The Use of Plasma Creatinine Concentration for Estimating Glomerular Filtration Rate in Infants, Children, and Adolescents

0031-3955/87 $0.00 + .20

Pediatric Nephrology

The Use of Plasma Creatinine Concentration for Estimating Glomerular Filtration Rate in Infants, Children, and Adolescents

George J. Schwartz, MD, * Luc P. Brion, MD, t and Adrian Spitzer, MD:j:

Glomerular filtration is the initial and generally the rate-limiting step in the renal excretory process. The measurement of glomerular filtration rate (GFR) provides the clinician with an overall estimate of renal function that enables him or her to prescribe fluids, electrolytes, and many therapeutic agents with greater safety than would otherwise be possible. The classic technique for measuring GFR requires the infusion of a substance that is filtered freely and is not reabsorbed, secreted, or metabolized by the kidney, as well as the timed collections of urine; agents used are inulin, 99mTc-DTPA, 125I-iothalamate,51Cr-EDTA, and polyfructosan. 4 , 10, 26, 29, 32, 39 After a steady-state concentration of the marker is attained in the plasma, multiple samples of blood and urine are collected over a 2- to 4-hour period, and renal clearance of the marker is calculated. For instance, inulin clearance (Cin) is calculated by averaging several determinations of DinV/Pin, where Uin is the urinary concentration of inulin in a given collection, V is the volume of urine excreted per minute, and Pin is the plasma concentration of inulin during the midpoint of each urine collection. Cin is e~pressed as ml per min or liters per day and represents the volume of blood that is cleared of inulin per unit of time, approximately 20 per cent of the total renal plasma flow. In children Cin is often corrected to 1. 73 m 2 of body surface area to facilitate comparisons between subjects of different sizes. Single-injection clearance yield results that are not significantly different from those obtained by classic techniques. 4 , 10,32,72,79,87

*Associate Professor of Pediatrics and Physiology/Biophysics tInstructor in Pediatrics, Division of Neonatology tProfessor of Pediatrics; Director, Division of Nephrology From the Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York

Pediatric Clinics of North America-Vo!. 34, No.3, June 1987

571

572

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The Creatinine Clearance as an Estimate of Glomerular Filtration Rate The measurement of GFR by Cin is laborious, time-consuming, sOllwwhat uncomfortable for the patient, and is subject to inaccuracies owing to the difficulty in obtaining complete urine collections in children. In addition, to attain a steady-state concentration of inulin in the blood, one has to estimate quite accurately the rate of its excretion, that is, the GFR. Finally, few laboratories are equipped to measure inulin, and many clinicians are reluctant to give their patients radioactive markers that are handled similarly to inulin by the kidney to obviate the difficult chemical determination of inulin. An expedient compromise is to measure the clearance of endogenous creatinine (Ccr) from a single plasma or serum value and one or more urine collections. A number of investigators have demonstrated that Ccr approximates GFR, especially when the kidney function is within the normal range 6 , 3\ studies performed by us in children have shown that the correlation coefficient between Ccr and Cin, when the latter ranges from 3 to 192 ml per min per 1. 73 m2, was excellent (0.94). Within the normal range of renal function, the ratio of Ccr to Cin was not significantly different from one (0.98 ± 0.02) (Fig. 1).6 At lower levels of GFR, Ccr tended to overestimate GFR, presumably due to the relatively larger contribution of the tubular secretion of creatinine to its urinary excretion12, 13; when Cin was less than 21 ml per min per 1.73 m 2, the ratio of Ccr to Cin was 1.18 ± 0.05, a value significantly greater than 1. 6 Even at these low levels of GFR, however, Ccr overestimated Cin by less than 20 per cent. In low birth weight (LBW) infants, conflicting results have been reported by investigators who have compared Cin with Ccr or with singleinjection Cin. 3, 8, 24, 25, 34, 83 Whereas several of them have found good agreement between Cin and Ccr,3, 8, 83 others have reported that Ccr underestimates Cin. 25 In addition, short-infusion or single-injection inulin clearances have generated values that exceed those obtained after 24 hours 200 100

