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Rheumatology Advance Access originally published online on October 25, 2006
Rheumatology 2007 46(4):649-652; doi:10.1093/rheumatology/kel360
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Urine protein-to-creatinine ratio in an untimed urine collection is a reliable measure of proteinuria in lupus nephritis

Y. Y. Leung, C. C. Szeto1, L. S. Tam1, C. W. K. Lam2, E. K. Li1, K. C. Wong1, S. W. Yu1 and E. W. Kun

Department of Medicine and Geriatrics, Tai Po Hosptial, 1Department of Medicine and Therapeutics, and 2Department of Chemical Pathology, Chinese University of Hong Kong, Hong Kong SAR.

Correspondence to: Y. Y. Leung, Department of Medicine and Geriatrics, Tai Po Hospital, 9 Chuen On Road, Taipo, N.T., Hong Kong SAR. E-mail: katyccc{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To evaluate the accuracy of urine protein-to-creatinine (P/C) ratio in an untimed urine specimen as compared with 24 h total protein excretion for measurement of proteinuria in patients with lupus nephritis.

Methods. Proteinuria in patients with lupus nephritis was assessed by 24 h total protein excretion and spot urine P/C ratio. Correlation and limits of agreement between the two methods were evaluated. The discriminant cutoff values for spot urine P/C ratio in predicting 24 h protein ‘threshold’ excretion of ≥0.3, ≥0.5, ≥1.0 and ≥3.5 g/day were determined using receiver operating characteristic curves.

Results. A total of 165 samples were available for assessment with 21.8% excluded due to inadequate collection. A strong correlation (r = 0.91, P < 0.0001) was found between spot urine P/C ratio and 24 h urine protein excretion. Bland–Altman plot showed the two tests had acceptable limits of agreement in low level of protein excretion (–0.86 to +0.92 g/day when protein excretion was <2.0 g/day). The limits became wider as the protein excretion increased. The spot urine P/C ratios of 0.45 (sensitivity 0.92; specificity 0.88), 0.7 (0.92; 0.89) and 1.84 (1.0; 0.86) mg/mg reliably predicted 24 h urine total protein equivalent ‘thresholds’ at ≥0.5, 1.0 and 3.5 g/day.

Conclusion. This study supports the recommendation of using spot urine P/C ratio in screening and monitoring proteinuria in patients with lupus nephritis. However, in assessing the exact amount of proteinuria, the urine P/C ratio may have unacceptably wide limits of agreement in high protein excretion range.

KEY WORDS: Proteinuria, Urine protein-to-creatinine ratio, Lupus nephritis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Quantifying proteinuria accurately and precisely is vital in the monitoring disease activity in patients with lupus nephritis. The measurement by 24 h urine collection has been regarded as the ‘gold standard’ [1]. However, such collection is cumbersome to use and frequently inaccurate due to collection errors [2, 3]. The urine protein-to-creatinine (P/C) ratio corrects for variations in urinary protein concentration due to hydration and is not affected by a decrease in urine output in patients with renal insufficiency. It is far more convenient than timed urine collections. The numerical outcome of the urine P/C ratio in mg/mg is roughly equal to the 24 h protein excretion in g/day/1.73 m2 body surface area. According to the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines of the US National Kidney Foundation, the urine albumin-to-creatinine ratio in an untimed urine specimen should replace protein excretion in a 24 h collection as the preferred method for measuring proteinuria. If the albumin-to-creatinine ratio is high (>500–1000 mg/mg), urine P/C ratio could be used [4]. The Renal Disease Subcommittee of the American College of Rheumatology (ACR) has recently adopted the utilization of spot urine P/C ratio of <0.2 mg/mg and 0.2–2.0 mg/mg as complete and partial remission criteria, respectively in proliferative and membranous lupus nephritis [5]. These recommendations were based on correlation studies. The ratio of protein or albumin-to-creatinine in an untimed urine sample has high correlation with 24 h urine total protein [2, 6]. This method has been validated in diabetic [7] and non-diabetic [8] nephropathy.

