Anakinra και ανοσολογικές μεταβολές στη νόσο COVID-19

Το φάσμα των ασθενών με COVID-19 είναι ευρύτατο και περιλαμβάνει ασθενείς που εμφανίζουν ήπια μόνο συμπτωματολογία έως πολύ σοβαρή που μπορεί να καταλήξει σε αναπνευστική ανεπάρκεια και θάνατο. Στη σοβαρή COVID-19 , ομάδα ασθενών εμφανίζει χαρακτηριστικά Συνδρόμου Ενεργοποίησης Μακροφάγων (MAS/sHLH). Η σοβαρή νόσος με MAS εκδηλώνεται μέσω της ενεργοποίησης του φλεγμονοσώματος και της ιντερλευκίνης 1 (IL-1). Ο καταρράκτης κυτταροκινών που ακολουθεί και ειδικά ο φαύλος κύκλος ενεργοποίησης της IL-1 αποτελεί πιθανό θεραπευτικό στόχο για τη σοβαρη COVID-19. Μια πιθανά αποτελεσματική προσέγγιση είναι να αποκλειστεί ο υποδοχέας της IL-1 με τη χορήγηση του anakinra. Σε ό,τι αφορά την χρήση του anakinra στη σοβαρή COVID-19 μένουν ακόμη να απαντηθούν ερωτήματα, όπως ο χρόνος έναρξης θεραπείας, η δοσολογία και η διάρκεια χορήγησης. Σημαντικό επίσης, ο προσδιορισμός βιοδεικτών για τη διάγνωση της ομάδας ασθενών που θα έχει μέγιστο όφελος από τη χορήγηση του anakinra, όπως η C-αντιδρώσα πρωτεΪνη, η φερριτίνη, η IL-6, ο δείκτης suPAR.Symptomatic COVID-19 varies widely, from mild disease to severe, respiratory distress or even death. A subgroup of patients with severe COVID-19 seem to have a condition that resembles Macrophage Activation Syndrome (MAS/sHLH). Severe COVID-19 with MAS is probably due to activation of the inflammasome and interleukin-1 (IL-1). The cytokine storm that follows, is a possible treatment target, especially the inflammatory loop of IL-1. An effective treatment could prove to be to block IL-1 receptor with the use of Anakinra. Although there is growing evidence about the use of Anakinra in severe COVID-19, there are still questions to be answered, such as when to start the treatment, in what dosage and how long. Another significant factor is the use of specific biomarkers to identify the group of patients that will benefit the most of this treatment, for example C-reactive protein, ferritin, IL-6, or suPAR

Citrate salts for preventing and treating calcium containing kidney stones in adults

Background: kidney stones affect people worldwide and have a high rate of recurrence even with treatment. Recurrences are particularly prevalent in people with low urinary citrate levels. These people have a higher incidence of calcium phosphate and calcium oxalate stones. Oral citrate therapy increases the urinary citrate levels, which in turn binds with calcium and inhibits the crystallisation thus reduces stone formation. Despite the widespread use of oral citrate therapy for prevention and treatment of calcium oxalate stones, the evidence to support its clinical efficacy remains uncertain.Objectives: the objective of this review was to determine the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones.Search methods: we searched the Cochrane Kidney and Transplant Specialised Register to 29 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.Selection criteria: we included randomised controlled trials (RCTs) that assessed the efficacy and adverse events associated with citrate salts for the treatment and prevention of calcium containing kidney stones in adults treated for a minimum of six months.Data collection and analysis: two authors assessed studies for inclusion in this review. Data were extracted according to predetermined criteria. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes.Main results: we included seven studies that included a total of 477 participants, most of whom had oxalate stones. Of these, three studies (247 participants) compared potassium citrate with placebo or no intervention; three (166 participants) compared potassium-sodium citrate with no intervention; and one (64 participants) compared potassium-magnesium citrate with placebo. Overall, quality of the reporting of the included studies was considered moderate to poor, and there was a high risk of attrition bias in two studies.Compared with placebo or no intervention, citrate therapy significantly reduced the stone size (4 studies, 160 participants: RR 2.35, 95% CI 1.36 to 4.05). New stone formation was significantly lower with citrate therapy compared to control (7 studies, 324 participants: RR 0.26, 95% CI 0.10 to 0.68). The beneficial effect on stone size stability was also evident (4 studies, 160 participants: RR 1.97, 95% CI 1.19 to 3.26). Adverse events were reported in four studies, with the main side effects being upper gastrointestinal disturbance and one patient reported a rash. There were more gastrointestinal adverse events in the citrate group; however this was not significant (4 studies, 271 participants: RR 2.55, 95% CI 0.71 to 9.16). There were significantly more dropouts due to adverse events with citrate therapy compared to control (4 studies, 271 participants: RR 4.45, 95% CI 1.28 to 15.50). The need for retreatment was significantly less with citrate therapy compared to control (2 studies, 157 participants: RR 0.22, 95% CI 0.06 to 0.89).Author's conclusions: nitrate salts prevent new stone formation and reduce further stone growth in patients with residual stones that predominantly contain oxalate. The quality of reported literature remains moderate to poor; hence a well-designed statistically powered multi-centre RCT is needed in order to answer relevant questions concerning the efficacy of citrate salts.</p

