Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial

Background. Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly

REIN : un outil au service de l’évaluation des pratiques

International audienceOn the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of its role in practices evaluation, the following key messages were retained.The evaluation of our practices allows improving them as proposed by the concept of the Edward Deming wheel (Plan, Do, Check, Act). Measurement also allows setting goals and targets.Where there are recommendations available, the REIN indicators allow comparison with the identified targets. The REIN registry is an interesting tool to observe the deployment and impact of the recommendations in dialysis units and to evaluate the professional practices taking into account the patients’ characteristics and the changes in the recommendations. Finally, the treatment indicators analysed using REIN data show the great diversity of practices from one region to another, the result of habits, training of nephrologists, the history of the care offered and sometimes the geography of the region and its population.À l’occasion des 20 ans du REIN (Réseau Epidémiologie et Information en Néphrologie), un travail de synthèse sur les apports du registre a été mené. Sur la question de REIN comme outil pour l’évaluation des pratiques, les messages clés suivants ont été retenus.L’évaluation de nos pratiques permet de les améliorer comme proposé par le concept de la roue d’Edward Deming (Plan, Do, Check, Act). Se mesurer permet également de fixer des objectifs et des cibles.Lorsque des recommandations sont disponibles, les indicateurs REIN permettent de se comparer aux cibles identifiées. Le registre REIN est un outil intéressant pour observer le déploiement et l’impact des recommandations dans les unités de dialyse et évaluer les pratiques professionnelles en tenant compte des caractéristiques des patients et de l’évolution des recommandations. Enfin, les indicateurs de prise en charge analysés à l’aide des données REIN montrent la grande diversité des pratiques d’une région à l’autre, fruit des habitudes, de la formation des néphrologues, de l’historique de l’offre de soins et parfois de la géographie de la région et de sa population

Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation

Matrix metalloproteinase 2 (MMP2) has been reported to be secreted by collagen-stimulated platelets, and active MMP2 has been shown to play a role in platelet aggregation. It has been demonstrated that MMP2 activation is dependent on the complex (membrane type 1 [MT1]-MMP/tissue inhibitor of MMP2 [TIMP2]) receptor and MMP2. We have investigated human platelets as a possible source of MT1-MMP, and we have studied its role in MMP2 activation and in platelet aggregation. Gelatin zymograms showed the existence of MMP2 at proforms (68 kd) and activated-enzyme forms (62-59 kd) in supernatants of resting and activated platelets, respectively. No gelatinolytic activity was associated with the platelet pellet after aggregation, suggesting a total release of MMP2 during cell activation. By Western blot analysis in nonreduced conditions, MT1-MMP was found on resting platelet membranes in 2 forms–the inactive 45-kd form and an apparent 89-kd form, which totally disappeared under reduced conditions. After platelet degranulation, only the 45-kd form was detected. Reverse transcription–polymerase chain reaction experiments showed the expression in platelets of messenger RNA encoding for MMP2, MT1-MMP, and TIMP2. Flow cytometry analysis showed that MT1-MMP, MMP2, and TIMP2 expressions were enhanced at the activated platelet surface. MMP inhibitors, recombinant TIMP2, and synthetic BB94 inhibited collagen-induced platelet aggregation in a concentration-dependent manner, indicating the role of activated MT1-MMP in the modulation of platelet function. In conclusion, our results demonstrate the expression of the trimolecular complex components (MT1-MMP/TIMP2/MMP2) by blood platelets as well as the ability of MMP inhibitors to modulate the aggregating response.</jats:p

Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation

AbstractMatrix metalloproteinase 2 (MMP2) has been reported to be secreted by collagen-stimulated platelets, and active MMP2 has been shown to play a role in platelet aggregation. It has been demonstrated that MMP2 activation is dependent on the complex (membrane type 1 [MT1]-MMP/tissue inhibitor of MMP2 [TIMP2]) receptor and MMP2. We have investigated human platelets as a possible source of MT1-MMP, and we have studied its role in MMP2 activation and in platelet aggregation. Gelatin zymograms showed the existence of MMP2 at proforms (68 kd) and activated-enzyme forms (62-59 kd) in supernatants of resting and activated platelets, respectively. No gelatinolytic activity was associated with the platelet pellet after aggregation, suggesting a total release of MMP2 during cell activation. By Western blot analysis in nonreduced conditions, MT1-MMP was found on resting platelet membranes in 2 forms–the inactive 45-kd form and an apparent 89-kd form, which totally disappeared under reduced conditions. After platelet degranulation, only the 45-kd form was detected. Reverse transcription–polymerase chain reaction experiments showed the expression in platelets of messenger RNA encoding for MMP2, MT1-MMP, and TIMP2. Flow cytometry analysis showed that MT1-MMP, MMP2, and TIMP2 expressions were enhanced at the activated platelet surface. MMP inhibitors, recombinant TIMP2, and synthetic BB94 inhibited collagen-induced platelet aggregation in a concentration-dependent manner, indicating the role of activated MT1-MMP in the modulation of platelet function. In conclusion, our results demonstrate the expression of the trimolecular complex components (MT1-MMP/TIMP2/MMP2) by blood platelets as well as the ability of MMP inhibitors to modulate the aggregating response.</jats:p

Switch from Hemodialysis to Peritoneal Dialysis: Does the Time Spent on Hemodialysis Impact Outcomes in Peritoneal Dialysis?

