Glomerular Filtration Rate in Healthy Living Potential Kidney Donors: A Meta-Analysis Supporting the Construction of the Full Age Spectrum Equation.

BACKGROUND: Normal kidney function or, more specifically, normal glomerular filtration rate (GFR) in men and women and its decline with age is still much debated today. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has gender (and race) multiplication factors, accounts for a decline that starts at very young age and assumes that the mean GFR is as high as 120-130 ml/min/1.73 m2 from a young age. The full age spectrum (FAS) estimated mean GFR is about 107 ml/min/1.73 m2 at a young age and remains constant until the age of 40 years and then starts to decline both in men and women. The aim of this research study was to give more insight into 'normal' GFR levels and the physiological decrease of kidney function with age and to use a meta-analysis to evaluate the mathematical construction of the FAS and the CKD-EPI equation. METHODS: We conducted a meta-analysis of published GFR measurements in healthy Caucasian living potential kidney donors (n = 5,482, 46.8% men). Only publications dating from 2000 were selected to avoid the possible influence of body surface area changes in the last decades on the indexed GFR, expressed in ml/min/1.73 m2. RESULTS: We found that the mean GFR ≈ 107 ml/min/1.73 m2 up to the age of 40 years, but renal decline begins beyond 40 years. No evidence could be found for any difference between men and women in the separate age groups. CONCLUSIONS: The current meta-analysis supports the mathematical form of the FAS equation, which matches the age/sex dependency of measured GFR for healthy potential living kidney donors.

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.

Can the height-independent Pottel eGFR equation be used as a screening tool for chronic kidney disease in children?

Determination of plasma creatinine (Pcr) should be associated to an estimation of glomerular filtration rate (eGFR). Pottel et al. established a height-independent equation, eGFR = 107.3/(Pcr/Q) where Q is the median of Pcr (Pottel-Belgium). The aims were to 1) determine a local height-independent equation (Pottel-Lyon), 2) evaluate the performance of these equations compared to the Schwartz 2009 and Schwartz-Lyon equations, and 3) evaluate the height-independent equations in laboratory routine. Therefore, 1) all first pediatric Pcr determination (December 2009-June 2011) were collected, and median of Pcr was determined for each 1-year age interval (Q-Lyon), 2) GFR was measured (mGFR) in 359 children (438 measures) and compared to eGFR, and 3) all first Pcr determination (January 2012-June 2013) were used to calculate eGFR with the Pottel-Lyon and the Pottel-Belgium equations. Pcr was determined by an IDMS-standardized enzymatic assay. In the population with a mGFR, the Pottel-Lyon and the Schwartz-Lyon showed the best performance (bias, P10 and P30). However, the performance in identifying patients with a mGFR < 75 mL/min/1.73 m(2) was similar for all the studied equations. CONCLUSION: The performance of the height-independent and dependent equations to identify mild renal dysfunction is similar. The height-independent Pottel equation could be proposed as an excellent screening tool for kidney disease when height information is not available. " WHAT IS KNOWN: " • Determination of plasma creatinine in children is rarely associated to an estimation of glomerular filtration rate due to the lack of height information. • Pottel et al. developed a height-independent equation (eGFR = 107.3/(Pcr/Q) where Q is the median of Pcr for each age class. " WHAT IS NEW: " • The performance of the height-independent (Pottel) or height-dependent (Schwartz) equations is similar to identify renal dysfunction (GFR < 75 mL/min/1.73 m (2) ) in children. • The height-independent Pottel equation could be an excellent screening tool for kidney disease in a general pediatric laboratory when height information is not available.

Routine serum creatinine measurements: how well do we perform?

