Hepatitis C virus seroprevalence and genotypes in patients with diffuse connective tissue diseases and spondyloarthropathies

Many extrahepatic manifestations, including rheumatic diseases, have been reported to be associated with hepatitis C virus (HCV) infection. In order to investigate the prevalence of HCV infection among patients with rheumatic diseases, in the present study we interviewed 367 patients and tested their blood samples for HCV antibodies (anti-HCV) by an enzyme-linked immunosorbent assay. Anti-HCV-reactive samples were retested for confirmation by a line immunoassay and also for HCV RNA detection by the polymerase chain reaction. HCV RNA-positive samples were genotyped by INNO-LIPA. An overall HCV infection prevalence of 1.9% (7/367) was found. Of the 7 HCV-infected patients, 4 had systemic lupus erythematosus and 3 rheumatoid arthritis, resulting in positivity rates of 2.3 and 3.4%, respectively. HCV RNA genotyping revealed the presence of subtypes 1a (57.1%), 1b (28.6%) and 3a (14.3%). The clinical course was favorable for all HCV-infected patients, except one, who died due to renal insufficiency related to lupus nephritis. These results demonstrate a low HCV infection prevalence among the population studied. In the few positive cases, we observed no adverse influence of this infection on the clinical evolution of the rheumatic disease.

Hemochromatosis (HFE) gene mutations in Brazilian chronic hemodialysis patients

Patients with chronic renal insufficiency (CRI) have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron). A C282Y heterozygous mutation was found in 7/201 (3.4%) and H63D homozygous and heterozygous mutation were found in 2/201 (1.0%) and 46/201 (22.9%), respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation) did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08). From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10). Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.

A randomized, double-blind, and placebo-controlled study with tranexamic acid of bleeding and fibrinolytic activity after primary coronary artery bypass grafting

Cardiopulmonary bypass is frequently associated with excessive blood loss. Platelet dysfunction is the main cause of non-surgical bleeding after open-heart surgery. We randomized 65 patients in a double-blind fashion to receive tranexamic acid or placebo in order to determine whether antifibrinolytic therapy reduces chest tube drainage. The tranexamic acid group received an intravenous loading dose of 10 mg/kg, before the skin incision, followed by a continuous infusion of 1 mg kg-1 h-1 for 5 h. The placebo group received a bolus of normal saline solution and continuous infusion of normal saline for 5 h. Postoperative bleeding and fibrinolytic activity were assessed. Hematologic data, convulsive seizures, allogeneic transfusion, occurrence of myocardial infarction, mortality, allergic reactions, postoperative renal insufficiency, and reopening rate were also evaluated. The placebo group had a greater postoperative blood loss (median (25th to 75th percentile) 12 h after surgery (540 (350-750) vs 300 (250-455) mL, P = 0.001). The placebo group also had greater blood loss 24 h after surgery (800 (520-1050) vs 500 (415-725) mL, P = 0.008). There was a significant increase in plasma D-dimer levels after coronary artery bypass grafting only in patients of the placebo group, whereas no significant changes were observed in the group treated with tranexamic acid. The D-dimer levels were 1057 (1025-1100) µg/L in the placebo group and 520 (435-837) µg/L in the tranexamic acid group (P = 0.01). We conclude that tranexamic acid effectively reduces postoperative bleeding and fibrinolysis in patients undergoing first-time coronary artery bypass grafting compared to placebo.

