Neutrophil Gelatinase-Associated Lipocalin in Peritoneal Dialysis-Related Peritonitis: Correlation with White Blood Cells over Time and a Possible Role as the Outcome Predictor.

INTRODUCTION: The present study aimed to monitor peritoneal neutrophil gelatinase-associated lipocalin (pNGAL) during peritonitis episodes and to enhance its diagnostic value by evaluating pNGAL at scheduled times in parallel with white blood cell (WBC) count. In addition, we investigated possible correlations between pNGAL and the etiology of peritonitis, evaluating it as a possible marker of the clinical outcome. METHODS: Twenty-two patients with peritoneal dialysis (PD)-related peritonitis were enrolled. Peritonitis was divided into Gram-positive, Gram-negative, polymicrobial, and sterile. WBC count and neutrophil gelatinase-associated lipocalin (NGAL) in PD effluent were measured at different times (days 0, 1, 5, 10, 15, and/or 20 and 10 days after antibiotic therapy discontinuation). NGAL was measured by standard quantitative laboratory-based immunoassay and by colorimetric NGAL dipstick (NGALds) (dipstick test). RESULTS: We found strong correlations between peritoneal WBC, laboratory-based NGAL, and NGALds values, both overall and separated at each time point. On day 1, we observed no significant difference in WBC, both NGALds (p = 0.3, 0.9, and 0.2) between Gram-positive, Gram-negative, polymicrobial, and sterile peritonitis. No significant difference has been found between de novo versus relapsing peritonitis for all markers (p > 0.05). We observed a parallel decrease of WBC and both NGAL in patients with favorable outcomes. WBC count and both pNGAL resulted higher in patients with negative outcomes (defined as relapsing peritonitis, peritonitis-associated catheter removal, peritonitis-associated hemodialysis transfer, peritonitis-associated death) at day 10 (p = 0.04, p = 0.03, and p = 0.05, respectively) and day 15 (p = 0.01, p = 0.04, and tendency for p = 0.005). There was a tendency toward higher levels of WBC and NGAL in patients with a negative outcome at day 5. No significant difference in all parameters was proven at day 1 (p = 0.3, p = 0.9, p = 0.2) between groups. CONCLUSION: This study confirms pNGAL as a valid and reliable biomarker for the diagnosis of PD-peritonitis and its monitoring. Its trend is parallel to WBC count during peritonitis episodes, in particular, patients with unfavorable outcomes.

Effects of preoperative high-oral protein loading on short- and long-term renal outcomes following cardiac surgery: a cohort study.

BACKGROUND: Post-cardiac surgery acute kidney injury (AKI) is associated with increased mortality. A high-protein meal enhances the renal blood flow and glomerular filtration rate (GFR) and might protect the kidneys from acute ischemic insults. Hence, we assessed the effect of a preoperative high-oral protein load on post-cardiac surgery renal function and used experimental models to elucidate mechanisms by which protein might stimulate kidney-protective effects. METHODS: The prospective "Preoperative Renal Functional Reserve Predicts Risk of AKI after Cardiac Operation" study follow-up was extended to postoperative 12 months for 109 patients. A 1:2 ratio propensity score matching method was used to identify a control group (n = 214) to comparatively evaluate the effects of a preoperative protein load and standard care. The primary endpoints were AKI development and postoperative estimated GFR (eGFR) loss at 3 and 12 months. We also assessed the secretion of tissue inhibitor of metalloproteases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), biomarkers implicated in mediating kidney-protective mechanisms in human kidney tubular cells that we exposed to varying protein concentrations. RESULTS: The AKI rate did not differ between the protein loading and control groups (13.6 vs. 12.3%; p = 0.5). However, the mean eGFR loss was lower in the former after 3 months (0.1 [95% CI - 1.4, - 1.7] vs. - 3.3 [95% CI - 4.4, - 2.2] ml/min/1.73 m2) and 12 months (- 2.7 [95% CI - 4.2, - 1.2] vs - 10.2 [95% CI - 11.3, - 9.1] ml/min/1.73 m2; p < 0.001 for both). On stratification based on AKI development, the eGFR loss after 12 months was also found to be lower in the former (- 8.0 [95% CI - 14.1, - 1.9] vs. - 18.6 [95% CI - 23.3, - 14.0] ml/min/1.73 m2; p = 0.008). A dose-response analysis of the protein treatment of the primary human proximal and distal tubule epithelial cells in culture showed significantly increased IGFBP7 and TIMP-2 expression. CONCLUSIONS: A preoperative high-oral protein load did not reduce AKI development but was associated with greater renal function preservation in patients with and without AKI at 12 months post-cardiac surgery. The potential mechanisms of action by which protein loading may induce a kidney-protective response might include cell cycle inhibition of renal tubular epithelial cells. Clinical trial registration ClinicalTrials.gov: NCT03102541 (retrospectively registered on April 5, 2017) and ClinicalTrials.gov: NCT03092947 (retrospectively registered on March 28, 2017).

