Estimation of the glomerular filtration rate in children and young adults by means of the CKD-EPI equation with age-adjusted creatinine values
Authors: Jonas Björk, Ulf Nyman, Anders Larsson, Pierre Delanaye, Hans Pottel
Journal: Kidney International (2020)

The CKD-EPI creatinine-based estimation equation for glomerular filtration rate (GFR) cannot be used in children, overestimates GFR in young adults, and its combination with the KDIGO recommended pediatric CKiD (Schwartz bedside) equation causes implausible increases in estimated GFR when switching from pediatric to adult care. By establishing sex-specific creatinine growth curves for children and young adults, creatinine levels of children and young adults below age 40 years were adjusted with 40 as assigned age and applied in the CKD-EPI equation. Validation was performed in 4005 children (2–17 years) and 3309 young adults (18–39 years) using metrics based on bias, precision, and accuracy including percentage of estimates within 30% (P30) of measured GFR (mGFR). Comparisons were made with the CKiD and Schwartz-Lyon equations in children. CKD-EPI with age-adjusted creatinine instead of actual age and creatinine led to extensive improvements in bias, precision, and accuracy at all ages, in both sexes and at all levels of mGFR. At mGFR below and above 75 mL/min/1.73m2, the P30 increased from 12% to 75% and 33% to 88% in children, respectively, and from 56% to 73% and 83% to 92% in young adults, respectively. In children adjusted CKD-EPI was more accurate than CKiD, especially above mGFR 75 mL/min/1.73m2 (P30 88% vs. 82%), while Schwartz-Lyon was more accurate than adjusted CKD-EPI at mGFR below 75 mL/min/1.73m2 (P30 81% vs. 75%). Thus, the proposed strategy based on age-adjusted creatinine in children and young adults makes the CKD-EPI equation applicable across the full spectrum of age and kidney function. The CKD-EPI creatinine-based estimation equation for glomerular filtration rate (GFR) cannot be used in children, overestimates GFR in young adults, and its combination with the KDIGO recommended pediatric CKiD (Schwartz bedside) equation causes implausible increases in estimated GFR when switching from pediatric to adult care. By establishing sex-specific creatinine growth curves for children and young adults, creatinine levels of children and young adults below age 40 years were adjusted with 40 as assigned age and applied in the CKD-EPI equation. Validation was performed in 4005 children (2–17 years) and 3309 young adults (18–39 years) using metrics based on bias, precision, and accuracy including percentage of estimates within 30% (P30) of measured GFR (mGFR). Comparisons were made with the CKiD and Schwartz-Lyon equations in children. CKD-EPI with age-adjusted creatinine instead of actual age and creatinine led to extensive improvements in bias, precision, and accuracy at all ages, in both sexes and at all levels of mGFR. At mGFR below and above 75 mL/min/1.73m2, the P30 increased from 12% to 75% and 33% to 88% in children, respectively, and from 56% to 73% and 83% to 92% in young adults, respectively. In children adjusted CKD-EPI was more accurate than CKiD, especially above mGFR 75 mL/min/1.73m2 (P30 88% vs. 82%), while Schwartz-Lyon was more accurate than adjusted CKD-EPI at mGFR below 75 mL/min/1.73m2 (P30 81% vs. 75%). Thus, the proposed strategy based on age-adjusted creatinine in children and young adults makes the CKD-EPI equation applicable across the full spectrum of age and kidney function. The Kidney Disease: Improving Global Outcomes guideline1Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1298) Google Scholar recommends the creatinine based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation2Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (13710) Google Scholar and the Chronic Kidney Disease in Children Study (CKiD, "Schwartz bedside") equation3Schwartz G.J. Munoz A. Schneider M.F. et al.New equations to estimate GFR in children with CKD.J Am Soc Nephrol. 