Frank Martens

An estimated glomerular filtration rate equation for the full age spectrum

BACKGROUND Glomerular filtration rate (GFR) is accepted as the best indicator of kidney function and is commonly estimated from serum creatinine (SCr)-based equations. Separate equations have been developed for children (Schwartz equation), younger and middle-age adults [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation] and older adults [Berlin Initiative Study 1 (BIS1) equation], and these equations lack continuity with ageing. We developed and validated an equation for estimating the glomerular filtration rate that can be used across the full age spectrum (FAS). METHODS The new FAS equation is based on normalized serum creatinine (SCr/Q), where Q is the median SCr from healthy populations to account for age and sex. Coefficients for the equation are mathematically obtained by requiring continuity during the paediatric-adult and adult-elderly transition. Research studies containing a total of 6870 healthy and kidney-diseased white individuals, including 735 children, <18 years of age, 4371 adults, between 18 and 70 years of age, and 1764 older adults, ≥70 years of age with measured GFR (inulin, iohexol and iothalamate clearance) and isotope dilution mass spectrometry-equivalent SCr, were used for the validation. Bias, precision and accuracy (P30) were evaluated. RESULTS The FAS equation was less biased [-1.7 (95% CI -3.4, -0.2) versus 6.0 (4.5, 7.5)] and more accurate [87.5% (85.1, 89.9) versus 83.8% (81.1, 86.5)] than the Schwartz equation for children and adolescents; less biased [5.0 (4.5, 5.5) versus 6.3 (5.9, 6.8)] and as accurate [81.6% (80.4, 82.7) versus 81.9% (80.7, 83.0)] as the CKD-EPI equation for young and middle-age adults; and less biased [-1.1 (-1.6, -0.6) versus 5.6 (5.1, 6.2)] and more accurate [86.1% (84.4, 87.7) versus 81.8% (79.7, 84.0)] than CKD-EPI for older adults. CONCLUSIONS The FAS equation has improved validity and continuity across the full age-spectrum and overcomes the problem of implausible eGFR changes in patients which would otherwise occur when switching between more age-specific equations.

Establishing age/sex related serum creatinine reference intervals from hospital laboratory data based on different statistical methods.

BACKGROUND This is a retrospective study on a large hospital database to establish age- and sex-related mean values and reference ranges for serum creatinine (Scr), obtained with an IDMS-traceable, enzymatic method, in a Caucasian population. METHODS The database was filtered for unique entries to reduce the presence of correlated and pathological data. Three different statistical methods, a non-parametric method, the Bhattacharya procedure and a non-linear fit of the cumulative Gaussian distribution were used to estimate the serum creatinine-age dependency for men and women, from birth till 100 years of age. RESULTS Scr increases with age, equal for boys and girls, up to 14 years and with a much steeper slope for boys than for girls between 14 and 20 years. We show that the Scr-age pattern is constant between 20 and 70 years with a mean of 0.90 mg/dL [0.63-1.16 mg/dL] for men and 0.70 mg/dL [0.48-0.93 mg/dL] for women. Above 70, Scr starts to slowly increase again. CONCLUSIONS Indirect methods confirm the available reference intervals from healthy-volunteer studies and add information on age-periods not covered by these studies. As such, indirect methods can be used complementary to healthy-volunteer studies.

A new equation to estimate the glomerular filtration rate in children, adolescents and young adults

BACKGROUND A new estimated glomerular filtration rate (eGFR) equation, designed for isotope dilution mass spectrometry-standardized serum creatinine (Scr), is presented for use in children, adolescent boys and girls and young adults. METHODS The new equation, eGFR = 107.3/(Scr/Q), is based on the concept of normalized Scr: Q is the normalization value and is considered as the Scr concentration for the average healthy child, adolescent or young adult of a specific height (L) and is modeled as a height-dependent polynomial of the fourth degree. RESULTS The well-known Schwartz equation [eGFR = kL/Scr, k = 0.413 (Schwartz) or k = 0.373 (Schwartz-Lyon)] for children between 1 and 14 years can be seen as a special case of the new equation for which the Q-polynomial is simplified to a linear equation: Q = 0.0035 × L (cm). The new eGFR equation has been validated in a data set of n = 750 children, adolescents and young adults aged 10-25, against the true GFR (inulin method), and outperforms the selected (but most used) creatinine-based eGFR equations for children, mainly in the healthy GFR region. CONCLUSIONS The new Q(height)-eGFR equation serves as an excellent screening tool for kidney disease in 1-25-year-old children, adolescents and young adults.

