- Email: [email protected]
Validation of the revised MDRD formula and the original Cockcroft and Gault formula for estimation of the glomerular filtration rate using Australian data
Pathology (June 2009) 41(4), pp. 379–382
CHEMICAL PATHOLOGY
Validation of the revised MDRD formula and the original Cockcroft and Gault formula for estimation of the glomerular filtration rate using Australian data GRAHAM R. D. JONES*{
AND
SEYED K. IMAM{{
*Department of Chemical Pathology, SydPath, St Vincent’s Hospital, Sydney, {Department of Medicine, University of NSW, Sydney, and {Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, NSW, Australia
Summary Aims: The estimation of glomerular filtration rate (eGFR) using the MDRD (Modification of Diet in Renal Disease) formula is a recommended practice in Australia, New Zealand and other countries. Since the original development of this formula, an international process to align assays for serum creatinine has been undertaken and a revised version of the MDRD formula has been produced for these assays. Additionally, the Cockcroft and Gault (C&G) formula remains recommended for drug dosing decisions, although there are different versions of the formula using either actual weight or calculated ideal body weight. We aimed to assess these formulae using Australian data. Methods: We assessed the revised MDRD and the C&G formulae by comparison with radio-isotope GFR measurements using patients routinely referred for this test. The MDRD was compared to GFR corrected for body surface area and the C&G to the uncorrected GFR. Results: The MDRD was shown to have the expected scatter of over +30% but with median values not significantly different from isotopic GFR measurements and without a systematic deviation due to age, gender, height, weight or body mass index (BMI). The original C&G formula generally provided a good estimate of GFR, however the use of ideal body weight rather than actual body weight produced an under-estimated GFR in this population which was more prominent with increasing age and BMI. Conclusions: The MDRD and original C&G formulae were found to be valid in an Australian setting. The C&G formula, when calculated using weight estimated from patient height, was found to underestimate GFR in some patients. Key words: GFR, creatinine, kidney disease, MDRD, Cockcroft and Gault formula. Abbreviations: BMI, body mass index; BSA, body surface area; C&GAMH, Australian Medicines Handbook modification of the Cockcroft and Gault formula; C&G-O, original Cockcroft and Gault formula; DTPA, diethylenetriaminepentaacetic acid; GFR, glomerular filtration rate; IDMS, isotope dilution mass spectrometry; MDRD, Modification of Diet in Renal Disease; PET, positron emission tomography; RCPA QAP, Royal College of Pathologists of Australasia Quality Assurance Programs. Received 7 January, revised 19 June, accepted 21 July 2008
INTRODUCTION The MDRD formula, named after the Modification of Diet in Renal Disease study, is recommended for use in Australasia for the routine estimation of glomerular filtration rate (eGFR) with every request for serum creatinine in adults.1 The original ‘4 variable’ MDRD formula (Table 1) was derived using creatinine measurements from a Beckman-Coulter CX3 analyser in the early 1990s.2 In 2006 the formula was revised for use with creatinine assays aligned with the international reference method, isotope dilution mass spectrometry (IDMS).3,4 This revised formula has been described as the ‘175’ version of the MDRD formula after the first coefficient of the equation (Table 1) and has been recommended for use in the USA5 and Australasia6 for IDMS-aligned creatinine assays. The Cockcroft and Gault formula (C&G) for estimation of creatinine clearance7 remains recommended for drug dosing decisions,8 although it was also derived and validated with serum creatinine assays in use prior to the introduction of the newer IDMS-aligned assays. There is added variability with the application of the C&G formula with variation in the recommended use of measured weight or ideal body weight estimated from patient height.8,9 The use of ideal body weight in place of actual body weight is a modification of the C&G formula to avoid over-estimating muscle mass in obese subjects with the version in the Australian Medicines Handbook using the lower of actual or ideal body weight (C&G-AMH)8 and the version in Therapeutic Guidelines using the ideal body weight in obese subjects (C&G-TG).9 Additionally C&G-AMH has a factor of +10% based on a subjective assessment of body frame. The performance of these versions of the C&G formula with IDMS aligned serum creatinine assays has not been previously investigated. A recent major analysis of the MDRD formula has been performed using previously published data on over 5000 subjects using mathematical corrections to adjust measured creatinine to values expected with IDMS assays.10 At the time of writing there are no validations of the revised MDRD formula using IDMS aligned assays for the original measurements, and specifically no such validations from Australia or New Zealand. We assess the performance of the revised MDRD formula using subjects with routine requests
Print ISSN 0031-3025/Online ISSN 1465-3931 # 2009 Royal College of Pathologists of Australasia DOI: 10.1080/00313020902884980
380
Pathology (2009), 41(4), June
JONES AND IMAM
for a formal GFR measurement using an IDMS-aligned creatinine assay, and also assess different versions of the performance of the C&G formula in this setting.