2009; 20: 629-637Crossref PubMed Scopus (2110) Google Scholar for estimation of glomerular filtration rate (eGFR) in adults and children, respectively. Their use in clinical practice is now widespread but they have some drawbacks. Flawed increases in renal function have been observed when switching from the height-dependent CKiD in pediatric care to the age-dependent CKD-EPI in adults.4Pottel H. Björk J. Bökenkamp A. et al.Estimating glomerular filtration rate at the transition from pediatric to adult care.Kidney Int. 2019; 95: 1234-1243Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Lack of height data in connection with creatinine analyses precludes automatic laboratory reporting of eGFR based on CKiD. In addition, the use of CKD-EPI is questionable in young adults owing to poor accuracy.5Nyman U. Grubb A. Larsson A. et al.The revised Lund-Malmö GFR estimating equation outperforms MDRD and CKD-EPI across GFR, age and BMI intervals in a large Swedish population.Clin Chem Lab Med. 2014; 52: 815-824Crossref PubMed Scopus (97) Google Scholar, 6Selistre L. de Souza V. Cochat P. et al.GFR estimation in adolescents and young adults.J Am Soc Nephrol. 2012; 23: 989-996Crossref PubMed Scopus (64) Google Scholar, 7Selistre L. Rabilloud M. Cochat P. et al.Comparison of the Schwartz and CKD-EPI equations for estimating glomerular filtration rate in children, adolescents, and adults: a retrospective cross-sectional study.PLoS Med. 2016; 13e1001979Crossref PubMed Scopus (36) Google Scholar, 8Björk J. Nyman U. Courbebaisse M. et al.Prospects for improved GFR estimation based on creatinine—results from a transnational multicentre study.Clin Kidney J. 2020; 13: 674-683Crossref PubMed Google Scholar Thus, there is a need for further development in the area of GFR estimation to extend the applicability of existing equations across the entire lifespan. We recently demonstrated how creatinine growth curves can be used to recalculate (adjust) childhood levels of serum creatinine to corresponding adult levels.9Björk J. Nyman U. Delanaye P. et al.A novel method for creatinine adjustment makes the revised Lund-Malmö GFR equation applicable in children.Scand J Clin Lab Invest. 2020; 80: 456-463Crossref PubMed Scopus (10) Google Scholar One advantage with this method is that it can be used with any preexisting adult equation to extend its applicability to children. We noted remarkable improvements in bias and accuracy of the Lund-Malmö Revised (LMR) equation when applying the equation on age-adjusted creatinine concentrations in children with CKD.9Björk J. Nyman U. Delanaye P. et al.A novel method for creatinine adjustment makes the revised Lund-Malmö GFR equation applicable in children.Scand J Clin Lab Invest. 2020; 80: 456-463Crossref PubMed Scopus (10) Google Scholar Using the same approach, the aim of the present study was to investigate if age-adjustment of serum creatinine concentrations can make the CKD-EPI equation applicable in children (2–17 years) and increase accuracy in young adults (18–39 years). The adjustment of creatinine values in children and young adults to age 40 years are illustrated in Figure 1 and explained in detail in Methods. The age-adjusted creatinine values were used in the original CKD-EPI2Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (13710) Google Scholar equation for GFR estimation in children (2–17 years) and young adults (18–39 years) with 40 years as assigned age in the equation (hence denoted CKD-EPI40). Basic characteristics of the included patients in the validation cohort are presented in Table 1 and the measurement procedures in Supplementary Table