Olga Jakob

Two Novel Equations to Estimate Kidney Function in Persons Aged 70 Years or Older

BACKGROUND In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclassify elderly persons in terms of their stage of chronic kidney disease. OBJECTIVE To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants. DESIGN Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation. SETTING Random community-based population of a large insurance company. PARTICIPANTS 610 participants aged 70 years or older (mean age, 78.5 years). INTERVENTION Iohexol plasma clearance measurement as gold standard. MEASUREMENTS GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy in the validation sample. RESULTS The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft-Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). LIMITATION There was no validation by an external data set. CONCLUSION The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C is not available, the BIS1 equation is an acceptable alternative. PRIMARY FUNDING SOURCE Kuratorium für Dialyse und Nierentransplatation (KfH) Foundation of Preventive Medicine.

A comparative analysis of the Work Ability Index

BACKGROUND The Work Ability Index (WAI) is a well-established instrument to measure work ability. However, the dimensionality of the WAI remains controversial. AIMS To identify the dimensionality of the WAI and to investigate dependencies of factors and subscales. METHODS The sample analysed in this study consisted of 371 subjects of different occupational groups (teachers, office workers, nursery school teachers and managers). The WAI was measured for all subgroups. Psychometric characteristics of the WAI were investigated using factor analyses with different numbers and different patterns of dependency among the factors. Chi-square analysis and the Comparative Fit Index were used to statistically assess fit quality. RESULTS The group of managers had to be excluded from the analysis as their results were probably overoptimistic due to reporting bias; thus, 324 subjects entered. The one-factor model and an orthogonal two-factor model did not fit the observed correlational structures. A satisfactory fit was obtained using a two-dimensional model with correlated factors. These factors could be interpreted as subjectively estimated work ability and objective health status. Only five of seven items of the WAI could be related unambiguously to one of both factors. CONCLUSIONS From our study, we conclude that using only the total score of the WAI is not adequate for population analysis of and assessment of work ability to individuals. Instead, the two-dimensional structure of the instrument must be taken into account.

Anti-dsDNA-NcX ELISA: dsDNA-loaded nucleosomes improve diagnosis and monitoring of disease activity in systemic lupus erythematosus

IntroductionThe objective of this study was to compare the clinical usefulness of the new anti-double-stranded DNA nucleosome-complexed enzyme-linked immunosorbent assay (Anti-dsDNA-NcX ELISA), which is based on dsDNA-loaded nucleosomes as antigens, with established test systems based on dsDNA or nucleosomes alone for systemic lupus erythematosus (SLE) diagnostics and determination of disease activity.MethodsSera from a cohort of 964 individuals comprising 207 SLE patients, 357 disease controls and 400 healthy donors were investigated using the Anti-dsDNA-NcX ELISA, Farr assay, Anti-dsDNA ELISA, Anti-nucleosome ELISA and Crithidia luciliae immunofluorescence (CLIF) assay, all of which are tests available from EUROIMMUN Medizinische Labordiagnostika AG (Lübeck, Germany). Receiver operating characteristic curve analyses were performed to compare the sensitivity and specificity of each assay. The test results yielded by these assays in a group of 165 fully characterized SLE patients were compared with the corresponding medical records.ResultsThe Anti-dsDNA-NcX ELISA was found to have a sensitivity of 60.9% and a specificity of 98.9% in all 964 individuals at the manufacturers cutoff of 100 U/ml. At a comparable specificity of 99%, the sensitivity amounted to 59.9% for the Anti-dsDNA-NcX ELISA, 54.1% for the Farr assay, 53.6% for the antinucleosome ELISA and 35.8% for the anti-dsDNA ELISA. The CLIF assay had a sensitivity of 28.0% and a specificity of 98.2%. The Anti-dsDNA-NcX ELISA correlated mostly with global disease activity in a cross-sectional analysis. In a longitudinal analysis of 20 patients with 69 patient visits, changes in Anti-dsDNA-NcX ELISA and antinucleosome ELISA results correlated highly with changes in disease activity over time.ConclusionsThe use of dsDNA-complexed nucleosomes as antigens in ELISA leads to optimized determination of diagnosis and disease activity in SLE patients and is available for clinical practice.

