[Clopidogrel- induced hepatotoxicity in hemodialyzed patient: a case report]. / Epatotossicità da clopidogrel in emodializzato: caso clinico.

Drug-induced liver injury is a frequent cause of acute liver failure. It may cause clinical manifestations ranging from simple alteration of the common liver function tests until more severe manifestations including encephalopathy, coagulopathy, and in many cases progressive multi-organ dysfunction. The condition, therefore, may be associated with higher morbidity and mortality as well as higher consumption of economic resources. In this paper, we present the case of a 71-year-old patient treated with hemodialysis, diabetic, with ischemic cardiopathy and severe peripheral vascular disease. The patient presented a progressive clinical deterioration with the development of ascites, jaundice and significant deterioration of liver function. Diagnostic studies have ruled out viral and immunological diseases and, in agreement with the score obtained from the Maria and Victorino scale, clopidogrel was identified as the major factor responsible for the damage. After the suspension of the drug, the follow-up has led to the complete and stable recovery of liver function.

Which vitamin D in CKD-MBD? The time of burning questions.

Vitamin D is a common treatment against secondary hyperparathyroidism in renal patients. However, the rationale for the prescription of vitamin D sterols in chronic kidney disease (CKD) is rapidly increasing due to the coexistence of growing expectancies close to unsatisfactory evidences, such as (1) the lack of randomized controlled trials (RCTs) proving the superiority of any vitamin D sterol against placebo on patients centered outcomes, (2) the scanty clinical data on head to head comparisons between the multiple vitamin D sterols currently available, (3) the absence of RCTs confirming the crescent expectations on nutritional vitamin D pleiotropic effects even in CKD patients, (4) the promising effects of vitamin D receptors activators (VDRA) against proteinuria and myocardial hypertrophy in diabetic CKD cohorts, and (5) the conflicting data on the impact on mortality of VDRA versus calcimimetic centered regimens to control CKD-MBD. The present review arguments these issues focusing on the opened questions that nephrologists should consider dealing with the prescription of nutritional vitamin D or VDRA and with the choice of a VDRA versus a calcimimetic based regimen in CKD-MBD patients.

Cardiac valve calcification: an immutable pathologic finding in chronic kidney disease?

Although less frequent than vascular calcification, cardiac valve calcification (CVC) is a relevant clinical problem affecting about 2%-10% of adults from the general population aged 75 years and older, and is 5- to 10-fold more prevalent in individuals with impaired kidney function. An expanding body of evidence suggests that mineral metabolism abnormalities aside from traditional cardiovascular risk factors are involved in CVC pathogenesis. Nonetheless, very few studies have investigated whether mineral metabolism manipulation impacts CVC. In this issue of the Journal of Nephrology, it is reported that a combination of low-phosphate diet and sevelamer may reduce CVC. Though the observational nature of that study and the lack of a control group significantly limit the generalizability of these results, they fit in with the ongoing debate on the role of chronic kidney disease mineral bone metabolism (CKD-MBD) in the pathogenesis of vascular disease and suggest the importance of mineral metabolism control in patients with CKD.

Acute and chronic effects of therapeutic apheresis.

In most patients only a few sessions of apheresis treatment are necessary to see the benefit. This is the case of immunological diseases when the production of a pathologic component is limited in time or in microcirculation disturbances when changes of vascular function may occur. In the first instance the acute effect is likely due to the removal of the corresponding antibody, while in the second case the improvement of the endothelium-dependent vasodilation and the reduction of blood viscosity play a major role. In long-term treatment, as in the case of patients affected by familial hypercholesterolemia, the chronic effects of apheresis may lead to the repair of morphological alterations in the vascular wall. We report the recovery from ulcers in two hemodialysis patients suffering from peripheral arterial disease as the result of twenty-two sessions of rheopheresis. The reasons that justify these chronic actions may involve pleiotropic effects that are different according to the apheresis technique used.

Genetic vulnerability to psychosis and cortical function: epistatic effects between DAAO and G72.

Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p < 0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder.

Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency.

BACKGROUND: The D-Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D-amino acid oxidase (DAO), which metabolizes D-serine, a co-agonist of NMDA-type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. AIMS: To examine the influence of G72 variation on brain function in the healthy population. METHOD: Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task-dependent functional connectivity during word generation was compared between different rs746187 genotypes. RESULTS: G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task-dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). CONCLUSIONS: Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D-amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis.

[Use of cinacalcet in clinical practice for the treatment of secondary hyperparathyroidism: analysis of the Italian data of the ECHO study]. / Utilizzo del cinacalcet nella pratica clinica per il trattamento dell'iperparatiroidismo secondario: analisi dei dati italiani dello studio osservazionale ECHO.