Risk factors associated with the death of patients hospitalized for juvenile systemic lupus erythematosus

We assessed the risk factors associated with death in patients hospitalized for juvenile systemic lupus erythematosus (JSLE) and evaluated the autopsy reports. A total of 57,159 hospitalizations occurred in our institution from 1994 to 2003, 169 of them involving 71 patients with JSLE. The most recent hospitalization of these patients was evaluated. Patients were divided into two groups based on mortality during hospitalization: those who survived (N = 53) and those who died (N = 18). The main causes of hospitalization were JSLE activity associated with infection in 52% and isolated JSLE activity in 44%. Univariate analysis showed that a greater risk of death was due to severe sepsis (OR = 17.8, CI = 4.5-70.9), systemic lupus erythematosus disease activity index (SLEDAI) ³8 (OR = 7.6, CI = 1.1-53.8), general infections (OR = 6.1, CI = 1.5-25), fungal infections (OR = 5.4, CI = 3.2-9), acute renal failure (OR = 5.1, CI = 2.5-10.4), acute thrombocytopenia (OR = 3.9, CI = 1.9-8.4), and bacterial infections (OR = 2.3, CI = 1.2-7.5). Stratified analysis showed that severe sepsis and SLEDAI ³8 were not confounder variables. In the multivariate analysis, logistic regression showed that the only independent variable in death prediction was severe sepsis (OR = 98, CI = 16.3-586.2). Discordance between clinical diagnosis and autopsy was observed in 6/10 cases. Mortality of hospitalized JSLE patients was associated with severe sepsis. Autopsy was important to determine events not detected or doubtful in dead patients and should always be requested.

Correlation between sodium and potassium excretion in 24- and 12-h urine samples

Low-sodium and high-potassium diets have been recommended as an adjunct to prevention and treatment of hypertension. Analysis of these nutrients in 24-h urine has been considered the reference method to estimate daily intake of these minerals. However, 24-h urine collection is difficult in epidemiological studies, since urine must be collected and stored in job environments. Therefore, strategies for shorter durations of urine collection at home have been proposed. We have previously reported that collecting urine during a 12-h period (overnight) is more feasible and that creatinine clearance correlated strongly with that detected in 24-h samples. In the present study, we collected urine for 24 h divided into two 12-h periods (from 7:00 am to 7:00 pm and from 7:00 pm to 7:00 am next day). A sample of 109 apparently healthy volunteers aged 30 to 74 years of both genders working in a University institution was investigated. Subjects with previous myocardial infarction, stroke, renal insufficiency, and pregnant women were not included. Significant (P < 0.001) Spearman correlation coefficients (r s) were found between the total amount of sodium and potassium excreted in the urine collected at night and in the 24-h period (r s = 0.76 and 0.74, respectively). Additionally, the 12-h sodium and potassium excretions (means ± SD, 95% confidence interval) corresponded to 47.3 ± 11.2%, 95%CI = 45.3-49.3, and 39.3 ± 4.6%, 95%CI = 37.3-41.3, respectively, of the 24-h excretion of these ions. Therefore, these findings support the assumption that 12-h urine collected at night can be used as a reliable tool to estimate 24-h intake/excretion of sodium and potassium.

Genetic aberrations in multiple myeloma characterized by cIg-FISH: a Brazilian context

Genetic abnormalities are critical prognostic factors for patients diagnosed with multiple myeloma (MM). This retrospective, multicenter study aimed to contribute with the genetic and clinical characterization of MM patients in a country with continental dimensions such as Brazil. Genetic abnormalities were assessed by cIg-fluorescent in situ hybridization (cIg-FISH) in a series of 152 MM patients (median age 55 years, 58.5% men). Overall, genetic abnormalities were detected in 52.7% (80/152) of patients. A 14q32 rearrangement was detected in 33.5% (n=51), including t(11;14), t(4;14) and t(14;16) in 18.4, 14.1, and 1% of cases, respectively. del(13q) was identified in 42.7% (n=65) of patients, of whom 49.2% (32/65) presented a concomitant 14q32 rearrangement. del(17p) had a frequency of 5.2% (n=8). del(13q) was associated with high plasma cell burden (≥50%, P=0.02), and del(17p) with advanced ISS stages (P=0.05) and extramedullary disease (P=0.03). t(4;14) was associated with advanced Durie-Salmon stages (P=0.008), renal insufficiency (P=0.01) and was more common in patients over 60 years old. This study reports similar frequencies of genetic abnormalities to most series worldwide, whereas the t(14;16) and del(17p), two high risk factors for newly diagnosed patients, exhibited lower frequencies. Our results expand the knowledge on the molecular features of MM in Brazil, a country where innovative therapies that could overcome a poor prognosis for some genetic abnormalities are not always available.