Clinical Assessment of Continuous Hemodialysis with the Medium Cutoff EMiC®2 Membrane in Patients with Septic Shock.

INTRODUCTION: At the time of renal replacement therapy, approximately 20% of critically ill patients have septic shock. In this study, medium cutoff (MCO) continuous venovenous hemodialysis (CVVHD) was compared to high-flux membrane continuous venovenous hemodiafiltration (CVVHDF) in terms of hemodynamic improvement, efficiency, middle molecule removal, and inflammatory system activation. METHODS: This is a monocenter crossover randomized study. Between December 31, 2017, and December 31, 2019, 20 patients with septic shock and stage 3 acute kidney injury (AKI) admitted to 2 Italian ICUs were enrolled. All patients underwent CVVHD with Ultraflux® EMiC®2 and CVVHDF with AV1000S® without washout. Each treatment lasted 24 h. RESULTS: Compared to AV1000S®-CVVHDF, EMIC®2-CVVHD normalized cardiac index (ß = -0.64; p = 0.02) and heart rate (ß = 5.72; p = 0.01). Interleukin-8 and myeloperoxidase removal were greater with AV1000S®-CVVHDF than with EMiC®2-CVVHD (ß = 0.35; p < 0.001; ß = 0.43; p = 0.03, respectively). Leukocytosis improved over 24 h in EMiC®2-CVVHD-treated patients (ß = 4.13; p = 0.03), whereas procalcitonin levels decreased regardless of the modality (ß = 0.89; p = 0.01) over a 48-h treatment period. Reduction rates, instantaneous plasmatic clearance of urea, creatinine, and ß2-microglobulin were similar across modalities. ß2-Microglobulin removal efficacy was greater in the EMiC®2 group (ß = 0-2.88; p = 0.002), while albumin levels did not differ. Albumin was undetectable in the effluent in both treatments. DISCUSSION: In patients with septic shock and severe AKI, the efficacy of uremic toxin removal was comparable between MCO-CVVHD and CVVHDF. Further, MCO-CVVHD was associated with improved hemodynamics. Fraction of filtration and transmembrane pressure reduction and the maintenance of equal efficacy might be the key features of CVVHD with MCO membranes in critically ill patients.

Influence of patients' clinical features at intensive care unit admission on performance of cell cycle arrest biomarkers in predicting acute kidney injury.

Objectives: Identification of acute kidney injury (AKI) can be challenging in patients with a variety of clinical features at intensive care unit (ICU) admission, and the capacity of biomarkers in this subpopulation has been poorly studied. In our study we examined the influence that patients' clinical features at ICU admission have over the predicting ability of the combination of urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein 7 (IGFBP7). Methods: Urinary [TIMP2]•[IGFBP7] were measured for all patients upon admission to ICU. We calculated the receiver operating characteristics (ROC) curves for AKI prediction in the overall cohort and for subgroups of patients according to etiology of ICU admission, which included: sepsis, trauma, neurological conditions, cardiovascular diseases, respiratory diseases, and non-classifiable causes. Results: In the overall cohort of 719 patients, 239 (33.2%) developed AKI in the first seven days. [TIMP2]•[IGFBP7] at ICU admission were significantly higher in AKI patients than in non-AKI patients. This is true not only for the overall cohort but also in the other subgroups. The area under the ROC curve (AUC) for [TIMP2]•[IGFBP7] in predicting AKI in the first seven days was 0.633 (95% CI 0.588-0.678), for the overall cohort, with sensitivity and specificity of 66.1 and 51.9% respectively. When we considered patients with combined sepsis, trauma, and respiratory disease we found a higher AUC than patients without these conditions (0.711 vs. 0.575; p=0.002). Conclusions: The accuracy of [TIMP2]•[IGFBP7] in predicting the risk of AKI in the first seven days after ICU admission has significant variability when the reason for ICU admission is considered.

