897 e2 Modification from a two compartment model to a one compartment model focusing on the renal elimination phase simplifies the pro cedure, reducing the number of required blood specimens to two Th[.]
897.e2 TRACER DISAPPEARANCE B Log [tracer] Slow α A β Fast 0 50 100 150 200 250 300 350 400 Time (min) • eFig 73.1 Plasma disappearance of filtration marker as a function of time after injection into blood The curve is composed of two components: the slow curve with slope a and intercept A and the fast curve with slope b and intercept B (Modified from Schwartz GJ, Furth SL Glomerular filtration rate measurement and estimation in chronic kidney disease Pediatr Nephrol 2007;22:1839–1848.) Modification from a two-compartment model to a one-compartment model focusing on the renal elimination phase simplifies the procedure, reducing the number of required blood specimens to two The GFR can then be derived from the slope of the slow curve but requires incorporation of a correction factor to compensate for overestimation of the GFR, which results from exclusion of the area under the fast curve.28–31 Appropriate timing of the specimens is critical to ensure an accurate estimation of the GFR The first sample must be obtained after the marker has equilibrated, typically hours after injection The second specimen is obtained approximately hours after injection However, in subjects with more advanced chronic kidney disease (CKD), this may need to be delayed further to minimize overestimation of the GFR, which can result from an inaccurate depiction of the lower slope of the plasma disappearance curve.30 The validity of the singlecompartment model may also be compromised in edematous states in which the volume of distribution is increased or with extravasation of the tracer at the injection site, as this decreases the actual dose delivered.29 Although plasma disappearance studies are time-consuming and too complex for routine clinical care, they are useful in cases for which GFR estimates not appear to be accurate Radioisotopes Plasma clearance studies are most commonly performed with radioisotopes that are more readily available and easier to assay than inulin Their major disadvantage is, of course, radiation exposure, which limits their use, particularly in children.32 51Cr-EDTA (chromium-51 ethylenediaminetetraacetic acid), 99mTc-DTPA (technetium-99m diethylenetriaminepentaacetic acid), and 125 I-Iothalamate (iodine-125) have been extensively studied and compared with inulin renal clearance.20,33 All are lowmolecular-weight compounds that are freely filtered by the glomerulus but differ slightly in protein binding and renal disposition 51 Cr-EDTA (292 Da) appears to have little protein binding, and its plasma clearance correlates well with inulin clearances It is commonly used in Europe but unavailable in the United States.30 99m Tc-DTPA (393 Da) is most frequently used in the United States but demonstrates variable accuracy in GFR measurements on the basis of product source, differences in protein binding, and potential dissociation of the chelate (t1/2 hours) during the study.34 125I-Iothalamate (614 Da) is a high-osmolar anionic contrast agent with some protein binding that also undergoes active secretion by the proximal tubule, contributing to overestimation of plasma clearance compared with inulin or EDTA.22 Nuclear GFR studies can also be performed using a gamma camera, which measures the renal uptake of the tracer to minutes after injection and can provide information regarding differential kidney function However, the estimated GFR obtained this way is not as accurate as with the plasma-sampling technique.30 To reduce radiation exposure, plasma clearance studies can also be performed using nonradiolabeled iothalamate, which can be measured by high-performance liquid chromatography (HPLC).35,36 898 S E C T I O N V I I Pediatric Critical Care: Renal measurements within 30% and 10%, respectively, of inulin GFR) Creatinine clearance was not accurate, and there was insufficient data to accurately assess the use of the plasma clearance of DTPA.48 Plasma Markers Creatinine Serum creatinine is the most commonly used laboratory study to assess renal function in clinical practice It is simple, convenient, and practical—requiring a single blood sample—and thus well suited for serial examination However, the relationship between serum creatinine and GFR is quite complex, being influenced by several factors other than GFR Therefore, at best, creatinine provides a crude estimate of the GFR As illustrated in Fig 73.2, serum creatinine bears an inverse, nonlinear relationship with GFR, but it lacks sensitivity to acute and small changes in GFR Notably, at low concentrations of serum creatinine corresponding to normal renal function, a substantial decrease in GFR may occur before being reflected by even a small increase in serum creatinine In contrast, at higher levels of serum creatinine associated with renal failure, the same absolute rise in creatinine reflects a much smaller loss of remaining renal function To a first approximation, every doubling of the serum creatinine represents a 50% decline in remaining GFR Ideally, an endogenous marker such as creatinine can serve as a useful surrogate for GFR if it is produced at a constant rate and eliminated only via the kidney at a rate equivalent to its production