Liesbeth Hoste

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.

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.

Abnormal glomerular filtration rate in children, adolescents and young adults starts below 75 mL/min/1.73 m2

BackgroundThe chronic kidney disease (CKD) classification system for children is similar to that for adults, with both mainly based on estimated glomerular filtration rate (eGFR) combined with fixed cut-off values. The main cut-off eGFR value used to define CKD is 60 mL/min/1.73 m2, a value that is also applied for children older than 2 years of age, adolescents and young adults.MethodsBased on a literature search, we evaluated inclusion criteria for eGFR in clinical trials or research studies on CKD for children. We also collected information on direct measurements of GFR (mGFR) in children and adolescents, with the aim to estimate the normal reference range for GFR. Using serum creatinine (Scr) normal reference values and Scr-based eGFR-equations, we also evaluated the correspondence between Scr normal reference values and (e)GFR normal reference values.ResultsBased on our literature search, the inclusion of children in published CKD studies has been based on cut-off values for eGFR of >60 mL/min/1.73 m2. The lower reference limits for mGFR far exceed this adult threshold. Using eGFR values calculated using Scr-based formulas, we found that abnormal Scr levels in children already correspond to eGFR values that are below a cut-off of 75 mL/min/1.73 m2.ConclusionsAbnormal GFR in children, adolescents and young adults starts below 75 mL/min/1.73 m2, and as abnormality is a sign of disease, we recommend referring children, adolescents and young adults with an (e)GFR of <75 mL/min/1.73 m2 for further clinical assessment.

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.

Renal function in children and adolescents with Duchenne muscular dystrophy

Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in Duchenne muscular dystrophy (DMD) patients. We aimed to establish a methodology to accurately assess their renal function. Twenty DMD patients (5-22 years) were included in this prospective study. After obtaining medical history, all patients underwent a clinical examination, 24-hour ambulatory blood pressure monitoring, ultrasound of the kidneys, direct GFR measurement ((51)Cr-EDTA, mGFR), complete blood and urine analysis. Seventeen of 20 patients were treated with corticosteroids and 5/20 with angiotensin converting enzyme inhibitor (lisinopril). No patient suffered from urinary tract infections or other renal diseases. Hypertension (systolic or diastolic blood pressure >P95) was found in 9/20 patients (8/9 patients were on steroid treatment) and a non-dipping blood pressure profile in 13/20 subjects (10/13 patients were on steroid treatment). Urinary protein to creatinine ratio was elevated in 17/18 patients, whereas 24-hour urine protein excretion was normal in all subjects. Median interquartile range (IQR) mGFR was 130.4 (29.1) mL/min/1.73 m(2). Hyperfiltration (mGFR >150 mL/min/1.73 m(2)) was found in 5/20 patients. Inverse correlation between mGFR and age was observed (R(2) = 0.45, p = 0.001). Serum creatinine based estimated GFR (eGFR) equations overestimated mGFR up to 300%. eGFR based on cystatin C Filler equation was closest to the mGFR (median eGFR (IQR) of 129.5 (39.7) mL/min/1.73 m(2)). Our study demonstrates a high prevalence of hyperfiltration and hypertension in children and adolescents with DMD. Because the majority of hypertensive patients were under corticosteroid treatment, the iatrogenic cause of hypertension cannot be excluded. Serum or urine creatinine measurements are of no value to evaluate renal function in DMD patients due to the reduced skeletal muscle mass.

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.

Measuring the glomerular filtration rate in different age groups using iohexol, the protocol from the Belgian iohexol study