A comprehensive LC‐MS‐based quantitative analysis of fentanyl‐like drugs in plasma and urine

Fentanyl, norfentanyl, alfentanil, sufentanil, remifentanil and 3-methylfentanyl are potent, short-acting, synthetic narcotic analgesics that are not revealed in standard opiate immunoassays. In this article, a fully validated analytical method for the determination of these fentanyl-type compounds in plasma and urine is presented, consisting of a liquid-liquid extraction followed by a LC-MS/MS analysis using electrospray ionisation in the positive ionisation mode. Fentanyl-d(5) and norfentanyl-d(5) were used as internal standards. The lower LOQ in plasma and urine was 0.1 ng/mL for fentanyl, norfentanyl, alfentanil, remifentanil and 3-methylfentanyl, and 0.2 ng/mL for sufentanil. The method proved linear over a concentration range of 0.2-50 ng/mL for sufentanil and 0.1-50 ng/mL for all other analytes, with correlation coefficients of 0.998 or better. The analytical procedure showed excellent selectivity and precision (all CVs below 15%) for all analytes. Accuracy was good, except for sufentanil, where deviations of more than 15% from nominal concentrations were observed. No matrix effects were observed, and stability of stock and internal standard solutions was within acceptability limits.

Demystifying ethnic/sex differences in kidney function: is the difference in (estimating) glomerular filtration rate or in serum creatinine concentration?

BACKGROUND The recent evaluation of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating the glomerular filtration rate (GFR) in multiple ethnicities has raised the question on how well this equation performs for African-American and Asian subjects. There is no doubt that serum creatinine (Scr) concentration differs between ethnicities and sexes. We show that creatinine-based equations for white populations may be inaccurate for estimating GFR in other ethnic/gender groups, especially in populations from Asia. METHODS This study presents a mathematical analysis of the CKD-EPI-equation complemented with a literature review of median and reference values for IDMS-standardized Scr-concentrations for multiple ethnicities. RESULTS The study shows that at equal eGFR-CKD-EPI-values, the ratio of Scr between females and males equals 0.79 and between other ethnicities/sexes and white males is constant too. From this information, it is possible to calculate mean Scr-values that correspond very well with literature values directly obtained from Scr-distributions in healthy white males and females and in black males, but the discrepancy is larger for other populations. CONCLUSIONS Our results confirm the criticism that has been raised for using the CKD-EPI-equation for these ethnicities. An alternative eGFR-model is proposed based on a population-normalized Scr that needs further validation.

Are eGFR equations better than IDMS-traceable serum creatinine in classifying chronic kidney disease?

Abstract Objective: In 2002, a uniform definition of chronic kidney disease (CKD) became widely accepted. The level of glomerular filtration rate (GFR) is the pivot for staging the disease. Because GFR is not readily measured in routine clinical practice, statistical models such as the Modification of Diet in Renal Disease (MDRD) equation have been proposed for estimating GFR. The MDRD equation is gaining worldwide acceptance in assisting the diagnosis and staging of CKD. Material and methods: We use theoretical and experimental considerations based on serum creatinine (Scr) measurements obtained with an enzymatic IDMS-traceable assay and compare CKD classifications based on Scr alone with classifications based on the eGFR-MDRD and eGFR-Mayo Clinic equations. Results: Based on recently published reference intervals for enzymatically determined Scr, we show that eGFR-MDRD<60 mL/min/1.73m2 corresponds extremely well with Scr>upper reference limit. The different CKD stages III, IV and V can be redefined using Scr alone, resulting in 97.5% agreement. Conclusion: We show that neither the MDRD study equation nor the Mayo Clinic equation add extra value to the information already contained in Scr itself. Because of the limited applicability of the eGFR equations, Scr has even more potential to assist in the diagnosis and classification of CKD than eGFR-MDRD.

New insights in glomerular filtration rate formulas and chronic kidney disease classification.

