Validation of metrological traceability of the new generation of Abbott Alinity alkaline phosphatase assay.

OBJECTIVES: Recently, Abbott Diagnostics marketed a new generation of Alinity enzyme assays, introducing a multiparametric calibrator [Consolidated Chemistry Calibrator (ConCC)] in place of or in addition to factor-based calibrations. For alkaline phosphatase (ALP), both calibration options are offered, i.e., with ConCC (ALP2) and with an experimental calibration factor (ALP2F). Both options are declared traceable to the 2011 IFCC reference measurement procedure (RMP). Before to replace the old generation (ALP1) with the new one, we decided to validate the trueness of ALP2/ALP2F. METHODS: Three approaches were employed: (a) preliminary comparison on 48 native frozen serum samples with ALP1, of which traceability to RMP was previously successfully verified; (b) examination of three banked serum pools (BSP) with values assigned by RMP; (c) direct comparison with RMP on a set of 24 fresh serum samples. Bias estimation and regression studies were performed, and the standard measurement uncertainty associated with ALP measurements on clinical samples (uresult) was estimated and compared with established analytical performance specifications (APS). ConCC commutability was also assessed. RESULTS: A positive proportional bias was found with both ALP2 and ALP2F when compared to ALP1 and RMP. This positive bias was confirmed on BSP: in average, +13.1 % for ALP2 and +10.0 % for ALP2F, respectively. uresult were 13.28 % for ALP2 and 10.04 % for ALP2F, both not fulfilling the minimum APS of 4.0 %. Furthermore, ConCC was not commutable with clinical samples. CONCLUSIONS: Our results unearth problems in the correct implementation of traceability of Alinity ALP2/ALP2F, with the risk for the new assay to be unfit for clinical purposes.

A data-driven approach to identify risk profiles and protective drugs in COVID-19.

As the COVID-19 pandemic is spreading around the world, increasing evidence highlights the role of cardiometabolic risk factors in determining the susceptibility to the disease. The fragmented data collected during the initial emergency limited the possibility of investigating the effect of highly correlated covariates and of modeling the interplay between risk factors and medication. The present study is based on comprehensive monitoring of 576 COVID-19 patients. Different statistical approaches were applied to gain a comprehensive insight in terms of both the identification of risk factors and the analysis of dependency structure among clinical and demographic characteristics. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2), but whether or not renin-angiotensin-aldosterone system inhibitors (RAASi) would be beneficial to COVID-19 cases remains controversial. The survival tree approach was applied to define a multilayer risk stratification and better profile patient survival with respect to drug regimens, showing a significant protective effect of RAASi with a reduced risk of in-hospital death. Bayesian networks were estimated, to uncover complex interrelationships and confounding effects. The results confirmed the role of RAASi in reducing the risk of death in COVID-19 patients. De novo treatment with RAASi in patients hospitalized with COVID-19 should be prospectively investigated in a randomized controlled trial to ascertain the extent of risk reduction for in-hospital death in COVID-19.

Reticulocyte dynamic and hemoglobin variability in hemodialysis patients treated with Darbepoetin alfa and C.E.R.A.: a randomized controlled trial.

BACKGROUND: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients. METHODS: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference. RESULTS: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa. CONCLUSIONS: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01666301.

A blended e-health intervention for improving functional capacity in elderly patients on haemodialysis: A feasibility study.

Introduction: Physical exercise showed to be beneficial for frail older adults on haemodialysis (HD). However, there are several obstacles hindering the regular practice of exercise, such as transportation difficulties, lack of time, fatigue and comorbidities. E-health in this regard has many potential advantages and could be useful for motivating HD patients to increase their level of physical activity. The aim of this study was to evaluate the feasibility of a blended e-health intervention for elderly HD patients who individually exercise at home while under remote supervision of a physiotherapist. Material and methods: Patients over 60 years of age with sufficient cognitive and motoric resources to perform a simple physical test battery and to use a tablet-computer were recruited from four HD outpatient facilities. Following baseline assessment at home, the participants were visited by a physiotherapist (PT). The PT set an individual exercise programme and explained how to use the web-based interface. During the 12 weeks of training, the PTs remotely supervised the patients' progress. At 12 weeks follow-up a second assessment took place. Results: Twenty-two patients were recruited to participate in the study. Seven patients dropped out of the blended programme and 15 patients concluded the programme. The average training frequency of the 15 participants concluding the study was 1.5 times a week [range 0.2-5.8]. The duration of a training session was between 20 and 40 min. The usability of the system was deemed positive. Regarding the efficacy of the intervention, no significant improvement of any measured parameter was found, and effect sizes were small to medium. Conclusion: A blended e-health intervention supported by a web-based application for exercising at home under remote supervision of a PT is feasible in a HD population including older patients. However, before planning a randomized controlled trial, strategies to increase the recruitment rate and the adherence to such a blended intervention should be further developed, e.g., to improve the recruitment procedures and lower the expectable drop-out rate. Furthermore, the dosage of the blended programme should be adapted to the patients' physical performance levels in future trials.The study was registered on the website clinicaltrials.gov with ID NCT04076488.

