Centres for Nephrology and
1 Rheumatology, Royal Free and University College Medical School, University College London and Departments of
2 Nuclear Medicine and
3 Clinical Biochemistry, The Royal Free Hospital, London, UK
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Abstract |
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Methods. Twenty-six patients (20 female, 6 male, median age 58 yr, age range 1280 yr) satisfied our criteria for inclusion in a retrospective comparison of measured and calculated GFR. GFR was measured using 51Cr-EDTA. The modified Cockcroft and Gault formula and equation 7 from the Modification of Diet in Renal Disease (MDRD) were used to calculate GFR.
Results. Eighteen out of 19 patients analysed with a serum creatinine concentration less than the upper limit of the normal range had a measured GFR outside the normal range. Three patients with a normal creatinine concentration had a measured GFR <60 ml/min and in each of these the calculated GFR was also abnormal. All patients with a measured GFR <60 ml/min were identified using both the MDRD and the modified Cockcroft and Gault formula to calculate GFR. The greatest correlation between measured and calculated GFR was seen when the MDRD formula, which employs demographic and serum variables, was used in patients with body surface area (BSA) >1.4 m2 who were not taking Iloprost (r=0.91). Use of the Cockcroft and Gault formula to calculate creatinine clearance with a correction factor for GFR, the inclusion of patients taking Iloprost and the inclusion of patients with BSA <1.4 m2 were all associated with a lower degree of correlation.
Conclusion. Serum creatinine is a poor marker of renal function in SSc patients. Calculating GFR from demographic and serum variables is a simple technique to identify SSc patients who have abnormal renal function. The authors recommend the use of the MDRD formula.
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Introduction |
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Serum creatinine concentration is commonly used as an index of renal function. However, serum creatinine depends on muscle mass and is not usually elevated until the glomerular filtration rate (GFR) has fallen to less than 50% of normal. Inulin clearance remains the gold standard for the measurement of GFR, but a variety of techniques are available in clinical practice. Clearance methods employing radionuclides are widely used and are sufficiently accurate to satisfy most clinical needs. Creatinine clearance may also be used as a measure of GFR but has significant methodological problems that limit its accuracy and reproducibility.
Calculating creatinine clearance or GFR is an alternative means of quantifying renal function and several formulae have been developed since the first description of this principle [3]. The Royal Free Hospital has a large cohort of patients with SSc and the data necessary to calculate creatinine clearance retrospectively are stored on a computerized database. Measurements of GFR using injection of the radionuclide ethylenediamine tetraacetate chromium 51 (51Cr-EDTA) have been carried out in a proportion of the SSc cohort and provide a benchmark for comparison with calculated GFR. We carried out a retrospective study to investigate the usefulness and limitations of two formulae to estimate GFR in SSc patients with stable plasma creatinine concentration.
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Methods |
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Inclusion criteria
Patients with a measured GFR and data for calculation of GFR who satisfied the American Rheumatism Association criteria for the diagnosis of SSc [4] were included.
Exclusion criteria
Patients taking drugs interfering with tubular secretion of creatinine or measurement of creatinine by the kinetic alkaline picrate method were excluded. Patients with greater than 15% variation in plasma creatinine in the 12 months prior to GFR and patients in whom measurement of creatinine and GFR were more than 8 days apart were also excluded.
GFR measurement
Where the expected GFR was greater than 30 ml/min a single-sample method was used [5]. Where the expected GFR was less than 30 ml/min but greater than 15 ml/min three samples were taken [6]. The results of measurements were all normalized to a body surface area (BSA) of 1.73 m2. A 3 MBq dose of 51Cr-EDTA was used in all measurements of GFR in this study.
Serum creatinine concentration
Serum creatinine was measured using a Roche/Hitachi Modular P analytical system with a blanked modification of the Jaffé reaction. The method is based on the Jaffé reaction as modified by Bartels et al. [7]. In order to avoid interference from high circulating bilirubin concentrations, samples were treated with potassium ferricyanide as described by O'Leary et al. [8].
Calculated GFR
GFR was calculated using equation 7 developed in the Modification of Diet in Renal Disease (MDRD) study [9]. This formula uses demographic and serum variables but does not require urine collection: GFR=170x[serum creatinine concentration (mg/dl)]-0.999x(age)-0.176x[serum urea nitrogen concentration (mg/dl)]-0.17x[albumin concentration (g/dl)])0.318x(0.762 if the patient is female)x(1.18 if the patient is black).
