Received 30 September 2004; accepted 26 April 2005 Available online 5 August 2005

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The European Journal of Heart Failure 8 (2006) 63 67 www.elsevier.

1 The European Journal of Heart Failure 8 (2006) The Modification of Diet in Renal Disease (MDRD) equations provide valid estimations of glomerular filtration rates in patients with advanced heart failure Eileen O Meara a, *, Kwok S. Chong b, Roy S. Gardner a, Allan G. Jardine c, James B. Neilly d, Theresa A. McDonagh e a Department of Cardiology, Western Infirmary, Glasgow, G11 6NT, United Kingdom b Department of Cardiology, Royal Infirmary, Glasgow, United Kingdom c Department of Nephrology, Western Infirmary, Glasgow, United Kingdom d Department of Nuclear Medicine, Royal Infirmary, Glasgow, United Kingdom e Department of Cardiology, Royal Brompton Hospital, London, United Kingdom Received 30 September 2004; accepted 26 April 2005 Available online 5 August 2005 Abstract Background: Glomerular filtration rate (GFR) has major prognostic implications in heart failure. Our objective was to validate the MDRD prediction equations for GFR in patients with advanced heart failure, and to compare their predictive performance to that of the Cockcroft Gault (CG) equation. Methods: We analysed GFR in 45 patients referred for heart transplantation evaluation. 51 Cr EDTA-measured GFR was compared to GFR estimates obtained by MDRD1 and MDRD2 equations, CG equation using actual body weight, and ideal body weight. Regression analyses and Pearson correlations were performed, and Bland and Altman plots were drawn. ROC curves were obtained to illustrate each equation s ability to predict a GFR less than 60 ml/min/1.73 m 2 (moderate renal impairment). Results: Patients had a mean age of 52 years, and 69% were in NYHA class III. The mean EDTA-measured GFR was 46.9T17.2 ml/min/ 1.73 m 2. The MDRD1 equation provided the best predictive model (narrowest limits of agreement; r =0.766, p <0.001), and the highest performance in predicting a GFR less than 60 ml/min/1.73 m 2 (area under curve: 0.901). Conclusions: MDRD equations, especially MDRD1, adequately predict GFR in advanced heart failure, with higher accuracy than the CG equation. MDRD1 also has higher performance in predicting a GFR less than 60 ml/min/1.73 m 2. D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Keywords: Heart failure; Glomerular filtration rate; Renal function; Modification of Diet in Renal Disease (MDRD); Heart transplantation 1. Background Creatinine is a poor indicator of renal function, and glomerular filtration rate (GFR) estimation is preferred in the assessment of renal function [1]. GFR is an independent prognostic marker in various heart failure * Corresponding author. Tel.: ; fax: address: eomeara16@yahoo.ca (E. O Meara). (HF) populations [2 5]. A GFR below 60 ml/min/1.73 m 2 is associated with complications of renal disease [1]. In patients with end-stage HF, irreversibly impaired renal function precludes eligibility for heart transplantation, and a simple method to accurately estimate renal function is of paramount importance. Although the Modification of Diet in Renal Disease (MDRD) equations [6,7] have been used to estimate GFR in HF studies [2 5], these have not been validated in patients with severe co-morbid conditions [1], including HF /$ - see front matter D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. doi: /j.ejheart

2 64 E. O Meara et al. / The European Journal of Heart Failure 8 (2006) Study objectives We sought to investigate the accuracy of the MDRD equation and its simplified version, MDRD-2, compared against 51 Chromium ethylenediaminetetraacetic acid ( 51 Cr EDTA)-measured GFR in advanced HF. We also examined the predictive value of the Cockcroft Gault (CG) equation [8], and assessed the effect of using ideal body weight (IBW) rather than actual body weight in our study population, as recommended for patients with potential volume overload [8]. 3. Methods 3.1. Patients In total, fifty-six 51 Cr EDTA GFR measurement tests were performed between July 2001 and January 2004 in patients who were referred to the Scottish Cardiopulmonary Transplant Unit for pre-transplant evaluation, and who were enrolled in a study on markers of prognosis in advanced HF [9]. All patients had given informed consent to participate in the latter study. Of these, there were 53 tests, performed in a stable clinical condition, for which corresponding biochemical data were available (in view of GFR estimations). Eight repeat tests were excluded, and therefore this analysis is based on a first GFR measurement in 45 different patients Measurements Serum creatinine was measured by using a kinetic alkaline picrate assay. Serum urea nitrogen (SUN) was measured by the urease method, and serum albumin by the bromocresol green method. Only laboratory values obtained within less than one week of the 51 Cr EDTA GFR measurement were used. Fig. 1. (a) through (d) illustrate the Bland and Altman plots [14,15], which compare each of the prediction equations studied with EDTA-measured GFR. Each value of egfr is compared to the corresponding measured value. The y axis shows the differences between these two values, and the x axis, the average of the two values, for each patient (in ml/min/1.73 m 2 ). The resulting upper and lower limits of agreement between the 2 methods are illustrated as dotted lines, and the middle line illustrates bias.