S1. Validation results stratified by age and measured GFR (mGFR) (<75 and ≥75 ml/min per 1.73 m2) are presented in Table 2 and by a more detailed mGFR stratification in Supplementary Tables S2 and S3. Extensive improvements in bias, and precision and accuracy were observed for CKD-EPI40 in both children and young adults at all mGFR levels. For example, the proportions of estimation errors not exceeding 30% of mGFR (P30) increased from 12% to 75% in children and from 56% to 73% in young adults at mGFR <75 ml/min per 1.73 m2. Corresponding figures at mGFR ≥75 ml/min per 1.73 m2 were increases from 33% to 88% in children and from 83% to 92% in young adults. The pediatric CKiD equation exhibited overestimations and was less accurate than CKD-EPI40 in children: 2.8 percentage points (pp) (95% confidence interval [CI] −0.2 to 5.8 pp) and 5.4 pp (95% CI 3.8 to 7.0 pp) lower P30 at mGFR <75 and ≥75 ml/min per 1.73 m2, respectively. However, Schwartz-Lyon was the most accurate equation at mGFR <75 ml/min per 1.73 m2 in children with 9.0 pp (95% CI 6.9 to 11.2 pp) and 6.2 pp (95% CI 3.7 to 8.7 pp) higher P30 accuracies than CKiD and CKD-EPI40, respectively. Schwartz-Lyon had a P30 accuracy (87%) similar to CKD-EPI40 in children with mGFR ≥75 ml/min per 1.73 m2 but was 4.6 pp (95% CI 3.5 to 5.8 pp) higher than CKiD.Table 1Patient characteristicsChildren (2–17 yr; n = 4005)Young adults (18–39 yr; n = 3309)Characteristic<75 ml/min per 1.73 m2 (n = 932)≥75 ml/min per 1.73 m2 (n = 3073)<75 ml/min per 1.73 m2 (n = 918)≥75 ml/min per 1.73 m2 (n = 2391)Female385 (41)1309 (43)400 (44)1156 (48)Age, yr12.8 (2.9–17.7)12.0 (2.5–17.8)23 (18–39)24 (18–39)Weight, kg41 (13–80)40 (13–84)63 (39–105)5 (42–105)Height, cm149 (89–181)1.48 (90–184)168 (147–188)170 (150–189)Body surface area, m21.31 (0.54–1.96)1.29 (0.56–2.03)1.72 (1.30–2.22)1.76 (1.37–2.26)Body mass index, kg/m218 (13–30)18 (14–29)22 (16–35)22 (16–34)Plasma/serum creatinine, μmol/L83 (37–275)48 (20–91)116 (61–339)69 (42–107)Adjusted plasma/serum creatinine to age 40, μmol/L120 (67–429)74 (38–121)122 (65–351)74 (44–113)Measured GFR, ml/min per 1.73 m258 (17–74)104 (77–172)55 (17–73)103 (77–143)Measured GFR, ml/min per 1.73 m2 <3095 (10)107 (12) 30–44134 (14)187 (20) 45–59264 (28)265 (29) 60–74439 (47)359 (39) 75–89679 (22)541 (23) 90–1191606 (52)1447 (61) ≥120788 (26)403 (17)GFR, glomerular filtration rate.Values are presented as n (%) or median (2.5th to 97.5th percentiles). Open table in a new tab Table 2Bias, precision, and accuracy of GFR estimating equations in children aged 2.0 to 17 years and adults aged 18 to 39 years stratified for mGFR <75 and ≥75 ml/min per 1.73 m2EquationBiasPrecisionAbsolute % errorP10, %P30, %Children, 2.0 to 17 yearsmGFR <75 ml/min per 1.73 m2 (n = 932) Schwartz-Lyon2.3 (1.5 to 3.1)14.713.0 (12.1 to 14.0)39.8 (36.7 to 42.9)80.8 (78.3 to 83.3) CKiD7.4 (6.2 to 8.3)18.016.2 (15.1 to 17.8)32.7 (29.7 to 35.7)71.8 (68.9 to 74.7) CKD-EPI400.0 (−0.8 to 1.1)18.516.1 (15.0 to 17.2)33.4 (30.3 to 36.4)74.6 (71.8 to 77.4) CKD-EPI50.7 (46.7 to 54.5)47.290.4 (85.4 to 95.5)2.6 (1.6 to 3.6)12.2 (10.1 to 14.3)mGFR ≥75 ml/min per 1.73 m2 (n = 3073) Schwartz-Lyon−5.6 (−6.4 to –4.6)26.213.8 (13.3 to 14.3)37.7 (36.0 to 39.5)86.7 (85.5 to 87.9) CKiD3.4 (2.4 to 4.4)30.314.5 (13.9 to 15.0)36.1 (34.4 to 37.8)82.1 (80.7 to 83.5) CKD-EPI40−7.8 (−8.6 to −7.2)26.213.3 (12.8 to 13.8)39.2 (37.5 to 40.9)87.5 (86.3 to 88.7) CKD-EPI44.8 (43.6 to 45.9)38.843.0 (41.7 to 44.2)8.3 (7.3 to 9.2)33.4 (31.8 to 35.1)Young adults, 18 to 39 yearsmGFR <75 ml/min per 1.73 m2 (n = 918) CKD-EPI403.3 (2.1 to 4.0)16.316.1 (14.7 to 17.1)34.4 (31.3 to 37.5)75.6 (72.2 to 79.0) CKD-EPI12.6 (11.3 to 13.9)21.626.1 (24.3 to 28.1)19.9 (17.4 to 22.5)55.6 (51.7 to 59.5)mGFR ≥75 ml/min per 1.73 m2 (n = 2391)CKD-EPI40−4.9 (−5.6 to −4.1)22.911.3 (10.7 to 11.8)45.0 (43.0 to 47.0)91.9 (90.6 to 93.1)CKD-EPI10.3 (9.4 to 11.4)24.514.0 (13.2 to 14.6)37.6 (35.7 to 39.6)83.3 (81.6 to 85.0)CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration original equation without adjustments; CKD-EPI40, CKD-EPI with age and creatinine values adjusted to 40 years for patients <40 years; CKiD, Chronic Kidney Disease in Children equation; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; mGFR, measured GFR.Median bias (eGFR − mGFR) and precision (interquartile range of eGFR − mGFR) are expressed in ml/min per 1.73 m2, accuracy as median absolute percentage error |eGFR − mGFR)|/mGFR, and P10 and P30 accuracy as percentage of GFR estimates within ±10% and ±30% of mGFR.Values in parentheses are 95% confidence intervals. Open table in a new tab GFR, glomerular filtration rate. Values are presented as n (%) or median (2.5th to 97.5th percentiles). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration original equation without adjustments; CKD-EPI40, CKD-EPI with age and creatinine values adjusted to 40 years for patients <40 years; CKiD, Chronic Kidney Disease in Children equation; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; mGFR, measured GFR. Median bias (eGFR − mGFR) and precision (interquartile range of eGFR − mGFR) are expressed in ml/min per 1.73 m2, accuracy as median absolute percentage error |eGFR − mGFR)|/mGFR, and P10 and P30 accuracy as percentage of GFR estimates within ±10% and ±30% of mGFR. Values in parentheses are 95% confidence intervals. A more detailed assessment of accuracy across levels of mGFR showed that P30 in children was >75% at mGFR 55–160 ml/min per 1.73 m2 for CKD-EPI40 but varied more than for Schwartz-Lyon (Figure 2a). CKD-EPI40 in young adults generally showed noticeable improvement in P30 accuracy compared with the original CKD-EPI equation at all mGFR levels <120 ml/min per 1.73 m2 (Figure 2b). The improvement in estimation performance of CKD-EPI40 was apparent in both females and males and in more detailed age stratifications (Supplementary Tables S4–S7). CKD-EPI40 exhibited P30 accuracy that was stable at all ages from 40 down to 5 years, at mGFR both below and above 75 ml/min per 1.73 m2 (Figure 3a and b ). In contrast, the accuracy of the original CKD-EPI equation began to drop already below age 40 at mGFR <75 ml/min per 1.73 m2 and below age 30 at mGFR ≥75 ml/min per 1.73 m2. Substandard accuracy in the youngest children was noted both for CKD-EPI40 and the two pediatric equations. Additional validations also included LMR18, i.e., the LMR equation with age and creatinine values adjusted to 18 years in children (LMR18),9Björk J. Nyman U. Delanaye P. et al.A novel method for creatinine adjustment makes the revised Lund-Malmö GFR equation applicable in children.Scand J Clin Lab Invest. 2020; 80: 456-463Crossref PubMed Scopus (10) Google Scholar and are presented in Supplementary Table S8. In CKD-EPI40, the age-adjustment of creatinine continues until age 40, whereas the adjustment stops at age 18 with LMR, which means that LMR18 yields the same estimates as the original LMR equation in all adults. Both CKD-EPI40 and LMR18 exhibited relatively low constant negative bias at all levels of eGFR in children, whereas increasing overestimations were observed at normal and high eGFR levels for both CKiD and Schwartz-Lyon (Supplementary Figure S1). Likewise, in young adults, CKD-EPI40 and LMR18 both had fairly constant and low bias at all levels of eGFR, whereas the overestimation of the original CKD-EPI increased at high eGFR-levels. However, the uncertainties of CKD-EPI40 and LMR18 were also substantial. For example, eGFR of 100 ml/min per 1.73 m2 for a young adult according to the CKD-EPI40 has an 80% accuracy interval from −24 to +20 ml/min per 1.73 m2, implying that true mGFR is between 80 and 