Creatinine clearance was calculated using the modified Cockcroft and Gault formula [10]: [creatinine clearance=1.2x(140age in yr)xweight (kg)x0.85 (if female)] divided by serum creatinine concentration (µmol/l).
We employed a further correction factor of 0.84, proposed by the MDRD study investigators [9], to convert creatinine clearance calculated by the Cockcroft and Gault formula to GFR.
Conversion of units for calculations
The MDRD formula was developed using non-SI units. The Royal Free Hospital database employs SI units. The following factors were employed to convert the database SI units to the non-SI units employed in MDRD equation 7: serum creatinine µmol/l to mg/dl, divide by 88.5; urea mmol/l to serum urea nitrogen mg/dl, multiply by 2.8; albumin g/l to g/dl, divide by 10.
Body surface area
BSA was estimated using the Haycock normogram [11].
Statistics
Correlation coefficients were calculated using Microsoft ExcelTM. A BlandAltman plot of residuals [12] was employed to identify systematic bias in estimates of GFR using the formulae described above.
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Results |
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Measured GFR in patients with serum creatinine concentration within the normal range
Eighteen out of 19 patients with measurements of serum creatinine below the upper limit of the normal range for their sex had a measured GFR outside the normal range at the Royal Free Hospital (100130 ml/min). Six out of 18 had a measured GFR less than 90 ml/min and 3/18 had a GFR of less than 60 ml/min. In each case the calculated GFR was also abnormal.
Measured GFR in patients with elevated serum creatinine concentration
The seven patients with elevated serum creatinine concentration all had measured GFRs of less than 60 ml/min. The calculated GFR using the Cockcroft and Gault formula in all cases was less than 47 ml/min. In 5/7 cases the MDRD-calculated GFR was less than 60 ml/min.
Measured GFR in patients with reduced serum creatinine concentration
Two female patients with serum creatinine less than 60 µmol/l both had measured GFRs greater than 95 ml/min.
Identification of patients with reduced GFR
This study included 10 patients with a measured GFR of less than 60 ml/min. Using the MDRD or Cockcroft and Gault formula to calculate GFR identified all 10 cases. In this subgroup of patients with significantly abnormal GFR, three female patients had a serum creatinine concentration of less than 97 µmol/l, the upper limit of normal for women at the Royal Free Hospital. Two further female patients had serum creatinine less than 120 µmol/l, the upper limit of normal quoted on printed and computer-accessed results, which is the upper limit of normal for males. In the remaining cases (four female, one male) serum creatinine was greater than 120 µmol/l (126187 µmol/l).
Correlation between calculated and measured GFR (51Cr-EDTA)
The relationship between calculated and measured GFR is shown in Figs 1 and 2. The highest correlation coefficient was seen between measured and calculated GFR when the MDRD formula, which employs demographic and serum variables, was used in patients with BSA >1.4 m2 who were not taking Iloprost (r=0.91) (Fig. 1
). Use of the Cockcroft and Gault formula, the inclusion of patients taking Iloprost and inclusion of patients with BSA <1.4 m2 were all associated with lesser correlation (r values are shown in Table 2)
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Precision of calculated GFR
The proportion of GFR estimates within 30 and 50% of the measured GFR was 82 and 89% resepectively for the MDRD study equation. Using the Cockcroft and Gault formula, 65% of the GFR estimates were within 50% of the measured GFR. A BlandAltman plot of residuals demonstrated the magnitude and consistency of the differences between calculated and measured values. The results of this technique are shown for calculated GFR using MDRD in Fig. 3 and for the corrected Cockcroft and Gault formula in Fig. 4
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Characteristics of patients with normal creatinine concentration and GFR <60 ml/min
Three female patients had a measured GFR less than 60 ml/min with a serum creatinine concentration <97 µmol/l. The demographic characteristics of the patients, weights, BSA and body mass indices, creatinine concentrations and their measured and calculated GFRs are shown in Table 3.