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of equilibration. 24 Some of these inconsistencies are due to differences in the laboratory techniques used to measure creatinine and inulin, to insufficient time allotted for equilibration of the inulin in plasma or to inadequate time intervals between samples, resulting in inaccurate tracing of the disappearance curve. 8, 16 We have compared the results of single-injection Cin calculated by double exponential slope analysis 72, 79 with simultaneously measured Ccr in 16 VLBW infants with gestational ages ranging between 28 and 32 weeks and postnatal ages between 2 and 21 days. The correlation coefficient between Ccr and Cin was 0.80, and the mean ratio of Ccr to Cin was 0.90 ± 0.06, not, significantly different from 1. 16 The fact that Ccr did not overestimate the GFR in these infants, despite their low values of Cin (4,9-21.6 ml per min per 1.73 m2) may be explained by an immaturityll,51, 67, 69, 76, 91, 95 of the organic anion and cation secretion mechanisms, which mediate creatinine secretion by the proximal tubule. 9 This study revealed, in addition, that the half-life of inulin in the plasma of these VLBW infants was 542 ± 63 minutes, indicating that single-injection inulin clearances performed over periods of 2 to 3 hours are very likely to yield inaccurate results. 16, 24 The Use of Plasma Creatinine Concentration for Estimating the Rate of Glomerular Filtration For reasons of convenience, plasma creatinine concentration (Pcr) is often used to assess the level of renal function in both acute and chronic conditions. Although formulas relating Pcr and GFR as a function of age and sex have been proposed,31, 42, 73 the value of Pcr is often considered sufficient for purposes such as the prescription of drugs, fluids, and electrolytes. Unfortunately, pediatricians are at a disadvantage in this regard, because Pcr depends on the age and sex of the patient, in addition to G FR. 30,50,57,75,77 The major factors influencing Pcr in infants and children are (1) the progressive increase in GFR, (2) the increase in muscle mass per unit of body size, and (3) during the early neonatal period, the load of exogenous (maternal) creatinine. In full-term babies, Pcr rises by 0.09 ± 0.04 mg per dl within a few hours of birth, probably because of the decrease in extracellular volume; it then decreases, reaching 0.4 mg per dl by the middle of the second postnatal week (Fig. 2). The half-time of the fall in Pcr is 2.1 days in full-term infants (Fig. 3), and substantially longer in premature babies (Table 1).16, 71, 77 After this initial decline, Pcr remains relatively stable for the ensuing 2 years of life (Table 1),16, 75, 77 reflecting the proportional increases in GFR and muscle mass (Tables 2 and 3). Beyond the age of 2 years Pcr increases (Fig. 2),50, 77 with male children attaining values progressively higher than those of female children, such that by 18 to 20 years of age Pcr is 0.9 ± 0.2 (SD) mg per dl in male subjects and 0.7 ± 0.2 in female subjects (Fig. 4).75 Despite the increase in Pcr, GFR corrected for body surface area remains nearly constant and does not differ significantly between male and female subjects (see Table 3), It should be evident that Pcr reflects GFR only under steady-state conditions. When GFR falls abruptly, such as in acute renal failure, it takes several days for Pcr to reach a new constant level. 31,53 Similarly, as renal

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failure is resolving, there may be a delay of several days before a stable value of Pcr is attained. Under these circumstances, serial determinations of Pcr and Ccr are the only reliable means of monitoring the progress of the patient. A similar situation may be observed in premature infants owing to substantial changes in GFR that can occur even within the confines of a prolonged urine collection. 7. 16, 24 The Estimation of GFR from Per

Measurement of Plasma Creatinine. Several methods are available for the measurement of creatinine concentration in body fluids (Table 4). The technique described by Jaffe, based on the colorimetric reaction with alkaline picrate, has low specificity because the reagent reacts with many interfering substances. 49, 54, 65, 66, 98 Values obtained overestimate the true creatinine by approximately 20 per cent for Pcr above 1. 0 mg per dl, and

Table 1. Normal Values of Per in Infants GESTATIONAL AGE (WKS)

1 week

POSTNATAL AGE

2-8 weeks

> 8 weeks

25-28 29-34 38-42

1.4 ± 0.8(1O)t 0.9 ± 0.3(27)t 0.5 ± 0.1(26)

0.9 ± 0.5(26)*t 0.7 ± 0.3(27)*t 0.4 ± 0.1(20)*t

0.4 ± 0.2(9)* 0.35(1) 0.4 ± 0.1(28)

Mean ± SD (n) in mg per dl, corrected age up to 15 months; data from ref. 16. *Significant decrease (p < 0.05) compared to previous age group. tSignificantly greater (p < 0.05) than corresponding value in full-term infants (38-42 weeks).

575

PLASMA CREATININE FOR ESTIMATING GLOMERULAR FILTRATION RATE

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Figure 3. Postnatal decrease in Pcr in full-term infants. Dots represent mean Pcr at specified age minus 0.39 mg per dl, the average for full term infants 1 to 52 weeks of age. (From Schwartz GJ, Feld LG, Langford DJ;77 with permission.)

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Table 2. "Normal" GFR in Infants (mllminll. 73m2 ) POSTNATAL AGE

GESTATIONAL AGE (WKS)

Cer

25--28

C A

29-34

c

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38-42

C A

1 week

11.0 0.64 15.3 1.22

± ± ± ±

5.4 (10)* 0.33* 5.6 (27)* 0.45*

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2--8 weeks

15.5 ± 6.2 (26)* 0.88 ± 0.42* 28.7 + 13.8 (27)*t 2.43 ± 1.27*t 65.8 ± 24.8 (20)t 11.15 ± 5.21 t

> 8 weeks 47.4 ± 21.5(9)*t 5.90 ± 5.92*t 51.4 (1) 10.8 95.7 ± 21. 7 (28)t 21.0 ± 6.4t

Mean ± SD (n» corrected age up to 15 months; from ref. 16. C = corrected (mllmin/1. 73m 2). A= absolute (mllmin). *Significantly less (p < 0.05) than corresponding value in full-term infants. tSignificantly increased (p < 0.05) compared to previous age group.