METHODS GFR was measured in subjects referred for formal GFR measurement using 99mTc-Diethylenetriaminepenta-acetic acid (DTPA) at the Department of Nuclear Medicine and Positron Emission Tomography (PET) at Liverpool Hospital. The studies were performed between January 2003 and April 2007. Serum creatinine was measured throughout the study using a Roche rate-blanked compensated Jaffe assay on one of two Roche Hitachi Modular analysers (Roche, Australia). This method has IDMSalignment claimed by the manufacturer and supported by a local study.11 Accuracy of the serum creatinine assay was confirmed by assessment of performance in the Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP) throughout the period of data collection. The eGFR was calculated using the MDRD ‘175’ formula. The C&G equation was applied using both the original version (C&G-O) and the version recommended in Australian Medicines Handbook (C&GAMH); however, the correction for heavy or light body frame was not included (Table 1). MDRD results were compared with DTPA results reported as mL/min/1.73m2 after correction for body surface area (BSA) and C&G results were compared with uncorrected results (mL/min). Overall agreement as well as the effect of age, gender, weight, BSA and body mass index (BMI) were assessed. For assessment of sex differences, TABLE 1
Equations
Original MDRD equation: eGFR (mL/min/1.73m2) ¼ 186 6 (S.Cr 6 0.0113)71.154 6 age70.203 6 F1 (F1 ¼ 1.0 for males and 0.742 for females) The revised MDRD equation for use with IDMS aligned creatinine assays (‘175’ equation): eGFR (mL/min/1.73m2) ¼ 175 6 (S.Cr 6 0.0113)71.154 6 age70.203 6 F1 (F1 ¼ 1.0 for males and 0.742 for females) The Cockcroft and Gault formula for estimation of creatinine clearance was used as follows (C&G-O):9 Creatinine clearance (mL/min) ¼ F2 6 (140 – age) 6 Wt/(0.815 6 S.Cr) (F2 ¼ 1.0 for males and 0.85 for females) The ideal body weight was calculated from patient height as follows and used in place of measured weight if it was lower (C&G-AMH)8 or if the patient was obese (C&G-TG):9 Ideal body weight ¼ 50 þ (Ht – 152) 6 0.45 – F3 (F3 ¼ 0 for males and 4.5 for females) For all equations the age is in years, weight (Wt) in kg, height (Ht) in cm and serum creatinine (S.Cr) in mmol/L.
TABLE 2
the male and female ratios of MDRD or C&G results to DTPA results were compared with the T-test. For assessment of other variables, the ratios were analysed in bins separated on the basis of the factor under consideration. The distribution of data in each bin was described with the median value and the 90% confidence limits of the median12 as well as the percentage of samples outside +30%. Statistical calculations were performed using Microsoft Excel (Microsoft, USA). No approval was sought from an institutional ethics committee as the process involved only retrospective review of previously collected data and no patient was identifiable from the presented information.