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD

Preservation of Anemia Control and Weekly ESA Dosage After Conversion from PEG-Epoetin Beta to Darbepoetin Alfa in Adult Hemodialysis Patients: The TRANSFORM Study

INTRODUCTION: There is scant real-world information on switching treatment for anemia associated with chronic kidney disease (CKD) from methoxy polyethylene glycol-epoetin beta (PEG-Epo) to darbepoetin alfa (DA). TRANSFORM was a multi-center, observational study designed to describe the time course of hemoglobin (Hb) concentration (primary outcome measure) and other parameters of clinical management of anemia in European hemodialysis patients in clinical practice before and after a switch from PEG-Epo to DA. METHODS: Eligible subjects were adult patients with CKD dialyzed at European dialysis centers for ≥26 weeks and treated with PEG-Epo for ≥14 weeks immediately prior to being switched to DA and no earlier than January 2011. Erythropoiesis-stimulating agent doses and Hb values were recorded for the 14-week pre-switch and 26-week post-switch periods. RESULTS: Of the 1,027 eligible patients enrolled at 42 hemodialysis centers in 7 European countries, 785 were included in analyses. Mean (95% confidence interval [CI]) Hb was generally stable: 11.19 (11.11, 11.26), 11.48 (11.40, 11.57), and 11.29 (11.20, 11.37) g/dL at month −1 pre-switch and months 3 and 6 post-switch, respectively. The geometric mean (95% CI) PEG-Epo dose at month −1 was 27.4 (26.0, 28.8) µg/week; DA dose was 29.4 (27.9, 30.9), 23.3 (21.9, 24.9), and 25.6 (24.1, 27.1) µg/week at months 1, 4, and 6, respectively. The geometric mean (95% CI) dose ratio at switching was 1.06 (1.01, 1.11). When stratifying by dose-ratio categories <0.8, 0.8–1.2, and >1.2 at switching, mean DA dose and Hb converged within narrow ranges by month 6 post-switch: 23.9–27.0 µg/week and 11.1–11.5 g/dL, respectively. Hb excursions <10 g/dL were less frequent post-switch versus pre-switch. CONCLUSION: Mean Hb values remained within a narrow range following switching from PEG-Epo to DA in this population of hemodialysis patients. Time trends of mean Hb and DA dose indicate that physicians titrated DA doses post-switch, to attain Hb concentrations comparable to those attained pre-switch with PEG-Epo. FUNDING: Amgen (Europe) GmbH, Zug, Switzerland. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-014-0161-5) contains supplementary material, which is available to authorized users

Normative data on the Bonn Risk Index for calcium oxalate crystallization in healthy children