576

GEORGE

J.

SCHWARTZ ET AL.

Table 3. Normal Values of GFR in Children and Adolescents SEX

Males and females Males Females

AGE(YR)

GFR (MUMIN/l. 73 M2)

2-12 13-21 13-21

133 ± 27 (295) 140 ± 30 (101) 126 ± 22 ( 75)

Mean ± SD (n) in mllminll. 73m2• Data from refs. 17, 74, 77, and 78 am} from Schwartz GJ, Brion LP: Unpublished observations 1986.

by up to 90 per cent for lower values. 44, 48 The degree of overestimation fm any individual measurement is impossible to predict. The first modification of the Jaffe technique was the addition of an initial adsorption phase. 4 This can be performed by using either Fuller's earth, Lloyd's reagent, or kaolin; this modification markedly alleviates the problem of interference. The addition of an initial dialysis step has also resulted in a decrease in interference (e.g., from cefoxitin) and has allowed automation (Technicon Auto Analyzer, SMAC).20, 55 The values obtained with this modified Jaffe method still tend to overestimate true creatinine by up to 20 per cent for concentrations of 0.9 mg per dl, but the variability is quite small (see Table 4). The need to obtain accurate measurements of creatinine, especially at the low concentrations prev~jling in healthy infants, has led us and others to modify the method further by using a'lower degree of dilution than that indicated in the standard Technicon procedure. This not only increases sensitivity but also decreases variability (see Table 4) for v~lues of Pcr less t~an 0.5 mg per d1. 6 • 7, 75 We also lengthened the time allowed for the dialysis of the blood sample, added two extra blanks between samples to minimize the carryover effect, and allowed 28 minutes (instead of the standard 5 min) for the run of each sample, With this technique there is an excellent coefficient of intra- and interassay variation, and the measureqlents are not affected by the presence of bilirubin35 or other, as yet unidentified, interfering substances (Schwartz GJ, Singleton A: Unpub-

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PLASMA CREATININE FOR ESTIMATl,NG GLOMERULAR FILTRATION RATE

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Ii shed observations, 1984-1985);35 the values obtained are substantially lower than those generated with the usual Technicon procedure. * U sing our modified method as a standard of reference we evaluated the results obtained with a Technicon SMAC instrument by performing paired measurements on samples of plasma with a creatinine concentration ranging between 0.3 and 2.0 mg per dl. The SMAC overestimated Pcr by 0.1 mg per dl, which represents an error of 10 to 25 per cent, depending on the absolute value of Pcr. 18, 21 Another technique aimed at decreasing interference and increasing speed is the kinetic analysis of the Jaffe reaction. 23, 47, 80 The method yields average results close to true creatinine values, but displays significant variability in the lower range of plasma creatinine concentrations. 23, 47, 80 This is of particular concern in infants and children, as shown by a direct comparison of the results obtained by our modified Technicon technique with those of a Beckman Astra 8 instrument. In 180 samples of blood with Pcr ranging from 0.3 to 2.0 mg per dl, the kinetic method yielded results that on average were not significantly different from those generated by the reference method. The correlation coefficient was lower and the degree of variability larger than those observed when the Technicon SMAC was used, however. 21 In addition to the scatter at low values of Pcr, there were both positive and negative interferences from a variety of substances (see Table 4).56 These effects were much greater than those observed with our modified Technicon method (see Table 4). Advantages of the kinetic method are its rapidity, and the small size of the sample necessary for the analysis (25 flol). It is not known whether a larger sample size would reduce variability, as it did for the modified Technicon AutoAnalyzer method. 6, 75 Recently, enzymatic techniques have become reliable enough to be used routinely. 15, 22. 61. 64, 84. 86, 92. 97 They provide excellent specificity, as reflected in results that are close to either the Jaffe reaction after Fuller's earth absorption or to the isotope dilution spectrometry measurements. 97 The most commonly used enzymatic methods include the amidohydrolasecreatinine kinase-pyruvate, kinase-lactate dehydrogenase technique, the creatinine-creatinase-sarcosinoxidase-peroxidase technique, and the iminohydrolase technique (see Table 4). Their major disadvantages, when used in the pediatric age group, are interference by bilirubin (for the creatininase technique), the relatively high coefficient of variation at values of plasma creatinine concentration less than 1.0 mg per dl and substantial interference by hemoglobin (amidohydrolase technique), and interference by 5 (for the amidohydrolase technique).62 It should be noted that most substances have not yet been evaluated for possible interference. Measurements performed by high-pressure liquid chromatography fluorocytosine (HPLC) have excellent coefficients of variation and specificity and no known interference. 1. 29. 43. 48 Cationic exchange and normal phase and reverse phase chromatographic methods have also been developed. A dilution mass spectrometry technique,44 which includes equilibration of the sample with labeled 13C-creatinine, ion exchange chromatography to separate creatinine from creatine, esterification of creatinine, and measurement *Because the values of Cer obtained by VerY/Per 0;: by kUPer, using our modified Teehnieon technique, are in close agreement with those obtained by Cin,6, 16, 74 we believe that the values of Per generated by this method approach those of the true creatinine.

