George J. Schwartz

New Equations to Estimate GFR in Children with CKD

The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.

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

The formula GFR = kL/Pcr can be used to estimate GFR in infants, children, and adolescents who have grossly normal body habitus and are in steady-state condition. GFR is expressed in ml/min per 1.73 m2 BSA, L represents body length in cm, Pcr represents plasma creatinine concentration in mg per dl and k is a constant of proportionality that reflects the relationship between urinary creatinine excretion and units of body size. The value of k varies as a function of age and sex being 0.33 in preterm infants, 0.45 in full-term infants, 0.55 in children and adolescent girls, and 0.70 in adolescent boys. The advantages of rapid determination, reasonable accuracy, and the avoidance of urine collection justify the use of this formula in pediatric patients.

Geometric method for measuring body surface area: A height-weight formula validated in infants, children, and adults†

Estimates of body surface area were made based on measurement of 81 subjects, ranging from premature infants to adults. SA was calculated geometrically for each subject from 34 body measurements, and the values obtained compared with those based on previously published formulas and graphs. The most widely used formula, that of Du Bois and Du Bois, increasingly underestimated SA as values fell below 0.7 m2; the disparity was greatest in the newborn infant (7.96%). Closer agreement was obtained with the equations and nomograms of Body, Brody, Faber and Melcher, and Sendroy and Cecchini, although minor deviations were noted in some age ranges. The formula SA (m2) = weight (kg)0.5378 X height (cm)0.3964 X 0.024265, derived from the measured data by multiple regression analysis, gave a good fit for all values of SA from less than 0.2 m2 to greater than 2.0 m2 (r = 0.998). This formula was used to construct nomograms for estimation of SA in infants, children, and adults from height (length) and weight.

Measurement and Estimation of GFR in Children and Adolescents

GFR is the best indicator of renal function in children and adolescents and is critical for diagnosing acute and chronic kidney impairment, intervening early to prevent end-stage renal failure, prescribing nephrotoxic drugs and drugs cleared by a failing kidney, and monitoring for side effects of medications. Renal inulin clearance was the gold standard for GFR but is compromised by lack of availability, difficult assays, and problems of collecting timed urine samples, especially in children with vesicoureteral reflux or bladder dysfunction. Creatinine clearance-based estimates of GFR are often used in pediatrics. The addition of cimetidine to eliminate creatinine secretion permits accurate measurement of GFR in those who can completely empty their bladders to provide timed urine collections. Radioisotopes are used in plasma disappearance GFR determinations; however, these are not ideal for use in children, especially for repeated studies. The plasma disappearance of iohexol serves as a promising alternative GFR marker, because it is safe and not radioactive, easily measured, not metabolized or transported by the kidney, and excreted primarily by glomerular filtration. GFR estimating equations, based on serum concentrations of creatinine or cystatin C, are popular clinically and in research studies. Efforts are ongoing to improve these estimating equations for children and make the results readily available to clinicians obtaining standard chemistry profiles, as is being done for adults. However, at this time, there is no dependable substitute for an accurately determined GFR, and iohexol plasma disappearance offers the best combination of safety, accuracy, and reproducible precision.

A simple estimate of glomerular filtration ratein full-term infants during the first year of life

An estimate of glomerular filtration rate has been derived for children from body length (L, incentimeters) and plasma creatinine (Pcr, in milligrams per deciliter): GFR=0.55L/Pcr. The near universality of this estimate in children led us to seek a similar formula for estimating GFR in full-term infants during the first year of life. We measured Pcr in 137 healthy infants and performed creatinine clearance (Ccr) studies in 63 of them aged ≥5 days. Beyond the first week, Pcr averaged 0.39±0.01 (0.10SD) mg/dl. The estimate of GFR from 0.55 L/Pcr overestimated Ccr by 24% ( P 2 ) in full-term infants between 1 and 52 weeks of age. Because the constant 0.45 and Pcr do not change significantly during this period, GFR can be approximated at the bedside from the body length of the healthy full-term infant (GFR=0.45 L/0.39=1.1 L).

A simple estimate of glomerular filtration rate in adolescent boys

We reexamined the relationship between creatinine clearance (Ccr) and body habitus in 212 girls and 356 boys, including 181 boys and 69 girls between 13 and 21 years of age. The use of formula Ccr = k L/Pcr, where k = 0.55 for the calculation of GFR, resulted in a significant underestimation of GFR in adolescent boys but was suitable for girls. In 51 adolescent boys the equation Ccr = 0.7 L/Pcr resulted in an accurate estimate of GFR. Regression analysis in 133 boys aged 3 to 21 years showed that the constant k increased gradually and linearly with age (r = 0.35, P less than 0.01). GFR could be better estimated for boys of any age by the linear bivariate equation Ccr = 1.5 (age) + 0.5 (L/Pcr), where age is given in years (r = 0.82, P less than 0.001). This equation yielded slightly better results than did 0.7 L/Pcr in 91 additional clearance studies performed in adolescent boys with native kidneys or functioning renal transplants. The larger value for the constant k (0.7) and the age correction for GFR reflect the greater rate of urinary creatine excretion (and thus muscle mass) per unit of body mass in adolescent boys.

Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study.

