Graham Jones

Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement.

Optimal detection and subsequent risk stratification of people with chronic kidney disease (CKD) requires simultaneous consideration of both kidney function (glomerular filtration rate [GFR]) and kidney damage (as indicated by albuminuria or proteinuria). Measurement of urinary albuminuria and proteinuria is hindered by a lack of standardisation regarding requesting, sample collection, reporting and interpretation of tests. A multidisciplinary working group was convened with the goal of developing and promoting recommendations that achieve consensus on these issues. The working group recommended that the preferred method for assessment of albuminuria in both diabetic and non‐diabetic patients is urinary albumin‐to‐creatinine ratio (UACR) measurement in a first‐void spot urine specimen. Where a first‐void specimen is not possible or practical, a random spot urine specimen for UACR is acceptable. The working group recommended that adults with one or more risk factors for CKD should be assessed using UACR and estimated GFR every 1–2 years, depending on their risk‐factor profile. Recommended testing algorithms and sex‐specific cut‐points for microalbuminuria and macroalbuminuria are provided. The working group recommended that all pathology laboratories in Australia should implement the relevant recommendations as a vital component of an integrated national approach to detection of CKD.

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations

The publication of the Australasian Creatinine Consensus Working Groups position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m2. Age‐related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m2 is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing. If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD‐EPI formula has been validated as a tool to estimate GFR in some populations of non‐European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.

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.

Defining analytical performance specifications: Consensus Statement from the 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine.

*Corresponding author: Sverre Sandberg, Norwegian Quality Improvement of Primary Care Laboratories (Noklus), Institute of Global Public Health and Primary Health Care, University of Bergen and Laboratory of Clinical Biochemistry, Bergen, Norway, E-mail: sverre.sandberg@isf.uib.no Callum G. Fraser: Centre for Research into Cancer Prevention and Screening, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, UK Andrea Rita Horvath: SEALS Department of Clinical Chemistry, Prince of Wales Hospital, Screening and Test Evaluation Program, School of Public Health, University of Sydney, and School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia Rob Jansen: Netherlands Foundation for Quality Assessment of Medical Laboratories (SKML), Radboud University, Nijmegen, The Netherlands Graham Jones: SydPath, St Vincent’s Hospital, Sydney, NSW, Australia Wytze Oosterhuis: Atrium-Orbis, Department of Clinical Chemistry and Haematology, Heerlen, The Netherlands Per Hyltoft Petersen: Norwegian Quality Improvement of Primary Care Laboratories (Noklus), Institute of Global Public Health and Primary Health Care, University of Bergen, Norway Heinz Schimmel: European Commission, Joint Research Centre, Institute for Reference Materials and Measurements (IRMM), Geel, Belgium Ken Sikaris: Sonic Healthcare and Melbourne University, Melbourne, Vic, Australia Mauro Panteghini: Centre for Metrological Traceability in Laboratory Medicine (CIRME), University of Milan, Milan, Italy Consensus Statement

The role of HbA1c in the diagnosis of diabetes mellitus in Australia

For many years, the diagnosis of diabetes has been made through the laboratory‐based measurement of fasting or random blood glucose levels, or using the oral glucose tolerance test. A glycated haemoglobin (HbA1c) level ≥ 6.5% (48 mmol/mol) is now also acceptable for diagnosing diabetes. Caution is needed in interpreting HbA1c test results in the presence of conditions affecting red blood cells or their survival time, such as haemoglobinopathies or anaemia.

Collective opinion paper on findings of the 2010 convocation of experts on laboratory quality.

Abstract As a part of a series of yearly meeting, in May 2010 over 40 medical laboratory opinion leaders, pathologists, clinical biochemists and physicians from Europe, Israel and South Africa gathered together in Bardolino, Italy to discuss issues and current challenges for laboratory medicine, including a) the use of biological variation 10 years after the Stockholm Conference; b) achieving quality in point-of-care testing; c) assessing risk and controlling sources of error in the laboratory; d) determining the appropriate frequency of quality control; and f) putting laboratory medicine at the core of patient care. The intended goal of the convocation was to give laboratory professionals from different countries and backgrounds the opportunity to share ideas, concerns and experiences in previously mentioned areas of interest. This paper provide a synopsis of the reports from each working group.

Study Protocol--accurate assessment of kidney function in Indigenous Australians: aims and methods of the eGFR study.

BackgroundThere is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function. However, differences in body build and body composition between Indigenous and non-Indigenous Australians suggest that creatinine-based estimates of glomerular filtration rate derived for European populations may not be appropriate for Indigenous Australians. The burden of kidney disease is borne disproportionately by Indigenous Australians in central and northern Australia, and there is significant heterogeneity in body build and composition within and amongst these groups. This heterogeneity might differentially affect the accuracy of estimation of glomerular filtration rate between different Indigenous groups. By assessing kidney function in Indigenous Australians from Northern Queensland, Northern Territory and Western Australia, we aim to determine a validated and practical measure of glomerular filtration rate suitable for use in all Indigenous Australians.Methods/DesignA cross-sectional study of Indigenous Australian adults (target n = 600, 50% male) across 4 sites: Top End, Northern Territory; Central Australia; Far North Queensland and Western Australia. The reference measure of glomerular filtration rate was the plasma disappearance rate of iohexol over 4 hours. We will compare the accuracy of the following glomerular filtration rate measures with the reference measure: Modification of Diet in Renal Disease 4-variable formula, Chronic Kidney Disease Epidemiology Collaboration equation, Cockcroft-Gault formula and cystatin C- derived estimates. Detailed assessment of body build and composition was performed using anthropometric measurements, skinfold thicknesses, bioelectrical impedance and a sub-study used dual-energy X-ray absorptiometry. A questionnaire was performed for socio-economic status and medical history.DiscussionWe have successfully managed several operational challenges within this multi-centre complex clinical research project performed across remote North, Western and Central Australia. It seems unlikely that a single correction factor (similar to that for African-Americans) to the equation for estimated glomerular filtration rate will prove appropriate or practical for Indigenous Australians. However, it may be that a modification of the equation in Indigenous Australians would be to include a measure of fat-free mass.

