The top-down approach to measurement uncertainty: which formula should we use in laboratory medicine?

Introduction: By quantifying the measurement uncertainty (MU), both the laboratory and the physician can have an objective estimate of the results’ quality. There is significant flexibility on how to determine the MU in laboratory medicine and different approaches have been proposed by Nordtest, Eurolab and Cofrac to obtain the data and apply them in formulas. The purpose of this study is to compare three different top-down approaches for the estimation of the MU and to suggest which of these approaches could be the most suitable choice for routine use in clinical laboratories. Materials and methods: Imprecision and bias of the methods were considered as components of the MU. The bias was obtained from certified reference calibrators (CRC), proficiency tests (PT), and inter-laboratory internal quality control scheme (IQCS) programs. The bias uncertainty, the combined and the expanded uncertainty were estimated using the Nordtest, Eurolab and Cofrac approaches. Results: Using different approaches, the expanded uncertainty estimates ranged from 18.9-40.4%, 18.2-22.8%, 9.3-20.9%, and 7.1-18.6% for cancer antigen (CA) 19-9, testosterone, alkaline phosphatase (ALP), and creatinine, respectively. Permissible values for MU and total error ranged from 16.0-46.1%, 13.1-21.6%, 10.7-26.2%, and 7.5-17.3%, respectively. Conclusion: The bias was highest using PT, followed by CRC and IQCS data, which were similar. The Cofrac approach showed the highest uncertainties, followed by Eurolab and Nordtest. However, the Eurolab approach requires additional measurements to obtain uncertainty data. In summary, the Nordtest approach using IQCS data was therefore found to be the most practical formula

Higher glucose level and systemic oxidative stress decrease the mean velocity index of the retinal artery during flickering light stimulation in type 1 diabetes

Aim To determine whether higher glucose level and systemic oxidative stress decrease mean velocity (MV) index of the central retinal artery (CRA) during flickering light stimulation in type 1 diabetes (T1D). Methods The study was performed in the period from 2008 to 2015 at the University Eye Clinic in Ljubljana. 41 patients with T1D and 37 participants without diabetes were included. MV in the CRA was measured using Doppler ultrasound diagnostics in basal conditions and during 8 Hz flickering light irritation. The plasma levels of glucose, fructosamine, 8-hydroxy-2’-deoxyguanosine (8-OHdG), triglycerides, cholesterol, and low-density lipoprotein (LDL) were measured. Results Patients with T1D had significantly higher levels of blood glucose (P < 0.001), fructosamine (P < 0.001), and 8-OHdG (P < 0.001), but there were no significant differences in triglycerides (P = 0.108), cholesterol (P = 0.531), and LDL (P = 0.645) between the groups. Patients with T1D also had a significantly lower MV index in the CRA (1.11 ± 0.15 vs 1.24 ± 0.23; P = 0.010). In the T1D group, a significant negative correlation was found between the level of glucose (r = −0.58; P < 0.001), fructosamine (r = −0.46; P = 0.003), 8-OHdG (r = −0.48; P = 0.002) and the MV index in the CRA. At the same time, in this group fructosamine and 8-OHdG levels had a separate effect on the MV index (adjusted R2 = 0.38, P < 0.001). Conclusion Higher glucose levels, the medium-term glucose level, and systemic oxidative stress could importantly reduce retinal vasodilatation during flickering light irritation in patients with T1

Proenkefalin A and protachykinin in ischemic neurological complications after cardiac surgery

Aim The evaluation of biomarkers of acute ischemic brain injury following surgical revascularization of the heart with the use of the heart-lung machine (cardiopulmonary bypass, CPB). Methods Twenty consecutive patients were divided into two groups: the first 10 patients received a potential neuroprotective human recombinant erythropoietin, while the remaining 10 comprised the control group. Neurological complications were monitored by measuring serum concentrations of neuropeptide proenkephalin A (PENK-A) and protachykinin A (PTA) before and in the first 5 days after surgery, comparing the neurological outcome with MRI examinations. Results Both the erythropoietin-treated group and control group were comparable with a non-significant difference shown for the postoperative concentrations of PENK-A and PTA. A comparison of serum concentrations of the biomarkers of 16 patients without brain ischemia and 4 patients with acute ischemia also displayed no significant differences, regardless of erythropoietin therapy. Conclusion In our pilot study the analysis of PENK-A and PTA serum concentrations might not be the strategy to enable the monitoring and evaluation of neuroprotective stroke treatment, but further studies are required to investigate its role in acute ischemic brain injury

Serum Klotho as a marker for early diagnosis of acute kidney injury after cardiac surgery