rate such that a steady state exists The serum concentration of the marker would then be expected to rise with renal impairment Serum creatinine, however, does not strictly fulfill these criteria Although creatinine production is relatively constant, it varies among and within individuals.49 It is derived from the nonenzymatic dehydration of muscle creatine and hence is highly dependent on muscle mass Consequently, in children, creatinine generation is affected by growth in addition to diet and illness, as seen with adults.49 The reference range for serum creatinine levels representing normal GFR will thus vary with age, size, and gender after puberty Thus, the relationship between GFR and serum creatinine is particularly complex in children Maturational changes in serum creatinine and GFR not parallel one another GFR is physiologically low at birth, whereas serum creatinine is elevated However, because of fetal-maternal-placental equilibration of creatinine, the elevated creatinine is not indicative of the infant’s renal function but rather indicates the mother’s function Plasma creatinine, mg/dL 0 30 60 90 120 GFR, mL/min • Fig 73.2 Idealized relation between the steady-state levels of serum creatinine and glomerular filtration rate (GFR) in adults When renal function is normal, a marked decrease in GFR can be associated with only a mild increase in serum creatinine Following birth, the GFR steadily increases, reaching adult levels over the next years Serum creatinine, on the other hand, declines over the first few weeks, becoming reflective of the infant’s renal function The creatinine level then remains stable until approximately years of age as muscle mass accrues proportionally to the increase in GFR Beyond years of age, when GFR per BSA has fully matured, the ongoing accretion of muscle results in a progressive rise in serum creatinine until adolescence, when adult levels are achieved (0.7 mg/dL for adolescent females and 0.9 mg/dL for adolescent males) Superimposition of a severe or chronic illness associated with malnutrition and muscle wasting makes the interpretation of GFR from serum creatinine alone even more difficult in children For example, at first glance, maintenance of a stable creatinine in a patient with a prolonged ICU course may be reassuring for preservation of renal function However, if significant muscle atrophy has occurred, this actually suggests deterioration of renal function In the steady state, when height is used as a surrogate for growth, there is a strong correlation of the parameter height/serum Cr (Ht/SCr) and GFR.50–52 The second requirement, that excretion of the marker occurs only by glomerular filtration, is also flawed in the case of creatinine Although the majority of serum creatinine is eliminated by glomerular filtration, a small but unpredictable amount is eliminated by tubular secretion and gastrointestinal degradation Proximal tubular secretion of creatinine typically accounts for approximately 10% of its elimination, although considerable interindividual and intraindividual variability exist.53 At normal levels of GFR, the impact of tubular secretion on GFR is minimal However, with deteriorating renal function, the proportion of secreted versus filtered creatinine increases, resulting in a lower serum creatinine than predicted for the true level of GFR, thus decreasing the sensitivity for serum creatinine to detect mild decreases in renal function.53 A similar phenomenon occurs in the setting of moderate-to-severe renal failure, when the bacterial degradation of creatinine within the gastrointestinal tract can become clinically significant, leading to a decrease in serum creatinine concentration.54,55 Failure to recognize the influence of tubular secretion and gastrointestinal elimination on serum creatinine values can result in overestimation of renal function and may lead to higher, inappropriate dosing of medications Conversely, in patients with advanced kidney injury, administration of medications (e.g., cimetidine, trimethoprim) that inhibit the tubular secretion of creatinine or administration of antibiotics that mitigate the gastrointestinal degradation of creatinine may result in an elevation of serum creatinine and subsequent underestimation of GFR without any true change in renal function If not appreciated, this may be misconstrued as worsening renal function and lead to potential underdosing of medications This issue is being addressed by integration of novel biomarkers that are capable of adjudicating and differentiating subclinical AKI, functional AKI, and damage-associated AKI (see Biomarkers of Acute Kidney Injury and the Next Generation).56–58 Third, the requirement for a steady state cannot be overemphasized When the GFR abruptly declines with AKI, the production rate of creatinine exceeds its clearance rate, leading to a gradual rise in serum creatinine that lags behind the true GFR During this period, serum creatinine does not accurately reflect the true GFR Nonetheless, serum creatinine is still typically used to estimate renal function, as better alternatives not currently exist However, use of the serum creatinine or creatinine-based estimating equations (presented later) to estimate GFR before the establishment of a new steady state will result in overestimation of renal function Similarly, during the recovery phase of