Assessment of a five-year survival on hemodialysis in Brazil: a cohort of 3,082 incident patients

Brazil has the third largest contingent of patients on maintenance hemodialysis (HD) worldwide. However, little is known regarding survival rate and predictors of mortality risk in that population, which are the purposes of this study. A total of 3,082 patients incident on HD, from 2000 to 2004, at 25 dialysis facilities distributed among 7 out of 26 states of Brazil were followed-up until 2009. Patients were 52 ± 16 years-old, 57.8% men, and 20.4%, diabetics. The primary outcome was all causes of mortality. Data were censored at five years of follow-up. The global five-year survival rate was 58.2%. In the Cox proportional model, variables associated with risk of death were: age (hazard ratio - HR = 1.44 per decade, p < 0.0001), diabetes (HR = 1.51, p < 0.0001), serum albumin (HR = 0.76 per g/dL, p = 0.001), creatinine (HR = 0.92 per mg/dL, p < 0.0001), and phosphorus (HR = 1.06 per mg/dL, p = 0.04). The present results show that the mortality rate on HD in this Brazilian cohort was relatively low, but the population is younger and with a lower prevalence of diabetes than the ones reported for developed countries.

The chronic kidney disease outcomes and practice patterns study Brazil (CKDopps-Brazil): Design, data and methodology

Introduction: The chronic kidney disease outcomes and practice patterns study (CKDopps) is an international observational, prospective, cohort study involving patients with chronic kidney disease (CKD) stages 3-5 [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, with a major focus upon care during the advanced CKD period (eGFR < 30 ml/min/1.73 m2)]. During a 1-year enrollment period, each one of the 22 selected clinics will enroll up to 60 advanced CKD patients (eGFR < 30 ml/min/1.73 m2 and not dialysis-dependent) and 20 earlier stage CKD patients (eGFR between 30-59 ml/min/1.73 m2). Exclusion criteria: age < 18 years old, patients on chronic dialysis or prior kidney transplant. The study timeline include up to one year for enrollment of patients at each clinic starting in the end of 2013, followed by up to 2-3 years of patient follow-up with collection of detailed longitudinal patient-level data, annual clinic practice-level surveys, and patient surveys. Analyses will apply regression models to evaluate the contribution of patient-level and clinic practice-level factors to study outcomes, and utilize instrumental variable-type techniques when appropriate. Conclusion: Launching in 2013, CKDopps Brazil will study advanced CKD care in a random selection of nephrology clinics across Brazil to gain understanding of variation in care across the country, and as part of a multinational study to identify optimal treatment practices to slow kidney disease progression and improve outcomes during the transition period to end-stage kidney disease.

Depressed cardiac autonomic modulation in patients with chronic kidney disease

Introduction: A dysfunctional autonomic nervous system (ANS) has also been recognized as an important mechanism contributing to the poor outcome in CKD patients, with several studies reporting a reduction in heart rate variability (HRV). Objective: Evaluate the sympathovagal balance in patients with chronic kidney disease on conservative treatment. Methods: In a cross-sectional study, patients with CKD stages 3, 4 and 5 not yet on dialysis (CKD group) and age-matched healthy subjects (CON group) underwent continuous heart rate recording during two twenty-minute periods in the supine position (pre-inclined), followed by passive postural inclination at 70° (inclined period). Power spectral analysis of the heart rate variability was used to assess the normalized low frequency (LFnu), indicative of sympathetic activity, and the normalized high frequency (HFnu), indicative of parasympathetic activity. The LFnu/HFnu ratio represented sympathovagal balance. Results: After tilting, CKD patients had lower sympathetic activity, higher parasympathetic activity, and lower sympathovagal balance than patients in the CON group. Compared to patients in stage 3, patients in stage 5 had a lower LFnu/HFnu ratio, suggesting a more pronounced impairment of sympathovagal balance as the disease progresses. Conclusion: CKD patients not yet on dialysis have reduced HRV, indicating cardiac autonomic dysfunction early in the course of CKD.

