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Estimating GFR From Serum Creatinine Concentration: Pitfalls of

GFR-Estimating Equations

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SSESSMENT OF glomerular filtration rate(GFR), the most frequently performed test

f kidney function, allows evaluation of theeverity of kidney failure, facilitates drug dosing,nd assists in evaluating uremic symptoms.1 Al-hough GFR can be measured directly by usingarenteral administration of inulin, iohexol, orothalamate, direct measurements commonly areot made because of cost, inconvenience, andonavailability of these tests to the vast majorityf patients with chronic kidney disease (CKD).owever, GFR often is estimated from serum

reatinine level and anthropometric and clinicalharacteristics of patients.

Creatinine clearance is directly proportional toreatinine generation and inversely proportionalo serum creatinine concentration. In practice,he broadly used Cockcroft-Gault formula2 useserum creatinine concentration, age, weight, andex to estimate creatinine clearance. It is basedn observations, reported by Cockcroft and Gault2

n 249 hospitalized patients aged 18 to 92 years,hat the generation of creatinine assessed byeans of 24-hour collection of urine is directly

roportional to weight, decreases with age, ands lower in women. The correlation coefficientetween their formula and creatinine clearanceas as good as the correlation coefficient be-

ween duplicate measurements of creatinine clear-nce. Thus, measurement of creatinine clearancesing timed urine collections does not provideore accurate estimates of GFR than prediction

quations.There are several pitfalls of this simple-to-use

ormula. First, body weight is an imperfect reflec-ion of creatinine generation because increasedody weight is associated more commonly withn increase in body fat or body water, edematousisorders, rather than an increase in muscle mass.3

econd, a variety of wasting illnesses, liver cir-

© 2005 by the National Kidney Foundation, Inc.0272-6386/05/4503-0021$30.00/0

idoi:10.1053/j.ajkd.2005.01.010

American Journal of10

hosis, and limb amputations often are associatedith a lower rate of creatinine generation thanould be reflected by body weight alone. Third,

he formula is calibrated to creatinine clearances the reference standard, not the direct measure-ent of GFR. Because creatinine is secreted in

he early stages of CKD, measurement of creati-ine clearance may substantially overestimatehe true GFR, especially in patients with CKDtage 2.4 A low-protein diet can reduce tubularreatinine secretion and creatinine generation,hereas antihypertensive therapy can reduce tu-ular secretion without influencing GFR.5 Fourth,erum creatinine also is influenced by creatininentake, such that a cooked-meat meal can substan-ially increase serum creatinine concentrationithout affecting creatinine clearance.6 Finally,rugs and other chemicals can interfere withreatinine secretion or estimation.7

Recognizing these limitations of the Cockcroft-ault and other creatinine clearance–based for-ulas, Levey et al8 developed an estimating

quation for GFR from knowledge of the serumreatinine concentration and other clinical char-cteristics, using directly measured GFR in 1,628articipants with CKD enrolled in the baselinehase of the Modification of Diet in Renal Dis-ase (MDRD) study. Because the MDRD for-ula is not calibrated to creatinine clearance, butFR, it addresses one shortcoming of the Cock-

roft-Gault equation. Furthermore, the MDRDormula does not use body weight in estimatingFR. Although blood urea nitrogen and serum

lbumin concentrations also were found to corre-ate with GFR (MDRD equation 7), contribu-ions of these two variables to the final equationre so small that Manjunath et al9 recommendedsimpler 4-component formula that includes justge, sex, race, and serum creatinine concentra-ion.

The abbreviated MDRD formula has beenhampioned by the National Kidney Foundation-idney Disease Outcomes Quality Initiative to

tage CKD.10 This formula also has been used tossess the prevalence of CKD in the generalopulation.11 Thus, performance characteristicsf this formula are of substantial public health

mportance. Accordingly, interest has emerged in

Kidney Diseases, Vol 45, No 3 (March), 2005: pp 610-613

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EDITORIAL 611

udging the accuracy and precision of this for-ula. To judge the adequacy of this formula, an

dequate sample size over a wide range of GFRalues and calibration of the serum creatinineeasurement to the reference standard are re-

uired.12 Furthermore, a reference standard forFR similar to that used in the MDRD studyould be required.In this issue of the American Journal of Kid-

ey Diseases, Zuo et al13 report performanceharacteristics of this formula in Chinese pa-ients. They studied 261 Chinese patients withtable CKD with a wide variety of causes ofidney disease.13 The proportion of patients withiabetes mellitus is not specifically reported, andlarger than usual percentage of patients had

bstructive uropathy (18.8%). The distributionf patients is between 30 and 90 patients in eachf the 5 stages of K/DOQI categories. The inves-igators were careful to exclude people withdema, cachexia, and amputation, thus obviatinghe pitfalls associated with estimation of GFRrom serum creatinine level. An appropriate ref-rence standard was used to measure GFR, anderformance of the MDRD equation 7, abbrevi-ted MDRD equation, and Cockcroft-Gault for-ulas was evaluated. The method of measuring

erum creatinine concentration (the Jaffé kineticeaction) was the same as that used in the MDRDtudy. Because the Hitachi autoanalyzer used inhis study consistently overestimates serum creat-nine compared with measurements made for the