Haemodynamic consequences of changing bicarbonate and calcium concentrations in haemodialysis fluids.

BACKGROUND: In a previous study we demonstrated that mild metabolic alkalosis resulting from standard bicarbonate haemodialysis induces hypotension. In this study, we have further investigated the changes in systemic haemodynamics induced by bicarbonate and calcium, using non-invasive procedures. METHODS: In a randomized controlled trial with a single-blind, crossover design, we sequentially changed the dialysate bicarbonate and calcium concentrations (between 26 and 35 mmol/l for bicarbonate and either 1.25 or 1.50 mmol/l for calcium). Twenty-one patients were enrolled for a total of 756 dialysis sessions. Systemic haemodynamics was evaluated using pulse wave analysers. Bioimpedance and BNP were used to compare the fluid status pattern. RESULTS: The haemodynamic parameters and the pre-dialysis BNP using either a high calcium or bicarbonate concentration were as follows: systolic blood pressure (+5.6 and -4.7 mmHg; P < 0.05 for both), stroke volume (+12.3 and +5.2 ml; P < 0.05 and ns), peripheral resistances (-190 and -171 dyne s cm(-5); P < 0.05 for both), central augmentation index (+1.1% and -2.9%; ns and P < 0.05) and BNP (-5 and -170 ng/l; ns and P < 0.05). The need of staff intervention was similar in all modalities. CONCLUSIONS: Both high bicarbonate and calcium concentrations in the dialysate improve the haemodynamic pattern during dialysis. Bicarbonate reduces arterial stiffness and ameliorates the heart tolerance for volume overload in the interdialytic phase, whereas calcium directly increases stroke volume. The slight hypotensive effect of alkalaemia should motivate a probative reduction of bicarbonate concentration in dialysis fluid for haemodynamic reasons, only in the event of failure of classical tools to prevent intradialytic hypotension.

Comparative analysis of the long-term effect of two families of high-flux polysulfone dialysers on platelet count: a retrospective cross-sectional study.

INTRODUCTION: Thrombocytopenia is a potential complication of hemodialysis (HD), and its occurrence has been described even with highly biocompatible polysulfone (PSf) membranes. Dialysis units routinely monitor platelet (PLT) count at the beginning of HD sessions. However, considering that the long-term effects on PLT count could easily be missed, the prevalence of HD-related thrombocytopenia could be underestimated. In the present study, we aimed to investigate the following: 1) the long-term impact of HD treatment on PLT count, comparing two families of dialysis membranes made up of similar PSfs; 2) whether the switch between the dialysis membranes studied significantly affects PLT count; and 3) the prevalence and the risk of HD-induced thrombocytopenia according to the dialysis membranes used. METHODS: A cross-sectional retrospective study was performed comprising 157 adult chronic HD patients. The HD membranes under investigation were of the series FX, Helixone® Fresenius (Filters A), and Polyflux® Gambro (Filters B). Patients were treated in 4 dialysis units in Southern Switzerland. Data were collected from a centralized computing platform. FINDINGS: PLT count significantly differs between Filters A and B with, respectively, 188 (153-243) ×10E9/L versus 214 (179-255) ×10E9/L (p=0.036). The prevalence of thrombocytopenia was higher for Filter A compared with Filter B (28.4% versus 12.8%; p<0.001). The switch from Filter A to Filter B significantly affected PLT count: from 189 (146-217) ×10E9/L to 217 (163-253) ×10E9/L (p<0.001; analysis on 26 patients). A linear random-intercept model confirmed the results (ß coefficient =35.214; SE =5.956; p<0.001). In a mixed-effects logistic regression model, the risk of thrombocytopenia for Filter B was 0.157 (CI =0.056-0.442). DISCUSSION: Our data suggest that among the PSf membranes studied, the FX membrane induced a lasting decrease in PLT count and caused significantly more thrombocytopenia. Prospective studies are warranted to verify our findings.

Hypokalaemia in hospitalised patients.