Association between indoxyl sulfate and bone histomorphometry in pre-dialysis chronic kidney disease patients

Introduction: Experimental studies have suggested that indoxyl sulfate (IS), a protein-bound uremic toxin, may be involved in the development of renal osteodystrophy. Objective: evaluate the association between IS levels and biochemical parameters related to mineral metabolism and bone histomorphometry in a cohort of pre-dialysis chronic kidney disease (CKD) patients. Methods: This is a post-hoc analysis of an observational study evaluating the association between coronary calcification and bone biopsy findings in 49 patients (age: 52 ± 10 years; 67% male; estimated glomerular filtration rate: 36 ± 17 ml/min). Serum levels of IS were measured. Results: Patients at CKD stages 2 and 3 presented remarkably low bone formation rate. Patients at CKD stages 4 and 5 presented significantly higher osteoid volume, osteoblast and osteoclast surface, bone fibrosis volume and bone formation rate and a lower mineralization lag time than CKD stage 2 and 3 patients. We observed a positive association between IS levels on one hand and the bone formation rate, osteoid volume, osteoblast surface and bone fibrosis volume on the other. Multivariate regression models confirmed that the associations between IS levels and osteoblast surface and bone fibrosis volume were both independent of demographic and biochemical characteristics of the study population. A similar trend was observed for the bone formation rate. Conclusion: Our findings demonstrated that IS is positively associated with bone formation rate in pre-dialysis CKD patients.

Comparison of baseline data between chronic kidney disease patients starting hemodialysis who live near and far from the dialysis center

Introduction: The treatment offered to chronic kidney disease (CKD) patients before starting hemodialysis (HD) impacts prognosis. Objective: We seek differences among incident HD patients according to the distance between home and the dialysis center. Methods: We included 179 CKD patients undergoing HD. Patients were stratified in two groups: "living near the dialysis center" (patients whose hometown was in cities up to 100 km from the dialysis center) or as "living far from the dialysis center" (patients whose hometown was more than 100 km from the dialysis center). Socioeconomic status, laboratory results, awareness of CKD before starting HD, consultation with nephrologist before the first HD session, and type of vascular access when starting HD were compared between the two groups. Comparisons of continuous and categorical variables were performed using Student's t-test and the Chi-square test, respectively. Results: Ninety (50.3%) patients were classified as "living near the dialysis center" and 89 (49.7%) as "living far from the dialysis center". Patients living near the dialysis center were more likely to know about their condition of CKD than those living far from the dialysis center, respectively 46.6% versus 28.0% (p = 0.015). Although without statistical significance, patients living near the dialysis center had more frequent previous consultation with nephrologists (55.5% versus 42.6%; p = 0.116) and first HD by fistula (30.0% versus 19.1%; p = 0.128) than those living far from the dialysis center. Conclusion: There are potential advantages of CKD awareness, referral to nephrologists and starting HD through fistula among patients living near the dialysis center.