Iohexol plasma clearance measurement in older adults with chronic kidney disease—sampling time matters

BACKGROUND Accurate and precise measurement of GFR is important for patients with chronic kidney disease (CKD). Sampling time of exogenous filtration markers may have great impact on measured GFR (mGFR) results, but there is still uncertainty about optimal timing of plasma clearance measurement in patients with advanced CKD, for whom 24-h measurement is recommended. This satellite project of the Berlin Initiative Study evaluates whether 24-h iohexol plasma clearance reveals a clinically relevant difference compared with 5-h measurement in older adults. METHODS In 104 participants with a mean age of 79 years and diagnosed CKD, we performed standard GFR measurement over 5 h (mGFR300) using iohexol plasma concentrations at 120, 180, 240 and 300 min after injection. With an additional sample at 1440 min, we assessed 24-h GFR measurement (mGFR1440). Study design was cross-sectional. Calculation of mGFR was conducted with a one compartment model using the Brochner-Mortensen equation to calculate the fast component. mGFR values were compared with estimated GFR values (MDRD, CKD-EPI, BIS1, Revised Lund-Malmö and Cockcroft-Gault). RESULTS In all 104 subjects, mGFR1440 was lower than mGFR300 (23 ± 8 versus 29 ± 9 mL/min/1.73 m(2), mean ± SD; P < 0.001). mGFR1440 was highly correlated with mGFR300 (r = 0.9). The mean absolute difference mGFR300 - mGFR1440 was 5.9 mL/min/1.73 m(2) corresponding to a mean percentage difference of 29%. In individuals with eGFRCKD-EPI ≤ 30 mL/min/1.73 m(2), percentage difference of mGFR300 and mGFR1440 was even higher (35%). To predict mGFR1440 from mGFR300, we developed the correction formula: mGFR1440 = -2.175 + 0.871 × mGFR300 (1-fold standard error of estimate: ±2.3 mL/min/1.73 m(2)). The GFR estimating equation with the best accuracy and precision compared with mGFR300 and mGFR1440 was the Revised Lund Malmö. CONCLUSIONS In elderly CKD patients, measurement of iohexol clearance up to 5 h leads to a clinically relevant overestimation of GFR compared with 24-h measurement. In clinical care, this effect should be bore in mind especially for patients with considerably reduced GFR levels. A new correction formula has been developed to predict mGFR1440 from mGFR300. For accurate GFR estimates in elderly CKD patients, we recommend the Revised Lund Malmö equation.

Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate.

BACKGROUND Cystatin C is increasingly used in glomerular filtration rate (GFR) estimation equations. The dependence of cystatin C results upon the analytical method has been a major source of controversy. METHODS Cystatin C was measured with non-standardized turbidimetric Roche Generation 1 and standardized nephelometric Siemens assays in 3666 and additionally with standardized Roche Generation 2 and Siemens in 567 blood samples of the Berlin Initiative Study. Cystatin C-based GFR was assessed with CKD-EPIcys (Chronic Kidney Disease Epidemiology) and CAPA (Caucasian, Asian, Pediatric, Adult) equations and the impact of the assays on GFR estimation was determined. Equation performance compared to measured GFR was evaluated. RESULTS Concordance of Roche Gen2 and Siemens was high with median difference of 0.003 ± 0.13 mg/L (limits of agreement: -0.12 to 0.12) and Passing Bablok correlation was essentially perfect. Roche Gen1 assay showed worse concordance with Siemens: median difference was 0.08 ± 0.13 mg/L (limits of agreement: -0.18 to 0.34) and correlation was inferior. Mean difference (± SD) of estimated GFRCKD-EPIcys was 0 ± 4 mL/min/1.73 m(2) for Gen2 and Siemens compared to -5 ± 8 with Gen1. Performance of GFR estimating equations was not influenced by the choice of Siemens or Gen2 assays. CONCLUSIONS Standardization of Roche Gen2 assay improved accuracy of cystatin C measurement compared to Siemens. It suggests only negligible method bias and results in equal performance of both assays when estimating GFR indicating that successful calibration has led to major progress in cystatin C analysis.