AKI, serum CHAPTER 73 Tests of Kidney Function in Children creatinine will underestimate the GFR as it will again lag behind the true GFR until the kidney clears the accumulated creatinine and reaches a new steady state Finally, analytic factors related to the creatinine assay itself provide another potential source of error when assessing GFR True creatinine levels can be measured by isotope dilution mass spectroscopy (IDMS) or HPLC, but these methods are expensive and not readily available for routine clinical use.59 Enzymatic creatinine assays, now available in many laboratories, exhibit greater specificity for creatinine than the conventional Jaffe (alkaline picrate) assay, resulting in 10% to 30% lower creatinine concentrations Enzymatic creatinine levels approximate HPLC values but can differ in their performance, some being more influenced by interfering substances than others Although problems with accuracy and precision still persist, the coefficient of variation using new autoanalyzers is now approximately 3% and significantly lower than for the Jaffe assay.49,60 Nonetheless, according to the College of American Pathologists in 2007, many laboratories continue to use a modified version of the Jaffe assay because it is less expensive than enzymatic assays.61 The Jaffe method, based on an alkaline picrate colorimetric reaction, tends to falsely elevate the true creatinine by up to 20% (for creatinine mg/dL) owing to the presence of interfering, noncreatinine chromogens, the most significant of which is serum total protein.62 This effect is greatest at the lower levels of creatinine typically observed in infants and children.61 By falsely elevating the true creatinine, the Jaffe creatinine underestimates the GFR Indeed, analytic variability is believed to play a greater role than biological variability in the day-to-day fluctuations of creatinine measurements.49 Speeckaert et al.62 published a correction accounting for the contribution of serum protein to Jaffe creatinine When applied, this correction yields a creatinine value more consistent with that obtained using an enzymatic creatinine assay An international effort to standardize creatinine measurements in clinical laboratories through use of a uniform assay and calibration materials was launched in the mid-2000s.62,62a,62b All creatinine assays can now be calibrated to adult International Federation of Clinical Chemistry (IFCC) standards However, the lowest IFCC standard is mg/dL, which is still considerably higher than normal creatinine values for young children and those with decreased muscle mass.59 Creatinine is affected by total body water As a concentrationderived solute, the diluent volume of a host affects the resulting concentration regardless of assay used for measurement Recent data describes clearly the change in AKI estimates based on creatinine 899 before and after adjusting for total body water volume Especially in pediatric patients, the change in total body water in relation to age is highly relevant and inversely related to change in creatinine concentration secondary to muscle mass development Emerging data are required to further explore the concept of “corrected creatinine.” However, this adjustment is a practical and pragmatic reconciliation of the concentration of creatinine and total net fluid balance state (high accumulation deemed “fluid overload”).63,64 Proper interpretation of the serum creatinine as a measure of GFR requires the physician to be knowledgeable about the clinical variables, physiologic processes, and analytic factors that can affect creatinine levels (Table 73.4) Although the clinical laboratory provides normative reference ranges alongside the results, clinicians should confirm that the reported references are age appropriate and also realize that if the patient has decreased muscle mass (e.g., spina bifida, anorexia), even these age-appropriate reference ranges will be incorrect Cystatin C The well-established limitations of serum creatinine highlight the critical need to identify alternative biomarkers of renal function that have improved sensitivity and specificity Some low-molecularweight proteins have been considered potential candidate markers, as they are excreted primarily by glomerular filtration and are produced at a relatively constant rate Several low-molecular-weight proteins have been considered but cystatin C, a 13-kDa cationic cysteine protease inhibitor produced at a constant rate by all nucleated cells, has shown the greatest promise Like creatinine, it is freely filtered at the glomerulus65 but, unlike serum creatinine, it is not secreted by the tubules Rather, it is completely reabsorbed and metabolized by the proximal tubule epithelial cells.66 In most studies, the production of cystatin C is not significantly affected by age, gender, and muscle mass, making it a particularly attractive marker in growing children, subjects with atypical body composition (e.g., malnutrition, anorexia, spina bifida, neuromuscular disease), and subjects experiencing rapid changes in muscle mass.67–69 Furthermore, in young children, the maturational changes associated with serum cystatin C follow those of the GFR better than serum creatinine Serum cystatin C levels are elevated at birth, presumably due to the physiologically lower GFR However, cystatin C, unlike creatinine, does not