Estimating glomerular filtration rate with creatinine-based equations by G. Virga

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1 Estimating glomerular filtration rate with creatinine-based equations by G. Virga Introduction Glomerular filtration rate (GFR) is traditionally considered the best overall index of kidney function. Estimating GFR from serum creatinine (scr) is a practical way to detect, assess and manage people with chronic kidney disease (CKD). The National Kidney Foundation - Kidney Disease Outcomes Quality Initiative (NKF- K/DOQI) recommends that patients with CKD or renal transplants should be classified in stages based on their GFR [1]. GFR is estimated from scr measurements to assess kidney function and the Cockcroft- Gault (C-G) and abbreviated MDRD (amdrd) formulas are recommended for this purpose in the K/DOQI guidelines [1]. Given its importance in clinical decisions (e.g. in considering living kidney donors, diagnosing initial kidney failure, establishing the dosage of pharmacological treatment, or prescribing dialysis) and in evaluating the effects of treatment, the accurate assessment of kidney function is crucial to nephrologists. Equations for estimating GFR In five of six studies, the error in the GFR estimated from Cr-based equations was found lower than the error in the GFR estimated from simultaneous Cr clearance (CL) using 24- hour urine collection [2]. Many formulas have been proposed in the last years, but I will focus on two Cr-based equations that have been extensively studied and widely applied, i.e. the C-G and the amdrd equations. C-G, GFR (ml/min)= [(1-age)*BW] / (72*sCr) (*.85 for females) [3], which needs to be normalized to a body surface area (BSA) of 1.73 m 2. amdrd, GFR (ml/min 1.73 m 2 )= 186*(sCr (-1.154) )*(age (-.3) ) (*.742 for females, *1.212 for Afro-Americans) [4]. The amdrd equation dose not require a body weight variable because it normalizes GFR to a standard BSA of 1.73 m 2. A new dual equation demanding a BSA normalization and validated by plasma CL of iohexol has recently been proposed: Virga, GFR (ml/min)= {[69.4-(.59*age)+(.79*BW)]/sCr}-3. for males and {[57.3-(.37*age)+(.51*BW)]/sCr}-2.9 for females [5]. Cr-based equations cannot be used to estimate GFR in cases with cirrhosis, paraplegia or pregnancy, under 18 years of age or, more generally, in individuals in an unsteady state. Methodological problems in comparing the performance of different equations The most important methodological problems in comparing the performance of different equations concern: 1. the standardization of assays for measuring scr concentrations, 2. the choice of the statistical method used for the comparison, and 3. the reference tracer(s) for the validation analysis. 1. An international effort to standardize the assay process has been undertaken, led by the National Kidney Disease Educational Program in the USA [6]. Isotope dilution mass spectrometry (IDMS) has been accepted as the reference method, and diagnostic companies are revising their assay methods to produce results aligned with this method [7]. The original amdrd should be used with the usual Cr methods that have not been calibrated so that they can be traced to IDMS, while the IDMS-traceable amdrd equation 1

