Kristin M. Aakre

Current Issues in Measurement and Reporting of Urinary Albumin Excretion

BACKGROUND Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. CONTENT The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the error-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences have been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no reference materials for either analyte in urine. The recommended reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethnicity) nor the continuous increase in risk related to albumin excretion. DISCUSSION Clinical needs have been identified for standardization of (a) urine collection methods, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.

Postanalytical external quality assessment of urine albumin in primary health care: an international survey.

BACKGROUND Microalbuminuria (MA) is recognized as an important risk factor for cardiovascular and renal complications in diabetes. We sought to evaluate how screening for MA is conducted and how urine albumin (UA) results are interpreted in primary care internationally. METHODS General practitioners (GPs) received a case history-based questionnaire depicting a male type 2 diabetes patient in whom UA testing had not been performed. Questions were related to type of urine sample used for UA testing, need for a repeat test, whether UA testing was performed in the office laboratory, and what changes in UA results were considered clinically important [critical difference (CD)]. Participants received national benchmarking feedback reports. RESULTS We included 2078 GPs from 9 European countries. Spot urine samples were used most commonly for first time office-based testing, whereas timed collections were used to a larger extent for hospital-based repeat tests. Repeat tests were requested by 45%-77% of GPs if the first test was positive. Four different measurement units were used by 70% of participants in estimating clinically important changes in albumin values. Stated CDs varied considerably among GPs, with similar variations in each country. A median CD of 33% was considered clinically important for both improvement and deterioration in MA, corresponding to an achievable analytical imprecision of 14%, when UA is reported as an albumin/creatinine ratio. CONCLUSIONS Guidelines on diagnosing MA are followed only partially, and should be made more practicable, addressing issues such as type of samples, measurement units, and repeat tests.

Weekly and 90-Minute Biological Variations in Cardiac Troponin T and Cardiac Troponin I in Hemodialysis Patients and Healthy Controls

BACKGROUND Myocardial infarction (MI) is diagnosed by the finding of a single cardiac troponin value above the 99th percentile and a significant time-dependent change in cardiac troponin concentration. The aim of this study was to determine the 90-min and weekly biological variations, the reference change value (RCV), and the index of individuality (II) of high-sensitivity cardiac troponin T (hs-cTnT) (Roche Diagnostics) and hs-cTnI (Abbott Diagnostics) in patients receiving hemodialysis (HD) and in healthy individuals. METHOD Blood samples were collected from 19 HD patients (on an HD-free day) and 20 healthy individuals at 90-min intervals over a 6-h period (between 08:30 and 14:30) and before the midweek HD treatment for 10 weeks. The within-person variation (CVi), between-person variation, RCV, and II were calculated. RESULTS During the 6-h sampling period, the concentrations of hs-cTnT (both groups) and hs-cTnI (HD patients only) decreased on average by 0.8% to 1.7% per hour, respectively. These declining trends were included in the calculation of a 90-min asymmetric RCV: -8%/+5% in HD patients (hs-cTnT), -18%/+21% in HD patients (hs-cTnI), -27%/+29% in healthy individuals (hs-cTnT), and -39%/+64% in healthy individuals (hs-cTnI). The II was low in both groups for both assays. The weekly CVi values were approximately 8% (hs-cTnT) and 15% (hs-cTnI) in both groups. CONCLUSIONS When using a cardiac troponin change of 20%-50% to diagnose an MI, the false-positive rate is likely to be lower for the hs-cTnT assay than for the hs-cTnI assay. The low II suggests that use of a diagnostic cutoff value can be omitted.

Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation

Abstract Background: Correct information provided by guidelines may reduce laboratory test related errors during the pre-analytical, analytical and post-analytical phase and increase the quality of laboratory results. Methods: Twelve clinical practice guidelines were reviewed regarding inclusion of important laboratory investigations. Based on the results and the authors’ experience, two checklists were developed: one comprehensive list including topics that authors of guidelines may consider and one consisting of minimal standards that should be covered for all laboratory tests recommended in clinical practice guidelines. The number of topics addressed by the guidelines was related to involvement of laboratory medicine specialists in the guideline development process. Results: The comprehensive list suggests 33 pre- analytical, 37 analytical and 10 post-analytical items. The mean percentage of topics dealt with by the guidelines was 33% (median 30%, range 17%–55%) and inclusion of a laboratory medicine specialist in the guideline committee significantly increased the number of topics addressed. Information about patient status, biological and analytical interferences and sample handling were scarce in most guidelines even if the inclusion of a laboratory medicine specialist in the development process seemingly led to increased focus on, e.g., sample type, sample handling and analytical variation. Examples underlining the importance of including laboratory items are given. Conclusions: Inclusion of laboratory medicine specialist in the guideline development process may increase the focus on important laboratory related items even if this information is usually limited. Two checklists are suggested to help guideline developers to cover all important topics related to laboratory testing.

How Well Do Laboratories Adhere to Recommended Clinical Guidelines for the Management of Myocardial Infarction: The CARdiac MArker Guidelines Uptake in Europe Study (CARMAGUE).

BACKGROUND We undertook an assessment of current use of evidence-based guidelines for the use of cardiac biomarkers in Europe (EU) and North America (NA). METHODS In 2013-2014 a web-based questionnaire was distributed via NA and EU biochemical societies. Questions covered cardiac biomarkers measured, analytical methods used, decision thresholds, and use of decision-making protocols. Results were collated using a central database and analyzed using comparative and descriptive nonparametric statistics. RESULTS In EU, returns were obtained from 442 hospitals, 50% central or university hospitals, and 39% from local hospitals from 35 countries with 395/442 (89%) provided an acute service. In NA there were 91 responses (63.7% central or university hospitals, 19.8% community hospitals) with 76/91 (83.5%) providing an acute service. Cardiac troponin was the preferred cardiac biomarker in 99.5% (EU) and 98.7% (NA), and the first line marker in 97.7% (EU) and 97.4% (NA). There were important differences in the choice of decision limits and their derivations. The origin of the information was also significantly different, with EU vs NA as follows: package insert, 61.9% vs 40%; publications, 17.1% vs 15.0%; local clinical or analytical validation choice, 21.0% vs 45.0%; P = 0.0003. CONCLUSIONS There are significant differences between EU and NA use of cardiac biomarkers. This probably relates to different availability of assays between EU and NA (such as high-sensitivity troponin assays) and different laboratory practices on assay introduction (greater local evaluation of assay performance occurred in NA).

How to conduct External Quality Assessment Schemes for the pre-analytical phase?

In laboratory medicine, several studies have described the most frequent errors in the different phases of the total testing process, and a large proportion of these errors occur in the pre-analytical phase. Schemes for registration of errors and subsequent feedback to the participants have been conducted for decades concerning the analytical phase by External Quality Assessment (EQA) organizations operating in most countries. The aim of the paper is to present an overview of different types of EQA schemes for the pre-analytical phase, and give examples of some existing schemes. So far, very few EQA organizations have focused on the pre-analytical phase, and most EQA organizations do not offer pre-analytical EQA schemes (EQAS). It is more difficult to perform and standardize pre-analytical EQAS and also, accreditation bodies do not ask the laboratories for results from such schemes. However, some ongoing EQA programs for the pre-analytical phase do exist, and some examples are given in this paper. The methods used can be divided into three different types; collecting information about pre-analytical laboratory procedures, circulating real samples to collect information about interferences that might affect the measurement procedure, or register actual laboratory errors and relate these to quality indicators. These three types have different focus and different challenges regarding implementation, and a combination of the three is probably necessary to be able to detect and monitor the wide range of errors occurring in the pre-analytical phase.