124 ml/min per 1.73 m2 with 80% probability (Supplementary Figure S1). Our novel method based on sex-specific creatinine growth curves makes it possible to adjust creatinine values during childhood and young adulthood to corresponding levels of a certain adult age. Using adjustment to age 40 years, our independent validation results suggest that this approach makes the CKD-EPI equation applicable for the full age spectrum, including young children, adolescents, and young adults regardless of their renal function. In fact, CKD-EPI40 generally outperformed the dedicated pediatric CKiD equation recommended by Kidney Disease: Improving Global Outcomes1Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1298) Google Scholar in all age groups, and without using data on height. The accuracy of CKD-EPI40 was similar to the LMR18-year equation when validated in the same pediatric cohort.9Björk J. Nyman U. Delanaye P. et al.A novel method for creatinine adjustment makes the revised Lund-Malmö GFR equation applicable in children.Scand J Clin Lab Invest. 2020; 80: 456-463Crossref PubMed Scopus (10) Google Scholar CKD-EPI40 exhibited ≥75% P30 accuracy at mGFR 55–160 ml/min per 1.73 m2, which included 87% of the children referred for GFR measurements in this pediatric nephrology setting. The estimated P30 accuracy was 86% at suggested CKD threshold for children of 75 ml/min per 1.73 m2.10Delanaye P. Jager K.J. Bokenkamp A. et al.CKD: a call for an age-adapted definition.J Am Soc Nephrol. 2019; 30: 1785-1805Crossref PubMed Scopus (72) Google Scholar Including height can improve precision and accuracy in children of all ages with CKD.11Schwartz G.J. Height: the missing link in estimating glomerular filtration rate in children and adolescents.Nephrol Dial Transplant. 2014; 29: 944-947Crossref PubMed Scopus (13) Google Scholar This was noted to some extent with the Schwartz-Lyon equation in the present study, but that equation also reached substandard P30 accuracy (<75%) when mGFR was <35 ml/min per 1.73 m2. Previous validation studies suggest that cystatin C–based GFR equations are more reliable than creatinine-based equations in children with severe CKD.12Björk J. Nyman U. Berg U. et al.Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children.Pediatr Nephrol. 2019; 34: 1087-1098Crossref PubMed Scopus (25) Google Scholar Caution is also warranted if eGFR(creatinine) is used in the youngest children age 2–5, for whom both CKD-EPI40 and the two pediatric equations exhibited substandard accuracy. CKD-EPI40 exhibited increased accuracy that was similar to LMR in young adults, owing to both reduced bias and improved precision. The reason for the overestimation when the CKD-EPI equation is used without age-adjusted creatinine values among young adults is the GFR decline of 0.7% per year across the entire lifespan implicated by the equation at a given creatinine level. However, renal function only starts to decline after age 40,13Pottel H. Hoste L. Yayo E. et al.Glomerular filtration rate in healthy living potential kidney donors: a meta-analysis supporting the construction of the full age spectrum equation.Nephron. 2017; 135: 105-119Crossref PubMed Scopus (33) Google Scholar but with the CKD-EPI equation an individual of age 18 will have 17% higher eGFR than an individual of age 40 with the same creatinine level. An obvious improvement of the original CKD-EPI equation is therefore to set age equal to 40 years in the equation for all patients younger than this threshold. It is less obvious which age should be chosen as to represent the plateau level of creatinine growth. We chose to recalculate creatinine levels to age 40 for simplicity reasons, although the empirical creatinine growth curves reached plateau levels already at age 25 for both males and females (Figure 1). Our proposed adjustment strategy for creatinine during childhood and young adulthood is generally applicable9Björk J. Nyman U. Delanaye P. et al.A novel method for creatinine adjustment makes the revised Lund-Malmö GFR equation applicable in children.Scand J Clin Lab Invest. 