equilibrate across the placenta Hence, the levels early after birth are more representative of the infant’s renal function than are creatinine levels and thus may facilitate the evaluation of renal function in newborns.70 Concurrent with the GFR increasing after birth, cystatin C levels decline to reach a TABLE Non–Glomerular Filtration Rate Factors Affecting Creatinine Levels in Children 73.4 SERUM CREATININE LEVEL Factor Increase Decrease Affecting creatinine generation Age (infancy through adolescence) Chronic illness; anorexia, malnutrition; neuromuscular disease (spina bifida, muscular dystrophy); liver disease Male gender (after puberty) Body habitus (amputation) Body habitus (muscular) Diet (vegetarian) Diet; consumption of cooked meat; creatine supplements Affecting creatinine elimination Impaired tubular secretion (trimethoprim, cimetidine) Tubular secretion Impaired extrarenal elimination (sterilization of gastrointestinal flora by antibiotics) Extrarenal elimination (gastrointestinal degradation) 900 S E C T I O N V I I Pediatric Critical Care: Renal plateau of 0.8 to 1.0 mg/dL by approximately 1.5 to 2.0 years of age.71 Beyond this age, serum cystatin C levels remain constant (until age 50 years), as does the GFR.67 Therefore, serum cystatin C levels may potentially facilitate the recognition of abnormal renal function, as growth is no longer a confounding variable.69 Furthermore, cystatin C has a shorter half-life than serum creatinine, making it more sensitive to acute and subtle changes in GFR.72,73 In a small study of healthy subjects, serum cystatin C demonstrated less interindividual variability (25%) than serum creatinine (93%), suggesting that it may be a better marker for detecting the onset of acute renal dysfunction However, the intraindividual variability greatly exceeded that of serum creatinine, limiting its usefulness to monitor the progression of CKD.74 Studies comparing the use of cystatin C to serum creatinine as a diagnostic marker of kidney function have yielded conflicting results Nonetheless, two meta-analyses, including adult and pediatric studies, suggest that cystatin C is superior or equivalent to serum creatinine as a marker of renal function.75,76 Specifically, cystatin C may be advantageous in populations with low or atypical muscle mass (e.g., spina bifida)77,78 and mild renal impairment.79 Changes in serum cystatin C levels may also potentially allow earlier detection of AKI Herget-Rosenthal et al.80 found that cystatin C levels rose to days earlier than serum creatinine in critically ill adults with AKI A meta-analysis in 2011 involving mainly adults concluded that serum cystatin C seems to be a good predictor of AKI.81 However, more recent studies in children have yielded conflicting results.82,83 Further investigation regarding the use of cystatin C to predict and define AKI is clearly necessary Estimating Equations Empiric formulas (Cockcroft-Gault for adults, Schwartz and Counahan-Barratt for children) were first developed in the 1970s to enhance the physician’s ability to calculate an estimated GFR (eGFR) and, in particular, to facilitate the recognition of chronic renal impairment.84–86 This is especially helpful in children for whom the serum creatinine corresponding to normal kidney function progressively increases during childhood until adult levels are achieved during adolescence The equations were developed in CKD populations and based on serum creatinine but incorporate clinical variables such as height, weight, age, and gender as surrogates for muscle mass However, because they are creatinine based, they are subject to some of the same constraints as use of serum creatinine alone For example, tubular creatinine secretion and technical issues related to the creatinine assay itself will influence eGFR results Nonetheless, these equations perform better than serum creatinine alone Current national guidelines now recommend that eGFRs be routinely reported alongside the creatinine value using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for adults and the updated “bedside” Schwartz formula for children Both formulas were developed using creatinine measurements calibrated to be traceable to an IDMS reference standard.87 Within the past decade, routine reporting of eGFRs has been implemented for adults but has been more challenging to implement for children because the equation is based on height, a parameter not routinely available in the laboratory electronic medical record.72 According to the College of American Pathologists, as of 2013, 90% of laboratories surveyed were reporting eGFRs along with creatinine for adults but less than 10% of laboratories surveyed were reporting eGFRs for children The ideal GFR estimating equation would be based on a standardized creatinine measurement, applicable across the full spectrum of renal function, and generalizable to a diverse population In 2009, the CKD-EPI creatinine equation was developed using standardized creatinine measurements in a diverse population of adults with and without renal dysfunction This was a substantial improvement over the 2006 Modification of Diet in Renal Disease (MDRD) equation, which was developed in adults with moderate CKD (GFR ,60 mL/ per 1.73 m2) and therefore systematically underestimated eGFR in patients with normal renal function or mild CKD.89 Limited studies assessing