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Table 4. Comparison of Methods of Measurement of Creatinine Concentration METHOD

Jaffe endpoint

Jaffe with Fuller's earth or Lloyd's reagent absorption

Jaffe with dialysis (Technicon)

PRECISION (COEFFICIENT OF VARIANCE)

ACCURACY (POSITIVE BIAS-OVERESTIMATION)

Reducing picrate: ascorbic acid, levulose, glucose, uric acid Reacting with picrate: pyruvic acid, acetone, acetoacetic acid, aminoacids, proteins, active methyl or methylene groups, cephalosporins, aminohippurate Negative interference: bilirubin, hemoglobin degradation products Fuller's earth: pyruvate, oxalate Lloyd's reagent: keto acids, indole, glycocyamine, various steroids, pigments

Variable depending on specific technique and Pcr concentration

CV 7-15% @ Pcr = 1.1 mgldl CV 3--10% @ Pcr = 5.1 mgldl

Same as endpoint method except decreased interference with protein-bound products (e.g., cefoxitin)

CV 4% @ Pcr = 5.1 mgldl CV 7% @ Pcr = 1.1 mgldl CV 9.5% @ Pcr = 0.8 mgldl 95% confidence limits: ±0.2 mgldl @ Pcr = 1.2 mgldl

SPECIFICITY (INTERFERENCE)

ROUTINE! AUTOMATION

REFERENCE NO.

PB 20% vs dilution mass spectrometry; PB 55% (range - 58 to +168%) vs HPLC; PB 88% vs HPLC @ Pcr of 0.6-0.7 mgldl

+/+

49

PB 5% @ Pcr < 1 mgldl, 20% @ Pcr > 1 mgldl vs dilution mass spectrometry; original reference PB 20% @ Pcr < 1 mgldl vs dilution mass spectrometry; PB 0.1 mgldl @ Pcr < 2 mgldl vs our method

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No interference with bilirubin even at high levels Moderate interference with cefoxitin (+ 0.1-0.3 mg/dl at therapeutic levels) Acetoacetic acid, cefoxitin, pyruvic acid, oxaloacetic acid, acetone Positive or negative (according to timing of measurement): cephalothin, phenacemide Negative: bilirubin, hemoglobin Amidohydrolase-creatinine kinase (1): hemolysis (negative interference), oxalate, lipema Creatinase-creatininase-sarcosine oxidase-peroxidase (2): bilirubin, reduced glutathione Iminohydrolase: cephaloridine, 5-Huorocytosine Yes

Yes

Abbreviations: CV = coefficient of variation. Pcr = plasma creatinine concentration. PB = positive bias (overestimation of creatinine concentration). General references cited include 31, 44, 54, 65, 66, 98.

CV (intrassay) 6.4% @ Pcr < 0.50; 3.5% @ Pcr = 0.50-0.99; 0.2% @ Pcr > 1.0; CV (interassay) 5.3% CV 15% day to day and 18.5% within run @ Pcr = 0.4-0.6 mg/dl; CV 12% @ Pcr = 1.0 mg/dl; CV 3% @ Pcr = 4.8 mg/dl (1): CV within run: 3.99% @ Pcr = 4 mg/dl; between run: 14% @ Pcr = 0.8 mg/dl; (2): CV 4.8% @ Pcr = 0.6 mg/dl CV (interassay) 3.6% @ Pcr = 1.3 mg/dl; (intrassay) 1.7% @ Pcr = 1.6 mg/dl CV 0.15-0.28%

± 0.05 mg/dl (our reference method)