OBJECTIVES Measuring the exact glomerular filtration rate (GFR) is difficult. Iohexol can be used instead of inulin or labeled EDTA or DTPA. In recent years, different studies have validated GFR-estimating equations in adults. Validation of these estimations in adolescents and elderly is lacking. With this study, we aim to develop a simplified (only 1-3 blood collections) iohexol protocol to measure the true GFR for patients of all ages and try to develop GFR-estimating equations for adolescents and the elderly. DESIGN AND SETTING Participants of different ages will be recruited: 50 adolescent (14-18 years) and 30 adults (20-65 years), 60 elderly (65-80 years) and 60 very elderly (80+ years old) stratified based on their GFR. Biometric data, serum creatinine and cystatin C will be measured. After injecting 5 mL iohexol, 9 blood samples will be taken between 20 and 360 min. First, the GFR will be calculated by using the double exponential decay method and different GFRs based on 1-3 blood samples, which will be compared with the GFR of the abovementioned 9 samples. Second, the GFR will be calculated by using new and existing equations and compared to the true GFR. DISCUSSION The availability of a reliable GFR measurement is important in situations such as screening patients for kidney donation or when taking potentially nephrotoxic treatments. This study will allow us to develop a simplified protocol for measuring the true GFR in all ages and will allow us to validate existing equations and develop new eGFR equations for adolescents and the elderly.

Is Body Surface Area the Appropriate Index for Glomerular Filtration Rate

Indexing glomerular filtration rate (GFR) for body surface area (BSA) is routine practice, but criticism has been raised on indexing GFR for BSA in children, obese and anorectic patients. Over the years other ways of indexing GFR have been proposed, including height, lean body mass, body weight, ideal weight, plasma volume, total body water and especially extracellular volume (ECV). Based on a literature review and on statistical analyses of GFR data of children, we consider the following main questions: Why do we normalize GFR for BSA? Is it really necessary to index GFR? And if so, are there other or better ways to normalize GFR?

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.

Response to the letter from Kallner: Comments on 'Does the type of creatinine assay affect creatinine clearance determination?'.

Dr Kallner states that enzymatic and kinetic Jaffe type assays measure different quantities and consequently it seems acceptable that the results are different. We want to emphasize that all assays measure creatinine and therefore we believe it should be the goal of these assays to come to the same results. We used Deming regression to estimate the constant and proportional deviation between assays. Deming regression accounts for errors in both assays and so there is no independent variable. The variance ratio of the errors in the X/Y variable is assumed to be constant across the measuring interval. However, this is a theoretical requirement that is never fulfi lled in practice. It is unclear how much the variance ratio may vary across the range of interest before the Deming regression results should be considered invalid. Moreover, the variance ratios of 2.4 and 3.2 are obtained from %CVs reported by the External Quality Evaluation of the Scientifi c Institute of Public Health in Brussels and not from our data. The impact of variance ratio differences in our data on the regression functions is limited. Therefore, the regression lines we presented are reliable and both slope and intercept can be used (within the margin of error) for estimating the effect of the differences between assays on creatinine clearance (CrCl) results. To present the results we followed the methodology of Bland and Altman [1]. Both the editors and reviewers of our article did not object to our way of presenting the data. Our plots clearly show constant and proportional bias. The limits of agreement could have been calculated taking into account the presence of both forms of bias. We agree that the analysis of the data could have been done in a more appropriate (and more complex) way, but this does not change the overall conclusion that Jaffe assay results differ from enzymatic assay results. This clear difference has an important impact on CrCl results. The CrCl presented in the fi gures were calculated using the measured serum and urine creatinine values of the patients in our study. We also presented a theoretical calculation of CrCl using the enzymatic method as the reference, and making use of the slopes and intercepts of the Deming regressions mentioned above. Our intention was to illustrate that the intercept in the Jaffe versus enzymatic serum creatinine regression, which cannot be ignored, is responsible for the difference in CrCl when obtained from Jaffe results. A weakness of our study is that we had no direct GFR measurements of our patient population available and therefore we used the CKD-EPI eGFR as the reference method [2]. We corrected creatinine clearances for BSA to express them in the same units (mL/min/1.73m 2 ) as the CKD-EPI eGFR results. We agree that the CKD-EPI estimation is imprecise as well, but it is considered to be the most unbiased eGFR equation and was therefore useful to make general conclusions [3]. Random error was equivalent for all CrCl results, whether they were obtained from enzymatic, compensated Jaffe or Jaffe type assays, but bias was the smallest in case of the Jaffe type assay. Finally, we could also have used Deming regression instead of ordinary least squares regression to compare CrCl with CKD-EPI eGFR, but we can assure you that the slope and intercept are not really different and thus, the fi nal conclusion does not change at all. We also agree that there is absolutely no better way to determine the kidney function of an individual patient than by performing a direct GFR measurement.