2020; 80: 456-463Crossref PubMed Scopus (10) Google Scholar. It has 4 important strengths: (i) the original coefficients of the GFR equation can be used, (ii) the same equation can be used for most patients across the entire lifespan without artificial changes in eGFR, e.g., when a child reaches adolescence or is transferred from pediatric to adult care, (iii) height is not necessary in the GFR estimation for most children, which renders it possible to automatically report eGFR by the laboratories, and (iv) well-established creatinine reference intervals for adults may be used if not available for children at certain age intervals. A specific strength of the present study was that the validation of eGFR was done in patients that were separate from the data used when the creatinine growth curves were established. The size of the validation cohort (4005 children and 3309 young adults) led to narrow CIs in the overall performance metrics (e.g., the statistical uncertainty in the estimated P30 accuracy was at most ±3 pp). The individual cohorts used for validation mainly included patients from 4 different European countries (Belgium, France, the Netherlands, and Sweden). Thus, we do not know to what extent the creatinine growth curves and the reported improvements in estimation accuracy for CKD-EPI40 are generalizable to non-European populations or specific ethnic groups. However, the same approach should be possible to use for other population groups and may render correction factors for ethnicity unnecessary. This would require that creatinine growth curves are established that take population-specific patterns of growth in muscle mass and creatinine levels during childhood and emerging adulthood into account. Another study limitation was the low proportion of patients with mGFR <60 ml/min per 1.73 m2: 12% among children and 17% among young adults. This most likely reflects the low population prevalence of CKD in these age groups, as the validation data were obtained from consecutive referrals for clearance measurements. Still, the 493 children with mGFR <60 ml/min per 1.73 m2 in the present study is far more than the 168 children used in the CKiD validation set,3Schwartz G.J. Munoz A. Schneider M.F. et al.New equations to estimate GFR in children with CKD.J Am Soc Nephrol. 2009; 20: 629-637Crossref PubMed Scopus (2110) Google Scholar and the 559 young adults at this mGFR level is more than twice the 256 young adults in the CKD-EPI external validation cohort.14Stevens L.A. Schmid C.H. Greene T. et al.Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) study equations for estimating GFR levels above 60 mL/min/1.73 m2.Am J Kidney Dis. 2010; 56: 486-495Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar The creatinine growth curves were mainly established based on patients with normal renal function. An implicit assumption is that the shape of the growth curves will be the same but shifted upward in patients with reduced renal function. The observed performance of CKD-EPI40 when validated in patients with decreased mGFR suggests that this assumption is reasonable. In conclusion, the present study shows how age-adjustment of creatinine in children and young adults can make the widely used CKD-EPI equation applicable across the full spectrum of age and renal function without changing its coefficients. Based on a general method for taking population differences in creatinine levels into account first suggested by Hoste et al.,15Hoste L. Dubourg L. Selistre L. et al.A new equation to estimate the glomerular filtration rate in children, adolescents and young adults.Nephrol Dial Transplant. 