Dyadic Relationship and Quality of Life Patients with Chronic Kidney Disease

AbstractIintroduction:Chronic Renal insufficiency (CRI) and dialysis treatment lead to a succession of situations for kidney chronic patient, which compromises his aspect, not only physically, and psychologically, with personal, family and social repercussions.Objective:(1) to verify the existence of differences of dyadic adjustment (DA) according to renal replacement treatment (RRT) and (2) verify the existence of differences quality of life (QOL) in accordance with the RRT.Methods:This is a cross-sectional study of a descriptive nature through surveys, exploratory and correlational. The sample consisted of 125 participants. Of these, 31 were to be made RRT by automated peritoneal dialysis (APD) and 94 hemodialysis (HD). Participants were selected from three renal centers: (1) Centro Renal da Prelada (Porto, Portugal), (2) Centrodial (S. João da Madeira, Portugal) and Centro Renal da Misericórdia de Paredes (Paredes, Portugal). The study was carried out for 6 months. The following instruments were applied: Socio-demographic and clinical questionnaire (SDCQ), Dyadic Adjustment Scale (DAS), World Health Organization Quality of Life (WHOQOL-Bref).Results:The results demonstrate the existence of statistically significant differences between the type of RRT and most areas of QOL, as well as the existence of statistically significant differences between the subscales of the DAS evaluated and the type of RRT.Conclusion:The present study demonstrates a greater commitment in terms of QOL of individuals undergoing treatment for HD when compared with those subjected to APD. It turns out, also, that DA is most strongly perceived by patients in APD than with HD.

Étude de la pharmacologie de ligands du récepteur EP4 de prostaglandine E2

La prostaglandine E2 est une hormone lipidique produite abondamment dans le corps, incluant dans le rein où elle agit localement pour réguler les fonctions rénales. Un couplage à la protéine Gαs menant à une production d’AMPc a classiquement été attribué au récepteur EP4 de PGE2. La signalisation d’EP4 s’est cependant avérée plus complexe et implique aussi un couplage aux protéines sensibles à la PTX Gαi et des effets reliés aux β-arrestines. Il y a maintenant plusieurs exemples de l’activation sélective de voies de signalisation indépendantes par des ligands des récepteurs couplés aux protéines G (RCPG), et ce concept désigné sélectivité fonctionnelle pourrait être exploité dans le développement de nouveaux médicaments plus spécifiques et efficaces. Dans une première étude, la puissance et l’activité intrinsèque d’une série de ligands d’EP4 pour l’activation de Gαs, Gαi et de la ß-arrestine ont été systématiquement déterminées relativement au ligand endogène PGE2. Dans ce but, trois essais de transfert d’énergie de résonance de bioluminescence (BRET) ont été adaptés pour évaluer les différentes voies dans des cellules vivantes. Nos résultats montrent une sélectivité fonctionnelle importante parmi les agonistes évalués et ont une implication pour l’utilisation d’analogues de la PGE2 dans un contexte expérimental et possiblement clinique, puisque leur spectre d’activité diffère de l’agoniste naturel. La méthodologie basée sur le BRET utilisée lors de cette première évaluation systématique d’une série d’agonistes d’EP4 devrait être applicable à l’étude d’autres RCPG. Dans une deuxième étude, des peptides reproduisant des régions juxtamembranaires extracellulaires du récepteur EP4 ont été conçus selon le raisonnement que des peptides ciblant des régions éloignées du site de liaison du ligand naturel ont le potentiel de ne moduler qu’une partie des activités du récepteur. L’insuffisance rénale aiguë est une complication médicale grave caractérisée par un déclin brusque et soutenu de la fonction rénale et pour laquelle il n’y a pas de traitement efficace à l’heure actuelle. Nos résultats montrent que le peptidomimétique dérivé d’EP4 optimisé (THG213.29) améliore significativement les fonctions rénales et les changements histologiques dans une insuffisance rénale aiguë induite par cisplatine ou par occlusion des artères rénales dans des rats Sprague-Dawley. Le THG213.29 ne compétitionnait pas la liaison de la PGE2 à EP4, mais modulait la cinétique de dissociation de la PGE2, suggérant une liaison à un site allostérique d’EP4. Le THG213.29 démontrait une sélectivité fonctionnelle, puisqu’il inhibait partiellement la production d’AMPc induite par EP4 mais n’affectait pas l’activation de Gαi ou le recrutement de la ß-arrestine. Nos résultats indiquent que le THG213.29 représente une nouvelle classe d’agent diurétique possédant les propriétés d’un modulateur allostérique non-compétitif des fonctions du récepteur EP4 pour l’amélioration des fonctions rénales suite à une insuffisance rénale aiguë.

