Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72291/1/j.1399-0012.2000.140301.x.pd

Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study

<p>Abstract</p> <p>Background</p> <p>Macrocytosis occurs in chronic hemodialysis (CHD) patients; however, its significance is unknown. The purpose of this study was to establish the prevalence and distribution of macrocytosis, to identify its clinical associations and to determine if macrocytosis is associated with mortality in stable, chronic hemodialysis patients.</p> <p>Methods</p> <p>We conducted a single-centre prospective cohort study of 150 stable, adult CHD patients followed for nine months. Macrocytosis was defined as a mean corpuscular volume (MCV) > 97 fl. We analyzed MCV as a continuous variable, in tertiles and using a cutoff point of 102 fl.</p> <p>Results</p> <p>The mean MCV was 99.1 ± 6.4 fl, (range 66-120 fl). MCV was normally distributed. 92 (61%) of patients had an MCV > 97 fl and 45 (30%) > 102 fl. Patients were not B12 or folate deficient in those with available data and three patients with an MCV > 102 fl had hypothyroidism. In a logistic regression analysis, an MCV > 102 fl was associated with a higher Charlson-Age Comorbidity Index (CACI) and higher ratios of darbepoetin alfa to hemoglobin (Hb), [(weekly darbepoetin alfa dose in micrograms per kg body weight / Hb in g/L)*1000]. There were 23 deaths at nine months in this study. Unadjusted MCV > 102 fl was associated with mortality (HR 3.24, 95% CI 1.42-7.39, P = 0.005). Adjusting for the CACI, an MCV > 102 fl was still associated with mortality (HR 2.47, 95% CI 1.07-5.71, P = 0.035).</p> <p>Conclusions</p> <p>Macrocytosis may be associated with mortality in stable, chronic hemodialysis patients. Future studies will need to be conducted to confirm this finding.</p

Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) is the major cause of death after renal transplantation. Not only conventional CVD risk factors, but also transplant-specific risk factors can influence the development of CVD in kidney transplant recipients.</p> <p>The main objective of this study will be to determine the incidence of post-transplant CVD after renal transplantation and related factors. A secondary objective will be to examine the ability of standard cardiovascular risk scores (Framingham, Regicor, SCORE, and DORICA) to predict post-transplantation cardiovascular events in renal transplant recipients, and to develop a new score for predicting the risk of CVD after kidney transplantation.</p> <p>Methods/Design</p> <p>Observational prospective cohort study of all kidney transplant recipients in the A Coruña Hospital (Spain) in the period 1981-2008 (2059 transplants corresponding to 1794 patients).</p> <p>The variables included will be: donor and recipient characteristics, chronic kidney disease-related risk factors, pre-transplant and post-transplant cardiovascular risk factors, routine biochemistry, and immunosuppressive, antihypertensive and lipid-lowering treatment. The events studied in the follow-up will be: patient and graft survival, acute rejection episodes and cardiovascular events (myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances and peripheral vascular disease).</p> <p>Four cardiovascular risk scores were calculated at the time of transplantation: the Framingham score, the European Systematic Coronary Risk Evaluation (SCORE) equation, and the REGICOR (Registre Gironí del COR (Gerona Heart Registry)), and DORICA (Dyslipidemia, Obesity, and Cardiovascular Risk) functions.</p> <p>The cumulative incidence of cardiovascular events will be analyzed by competing risk survival methods. The clinical relevance of different variables will be calculated using the ARR (Absolute Risk Reduction), RRR (Relative Risk Reduction) and NNT (Number Needed to Treat).</p> <p>The ability of different cardiovascular risk scores to predict cardiovascular events will be analyzed by using the c index and the area under ROC curves. Based on the competing risks analysis, a nomogram to predict the probability of cardiovascular events after kidney transplantation will be developed.</p> <p>Discussion</p> <p>This study will make it possible to determine the post-transplant incidence of cardiovascular events in a large cohort of renal transplant recipients in Spain, to confirm the relationship between traditional and transplant-specific cardiovascular risk factors and CVD, and to develop a score to predict the risk of CVD in these patients.</p