Can Changes in Troponin Results Be Useful in Diagnosing Myocardial Infarction

In 1979, the WHO defined 3 specific criteria for use in the diagnosis of myocardial infarction (MI)1 : (a) clinical symptoms typical for ischemic heart disease, (b) specific electrocardiogram changes, and (c) a typical change in serial measurements of cardiac enzymes (1). Later definitions have continued in the mold of listing specific criteria, and in the current definition of MI, a characteristic increase and/or decrease in a cardiac biomarker with at least 1 result >99 percentile of a healthy population and evidence of myocardial ischemia (either specific symptoms or electrocardiographic or ultrasound findings) are mandatory (2). During the last decade, troponin T or I molecules, which are found only in myocardial cells and released after cell necrosis, have been the preferred cardiac biomarkers because of their high sensitivity and specificity (3), although myocardial cell necrosis can be seen in conditions other than myocardial ischemia (renal failure, sepsis, treatment with cardiotoxic drugs, myocarditis, and so on). A common problem in clinical practice is how to diagnose an acute MI in a patient who already has increased troponin concentrations. The National Academy of Clinical Biochemistry has suggested that a 20% increase in troponin results can be used to diagnose an ischemic event. This recommendation is based on analytical variation for troponin analysis alone, without taking biological variation into account (4). Recently, troponin assays with better analytical sensitivity have become commercially available. These assays not only have opened up new diagnostic opportunities but also have challenged our understanding of ischemic heart disease, because the assays can detect low troponin concentrations, even in the healthy population (5)(6). The natural fluctuations of troponin concentrations around a homeostatic set point (i.e., within-person biological variation) as well as the between-person biological variation can be established, as is reported by Vasile et al. in …

Self‐monitoring of blood glucose in patients with diabetes who do not use insulin—are guidelines evidence‐based?

Diabet. Med. 29, 1226–1236 (2012)

Reflective testing: adding value to laboratory testing

Abstract Reflective testing is a procedure in which the laboratory specialist adds additional tests and/or comments to an original request, after inspection (reflection) of the results. It can be considered as an extension of the authorization process where laboratory tests are inspected before reporting to the physician. The laboratory specialist will inevitably find inconclusive results, and additional testing can contribute to make the appropriate diagnosis. Several studies have been published on the effects of reflective testing. Some studies focus on the opinion of the general practitioners or other clinicians, whereas other studies were intended to determine the patient’s perspective. Overall, reflective testing was judged as a useful way to improve the process of diagnosing (and treating) patients. There is to date scarce high quality scientific evidence of the effectiveness of this procedure in terms of patient management. A randomized clinical trial investigating this aspect is however ongoing. Cost effectiveness of reflective testing still needs to be determined in the future. In conclusion, reflective testing can be seen as a new dimension in the service of the clinical chemistry laboratory to primary health care. Additional research is needed to deliver the scientific proof of the effectiveness of reflective testing for patient management.

Analytical Bias Exceeding Desirable Quality Goal in 4 out of 5 Common Immunoassays: Results of a Native Single Serum Sample External Quality Assessment Program for Cobalamin, Folate, Ferritin, Thyroid-Stimulating Hormone, and Free T4 Analyses

BACKGROUND We undertook this study to evaluate method differences for 5 components analyzed by immunoassays, to explore whether the use of method-dependent reference intervals may compensate for method differences, and to investigate commutability of external quality assessment (EQA) materials. METHODS Twenty fresh native single serum samples, a fresh native serum pool, Nordic Federation of Clinical Chemistry Reference Serum X (serum X) (serum pool), and 2 EQA materials were sent to 38 laboratories for measurement of cobalamin, folate, ferritin, free T4, and thyroid-stimulating hormone (TSH) by 5 different measurement procedures [Roche Cobas (n = 15), Roche Modular (n = 4), Abbott Architect (n = 8), Beckman Coulter Unicel (n = 2), and Siemens ADVIA Centaur (n = 9)]. The target value for each component was calculated based on the mean of method means or measured by a reference measurement procedure (free T4). Quality specifications were based on biological variation. Local reference intervals were reported from all laboratories. RESULTS Method differences that exceeded acceptable bias were found for all components except folate. Free T4 differences from the uncommonly used reference measurement procedure were large. Reference intervals differed between measurement procedures but also within 1 measurement procedure. The serum X material was commutable for all components and measurement procedures, whereas the EQA materials were noncommutable in 13 of 50 occasions (5 components, 5 methods, 2 EQA materials). CONCLUSIONS The bias between the measurement procedures was unacceptably large in 4/5 tested components. Traceability to reference materials as claimed by the manufacturers did not lead to acceptable harmonization. Adjustment of reference intervals in accordance with method differences and use of commutable EQA samples are not implemented commonly.