Anemia and chronic kidney disease are potential risk factors for mortality in stroke patients : a historic cohort study

Rapport de synthèseApproche et objectifL'objectif de la recherche était de préciser les relations existant entre l'insuffisance rénale chronique, l'anémie et l'accident vasculaire cérébral parmi des patients hospitalisés au Centre Hospitalier Universitaire Vaudois (CHUV) pour un accident vasculaire cérébral (AVC). Les auteurs ont déterminé la prévalence de l'anémie et de l'insuffisance rénale chronique parmi ces patients et examiné s'ils sont des facteurs de risque indépendants de la mortalité suite à un AVC.L'insuffisance rénale chronique est associée à un risque élevé de développer un AVC. L'anémie est une complication et une conséquence fréquente qui découle de l'insuffisance rénale chronique et est également un facteur de risque pour les maladies cérébro- et cardiovasculaires.MéthodeLa présente étude de cohorte rétrospective se base sur le registre des AVC du CHUV et inclut tous les patients traités suite à un premier AVC au service de neurologie du CHUV entre les années 2000 et 2003.Les variables utilisées pour l'analyse sont les caractéristiques démographiques, l'insuffisance rénale chronique, le débit de filtration glomérulaire.(GFR), l'anémie et d'autres facteurs de risque d'AVC. Ils ont été récoltés au moyen du système informatique du laboratoire du CHUV, d'entretiens téléphoniques (patients ou proches) et du registre des AVC du CHUV.L'insuffisance rénale chronique a été calculée sur base de la ,,Kidney Disease Outcomes Quality Initiative (K/DOQI)-CKD Classification", laquelle est divisée en cinq stades. L'anémie a été définie par une hémoglobine de < 120g/L pour les femmes et < 130g/L pour les hommes.Les analyses statistiques réalisées sont des tests Chi-carré, des tests de Τ ainsi que des courbes de Kaplan-Meier et le modèle de régression de Cox.RésultatsParmi 890 patients adultes avec un AVC, le GFR moyen était de 64.3 ml/min/1.73 m2, 17% souffraient d'anémie et 10% sont décédés pendant la première année après la sortie de l'hôpital, suite à l'"AVC index". Parmi ceux-ci, 61% avaient une insuffisance rénale chronique de stade 3-5 et 39% de stade 1 ou 2 selon les critères de K/DOQI.D'autre part un taux d'hémoglobine élevé a pu être associé à un risque moins élevé de mortalité un an après la sortie de l'hôpital.Conclusion et perspectiveNous avons constaté que l'anémie ainsi que l'insuffisance rénale chronique sont fréquents parmi les patients souffrant d'un AVC et qu'ils sont des facteurs de risque d'un taux de mortalité élevé après un an. En conséquence, il pourrait être utile de traiter les patients souffrant d'anémie et d'insuffisance rénale dès que possible afin de diminuer les complications et comorbidités résultants de ces maladies.La perspective est de rendre les cliniciens attentif à l'importance de l'insuffisance rénale et de l'anémie parmi les patients ayants développé un AVC, ainsi que d'initier le traitement approprié afin de diminuer les complications, les comorbidités ainsi que les récidives d'un AVC. L'efficacité et l'économicité des interventions visant à améliorer le pronostic chez les patients présentant un AVC et souffrant d'une insuffisance rénale chronique et / ou d'une anémie doivent être évaluées par des études appropriées.

Expression of killer cell immunoglobulin-like receptors (KIRs) by natural killer cells during acute CMV infection after kidney transplantation.

Human cytomegalovirus (CMV) infection may be a serious complication related to immunosuppression after solid organ transplantation. Due to their cytotoxicity, T-cells and natural killer (NK) cells target and clear the virus from CMV-infected cells. Although immunosuppressive drugs suppress T-cell proliferation and activation, they do not affect NK cells that are crucial for controlling the infection. The regulation of NK cells depends on a wide range of activating and inhibitory receptors such as the family of killer-cell immunoglobulin-like receptors (KIRs). Several human genetic studies have demonstrated the association of KIR genes with the clearance of infections. Since the respective activities of the different KIR proteins expressed by NK cells during CMV infection have not been extensively studied, we analyzed the expression of KIRs in a cohort of 22 CMV-IgG(+) renal transplant patients at the time of CMV reactivation, after antiviral therapy and 6 months later. Our data revealed a marked expression of KIR3DL1 during the acute phase of the reactivation. We set up an in vitro model in which NK cells, derived either from healthy donors or from transplanted patients, target allogeneic fibroblasts, CMV-infected or uninfected. Our results demonstrate a significant correlation between the lysis of CMV-infected fibroblasts and the expression of KIR3DL1. Blocking experiments with antibodies to MHC-I, to NKG2D and to NKG2C confirmed the importance of KIR3DL1. Consequently, our results suggest that KIR proteins and especially KIR3DL1 could play an important role during CMV-infection or CMV reactivation in immunosuppressed patients.