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with a gas chromatograph-mass spectrometer has a coefficient of variation of only 0.18 per cent, and it is specific and reproducible. 94 Both HPLC and dilution mass spectrometry yield results significantly lower than those obtained with the Jaffe technique, even with Fuller's earth absorption, close to those obtained from kinetic and the enzymatic methods (see Table 4). None of these newer techniques has reached the stage of development required for routine laboratory application. , In summary, it is important for the clinician to know the characteristics of the technique used in his or her laboratory. Testing will indicate whether the results have a significant inter- or intra-assay variability, which may generate as much as 80 per cent of the total variability (the other 20 per cent are of clinical nature).68 The precision of the laboratory can be ascertained quickly by dividing a patient's plasma or serum sample in two and sending one half for analysis one day and the other half the next day. In our laboratory, the values of a plasma specimen with a creatinine of 0.8 mg per dl differ by less than 0.1 mg per dl more than 90 per cent of the time when tested on two consecutive days (Schwartz GJ, Singleton A, Spitzer A: Unpublished observations, 1984-1986). In a routine hospital laboratory one would like to find that at least 50 to 75 per cent of the paired values agree to within 0.1 mg per dl within the normal range of plasma creatinine (approximate coefficient of variation less than 12 per cent). Larger discrepancies necessitate an improvement in methodology, since a difference of 0.2 mg per dl in a sample with a true creatinine of 0.7 mg per dl represents a relative error of 29 per cent. An error of such magnitude would seriously hamper the use of Pcr as an estimate of GFR. Accuracy is best assessed by comparing the results of a given laboratory with those of a reference laboratory on the same samples. A rough appraisal of the accuracy of a given method can be made by comparing values obtained in children who are free of renal disease with those included in this article (see Table 1 and Figs. 2 and 4). Rationale for the Formula CFR = kLIPcr. The complex relationship between Pcr and GFR during growth has prompted investigators to develop empirical formulas for estimating GFR by linking Pcr with some parameter of body size or age. Using body length (L), we and others derived a formula that yields values of GFR that correlate very closely with those obtained from Ccr and Cin. 27, 74 The equation is GFR = kUPer,

where CFR is expressed in ml per min per 1.73 m2, L represents body length in cm, Per is plasma creatinine in mg per dl, and k, a constant of proportionality, is a function of urinary creatinine excretion per unit of body size. 77, 78 This equation has been widely used in the past decade. 36, 63, 70, 80, 81, 99

The Measurement of k. One method for calculating the value of k is by regression analysis. 66 Individual values of LlPcr are correlated with the actual Ccr or Cin. Figure 5 shows the regression line of Ccr (y axis) versus LlPcr (x axis) obtained in appropriate for gestional age (AGA) low birth weight (LBW, birth weight < 2500 gm) infants with a corrected age (postnatal + gestational age in weeks - 40) of up to 15 months. 16 The slope of the line yields a value of k of 0.34, and a standard error of the slope of 0.02.

PLASMA CREATININE FOR ESTIMATING GLOMERULAR FILTRATION RATE

Figure 5. Ccr is plotted against UPcr; the slope of the regression line is the value of r. These data were obtained from 118 LBW appropriate for gestational age infants (birthweight less than 2500 gms) with a corrected age (postnatal + gestational age - 40 weeks) of 25 to 105 weeks. The intercept is not statistically different from zero and the slope is 0.34. (From Brion LP, Fleischman AR, McCarton C, et al;16 with permission.)

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For this particular sample k = 0.33 ± 0.01. In general, with large and normally distributed sample populations, the mean value of k agrees to within 0.01 with the value calculated by regression analysis. 16, 77 The Value ofk in Children. Under steady-state conditions, k is directly proportional to the muscle component of body weight, which correlates reasonably well with daily urinary creatinine excretion rates, 45, 89 During growth, and especially after the postnatal and pubertal surges, one would expect to find differences in the percentage of muscle mass among various age groups. By statistically comparing the various age and sex groups of infants and children, we have found relatively clear-cut groupings that provide simple and easy-to-remember value of k: 0.33 in LBW infants, * 0.45 in full-term AGA infants up to one year or more of postnatal life, 0,55 in children starting at age 2 and in adolescent girls, and 0.70 in adolescent boys, commencing with the pubertal changes in body habitus (Table 5).16, 74, 77, 78 There are insufficient studies to determine values of k during the second year of life, Preliminary findings indicate that k may be 0.33 in LBW infants and 0.45 in full-term infants up to 18 months (Schwartz GJ, Brion LP: Unpublished observations, 1986). U sing the Talbot coefficient of 1 gm of urinary creatinine excretion per 17.9 kg of muscle mass,45, 89 we have calculated that a value of k equalling 0,55 corresponds to a muscle mass of approximately 39 per cent of t~ body weight. 77 Several investigators have noted that the use of k = 0.55 often results in inaccurate estimates of GFR. 2,28,33,40,58 We compared the results obtained from the formula GFR = kUPcr with those obtained by Cin in the same patients and found that there was very good agreement between the two sets of values. 16, 74 This led us to believe that one of the most common reasons for the lack of concordance is the inaccurate measurement of GFR. Additional contributing factors include sudden variations in renal function, as in an intensive care setting, and a 'deviation from the ideal body habitus, to which the constant 0.55 applies. *When performed on nonhemolyzed samples of blood from low birth weight neonate infants, the amidohydrolase technique yielded values of plasma creatinine concentration similar to those obtained with our modified Technicon method; however, these values generally exceeded 1. 0 mg per dl.