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Discussion |
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Creatinine is formed by the non-enzymatic dehydration of muscle creatine and the principal determinants of the serum creatinine are muscle mass and GFR. However, the relationship between creatinine and GFR is not linear. The gold standard for measurement of GFR is the clearance of inulin. However, this procedure requires a steady-state plasma concentration and urine collection and it is too costly and time-consuming for routine clinical practice. 51Cr-EDTA clearance is a widely accepted and accurate substitute [6]. Subsequently, other isotope clearance methods have been validated, employing labelled iodothalamate and diethylenetriamine-pentacetic acid (DTPA) [13]. Although creatinine clearance is widely used in clinical practice, it is a crude means of estimating renal function. The relative contributions of tubular secretion of creatinine and extrarenal elimination of creatinine to the measured creatinine clearance increase with falling GFR, exaggerating the discrepancy between the clearance of creatinine and inulin. Urinary creatinine equilibrates slowly after changes in muscle mass [14] or dietary protein intake [15], further limiting the utility of creatinine clearance. Although some measure of the completeness of urine collections can be obtained by measuring the total creatinine in the specimen [16], the difficulty of obtaining complete, precisely timed urine collections is the greatest obstacle limiting the accuracy of this technique.
Creatinine-based methodology is further hampered by the requirement for accurate measurement of creatinine. Creatinine is commonly measured by the modified Jaffé reaction, using the reaction of creatinine with alkaline picrate to form an orange-red Janovsky complex. Unfortunately, plasma contains other chromogens that react to give a similar colour change. Enzyme-based methods and high-performance liquid chromatographic techniques are available, although in our experience enzyme-based methods do not provide greater precision (M. Thomas, unpublished observations). A number of anionic and cationic drugs affect tubular secretion of creatinine, raising the serum creatinine concentration and reducing the measured or calculated creatinine clearance. The best-recognized examples are cimetidine [17] and trimethoprim [18], but this effect may also be observed with triamterene, spironolactone, amiloride and probenecid. Patients taking such medications were excluded from our study. The measurement of true plasma creatinine concentration may have a coefficient of variation of up to 7% for replicate measurements of the same sample around a value of 120 µmol/l [19, 20]. The coefficient of variation for replicate measurements of true plasma creatinine in the Royal Free Hospital laboratory, using the method described in this study, is less than 1%.
The prediction of the GFR from the plasma creatinine concentration has been widely debated since the first description by Cockcroft and Gault [3]. The accuracy and extent to which the results of a formula can be extrapolated to a population of interest depends on the population in which any formula was derived. Cockcroft and Gault derived their formula from creatinine measurements in a cohort of 249 patients of whom only 4% were female. Revisions of the original formula and newer formulae incorporating a number of clinical and demographic variables have been proposed subsequently. Our study population, unlike the groups used to develop both formulae employed in this study, was predominantly female. The r value for correlation between measured GFR and calculated GFR for the men in our study, all of whom had BSA >1.7 m2 and body mass index >19, was >0.91 whether the MDRD or the Cockcroft and Gault formula was used. However, the very good correlation between measured and calculated GFR observed in our study overall suggests that the correction factors adopted for female sex in the MDRD and Cockcroft and Gault equations are appropriate for female patients with SSc. We have demonstrated reduced correlation with BSA <1.4 m2 and it is likely that extremely small size is at least as important as female sex when considering the utility of equations to calculate GFR.
The MDRD study group developed a series of equations to predict GFR using demographic variables and clinical data, including serum creatinine measured using a kinetic alkaline picrate method. The equations were developed by stepwise regression applied to a cohort of 1070 patients with reduced GFR secondary to a wide range of kidney diseases. Subsequently, the prediction equations developed by the MDRD study group were tested in a validation cohort of a further 558 patients. We have employed MDRD equation 7, containing serum and patient variables, and MDRD equation 2, which corrects for the systematic overestimation of GFR by the modified Cockcroft and Gault formulae [9].