2 (using 175 instead of 186 as the coefficient in the equation) [8] should be used only with the Cr methods that have been calibrated so as to be IDMS-traceable. 2. In order to validate an equation for estimating GFR a general agreement is desirable. An estimate is called valid if it is both accurate and precise. The best accuracy index is probably the mean absolute percentage error (MAPE) together with the relative accuracy (percentage of GFR estimates lying within %, % and 5% of measured GFR) (Table 1). The best way to express the precision is as the standard deviation of the difference between the surrogate estimates and the GFR [2]. This quantity can be assessed by calculating the Root Mean Square Error (RMSE) for an equation: the smaller the RMSE, the greater the precision of the formula. Instead of the bias (mean error), the mean percentage error (MPE) is probably more useful for representing the mean global tendency of an equation to under- or over-estimate the true GFR. It is only very seldom that a published equation s validation includes all the accuracy and precision indexes. 3. As nicely explained by Lin et al. [9], the performance of an equation for estimating GFR can vary widely depending on the tracer used for its validation. In healthy subjects, accuracy to within % of the C-G equation was 73% if Tc-DTPA was used, but only 45% using iothalamate; and for the amdrd formula, the percentages were 49% and 78%, respectively [9] (Table 1). If an equation like the amdrd has been developed using the CL of a given tracer, i.e. iothalamate, then the equation can be expected to benefit from a certain advantage when it is compared with other equations using iothalamate as the reference tracer, so comparisons between equations should be drawn using different tracers from those used to develop the equations. Moreover, since the accuracy of the equations is tested using tracers, we need to bear in mind that the measurement error of these filtration markers ranges from 5 to % (within a single CL procedure or between CL procedures on different days) []. Comparison between the performance of the C-G and amdrd equations It has been demonstrated that the C-G formula can overestimate GFR at low renal function levels [11,12,13] and underestimate high GFR values [14]. Other GFR overestimation biases have been demonstrated for overweight [11,12], young [12] and female [12] individuals. The amdrd equation clearly underestimates GFR in cases with high renal function levels [9,11,12,14,15] and Levey emphasized the need for caution in applying the amdrd formula to individuals with a scr within the normal range because it has not been validated in people without renal disease [16]. That the amdrd underestimates GFR was also recently demonstrated in renal failure [13,15], in females [12,15] and in overweight patients [12,17], while the opposite is true of lean subjects [17]. Both Tidman et al. [18], using iohexol CL in CKD patients, and Zahran et al. [19], using inulin CL in renal transplanted subjects, came to the same conclusion: the BSA-modified C-G equation is more accurate in CKD stages 1-2 (GFR> 6 ml/min) than the amdrd equation, while the latter is better for stages (GFR< 6 ml/min). In the future, the recently-proposed Virga equation (Figs.1-2-3) may be able to replace the C-G for estimating GFR in CKD stages 1-2, mainly because it has a lower overestimating effect with increasing body weight, and because it has a dedicated formula for females [5]. 2

3 Table 1. Comparison between C-G and amdrd equations in terms of relative accuracy ± -% C-G amdrd Tracer Reference Healthy within % 73% 49% Tc-DTPA [9] within % 54% Iothalamate [14] within % 45% 78% Iothalamate [9] within % 85% 86% Iothalamate [] CKD within % 59% 28% Iohexol [21] within % 58% Tc-DTPA [22] within % 79% 74% Iohexol [5] within % 69% 8% Iohexol [18] within 25% 85% 78% Inulin [23] Transplanted within % 67% Tc-DTPA [24] within % 84% 8% Tc-DTPA [25] within % 57% 76% Iohexol [26] Fig.1 Young males (cm 175, 25 years old, scr 1. mg/dl), left, and young females (cm 165, 25 years old, scr.85 mg/dl), right, with normal kidney function and body weight (BW) from 6 to 1 kg. The C-G formula increasingly estimates GFR as BW rises, and more so among females. The amdrd formula estimates GFR to be below normal (< 9 ml/min 1.73) for all BW in both populations (CKD stage 2, mild renal failure). Adapted from Virga et al. [5] and reprinted with permission BW (Kg) 8 BW (Kg) Legend: GFR estimated by the C-G (x), amdrd ( ) and Virga ( ) equations 3

4 Fig.2 Young normal-weight males (cm 175, kg 7, 25 years old), left, and young normalweight females (cm 165, kg 6, 25 years old), right. In end-stage renal disease (GFR= 5 ml/min 1.73 m 2 ) there are no differences of clinical interest between the GFR estimated by the amdrd and the Virga equations. Adapted from Virga et al. [5] and reprinted with permission Fig.3 Elderly normal-weight males (cm 175, kg 7, 75 years old), left, and females (cm 165, kg 6, 8 years old), right, with scr from 1. to 12. mg/dl. In severe renal failure (GFR< ml/min 1.73), there are no differences of clinical interest in the GFR estimated by the three equations. Adapted from Virga et al. [5] and reprinted with permission Conclusions The use of Cr-based equations to assess GFR makes good sense in clinical practice, subject to their limitations when it comes to cirrhotic, paraplegic, amputated or pregnant individuals and unsteady state subjects. The BSA-normalized C-G equation for cases of normal or near-normal renal function, and the amdrd formula for certain renal failure are the most accurate tools for this purpose. The completion of the international effort to standardize the methods for assaying scr concentration will lead to a significant improvement in the estimation of GFR. A general agreement on the best tracer and the most suitable statistical analysis for evaluating old and new equations would also be desirable. 4