RESULTS During the study period 200 GFR studies were performed on 198 subjects. Results of 28 studies were not included due to creatinine measurements being performed more than 30 days prior to the GFR study. For subjects with multiple studies, only the first study was included. Results of three studies were excluded from the analysis as outliers, as the creatinine-based estimates of GFR were over twice the results of the formal GFR study. The creatinine measurements for subjects included in the analysis were made up to 29 days prior to the GFR measurement, with a median of 4 days. The study population included 98 men and 69 women. Detailed demographics and summary data are shown in Table 2. RCPA QAP external quality assurance data demonstrated that the serum creatinine assay performed as expected with end-of-cycle results showing regression lines very close to the median for the method throughout the entire period of the study. There was no difference between the male and female ratios of MDRD, C&G-O or C&G-AMH to DTPA. The results were as follows: MDRD/DTPA: average male ratio 0.98, average female ratio 0.97, p value 0.69; C&G-O/ DTPA: 0.99, 1.05, 0.19; C&G-AMH: 0.83, 0.77, 0.09. Variations in the ratios of MDRD with DTPA GFR are shown in Fig. 1 for a range of variables. The median of MDRD results was not significantly different from that of DTPA for all bins of GFR values up to 120 mL/min. Although the median MDRD was slightly less than the median DTPA, for DTPA results below 90 mL/min/1.73m2 more MDRD results were over 30% higher than DTPA (n ¼ 14, 11%) than were over 30% lower (n ¼ 7, 6%, Fig. 1A) giving a total of 83% within +30% for this range. The influence of various other factors on the ratio of
Subject demographics All (n ¼ 167)
Male (%) Age (years) Weight (kg) Ideal body weight (kg) BMI (kg/m2) Height (cm) BSA (m2) Creatinine (mmol/L) DTPA GFR (mL/min/1.73m2) MDRD (mL/min/1.73m2) Cockcroft and Gault (mL/min) C&G-AMH (mL/min)
Male (n ¼ 98)
Female (n ¼ 69)
Median
Range
Median
Range
Median
Range
57 65 74 60 27.3 164 1.82 92 75 68 70 57
20–100 40–129 33–86 14.9–51.0 138–192 1.24–2.53 39–1020 5–150 5–143 10–206 7–166
67 75 67 27.2 171 1.90 100 73 67 69 58
26–100 46–125 49–86 15.8–42.7 151–192 1.47–2.53 52–1020 5–121 5–138 10–206 7–166
62 71 49 28.1 156 1.67 74 79 69 70 53
20–89 40–129 33–68 14.8–51.0 138–177 1.24–2.24 39–340 22–150 11–143 15–200 10–112
REVISED MDRD FORMULA VALIDATION
MDRD to DTPA GFR results was also examined. Patients less than 50 years of age had slightly lower median MDRD than DPTA results, as did patients over 80 years (Fig. 1B). No significant effect was seen on MDRD values for BMI (Fig. 1C), weight, height or BSA (data not shown). The performance of C&G-O and C&G-AMH are also shown in Fig. 1. The median of the C&G-O results was also not different from DTPA for GFR results up to 120 mL/ min and for DPTA values less than 90 mL/min/1.73m2, 19 C&G-O results (15%) were over 30% higher than DTPA and 11 (9%) were over 30% lower, making a total of 76% within +30%. By contrast, the C&G-AMH formula produced results with a consistent negative bias of the C&G-AMH medians as compared to DTPA for all bins of results with a GFR 4 30 mL/min/1.73m2, with 46 results (37%) less than 90 mL/min over 30% below than DTPA results and only three (2%) over 30% high, making a total of 61% within +30%. This is seen especially in older subjects and subjects with high values for BMI (Fig. 1H,I). The effect of using the TG modification of the C&G formula is to produce results which are, on average, between the other two versions of the formula (data not shown).
DISCUSSION The data presented support the use of the revised ‘175’ MDRD formula for eGFR calculations using IDMS-
381
aligned creatinine assays. The formula is shown to be appropriate for a wide range of demographic variables such as gender, age, height, weight, BMI and BSA and to be suitable for use for values up to at least 90 mL/min/1.73m2. The results show considerable scatter of the MDRD estimate compared to formally measured GFR with only 83% of results within +30%, a finding consistent with previous publications. Some of this scatter will be due to variability in measurement of serum creatinine and in the formal GFR measurements, as well as the limitations due to the formula. The original C&G formula, when applied using an IDMS-aligned creatinine assay, also performed well compared to formal GFR measurements. This is a somewhat unexpected finding as the clearance of creatinine should be higher than the GFR due to tubular secretion and gastro-intestinal losses. It is also surprising as IDMS-aligned creatinine assays tend to give lower results than older assays due to removal of the effect of non-creatinine chromogens, a change which would tend to increase the calculated C&G result. The previous large combined analysis showed median differences of 10–20% with C&G being higher than the measured GFR.13 These data vary from the current study as the patients were younger, with a mean age of 47 years compared to 62 years in our study, and older subjects are known to have a relatively lower C&G result compared to MDRD results.
FIG. 1 (A–C) Influence of various factors on the ratio of MDRD to DTPA GFR (both in mL/min/1.73m2, left side panels), (D–F) Cockcroft and Gault to DTPA GFR (both in mL/min, middle panels), and (G–I) Cockcroft and Gault based on ideal body weight to DPTA GFR (both in mL/min, right hand panels). Crosses, individual data points; black diamonds and thick solid lines, median values of data bins; grey diamonds and thin solid lines, 10th and 90th centile confidence intervals for median result; thin dashed lines, differences of +30%. (A, D, G) Effect of GFR (mL/min/1.73m2). (B, E, H) Effect of age (years). (C, F, I) Effect of BMI (kg/m2). The bin size and number of data points in each bin is shown for the MDRD data with the same bins used for the middle and right side panels. For clarity a single data point was excluded from Fig. C, F and I (BMI ¼ 51; MDRD/DTPA ¼ 0.92; C&G/DTPA ¼ 1.55; C&GAMH/DTPA ¼ 0.62).