Tissue inhibitor metalloproteinase-2 (TIMP-2) • IGF-binding protein-7 (IGFBP7) levels are associated with adverse outcomes in patients in the intensive care unit with acute kidney injury.

The G1 cell cycle inhibitors tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as novel biomarkers for the prediction of moderate to severe acute kidney injury (AKI) risk. However, the prognostic value of [TIMP-2]•[IGFBP7] in predicting adverse outcomes in intensive care unit (ICU) patients with AKI was not previously described. To evaluate this, we conducted a cohort study, measuring [TIMP2]•[IGFBP7] levels in critically ill patients admitted to the ICU and classified the patients as NephroCheck (NC) (+) or NC (-) according to [TIMP-2]•[IGFBP7] values and AKI (+) or AKI (-) according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We then evaluated the incidence of continuous renal replacement therapy initiation, all-cause mortality and a composite endpoint of both in the four groups. Baseline [TIMP-2]•[IGFBP7] values were available for 719 patients, of whom 239 developed AKI and 151 met the composite endpoint. Compared to NC (-)/AKI (+) patients, NC (+)/AKI (+) patients had a significant risk of ICU mortality and the composite endpoint. Kaplan-Meier curves showed that the survival estimate for the composite endpoint of NC (+)/AKI (+) patients was 34.4%; significantly worse than NC (-)/AKI (+) patients (67.4%). Multivariate analyses showed strong association between NC positivity and the composite endpoint. The inflammatory marker, procalcitonin, was an additional prognostic biomarker to compare and confirm the incremental value of NephroCheck. No association between procalcitonin and the composite endpoint was found, especially in patients with AKI, suggesting that NephroCheck may be more kidney specific. Thus, the [TIMP-2]•[IGFBP7] values can serve to identify patients with AKI at increased risk for adverse outcomes in the ICU.

Analytical Assessment of the New Roche Cobas t 711 Fully Automated Coagulation Analyzer.

This study aimed to provide a preliminary evaluation of the analytical performance of the new Roche COBAS T 711: fully automated coagulation analyzer, which uses both liquid and lyophilized reagent cassettes. The analytical assessment included analysis of imprecision and linearity of prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen on COBAS T 711: analyzer. Test results of 120 routine plasma samples were also compared with those obtained using two other coagulation analyzers (Instrumentation Laboratory ACL TOP 700 and Stago STA-R MAX). The accuracy, imprecision, and comparability of manual and automatic lyophilized material resuspension were also evaluated using 200 routine plasma samples. Overall, automatic resuspension was found to be more precise than, and equally accurate as, manual reconstitution, with coefficient of variations (CV%) three- to sixfold lower compared with manual reconstitution. The analytical imprecision was found to be excellent, as attested by total CV% of 0.7% for PT, 1.7 to 1.8% for APTT, and 1.9 to 3.2% for fibrinogen. Linearity was excellent over a clinically significant range of PT, APTT, and fibrinogen values, displaying correlation coefficients comprised between 0.994 and 0.999. Methods comparison studies revealed that results of PT, APTT, and fibrinogen on COBAS T 711: are globally aligned with those obtained using identical plasma samples on IL ACL TOP 700 and Stago STA-R MAX, displaying correlation coefficients of 0.97 for PT, 0.81 and 0.88 for APTT, 0.90 and 0.94 for fibrinogen, respectively. In conclusion, the results of this preliminary evaluation demonstrate that PT, APTT, and fibrinogen on COBAS T 711: coagulation analyzer displays excellent performance for routine use in clinical laboratories.

Persistent decrease of renal functional reserve in patients after cardiac surgery-associated acute kidney injury despite clinical recovery.