3 E. O Meara et al. / The European Journal of Heart Failure 8 (2006) Measured GFR was obtained by the slope-intercept method, using 4 plasma samples withdrawn between 2 and 5 h after injection of 51 Cr-EDTA, as detailed in the British Nuclear Medicine Society clinical procedural guidelines for GFR estimation [10]. Corrections were made using the Brochner Mortensen equation [11] and GFR was expressed as absolute values and corrected a for body surface area (BSA) of 1.73 m 2. Tightness of fit of the single exponential was verified using a graphical plot. Estimated GFR (egfr) were obtained by 4 methods (equations): (1) MDRD-1 equation: GFR (expressed in ml/min/1.73 m 2 )=170[plasma creatinine] [age] [0.762 if patient is female] [1.180 if patient is black] [SUN] [albumin] (2) MDRD-2 (abbreviated) equation: GFR (expressed in ml/min/1.73 m 2 )=186[Pcr] [age] [0.742 if patient is female] [1.212 if patient is black] (3) Cockcroft Gault formula normalized to a body surface area of 1.73 m 2, (Creatinine clearance, expressed in ml/min/1.73 m 2 ): GFR (males)=1.23 Weight (Kg)[140 age] /plasma creatinine (Amol/l)1.73/ BSA, GFR (females)=1.03weight (Kg) [140 age]/plasma creatinine (Amol/l) 1.73 /BSA, where BSA(m 2 )=¾[weight (Kg)height (cm) /3600] [12] (4) Cockcroft Gault formula using ideal body weight (IBW) and normalized to a body surface area of 1.73 m 2 : see Eq. 3, where weight is IBW [13], except when actual body weight (ABW) was lower than IBW, in which case ABW was used: IBW (males) =51.65+(1.85(height 60)) IBW (females)=48.67+(1.65(height 60)) Statistical analyses 51 Cr EDTA measured GFR was the reference method, against which calculated estimates of GFR were compared. Regression analyses and Pearson correlation coefficients were obtained using log-transformed data. The mean and median absolute differences were calculated from absolute difference = predicted value - measured value. Bias was calculated using the following equation: MEðmean errorþ ¼ ~ n i¼1 ðpe i Þ=n where pe i = predicted (estimated) value - true (measured) value, and n =sample size. Minitab version 13 was used for statistical analyses. Bland and Altman plots [14,15] were drawn to illustrate the limits of agreement between each prediction equation and the measured GFR (MedCalc Statistical Software) (Fig. 1). Sensitivity and specificity were calculated for each equation s ability to predict a GFR less than 60 ml/min/1.73 m 2, and their relative accuracies, with respect to this cut-point, were illustrated by Receiver Operating Characteristic (ROC) curves. 4. Results The baseline characteristics of the 45 patients are summarised in Table 1. The severity of heart failure in this group is reflected by 98% being in NYHA class III or IV, the mean ejection fraction of 11.6% (by radionuclide ventriculography), and very low peak oxygen consumptions (VO 2 max). However, the median heart failure survival score [16] indicates a moderate risk group, a category where medical therapy may be preferred to heart transplantation in some cases (considering risks versus benefits). Only 9% of patients had a history of diabetes, as evidence of end-organ damage precludes eligibility for heart transplantation. BMI ranged from 21 to 44 Kg/m 2 in this population, and 13 of the 45 patients (29%) had a BMI higher than 30 Kg/m 2 at the time of their GFR measurement. The range in difference between IBW and actual body weight (ABW), in % of IBW, varied between 1% and 96% (2 extreme values, higher than 50%), the median difference was 29%, with a mean of 29.8T20.5%. There were 13 of 45 patients (29%) who had an ABW within 15% of their IBW, reflecting a value higher than IBW in a majority. Patients who were judged candidates for heart transplant had an abdominal ultrasound, and amongst the 36 patients in whom the latter test was Table 1 Baseline characteristics (n =45) Age at GFR (years, meantsd) 52T8 Male sex (%) 34 (76) Body mass index (Kg/m 2, mean) 28T4 Body surface area (m 2, mean) 2.00T0.21 Diabetes mellitus (%) 4 (9) Coronary artery disease (%) 21 (47) Heart failure aetiology (IHD/DCM/other) (%) 19 (42)/23(51)/3(7) NYHA class (II/III/IV) (%) 1 (2)/31(69)/13(29) Left ventricular ejection fraction (%, mean) a 11.6T5.5 Peak oxygen consumption (ml/min/kg, mean) 10.2T2.5 Mean arterial blood pressure (mmhg) 75.6T10.2 Heart failure survival score b,c (median, 7.41( ) interquartile range) Kidney size d (abnormal/normal/unknown) (%) 6(13)/30(67)/9(20) Medication (%) ACE inhibitors or ARBS 95.6 Beta-blocker 82.2 Spironolactone 60.0 Diuretics (loop or thiazide) 97.8 Laboratory analyses Serum creatinine (Amol/L) 130.2T23.4 Serum urea nitrogen (mmol/l) 10.4T5.1 Serum albumin (g/l) 42.8T2.9 IHD, ischaemic heart disease; DCM, dilated cardiomyopathy. a Measured by radionuclide ventriculography. b Non-normally distributed; median and interquartile range presented. c Previously described in Circulation 1997; 95: d Measured by abdominal ultrasound.