An estimated 650,000 Americans will have ESRD by 2010. Young adults with kidney failure often develop progressive chronic kidney disease (CKD) in childhood and adolescence. The Chronic Kidney Disease in Children (CKiD) prospective cohort study of 540 children aged 1 to 16 yr and have estimated GFR between 30 and 75 ml/min per 1.73 m2 was established to identify novel risk factors for CKD progression; the impact of kidney function decline on growth, cognition, and behavior; and the evolution of cardiovascular disease risk factors. Annually, a physical examination documenting height, weight, Tanner stage, and standardized BP is conducted, and cognitive function, quality of life, nutritional, and behavioral questionnaires are completed by the parent or the child. Samples of serum, plasma, urine, hair, and fingernail clippings are stored in biosamples and genetics repositories. GFR is measured annually for 2 yr, then every other year using iohexol, HPLC creatinine, and cystatin C. Using age, gender, and serial measurements of Tanner stage, height, and creatinine, compared with iohexol GFR, a formula to estimate GFR that will improve on traditional pediatric GFR estimating equations when applied longitudinally is expected to be developed. Every other year, echocardiography and ambulatory BP monitoring will assess risk for cardiovascular disease. The primary outcome is the rate of decline of GFR. The CKiD study will be the largest North American multicenter study of pediatric CKD.

Carbon dioxide causes exocytosis of vesicles containing H+ pumps in isolated perfused proximal and collecting tubules.

In the turtle bladder it has recently been shown that CO2 stimulates H+ secretion, at least in part, by causing fusion of vesicles enriched in H+ pumps with the luminal plasma membrane. To test for the presence of this mechanism in the kidney we perfused collecting ducts and proximal straight tubules on the stage of an inverted epifluorescence microscope with fluorescein isothiocyanate dextran (70,000 mol wt) in CO2-free medium. After washout we noted punctate fluorescence in endocytic vesicles in some collecting ducts and in all proximal straight tubule cells. More cells took up fluorescent dextran in outer medullary than in cortical collecting ducts. Using the pH dependence of the excitation spectrum of fluorescein we found the pH of the vesicles to be acid (approximately pH 6). Addition of proton ionophores increased vesicular pH by 0.6 +/- 0.1 U, suggesting that the acidity of the vesicles was caused by H+ pumps. CO2 added to the medium (25 mmHg, pH 7.6 at 37 degrees C) reduced fluorescence intensity by 24 +/- 5% in cortical collecting ducts, 27 +/- 5% in medullary collecting ducts, and 25 +/- 5% in proximal straight tubules. Since this effect was prevented by the prior addition of colchicine to the bath, we believe that CO2 caused a decrease in cytoplasmic fluorescence by stimulating exocytotic fusion of the vesicles and thereby secretion of fluorescent dextran. This exocytotic fusion also occurred when tubules that were loaded with fluorescent dextran at a pCO2 of 37 mmHg were exposed isohydrically to a pCO2 of 114 mmHg; the mean decrease was 53 +/- 4%. We conclude that some cells in the collecting ducts and all cells in the proximal straight tubule incorporate fluorescent dextran into the apical cytoplasmic vesicles and acidify them with H+ pumps. CO2 causes fusion of these vesicles with the luminal membrane, but whether CO2 stimulates H+ secretion by increasing the number of functioning H+ pumps remains to be determined.

Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C.

The Chronic Kidney Disease in Children study is a cohort of about 600 children with chronic kidney disease (CKD) in the United States and Canada. The independent variable for our observations was a measurement of glomerular filtration rate (GFR) by iohexol disappearance (iGFR) at the first two visits one year apart and during alternate years thereafter. In a previous report, we had developed GFR estimating equations utilizing serum creatinine, blood urea nitrogen, height, gender and cystatin C measured by an immunoturbidimetric method; however the correlation coefficient of cystatin C and GFR (-0.69) was less robust than expected. Therefore, 495 samples were re-assayed using immunonephelometry. The reciprocal of immunonephelometric cystatin C was as well correlated with iGFR as was height/serum creatinine (both 0.88). We developed a new GFR estimating equation using a random 2/3 of 965 person-visits and applied it to the remaining 1/3 as a validation data set. In the validation data set, the correlation of the estimated GFR with iGFR was 0.92 with high precision and no bias; 91% and 45% of eGFR values were within 30% and 10% of iGFR, respectively. This equation works well in children with CKD in a range of GFR from 15 to 75 ml/min per 1.73 m2. Further studies are needed to establish the applicability to children of normal stature and muscle mass, and higher GFR.

Plasma creatinine and urea concentration in children: Normal values for age and sex

cytes forming rosettes with sheep erythrocytes and HTL antigen negative lymphocytes interacting with antigenantibody-complement complexes, Clin EXp lmmunol 14:319, 1973. 2. Yata J, and Tsukimoto I: Maturation of cell surface structure of human B. lymphocytes, Lancet 2:1435, 1972. 3. Darzynkiewicz Z, and Jacobson B: HEPES-buffered media in lymphocyte cultures, Proc Soc Exp Biol Med 136:387, 1971. 4. Lar~dolt RF: Das Knochenmark bei Pertussis, Helv Med Acta 2:153, 1945. 5. Morse SI: Studies on the lymphocytosis induced in mice by bordetella pertussis, J Exp Med 121:49, 1965. 6. Morse SI, and Riester SK: Studies on the leukocytosis and lympbocytosis induced by bordetella pertussis. II. The effect of pertussis vaccine on the thoracic duc~ lymph and lymphocytes on mice, J Exp Med 125:619, 1967. 7. Morse S!, and Riester SK: Studies on the leukocytosis and lymphocytosis induced by bordetella pertussis. I. Radioautographic analysis of the circulating cells in mice undergoing pertussis-induced hyperleukocytosis, J Exp Med 125:401, 1967. 8. Miale J B: Laboratory medicine: Hematology, ed 4, St. Louis, 1972, The C. V. Mosby Company, p 906.