382
Pathology (2009), 41(4), June
JONES AND IMAM
The use of the ideal body weight in place of the actual body weight produced a marked negative bias in C&G results compared to formal GFR measurements. This is expected mathematically as the median ideal body weight was only 60 kg compared to the median measured body weight of 74 kg, indicating a median reduction in C&G results of about 20%. Variations of the C&G formula include the use of ideal body weight estimated from patient height as a method to mitigate the contribution of excess body fat to the measured weight8,9 so it is of interest that this correction becomes progressively less accurate as BMI increases (Fig. 1I). The recommendation to use C&G values for drug dosing decisions may be based on clinical studies where toxicity and efficacy were originally assessed with this formula, and in this case the important issue is correspondence with results obtained in those studies rather than with the formally measured GFR. However the change in creatinine assays, together with other factors, may have lead to changes in the performance of this equation over time. A revision of the assessment of renal function for drug dosing decisions is urgently required. Limitations to this study include the limited sample size and the nature of the population being tested, which represents a specific group referred for specialised renal assessment and there may be limitations in generalising this to the population where the eGFR is in widespread use. Although the subjects are likely to have stable renal function, the delay between serum creatinine measurement and GFR measurement may add some variability. It should also be recognised that there is variation between methods for formal GFR measurement and this may be a cause of different results in other studies.13 This study has the advantage of using a serum creatinine assay and a GFR measurement method that are both in routine use in Australia. In summary, the ‘175’ MDRD formula for IDMSaligned assays showed a good correlation with formally measured GFR using an IDMS-aligned creatinine assay. The formula was robust for a wide range of variation in patient characteristics. The original C&G equation using the IDMS-aligned creatinine assay correlated well with measured GFR, although low results were seen in patients over 70 years of age. By contrast, the modification of the C&G formula using an estimate of ideal body weight consistently under-estimated the true GFR.
ACKNOWLEDGEMENTS We would like to recognise the input of Dr John Chu of the Department of Nuclear Medicine and PET, Liverpool Hospital who passed away prior to submission of the paper and thank Frank Alvaro from South Western Area Pathology Service Biochemistry Department for provision of quality assurance data for the creatinine assays. Address for correspondence: Dr G. R. D. Jones, Department of Chemical Pathology, St Vincent’s Hospital, Sydney, Victoria St, Darlinghurst, NSW 2010, Australia. E-mail: [email protected]
References 1. Australasian Creatinine Consensus Working Group. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement. Med J Aust 2005; 183: 138–41. 2. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70. 3. 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 2006; 145: 247–54. 4. Levey AS, Coresh J, Greene T, et al. for Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values Clin Chem 2007; 53: 766–72. 5. National Kidney Disease Education Program. Laboratory reporting. http://www.nkdep.nih.gov/resources/laboratory_reporting. htm (accessed 8 November 2007). 6. Mathew TH, Johnson DW, Jones GRD. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: revised recommendations. Med J Aust 2007; 187: 459–63. 7. Cockcroft D, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41. 8. Prescribing in renal impairment. In: Australian Medicines Handbook 2007. Adelaide: AMH, 2007. (eAMH accessed via Clinical Information Access Project, http://www.ciap.health.nsw.gov.au/, 3 January 2008.) 9. Creatinine clearance and ideal body weight calculators. Therapeutic Guidelines. Melbourne: Therapeutic Guidelines, November 2007. (eTG accessed via Clinical Information Access Project, http:// www.ciap.health.nsw.gov.au/, 3 January 2008) 10. Stevens LA, Manzi J, Levey AS, et al. Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database. Am J Kidney Dis 2007; 50: 21–35. 11. Peake M, Whiting M. Measurement of serum creatinine – current status and future goals. Clin Biochem Rev 2006; 27: 173–84. 12. Bland M. Confidence intervals for a median and other quantiles. In: Bland M. An Introduction to Medical Statistics. 3rd ed. Oxford: Oxford University Press, 2000. http://www-users.york.ac.uk/*mb55/intro/ cicent.htm (accessed 5 June 2008). 13. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006; 354: 2473–83.