The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension.

BACKGROUND: Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model. CONCLUSIONS/SIGNIFICANCE: These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

Right-sided vegetation unmasks aortic endocarditis

Echocardiography is a key tool in the diagnosis of infective endocarditis. Although transthoracic echocardiography is the first step in the work-up, transoesophageal echocardiography is mandatory for the evaluation of the exact extent of the infectious process. Indeed, perivalvular abscess can fistulate towards different heart chambers, leading sometimes to critical clinical situations.

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function.

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

Anemia and chronic kidney disease are associated with poor outcomes in heart failure patients.

BACKGROUND: Chronic kidney disease (CKD) has been linked to higher heart failure (HF) risk. Anemia is a common consequence of CKD, and recent evidence suggests that anemia is a risk factor for HF. The purpose of this study was to examine among patients with HF, the association between CKD, anemia and inhospital mortality and early readmission. METHODS: We performed a retrospective cohort study in two Swiss university hospitals. Subjects were selected based the presence of ICD-10 HF codes in 1999. We recorded demographic characteristics and risk factors for HF. CKD was defined as a serum creatinine > or = 124 956;mol/L for women and > or = 133 micromol/L for men. The main outcome measures were inhospital mortality and thirty-day readmissions. RESULTS: Among 955 eligible patients hospitalized with heart failure, 23.0% had CKD. Twenty percent and 6.1% of individuals with and without CKD, respectively, died at the hospital (p < 0.0001). Overall, after adjustment for other patient factors, creatinine and hemoglobin were associated with an increased risk of death at the hospital, and hemoglobin was related to early readmission. CONCLUSION: Both CKD and anemia are frequent among older patients with heart failure and are predictors of adverse outcomes, independent of other known risk factors for heart failure.

A new electrocardiographic criteria for discriminating between Brugada types 2 and 3 patterns and incomplete right bundle branch block

Le syndrome de Brugada, une affection rythmique du sujet jeune potentiellement fatale, se manifeste sur l'ECG par un bloc de branche droit (BBD) complet, avec sus-décalage majeur du segment ST et inversion des ondes Τ de V1 à V3 appelé pattern de type 1. Cette présentation peut être intermittente. Les manifestations incomplètes du syndrome de Brugada sont appelées patterns de types 2 ou 3, et sont caractérisées par un BBD incomplet et un sus-décalage ST plus ou moins prononcé dans les dérivations V-, et V2 de l'ECG. Cette description, cependant, est aussi celle du BBD incomplet fréquemment rencontré chez les sujets jeunes, de moins de 40 ans, et présent dans 3% de la population. Bo nombre de ces sujets sont donc référés pour une recherche de syndrome de Brugada. Le but de cette thèse est donc d'évaluer de nouveaux critères permettant de discriminer les BBD incomplets, banals, des sujets porteurs d'un syndrome de Brugada de types 2 ou 3. Trente-huit patients avec un pattern de Brugada de types 2 et 3, référés pour un test médicamenteux utilisant un antiarythmique révélant un pattern de type 1 chez les sujets porteurs, ont été inclus dans l'étude. Avant le test médicamenteux, deux angles ont été mesurés sur les dérivations Vi et/ou V2 : a, l'angle entre une ligne verticale et la descente de l'onde r', et β, l'angle entre la montée de l'onde S et la descente de l'onde r'. Les mesure à l'état basai des deux angles, seules ou combinées avec la durée du QRS, on été comparées entre les patients avec une épreuve pharmacologique positive et ceux dont l'épreuve s'est révélée négative (i.e. servant de groupe contrôle car porteur d'un véritable BBD incomplet). Des courbes ROC ont été établies afin de déterminer les valeurs d'angles les plus discriminantes. La moyenne des angles β était significativement plus petite chez les 14 patients avec un test pharmacologique négatif comparé aux 24 patients avec un test positif. La valeur optimale pour l'angle β était de 58°, ce qui donnait une valeur prédictive positive de 73% et une valeur prédictive négative de 97% pour une conversion en pattern de type 1 lors du test pharmacologique. L'angle α était un peu moins sensible et spécifique que β. Quand les angles étaient combinés à la durée du QRS, on observait une discrète amélioration de la discrimination entre les deux populations. Notre travail permet donc, chez des patients suspects d'un syndrome de Brugada, de discriminer entre un BBD incomplet et les patterns de Brugada types 2 et 3 en utilisant un critère simple basé sur l'ECG de surface potentiellement applicable au lit du patient

Pain assessment in PICU and NICU: Have we got it right?