However, correlation and agreement between two measuring methods are different matters. The agreement between two methods should be assessed before replacing one with the other. There is also paucity of data regarding the utility of urine P/C ratio in monitoring proteinuria in patients with lupus nephritis [9, 10]. The aim of this study is to evaluate the agreement of urine P/C ratio in untimed specimens with proteinuria measured by 24 h urinary collection in patients with lupus nephritis.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Proteinuria in patients with biopsy proven lupus nephritis attending a specialist clinic of a regional hospital in Hong Kong Special Administrative Region was assessed. This study was conducted from 20 January to 30 June 2006. Demographic data including age, sex, body weight and height were collected during clinic visits. Body weight was measured to the nearest 0.1 kg by a standard bean balance. Body height was measured to the nearest 0.5 cm without shoes. The total body surface area (TBSA) was calculated by the DuBois and DuBois formula [11]. Disease activity and damage were calculated by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) [12] and Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index for systemic lupus erythematosus [13] were calculated during clinic visits. Urinary sediment studies were carried out on the day of spot urine collection. Collection of 24 h urine for total protein and creatinine measurement was performed for routine monitoring of their disease activities. Patients were instructed to collect untimed spot urine on the next day after the 24 h urine collection. The adequacy of the 24 h collection was assessed by comparing the total creatinine in the sample with the predicted creatinine 28 – (0.2 x age) x kg in men and [23.8 – (0.17 x age) x kg in women in mg/day] [14]. Under collection was defined by (predicted creatinine – measured creatinine)/predicted creatine > 0.2 and was excluded from analysis. Urine protein and creatinine concentrations were measured, respectively, by Benzethonium chloride turbidimetry and the compensated Jaffe method (D & P Modular analyzer, Roche Diagnostics Corp, Indianapolis, IN, USA). Protein excretion was standardized to g/1.73 m2 body surface area/day with a factor of 1.73/TBSA. Blood samples for complete blood picture, renal function tests were taken on the day of 24 h urine collection for calculation of SLEDAI-2K. Glomerular filtration rates (GFR) were calculated by the modification of diet in renal disease (MDRD) equation [15]. The study protocol was reviewed and approved by the Joint Chinese University of Hong Kong—New Territories East cluster (CUHK-NTEC) clinical research ethics committees and patients’ written consents were obtained.

Statistical analysis
The Spearman's correlation between the spot urine P/C ratio and 24 h urine total protein were performed by the Statistical Package for Social Science (Windows version 12, SPSS Inc., Chicago, IL, USA). The limits of agreement between the two parameters were analysed by the Bland–Altman Plot [16], using the Med Calc statistical software version 7.6.0 (demo version). This method depicts the mean difference and 95% confidence interval of the difference, and gives the limit of agreement as mean difference ± 1.96 S.D. The discriminant cutoff values, sensitivity and specificities of spot urine P/C ratio were tested for predicting 24 h protein excretion ‘threshold’ of ≥0.3, ≥0.5, ≥1.0 and ≥3.5 g/day using receiver operating characteristic (ROC) curves. A ROC curve is a graphical plot of the sensitivity vs (1 – specificity) for a binary classifier system. It evaluates the prediction with sensitivity, specificity and area under ROC at varying discrimination thresholds.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
A total of 165 paired urine samples from 109 patients were collected, with 21.8% of samples excluded for assessment because of inadequate collection. Of the remaining 129 samples from 82 patients, the median (interquantile range, IQR) age was 41 (32–47) yrs, 6 (7.3%) were men and 76 (92.7%) were women. The majority of patients (95.3%) were on prednisolone at a dose of 5.95 (5.0–7.5) mg/day. SLEDAI-2K, GFR by MDRD equation and 24 h urine total protein were 5.48 (2–8), 73.62 (47.1–93.8) ml/min/1.732 and 0.73 (0.22–1.47) g/day (Table 1). None of the patients was taking cimetidine, cotrimoxazole or any other medication that may affect renal creatinine excretion.


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  		TABLE 1. Demographic data of the cohort of patients with lupus nephritis

 
There was a strong correlation between spot urine P/C ratio and 24 h urine total protein (r = 0.91, P < 0.001; Fig. 1). However, wider deviation from the line of identity was noticed in higher protein excretion levels. Age, SLEDAI-2K and current steroid dosage have no correlation with the 24 h urine total protein or spot urine P/C ratio. Using the Bland–Altman plot, the limits of agreement between spot urine P/C ratio and 24 h urine total protein were wider at higher levels of protein excretion. These limits were reasonable and similar across a wide range of protein excretion when data were log-transformed (Fig. 2). Taking protein excretion < 2.0 g/day, the limits of agreement of spot urine P/C ratio and 24 h urine total protein were +0.92 and –0.86 g/day. With protein excretion <1.5 g/day, the limits of agreement were +0.87 and –0.80 g/day.


Figure 1
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  		FIG. 1. Scattered diagram of spot urine P/C ratio and 24 h urine total protein. P/C ratio, protein-to-creatinine ratio.

 

Figure 2
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  		FIG. 2. (A) Limits of agreement of spot urine protein-to-creatinine (P/C) ratio and 24 h urinary total protein. (B) limits of agreement of log transformed spot urine P/C ratio and 24 h urine total protein. P/C ratio, protein-to-creatinine ratio.

 
Using the ROC curves, the urine P/C ratio discriminant values of 0.37, 0.45, 0.7 and 1.84 mg/mg reliably predicted 24 h urine total protein ≥0.3, 0.5, 1.0 and 3.5 g/day, respectively (Table 2).


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  		TABLE 2. Discriminant spot urine P/C ratio that predict ‘threhold’ proteinuria at ≥0.3, 0.5, 1.0 and 3.5 g/day

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Quantification of proteinuria is vital for monitoring disease activity and the response to therapies in patients with lupus nephritis [1, 17]. Until recently, utilizing 24 h urine total protein has been the standard of practice. As 24 h urinary collections are cumbersome and frequently unreliable due to inadequate collection, a reliable and easy measure like the spot urine P/C ratio would be ideal in clinical practice. Patients in this study were young and represented a highly trained group in 24 h urinary collection. However, more than 20% of 24 h urinary collections were inadequately collected as defined by measured creatinine production <20% of the predicted. This implies an intrinsic problem with timed urinary collection method and makes it highly unreliable.