Background: Cardiac surgery is a leading cause of acute kidney injury (AKI). Such AKI patients may develop progressive chronic kidney disease (CKD). Others, who appear to have sustained no permanent loss of function (normal serum creatinine), may still lose renal functional reserve (RFR). Methods: We extended the follow-up in the observational 'Preoperative RFR Predicts Risk of AKI after Cardiac Surgery' study from hospital discharge to 3 months after surgery for 86 (78.2%) patients with normal baseline estimated glomerular filtration rate (eGFR), and re-measured RFR with a high oral protein load. The primary study endpoint was change in RFR. Study registration at clinicaltrials.gov Identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759. Results: At 3 months, three patients developed new CKD. All remaining patients continued to have a normal eGFR (93.3 ± 15.1 mL/min/1.73 m2). However, when stratified by post-operative AKI and cell cycle arrest (CCA) biomarkers, AKI patients displayed a significant decrease in RFR {from 14.4 [interquartile range (IQR) 9.5 - 24.3] to 9.1 (IQR 7.1 - 12.5) mL/min/1.73 m2; P < 0.001} and patients without AKI but with positive post-operative CCA biomarkers also experienced a similar decrease of RFR [from 26.7 (IQR 22.9 - 31.5) to 19.7 (IQR 15.8 - 22.8) mL/min/1.73 m2; P < 0.001]. In contrast, patients with neither clinical AKI nor positive biomarkers had no such decrease of RFR. Finally, of the three patients who developed new CKD, two sustained AKI and one had positive CCA biomarkers but without AKI. Conclusions: Among elective cardiac surgery patients, AKI or elevated post-operative CCA biomarkers were associated with decreased RFR at 3 months despite normalization of serum creatinine. Larger prospective studies to validate the use of RFR to assess renal recovery in combination with biochemical biomarkers are warranted.

Current understanding and future directions in the application of TIMP-2 and IGFBP7 in AKI clinical practice.

NephroCheck® is the commercial name of a combined product of two urinary biomarkers, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), expressed as [TIMP-2]·[IGFBP7], used to identify patients at high risk of acute kidney injury (AKI). AKI is a common and harmful complication especially in critically-ill patients, which can induce devastating short- and long-term outcomes. Over the past decade, numerous clinical studies have evaluated the utility of several biomarkers (e.g. neutrophil gelatinase-associated lipocalin, interleukin-18, liver-type fatty acid binding protein and kidney injury molecule-1, cystatin C) in the early diagnosis and risk stratification of AKI. Among all these biomarkers, [TIMP-2]·[IGFBP7] was confirmed to be superior in early detection of AKI, before the decrease of renal function is evident. In 2014, the US Food and Drug Administration permitted marketing of NephroCheck® (Astute Medical) (measuring urinary [TIMP-2]·[IGFBP7]) to determine if certain critically-ill patients are at risk of developing moderate to severe AKI. It has since been applied to clinical work in many hospitals of the United States and Europe to improve the diagnostic accuracy and outcomes of AKI patients. Now, more and more research is devoted to the evaluation of its application value, meaning and method in different clinical settings. In this review, we summarize the current research status of [TIMP-2]·[IGFBP7] and point out its future directions.

Presepsin and Procalcitonin Levels as Markers of Adverse Postoperative Complications and Mortality in Cardiac Surgery Patients.

Backgound: This study was aimed at evaluating the presepsin and procalcitonin levels to predict adverse postoperative complications and mortality in cardiac surgery patients. METHODS: A total of 122 cardiac surgery patients were enrolled for the study. Presepsin and procalcitonin levels were measured 48 h after the procedure. The primary endpoints were adverse renal, respiratory, and cardiovascular outcomes and mortality. RESULTS: Presepsin and procalcitonin levels were significantly higher in patients with adverse renal and respiratory outcome (p < 0.001 and 0.0081). The presepsin levels were significantly higher in patients with adverse cardiovascular outcome (p = 0.023) and the procalcitonin values in patients with sepsis (p = 0.0013). Presepsin levels were significantly higher in patients who died during hospitalization (382 pg/mL, interquartile range [IQR] 243-717.5 vs. 1,848 pg/mL, IQR 998-5,451.5, p = 0.049). In addition, the predictive value for in-hospital, 30-days, and 6-months mortality was higher for presepsin, with a significant difference between the 2 biomarkers (p = 0.025, p = 0.035, p = 0.003; respectively). Presepsin and procalcitonin seem to have comparable predictive value for adverse renal, cardiovascular, and respiratory outcome in cardiac surgery patients. Although a positive trend was notable for presepsin and adverse renal outcome (area under the ROC [receiver operating characteristic] curves [AUC] of 0.760, 95% CI 0.673-0.833 versus procalcitonin: AUC 0.692; 95% CI 0.601-0.773): no statistically significant difference was evident between the AUC of the 2 biomarkers (p = 0.25). CONCLUSIONS: Presepsin and -procalcitonin seem to have comparable predictive value for -adverse renal, cardiovascular, and respiratory outcome in cardiac surgery patients. Also, presepsin possesses a better predictive value for in-hospital, 30-days, and 6-months mortality.