BACKGROUND The MDRD Study equation is the most popular equation for estimating the glomerular filtration rate (eGFR) from serum creatinine (Scr), age, sex and race. Many articles deal with ethnic factors, correcting the MDRD Study equation for different populations, with more or less success. The new CKD-EPI equation introduced the concept of a population-normalized Scr in the eGFR equation for white men (Scr/0.90) and white women (Scr/0.70). METHODS We introduce alternative mathematical forms for the MDRD Study equation and the CKD-EPI equation, using the concept of a population-normalized Scr, resulting in a more general and mathematically less complicated form for the eGFR equation. RESULTS We show that the normalization constant corresponds to the mean Scr-value for the specific healthy population. We compared the established equations with the new alternative forms, and show that the differences are minimal. The sex/race dependency is completely comprehended in the normalization constant, making the alternative eGFR equations independent of sex and race. CONCLUSION The age-dependency of eGFR remains and consequently age-dependent cutoff values for the classification of Chronic Kidney Disease (CKD) look more appropriate, contrary to the current classification rules. The population-normalized Scr which is independent of age, sex and race may serve as an alternative for the classification of CKD.

Application of the Characteristic Function to Evaluate and Compare Analytical Variability in an External Quality Assessment Scheme for Serum Ethanol

BACKGROUND As a cornerstone of quality management in the laboratory, External Quality Assessment (EQA) schemes are used to assess laboratory and analytical method performance. The characteristic function is used to describe the relation between the target concentration and the EQA standard deviation, which is an essential part of the evaluation process. The characteristic function is also used to compare the variability of different analytical methods. METHODS We fitted the characteristic function to data from the Belgian External Quality Assessment program for serum ethanol. Data included results from headspace gas chromatography and the enzymatic methods of Abbott, Roche, Siemens, and Ortho-Clinical Diagnostics. We estimated the characteristic function with weighted nonlinear regression. By introducing dummy variables, we rewrote the original formula of the characteristic function to assess statistical inference for comparing the variability of the different analytical methods. RESULTS The characteristic function fitted the data precisely. Comparison between methods showed that there was little difference between the estimated variability for low concentrations, and that the increase in SD with increasing target concentration was slower for Abbott and Roche than for the other methods. CONCLUSIONS The characteristic function can successfully be introduced in clinical schemes, although its applicability to fit the data should always be assessed. Because of its easy parameterization, it can be used to assess differences in performance between analytical methods and to assess laboratory performance. The characteristic function also offers an alternative framework for coefficients of variation to describe variability of analytical methods.

Does the type of creatinine assay affect creatinine clearance determination

Abstract Background. A creatinine clearance (CrCl) is still often requested to estimate the glomerular filtration rate (GFR) in clinical practice. However, the diversity of serum and urine creatinine (Scr, Ucr) assays leads to different CrCl-results which are here compared with each other and with the CKD-EPI eGFR-formula. Methods. We collected information on urine volume, Ucr and Scr using Roches enzymatic (E), compensated Jaffe (CJ) and Jaffe (J) assay for 589 patients. To allow comparison with the CKD-EPI prediction results, CrCl was normalized for body surface area. Results. Differences between CrCl-E and CrCl-CJ are rather small as opposed to the large differences with CrCl-J. However, two compensating errors in the CrCl-J calculation result in a closer agreement with CKD-EPI eGFR, than between CrCl-CJ or CrCl-E and CKD-EPI eGFR. The explained variance R2 in all three cases is smaller than 0.66, demonstrating the very large scatter of the data around the regression line. Conclusions. CrCl determination is very assay-dependent. Although many clinical labs have switched to ID-GC/MS-standardized assays (E and CJ) for the determination of Scr and Ucr to improve analytical accuracy, the increased deviation of the normalized CrCl from the CKD-EPI prediction illustrates that the use of CrCl remains questionable for clinical practice. When a CrCl is requested, we would even recommend clinical labs who work with compensated Jaffe assays not to compensate the Scr-J value.

Assay-dependence of creatinine clearance and comparison with CKD-EPI estimated glomerular filtration rate formula

The first harmonization step on cystatin C, with the aim to introduce the first ERM-DA471/IFCC cystatin C calibrator and one worldwide company-independent EGFR equation