CHEMICAL PATHOLOGY
Validation of the revised MDRD formula and the original Cockcroft and Gault formula for estimation of the glomerular filtration rate using Australian data GRAHAM R. D. JONES*{
AND
SEYED K. IMAM{{
*Department of Chemical Pathology, SydPath, St Vincent’s Hospital, Sydney, {Department of Medicine, University of NSW, Sydney, and {Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, NSW, Australia
Summary Aims: The estimation of glomerular filtration rate (eGFR) using the MDRD (Modification of Diet in Renal Disease) formula is a recommended practice in Australia, New Zealand and other countries. Since the original development of this formula, an international process to align assays for serum creatinine has been undertaken and a revised version of the MDRD formula has been produced for these assays. Additionally, the Cockcroft and Gault (C&G) formula remains recommended for drug dosing decisions, although there are different versions of the formula using either actual weight or calculated ideal body weight. We aimed to assess these formulae using Australian data. Methods: We assessed the revised MDRD and the C&G formulae by comparison with radio-isotope GFR measurements using patients routinely referred for this test. The MDRD was compared to GFR corrected for body surface area and the C&G to the uncorrected GFR. Results: The MDRD was shown to have the expected scatter of over +30% but with median values not significantly different from isotopic GFR measurements and without a systematic deviation due to age, gender, height, weight or body mass index (BMI). The original C&G formula generally provided a good estimate of GFR, however the use of ideal body weight rather than actual body weight produced an under-estimated GFR in this population which was more prominent with increasing age and BMI. Conclusions: The MDRD and original C&G formulae were found to be valid in an Australian setting. The C&G formula, when calculated using weight estimated from patient height, was found to underestimate GFR in some patients. Key words: GFR, creatinine, kidney disease, MDRD, Cockcroft and Gault formula. Abbreviations: BMI, body mass index; BSA, body surface area; C&GAMH, Australian Medicines Handbook modification of the Cockcroft and Gault formula; C&G-O, original Cockcroft and Gault formula; DTPA, diethylenetriaminepentaacetic acid; GFR, glomerular filtration rate; IDMS, isotope dilution mass spectrometry; MDRD, Modification of Diet in Renal Disease; PET, positron emission tomography; RCPA QAP, Royal College of Pathologists of Australasia Quality Assurance Programs. Received 7 January, revised 19 June, accepted 21 July 2008
INTRODUCTION The MDRD formula, named after the Modification of Diet in Renal Disease study, is recommended for use in Australasia for the routine estimation of glomerular filtration rate (eGFR) with every request for serum creatinine in adults.1 The original ‘4 variable’ MDRD formula (Table 1) was derived using creatinine measurements from a Beckman-Coulter CX3 analyser in the early 1990s.2 In 2006 the formula was revised for use with creatinine assays aligned with the international reference method, isotope dilution mass spectrometry (IDMS).3,4 This revised formula has been described as the ‘175’ version of the MDRD formula after the first coefficient of the equation (Table 1) and has been recommended for use in the USA5 and Australasia6 for IDMS-aligned creatinine assays. The Cockcroft and Gault formula (C&G) for estimation of creatinine clearance7 remains recommended for drug dosing decisions,8 although it was also derived and validated with serum creatinine assays in use prior to the introduction of the newer IDMS-aligned assays. There is added variability with the application of the C&G formula with variation in the recommended use of measured weight or ideal body weight estimated from patient height.8,9 The use of ideal body weight in place of actual body weight is a modification of the C&G formula to avoid over-estimating muscle mass in obese subjects with the version in the Australian Medicines Handbook using the lower of actual or ideal body weight (C&G-AMH)8 and the version in Therapeutic Guidelines using the ideal body weight in obese subjects (C&G-TG).9 Additionally C&G-AMH has a factor of +10% based on a subjective assessment of body frame. The performance of these versions of the C&G formula with IDMS aligned serum creatinine assays has not been previously investigated. A recent major analysis of the MDRD formula has been performed using previously published data on over 5000 subjects using mathematical corrections to adjust measured creatinine to values expected with IDMS assays.10 At the time of writing there are no validations of the revised MDRD formula using IDMS aligned assays for the original measurements, and specifically no such validations from Australia or New Zealand. We assess the performance of the revised MDRD formula using subjects with routine requests
Print ISSN 0031-3025/Online ISSN 1465-3931 # 2009 Royal College of Pathologists of Australasia DOI: 10.1080/00313020902884980
380
Pathology (2009), 41(4), June
JONES AND IMAM
for a formal GFR measurement using an IDMS-aligned creatinine assay, and also assess different versions of the performance of the C&G formula in this setting.
