The Effect of Sevelamer on Serum Levels of Gut-Derived Uremic Toxins: Results from In Vitro Experiments and A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial

International audienceHigh serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 microg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m(2)) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 microg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 +/- 3.4%) and pH 6 (mean reduction: 38.7 +/- 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: -0.12, 0.26 and -0.06 microg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 microg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA

Impact des échanges plasmatiques au cours des hémorragies alvéolaires graves associées aux vascularites associées aux ANCA

International audienceIntroductionLes hémorragies intra-alvéolaires (HIA) sont responsables d’une mortalité élevée au cours des vascularites associées aux ANCA (VAA) [1]. Les échanges plasmatiques (EP) ont été proposés en traitement d’induction des VAA graves en association au traitement standard, en particulier pour les glomérulonéphrites rapidement progressives et les HIA graves. L’essai PEXIVAS n’a pas montré de supériorité des EP sur la mortalité chez les patients présentant une VAA sévère avec insuffisance rénale et/ou HIA [2]. Néanmoins, seuls 27 % des patients inclus avaient une HIA et moins de 9 % d’entre eux avaient une HIA sévère définie par une SpO2 < 85 % en air ambiant ou le recours à la ventilation mécanique. Cette population de patients graves pourrait bénéficier des EP comme l’ont suggéré des résultats ancillaires de l’essai PEXIVAS, avec une mortalité à 90 jours de 16,1 % dans le groupe EP versus 30 % dans le groupe sans EP [3]. L’objectif de cette étude est d’étudier l’effet des EP sur la mortalité des patients hospitalisés pour une VAA avec HIA grave.Patients et méthodesIl s’agit d’une étude rétrospective multicentrique française incluant des patients ayant présenté une HIA grave au cours d’une poussée de granulomatose avec polyangéite (GPA) ou polyangéite microscopique (PM) au cours des 10 dernières années. Le critère de jugement principal était la mortalité à 30 jours (J30). Les analyses univariées ont été réalisées avec un test du χ2 ou de Fisher pour les variables catégorielles, ou un test de Mann-Whitney pour les variables quantitatives. L’analyse du critère de jugement principal a été réalisée par un modèle de Cox pour prendre en compte les données censurées, avec ajustement sur les facteurs de confusion définis a priori.RésultatsNous avons inclus 186 patients issus de 40 centres (88 GPA et 91 PM, âge médian 66 ans [53; 75], 46,7 % d’hommes). Les ANCA étaient positifs chez tous les patients (anti-PR3 46,2 %, anti-MPO 54,3 %). En plus du traitement standard, 144 patients ont reçu des EP (77,4 %) et 42 n’en ont pas reçu (22,6 %). Les patients traités par EP étaient plus sévères que les patients sans EP avec une atteinte rénale significativement plus fréquente dans le groupe EP (94,2 vs. 84,6 %, p < 0,05) et un débit de filtration glomérulaire significativement inférieur chez les patients traités par EP (DFG médian à 25 mL/min/1,73 m2 vs 41 mL/min/1,73 m2, p < 0,05). La ventilation mécanique n’était pas significativement plus utilisée dans le groupe EP (52,1 % vs 41,5 % p = 0,23). Les patients du groupe EP recevaient significativement plus souvent des bolus de méthylprednisolone (97,2 % vs 88,1 %, p < 0,05) et du cyclophosphamide (78,5 % vs 54,8 %, p < 0,01). Le score BVAS était en revanche comparable entre les groupes (23,1 dans le groupe EP vs 21,4 dans le groupe sans EP, p = 0,18).Sans ajustement sur les facteurs associés à l’utilisation des EP, la mortalité à J30 était comparable entre les 2 groupes (14,1 % vs 14,3 %, p = 0,97), avec un hazard ratio pour la mortalité à J30 de l’admission en réanimation à 1,2 [IC95 % 0,4–3,1], p = 0,8), de même que la mortalité à J90, J180 et aux dernières nouvelles. Après ajustement sur les facteurs de confusion (valeur maximale de créatininémie, âge, score de gravité à l’admission et nécessité d’une ventilation invasive), la réalisation d’EP n’était toujours pas associée à la survie dans cette étude (HR 0,9 [IC95 % 0,3–2,4], p = 0,8).ConclusionDans cette large étude, nous observons que les EP restent largement utilisés en France dans les HIA sévères au cours des VAA. Cette première analyse avec ajustement ne retrouve pas d’impact des EP sur la mortalité précoce, mais une analyse avec émulation est en cours pour préciser ces résultats

ANCA-Negative Pauci-immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification

RATIONALE & OBJECTIVE: Pauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis. FINDINGS: Median age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n=9[12%]), malignancy-associated (n=6[8%]), and primary (n=57[77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n=56[98%]), cyclophosphamide (n=37[65%]), and rituximab (n=5[9%]). Maintenance treatment consisted mainly of corticosteroids (n=42[74%]), azathioprine (n=18[32%]), and mycophenolate mofetil (n=11[19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate<15mL/min/1.73m(2)). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed. LIMITATIONS: Retrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits. CONCLUSIONS: Within the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments

Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial

BACKGROUND: Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy. METHODS: This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed. FINDINGS: Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0-25) in the delayed strategy and 10 days (IQR 0-24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09-2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups. INTERPRETATION: In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm. FUNDING: Programme Hospitalier de Recherche Clinique

Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial

Background: There is controversy regarding the optimal renal-replacement therapy (RRT) modality for critically ill patients with acute kidney injury (AKI). Methods: We conducted a secondary analysis of the STandard versus Accelerated Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial to compare outcomes among patients who initiated RRT with either continuous renal replacement therapy (CRRT) or intermittent hemodialysis (IHD). We generated a propensity score for the likelihood of receiving CRRT and used inverse probability of treatment with overlap-weighting to address baseline inter-group differences. The primary outcome was a composite of death or RRT dependence at 90-days after randomization. Results: We identified 1590 trial participants who initially received CRRT and 606 who initially received IHD. The composite outcome of death or RRT dependence at 90-days occurred in 823 (51.8%) patients who commenced CRRT and 329 (54.3%) patients who commenced IHD (unadjusted odds ratio (OR) 0.90; 95% confidence interval (CI) 0.75-1.09). After balancing baseline characteristics with overlap weighting, initial receipt of CRRT was associated with a lower risk of death or RRT dependence at 90-days compared with initial receipt of IHD (OR 0.81; 95% CI 0.66-0.99). This association was predominantly driven by a lower risk of RRT dependence at 90-days (OR 0.61; 95% CI 0.39-0.94). Conclusions: In critically ill patients with severe AKI, initiation of CRRT, as compared to IHD, was associated with a significant reduction in the composite outcome of death or RRT dependence at 90-days