Since 2002, the US National Kidney Foundation has recommended replacement of 24 h urine collection for quantifying proteinuria with spot urine P/C ratio. The Renal Subcommittee of the ACR has also adopted spot urine P/C ratio of <0.5 g/day as one of the remission criteria for lupus nephritis in 2006. These recommendations are based on correlation studies. The correlation coefficient measures the strength of a relation between the two variables, but not the agreement between them. A new method should be tested with sufficient agreement before an old method could be replaced. Few studies have investigated the agreement between 24 h urine total protein and spot urine P/C ratio while none evaluated the use of spot urine P/C ratio in patients with lupus nephritis. Our study simulated the use of spot urine P/C ratio in a real clinic setting among patients with lupus nephritis, and aimed to evaluate the limits of agreement between this alternative parameter and the 24 h urine total protein.

We found a strong correlation between spot urine P/C ratio and 24 h urine total protein. The two tests have acceptable limits of agreement in patients with proteinuria around 0.5–2 g/day. The limits of agreement became wider as the proteinuria increased. On the Bland–Altman plot, the limits of agreement became similar over a wide range of urinary protein excretion values when the data were log-transformed. This implies reasonable agreement in the ‘usual’ range of proteinuria (~0.5–2 g/day), but a large absolute difference between the two methods occurred as proteinuria excretion increased. This result was not explained by inadequate 24 h urine collection, age, sex and whether or not the spot urine was collected on the same day. Studies of other patient groups that examined the agreement between urine albumin or P/C ratio and 24 h urine total protein also reported wide limits of agreement especially at high levels of protein excretion despite very good correlation [18–20].

In most clinical settings, physicians look at the ‘threshold’ of 24 h protein excretion rather than absolute values. For example, 24 h urine total protein <0.5 g/day has been used as one of the remission criteria and scores were given in the SLEDAI-2K if persistent proteinuria was higher than this level. Proteinuria of >1 g/day is considered as clinically significant or a threshold to recommend renal biopsy, while proteinuria >3.5 g/day is severe in the nephrotic range. The discriminant values for spot urine P/C ratio to predict 24 h urine total protein at these ‘threshold’ levels were calculated with good sensitivity, specificity and area under ROC curve. A proportion of patients would not have complete collection and the spot urine P/C ratio becomes the only ‘reliable’ test. The sensitivity and specificity described here would, therefore, be an underestimate. In general, a spot urine P/C ratio > 0.45 mg/mg and >0.7 mg/mg should predict reliably proteinuria of >0.5 and >1.0 g/day, respectively; while a spot urine P/C ratio >1.85 mg/mg predicts nephrotic range of proteinuria. These discriminant spot urine P/C ratios serve well in clinical decision-making and research methodology as the remission criteria. However, when the exact amount of proteinuria is to be assessed, the spot urine P/C ratio will only be within the acceptable limits of agreement if protein excretion is reasonably low.

In the present study, we have recruited patients with various degrees of renal impairment and proteinuria. It is unlikely that a higher number of patients would substantially alter the study result. In fact, previous studies showed that the effect size of different renal function on the precision of urine P/C ratio is minimal [3, 6, 21]. It should be noted that we have excluded patients who are treated with cimetidine or cotrimoxazole, which would affect renal excretion of creatinine. A small proportion of patients are taking ciclosporin A or cyclophosphamide, which may affect renal function. However, neither ciclosporin nor cyclophosphamide selectively affects renal tubular creatinine handling. Analysis of our data after excluding patients taking ciclosporin A or cyclophosphamide yields similar results (details not shown). Previous study on renal transplant recipients, most of whom were treated with ciclosporin A, showed that urine P/C ratio was a reliable method for quantification of proteinuria in this group of patients [22].

Despite wide confidence intervals, we have demonstrated good correlation and limits of agreement between the spot urine P/C ratio and 24 h urine total protein across a wide range of proteinuria. This present study supports the recommendation of using spot urine P/C ratio in screening and monitoring significant proteinuria in patients with lupus nephritis. The urine spot P/C ratio of 0.37, 0.45, 0.7 and 1.84 mg/mg reliably predict 24 h urine total protein equivalent ‘threshold’ at ≥0.3, 0.5, 1.0 and 3.5 g/day. However, in assessing the exact amount of proteinuria, the urine P/C ratio may have unacceptably wide limits of agreement at the high protein excretion range.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We are indebted to Ms Li Wai-Ching for assistance in data collection and Mr Wang Gang for performing urinalysis.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Gourley MF, Austin HA 3rd, Scott D, et al. (1996) Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 125:549–57.[Abstract/Free Full Text]
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Submitted 23 August 2006; revised version accepted 19 September 2006.
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