Pain assessment in critically ill infants and nonverbal children remains a challenge for health professionals. Despite the numerous pain observational measures that have been developed or adapted for infants and children with impaired communication, pain prevalence in paediatric and neonatal intensive care unit remains too high. As pain assessment has been recognised as a pre-requisite for appropriate pain management, much effort was put in the validation or the adaptation of pain measures with little emphasis on implementation of these instruments into practice. Only a few studies demonstrated the benefit of using standardised protocols for the management of pain to guide practice with variable effects. When standardised protocols are undeniably useful in practice, they do not replace health professionals' clinical reasoning necessary to care for individuals. The diversity of the PICU population makes that pain scores need to be interpreted within its clinical context. This session will present pain assessment as a complex transaction that describes structured clinical reasoning from expert nurses that goes beyond the "silver" standard of hetero-evaluation of pain in non-communicative children. Besides pain scores, several patients and nurses factors play a major role in making decisions about analgesia and/or sedation. Patient's clinical instability, change in patient's clinical status, source for observed agitated behaviour, patient's known reactions to analgesia and sedation and anticipation of risks are factors that should be taken into account when implementing pain assessment and management guidelines in PICU and NICU.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Transcatheter aortic "valve-in-valve" for degenerated bioprostheses: Choosing the right TAVI valve.

Bioprosthetic aortic valve replacement is the treatment of choice for patients over 65 years of age suffering from aortic valve disease, and for younger patients with contraindications to long-lasting anticoagulation. Despite several technical improvements to reduce the risk of structural valve degeneration (SVD), the risk of SVD still exists, in particular for hemodialysis patients and patients under 60 years of age at surgery. Redo open heart surgery is the treatment of choice in case of valve degeneration, but caries a higher surgical risk when elderly patients with comorbidities are concerned. In the last 5 years, transcatheter aortic "valve-in-valve" procedures represent a valid alternative to standard redo surgery in selected patients. Valve-in-valve procedures represent a less invasive approach in high-risk patients and the published results are very encouraging. Technical success rates of 100% have been reported, as have the absence of paravalvular leaks, acceptable trans-valvular gradients (depending on the size of the original bioprosthesis), and low complication rates. The current article focuses on choosing the correct transcutaneous valve to match the patient's existing bioprosthesis for valve-in-valve procedures.

Cystatin C as a marker of early changes of renal function in Fabry nephropathy.

BACKGROUND: A sensitive, feasible and reproducible marker for renal function is necessary to evaluate the clinical efficacy of enzyme replacement therapy (ERT) in Fabry nephropathy. Serum creatinine has some limitations and cystatin C has been proposed, in other nephropathies, as a useful marker of renal function. The use of cystatin C as a marker of glomerular filtration rate (GFR) was investigated in Fabry patients receiving ERT. METHODS: Renal function was evaluated with serum creatinine, serum cystatin C and estimated GFR (through Modification of Diet in Renal Disease [MDRD], Cockcroft-Gault [C&G] and Hoek formulae) in 21 Fabry patients receiving ERT with agalsidase alfa for 3 years and in 13 Fabry patients receiving agalsidase alfa for 4 years. RESULTS: During years of ERT while serum creatinine remained stable, cystatin C values showed a significant, increasing trend right from the first year of ERT. CONCLUSIONS: In Fabry disease, cystatin C is a sensitive and reliable marker of renal function, and it should be taken into account when evaluating GFR trends during ERT.

Exaggerated exercise-induced pulmonary hypertension causes lung water accumulation and right ventricular dysfunction in patients with chronic mountain sickness

Background: Chronic mountain sickness (CMS) is characterized by exaggerated exercise-induced pulmonary hypertension. Evidences suggests that exercise may cause lung fluid accumulation at high altitude. We hypothesized that, in patients with CMS, exercise causes lung fluid accumulation.Methods: In 21 male CMS patients and 20 matched healthy controls born and permanently living in La Paz (Bolivia, 3600m) we assessed with echocardiogram, pulmonary artery pressure (PASP), right and left ventricular function and ultrasoundlung comets (ULCs, a marker of lung fluid accumulation) at rest and during mild bicycle exercise (10 min at 50W).Results: CMS patients presented a more than 2-fold greater exercise-induced increase in pulmonary artery pressure than controls (17.1±8.3 vs 7.2±7.9 mmHg, P=0.003). This exaggerated PASP response to exercise was associated with a roughly 3-fold greater increase in UCLs in patients with CMS than in controls (6.3±5.1 vs. 2.1±5.3, p<0.05), and there existed a significant relationship between PASP and UCLs (r=0.44, p<0.001). Finally, TDI on lateral tricuspid annulus decreased during exercise in patients with CMS (from 13.2±3.2 to 11.5±2.1 cm s-1, p=0.03), but increased in controls (from 13.1±2.9 to 14.9±2.6 cm s-1 , p=0.04). Left ventricular function remained unaltered in the 2 groups.Conclusions: we provide the first direct evidence in CMS patients that exaggerated exercise-induced pulmonary hypertension causes rapid lung fluid accumulation and right ventricular dysfunction. We speculate that in patients with CMS these two phenomena contribute to reduced exercise performances and Figure 1 increased cardiovascular morbidity and mortality that characterise these subjects.