Background: Early diagnosis of acute kidney injury (AKI) after cardiac surgery is based on serum creatinine which is neither a specific nor a sensitive biomarker. In our study, we investigated the role of serum Klotho in early prediction of AKI after cardiac surgery using cardiopulmonary bypass (CPB). Methods: The included patients were classified into three groups according to AKI stages using KDIGO criteria. The measurements of creatinine and Klotho levels in serum were performed before surgery, at the end of CPB, 2 hours after the end of CPB, 24 hours and 48 hours postoperatively. Results: Seventy-eight patients were included in the study. A significant increase of creatinine levels (p<0.001) was measured on the first day after the surgery in both AKI groups compared to the non-AKI group. However, a significant difference between AKI-2 and AKI-1 groups (p=0.006) was not measured until the second day after the operation. Using decision trees for classification of patients with a higher or lower risk of AKI we found out that Klotho discriminated between the patients at low risk of developing more severe kidney injury in the first hours after surgery and the patients at high risk better than creatinine. Adding also the early measurements of creatinine in the decision tree model further improved the prediction of AKI. Conclusions: Serum Klotho may be useful to discriminate between the patients at lower and the patients at higher risk of developing severe kidney injury after cardiac surgery using CPB already in the first hours after surgery.Uvod: Rana dijagnoza akutnog oštećenja bubrega (AKI) posle operacije srca se zasniva na kreatininu u serumu koji nije ni specifičan ni osetljiv biomarker. U našoj studiji, istraživali smo ulogu serumskog Klotho-a u ranom predvi|anju AKI nakon operacije srca koristeći kardiopulmonarni bajpas (CPB). Metode: Uključeni pacijenti su klasifikovani u tri grupe u skladu sa AKI fazama po KDIGO kriterijumu. Merenje kreatinina i Klotho-a u serumu je bilo izvedeno pre operacije, krajem CPB, dva sata nakon završetka CPB, 24 sati i 48 sati postoperativno. Rezultati: U studiju je uključeno sedamdeset osam pacijenata. Povišenje nivoa kreatinina prvi dan posle operacije je bilo značajno (p < 0,001) u obe AKI grupe u pore|enju sa non-AKI grupom, a značajna razlika izme|u grupa AKI-2 i AKI-1 (p = 0,006) bila je izmerena tek drugi dan posle operacije. Upotreba stabla odlučivanja za klasifikaciju pacijenata sa manjim i sa ve}im rizikom od razvijanja oštećenja bubrega pokazala je da je Klotho u prvim satima nakon operacije bolji od kreatinina u diferencijaciji između pacijenata sa manjim i pacijenata sa većim rizikom od oštećenja bubrega. Predviđanje razvoja težeg oštećenja bubrega bilo je još bolje sa dodatnim uključivanjem ranih rezultata kreatinina u model. Zaključak: Serumski Klotho može biti koristan za diferencijaciju izme|u pacijenata sa manjim i pacijenata sa većim rizikom od razvijanja težeg oštećenja bubrega posle operacije srca koristeći CPB već u prvim satima nakon operacije

Validity of Klotho, CYR61 and YKL-40 as ideal predictive biomarkers for acute kidney injury: review study

ABSTRACT CONTEXT AND OBJECTIVE: Acute kidney injury (AKI) is still a headache for clinicians and scientists as a possible reason for increased death among intensive care unit (ICU) patients after invasive cardiac surgery. Furthermore, the diagnostic process for AKI using conventional biomarkers is not sufficient to ensure early warning of this condition because of the morbid influence of non-renal factors that definitively delay the time for the prognosis. These imposed limitations have led to significant amounts of research targeted towards identifying novel biomarkers for AKI with a sustained degree of sensitivity and specificity. Here, we reviewed previous studies conducted on the Klotho, CYR61 and YKL-40 biomarkers in relation to AKI. DESIGN AND SETTING: Review of the literature conducted in the Institute of Clinical Chemistry & Biochemistry, Ljubljana University Medical Center, Slovenia. METHODS: The literature was searched in PubMed and the Cochrane Library. From the database of this specialty, we selected 17 references that matched our context for detailed analysis and further investigation. RESULTS: The studies reviewed showed notable differences in their results relating to the diagnostic impact of Klotho, CYR61 and YKL-40 on early prediction of AKI. CONCLUSIONS: The results regarding the Klotho, CYR61 and YKL-40 biomarkers showed markedly equivocal performance in the previous studies and did not fulfill the expectations that these factors would form valid possible biomarkers for AKI

Enhanced detection of cardiac surgery-associated acute kidney injury by composite biomarker panel in patients with normal preoperative kidney function

We have shown recently that minor subclinical creatinine dynamic changes enable excellent de-tection of acute kidney injury (AKI) within 6-12 hours after cardiac surgery. The aim of the pre-sent study was to examine combination of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC) and creatinine for enhanced AKI detection early after cardiac surgery. Elective patients with normal renal function undergoing cardiac surgery using cardiopulmonary bypass were enrolled. Concentrations of plasma NGAL, serum CysC and serum creatinine concentra-tions were determined after induction of general anaesthesia, at termination of cardiopulmo-nary bypass and 2 hours thereafter. Out of 119 enrolled patients 51 (43%) developed AKI. A model utilizing NGAL, CysC and creatinine triple biomarker panel including sequential rela-tive changes provides better prediction of cardiac surgery-associated acute kidney injury then any biomarker alone already 2 hours after the termination of cardiopulmonary bypass. The area under receiver-operator curve was 0.77, sensitivity 77% and specificity 68%