Estimating kidney function and use of oral antidiabetic drugs in elderly

The prevalence of diabetes mellitus (DM) and renal impairment rises with age making regular estimation of glomerular filtration rate (eGFR) in older diabetics necessary. This study investigated the differences among available estimating equations in assessing eGFR in older diabetics and examined the use of oral antidiabetic drugs (OADs) in relation to renal function. Patients with DM were participants of the Berlin Initiative Study (BIS), a population‐based cohort study initiated in 2009 in Berlin, Germany, to evaluate kidney function in people ≥70 years. GFR was estimated with the creatinine‐based CKD‐EPICREA (Chronic Kidney Disease Epidemiology Collaboration), the MDRD (Modification of Diet in Renal Diseases) and the BIS1 equation and was directly measured (mGFR) with iohexol clearance as a gold standard in a subgroup (n = 137). Creatinine clearance was estimated with the Cockcroft–Gault equation (CrCl). DM prevalence was 26% (539 of 2070 overall participants). The antidiabetic drugs most commonly used among OAD patients were metformin (67%), glimepiride (27%) and glibenclamide (14%). Three of ten metformin patients had a CrCl <60 mL/min. Compared to mGFR, the mean differences of filtration rates calculated by MDRD, CKD‐EPICREA and BIS1 were +8.9, +6.7 and −1.8 mL/min/1.73 m2, respectively. Summing up, many patients with a CrCl <60 mL/min received metformin, although this represents a contraindication in Germany. Glibenclamide was commonly used despite its classification as potentially inappropriate medication in older adults. Finally, BIS1 performed better in estimating GFR in older diabetics than MDRD or CKD‐EPICREA.

Predictors of the discrepancy between calendar and biological age

BACKGROUND The rate of ageing can differ considerably between individuals. This might result in major differences between calendar age (CA) and biological age (BA). AIMS To identify work- and health-related predictors of the discrepancy between CA and BA. METHODS The sample analysed in this study consisted of 371 subjects of different occupational groups (teachers, office workers, nursery school teachers and managers). BA was measured with the vitality measuring station, which recorded 45 vitality indicators of physical, mental and social functions. Work ability index, effort-reward imbalance and relaxation inability were measured to determine work- and health-related predictors. RESULTS The greatest discrepancy between CA and BA (9 years) was found for the subgroup of managers, followed by female teachers (5 years). Managers showed also the best results in work ability, the effort-reward balance and relaxation ability. By means of multiple regression analysis, particularly mental attitudes and resources towards work, occupational reward and the body fat percentage were identified as relevant predictors for the discrepancy between CA and BA. CONCLUSIONS Our study indicates that not only health- but also work-related factors are associated with vitality and BA of employees. We assume that measures focused on promoting of health (healthy diet and physical activities) and improving working conditions (e.g. job satisfaction and social support and stress prevention) may also affect the ageing process positively.

An efficient approach for glomerular filtration rate assessment in older adults.

AIMS Assessment of glomerular filtration rate (GFR) is crucial because the GFR value defines the stage of chronic kidney disease and determines the adjustment of drug dosage. The aim was to investigate a new method for the accurate determination of GFR in older adults based on the combination of an exogenous filtration marker, iohexol, and an endogenous marker, serum creatinine or cystatin C. METHODS We combined variables for the estimation of GFR with a reduced set of measurements of the marker iohexol. In a population-based sample of 570 subjects (≥70 years old) from the Berlin Initiative Study (BIS), we investigated the following: (i) the BIS1 and BIS2 equations based on age, gender and serum creatinine with or without serum cystatin C; (ii) equations based on one or two iohexol measurements; and (iii) equations based on the combination of variables from BIS1 or BIS2 with iohexol measurements. The reference standard was based on eight iohexol measurements. The cut-off value of 60 ml min(-1) (1.73 m)(-2) was chosen to assess accuracy. Equations were constructed using a learning sample (n = 285) and an independent validation sample (n = 285). RESULTS Misclassification rates were 17.2% (BIS1), 11.6% (BIS2), 14.7% [iohexol measurement at 240 min (iohexol240 )], 7.0% (iohexol240 combined with variables included in BIS1) and 6.7% (iohexol240 combined with variables included in BIS2). Misclassification rates did not decrease significantly after inclusion of two or three iohexol measurements. CONCLUSIONS Combined strategies for the determination of GFR lead to a relevant increase of diagnostic validity.

Cystatin C standardization decreases assay variation and improves assessment of GFR

Natalie Ebert1, Pierre Delanaye2, Mike Shlipak3, Olga Jakob4, Peter Martus5, Jens Gaedeke6, Mirjam Schuchardt6, Markus van der Giet6, Jan Bartel7, Etienne Cavallier8 and Elke Schaeffner9 Charite, Nephrology, Berlin, GERMANY, University Sart-Tilman, Nephrology, Liege, BELGIUM, UCSF, Gen Int Med, San Francisco, CA, Charite, Biostat, Berlin, GERMANY, EKUniv, Biostat, Tubingen, GERMANY, Charite, Nephrol, Berlin, GERMANY, Labor Limbach, Clin Chem, Heidelberg, GERMANY, Univ Sart-Tilman, Clin Chem, Liege, BELGIUM, Charite, Pub Health, Berlin, GERMANY