METHODS GFR was measured in subjects referred for formal GFR measurement using 99mTc-Diethylenetriaminepenta-acetic acid (DTPA) at the Department of Nuclear Medicine and Positron Emission Tomography (PET) at Liverpool Hospital. The studies were performed between January 2003 and April 2007. Serum creatinine was measured throughout the study using a Roche rate-blanked compensated Jaffe assay on one of two Roche Hitachi Modular analysers (Roche, Australia). This method has IDMSalignment claimed by the manufacturer and supported by a local study.11 Accuracy of the serum creatinine assay was confirmed by assessment of performance in the Royal College of Pathologists of Australasia Quality Assurance Program (RCPA QAP) throughout the period of data collection. The eGFR was calculated using the MDRD ‘175’ formula. The C&G equation was applied using both the original version (C&G-O) and the version recommended in Australian Medicines Handbook (C&GAMH); however, the correction for heavy or light body frame was not included (Table 1). MDRD results were compared with DTPA results reported as mL/min/1.73m2 after correction for body surface area (BSA) and C&G results were compared with uncorrected results (mL/min). Overall agreement as well as the effect of age, gender, weight, BSA and body mass index (BMI) were assessed. For assessment of sex differences, TABLE 1
Equations
Original MDRD equation: eGFR (mL/min/1.73m2) ¼ 186 6 (S.Cr 6 0.0113)71.154 6 age70.203 6 F1 (F1 ¼ 1.0 for males and 0.742 for females) The revised MDRD equation for use with IDMS aligned creatinine assays (‘175’ equation): eGFR (mL/min/1.73m2) ¼ 175 6 (S.Cr 6 0.0113)71.154 6 age70.203 6 F1 (F1 ¼ 1.0 for males and 0.742 for females) The Cockcroft and Gault formula for estimation of creatinine clearance was used as follows (C&G-O):9 Creatinine clearance (mL/min) ¼ F2 6 (140 – age) 6 Wt/(0.815 6 S.Cr) (F2 ¼ 1.0 for males and 0.85 for females) The ideal body weight was calculated from patient height as follows and used in place of measured weight if it was lower (C&G-AMH)8 or if the patient was obese (C&G-TG):9 Ideal body weight ¼ 50 þ (Ht – 152) 6 0.45 – F3 (F3 ¼ 0 for males and 4.5 for females) For all equations the age is in years, weight (Wt) in kg, height (Ht) in cm and serum creatinine (S.Cr) in mmol/L.
TABLE 2
the male and female ratios of MDRD or C&G results to DTPA results were compared with the T-test. For assessment of other variables, the ratios were analysed in bins separated on the basis of the factor under consideration. The distribution of data in each bin was described with the median value and the 90% confidence limits of the median12 as well as the percentage of samples outside +30%. Statistical calculations were performed using Microsoft Excel (Microsoft, USA). No approval was sought from an institutional ethics committee as the process involved only retrospective review of previously collected data and no patient was identifiable from the presented information.