Predicting Acute Kidney Injury in Intensive Care Unit Patients: The Role of Tissue Inhibitor of Metalloproteinases-2 and Insulin-Like Growth Factor-Binding Protein-7 Biomarkers.

BACKGROUND: Acute kidney injury (AKI) diagnosis is based on a rise in serum creatinine and/or fall in urine output. It has been shown that there are patients that fulfill AKI definition but do not have AKI, and there are also patients with evidence of renal injury who do not meet any criteria for AKI. Recently the innovative and emerging proteomic technology has enabled the identification of novel biomarkers that allow improved risk stratification. METHODS: Tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7) were measured to a cohort of 719 consecutive patients admitted to Intensive Care Unit (ICU). The primary endpoint was the evaluation of clinical performances of the biomarkers focusing on the probability do develop AKI in the first 7 days. RESULTS: The Kaplan-Meier analysis considering the first 7 days of ICU stay suggested a lower risk of developing AKI (p < 0.0001) for patients with a negative (<0.3; TIMP-2*IGFBP7) test. CONCLUSION: (TIMP-2*IGFBP7) at ICU admission has a good performance in predicting AKI, especially in the first 4 days in ICU.

Cerebrospinal fluid analysis and the determination of oligoclonal bands.

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroinflammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Procalcitonin and Interleukin-6 Levels: Are They Useful Biomarkers in Cardiac Surgery Patients?

BACKGROUND/AIM: Cardiac surgery-associated acute kidney injury is an independent predictor of chronic renal disease and mortality. The scope of this study was to determine the utility of procalcitonin (PCT) and plasma interleukin-6 (IL-6) levels in predicting renal outcome and mortality in these patients. METHODS: PCT and plasma IL-6 levels of 122 cardiac surgery patients were measured at 48 h after the surgical procedure. Primary endpoints were adverse renal outcome and mortality. Secondary endpoints were length of stay, bleeding, and number of transfusions. RESULTS: PCT was found to be a better predictor of adverse renal outcome than IL-6. IL-6 seemed to be a better predictor of both 30-day and overall mortality than PCT. Neither PCT nor IL-6 levels were found to be good predictors of intensive care unit stay and bleeding. CONCLUSION: PCT may be considered a good predictor of adverse renal outcome in cardiac surgery patients, whereas IL-6 seems to possess a good predictive value for mortality in this population of patients.

A comparison of three commercial platforms for urinary NGAL in critically ill adults.

BACKGROUND: Early biomarkers for acute kidney injury (AKI) diagnosis are needed since an increase in serum creatinine levels is a late marker. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising AKI biomarkers. Prior to routine clinical use, it is necessary to evaluate and validate a high-throughput commercially available method for NGAL detection. The aim of this study was to do an independent validation and comparison of the analytical performance of three different commercially available urine NGAL (uNGAL) assays. METHODS: Urine samples (n=110) were obtained from various patient groups with and without AKI. All urine samples were processed using Architect NGAL assay, Siemens Advia® 2400 NGAL test, and Siemens Dimension Vista® NGAL Test™, based on the three different platforms. RESULTS: Overall, there was good agreement among the three assays: Spearman's rank correlation coefficient between Architect and Vista was 0.989 (95% confidence interval [CI], 0.983-0.993), between Architect and Advia, 0.962 (95% CI, 0.937-0.977), between Vista and Advia 2400, 0.975 (95% CI, 0.961-0.984). We observed a negative bias of Architect compared with the other assays: comparing Architect to Vista, the mean bias was -55.7 ng/mL (95% CI, -74.3 to -37.0 ng/mL); comparing Architect to Advia 2400, the mean bias was -40.9 ng/mL (95% CI, -56.4 to -25.4 ng/nL). The bias is proportional to the concentration of uNGAL and is more pronounced at higher levels, while irrelevant near the tested cutoff levels of 100 and 190 ng/mL. Comparing Vista and Advia 2400, the mean bias was 10.1 ng/mL (95% CI, 1.5-18.8 ng/mL). Intra-assay imprecision was generally acceptable across all assays; coefficient of variation ranged from 0.8% to 5.3%. CONCLUSIONS: All three methods for uNGAL showed acceptable performance for the tested parameters and are comparable with each other at clinically relevant cutoffs. However, Architect yields lower results than the other two methods, with a bias more pronounced at higher uNGAL concentrations, suggesting additional standardization efforts will likely be necessary to better harmonize the uNGAL methods at various clinically relevant cutoffs.