Performance of Direct Estradiol Immunoassays with Human Male Serum Samples

BACKGROUND Steroid immunoassays originally required solvent extraction, chromatography, and structurally authentic tracers to avoid interference from steroid cross-reactivity and matrix effects. The demand for steroid assays has driven assay simplification, bypassing this triplet of validity criteria to allow use of unextracted serum, which has introduced bias and nonspecificity at low steroid concentrations. We aimed to evaluate the performance of commercial direct estradiol (E2) immunoassays relative to the reference method of LC-MS and compared serum E2 measurements from each assay with biomarkers of estrogen action. METHODS We measured serum E2 in duplicate using 5 commercial direct immunoassays and LC-MS in a nested cohort of 101 healthy, asymptomatic men >40 years old from the Healthy Man Study. For each immunoassay, we evaluated the detectability and distribution of serum E2 measurements, CV, and bias (relative to LC-MS) by Passing-Bablok regression and deviance plots. RESULTS Three assays detected E2 in all samples, whereas E2 was detected in only 53% and 72% of samples by 2 other assays. All 5 assays had positive biases, ranging from 6% to 74%, throughout their ranges. CVs were lower with 4 immunoassays than with LC-MS. LC-MS, but none of the direct immunoassays, correlated with serum testosterone and sex steroid-binding globulin. CONCLUSIONS The positive bias of direct E2 immunoassays throughout their working range reflects the nonspecific effects of steroid cross-reactivity and/or matrix interference arising from the violation of the triplet validity criteria for steroid immunoassay.

Accurate assessment of kidney function in indigenous Australians: the estimated GFR study.

Study equation (8.9 [95% CI, 7.9-11.1] mL/min/1.73 m 2 less than mGFR) than with the CKD-EPI equation (3.8 [95% CI, 2.5-5.6] mL/min/1.73 m 2 less than mGFR). Stratified by mGFR group (Table S1), bias was greatest in indigenous participants with mGFR 90 mL/min/1.73 m 2 when the MDRD Study equation was used, but improved with use of the CKD-EPI equation (without the correction factor). The accuracy of eGFR was not significantly different between the 2 equations. Thus, the magnitude of bias using the MDRD Study equation in indigenous participants was similar with or without use of theAfrican American correction factor; however, the direction of bias differed (GFR was overestimated with the correction factor and underestimated without it). For the CKD-EPI equation, bias and accuracy were improved significantly by omitting the correction factor. WithomissionoftheAfricanAmericancorrectionfactor,eGFRCKDEPI provided a reasonably unbiased and accurate estimate of GFR, whereas the MDRD Study equation significantly underestimated GFRinIndigenousAustralians(comparedwithnonindigenousAustralians). This may relate to inherent limitations of the MDRD Study equation rather than body build or other differences in Indigenous Australians.The CKD-EPI equation has been shown to perform better at higher mGFRs (approximately 60 mL/min/1.73 m 2 ), and the MDRD Study performs better at lower GFRs. 9 The mean mGFR of the Indigenous Australian cohort (93 mL/min/1.73 m 2 ) was closer to that of the CKD-EPI than the MDRD development cohort, and this

Harmonization: the sample, the measurement, and the report.

Harmonization of clinical laboratory results means that results are comparable irrespective of the measurement procedure used and where or when a measurement was made. Harmonization of test results includes consideration of pre-analytical, analytical, and post-analytical aspects. Progress has been made in each of these aspects, but there is currently poor coordination of the effort among different professional organizations in different countries. Pre-analytical considerations include terminology for the order, instructions for preparation of the patient, collection of the samples, and handling and transportation of the samples to the laboratory. Key analytical considerations include calibration traceability to a reference system, commutability of reference materials used in a traceability scheme, and specificity of the measurement of the biomolecule of interest. International organizations addressing harmonization include the International Federation for Clinical Chemistry and Laboratory Medicine, the World Health Organization, and the recently formed International Consortium for Harmonization of Clinical Laboratory Results (ICHCLR). The ICHCLR will provide a prioritization process for measurands and a service to coordinate global harmonization activities to avoid duplication of effort. Post-analytical considerations include nomenclature, units, significant figures, and reference intervals or decision values for results. Harmonization in all of these areas is necessary for optimal laboratory service. This review summarizes the status of harmonization in each of these areas and describes activities underway to achieve the goal of fully harmonized clinical laboratory testing.