RESULTS During the study period 200 GFR studies were performed on 198 subjects. Results of 28 studies were not included due to creatinine measurements being performed more than 30 days prior to the GFR study. For subjects with multiple studies, only the first study was included. Results of three studies were excluded from the analysis as outliers, as the creatinine-based estimates of GFR were over twice the results of the formal GFR study. The creatinine measurements for subjects included in the analysis were made up to 29 days prior to the GFR measurement, with a median of 4 days. The study population included 98 men and 69 women. Detailed demographics and summary data are shown in Table 2. RCPA QAP external quality assurance data demonstrated that the serum creatinine assay performed as expected with end-of-cycle results showing regression lines very close to the median for the method throughout the entire period of the study. There was no difference between the male and female ratios of MDRD, C&G-O or C&G-AMH to DTPA. The results were as follows: MDRD/DTPA: average male ratio 0.98, average female ratio 0.97, p value 0.69; C&G-O/ DTPA: 0.99, 1.05, 0.19; C&G-AMH: 0.83, 0.77, 0.09. Variations in the ratios of MDRD with DTPA GFR are shown in Fig. 1 for a range of variables. The median of MDRD results was not significantly different from that of DTPA for all bins of GFR values up to 120 mL/min. Although the median MDRD was slightly less than the median DTPA, for DTPA results below 90 mL/min/1.73m2 more MDRD results were over 30% higher than DTPA (n ¼ 14, 11%) than were over 30% lower (n ¼ 7, 6%, Fig. 1A) giving a total of 83% within +30% for this range. The influence of various other factors on the ratio of
Subject demographics All (n ¼ 167)
Male (%) Age (years) Weight (kg) Ideal body weight (kg) BMI (kg/m2) Height (cm) BSA (m2) Creatinine (mmol/L) DTPA GFR (mL/min/1.73m2) MDRD (mL/min/1.73m2) Cockcroft and Gault (mL/min) C&G-AMH (mL/min)
Male (n ¼ 98)
Female (n ¼ 69)
Median
Range
Median
Range
Median
Range
57 65 74 60 27.3 164 1.82 92 75 68 70 57
20–100 40–129 33–86 14.9–51.0 138–192 1.24–2.53 39–1020 5–150 5–143 10–206 7–166
67 75 67 27.2 171 1.90 100 73 67 69 58
26–100 46–125 49–86 15.8–42.7 151–192 1.47–2.53 52–1020 5–121 5–138 10–206 7–166
62 71 49 28.1 156 1.67 74 79 69 70 53
20–89 40–129 33–68 14.8–51.0 138–177 1.24–2.24 39–340 22–150 11–143 15–200 10–112
REVISED MDRD FORMULA VALIDATION
MDRD to DTPA GFR results was also examined. Patients less than 50 years of age had slightly lower median MDRD than DPTA results, as did patients over 80 years (Fig. 1B). No significant effect was seen on MDRD values for BMI (Fig. 1C), weight, height or BSA (data not shown). The performance of C&G-O and C&G-AMH are also shown in Fig. 1. The median of the C&G-O results was also not different from DTPA for GFR results up to 120 mL/ min and for DPTA values less than 90 mL/min/1.73m2, 19 C&G-O results (15%) were over 30% higher than DTPA and 11 (9%) were over 30% lower, making a total of 76% within +30%. By contrast, the C&G-AMH formula produced results with a consistent negative bias of the C&G-AMH medians as compared to DTPA for all bins of results with a GFR 4 30 mL/min/1.73m2, with 46 results (37%) less than 90 mL/min over 30% below than DTPA results and only three (2%) over 30% high, making a total of 61% within +30%. This is seen especially in older subjects and subjects with high values for BMI (Fig. 1H,I). The effect of using the TG modification of the C&G formula is to produce results which are, on average, between the other two versions of the formula (data not shown).
DISCUSSION The data presented support the use of the revised ‘175’ MDRD formula for eGFR calculations using IDMS-
381
aligned creatinine assays. The formula is shown to be appropriate for a wide range of demographic variables such as gender, age, height, weight, BMI and BSA and to be suitable for use for values up to at least 90 mL/min/1.73m2. The results show considerable scatter of the MDRD estimate compared to formally measured GFR with only 83% of results within +30%, a finding consistent with previous publications. Some of this scatter will be due to variability in measurement of serum creatinine and in the formal GFR measurements, as well as the limitations due to the formula. The original C&G formula, when applied using an IDMS-aligned creatinine assay, also performed well compared to formal GFR measurements. This is a somewhat unexpected finding as the clearance of creatinine should be higher than the GFR due to tubular secretion and gastro-intestinal losses. It is also surprising as IDMS-aligned creatinine assays tend to give lower results than older assays due to removal of the effect of non-creatinine chromogens, a change which would tend to increase the calculated C&G result. The previous large combined analysis showed median differences of 10–20% with C&G being higher than the measured GFR.13 These data vary from the current study as the patients were younger, with a mean age of 47 years compared to 62 years in our study, and older subjects are known to have a relatively lower C&G result compared to MDRD results.
FIG. 1 (A–C) Influence of various factors on the ratio of MDRD to DTPA GFR (both in mL/min/1.73m2, left side panels), (D–F) Cockcroft and Gault to DTPA GFR (both in mL/min, middle panels), and (G–I) Cockcroft and Gault based on ideal body weight to DPTA GFR (both in mL/min, right hand panels). Crosses, individual data points; black diamonds and thick solid lines, median values of data bins; grey diamonds and thin solid lines, 10th and 90th centile confidence intervals for median result; thin dashed lines, differences of +30%. (A, D, G) Effect of GFR (mL/min/1.73m2). (B, E, H) Effect of age (years). (C, F, I) Effect of BMI (kg/m2). The bin size and number of data points in each bin is shown for the MDRD data with the same bins used for the middle and right side panels. For clarity a single data point was excluded from Fig. C, F and I (BMI ¼ 51; MDRD/DTPA ¼ 0.92; C&G/DTPA ¼ 1.55; C&GAMH/DTPA ¼ 0.62).