Copeptin levels and kidney function in ADPKD: case-control study.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Studies have suggested a possible prognostic role of copeptin in determining the rate of progressive kidney function decline in ADPKD patients. However, it remains unresolved whether the changes in copeptin levels are specific for ADPKD or merely reflect a decline in glomerular filtration rate (GFR) regardless of the etiology of chronic kidney disease (CKD). METHODS: We performed a case-control study in ADPKD and non-ADPKD (control) patients. Patients were categorized based on the GFR-category (G-stage, KDIGO). We evaluated urea, creatinine, cystatin C, and copeptin in plasma and correlated these levels with estimated glomerular filtration rate (eGFR) (CKD-EPI). All p-values were two sided, and p < 0.05 was considered as statistically significant. RESULTS: We enrolled 112 ADPKD and 112 control patients. The median copeptin level was 10.72 (interquartile range (IQR) 5.21 - 26.21) pmol/L in the ADPKD group and 12.32 (IQR 4.47 - 30.73) pmol/L in the control group. The median copeptin level increased according to the G-stage in a progressive fashion and remained statistically significant across all G-stages and in both groups. Copeptin levels were not significantly different between ADPKD and control groups. We found a significant inverse correlation between copeptin level and eGFR (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) in the ADPKD, r = -0.81 (p < 0.001), and in the control group, r = -0.76 (p < 0.001). CONCLUSIONS: Copeptin levels seem to be strongly correlated with renal function rather than the presence of ADPKD. Further prospective studies need to evaluate its role as a prognostic marker in the early stage of CKD for ADPKD progression.

Rheumatoid factor isotypes in rheumatoid arthritis diagnosis and prognosis: a systematic review and meta-analysis.

OBJECTIVE: The first biomarker associated with the rheumatoid arthritis is rheumatoid factor (RF) and since the earliest reports a role has been proposed in the diagnosis and in the prediction of clinical features and outcome. The study of RF isotypes has further attempted to improve diagnostic accuracy and identify specific subgroups of patients. The main objective of this study is to provide an analysis of the literature on the role of RF isotypes in the diagnosis and prognosis of rheumatoid arthritis (RA). METHODS: We performed a systematic literature review and meta-analysis on the role of RF isotypes in RA (only in English, from PubMed, search terms: "rheumatoid factor isotypes", "diagnosis", "prognosis" and "rheumatoid arthritis", last search 31 July 2022, two independent assessment of quality and biases, results included in tables and in the meta-analysis). RESULTS: Thirty-six articles were examined (7517 patients). Testing all RF isotypes with latex test or nephelometry allows for the highest sensitivity (68.6%, 95% CI 66.2% to 71.0%); nonetheless, the determination of IgA isotype provides the highest specificity (91.4%, 95% CI 90.8% to 92.0%) and the highest positive likelihood ratio (7.7, 95% CI 5.7 to 10.4). When testing IgM isotype the highest diagnostic OR (21.7, 95% CI 16.1 to 29.3) is reached. When analysing anti-citrullinated protein antibodies, RF isotype determination increases diagnostic accuracy. On the other hand, these do not provide relevant prognostic information, as results are conflicting. CONCLUSIONS: Testing RF allows the highest sensitivity, while IgA isotype the highest specificity and positive likelihood ratio for RA diagnosis. On the other hand, determination of RF isotypes dose not allow prognostic information, as data are limited and heterogeneous.

Analysis of annual distributions of hemoglobin A2 values as a method to test for HbA2 standardization.

BACKGROUND AND AIMS: The monitoring of yearly distributions of HbA2 measured has been indicated as a reliable indicator of worldwide standardization. MATERIALS AND METHODS: Measurements/year of HbA2 have been collected over three consecutive years in 15 Italian laboratories each using the same analytical method over three years period. HbA2 distributions, cleaned of replicated measurements, were compared by the overlapping area of the raw probability density functions expressed by coefficient eta (η), and by comparing the reference intervals for the central part of each distribution estimated by the indirect method refineR using the R package "refineR". RESULTS: According to the overlapping areas analysis the distributions/year of the data provided by 4 centers able to perform at least 1000 measurements/year were similar in 2 consecutive years. Moreover, the reference intervals provided by 2 centers using the same analytical methods in two separate locations over the three consecutive years, were very similar. The highest overlap (99.7 %) was observed in one center over two consecutive years. The overlapping areas were very high (93.6-95.7%) in 8 out of 9 inter-comparisons. CONCLUSION: Despite the limitations of this study the yearly distribution of the HbA2 measured in various centers appears a reliable tool to test HbA2 standardization over different centers using different analytical methods.