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Switch from hemodialysis (HD) to peritoneal dialysis (PD) is unfrequent, but incentive strategies to perform PD can lead to an increase of these transitions. However, data on transitioning from HD to PD are scarce. We hypothesized that time spent on HD before transfer to PD would impact PD outcomes. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This registry-based, nationwide study analyzed patients transferred from HD to PD. Patients who began HD between January 2008 and December 2016 were included. Cox and Fine and Gray regression models were used to explore the relationship between time spent on HD before PD and outcomes in PD: PD cessation for death or retransfer to HD (composite endpoint); for death; and for retransfer to HD. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Over the study period, 1,985 of the 77,587 HD starters (3%) were transferred to PD. The median time spent on HD before transfer to PD was 1.94 months (interquartile range [IQR] 1.02–4.01). The median survival time on PD after this transition was 20 months (IQR 18–21). Time spent on HD before PD was associated with increased risk of death or retransfer to HD (cause-specific hazard ratio [cs-HR] 1.01, 95% confidence interval [CI]: 1–1.02 for a 1-month increase) and death (cs-HR 1.02, 95% CI: 1.01–1.03) but not with retransfer to HD censored on death (cs-HR 1.00, 95% CI: 0.99–1.01). The results were similar when considering competing events. &lt;b&gt;&lt;i&gt;Discussion/Conclusion:&lt;/i&gt;&lt;/b&gt; Switch from HD to PD is rare in France. Time spent on HD before transfer is associated with patient survival but not with retransfer to HD. </jats:p

Effect of emergency start and central venous catheter on outcomes in incident hemodialysis patients: a prospective observational cohort

International audienceBackground: Unfavorable conditions at hemodialysis inception reduce the survival rate. However, the relative contribution to outcomes of predialysis follow-up, symptoms, emergency start or central venous catheter (CVC) is unknown.Methods: We analyzed the determinants of survival according to dialysis initiation conditions in the nationwide REIN registry, using two methods based either on clinical classification or data mining. We divided patients into four groups according to dialysis initiation (emergency vs planned, symptoms or not, previous follow-up). "Followed planned starters" began dialysis as outpatients and with an arteriovenous fistula (AVF). "Followed symptomatic non-urgent starters" were patients who started earlier because of any non-urgent symptomatic event. "Followed urgent starters" had seen a nephrologist before inception but started dialysis in an emergency condition. "Unknown urgent starters" were patients without any follow-up and who had a CVC at inception.Results: "Followed urgent" starters had the lowest 2-year survival rate (66.8%) compared to "followed planned" (77.3%), "followed symptomatic non urgent" (79.2%), and "unknown urgent" (71.7%). Compared to other groups, the risk of mortality was lower in followed symptomatic non urgent (HR 0.86 95% CI 0.75-0.99) and higher in followed urgent starters (HR 1.05 (95% CI 0.94-1.18). In data mining Classification And Regression Tree regrouping in five categories, the lowest 2-year survival (52.3%) was in over 70-year-old starters with a CVC. The survival was 93.2% in under 57-year-old patients without active cancer, 82.5% in 57-70-year-old individuals without cancer, 72.4% in over 70-year-old patients without CVC and 61.4% in under 70-year-old subjects with cancer. The hazard ratio of data mining categories varied between 2.12 (95% CI 1.73-2.60) in 57-70-year-old subjects without cancer and 4.42 (95% CI 3.64-5.37) in over 70-year-old patients with CVC. Therefore, regrouping incident patients into five data mining categories, identified by age, cancer, and CVC use, could discriminate the 2-year survival in patients starting hemodialysis.Conclusions: Although each classification captured different prognosis information, both analyses showed that starting hemodialysis on a CVC has more dramatic outcomes than emergency start per se

Soluble latent membrane-type 1 matrix metalloprotease secreted by human mesangial cells is activated by urokinase

Soluble latent membrane-type 1 matrix metalloproteinase secreted by human mesangial cells is activated by urokinase.BackgroundMatrix metalloprotease 2 (MMP2) is secreted in a latent inactive form (pro-MMP2) that is activated on the cell surface by a membrane-type 1 MMP (MT1-MMP) in the presence of the tissue inhibitor of MMP (TIMP2). In spite of evidence for the synthesis of MT1-MMP shown by immunoblotting, immunocytochemistry and RT-PCR, and of TIMP2, MMP2 was found exclusively in a latent form in human mesangial cells (HMC) serum-free culture medium.Methods and ResultsOn purified membranes of HMC, MT1-MMP was found in a 63 kD latent form and as a faint band of 55 kD. The 55 kD band was also present in the ultracentrifuged conditioned medium and likely represented MT1-MMP cleaved from its transmembrane domain, since Northern blot analysis showed only one transcription product. The addition of urokinase plasminogen activator (uPA, 100nm) to HMC membranes induced the activation of pro-MMP2 via the activation of latent membrane-associated MT1-MMP as reflected by the cleavage of the 63 and 55 kD forms. In addition, when the conditioned medium was successively incubated with uPA and α2-macroglobulin and analyzed by immunoblotting, MT1-MMP decreased, indicating that the soluble MT1-MMP was in a latent form and was activated by uPA.ConclusionOur results provide the first evidence, to our knowledge, of the existence of a soluble latent form of MT1-MMP secreted by primary human cells in culture, confirming that MT1-MMP is an ectoenzyme, and show that uPA can regulate MT1-MMP activity in a soluble phase