582

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Figure 6. Histogram of the individual values of k obtained in the sample of LBW infants described in Figure 5. 77 per cent of the values are between 0.2 and 0.5 mg/cmllOO minii. 73m 2 •

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Factors Affecting the Value of k. Even within each age group, the value of k is not the same for all patients and may not remain the same for a given patient during a major change in body habitus. A histogram of k values in LBW infants up to a corrected age of 15 months shows a good deal of scatter (Fig. 6). This reflects the variability in body composition as well as a number of other factors, such as differences in diet and creatinine excretion, errors in collection of urine, and inaccuracies in the measurement of creatinine. However, three quarters of the values fall within the relatively narrow range of 0.2 to 0.5 (see Fig. 6). Histograms with similar confidence intervals are found in the other age and sex groups (Table 5), indicating the reliability of kLlPcr as an estimate of GFR in most cases. To assess specifically the effect of growth on the value of k, we performed sequential water-loaded creatinine clearances in 25 growing children. During an average of 3.0 ± 0.4 (SE) years, these children gained 15.0+ 1.9 cm of height and 7.7 ± 1.4 kg of weight; however, the mean value ofk did not change significantly,(ilk = 0.03±0.22, p>O.1 by paired t-test) (Brion LP, Schwartz GJ: Unpublished observations, 1986). From these studies we can conclude that on average, k changes very little during normal growth and provides a satisfactory estimate of GFR, even while the accretion of muscle mass causes the plasma creatinine concentration to rise. It is known from anatomic data and creatinine excretion measurements that both obesity89 and malnutrition 46 • 82, 93 are associated with a decrease in the percentage of body weight that is muscle and, in the latter case, a decrease in body protein content. 5 We have obtained preliminary data for k in small for gestational age infants l6 and in anorectic teenagers (Table 6A).17 In each of these groups the value of k is lower, although not always significantly different from that corresponding to a respective well-nourished group matched for age and sex. Particularly striking in this regard are the values for the small for gestational age (SGA) term infants and the adolescent Table 5. Mean Values and Histograms of k AGE GROUP

LBW infants :5 1 year Full-term infants :5 1 year Children 2-12 years Females 13-21 years Males 13-21 years

K

K

PERCENT

(MEAN VALUE)

(RANGE)

WITHIN RANGE

0.33 0.45 0.55 0.55 0.70

0.20-0.50 0.30-0.70 0.40-0.70 0.40-0.70 0.50-0.90

77 79 83 77 82

PLASMA CREATININE FOR ESTIMATING GLOMERULAR FILTRATION RATE

583

Table 6. Values of k in Normal and Malnourished Children of Different Age Groups AGE GROUP

GA 25-34 week; corrected age up to 15 months GA 38-42 week; postnatal age up to 12 months 2-12 years 13-21 years 13-21 years

SEX

NORMAL

MALNOURISHED

M+F

0.34 ± 0.01(118)

0.31 ± 0.04(12) (SGA)

M+F

0.44 ± 0.02(63)t

0.33 ± 0.02(10)* (SGA)

M+F F M

0.56 ± 0.01(51)t 0.59 ± 0.02(52) 0.73 ± 0.05(52)t

0.31 ± 0.03(5)* (LGA)

0.58 ± 0.03(32) 0.49 ± 0.07(9)*

Mean ± SE (n); malnourished infants were SGA; malnourished adolescents were anorectic patients. *Significantly different (p < 0.05) from well-nourished group. tSignificantly different (p < 0.05) from age group above. From refs. 16,17, and 77 and from Schwartz G}, Brion LP: Unpublished observations, 1986.

males with eating disorders (Table 6).16. 17 Because no reduction in k was noted in the anorectic female subjects, we subdivided the group according to the degree of malnutrition and found a two-phased pattern of evolution. When body weight was above 80 per cent of the expected weight for length (grade I of acute malnutrition or mild malnutrition), k was 0.64±0.05 (Table 7). When body weight was below 80 per cent of the expected weight for length (grades II and III of acute malnutrition or moderate-to-severe malnutrition), k was significantly less, equaling 0.53 ± 0.03. Thus, in mild malnutrition, female adolescents tend to lose only the extra fat they had gained at puberty, whereas in more severe malnutrition they lose muscle in addition. A similar analysis performed in teenage male subjects revealed a k of 0.58 ± 0.10 with mild malnutrition and 0.38 ± 0.06 with moderate-tosevere malnutrition, indicating a loss of the muscle component of body weight even with mild degrees of acute malnutrition; the loss becomes larger in cases of severe malnutrition: Talbot showed that the muscle mass in obese patients is relatively smaller than in those of average weight. 89 One would therefore expect that the value of k should be lower in obese subjects, commensurate with the relative reduction in per cent muscle mass. Indeed, we found a lower value of k in a limited sample of large for gestational age (LGA) infants (Table 6).16 It is therefore apparent that the value of k is critically dep~ndent on body habitus, as well as on age and sex. Table 7. Values of k in Anorectic Children as a Function of Wasting DEGREE OF WASTING