Evaluating the role of a fully automated SARS-CoV-2 antigen ECLIA immunoassay in the management of the SARS COV 2 pandemic on general population.

OBJECTIVES: Chemiluminescence immunoassay (CLIA) automated assays (fourth-generation antigen test) for SARS-CoV-2 detection are promising because of their analytical productivity, but have lower sensitivity and specificity than rt-PCR assays. The authors of this paper evaluated a recent immunoassay implemented on Siemens Atellica IM, investigating how much this could affect the actual feasibility of this diagnostic during the pandemic. METHODS: From the three-day routine 134 positive and 241 negative swab samples by rt-PCR test were evaluated, selected as 1/3 positive - 2/3 negative. RESULTS: Using rt-PCR as gold standard, the specificity of immunoassay was 96.7%, while sensitivity was 68.0%. Sensitivity is inversely proportional to the viral load: 100% for cycles threshold (CT) values from 14 to 29, 95% until 30 CT, then 85, 74, 72, 68%, for 31-35 CT respectively. CONCLUSIONS: Our study confirms the reliability of the fourth-generation antigen assay in recognizing negative samples. Conversely, sensitivity appears to be less reliable (68.0%) than reported in the literature. This could be due to a non-randomized study group: many swab samples were taken from patients with expected low viral load (hospitalized for COVID for more than 10-12 days or asymptomatic patients for epidemiological surveillance). The strong correlation of sensitivity and viral load could prove significant to track the infectiousness of infected people, as previous studies reported that a viral load of at least 10E6 copies of RNA/mL, corresponding to 25 CT, is the threshold of transmission of the disease.

Subclinical AKI and Clinical Outcomes in Elderly Patients Undergoing Cardiac Surgery: Diagnostic Utility of NGAL versus Standard Creatinine Increase Criteria.

BACKGROUND: Acute kidney injury (AKI) is a common and serious postoperative complication in patients undergoing cardiac surgery and its incidence is particularly high among elderly patients. Cardiac surgery-associated AKI (CSA-AKI) represents the second most common cause of AKI in the intensive care unit but its true incidence could be underestimated, especially in elderly population. The current biomarkers of AKI are unreliable and delayed during acute changes in kidney function. In the setting of subclinical AKI (SAKI), biomarkers of tubular damage, such as NGAL, seem to be an early indicator of kidney damage. The aim of this study was to investigate NGAL utility in the SAKI diagnosis in the first 48 h after cardiac surgery and its helpfulness in predicting adverse clinical outcomes in comparison to current criteria for AKI. METHODS: This is an observational study of 72 patients admitted to San Bortolo's cardiac surgery department for elective cardiosurgical procedure enrolled over a 5-months period. All patients underwent peripheral venous sample 48 h after cardiac surgery to assess plasmatic creatinine (48Cr) and NGAL (48pNGAL) in addition to exams already foreseen by clinical practice. For each patient we studied renal, respiratory and cardiovascular outcome during hospitalization as well as 30 days and 6 months mortality. Creatinine Increase AKI (CrIAKI) was defined by 48CrI ≥0.3 mg/dL and SAKI was defined by 48pNGAL ≥100 pg/dL. We also assessed Respiratory (ArespO) as well as Cardiovascular (ACvO) outcome. RESULTS: Thirty days mortality was 8.3% (6 patients) and 6 months mortality was 12.5% (9 patients). A total of 27 patients (37.5%) presented AKI according to KDIGO (4) and 4 (5.5%) needed renal replacement therapy (RRT). SAKI was significantly associated with 30 days mortality (p = 0.0238), 6 months mortality (p = 0.002), Adverse renal outcome (ARenO) (p = 0.004) and need for RRT (p = 0.005). CrIAKI was significantly associated with 30 days mortality (p = 0.009) and ARenO (p = 0.0001), but not with 6 months mortality nor need for RRT.