2014; 29: 1082-1091Crossref PubMed Scopus (87) Google Scholar we have previously established creatinine growth curves from a pooled reference cohort of patients aged 2–40 years obtained from non-nephrology units at 3 different hospitals: (i) Kortrijk, Belgium, in 2005–2007 (n = 9634), (ii) Liege, Belgium, in 2019 (n = 9123), and (iii) Uppsala, Sweden, in 2015–2019 (n = 64,410).9Björk J. Nyman U. Delanaye P. et al.A novel method for creatinine adjustment makes the revised Lund-Malmö GFR equation applicable in children.Scand J Clin Lab Invest. 2020; 80: 456-463Crossref PubMed Scopus (10) Google Scholar The pooled reference cohort included 83,157 samples in total (46,601 females and 36,556 males. median age 27 years). Median (2.5th, 97.5th percentiles) serum creatinine values for females and males at 40 years of age were 63 μmol/L (44, 103 μmol/L) and 80 μmol/L (58, 116 μmol/L), respectively. The creatinine growth curves were fitted separately for males and females using linear regression with fractional polynomials of age as independent variable (Figure 1):Males:ln(Cr)=3.200+0.259×Age−0.543×ln(Age)−0.00763×Age2+0.0000790×Age3Females:ln(Cr)=3.080+0.177×Age-0.223×ln(Age)-0.00596×Age2+0.0000686×Age3,where Cr is the actual creatinine value measured in μmol/L and ln is the natural logarithm. The estimated geometric means of plasma/serum creatinine concentrations at each age obtained from the growth curves for both males and females were consistently within the laboratory-specific reference intervals for plasma/serum creatinine (Supplementary Table S9). The creatinine growth curves can be used to adjust actual creatinine values (Cr) of children and young adults to an equivalent adult level at a particular threshold age, referred to as age-adjusted creatinine (denoted Ĉr). In the present study, we used age 40 years as threshold in the CKD-EPI equation in order to remediate the overestimation of GFR noted in the transition to young adulthood.4Pottel H. Björk J. Bökenkamp A. et al.Estimating glomerular filtration rate at the transition from pediatric to adult care.Kidney Int. 2019; 95: 1234-1243Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar The plasma/serum creatinine median values (2.5, 97.5 percentiles) for women (n = 945) and men (n = 778) aged 40 years in the pooled reference cohort were 63 (44, 103) μmol/L and 80 (58, 116) μmol/L, respectively. The recalculation of creatinine among children and young adults (2–39 years) to age 40 was done using the following expressions derived from the creatinine growth curves:Males:ln(Cˆr)=ln(Cr)+0.259×(40-Age)-0.543×ln(40/Age)-0.00763×(402-Age2)+0.0000790×(403-Age3)Females:ln(Cˆr)=ln(Cr)+0.177×(40-Age)-0.223×ln(40/Age)-0.00596×(402-Age2)+0.0000686×(403-Age3). For patients younger than 40 years, age = 40 was used in the adjusted CKD-EPI equation (CKD-EPI40), i.e., GFR was estimated as though the patient was age 40 regardless of his or her actual age. For patients aged ≥40 years, actual age and creatinine (i.e. Ĉr = Cr) are used, which means that CKD-EPI40 yields the same estimates as the original CKD-EPI equation. Thus, CKD-EPI40 uses the original CKD-EPI coefficients2Levey A.S. Stevens L.A. Schmid C.H. et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (13710) Google Scholar and can be expressed in the following way:Female Cˆr≤62μmol/L:144×(Cˆr/62)-0.329×0.993max(Age;40)Female Cˆr>62μmol/L:144×(Cˆr/62)-1.209×0.993max(Age;40)Male Cˆr≤80μmol/L:141×(Cˆr/80)-0.411×0.993max(Age;40)Male Cˆr>80μmol/L:141×(Cˆr/80)-1.209×0.993max(Age;40),where Ĉr represents age-adjusted creatinine (age 2–39) or actual creatinine (age ≥40) and max(Age;40) represents the maximum of actual age and 40 years. 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