MALE

FEMALE

Moderate-severe (W/Wp50 < 0.80) Mild (W/Wp50 > 0.80) Normal Controls (matched for age)

0.38 ± 0.06(4)*t 0.58 ± 0.10(3) 0.70 ± 0.02(112)

0.53 ± 0.03(18)* 0.64 ± 0.05(14) 0.63 ± 0.02(62)

Mean ± SE (n); W/Wp50 is body weight divided by 50th percentile weight for body height. *Significantly less (p < 0.05) than the mildly wasted group. tSignificantly less (p < 0.05) than normal controls.

584

GEORGE]. SCHWARTZ ET AL.

The values of k in Table 5 apply primarily to children of average build. When there are large deviations from the average physique such as with obesity, malnutrition, limb amputations, or deviant body size and shape, a unique determination of k may be necessary. This can be obtained from an accurately measured Ccr: k = Ccr Pcr/L

Subsequently, one may estimate GFR from kUPcr, provided that no major changes occur in k (i. e., in the patient's body habitus). For example, refeeding an anorectic teenager in the hospital may increase the percentage of muscle mass 14 and thus the value for k. This problem is further compounded by the fact that severe protein-calorie malnutrition may lead to a reduction in GFR52 and sometimes to higher values of Pcr than appropriate for the reduced muscle mass (Schwartz GJ: Unpublished observations, 1984-1986). Under these circumstances, unless a lower value of k is chosen, the formula kUPcr could markedly overestimate GFR and possibly obscure a diagnosis of renal insufficiency. Constancy of k cannot be assumed even for subjects of normal size because of variations in body composition. 37 For instance, cardiac patients have lower percentages of muscle mass than normal subjects. 38 Also, patients with ongoing severe chronic renal failure have been found to excrete less creatinine per unit of body size, allegedly because of altered biosynthesis or metabolism of creatinine. 60 Anthropometric Formulas for Estimating GFR We have shown that different values of k are needed to estimate GFR in full-term and in premature infants (see Tables 5 and 6). Since k is a function of urinary creatinine excretion per unit of lean body mass,78 and muscle mass can be estimated from urinary creatinine excretion, it became apparent to us that an anthropometric assessment of muscle mass may be substituted fQr the numerator kL when an estimate of GFR is needed in such infants.16 The major requirement is a convenient and reproducible measurement of a particular muscle along with the assumption that this measurement is representative of the infant's total muscle mass. It was already recognized that in older children90 ;md adults 45. 46 that the estimations of muscle mass derived from urinary creatinine excretion correspond rather well to values of muscle mass obtained from anatomic studies. 96 That this also applies to infants59. 85 was demonstrated by us in a heterogeneous (large, small, and appropriate for gestational age) group of preterm and fullterm infants with a corrected age of 28 to 105 weeks. 16 To avoid difficulties in choosing appropriate values of k, particularly in LBW infants, we first correlated upper arm muscle area (AMA) and arm muscle volume (AMV) with daily urinary creatinine excretion. The upper arm circumference (UAC) was corrected for the skinfold thickness (SFT) found above the biceps and triceps muscles, and AMA was calculated from AMA = (UAC(cm) - 0.314 SFT{mm))2/12.57 '6

where 0.314 is '11'/10 to correct for the measurement of SFT in mm, and 12.57 is 4'11', the factor that converts the square of a circumference to area,

PLASMA CREATININE FOR ESTIMATING GLOMERULAR FILTRATION RATE

585

The AMV requires, in addition, the measurement of the upper-arm length (from the olecranon to the acromion):

'iU2.

AMV = AMA x upper arm length

During the first year of postnatal life there was an excellent correlation between urinary creatinine excretion and either AMA (r=O.91), or AMV (r = 0.94), in infants of varying size, muscle mass, and maturity.16 These strong correlations have allowed us to generate least square linear equations for estimating absolute GFR from upper-arm muscle mass and plasma creatinine concentrations in LBW infants: Ccr (mllmin)

=

-0.14

+

0.41 AMAlPcr, r

=

0.95

or Ccr (ml/min)

=

0.35

+

0.031 AMV/Pcr, r

=

0.98 (Fig. 7)'6

Absolute Ccr can be corrected for body surface area (BSA) by: Ccr (mllmin/1. 73m 2 ) = Ccr (ml/min) x 1. 73/BSA *