4 66 E. O Meara et al. / The European Journal of Heart Failure 8 (2006) Table 2 Estimated GFR (egfr), compared against 51 Cr-EDTA GFR measurements* Prediction equation egfr ml/min/ 1.73 m 2 (meantsd) Mean absolute difference a Median absolute Bias b R 2 (adj.) c Pearson difference a correlation d MDRD T % MDRD T % CG f 59.7T % CG g IBW 46.9T % AUC-ROC e GFR<60 ml/min/1.73 m 2 a Difference between egfr and measured value, expressed in ml/min/1.73 m 2. b Bias is the mean prediction error, as described in the Methods section. c Percent variability in egfr explained by each regression model: predictive ability of the model. d p <0.001 for all three correlations. e Area under ROC curve, illustrating performance of each equation to predict GFR<60 ml/min/1.73 m 2. f Cockcroft Gault equation, with each GFR estimate normalized to a body surface area of 1.73 m 2. g Cockcroft Gault equation, using ideal body weight (IBW), except when IBW was higher than the actual body weight, in which case the latter was used. GFR estimates normalized to a body surface area of 1.73 m 2. * The mean GFR measured by 51 Cr-EDTA is 46.9T17.2 ml/min/1.73 m 2. performed, only 6 (17%) had reduced (abnormal) kidney size (less than 10 cm in at least in one kidney), which can be associated with irreversible renal damage. The mean measured GFR ( 51 Cr-EDTA GFR) was 46.9T17.2 ml/min/1.73 m 2. Only 1 of 45 (2%) patients had a measured GFR > 90 ml/min/1.73 m 2 (considered normal), nine of 45 patients (20%) had mild renal impairment (measured GFR between ml/min/1.73 m 2 ), a majority (28 / 45 = 62%) had moderate renal impairment (GFR between ml/min/1.73 m 2 ), and 7/45 (16%) had severe renal dysfunction (GFR <30 ml/min/1.73 m 2 ). The means of laboratory values used to calculate egfr for the corresponding 51 Cr-EDTA GFR measurements, are included in Table 1. The performances of each prediction equation used in this study are shown in Table 2. The Cockcroft Gault creatinine clearance prediction equation, when normalized to a body surface area of 1.73 m 2, overestimated GFR by 13 ml/min/1.73 m 2 (bias, or mean systematic error). In the original publication on MDRD prediction equation [6], a correction factor of 0.84 was used to calculate the CG estimate of GFR, in order to account for the average overestimation of GFR by 16% when using the CG creatinine clearance prediction equation. When using a correction factor of 0.84 in Eq. 3, the predictive value of CG (normalized to a BSA of 1.73 m 2 ) was not modified in our study population (data not shown). Conversely, using ideal body weight (IBW) rather than actual body weight (except when ABW was lower than IBW) completely abolished the bias observed with the CG equation. This could reflect a degree of fluid overload in some of our patients, despite a stable clinical condition. Using IBW had indeed been advocated by Cockcroft and Gault [8] in such circumstances. The predictive ability of the CG equation was nonetheless poorer than that of either MDRD equations; the correlations were lower, and the Bland and Altman plots illustrate larger limits of agreement with CG equations (whether using ABW or IBW i.e., Eqs. 3 Fig. 2. Receiver Operating Characteristic (ROC) curves, illustrating the accuracy of each equation in predicting a GFR<60 ml/min/1.73 m 2 (moderate renal impairment) [1]. AUC: area under the curve. CI: confidence interval.