DRD study, an adjustment for this error wasade.The major findings of the study are that theDRD equation underestimates GFR in patientsith CKD stage 1, whereas it overestimates GFR

n those with CKD stages 4 and 5. Approxi-ately 25% of results estimated using eitherDRD equation, but only 20% of results esti-ated using the Cockcroft-Gault equation, wereore than 50% off the true GFR value. By

omparison, in a white population, 29% of re-ults estimated using MDRD equation 7, 18%sing the abbreviated MDRD equation, and only2% using the Cockcroft-Gault equation wereore than 50% off the measured GFR value.14

It is not surprising that the formula based onerum creatinine concentration did not performell. First, performance of the MDRD formula is

ependent on ethnicity. Because only a small m

umber of people of Chinese descent were usedn the original validation of the formula, it is nourprise that the formula did not perform well inhis population. Second, because creatinine isecreted into the proximal tubule in early stagesf CKD, it is expected that serum creatinineould change little in early stages of CKD.15

ecause the MDRD study did not have enoughatients with relatively well-preserved GFR, itas not calibrated to this level of kidney func-

ion. Even if MDRD GFR was measured inatients with early kidney disease, it is unlikelyo improve the precision and accuracy of theFR estimate because of tubular secretion of

reatinine in patients with early CKD. In patientsith normal serum creatinine levels, absoluteFR14,16 or change in GFR16 cannot be assessed

eliably from GFR-estimating equations.What alternatives exist for the clinician in

ituations in which the MDRD equation does noterform well? In patients with early-stage CKD,n emerging GFR marker is serum cystatin Concentration.17,18 Cystatin C is not secreted inatients with early stages of CKD and may beore sensitive in detecting early-stage CKD.nother attractive technique is to use oral cimeti-ine to block tubular creatinine secretion andstimate creatinine clearance using the Cockcroft-ault formula19 or measure renal creatinine clear-

nce.20 Results of creatinine clearance measuredith 800 mg of cimetidine administered every 8ours for 3 doses are close to those obtainedsing a standard GFR marker.19 Using an enzy-atic assay instead of a colorimetric serum creat-

nine assay further improves results of the cime-idine-assisted GFR assessment.21 In patients withdvanced kidney disease, urea is reabsorbed byhe renal tubule. The arithmetic mean of renalrea and renal creatinine clearance are a goodpproximation of kidney function in such andvanced state of kidney disease,22 in which theDRD equation overestimates GFR.From the clinical perspective, users of this

ormula must recognize that the MDRD for-ula, as well as other creatinine clearance

ormulas, is only an estimate of GFR. Becausereatinine has inherent errors as a marker oflomerular function, all formulas that rely onerum creatinine will share these errors inFR. If estimates in individual patients are

ade, wide margins of error are likely to be

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ecognized if GFR is measured simultaneously.n other words, the prediction interval for thestimate in an individual is likely to be wide.lthough precision in the MDRD formula maye sufficient to accurately stage a patient withespect to CKD, following up the progressionf kidney disease with the MDRD formula willave the same shortcomings that are shared byeasurements of serum creatinine concentra-

ion.4,23,24 However, from the study of Zuo etl,13 it appears that the most convenient way tostimate GFR in Chinese patients is to useFR estimated by means of the Cockcroft-ault formula without the gender correction.uch estimation can be performed at the bed-ide by multiplying the Cockcroft-Gault creat-nine clearance by 0.84 and can facilitate clini-al decision making in Chinese patients. TheDRD formula in Chinese patients was not

uperior to the Cockcroft-Gault method; there-ore, in my opinion, the more cumbersome-to-se MDRD formula is not necessary in Chi-ese patients. Even in the larger MDRD study,hen the Cockcroft-Gault formula was cor-

ected for overestimation of GFR by multiply-ng the result by 0.84, it predicted 86.6% of theariance of the logarithm of GFR comparedith the MDRD formula, which predicted0.3% of the variance. Thus, if access to aomputer is not available, “back-of-the-enve-ope” calculations using the Cockcroft-Gaultormula are worth performing.

Rajiv Agarwal, MDAssociate Professor of Medicine

Indiana University and VAMCIndianapolis, Indiana

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alidity of rapid estimation of glomerular filtration rate inype 2 diabetic patients with normal renal function. Nephrolial Transplant 14:615-619, 199917. Mussap M, Dalla VM, Fioretto P, et al: Cystatin C is aore sensitive marker than creatinine for the estimation ofFR in type 2 diabetic patients. Kidney Int 61:1453-1461,00218. Risch L, Blumberg A, Huber A: Rapid and accurate

ssessment of glomerular filtration rate in patients with renalransplants using serum cystatin C. Nephrol Dial Transplant4:1991-1996, 199919. Ixkes MC, Koopman MG, Van Acker BA, Weber JA,

risz L: Cimetidine improves GFR-estimation by the Cock-roft and Gault formula. Clin Nephrol 47:229-236, 1997

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21. Kemperman FA, Silberbusch J, Slaats EH, et al:lomerular filtration rate estimation from plasma creati-ine after inhibition of tubular secretion: Relevance of thereatinine assay. Nephrol Dial Transplant 14:1247-1251,99922. Lavender S, Hilton PJ: The measurement of glomer-

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rogressive renal disease. Modification of Diet in Renalisease (MDRD) Study Group. Kidney Int Suppl 27:S73-80, 198924. Walser M, Drew HH, LaFrance ND: Creatinine mea-

urements often yield false estimates of progression in

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