These equations yield accurate values for GFR in a very heterogeneous sample of LBW infants, wherein at least two, and possibly three, different values ofk would be needed to estimate GFR from body length and plasma creatinine concentration (Tables 5 and 6). The possibilities of estimating accurately GFR from a single value of k in older children and adolescents with a variety of different types of body habitus is intriguing and needs to be tested. Data from direct measurements of muscle mass in the upper arm could be fitted as above into linear equations: GFR = a,

+ b, AMAlPcr and

GFR = a2

+ b2 AMV/Pcr

where a l and hi are least square regression coefficients (intercepts and slopes, respectively). The correlations may prove to be less strong in older children, because upper-arm muscle becomes less representative of overall muscle mass, particularly in physically active subjects l7 ; for example, arm muscle is less representative than thigh muscle in a ballet dancer. Perhaps an average sampling of leg and arm muscle would improve the correlation: GFR = a,

+ b, (AMA +

TMA) /2Pcr

GFR = a"

and b2 (AMV

TMV) /2Pcr

+

+

where TMA and TMV are thigh muscle area and volume, respectively. In children with gross musculoskeletal deformities, conventional anthropometric measurements may not be true indicators of muscle mass. 19 In patients with meningomyelocele, for example, GFR may be better measured from Pcr and arm span, rather than body length, because arm span may provide a better estimate of muscle mass. 19 *Because the changes in GFR did not correlate well with those in body surface area during infancy (Table 2) and the measurement of the latter adds an additional uncertainty to GFR, some pediatricians have used more extensively absolute values of GFR (ml per min), especially in the neonatal period. 7, 8, 16

GEORGE

586

-e

J.

•

20

.6

"e

~

u

SCHWARTZ ET AL.

r=0.98

16 12

(.)

....l&J

8

~

...J

0

U)

4

III

ct

0

0

100

200

300

400

500

600

ARM MUSCLE VOLUME I Per

(em 3 Img Idl) Figure 7. Prediction of abslute Ccr in ml per min f;om the ratio of arm muscle volume (AMV) to Pcr in 41 infants including 4 AGA and 1 LGA full-term infants and 30 AGA and 6 SGA preterm infants, with a corrected age (postnatal + gestational age in weeks - 40) of up to 105 weeks. Arm muscle volume was calculated from arm circumference, bicipital and tricipital skinfold thicknesses, and upper arm length, whereas urinary creatinine excretion (UcrV) was obtained from an 8-12 hour collection without urine loss. This allows the prediction of the Ccr for any body habitus, as opposed to the formula, Ccr = KL + Pcr, which assumes that the infant is part of a population with a relatively homogeneous body composition (that is, muscle mass per unit body size). (From Brion LP, Fleischman AR, McCarton C, et aI, J Pediatr (in press); with permission.)

CONCLUSIONS

The formula GFR = kLlPcr can be used to estimate GFR accurately in infants and children with grossly normal body habitus. The advantages of this approach include the rapid determination and the avoidance of urine collections. The use ofkLlPcr is superior to Pcr alone because the creatinine value is critically dependent on the percentage of muscle mass, in addition to renal function. Moreover, it is easier to grasp clinically significant changes when dealing with large (GFR) rather than small (Pcr) numbers: for example, a change in GFR of 40 ml per min per 1.73 m2 would correspond to a change in Pcr of only 0.2 mg per dl. When a patient has a body habitus that deviates markedly from normal, more elaborate methods for measuring GFR are required. These include endogenous Ccr, double exponential plasma disappearance of a marker, and standard clearances based on the infusion of inulin. Alternatively, the constant k for that patient may be derived from the equation k = GFR PcrlL. Yet another possibility is to use a formula combining Pcr and an anthropometric measurement of muscle mass; however, studies are needed to validate this approach beyond the preliminary results obtained in LBW infants (Fig. 7).16 For most pediatric subjects, GFR can be simply and reliably estimated from kLlPcr. The value of k for LBW infants during the first year of life is

PLASMA CREATININE FOR ESTIMATING GLOMERULAR FILTRATION RATE

587

0.33, for full-term appropriate for gestational age infants during the first year of life is 0.45, for children and adolescent girls is 0.55, and for adolescent boys is 0.70. When malnutrition or obesity is present, k tends to be lower than these values (see Tables 6 and 7). It should be reiterated that accuracy (within 5 per cent of true creatinine concentration) and precision « 10 per cent coefficient of variation in the measurement of Pcr) critically affect the validity of this estimate of G FR. ACKNOWLEDGMENTS Supported in part by the New York chapter of the American Heart Association and by grants HD 13232 (Schwartz GJ) and AM28477 (Spitzer A) from the Public Health Service. Dr. Schwartz is an Established Investigator of the American Heart Association. We thank the nurses of the Bronx Municipal Hospital Center and of the Hospital of the Albert Einstein College of Medicine for their assistance, Ms. D. Cozzi and R. Gray for typing the article, and Dr. A. Delferiere and Mr. A. Singleton for technical assistance.

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