the application of these adult formulas in children have shown them to be inaccurate.90–93 In pediatrics, the Schwartz formula has been most commonly used to predict GFRs The original Schwartz formula was developed in the 1970s and based on a modified Jaffe creatinine, using inulin clearance as the reference standard The GFR is related to serum creatinine, using length as a surrogate for muscle mass and an empiric constant to account for age- and gender-related differences in body composition: eGFR k L/SCr where eGFR is estimated GFR in mL/min per 1.73 m2, L is length in cm, SCr is serum creatinine in mg/dL, and k is an empiric constant (i.e., 0.45 for term infants through the first year of life, 0.55 for children and adolescent females, and 0.7 for adolescent males).61,86 The simplicity of the formula makes it convenient and practical for use at the bedside, although knowledge of the patient’s height is required Counahan-Barratt developed a similar formula using 51Cr-EDTA plasma disappearance as the reference standard.85 However, this formula uses a single constant with a lower value, attributed to a difference in creatinine assays: eGFR (mL/min/1.73m ) 0.43 L/SCr It is now well recognized that Schwartz’s original formula systematically overestimates GFRs, most likely due to a change in creatinine methodology over the years from the Jaffe assay to an IDMS-referenced enzymatic assay.43 As noted earlier, enzymatic creatinine levels in infants and children tend to run lower than Jaffe creatinine levels In 2009, using data from the Chronic Kidney Disease in Children Study (CKiD Study), Schwartz et al developed an updated “bedside” formula on the basis of an IDMS traceable enzymatic creatinine assay using the plasma disappearance of iohexol as the reference standard: eGFR 0.413 L/SCr Here, length (L) is in centimeters and serum creatinine (SCr) is in mg/dL.50 Notably, this is the first multicenter study to generate an estimating formula in children with moderate CKD (GFR range, 15–75 mL/min per 1.73 m2) Using the updated Schwartz formula, approximately 80% of eGFR values fell within 30% of the GFR measured by iohexol plasma disappearance and 37% fell within 10%.72 However, similar to the situation with the MDRD equation developed in adults with CKD, the accuracy of the updated bedside Schwartz equation in predicting eGFRs for children with mild CKD or normal renal function is unclear.50 In a cohort of children who had measured GFRs by inulin ranging from 17 to 150 mL/min per 1.73 m2, Gao et al.94 found that the Schwartz formula performed well within the GFR range (15–103 mL/min per 1.73 m2) but overestimated GFRs at higher levels of measured GFRs Staples et al.95 compared the updated Schwartz formula with GFRs measured by iothalamate in a broad pediatric range and found good agreement, even at higher levels of GFR Other investigators have found that the updated Schwartz formula does not perform as well when renal function is normal, but the direction of bias varied by study.93,95,96 CHAPTER 73 Tests of Kidney Function in Children Other pediatric estimating formulas have been proposed in the past decade.97,98 Some are considerably more complex, not more accurate, and not easily used at the bedside.97,98 Pottel’s group99 recently developed an estimating equation for children on the basis of a population normalized serum creatinine value Q (average creatinine for healthy children of a specific age) generated from a large Belgian hospital database: eGFR 5107.3/(SCr /Q ) Using the concept of a population normalized serum creatinine, they developed and validated two new eGFR equations for use in children, adolescents, and young adults.100 In one, Q is based on height (Qheight), whereas in the other, Q is height independent and based on age and gender (Qage) Though both equations have been validated in a Belgian cohort, the Qheight-based equation was more accurate across all ages and levels of renal function It also performed better in underweight subjects, further supporting the premise that height can be used as a good surrogate for muscle mass The heightindependent Qage-based equation, however, may potentially allow development of a screening tool for renal dysfunction in children.52 Further studies are necessary to assess the applicability of this formula and validity of the technique in other pediatric populations Given the limitations of creatinine, cystatin C–based GFR-estimating equations have also been developed in an effort to improve accuracy Several have been published for use in both adults and children.89,97,101,102 They vary in accuracy and precision but appear at least as good as the creatinine-based equation89 for the general population In high-risk populations with reduced muscle mass— such as oncology patients, hematopoietic stem cell transplant recipients, patients with spina bifida/muscular dystrophy, and patients with spinal cord injury—cystatin C–based formulas seem to more accurately estimate the measured GFR than creatinine-based equations.77,103–106 However, cystatin C is not readily available in many hospital laboratories, it is more expensive, and assays have not been standardized in the United States.71 Incorporation of both creatinine and cystatin C into the estimating formula appears to provide a better estimate than either one alone.52,89 Using data from the CKiD