Test performance of faecal occult blood testing for the detection of bowel cancer in people with chronic kidney disease (DETECT) protocol

<p>Abstract</p> <p>Background</p> <p>Cancer is a major cause of mortality and morbidity in patients with chronic kidney disease (CKD). In patients without kidney disease, screening is a major strategy for reducing the risk of cancer and improving the health outcomes for those who developed cancers by detecting treatable cancers at an early stage. Among those with CKD, the effectiveness, the efficacy and patients' preferences for cancer screening are unknown.</p> <p>Methods/Design</p> <p>This work describes the protocol for the DETECT study examining the effectiveness, efficiency and patient's perspectives of colorectal cancer screening using immunochemical faecal occult blood testing (iFOBT) for people with CKD. The aims of the DETECT study are 1) to determine the test performance characteristics of iFOBT screening in individuals with CKD, 2) to estimate the incremental costs and health benefits of iFOBT screening in CKD compared to no screening and 3) to elicit patients' perspective for colorectal cancer screening in the CKD population. Three different study designs will be used to explore the uncertainties surrounding colorectal cancer screening in CKD. A diagnostic test accuracy study of iFOBT screening will be conducted across all stages of CKD in patients ages 35-70. Using individually collected direct healthcare costs and outcomes from the diagnostic test accuracy study, cost-utility and cost-effective analyses will be performed to estimate the costs and health benefits of iFOBT screening in CKD. Qualitative in-depth interviews will be undertaken in a subset of participants from the diagnostic test accuracy study to investigate the perspectives, experiences, attitudes and beliefs about colorectal cancer screening among individuals with CKD.</p> <p>Discussion</p> <p>The DETECT study will target the three major unknowns about early cancer detection in CKD. Findings from our study will provide accurate and definitive estimates of screening efficacy and efficiency for colorectal cancer, and will allow better service planning and budgeting for early cancer detection in this at-risk population.</p> <p>The DETECT study is also registered with the Australia New Zealand Clinical Trials Registry <a href="http://www.anzctr.org.au/ACTRN12611000538943.aspx">ACTRN12611000538943</a></p

The role of reactive oxygen species in apoptosis of the diabetic kidney

Increased levels of reactive oxygen species (ROS) by hyperglycemia can induce apoptosis of renal cells and diabetic nephropathy. The redox balance in the renal cell seems, therefore, of the utmost importance. ROS-mediated apoptosis may be further aggravated by an inadequate cytoprotective response against ROS. When there are insufficient cytoprotective and ROS scavenging molecules, ROS lead to considerable cellular damage and to a point of no return in apoptosis. Induction of cytoprotective proteins may prevent or attenuate apoptosis, renal cell injury, and finally diabetic nephropathy. Here, we discuss some mechanisms of apoptosis and several strategies that have been probed to ameliorate, or to prevent apoptosis in the diabetic kidney

Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected

Authenticity and Racism: Young boys in three inner city primary schools in Dublin

This paper examines the role of authenticity as a moral orientation and social evaluation in practices of racism. It will argue that discursive conceptions of authenticity disguise and legitimise racism within micro encounters. Using evidence from a qualitative study of minority children in Ireland, this paper explores how perceptions of ‘authenticity’ are bound within racist and gendered conceptions of whom can be said to legitimately embody nationally and locally authorised dispositions and identity markers. The specific context of how this played out through the locality of north Dublin and constructed notions of Irishness is examined. The wider implications of a discourse of authenticity are discussed in relation to assumptions of similarity, adaptation and integration. This paper contributes two unique insights, firstly, that the passive body (one’s appearance) has a central role in perceptions of authenticity and, secondly, that similarity in one’s active body (dispositions and tastes) does not necessarily act as a bridge to bring racialised groups together or facilitate integration