QUESTIONS UNDER STUDY: Hypokalaemia in inpatients is common, and is associated with morbidity and mortality. Its management is risky and not always effective. We launched an educational programme with the aim of increasing the rate of potassium normalisation during hospital stay, and of reducing unmonitored cases. METHODS: The project consisted of three phases: (I) retrospective analysis on 26 471 patients hospitalised in 2012 in five acute care hospitals of southern Switzerland (Ente Ospedaliero Cantonale, EOC) with identification of improvement goals on a sample survey (588 cases of hypokalaemia); (II) revision of internal guidelines, and implementation of educational activities in one of the five hospitals (Ospedale Regionale di Locarno, ODL); (III) follow-up analysis on the 26 726 patients hospitalised in 2014 and second sampling to complete the evaluation of the efficacy of the intervention. RESULTS: Phase I, ODL vs EOC: prevalence of hypokalaemia, 21.7 vs 23.2% (p <0.05); treated 53.1 vs 56.5% (not significant); normalisation 62.4 vs 61.1% (ns); absence of monitoring 18.3 vs 21.1% (p <0.05); time to normalisation 3.0 ± 2.7 vs 2.8 ± 2.4 days (ns); secondary hyperkalaemia 1.1 vs 1.4% (ns). Length of stay hypokalaemic vs normokalaemic 11.2 ± 11.7 vs 6.6 ± 7.9 days (p <0.001); falls 3.5 vs 1.7% (p <0.001), deaths 5.1 vs 3.1% (p <0.001). The severity/performance ratio suggested inefficiency. Phase III, ODL 2012 vs ODL 2014: treated 53.1 vs 75.7% (p <0.001); normalisation 62.4 vs 69.7% (p <0.01); absence of monitoring 20.1 vs 8.7 (p <0.01); time to normalisation 3.1 ± 2.7 vs 2.4 ± 2.6 days (ns); secondary hyperkalaemia 1.1 vs 1.8% (ns). CONCLUSIONS: The management of hypokalaemia is characterised by dysfunctions; it can, however, be ameliorated by the implementation of internal guidelines and targeted educational activities. The length of hospital stay is increased in patients with hypokalaemia, shifting the expected length of hospital stay based on the Swiss Diagnosis Related Group classification.

Assessment of subjective and hemodynamic tolerance of different high- and low-flux dialysis membranes in patients undergoing chronic intermittent hemodialysis: a randomized controlled trial.

Clinical experience and experimental data suggest that intradialytic hemodynamic profiles could be influenced by the characteristics of the dialysis membranes. Even within the worldwide used polysulfone family, intolerance to specific membranes was occasionally evoked. The aim of this study was to compare hemodynamically some of the commonly used polysulfone dialyzers in Switzerland. We performed an open-label, randomized, cross-over trial, including 25 hemodialysis patients. Four polysulfone dialyzers, A (Revaclear high-flux, Gambro, Stockholm, Sweden), B (Helixone high-flux, Fresenius), C (Xevonta high-flux, BBraun, Melsungen, Germany), and D (Helixone low-flux, Fresenius, Bad Homburg vor der Höhe, Germany), were compared. The hemodynamic profile was assessed and patients were asked to provide tolerance feedback. The mean score (±SD) subjectively assigned to dialysis quality on a 1-10 scale was A 8.4 ± 1.3, B 8.6 ± 1.3, C 8.5 ± 1.6, D 8.5 ± 1.5. Kt/V was A 1.58 ± 0.30, B 1.67 ± 0.33, C 1.62 ± 0.32, D 1.45 ± 0.31. The low- compared with the high-flux membranes, correlated to higher systolic (128.1 ± 13.1 vs. 125.6 ± 12.1 mmHg, P < 0.01) and diastolic (76.8 ± 8.7 vs. 75.3 ± 9.0 mmHg; P < 0.05) pressures, higher peripheral resistance (1.44 ± 0.19 vs. 1.40 ± 0.18 s × mmHg/mL; P < 0.05) and lower cardiac output (3.76 ± 0.62 vs. 3.82 ± 0.59 L/min; P < 0.05). Hypotension events (decrease in systolic blood pressure by >20 mmHg) were 70 with A, 87 with B, 73 with C, and 75 with D (P < 0.01 B vs. A, 0.05 B vs. C and 0.07 B vs. D). The low-flux membrane correlated to higher blood pressure levels compared with the high-flux ones. The Helixone high-flux membrane ensured the best efficiency. Unfortunately, the very same dialyzer correlated to a higher incidence of hypotensive episodes.

Frequency and severity of pain and symptom distress among patients with chronic kidney disease receiving dialysis.

QUESTION UNDER STUDY: Data on pain management in haemodialysis patients with end-stage renal disease are scanty. Our study aimed to collect information on the frequency and severity of pain and symptom distress among long-term dialysis patients in southern Switzerland. METHODS: Patients with chronic kidney disease stage 5, on dialysis, treated in five nephrology units in southern Switzerland, who had given informed consent and were able to complete the survey, were interviewed to assess pain and correlated symptoms using a Visual Analogue Scale (VAS), the Brief Pain Inventory and the Edmonton Symptom Assessment System. To evaluate the impact of symptoms, the Instrumental Activities of Daily Living questionnaire was used. RESULTS: One hundred and twenty-three patients, aged 36-90 years and with a mean time on dialysis of 3.5 years, were interviewed. Pain was experienced by 81 patients during the 4 weeks before the interview: 68 had chronic pain; 66 reported pain intensity higher than 5 on the VAS; 35 identified musculoskeletal pain as the most disturbing pain. Five patients used drugs to cope with pain during the night. Asthenia and fatigue were prevalent concomitant symptoms. Asthenia, fatigue, sleep disturbances, dyspnoea, loss of appetite, nausea/vomiting and anxiety were correlated with pain. The majority of the patients reported that their pain limited their daily life activities. CONCLUSIONS: Pain severity and symptom distress in dialysis patients are important, but underestimated and undertreated. They interfere with sleep quality and daily living. Routine assessment of pain burden, pain management similar to that used in palliative care, and adequate analgesic use to treat specific dialysis-associated pain syndromes should be considered in guidelines.