study, Schwartz et al.51 developed a new multivariate eGFR equation incorporating both cystatin C and serum creatinine in addition to height, blood urea nitrogen (BUN), and gender: eGFR 39.8 [height (m)/SCr (mg/dL)0.456 ] [1.8/cystatin C (mg/dL)]0.418 [30/BUN (mg/dL)0.079 ] [1.076]gender [height (m)/1.4]0.179 where gender for male and for female Using this formula, over 90% of the eGFRs were within 30% of the GFR measured by iohexol, the reference standard for this study, and 48% were within 10%.50,51 The equation is valid in the range of 15 to 75 mL/min per 1.73 m2 and uses a standardized creatinine measurement and nephelometric assay for cystatin C.51 The cystatin C values have not yet been referenced to an IFCC calibration A bedside cystatin C formula has also been generated, eGFR 70.69 [cystatin C]20.931, to facilitate use in the clinical setting.51 Summary of Recommendations Regarding Use of Glomerular Filtration Rate Estimating Equations Serum creatinine alone does not reliably indicate renal function and should be replaced by a GFR prediction formula, as this 901 accounts for the non-GFR determinants of serum creatinine For adults, KDIGO recommends that the 2009 CKD-EPI creatininebased equation be used to routinely assess renal function For individuals in whom the creatinine-based equation may be inaccurate (e.g., malnourished patients), cystatin C and combined cystatin C–creatinine-based estimates are recommended as confirmatory tests For children, KDIGO recommends use of the updated bedside Schwartz formula (creatinine based) For those in whom a more precise estimate is needed or in whom the use of a creatinine-based formula may be inaccurate, Schwartz et al.52 suggest confirmation with a cystatin C–based formula If the two estimates are similar (within 10%–15% agreement), use of the more complex multivariate cystatin C–creatinine formula provides an eGFR, which approximates the measured GFR However, if the univariate creatinine-based and cystatin C–based eGFRs are discrepant, a measured GFR is recommended Proper use of a GFR estimating formula requires the clinician to be cognizant of the population from which it was derived and its range of measured GFR, as well as the analytes and assay methods used Finally, it should be reemphasized that none of the GFR estimating equations is truly appropriate for assessing renal function in the non–steady state, such as AKI However, a more suitable alternative does not exist, leading to their ongoing use in non–steady-state situations in which the imprecision will be even greater Neonatal Renal Function Accurate assessment of renal function is even more challenging in the neonate Renal clearance and plasma disappearance studies are not practical The limitations to the interpretation of serum creatinine discussed earlier are further confounded by the unique physiology of newborns As noted previously, due to maternalfetal equilibration of creatinine across the placenta, serum creatinine at birth reflects the mother’s renal function For full-term infants, serum creatinine begins falling after birth as the GFR increases, resulting in excretion of the maternal load of creatinine Serum creatinine becomes reflective of the full-term infant’s renal function by approximately week of age On the other hand, premature infants born before the completion of nephrogenesis at 36 weeks’ gestation have significantly lower GFR at birth than full-term infants and experience a slower maturational increase in GFR, which can result in an initial rise in serum creatinine during the first few days of life.107 Thus, serum creatinine takes longer to become reflective of the preterm infant’s renal function Use of a creatinine-based definition for AKI becomes especially challenging in neonates as renal dysfunction may manifest not only as the traditional rise in serum creatinine but also as a failure for the creatinine to decline at an appropriate rate Additionally, there are methodologic issues, as Jaffe creatinines are less accurate at lower concentrations typical for a neonate Novel biomarkers have been explored in neonatal populations but continue to require refinement The absolute values of “normal” are not yet clear.108 Given the challenges associated with developing estimating equations in neonates, Abitbol et al.109 sought to validate existing pediatric GFR estimating formulas in the neonatal population making use of historical controls with GFRs measured by inulin clearance Creatinine-based pediatric equations underestimated GFR when applied to neonates, whereas cystatin C–based and the Zappitelli combined cystatin C–creatinine-based equations correlated best with the measured GFRs Treiber et al.110 recently developed a neonatal cystatin C–based eGFR equation, which incorporates BSA and kidney ... male and for female Using this formula, over 90% of the eGFRs were within 30% of the GFR measured by iohexol, the reference standard for this study, and 48% were within 10%.50,51 The equation... Schwartz formula, approximately 80% of eGFR values fell within 30% of the GFR measured by iohexol plasma disappearance and 37% fell within 10%.72 However, similar to the situation with the MDRD... change in renal function If not appreciated, this may be misconstrued as worsening renal function and lead to potential underdosing of medications This issue is being addressed by integration