5 E. O Meara et al. / The European Journal of Heart Failure 8 (2006) or 4) than with MDRD equations. The ROC curves also illustrate that MDRD1 has the highest accuracy (amongst the 4 equations compared) in correctly identifying a GFR<60 ml/min/1.73 m 2 (Fig. 2). 5. Conclusions The MDRD equations provide reasonably precise and accurate estimations of renal function in patients with advanced heart failure. The Cockcroft Gault equation more largely overestimates GFR, but bias can be corrected using IBW rather than ABW. However, MDRD equations predict GFR with higher accuracy, especially MDRD1, and should be used if precise estimates are required. They also directly provide egfr normalized to a BSA of 1.73 m 2, allowing simpler application of current nephrology guidelines. In addition, in this study population, MDRD1 has the best performance in predicting a GFR less than 60 ml/min/1.73 m 2, a value below which complications of renal impairment appear [1]. This study involved a relatively small sample of middleaged patients referred for heart transplant evaluation. Our findings may not be applicable to patients with other severe co-morbidities, to elderly patients with heart failure, to patients with less advanced HF or milder degrees of renal dysfunction. All patients included in this study were Caucasians, and our results may not extend to other ethnicities. Laboratory calibration for plasma creatinine concentration measurement may vary between laboratories, and cause differences in GFR estimations, especially at higher GFR values [17]. We could not address this issue in a single-centre study. Using 125 -I-Iothalamate rather than 51 Cr-EDTA, as in the original MDRD study, might have slightly modified the results. However, 51 Cr-EDTA is considered accurate, and is widely used and accepted as a radionuclide GFR-measurement method [18,19]. The gold standard of inulin clearance requires a 24-h collection, often unreliable without bladder catheterisation [19]. Subjecting future heart transplant recipients to more invasive procedures with infectious potential is not desirable. Acknowledgements We would like to thank Marieve Cossette and Farida Dabouz, biostatistitians at the Montreal Heart Institute Research Centre, for their help on statistical analyses. [2] Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2001;38: [3] McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002;13: [4] Anavekar NS, McMurray JJV, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004; 315(13): [5] McAlister FA, Ezekowitz J, Tonelli MR, Armstrong PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation 2004;109: [6] Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130: [7] Levey AS, Greene T, Kusek J, Beck GJ, Group MS. A simplified equation to predict glomerular filtration rate from serum creatinine (Abstract). J Am Soc Nephrol 2000;11(A0828). [8] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: [9] Gardner RS, Özalp F, Murday AJ, Robb SD, McDonagh TA. N- terminal pro-brain natriuretic peptide: a new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J 2003;24: [10] Fleming JS, Zivanovic MA, Blake GM, Burniston M, Cosgriff PS. Guidelines for the measurement of glomerular filtration rate using plasma sampling. British Nuclear Medicine Society Clinical Procedure Guidelines; 2004 April. [11] Brochner-Mortensen J. A simple method for the determination of glomerular filtration rate. Scand J Clin Lab Invest 1972;30: [12] Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317(17):1098. [13] Robinson JD, Lupkiewicz SM, Palenik L, Lopez LM, Ariet M. Determination of ideal body weight for drug dosage calculations. Am J Hosp Pharm 1983;40: [14] Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;i: [15] Ludbrook J. Statistical techniques for comparing measurers and methods of measurement: a critical review. Clin Exp Pharmacol Physiol 2002;29(7): [16] Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95: [17] Coresh J, Astor BC, McQuillan G, Kusek J, Greene T, Van Lente F, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 2002;39(5): [18] Rossing K, Christensen PK, Hovind P, Tarnow L, Rossing P, Parving HH. Progression of nephropathy in type 2 diabetic patients. Kidney Int 2004;66(4): [19] Brenner BM. Brenner & Rector s the kidney. 7th ed. Elsevier Chapter 24. References [1] Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:

Evaluation of the Cockroft Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients

Original article Annals of Oncology 15: 291 295, 2004 DOI: 10.1093/annonc/mdh079 Evaluation of the Cockroft Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients G.