Facteurs de risque d’insuffisance rénale chronique chez les greffés cardiaques : du phénotype aux tests pharmacogénomiques

L’insuffisance rénale chronique (IRC) est un problème majeur fréquemment rencontré chez les greffés cardiaques. Les inhibiteurs de la calcineurine, pierre angulaire de l’immunosuppression en transplantation d’organes solides, sont considérés comme une des principales causes de dysfonction rénale postgreffe. Plusieurs autres éléments tels que les caractéristiques démographiques, cliniques et génétiques du receveur contribuent également au phénomène, mais il demeure plutôt difficile de déterminer quels sont les patients les plus à risque de développer une IRC après la transplantation. Ainsi, la découverte de nouveaux marqueurs génétiques de dysfonction rénale pourrait un jour mener à l’individualisation de la thérapie immunosuppressive selon le profil génétique de chaque patient. Or, on ne connaît pas les opinions des greffés à l’égard des tests pharmacogénomiques et l’on ne sait pas si celles-ci diffèrent des opinions exprimées par les individus en bonne santé. Cette thèse de doctorat a donc pour objectifs : 1- De décrire l’évolution de la fonction rénale à très long terme après la transplantation et d’identifier les marqueurs démographiques et phénotypiques associés à l’IRC postgreffe cardiaque; 2- D’identifier les marqueurs génétiques associés à la néphrotoxicité induite par les inhibiteurs de la calcineurine; 3- D’évaluer et de comparer les attitudes des patients et des individus en bonne santé par rapport à l’intégration clinique potentielle des marqueurs pharmacogénomiques. Trois projets ont été réalisés pour répondre à ces questions. Le premier repose sur une analyse rétrospective de l’évolution de la fonction rénale chez les patients greffés au sein de notre établissement entre 1983 et 2008. Nous y avons découvert que le déclin de la fonction rénale se poursuit jusqu’à 20 ans après la transplantation cardiaque et que les facteurs de risque d’IRC incluent entre autres l’âge avancé, le sexe féminin, la dysfonction rénale prégreffe, l’hypertension, l’hyperglycémie et l’utilisation de la prednisone. Le deuxième projet est une étude pharmacogénomique s’intéressant aux déterminants génétiques de la néphrotoxicité induite par les inhibiteurs de la calcineurine. Elle nous a permis d’illustrer pour la première fois qu’un polymorphisme génétique lié à PRKCB (gène codant pour la protéine kinase C-β) est associé avec la fonction rénale des patients greffés cardiaques, alors que cela n’est probablement pas le cas pour les polymorphismes de TGFB1 (gène codant pour le transforming growth factor-β1). La troisième section de cette thèse rapporte les résultats d’un questionnaire dont le but était de comparer les attitudes envers les tests pharmacogénomiques parmi un groupe de personnes en bonne santé, de patients greffés cardiaques et de patients souffrant d’insuffisance cardiaque. Cette étude a démontré que, bien que l’enthousiasme pour la pharmacogénomique soit partagé par tous ces individus, les craintes liées à la confidentialité et aux répercussions potentielles sur l’emploi et les assurances sont plus prononcées chez les personnes en bonne santé. En résumé, les travaux issus de cette thèse ont révélé que l’identification précoce des patients greffés cardiaques les plus susceptibles de présenter une détérioration de la fonction rénale ainsi que l’adoption d’une approche thérapeutique individualisée reposant notamment sur les applications cliniques de la pharmacogénomique pourraient éventuellement permettre de freiner cette complication postgreffe.