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Rheumatology 2001; 40: 324-328
© 2001 British Society for Rheumatology

Chromium-51 ethylenediamine tetraacetic acid glomerular filtration rate: a better predictor than glomerular filtration rate calculated by the Cockcroft–Gault formula for renal involvement in systemic lupus erythematosus patients

T. Godfrey, M. J. Cuadrado, C. Fofi, I. Abbs1, M. A. Khamashta, T. Nunan2 and G. R. V. Hughes

Lupus Research Unit, The Rayne Institute,
1 Nephrology and
2 Nuclear Medicine Department, St Thomas' Hospital, London SE1 7EH, UK


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To investigate whether the ethylenediamine tetraacetic acid (EDTA) glomerular filtration rate (GFR) is a better indicator of the degree of renal involvement than serum creatinine concentration or creatinine clearance calculated by the Cockroft–Gault formula.

Methods. We studied prospectively all systemic lupus erythematosus (SLE) patients with normal or borderline serum creatinine concentration (<110 µmol/l) and urinary sediment abnormalities and/or proteinuria in the last 2 yr. EDTA-GFR, serum creatinine concentration, calculated creatinine clearance (Cockroft–Gault formula) and 24-h urine protein were determined at the same time. Renal biopsies were performed in patients with low values of EDTA-GFR or significant proteinuria.

Results. Twenty-three patients were identified, of whom 22 were females. The average age of the patients was 31.6±8.2 yr. Biopsies were assigned to WHO classes as follows: class II, 1 patient; class III, 6 patients; class IV, 10 patients; class V, 6 patients. The average serum creatinine concentration, EDTA-GFR and calculated creatinine clearance were 79.8±mol/l, 74.5 ml/min and 97 ml/min respectively. EDTA-GFR showed abnormal values (<80 ml/min) in 15 of the 23 patients (65.2%) while calculated creatinine clearance was abnormal (<80 ml/min) in three of the 23 patients (13%) (P<0.001). Using the Pearson correlation test, we did not find any correlation between EDTA-GFR or creatinine clearance values and the sum of activity and chronicity indices.

Conclusion. GFR performed by EDTA-GFR correctly predicted renal involvement in SLE patients, whereas GFR calculated by the Cockcroft–Gault formula may have underestimated renal function. Significant numbers of patients with WHO class III, IV or V lupus nephritis may be missed if biochemical creatinine clearance or serum creatinine concentration alone is used to assess renal disease.

KEY WORDS: Creatinine clearance, Predictive value, Diagnosis, Lupus nephritis.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Renal involvement in systemic lupus erythematosus (SLE) varies from mild haematuria/proteinuria to rapidly progressive renal impairment with significant morbidity. There is evidence that early identification of renal involvement and treatment may improve the prognosis [1, 2]. Early indicators for a renal biopsy in a SLE patient include the presence of dysmorphic red cells and/or erythrocyte casts and/or proteinuria >=0.5 g/24 h. Measurement of renal function should aid the decision to biopsy, but in our experience it is sometimes not appreciated by rheumatologists and general practitioners that a serum creatinine concentration within the normal range for age and weight and a normal biochemical creatinine clearance do not exclude significant lupus nephritis. The reassurance of a ‘normal’ plasma creatinine concentration may delay the decision to perform a renal biopsy and institute effective treatment. Determination of biochemical creatinine clearance by 24-h urine creatinine collection provides a more accurate estimation of the glomerular filtration rate (GFR) than serum creatinine concentration alone, but is often inconvenient for patients and can be inaccurate for a number of reasons [3, 4]. Some studies have compared GFR with the Cockcroft–Gault-derived creatinine clearance in patients with proliferative lupus nephritis [5]. In the non-SLE population, the Cockcroft and Gault formula [6] for estimating GFR from serum creatinine concentration has been shown to correlate with 24-h urine creatinine clearance [7–9] and, in some studies, has proven more accurate [10]. This formula is used to detect the onset of renal insufficiency and to assist in clinical decisions in patients with renal involvement. True GFR can also be measured by the renal clearance of an exogenous marker that is freely filtered by the kidney rather than being secreted or absorbed, such as inulin. Inulin clearance provides the most precise method of measuring GFR but is not suitable for clinical practice because it is expensive and requires continuous i.v. infusion [11]. Therefore, labelled compounds such as chromium-51 ethylenediamine tetraacetic acid ([51Cr]EDTA) have been developed as a filtration marker. Simultaneous measurement of these isotopic markers and of inulin by standard techniques gave comparable results [12–14]. The aim of this study was to investigate whether EDTA-GFR is a better indicator of significant renal involvement than serum creatinine or creatinine clearance calculated by the Cockcroft–Gault formula in patients with serum creatinine levels within the normal range for age and weight.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
We studied prospectively all consecutive SLE patients with serum creatinine levels within the normal range (<110 µmol/l) and urinary sediment abnormalities and/or significant proteinuria (>=0.5 g/24 h) in the last 2 yr. All patients fulfilled SLE classification criteria [15]. EDTA-GFR, serum creatinine concentration, calculated creatinine clearance (Cockroft–Gault formula) and 24-h urine protein were measured at the same time. Renal biopsies were performed in those patients with low values of EDTA-GFR or significant proteinuria. Three MBq of [51Cr]EDTA was given i.v. and the elimination rate of the tracer was measured in plasma samples [16] 2, 3 and 4 h after injection. Biopsy samples were processed by microscopy, immunofluorescence and electron microscopy according to standard procedures. Renal biopsies were evaluated according to the WHO classification criteria. Activity and chronicity indices were measured according to the method of Austin et al. [17]. Statistical analysis was performed using the Pearson correlation test and the {chi}2 test.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Twenty-three patients were studied. There were 22 females, and the average age was 31.6±8.2 yr (range16–58). The renal biopsies were assigned to the following WHO classes: class II, 1 patient; class III, 6 patients; class IV, 10 patients; class V, 6 patients. The average serum creatinine concentration was 79.8 µmol/l, EDTA-GFR 74.5 ml/min and calculated creatinine clearance 97 ml/min. Thirteen patients had proteinuria of >1.0 g/day, 17 had haematuria of >=2+ and 19 were positive for double-stranded DNA (dsDNA). Individual values of these parameters, WHO classification of biopsy, and activity and chronicity indices of renal biopsies are shown in Table 1Go. EDTA-GFR showed abnormal values (<80 ml/min) in 15 of the 23 patients (65.2%), while the calculated creatinine clearance was abnormal (>=80 ml/min) in three of the 23 patients (13%) (P<0.001) (Fig. 1Go). Lowest values of EDTA-GFR were found in patients with WHO classes III and IV, but there was no statistically significant association between EDTA-GFR and the WHO class of renal biopsy. Using the Pearson correlation test, we did not find any correlation between EDTA-GFR and anti-dsDNA antibody titre, 24-h urine protein, serum creatinine concentration or the activity or chronicity indices.