382
Pathology (2009), 41(4), June
JONES AND IMAM
The use of the ideal body weight in place of the actual body weight produced a marked negative bias in C&G results compared to formal GFR measurements. This is expected mathematically as the median ideal body weight was only 60 kg compared to the median measured body weight of 74 kg, indicating a median reduction in C&G results of about 20%. Variations of the C&G formula include the use of ideal body weight estimated from patient height as a method to mitigate the contribution of excess body fat to the measured weight8,9 so it is of interest that this correction becomes progressively less accurate as BMI increases (Fig. 1I). The recommendation to use C&G values for drug dosing decisions may be based on clinical studies where toxicity and efficacy were originally assessed with this formula, and in this case the important issue is correspondence with results obtained in those studies rather than with the formally measured GFR. However the change in creatinine assays, together with other factors, may have lead to changes in the performance of this equation over time. A revision of the assessment of renal function for drug dosing decisions is urgently required. Limitations to this study include the limited sample size and the nature of the population being tested, which represents a specific group referred for specialised renal assessment and there may be limitations in generalising this to the population where the eGFR is in widespread use. Although the subjects are likely to have stable renal function, the delay between serum creatinine measurement and GFR measurement may add some variability. It should also be recognised that there is variation between methods for formal GFR measurement and this may be a cause of different results in other studies.13 This study has the advantage of using a serum creatinine assay and a GFR measurement method that are both in routine use in Australia. In summary, the ‘175’ MDRD formula for IDMSaligned assays showed a good correlation with formally measured GFR using an IDMS-aligned creatinine assay. The formula was robust for a wide range of variation in patient characteristics. The original C&G equation using the IDMS-aligned creatinine assay correlated well with measured GFR, although low results were seen in patients over 70 years of age. By contrast, the modification of the C&G formula using an estimate of ideal body weight consistently under-estimated the true GFR.
ACKNOWLEDGEMENTS We would like to recognise the input of Dr John Chu of the Department of Nuclear Medicine and PET, Liverpool Hospital who passed away prior to submission of the paper and thank Frank Alvaro from South Western Area Pathology Service Biochemistry Department for provision of quality assurance data for the creatinine assays. Address for correspondence: Dr G. R. D. Jones, Department of Chemical Pathology, St Vincent’s Hospital, Sydney, Victoria St, Darlinghurst, NSW 2010, Australia. E-mail: [email protected]
References 1. Australasian Creatinine Consensus Working Group. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement. Med J Aust 2005; 183: 138–41. 2. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70. 3. 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 2006; 145: 247–54. 4. Levey AS, Coresh J, Greene T, et al. for Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values Clin Chem 2007; 53: 766–72. 5. National Kidney Disease Education Program. Laboratory reporting. http://www.nkdep.nih.gov/resources/laboratory_reporting. htm (accessed 8 November 2007). 6. Mathew TH, Johnson DW, Jones GRD. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: revised recommendations. Med J Aust 2007; 187: 459–63. 7. Cockcroft D, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41. 8. Prescribing in renal impairment. In: Australian Medicines Handbook 2007. Adelaide: AMH, 2007. (eAMH accessed via Clinical Information Access Project, http://www.ciap.health.nsw.gov.au/, 3 January 2008.) 9. Creatinine clearance and ideal body weight calculators. Therapeutic Guidelines. Melbourne: Therapeutic Guidelines, November 2007. (eTG accessed via Clinical Information Access Project, http:// www.ciap.health.nsw.gov.au/, 3 January 2008) 10. Stevens LA, Manzi J, Levey AS, et al. Impact of creatinine calibration on performance of GFR estimating equations in a pooled individual patient database. Am J Kidney Dis 2007; 50: 21–35. 11. Peake M, Whiting M. Measurement of serum creatinine – current status and future goals. Clin Biochem Rev 2006; 27: 173–84. 12. Bland M. Confidence intervals for a median and other quantiles. In: Bland M. An Introduction to Medical Statistics. 3rd ed. Oxford: Oxford University Press, 2000. http://www-users.york.ac.uk/*mb55/intro/ cicent.htm (accessed 5 June 2008). 13. Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006; 354: 2473–83.