Bonn Risk Index (BRI) is being used for the assessment of urinary calcium oxalate (CaOx) crystallization. There are no published data regarding BRI during growth. The objective of this study was to establish age- and sex-dependent BRI values in healthy children and adolescents. A total of 1,050 Caucasian subjects aged 3–18 years (525 males, 525 females) without a history of kidney stone disease were enrolled in the cross-sectional study. The study group was divided into 15 ranges according to age, each comprising 70 subjects. Urinary ionized calcium [Ca(2+)] was measured using a selective electrode while the onset of spontaneous crystallization was determined using a photometer and titrating with 40 mmol/L ammonium oxalate (Ox(2−)). The calculation of BRI value was based on the ratio of [Ca(2+)] to the required amount of ammonium oxalate added to 200 ml of urine to induce crystallization. The median BRI was 0.26 1/L and the values of the 5th and 95th percentiles were 0.06 1/L and 1.93 1/L, respectively. BRI correlated positively with body-area-related BRI (1/L × 1.73 m(2)) (R = 0.18; P < 0.05), whereas a negative correlation was found between BRI and body weight (1/L × kg) (R = −0.85; P < 0.05). Neither sex nor age differences were detected in BRI across studied children and adolescents. The values of Bonn Risk Index were constant during growth and there was a limited influence of age and sex on BRI in children over 3 years of age. The BRI may be valuable in the evaluation of pediatric patients at risk for kidney stones, particularly if the BRI from stone formers is demonstrated to be higher than in normal children

Family history in stone disease: how important is it for the onset of the disease and the incidence of recurrence?

The aim of this study was to evaluate the possible effect of a positive family history on the age at the onset of urinary stone disease and the frequency of subsequent symptomatic episodes relating to the disease. Between March 2006 and April 2009, patients with either a newly diagnosed or a previously documented stone disease were included in the study program. They were required to fill in a questionnaire and divided into two groups according to the positive family history of stone disease; group I comprised patients with a family history for urinary calculi and group II those without. Depending on the data obtained from questionnaires, all patients were evaluated in detail with respect to the age at the onset of the stone disease, stone passage and interventions over time, time to first recurrence (time interval between the onset of the disease and the first recurrence), number of total stone episodes and recurrence intervals. 1,595 patients suffering from urolithiasis with the mean age of 41.7 (14–69 years) were evaluated with respect to their past history of the disease. There were 437 patients in group I and 1,158 in group II. There was no statistically significant difference between the mean age value of two groups (P = 0.09). When both genders in group I were analyzed separately, female patients tended to have higher rate of family history positivity than males. Comparative evaluation of the age at the onset of the disease between the two groups did reveal that stone formation occured at younger ages in patients with positive family history [P = 0.01 (males), P = 0.01 (females)] and the mean age of onset of the disease was lower in males than females in group I (P = 0.01). Patients in group I had relatively more stone episodes from the onset of the disease [P < 0.01 (2–4 episodes), P < 0.01 (≥5 episodes)]. Male patients were associated with higher number of stone episodes (P = 0.01). Mean time interval between recurrences was noted to be significantly shorter in group I patients when compared with patients in group II [P < 0.01 (males), P = 0.02 (females)]. In conclusion, our results showed that urinary stone formation may occur at younger ages and that the frequency of symptom episodes may be higher in patients with a positive family history. We believe that the positive family history for urinary stone disease could give us valuable information concerning the onset as well as the severity of the disease

Medical treatment of pediatric urolithiasis

In recent years the incidence of pediatric stone disease has increased several fold, mostly due to hypercalciuria and hypocitraturia. The goal of medical treatment is to protect the patient from formation of new stones and expansion of existing ones. The non-pharmacological means to address stone disease include high fluid intake and, frequently, modification of nutritional habits. The pharmacological treatment is based on the chemical composition of the stone and the biochemical abnormalities causing its formation; hence, chemical analysis of the stone, urine and blood is of paramount importance and should be done when the first stone is detected. This review discusses the current options of medical treatment of pediatric urolithiasis