Several studies have shown that, compared with standard therapy, cinacalcet reduces parathyroid hormone (PTH) as well as calcium and phosphorus levels in dialysis patients with secondary hyperparathyroidism (SHPT). The ECHO study evaluated cinacalcet use in actual clinical practice. ECHO enrolled 1865 patients treated with cinacalcet at 187 sites in 12 European countries. In Italy 263 patients were enrolled at 20 sites. The primary objective of the study was to evaluate K/DOQI target achievement in SHPT dialysis patients after the introduction of cinacalcet. Patients on cinacalcet treatment between July 2005 and October 2006 were enrolled and data were collected from 6 months prior to starting cinacalcet up to 12 months after. No treatment algorithm was provided to the investigators. Italian patients had suboptimally controlled SHPT at baseline according to K/DOQI targets (median PTH 760 pg/mL, P 5.4 mg/dL, Ca 9.7 mg/dL). After 1 year of cinacalcet treatment a reduction of PTH (-53.4%), Ca (-7.3%), P (-4.6%) and Ca x P (-14.4%) was observed. The proportion of patients that reached the K/DOQI targets after 1 year of cinacalcet treatment was higher compared to baseline for all parameters (PTH 32% vs 5%; Ca 48% vs 35%; P 59% vs 55%, Ca x P 82% vs 64%). The Italian ECHO data show that cinacalcet treatment increases the proportion of patients achieving the K/DOQI targets for PTH, Ca, P and Ca x P, confirming the effectiveness of cinacalcet in clinical practice in Italy. These findings are consistent with the phase III study results on cinacalcet use in dialysis patients in Europe.

Differential effects of DAAO on regional activation and functional connectivity in schizophrenia, bipolar disorder and controls.

Recent studies have identified DAAO as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene affects brain function to increase vulnerability to these disorders. We examined the impact of DAAO genotype (rs3918346) on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy controls. We tested the hypothesis that a variation in DAAO genotype would be associated with altered prefrontal function and altered functional connectivity in schizophrenia and bipolar disorder. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 121 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar disorder and 48 healthy volunteers. We then used statistical parametric mapping (SPM) and psycho-physiological interaction (PPI) analyses to estimate the main effects of diagnostic group, the main effect of genotype, and their interaction on brain activation and on functional connectivity. Inferences were made at p<0.05, after correction for multiple comparisons across the whole brain. In the schizophrenia group relative to the control group, patients with one or two copies of the T allele showed lower deactivation in the left precuneus and greater activation in the right posterior cingulate gyrus than patients with two copies of the C allele. This diagnosis×genotype interaction was associated with differences in the functional connectivity of these two regions with other cortical and subcortical areas. In contrast, there were no significant effects of diagnosis or of genotype in comparisons involving bipolar patients. Our results suggest that genetic variation in DAAO has a significant impact on both regional activation and functional connectivity, and provide evidence for a diagnosis-dependent pattern of gene action.

Effects of stressful life events on human brain structure: a longitudinal voxel-based morphometry study.

Although stressful life events (SLEs) have been associated with an increased risk of illness and mental disorder, their impact on brain anatomy remains poorly understood. Using a longitudinal design, we tested the hypothesis that SLEs are significantly associated with changes in gray matter volume (GMV) in brain regions previously implicated in post-traumatic stress disorder (PTSD) in a group of clinically healthy adults. Magnetic resonance imaging was used to acquire an anatomical scan from 26 subjects (13 males and 13 females; mean age ± SD: 25.2 ± 4.3 years), with no psychiatric diagnosis, at two time points with a 3-month interval. Voxel-based morphometry was used to examine an association between SLEs and gray matter changes during this period. The number of SLEs was associated with a decrease in GMV in the anterior cingulate, hippocampus, and parahippocampal gyrus (p < 0.001). In contrast, there were no areas where the number of SLEs was associated with an increase in GMV. These results provide evidence that, in adults with no formal psychiatric diagnosis, SLEs are associated with GMV decreases in a subset of regions implicated in PTSD, and that these alterations can be observed within a period as short as 3 months.

Serum fetuin-A levels link inflammation and cardiovascular calcification in hemodialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality in hemodialysis (HD). An elevated incidence of cardiovascular calcifications (CVC) is observed in HD. Fetuin-A is an important inhibitor of CVC. Reduced fetuin-A levels associate with inflammation and increased cardiovascular (CV) mortality in HD. In this study we investigated the association of fetuin-A levels and CVC. METHOD: We evaluated a cohort of 115 patients (67 males), aged 63 +/- 16 years with a HD vintage >or=9 months. Presence of CVC was assessed by ultrasound imaging of the abdominal aorta, common carotid arteries, bilateral ilio-femoral axis, aortic and mitral cardiac valves. The presence of CVC was analyzed as a CVC score (CVCS) (0-7) according to the number of CVC sites. Patients were arbitrary stratified in three groups: group I (CVCS = 0), group II (0 < CVCS < 6) and group III (CVCS >or= 6). Patients without CVC were younger, non-diabetic and with a negative history for CV events. RESULTS: Patients with evidence of CVC in more than 5 sites had lower serum fetuin-A levels (0.41 +/- 0.22 g/l) compared to patients with CVCS = 0 (0.51 +/- 0.17 g/l, p = 0.048). In addition a worse CVCS was associated with higher serum levels of C-reactive protein (p = 0.002) and fibrinogen (p < 0.001). Serum fetuin-A levels lower than 0.290 g/l were associated with higher risk of a worse CVCS, independently from traditional risk factors. CONCLUSION: Chronic inflammation in HD patients leads to lower serum fetuin-A levels. The present study confirms the independent and significant association between reduced serum fetuin-A levels and multi-site CVC in HD.