Tacrolimus-induced nephrotoxicity and genetic variability:A review

Background: Calcineurin inhibition (CNI) is the mainstay of immunosuppressant therapy for most solid organ transplant patients. High tacrolimus levels are related with acute nephrotoxicity, but the relationship with chronic toxicity is less clear. Variation in disposition of tacrolimus is associated with genetic variation in CYP3A5. Hence, could genetic variation in CYP3A5 or other genes involved in tacrolimus disposition and effect be associated with a risk for tacrolimus-induced nephrotoxicity? To perform a review of the literature and to identify if genetic variation in CYP3A5 or other genes involved in tacrolimus disposition or effect may be associated with tacrolimus-induced nephrotoxicity and/or renal dysfunction in solid organ transplant recipients. Material/Methods: Pubmed/Medline, Embase and Google were searched from their inception till November 8th 2010 with the search terms 'tacrolimus', 'genetics', and 'nephrotoxicity' or 'renal dysfunction'. References of relevant articles were screened as well. Results: We identified 13 relevant papers. In kidney recipients, associations between donor ABCB1, recipient CCR5 genotype and tacrolimus-induced nephrotoxicity were found. CYP3A5 genotype studies in kidney recipients yielded contradictory results. In liver recipients, a possible association between recipient ACE, CYP3A5, ABCB1 and CYP2C8 genetic polymorphisms and tacrolimus-induced nephrotoxicity was suggested. In heart recipients, TGF-β genetic polymorphisms were associated with tacrolimus-induced nephrotoxicity. The quality of the studies varied considerably. Conclusions: Limited evidence suggests that variation in genes involved in pharmacokinetics (ABCB1 and CYP3A5) and pharmacodynamics (TGF-β, CYP2C8, ACE, CCR5) of tacrolimus may impact a transplant recipients' risk to develop tacrolimus-induced nephrotoxicity across different transplant organ groups.</p

Common and gender-specific associations with cocaine use on gray matter volume: Data from the ENIGMA addiction working group

Gray matter volume (GMV) in frontal cortical and limbic regions is susceptible to cocaine-associated reductions in cocaine-dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue-induced craving and stress reactivity. The variability of GMV in select brain areas between men and women (e.g., limbic regions) underscores the importance of exploring interaction effects between gender and cocaine dependence on brain structure. Therefore, voxel-based morphometry data derived from the ENIGMA Addiction Consortium were used to investigate potential gender differences in GMV in CD individuals compared to matched controls (CTL). T1-weighted MRI scans and clinical data were pooled from seven sites yielding 420 gender- and age-matched participants: CD men (CDM, n = 140); CD women (CDW, n = 70); control men (CTLM, n = 140); and control women (CTLW, n = 70). Differences in GMV were assessed using a 2 × 2 ANCOVA, and voxelwise whole-brain linear regressions were conducted to explore relationships between GMV and duration of cocaine use. All analyses were corrected for age, total intracranial volume, and site. Diagnostic differences were predominantly found in frontal regions (CD < CTL). Interestingly, gender × diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CDW < CTLW). Further, lower right hippocampal GMV was associated with greater cocaine duration in CDM. Given the importance of the anterior insula to interoception and the hippocampus to learning contextual associations, results may point to gender-specific mechanisms in cocaine addiction

Gene by Disease Interaction on Orbitofrontal Gray Matter in Cocaine Addiction

Chronic cocaine use has been associated with structural deficits in brain regions having dopamine receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. We therefore examined variations in gray matter volume (GMV) as a function of lifetime drug use and the monoamine oxidase A (MAOA) genotype in cocaine use disorders (CUD) and healthy controls

Long-term impacts of prenatal synthetic glucocorticoids exposure on functional brain correlates of cognitive monitoring in adolescence

The fetus is highly responsive to the level of glucocorticoids in the gestational environment. Perturbing glucocorticoids during fetal development could yield long-term consequences. Extending prior research about effects of prenatally exposed synthetic glucocorticoids (sGC) on brain structural development during childhood, we investigated functional brain correlates of cognitive conflict monitoring in term-born adolescents, who were prenatally exposed to sGC. Relative to the comparison group, behavioral response consistency (indexed by lower reaction time variability) and a brain correlate of conflict monitoring (the N2 event-related potential) were reduced in the sGC exposed group. Relatedly, source localization analyses showed that activations in the fronto-parietal network, most notably in the cingulate cortex and precuneus, were also attenuated in these adolescents. These regions are known to subserve conflict detection and response inhibition as well as top-down regulation of stress responses. Moreover, source activation in the anterior cingulate cortex correlated negatively with reaction time variability, whereas activation in the precuneus correlated positively with salivary cortisol reactivity to social stress in the sGC exposed group. Taken together, findings of this study indicate that prenatal exposure to sGC yields lasting impacts on the development of fronto-parietal brain functions during adolescence, affecting multiple facets of adaptive cognitive and behavioral control

Valuing Health Gain from Composite Response Endpoints for Multisystem Diseases

Objectives: This study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. Methods: Data from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. Results: Within the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. Conclusions: Bespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation

The mRNA Expression and Circulating Levels of Visfatin and Their Correlation with Coronary Artery Disease Severity and 25-Hydroxyvitamin D

It is evident that coronary artery disease (CAD) is closely associated with abnormal glucose and lipid metabolism. Notably, dysregulation of inflammatory pathways and immune system also contribute to CAD development. Recently, it has been suggested that visfatin, a proinflammatory adipocytokine, may be involved in several inflammatory and metabolic diseases. In this study, we evaluated the serum visfatin levels and its mRNA expression in peripheral blood mononuclear cells (PBMCs) from CAD patients compared with control subjects. We also studied the correlation between visfatin gene expression and serum levels with clinical and metabolic parameters. This study was conducted on 56 male patients with CAD confirmed by angiography and 30 healthy men as controls. CAD severity was determined based on the number of vessels. Study of gene expression in PBMCs was performed using real time-PCR, and serum levels of visfatin and 25-hydroxyvitamin D were measured by ELISA. We found that serum visfatin levels and its gene expression in PBMCs were increased in patients with CAD compared with the control group (p=0.027 and p=0.016, respectively). Also, visfatin gene expression was positively correlated with visfatin levels and both these variables had a strong positive correlation with the severity of CAD. It appears that elevated mRNA expression and circulating level of visfatin might be of relevance to the pathogenesis and severity of CAD. However, further studies are necessary to better clarify the associations between visfatin and CAD. © Georg Thieme Verlag KG Stuttgart · New York