The MDRD study equation has been validated by other investigators. In the largest such study, the MDRD study equation was applied in a group of 1703 African-American hypertensives with and without renal impairment. This study, in which creatinine was measured by a kinetic alkaline picrate assay and GFR by iothalamate clearance [21], reproduced the findings of the MDRD study. The MDRD formula was found to be more accurate than creatinine clearance or Cockcroft and Gault-calculated creatinine clearance [21]. Broekroelofs et al. [22] found that the MDRD and Cockcroft and Gault formulae consistently overestimated GFR measured by [125I] iothalamate clearance in patients with progressive decline in renal function following lung transplantation. The authors conclude that the MDRD formula has greater sensitivity than the Cockcroft and Gault formula or a reciprocal creatinine plot when evaluating change in renal function. The MDRD study equation has been demonstrated to estimate GFR accurately in a group of 321 renal transplant recipients [23].
Studies that have addressed the correlation between simultaneously performed radionuclide clearance assays of GFR, creatinine-based GFR calculations and measured creatinine clearance may clarify whether creatinine clearance offers additional precision when compared with calculated GFR. Apart from the AASK study [21], this comparison has only been made in small cohorts of heart transplant recipients and potential kidney donors. Calculated creatinine clearance, converted to GFR using the formula GFR+14.6+(0.751xcalculated creatinine clearance), was found to have a closer correlation with GFR, measured using a 99mTc-DTPA method, than calculated creatinine clearance in heart transplant recipients [24]. The investigators do not indicate the effect of a similar correction factor on the correlation of measured creatinine clearance. A comparison between measured GFR (DTPA method), creatinine clearance and calculated GFR has also been performed in potential live kidney donors with low or inconsistent measured creatinine clearance [25]. The Cockcroft and Gault and MDRD formulae performed better than creatinine clearance and were further improved by correcting GFR by height rather than BSA. The authors suggest that this strategy could be used to decide which potential donors require an isotopic GFR and propose to evaluate this prospectively. There seems little evidence that measured creatinine clearance offers an advantage over a calculated GFR.
In the general population, a considerable proportion of patients with an abnormal calculated GFR may not be identified by screening based on serum creatinine [26]. Our three patients with a normal creatinine concentration and significantly abnormal measured and calculated GFRs (Table 3) demonstrate that the use of serum creatinine concentration as an index of renal function without a normal range corrected for sex, age and muscle mass may be misleading. The muscle mass of these three patients is likely to lie outside the normal range of the population used to generate a reference range for serum creatinine, and this may well explain the apparent discrepancy of normal creatinine concentrations and significantly abnormal GFRs. The identification of patients with renal impairment has several clinical benefits. SSc syndromes overlap with other diseases and the optimal management of renal involvement in these conditions may require renal biopsy. Consideration of renal function is essential before prescribing a wide range of therapies and many medications require dose reduction or alteration of dosing interval. The disease-modifying drugs cyclophosphamide and methotrexate are good examples. Avoiding nephrotoxic insults and exemplary blood pressure control are likely to improve renal survival in chronic renal failure whatever the aetiology.
Correctly identifying renal impairment may be important in the design of future intervention and natural history studies. The presence or absence of renal involvement may allow further subdivision of SSc subsets. Combining clinical information with serological and immunogenetic markers may allow further insights into the pathogenesis and provide prognostic information to inform patients and guide treatment.
Performing an isotopic GFR on every SSc patient at each clinic attendance is clearly not a practical proposition. Equally, we have demonstrated that serum creatinine measurements alone fail to identify patients whose GFR is sufficiently abnormal to provoke alterations in their management. The Cockcroft and Gault formula appears to overestimate GFR systematically when the measured GFR is between 60 and 90 ml/min. Such an error might be expected to occur at GFRs less than 50 ml/min, when the contribution of creatinine secretion to creatinine clearance becomes more significant, and we do not have an explanation for our observation. In the light of the lack of precision of the Cockcroft and Gault formula in this range of GFRs, where calculated GFRs may have their greatest utility, and the greater correlation seen with the MDRD formula, we suggest that the MDRD formula is used to calculate GFR for all patients with SSc.
It is worth considering how far our results can be extrapolated. Our cohort had stable renal function and was predominantly white and female. Our results suggest that very small size and concurrent use of Iloprost limit the precision of calculated creatinine clearance. We suggest that, in patients with a stable creatinine whose BSA is greater than 1.4 m2, calculated GFR is a useful screening test to identify renal impairment. Where these conditions are not met or where a very precise measurement of GFR is required, patients should be referred for an isotopic GFR.
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Acknowledgments |
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Notes |
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References |
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