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  		TABLE 1. Characteristics of renal involvement in 23 SLE patients

 


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  		FIG. 1. (A) Creatinine clearance (ml/min) and serum creatinine values (µmol/l) in the 23 patients. Only three patients showed a low level of creatinine clearance. (B) EDTA-GFR (ml/min) and serum creatinine values (µmol/l) in the same 23 patients. Fifteen patients with normal serum creatinine showed a low EDTA-GFR value (<80 ml/min).

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Our results showed that EDTA-GFR is a better predictor of renal involvement than either serum creatinine concentration or creatinine clearance calculated by the Cockroft–Gault formula. A good correlation between creatinine clearance calculated by the Cockroft–Gault formula and 24-h urinary creatinine clearance has been described [8], suggesting that 24-h urinary creatinine clearance would also be a poor predictor of renal function. Recent studies add support to this argument. Levey et al. [18] found that 24-h urine creatinine clearance overestimated true GFR by 19% and creatinine clearance predicted by the Cockcroft–Gault formula overestimated GFR by 16%. Nielsen et al. [19] showed that valid estimates of GFR could not be obtained by estimation of creatinine clearance from the Cockcroft–Gault formula or from serum creatinine concentration in diabetic patients with normal renal function. Estimated GFR by the Cockcroft–Gault formula can be improved by a technique that blocks tubular secretion of creatinine [20, 21], but the technique is still subject to collection error.

Several studies have demonstrated that there is not a good correlation between the Cockcroft–Gault formula and GFR estimated by labelled compounds such as [99mTc]diethylene triaminepenta-acetic acid (DTPA), [125I]iothalamate, iohexol and EDTA [11, 22]. In our study, 15 of 23 patients with normal serum creatinine had an abnormal EDTA-GFR. Creatinine clearance calculated by the Cockcroft–Gault formula showed abnormal values only in three of the 23 patients. In fact, if the detection of renal insufficiency was reliant only on serum creatinine concentration and creatinine clearance calculated by the Cockcroft–Gault formula, we would have missed 12 patients with biopsy-proven lupus nephritis.

Renal biopsy was performed in our patients because of abnormalities of urine sediment and/or heavy proteinuria and/or a diminished EDTA-GFR. The indications for renal biopsy in SLE patients are controversial [23]. Some physicians delay performing renal biopsy in patients with urinary abnormalities until an increase in serum creatinine concentration or a reduction in creatinine clearance occurs. Our results argue that normal serum creatinine concentration and Cockcroft–Gault creatinine clearance do not exclude the possibility of significant renal involvement and should not be used to determine the indication for renal biopsy. The EDTA-GFR is a very useful tool that can aid decision-making in patients with SLE and urinary abnormalities [24, 25].

The major drawback of using [51Cr]EDTA and other radiolabelled compounds is their relatively poor safety, although the radiation exposure of the patient for a single GFR test is similar to that for a standard X-ray. GFR measured by [51Cr]EDTA can be overestimated in patients with severe oedema [25]. Other limitations are the exclusion of certain patients, such as children and pregnant women [11].

In conclusion, significant numbers of patients with WHO class III, IV and V lupus nephritis may be missed if calculated creatinine clearance alone is used to predict renal involvement in SLE patients with normal serum creatinine concentration. We therefore suggest that EDTA-GFR should be performed in any SLE patient with suspected renal involvement even when the serum creatinine concentration and creatinine clearance are normal.


   Acknowledgments
 
This work was supported by Lupus UK and the St Thomas' Lupus Trust.


   Notes
 
Correspondence to: M. A. Khamashta. Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 7 April 2000; Accepted 2 October 2000


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