the only recommendation presently published is for an arbitrary doubling of the starting tacrolimus dose in CYP3A5 expressors. For cyclosporine, sirolimus, and corticosteroids, the presently available pharmacogenetic information does not permit pharmacokinetic predictions. The pharmacodynamics of immunosuppressants, as evidenced by effects on acute rejection or adverse drug effects, have considerably more potential for prediction by pharmacogenetic models. Drug-resistant rejection, nephrotoxicity, steroid resistance and osteonecrosis, and even patient survival may ultimately be predicted by models incorporating multiple gene polymorphisms and other critical patient information. At this point, treatment algorithms can be developed that will allow us to individualize a transplant patient's immunosuppressive therapy.     

Therapeutic monoclonal antibody concentration monitoring: free or total?

Most therapeutic monoclonal antibodies are designed to bind a specific antigen to elicit pharmacological effects. Accurate quantification of a therapeutic monoclonal antibody in biological matrices is essential for assessing its pharmacokinetics and selecting an effective dosing regimen. Therapeutic antibodies may exist in free, partially bound and fully bound forms in the bloodstream. The choice of which form(s) to measure and how to measure them is gaining much attention with the increase in the number of soluble therapeutic targets. This article will review the bioanalytical methods used in supporting the clinical development of the US FDA-approved therapeutic monoclonal antibodies and also discuss how different factors, such as assay format, target and antibody concentrations, and sample dilutions, can have an impact on the measurement of each form of antibody. Appreciation of which form of drug is being measured and what factors may impact measurement under different conditions are important for interpretation of the pharmacokinetics of therapeutic antibodies.     

The use of CPR in New Zealand: is it always lawful?

Since its development in the early 1960s, the use of CPR in the hospital setting has undergone intriguing changes. After initially being used very selectively, at the discretion of the doctor, the use of CPR rapidly expanded to the point that it was promptly begun on all patients having a cardiac arrest in hospital, regardless of the underlying illness. However, it soon became evident that the use of CPR on all patients created problems. In response to this, DNR orders were developed. The standard policy of New Zealand hospitals is now for CPR to be attempted on all patients having a cardiac arrest unless a DNR order is in place. We argue that this approach is not consistent with New Zealand law and that current policies should be amended to bring them into line with the Code of Rights and New Zealand law generally.     

Inadequate stocking of antidotes in Taiwan: is it a serious problem?

OBJECTIVE: Insufficient hospital stock of a variety of poisoning antidotes is a worldwide problem. In an attempt to establish an antidote storage and distribution system for the response of the various poisoning accidents, we conducted a nationwide survey to characterize the current availability of selected antidotes and their anticipated need in Taiwan. MATERIALS AND METHODS: A questionnaire was mailed to 834 hospitals to gather information on the availability, anticipated need, and preferred purchase policy of 20 selected antidotes. A survey on the availability of cyanide antidote in 523 cyanide-handling facilities and their neighboring hospitals was also conducted. RESULTS: Hospitals of different size and service levels had a statistically significant difference in response rates. Except for pyridoxine, the availability and anticipated need for antidotes also varied significantly among different hospital groups. We found that physostigmine, cyanide antidote kit, BAL, EDTA, methylene blue, Vipera Russell formosensis antivenin, and botulism antitoxin were not available in most (>90%) hospitals. Interestingly, these antidotes are also among the most needed antidotes. Most hospitals preferred a government-ordered purchase of antidotes. In the survey of cyanide-processing facilities, a response rate of 24.1% was obtained and only 9.3% of these 107 facilities that both replied to the questionnaire and continued handling cyanide products had stocked cyanide antidote. It is noteworthy that cyanide antidote was also frequently lacking in the neighboring hospitals. CONCLUSIONS: The appropriate storage of antidotes in hospitals or workplaces in rural areas is instrumental in the timely treatment of certain poisonings, while nationwide unavailability is the critical problem. Raising awareness of the importance of antidotes by education, regular review of antidote storage, distribution plans, and appropriate legislation might provide solutions.