5 References 1. National Kidney Foundation/DOKI Clinical Practice Guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2; 39:S Walser M: Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis 1998; 32: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: Levey AS, Greene T, Kusek JW, et al. A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol ; 11: A Virga G, Gaspari F, Thomaseth K, et al. A new equation for estimating renal function using age, body weight and serum creatinine. Nephron Clin Pract 7; 5:c43-c National Kidney Disease Educational Program. Creatinine Standardization Program. http// (accessed Apr 7). 7. Mathew TH, Johnson DW, Jones GR on behalf of the Australasian Creatinine Consensus Working Group. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: revised recommendations. Med J Aust. 7; 187: Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 6; 145: Lin J, Knight EL, Hogan ML, et al. A comparison of prediction equations for estimating glomerular filtration rate in adults without kidney disease. J Am Soc Nephrol 3; 14: Stevens LA, Coresh J, Greene T, et al. Assessing kidney function measured and estimated glomerular filtration rate. New Engl J Med 6; 354: Poggio ED, Wang X, Greene T, et al. Performance of the Modification of Diet in Renal Disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol 5; 16: Froissart M, Rossert J, Jacquot C, et al. Predictive performance of the Modification of Diet in Renal Disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol 5; 16: Kuan Y, Hossain M, Surman J, et al. GFR prediction using the MDRD and Cockcroft and Gault equations in patients with end-stage renal disease. Nephrol Dial Transplant 5; : Rule AD, Gussak HM, Pond GR, et al. Measured and estimated GFR in healthy potential kidney donors. Am J Kidney Dis 4; 43: Cirillo M, Anastasio P, De Santo NG. Relation of gender, age, and body mass index to errors in predicted kidney function. Nephrol Dial Transplant 5; : Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 1: Beddhu S, Samore MH, Roberts MS, et al. Creatinine production, nutrition, and glomerular filtration rate estimation. J Am Soc Nephrol 3; 14: Tidman M, Sjöström P, Jones I. A comparison of GFR estimating formulae based upon s-cystatin Cand s-creatinine and a combination of the two. Nephrol Dial Transplant 7 Oct 2; [Epub ahead of print]. 19. Zahran A, Qureshi M, Shoker A. Comparison between creatinine and cystatin C-based GFR equations in renal transplantation. Nephrol Dial Transplant 7; 22: Poggio ED, Wang X, Greene T, et al. Performance of the Modification of Diet in Renal Disease and Cockcroft-Gault equations in the estimation of GFR in health and in chronic kidney disease. J Am Soc Nephrol 5; 16:

6 21. Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2; 13: Zuo L, Ma Y-C, Zhou Y-H, et al. Application of GFR-estimating equations in Chinese patients with chronic kidney disease. Am J Kidney Dis 5; 45: Rostoker G, Andrivet P, Pham I, et al. A modified Cockcroft-Gault formula taking into account the body surface area gives a more accurate estimation of the glomerular filtration rate. J Nephrol 7; : Pöge U, Gerhardt T, Stoffel-Wagner B, et al. Cystatin C-based calculation of glomerular filtration rate in kidney transplant recipients. Kidney International 6; 7: White C, Akbari A, Hussain N, et al. Chronic kidney disease stage in renal transplantation classification using cystatin C and creatinine-based equations. Nephrol Dial Transplant 7; 22:13-. Epub 7 Jun. 26. Gaspari F, Ferrari S, Stucchi N, et al. Performance of different prediction equations for estimating renal function in kidney transplantation. Am J Transplant 4; 4:

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