BACKGROUND: The first aim of the study was to investigate the accuracy and intra-laboratory variation of serum creatinine measurements in clinical laboratories in Flanders. The second purpose was to check the effect of this variation in serum creatinine concentration results on the calculated estimated glomerular filtration rate (eGFR) and the impact on classification of patients into a chronic kidney disease (CKD) stage. METHODS: 26 routine instruments were included, representing 13 different types of analyzers from 6 manufacturers and covering all current methodologies (Jaffe, compensated Jaffe, enzymatic liquid and dry chemistry methods). Target values of five serum pools (creatinine concentrations ranging from 35 to 934 µmol/L) were assigned by the gold standard method (ID-GC/MS). RESULTS: Intra-run CV (%) (n = 5) and bias (%) from the target values were higher for low creatinine concentrations. Especially Jaffe and enzymatic dry chemistry methods showed a higher error. The calculated eGFR values corresponding with the reported creatinine concentration ranges resulted in a different CKD classification in 47% of cases. CONCLUSIONS: Although most creatinine assays claim to be traceable to the gold standard (ID-GC/MS), large inter-assay differences still exist. The inaccuracy in the lower concentration range is of particular concern and may lead to clinical misinterpretation when the creatinine-based eGFR of the patient is used for CKD staging. Further research to improve harmonization between methods is required.

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.

Abnormal glomerular filtration rate in children, adolescents and young adults starts below 75 mL/min/1.73 m(2).

BACKGROUND: The 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 m(2), a value that is also applied for children older than 2 years of age, adolescents and young adults. METHODS: Based 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. RESULTS: Based 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 m(2). 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 m(2). CONCLUSIONS: Abnormal GFR in children, adolescents and young adults starts below 75 mL/min/1.73 m(2), 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 m(2) for further clinical assessment.

Measuring glomerular filtration rate using 51Cr-EDTA: body surface area normalization before or after Bröchner-Mortensen correction?

BACKGROUND: Guidelines for measuring glomerular filtration rate (GFR) using Cr-EDTA require normalizing of GFR for body surface area (BSA) before applying the Bröchner-Mortensen (BM) correction. The guideline explicitly mentions the importance of performing BSA normalization before BM correction and that this is particularly important in children in whom the effects of BSA normalization are largest. MATERIALS AND METHODS: We theoretically showed that the order of applying BM correction and BSA indexing is indeed important for patient populations having a low BSA and a high slow GFR. We then compared the exact GFR, obtained from the double-exponential concentration-time curve in Duchenne muscular dystrophy (DMD) patients, with the GFR obtained from the slow compartment method using the BM correction. RESULTS: The median GFR for the 20 DMD patients obtained from the BSA-BM order deviates 5.40% from the exact GFR (P=0.0006), whereas the median GFR obtained from the BM-BSA order deviates only -0.05% (P>0.05) from the exact GFR, resulting in a median of differences of 5.50% between the two methods (P<0.0001). CONCLUSION: The correct order of application in this DMD population should be BM correction first, followed by BSA indexing, and not vice versa. In general, the order of applying the BM correction and BSA normalization becomes more important with increasing slow GFR and extreme low BSA. The order of application is of less importance for people with normal BSA and/or normal GFR.

Does the type of creatinine assay affect creatinine clearance determination?

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 Roche's 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 R(2) 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.

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.

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.

A simple height-independent equation for estimating glomerular filtration rate in children.

BACKGROUND: The chronic kidney disease (CKD) classification system for children is similar to the CKD classification system for adults, using estimated glomerular filtration rate (eGFR) combined with fixed cut-off values of 60, 30, and 15 ml/min/1.73 m(2) for CKD stages III, IV, and V, respectively. To estimate GFR in children, eGFR-equations are used that require serum creatinine (Scr), but also height information, which is normally not available in clinical laboratory databases. METHODS: This retrospective study is based on data from two different databases, one that has previously been used to develop the Flanders Metadata equation for children and one database including 353 children who underwent (51)Cr-EDTA GFR, serum creatinine, height, and weight measurements. RESULTS: A height-independent eGFR equation based on the concept of a population-normalized Scr, presented before for adults, is extended to children: eGFR = 107.3/(Scr/Q), with Q the median Scr for healthy children of a particular age. This equation is validated against direct measurements of GFR, and against the updated Schwartz and Flanders Metadata equation. CONCLUSIONS: The new simple height-independent equation performs very well and should make (mass) screening of kidney function in children easier.

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.